U.S. patent application number 16/645341 was filed with the patent office on 2021-06-03 for small molecule inhibitors of ebola and lassa fever viruses and methods of use.
The applicant listed for this patent is THE BRIGHAM AND WOMEN'S HOSPITAL, INC., President and Fellows of Harvard College. Invention is credited to James Cunningham, Kyungae Lee, Hu Liu, Ye Tian.
Application Number | 20210163454 16/645341 |
Document ID | / |
Family ID | 1000005435821 |
Filed Date | 2021-06-03 |
United States Patent
Application |
20210163454 |
Kind Code |
A1 |
Cunningham; James ; et
al. |
June 3, 2021 |
SMALL MOLECULE INHIBITORS OF EBOLA AND LASSA FEVER VIRUSES AND
METHODS OF USE
Abstract
Disclosed herein are compounds having a structure of formula
(I), compositions and methods useful for the treatment of a disease
or infection, such as a viral infection (e.g., Ebola), cancer and
obesity: ##STR00001## wherein A is N or CR.sup.8; Z is ##STR00002##
E is selected from optionally substituted alkyl, cycloalkyl,
arylalkyl, cycloalkylalkyl, amino, alkoxy, cycloalkyloxy, and
cycloalkylamino; R.sup.1 is selected from optionally substituted
aryl and heteroaryl, R.sup.2 and R.sup.3 are independently selected
from H, deutero, optionally substituted alkyl, haloalkyl, or
R.sup.2 and R.sup.3, together with the carbon to which they are
bound, combine to form a carbonyl; and R.sup.8 is selected from H,
deutero, halo, hydroxyl, cyano, amino, alkyl, alkoxy, carboxy,
alkoxycarbonyl, and aminocarbonyl, provided that E is not
##STR00003##
Inventors: |
Cunningham; James;
(Wellesley, MA) ; Liu; Hu; (Chestnut Hill, MA)
; Tian; Ye; (Jinan, CN) ; Lee; Kyungae;
(Allston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
President and Fellows of Harvard College
THE BRIGHAM AND WOMEN'S HOSPITAL, INC. |
Cambridge
Boston |
MA
MA |
US
US |
|
|
Family ID: |
1000005435821 |
Appl. No.: |
16/645341 |
Filed: |
September 10, 2018 |
PCT Filed: |
September 10, 2018 |
PCT NO: |
PCT/US2018/050238 |
371 Date: |
March 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62556066 |
Sep 8, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 213/75 20130101;
C07D 215/12 20130101; C07D 213/647 20130101; C07D 231/56 20130101;
A61P 31/12 20180101; C07D 211/62 20130101; C07B 2200/05 20130101;
C07D 213/68 20130101; C07D 209/14 20130101; C07D 211/16 20130101;
C07D 405/12 20130101; C07D 295/185 20130101 |
International
Class: |
C07D 405/12 20060101
C07D405/12; A61P 31/12 20060101 A61P031/12; C07D 213/68 20060101
C07D213/68; C07D 295/185 20060101 C07D295/185; C07D 215/12 20060101
C07D215/12; C07D 231/56 20060101 C07D231/56; C07D 213/647 20060101
C07D213/647; C07D 209/14 20060101 C07D209/14; C07D 211/62 20060101
C07D211/62; C07D 211/16 20060101 C07D211/16; C07D 213/75 20060101
C07D213/75 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with government support under Grant
No. 5U19AI109740, awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A compound represented by formula (I): ##STR00451## or a
pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein A is N or
CR.sup.8; Z is ##STR00452## E is selected from optionally
substituted alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl, amino,
alkoxy, cycloalkyloxy, and cycloalkylamino; R.sup.1 is selected
from optionally substituted aryl and heteroaryl, R.sup.2 and
R.sup.3 are independently selected from H, deutero, optionally
substituted alkyl, haloalkyl, or R.sup.2 and R.sup.3, together with
the carbon to which they are bound, combine to form a carbonyl; and
R.sup.8 is selected from H, deutero, halo, hydroxyl, cyano, amino,
alkyl, alkoxy, carboxy, alkoxycarbonyl, and aminocarbonyl; provided
that E is not ##STR00453##
2. The compound of claim 1, wherein A is N.
3. The compound of claim 1, wherein E is ##STR00454## R.sup.10,
R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each independently H
or halo; or R.sup.10 and R.sup.12 combine to form a 3-, 4-, or
5-membered ring. and R.sup.20, R.sup.21, R.sup.23, R.sup.24, and
R.sup.25 are each independently H, halo, or alkyl; or R.sup.23 and
R.sup.24 combine to form a 3-, 4-, or 5-membered ring.
4-7. (canceled)
8. A compound of claim 1, wherein E is ##STR00455## and Y.sup.1 is
selected from O, NR.sup.27, and CR.sup.28R.sup.29; Y.sup.2 is
selected from O, NR.sup.30, and CR.sup.31R.sup.32; R.sup.26,
R.sup.28, R.sup.29, R.sub.31, and R.sup.32 are each independently
H, halo, optionally substituted alkyl or haloalkyl; R.sup.27 is
selected from H and alkyl; R.sup.30 is selected from H,
##STR00456## R.sup.d is selected from alkyl, cycloalkyl,
heterocyclyl, aryl, or heteroaryl; or R.sup.26 and R.sup.29 combine
to form a 3-, 4-, or 5-membered ring.
9. The compound of claim 8, wherein R.sup.d is methyl.
10. The compound of claim 8, wherein R.sup.26 and R.sup.29 combine
to form a 3-membered ring.
11. The compound of claim 8, wherein R.sup.31 and R.sup.32 are each
halo.
12. The compound of claim 11, wherein R.sup.31 and R.sup.32 are
each F.
13. The compound of claim 8, wherein E is ##STR00457##
14-37. (canceled)
38. The compound of claim 1, wherein R.sup.1 is ##STR00458## L is
##STR00459## R.sup.f are each independently selected from H, alkyl,
and cycloalkyl. R.sup.9 is selected from H, optionally substituted
alkyl, amino, cycloamino, cycloalkyl, heterocyclyl, aryl, and
heteroaryl; and n is an integer selected from 0, 1 or 2.
39. The compound of claim 38, wherein R.sup.9 is phenyl or
pyridinyl optionally substituted with deutero, alkyl, alkenyl,
alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy,
hydroxyalkyl, aminoalkyl fluoroalkyloxy, sulfhydryl, alkylthio,
haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic
acid, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl,
fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl,
alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl,
N-aralkyl-N-alkylamino sulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, alkylsulfonylamino,
arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino,
alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino,
aralkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, N-aralkyl-N-alkylamino carbonyl cyano,
nitro, azido, phosphinyl, phosphoryl including phosphine oxide and
phosphonate, silyl, silyloxy, cyclic acetal, aryl, heteroaryl.
40. The compound of claim 38, wherein R.sup.9 is phenyl or
pyridinyl optionally substituted with halo, amino, amide, cyano,
carboxy, alkoxycarbonyl, lower cycloalkyl, sulfonamide, phosphine
oxide, phosphoryl, sulfoxide, sulfone, alkyl, or lower
cycloalkyl.
41. The compound of claim 38, wherein R.sup.9 is phenyl.
42. The compound of claim 38, wherein R.sup.9 is ##STR00460##
##STR00461##
43. The compound of claim 1, wherein Z is ##STR00462## ##STR00463##
##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468##
##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473##
##STR00474## ##STR00475## ##STR00476## ##STR00477##
##STR00478##
44. A compound represented by formula (II) ##STR00479## or a
pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein R.sup.a,
R.sup.b, and R.sup.c are independently selected from H, halo,
hydroxy, optionally substituted alkyl, optionally substituted
alkoxy, optionally substituted aryl, and optionally substituted
heteroaryl; R.sup.5 and R.sup.6 are independently selected from H,
deutero, and alkyl, or R.sup.5 and R.sup.6, together with the
carbon to which they are bound, combine to form a carbonyl; and
R.sup.7 is ##STR00480## ##STR00481## ##STR00482## ##STR00483##
##STR00484## ##STR00485##
45-48. (canceled)
49. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
50. A method of treating or preventing a viral infection in a
subject comprising administering to the subject a therapeutically
effective amount of a compound of claim 1.
51-57. (canceled)
58. A method of treating a disease in a subject comprising
administering to the subject a therapeutically effective amount of
a compound of claim 1, wherein the disease is cancer, obesity, or
AIDS.
59-61. (canceled)
62. A compound or a pharmaceutically acceptable salt thereof,
selected from: ##STR00486## ##STR00487## ##STR00488## ##STR00489##
##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494##
##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499##
##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504##
##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509##
##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514##
##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519##
##STR00520## ##STR00521## ##STR00522##
63. The compound of claim 1, wherein the compound has the
structure: ##STR00523## or a pharmaceutically acceptable salt
thereof.
Description
RELATED APPLICATION
[0001] This application claims the benefit of priority to U.S.
Provisional patent Application Ser. No. 62/556,066, filed Sep. 8,
2017. This application is hereby incorporated by reference in its
entirety.
BACKGROUND
[0003] Ebola virus (EboV) is a highly pathogenic enveloped virus
that causes outbreaks of zoonotic infection in Africa. EboV is
transmitted by close contact and virus levels increase by
75-fold/day for several days after initial infection. The clinical
symptoms are manifestations of the massive production of
pro-inflammatory cytokines in response to infection and in many
outbreaks, mortality exceeds 75%. The endothelial cell dysfunction
associated with "cytokine storm" results in capillary leak,
hypovolemic shock, disseminated intravascular coagulation and
inadequate perfusion of major organs. The unpredictable onset, ease
of transmission, rapid progression of disease, high mortality and
lack of effective vaccine or therapy have created a high level of
public concern about EboV. Current therapy is supportive; there is
no effective anti-EboV vaccine or therapy. Therefore, development
of anti-EboV drugs is a high priority.
[0004] Screening of a small molecule library against infection by
vesicular stomatitis virus (VSV) particles engineered to express
the EboV GP and to encode luciferase marker has identified a novel
benzylpiperazine adamantane diamide, 3.0, that inhibits infection
of Vero cells by vesicular stomatitis virus particles (VSV)
pseudotyped with EboV Zaire GP, but not with VSV (1 or Lassa fever
virus (LFV) GP.
##STR00004##
SAR around the 3.0 series identified other compounds, including
3.47, with increased potency against EboV GP-dependent
infection.
##STR00005##
[0005] Studies of compounds 3.0 and 3.47 established that they are
effective anti-Ebola agents as they target host protein
Niemann-Pick C1 (NPC1), a multi-span protein that resides in
lysosomes and mediates transport of cholesterol into cells and
binds to the Ebola virus (EboV) glycoprotein, which is essential
for infection. Thus, 3.0/3.47 and related compounds are candidate
anti-EboV agents (see, for example, US Patent Application
publication number 2014329834 to Cunningham, J. et al.).
SUMMARY
[0006] One aspect disclosed herein are compounds represented by
formula I:
##STR00006##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein A, E, Z,
R.sup.1, R.sup.2, R.sup.3, and R.sup.8 are as defined in the
specification.
[0007] In another aspect, the invention relates to compounds
represented by formula II
##STR00007##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein R.sup.a,
R.sup.b, R.sup.c, R.sup.5, R.sup.6, and R.sup.7 are as defined in
the specification.
[0008] In some embodiments, the invention relates to pharmaceutical
compositions of a compound of Formula (I) or Formula (II), and a
pharmaceutically acceptable carrier.
[0009] The invention further relates to methods of treating or
preventing a viral infection in a subject comprising administering
to the subject a compound of the invention.
[0010] The invention still further relates to methods of treating
or preventing a disease (e.g., cancer, obesity, HIV/AIDS) in a
subject comprising administering to the subject a compound of the
invention.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1 depicts a possible model of 3.47 targeting NPC1 and
inhibiting EboV binding and infection.
[0012] FIG. 2 depicts a dose response curve showing the inhibition
of Ebola virus (Kikwit) by certain compounds disclosed herein
(1412, 1413, 1466, 1476). Compound 1466 is also referred to herein
as the (-)-entantiomer of 1413 (i.e., (-)-1413).
[0013] FIG. 3 depicts a dose response curve showing the inhibition
of Ebola virus (Makona) by certain compounds disclosed herein
(1412, 1413, 1466, 1476). Compound 1466 is also referred to herein
as the (-)-entantiomer of 1413 (i.e., (-)-1413).
[0014] FIG. 4 depicts a dose response curve showing the inhibition
of Ebola virus (Mayinga) by certain compounds disclosed herein
(1412, 1413, 1466, 1476). Compound 1466 is also referred to herein
as the (-)-entantiomer of 1413 (i.e., (-)-1413).
[0015] FIG. 5 depicts a dose response curve showing the inhibition
of Ebola virus (Kikwit) by certain compounds disclosed herein
(1477, 1478).
[0016] FIG. 6 depicts a dose response curve showing the inhibition
of Ebola virus (Makona) by certain compounds disclosed herein
(1477, 1478).
[0017] FIG. 7 depicts a dose response curve showing the inhibition
of Ebola virus (Makona) by certain compounds disclosed herein
(1477, 1478).
[0018] FIG. 8 depicts a scheme showing the effects of structural
changes on the pharmacokinetic properties of compounds disclosed
herein.
[0019] FIG. 9 depicts a plot showing CYP3A4 inhibition improves the
T.sub.1/2 of compound 1412.
DETAILED DESCRIPTION
Overview
[0020] In certain aspects, the invention provides substituted
piperazine and piperidine compounds, and pharmaceutical
compositions thereof. In particular, such compounds can be used as
anti-viral agents, anti-cancer agents or anti-obesity agents.
Definitions
[0021] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e. to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0022] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0023] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of," "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0024] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0025] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0026] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
[0027] The definition of each expression, e.g., alkyl, m, n, and
the like, when it occurs more than once in any structure, is
intended to be independent of its definition elsewhere in the same
structure.
[0028] The term "substituted" refers to moieties having
substituents replacing a hydrogen on one or more carbons of the
backbone. It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. The permissible
substituents can be one or more and the same or different for
appropriate organic compounds. For purposes of this invention, the
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valences of the heteroatoms. Substituents can
include any substituents described herein, for example, a halogen,
a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a
formyl, or an acyl), a thiocarbonyl (such as a thioester, a
thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a
phosphate, a phosphonate, a phosphinate, an amino, an amido, an
amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an
alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
heteroaromatic moiety. It will be understood by those skilled in
the art that substituents can themselves be substituted, if
appropriate. Unless specifically stated as "unsubstituted,"
references to chemical moieties herein are understood to include
substituted variants. For example, reference to an "aryl" group or
moiety implicitly includes both substituted and unsubstituted
variants.
[0029] The term "lower" when appended to any of the groups listed
below indicates that the group contains less than seven carbons
(i.e. six carbons or less). For example "lower alkyl" refers to an
alkyl group containing 1-6 carbons, and "lower alkenyl" refers to
an alkenyl group containing 2-6 carbons.
[0030] The term "saturated," as used herein, pertains to compounds
and/or groups which do not have any carbon-carbon double bonds or
carbon-carbon triple bonds.
[0031] The term "unsaturated," as used herein, pertains to
compounds and/or groups which have at least one carbon-carbon
double bond or carbon-carbon triple bond.
[0032] The term "aliphatic," as used herein, pertains to compounds
and/or groups which are linear or branched, but not cyclic (also
known as "acyclic" or "open-chain" groups).
[0033] The term "cyclic," as used herein, pertains to compounds
and/or groups which have one ring, or two or more rings (e.g.,
spiro, fused, bridged).
[0034] The term "aromatic" refers to a planar or polycyclic
structure characterized by a cyclically conjugated molecular moiety
containing 4n+2 electrons, wherein n is the absolute value of an
integer. Aromatic molecules containing fused, or joined, rings also
are referred to as bicyclic aromatic rings. For example, bicyclic
aromatic rings containing heteroatoms in a hydrocarbon ring
structure are referred to as bicyclic heteroaryl rings.
[0035] The term "hydrocarbon" as used herein refers to an organic
compound consisting entirely of hydrogen and carbon.
[0036] The term "heteroatom" as used herein refers to an atom of
any element other than carbon or hydrogen. Illustrative heteroatoms
include boron, nitrogen, oxygen, phosphorus, sulfur and
selenium.
[0037] The term "alkyl" means an aliphatic or cyclic hydrocarbon
radical containing from 1 to 12 carbon atoms. Representative
examples of alkyl include, but are not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,
n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylcyclopentyl, and
1-cyclohexylethyl.
[0038] In some instances, the number of carbon atoms in a
hydrocarbon substituent (i.e., alkyl, cycloalkyl, etc.) is
indicated by the prefix "Cx-Cy-" or "Cx-y", wherein x is the
minimum and y is the maximum number of carbon atoms in the
substituent. For example, the term "Cx-yalkyl" refers to
substituted or unsubstituted saturated hydrocarbon groups,
including straight-chain alkyl and branched-chain alkyl groups that
contain from x to y carbons in the chain, including haloalkyl
groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. Thus,
for example, "C1-C6-alkyl" or "C1-6 alkyl" refers to an alkyl
substituent containing from 1 to 6 carbon atoms. Illustrating
further, C3-C6-cycloalkyl or C3-6-cycloalkyl refers to saturated
cycloalkyl containing from 3 to 6 carbon ring atoms. The terms
"C2-yalkenyl" and "C2-yalkynyl" refer to substituted or
unsubstituted unsaturated aliphatic groups analogous in length and
possible substitution to the alkyls described above, but that
contain at least one double or triple bond respectively.
[0039] The term "alkylene" is art-recognized, and as used herein
pertains to a bidentate moiety obtained by removing a hydrogen atom
from an alkyl group, as defined above.
[0040] The term "alkenyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbons
and containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0041] The term "alkenyl", as used herein, refers to an aliphatic
group containing at least one double bond and is intended to
include both "unsubstituted alkenyls" and "substituted alkenyls",
the latter of which refers to alkenyl moieties having substituents
replacing a hydrogen on one or more carbons of the alkenyl group.
Such substituents may occur on one or more carbons that are
included or not included in one or more double bonds. Moreover,
such substituents include all those contemplated for alkyl groups,
as discussed below, except where stability is prohibitive. For
example, substitution of alkenyl groups by one or more alkyl,
carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is
contemplated.
[0042] The term "alkynyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0043] The term "aryl" as used herein include substituted or
unsubstituted single-ring aromatic groups in which each atom of the
ring is carbon. Preferably the ring is a 5- to 7-membered ring,
more preferably a 6-membered ring. The term "aryl" also includes
polycyclic ring systems having two or more cyclic rings in which
two or more carbons are common to two adjoining rings wherein at
least one of the rings is aromatic, e.g., the other cyclic rings
can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Aryl groups include phenyl,
naphthyl or anthracenyl group. The aryl groups of the present
invention may be substituted with 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of deutero, alkyl,
alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy,
alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy,
haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, aknylcarbonyl, carboxy,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, aknylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfonyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl including phosphine oxide and phosphonate, silyl,
silyloxy, cyclic acetal, and any of said substituents bound to the
heterocyclyl group through an alkylene moiety (e.g. methylene).
[0044] The term "carbocyclyl" as used herein means monocyclic or
multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical
containing from 3 to 12 carbon atoms that is completely saturated
or has one or more unsaturated bonds, and for the avoidance of
doubt, the degree of unsaturation does not result in an aromatic
ring system (e.g. phenyl). Examples of carbocyclyl groups include
1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl,
3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl. The
carbocyclyl groups of the invention may be substituted 1, 2, 3, 4
or 0.5 substituents independently selected from the group
consisting of deutero, alkyl, alkenyl, alkynyl, halo, haloalkyl,
fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy,
sulfhydryl, alkylthio, haloalkylthio, fluoroalkylthio, alkenylthio,
alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl,
fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl,
alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic
acid, alkylsulfinyl, haloalkylsulfinyl, fluroralkylsulfinyl,
alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl,
haloalkoxysulfinyl, fluroralkoxysulfinyl, alkenyloxysulfinyl,
alkynyloxysulfinyl, aminosulfinyl, formyl, alkylcarbonyl,
haloalkylcarbonyl, fluoroalkylcarbonyl, alkenyl carbonyl,
alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl,
fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,
alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy,
alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy,
haloalkylsulfonyloxy, fluoroalkylsulfonyloxy, alkenylsulfonyloxy,
alkynylsulfonyloxy, haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl including phosphine oxide and phosphonate, silyl,
silyloxy, and any of said substituents bound to the heterocyclyl
group through an alkylene moiety (e.g. methylene).
[0045] The term "arylene," is art-recognized, and as used herein
pertains to a bidentate moiety obtained by removing a hydrogen atom
from an aryl ring, as defined above.
[0046] The term "arylalkyl" or "aralkyl" as used herein means an
aryl group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of aralkyl include, but are not limited to, benzyl,
2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
[0047] The term "arylalkenyl" embraces aryl-substituted alkenyl
radicals. Preferable arylalkenyl radicals are "lower arylalkenyl"
radicals having aryl radicals attached to alkenyl radicals having
two to six carbon atoms. Examples of such radicals include phenyl
ethenyl. The aryl in said arylalkenyl may be additionally
substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[0048] The term "arylalkynyl" embraces aryl-substituted alkynyl
radicals. Preferable arylalkynyl radicals are "lower arylalkynyl"
radicals having aryl radicals attached to alkynyl radicals having
two to six carbon atoms. Examples of such radicals include
phenylethynyl. The aryl in said aralkyl may be additionally
substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The
terms benzyl and phenylmethyl are interchangeable.
[0049] The term "cycloalkenyl" includes carbocyclic groups have one
or more carbon-carbon double bonds. Preferred cycloalkenyl groups
include C3-C6 rings. For example, cyclopentenyl, cyclopentadienyl,
cyclohexenyl and cycloheptadienyl.
[0050] The term "heterocyclyl", as used herein refers to a radical
of a non-aromatic, ring systems, including, but not limited to,
monocyclic, bicyclic and tricyclic rings, which can be completely
saturated or which can contain one or more units of unsaturation,
for the avoidance of doubt, the degree of unsaturation does not
result in an aromatic ring system, and have 3 to 12 atoms including
at least one heteroatom, such as nitrogen, oxygen, or sulfur. For
purposes of exemplification, which should not be construed as
limiting the scope of this invention, the following are examples of
heterocyclic rings: azepines, azetidinyl, morpholinyl,
oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl
pyrrolidinyl, quinuclidinyl thiomorpholinyl, tetrahydropyranyl and
tetrahydrofuranyl. The heterocyclyl groups of the invention are
substituted with 0, 1, 2, 3, 4 or 5 substituents independently
selected from the group consisting of deutero, alkyl, alkenyl,
alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy,
fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkenylthio, alkenylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl,
aminosulfinyl, formyl, alkylcarbonyl haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl including phosphine oxide and phosphonate, silyl,
silyloxy, and any of said substituents bound to the heterocyclyl
group through an alkylene moiety (e.g. methylene).
[0051] The term "heterocycloalkyl", as used herein, refers to an
alkyl group substituted with a heterocycle group.
[0052] The term "cyclic acetal" refers to a bidentate moiety
represented by --O-alkylene-O--. Representative examples of cyclic
acetals include, but are not limited to, methylenedioxy,
ethylenedioxy, propylenedioxy, butylenedioxy;
[0053] The term "heteroaryl" as used herein refers to a radical of
an aromatic ring, including, but not limited to, monocyclic,
bicyclic and tricyclic rings, which has 3 to 12 atoms including at
least one heteroatom, such as nitrogen, oxygen, or sulfur. For
purposes of exemplification, which should not be construed as
limiting the scope of this invention: azaindolyl, benzo(b)thienyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl,
imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl,
isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl,
oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl,
pyrimidinyl pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,
pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,
thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,
thienyl, thiomorpholinyl, triazolyl or tropanyl. The heteroaryl
groups of the invention may be substituted with 1, 2, 3, 4 or 5
substituents independently selected from the group consisting of
deutero, alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl,
hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy,
heterocyclyloxy, haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio,
haloalkylthio, fluoroalkylthio, alkenylthio, alkynylthio, sulfonic
acid, alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl including phosphine oxide and phosphonate, silyl,
silyloxy, and any of said substituents bound to the heteroaryl
group through an alkylene moiety (e.g. methylene).
[0054] The term "heteroarylene," is art-recognized, and as used
herein pertains to a bidentate moiety obtained by removing a
hydrogen atom from a heteroaryl ring, as defined above.
[0055] The term "heteroarylalkyl" or "heteroaralkyl" as used herein
means a heteroaryl, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heteroarylalkyl include, but are not
limited to, pyridin-3-ylmethyl and 2-(thien-2-yl)ethyl.
[0056] The term "halo" or "halogen" means --Cl, --Br, --I or
--F.
[0057] The term "haloalkyl" means an alkyl group, as defined
herein, wherein at least one hydrogen is replaced with a halogen,
as defined herein. Representative examples of haloalkyl include,
but are not limited to, chloromethyl, 2-fluoroethyl,
trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
[0058] The term "fluoroalkyl" means an alkyl group, as defined
herein, wherein all the hydrogens are replaced with fluorines.
[0059] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl. Even more preferred are lower
hydroxyalkyl radicals having one to three carbon atoms.
[0060] The term "hydroxy" as used herein means an group.
[0061] The term "oxy" refers to a --O-- group.
[0062] The term "alkoxy" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy. The terms "alkenyloxy",
"alkyloxy", "carbocyclyloxy", and "heterocyclyloxy" are likewise
defined.
[0063] The term "cycloalkyloxy" refers to a cycloakyl group having
an oxygen attached thereto.
[0064] The term "haloalkoxy" as used herein means an alkoxy group,
as defined herein, wherein at least one hydrogen is replaced with a
halogen, as defined herein. Representative examples of haloalkoxy
include, but are not limited to, chloromethoxy, 2-fluoroethoxy,
trifluoromethoxy, and pentafluoroethoxy. The term "fluoroalkyloxy"
is likewise defined.
[0065] The term "aryloxy" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen.
[0066] The term "heteroaryloxy" as used herein means a heteroaryl
group, as defined herein, appended to the parent molecular moiety
through an oxygen. The terms "heteroaryloxy" is likewise
defined.
[0067] The term "arylalkoxy" or "arylalkyloxy" as used herein means
an arylalkyl group, as defined herein, appended to the parent
molecular moiety through an oxygen. The term "heteroarylalkoxy" is
likewise defined. Representative examples of aryloxy and
heteroarylalkoxy include, but are not limited to,
2-chlorophenylmethoxy, 3-trifluoromethyl-phenylethoxy, and
2,3-dimethylpyridinylmethoxy.
[0068] The term "sulfhydryl" or "thio" as used herein means a --SH
group.
[0069] The term "alkylthio" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
sulfur. Representative examples of alkylthio include, but are not
limited, methylthio, ethylthio, tert-butylthio, and hexylthio. The
terms "haloalkylthio", "fluoroalkylthio", "alkenylthio",
"alkynylthio", "carbocyclylthio", and "heterocyclylthio" are
likewise defined.
[0070] The term "arylthio" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
sulfur. The term "heteroarylthio" is likewise defined.
[0071] The term "arylalkylthio" or "aralkylthio" as used herein
means an arylalkyl group, as defined herein, appended to the parent
molecular moiety through an sulfur. The term "heteroarylalkylthio"
is likewise defined.
[0072] The term "sulfonyl" as used herein refers to
--S(.dbd.O).sub.2-- group.
[0073] The term "sulfonic acid" as used herein refers to
--S(.dbd.O).sub.2OH.
[0074] The term "alkylsulfonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl. The terms "haloalkylsulfonyl",
"fluoroalkylsulfonyl", "alkenylsulfonyl", "alkynylsulfonyl",
"carbocyclylsulfonyl", "heterocyclylsulfonyl", "arylsulfonyl",
"aralkylsulfonyl", "heteroarsulfonyl" and "heteroaralkylsulfonyl"
are likewise defined.
[0075] The term "alkoxysulfonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl. The terms
"haloalkoxysulfonyl", "fluoroalkoxysulfonyl", "alkenyloxysulfonyl",
"alkynyloxysulfonyl", "carbocyclyloxysulfonyl",
"heterocyclyloxysulfonyl", "aryloxysulfonyl", "aralkyloxysulfonyl",
"heteroaryloxysulfonyl" and "heteroaralkyloxysulfonyl" are likewise
defined.
[0076] The term "aminosulfonyl" as used herein means an amino
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group.
[0077] The term "alkylaminosulfonyl" includes
"N-alkylaminosulfonyl" and "N, N-dialkylaminosulfonyl" where
sulfamyl radicals are independently substituted, respectively, with
one alkyl radical, or two alkyl radicals. More preferred
alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals
having one to six carbon atoms. Even more preferred are lower
alkylaminosulfonyl radicals having one to three carbon atoms.
Examples of such lower alkylaminosulfonyl radicals include
N-methylaminosulfonyl, N-ethylaminosulfonyl and
N-methyl-N-ethylaminosulfonyl.
[0078] The terms "N-arylaminosulfonyl" and
"N-alkyl-N-arylaminosulfonyl" denote sulfamyl radicals substituted,
respectively, with one amyl radical, or one alkyl and one aryl
radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are
"lower N-alkyl-N-arylsulfonyl"radicals having alkyl radicals of one
to six carbon atoms. Even more preferred are lower
N-alkyl-N-arylsulfonyl radicals having one to three carbon atoms.
Examples of such lower N-alkylN-aryl-aminosulfonyl radicals include
N-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl.
Examples of such N-aryl-aminosulfonyl radicals include
N-phenylaminosulfonyl.
[0079] The term "arylalkylaminosulfonyl" embraces aralkyl radicals
as described above, attached to an aminosulfonyl radical. More
preferred are lower arylalkylaminosulfonyl radicals having one to
three carbon atoms.
[0080] The term "heterocyclylaminosulfonyl" embraces heterocyclyl
radicals as described above, attached to an aminosulfonyl
radical.
[0081] The term "sulfinyl" as used herein refers to --S(.dbd.O)--
group. Sulfinyl groups are as defined above for sulfonyl groups.
The term "sulfinic acid" as used herein refers to
--S(.dbd.O)OH.
[0082] The term "carbonyl" as used herein means a --C(.dbd.O)--
group.
[0083] The term "alkylcarbonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The terms "haloalkylcarbonyl", "fluoroalkylcarbonyl",
"alkenylcarbonyl", "alkynylcarbonyl", "carbocyclylcarbonyl",
"heterocyclylcarbonyl", "arylcarbonyl", "aralkylcarbonyl",
"heteroarylcarbonyl", and "heteroaralkylcarbonyl" are likewise
defined.
[0084] The terms "arylcarbonyl" denotes carbonyl radicals
substituted with an aryl radical.
[0085] The terms "heteroarylcarbonyl" denotes carbonyl radicals
substituted with a heteroaryl radical.
[0086] The terms "cycloalkylcarbonyl" denotes carbonyl radicals
substituted with a cycloalkyl radical.
[0087] The terms "heterocyclylcarbonyl" denotes carbonyl radicals
substituted with a heterocyclyl radical.
[0088] The term "aminocarbonyl" when used by itself or with other
terms such as "aminocarbonylalkyl", "N-alkylaminocarbonyl",
"N-arylaminocarbonyl", "N, N-dialkylaminocarbonyl",
"N-alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl" and
"N-alkyl-N-hydroxyaminocarbonylalkyl", denotes an amide group of
the formula H2NC(.dbd.O)--.
[0089] The terms "N-alkylaminocarbonyl" and "N,
N-dialkylaminocarbonyl" denote aminocarbonyl radicals which have
been substituted with one alkyl radical and independently with two
alkyl radicals, respectively. More preferred are "lower
alkylaminocarbonyl" having lower alkyl radicals as described above
attached to an aminocarbonyl radical.
[0090] The terms "N-arylaminocarbonyl" and
"N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals
substituted, respectively, with one aryl radical, or one alkyl and
one aryl radical.
[0091] The term "thiocarbonyl" as used herein means a --C(.dbd.S)--
group.
[0092] The term "formyl" as used herein means a --C(.dbd.O)H
group.
[0093] The term "carboxy" as used herein means a --CO.sub.2H
group.
[0094] The term "alkoxycarbonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The terms
"haloalkoxycarbonyl", "fluoroalkoxycarbonyl", "alkenyloxycarbonyl",
"alkynyloxycarbonyl", "carbocyclyloxycarbonyl",
"heterocyclyloxycarbonyl", "aryloxycarbonyl", "aralkyloxycarbonyl",
"heteroaryloxycarbonyl", and "heteroaralkyloxycarbonyl" are
likewise defined.
[0095] The term "alkylcarbonyloxy" as used herein means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy. The terms
"haloalkylcarbonyloxy", "fluoroalkylcarbonyloxy",
"alkenylcarbonyloxy", "alkynylcarbonyloxy",
"carbocyclylcarbonyloxy", "heterocyclylcarbonyloxy",
"arylcarbonyloxy", "aralkylcarbonyloxy", "heteroarylcarbonyloxy",
and "heteroaralkylcarbonyloxy" are likewise defined.
[0096] The term "alkylsulfonyloxy" as used herein means an
alkylsulfonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. The terms
"haloalkylsulfonyloxy", "fluoroalkylsulfonyloxy",
"alkenylsulfonyloxy", "alkynylsulfonyloxy",
"carbocyclylsulfonyloxy", "heterocyclylsulfonyloxy",
"arylsulfonyloxy", "aralkylsulfonyl oxy", "heteroarylsulfonyoxy",
"heteroaralkylsulfonyloxy", "haloalkoxysulfonyloxy",
"fluoroalkoxysulfonyloxy", "alkenyloxysulfonyloxy",
"alkynyloxysulfonyloxy", "carbocyclyloxysulfonyloxy",
"heterocyclyloxysulfonyloxy", "aryloxysulfonyloxy",
"aralkyloxysulfonyloxy", "heteroaryloxysulfonyloxy" and
"heteroaralkyloxysulfonyloxy",
[0097] The term "amide", as used herein, refers to a group
##STR00008##
[0098] wherein each R.sup.10 independently represent a hydrogen or
hydrocarbyl group, or two R.sup.10 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0099] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines and salts thereof,
e.g., a moiety that can be represented by
##STR00009##
[0100] wherein each R.sup.10 independently represents a hydrogen or
a hydrocarbyl group, alkyl, haloalkyl, fluoroalkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl,
aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, the
sulfonyl, sulfinyl groups defined above; or two R.sup.10 are taken
together with the N atom to which they are attached complete a
heterocycle having from 4 to 8 atoms in the ring structure.
Representative examples include, but are not limited to
methylamino, acetylamino, and dimethylamino
[0101] The term "cycloalkylamino", as used herein refers to an
amino group substituted with a cycloalkyl group.
[0102] The term "aminoalkyl", as used herein, refers to an alkyl
group substituted with an amino group. More preferred aminoalkyls
include "lower aminoalkyl" having one to six carbon atoms and one
or more amino radicals. Examples include aminomethyl, aminoethyl,
aminopropyl, aminobutyl and aminohexyl.
[0103] The term "alkylamino", as used herein, refers to an amino
group substituted with at least one alkyl group, e.g., N-alkylamino
and N, N-dialkylamino. Examples include N-methylamino,
N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the
like.
[0104] The term "arylamino" denotes amino groups which have been
substituted with one or two aryl groups, such as N-phenylamino. The
"acylamino" radicals may be further substituted on the aryl group
as defined herein.
[0105] The term "heteroarylamino" denotes amino groups which have
been substituted with at least one heteroaryl group, such as
N-thienylamino. The "heteroarylamino" may be further substituted on
the heteroaryl group as defined herein.
[0106] The term "aralkylamino" denotes amino groups which have been
substituted with at least one aralkyl group. Examples include
N-benzylamino. The "aralkylamino" radicals may be further
substituted on the aryl ring portion of the radical.
[0107] The terms "N-aralkyl-N-alkylamino" and "N-alkyl-N-arylamino"
denote amino groups which have been substituted with one aralkyl
and one alkyl, or one aryl and one alkyl, respectively.
[0108] The term "cyano" as used herein means a --C.ident.N
group.
[0109] The term "nitro" as used herein means a --NO.sub.2
group.
[0110] The term "azido" as used herein means a --N.sub.3 group.
[0111] The term "phosphonyl" as used herein includes --PH.sub.3 and
substituted derivatives thereof wherein one, two or three of the
hydrogens are independently replaced with substituents selected
from the group consisting of alkyl, haloalkyl, fluoroalkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, haloalkoxy, fluoroalkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aryloxy, aralkyloxy,
heteroaryloxy, heteroaralkyloxy, and amino.
[0112] The term "phosphine oxide" as used herein includes
--P(O)R.sub.2, wherein R is alkyl, aryl, heteroaryl.
[0113] The term "phosphoryl" as used herein refers to
--P(.dbd.O)OH.sub.2 and substituted derivatives thereof wherein one
or both of the hydroxyls are independently replaced with
substituents selected from the group consisting of alkyl,
haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy,
haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy,
heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy,
heteroaralkyloxy, and amino.
[0114] The term "sulfate" is art-recognized and refers to the group
--OSO.sub.3H, or a pharmaceutically acceptable salt thereof.
[0115] The term "sulfonamide" is art-recognized and refers to the
group represented by the general formulae
##STR00010##
wherein R.sup.9 and R.sup.10 independently represents hydrogen or
hydrocarbyl, such as alkyl, or R.sup.9 and R.sup.10 taken together
with the intervening atom(s) complete a heterocycle having from 4
to 8 atoms in the ring structure.
[0116] The term "sulfoxide" is art-recognized and refers to the
group --S(O)--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0117] The term "sulfonate" is art-recognized and refers to the
group SO.sub.3H, or a pharmaceutically acceptable salt thereof.
[0118] The term "sulfone" is art-recognized and refers to the group
--S(O).sub.2--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0119] The terms triflyl, tosyl, mesyl, and nonaflyl are
art-recognized and refer to trifluoromethanesulfonyl,
p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl
groups, respectively. The terms triflate, tosylate, mesylate, and
nonaflate are art-recognized and refer to trifluoromethanesulfonate
ester, p-toluenesulfonate ester, methanesulfonate ester, and
nonafluorobutanesulfonate ester functional groups and molecules
that contain said groups, respectively.
[0120] The term "silyl" as used herein includes H.sub.3Si-- and
substituted derivatives thereof wherein one, two or three of the
hydrogens are independently replaced with substituents selected
from alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, aralkyl heteroaryl, and heteroaralkyl.
Representative examples include trimethylsilyl (TMS),
tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl
(TBS/TBDMS), triisopropylsilyl (TIPS), and
[2-(trimethylsilyl)ethoxy]methyl (SEM).
[0121] The term "silyloxy" as used herein means a silyl group, as
defined herein, is appended to the parent molecule through an
oxygen atom.
[0122] In the compounds of this invention any atom not specifically
designated as a particular isotope is meant to represent any stable
isotope of that atom. Unless otherwise stated, when a position is
designated specifically as "H" or "hydrogen", the position is
understood to have hydrogen at its natural abundance isotopic
composition. Also unless otherwise stated, when a position is
designated specifically as "D" or "deuterium", the position is
understood to have deuterium at an abundance that is at least 3340
times greater than the natural abundance of deuterium, which is
0.015% (i.e., at least 50.1% incorporation of deuterium). For
example, it is understood that the carbons in the following
moieties may be bound to any stable isotope of hydrogen is
exemplary representations such as
##STR00011##
and the like.
[0123] The abbreviations Me, Et, Ph, Bn, Tf, Nf, Ts, and Ms
represent methyl, ethyl, phenyl, benzyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl,
respectively. A more comprehensive list of the abbreviations
utilized by organic chemists of ordinary skill in the art appears
in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled
Standard List of Abbreviations.
[0124] The term "viral infection" as used herein refers to
infection by a viral pathogen wherein there is clinical evidence of
the infection based on symptoms or based on the demonstration of
the presence of the viral pathogen in a biological sample from the
individual. As used herein an "individual" refers to an animal,
preferably a mammal, including both non-human mammals and humans,
and more preferably, refers to a human.
[0125] The expression "effective amount" when used to describe
therapy to an individual suffering from a viral infection refers to
the amount of a compound that results in a therapeutically useful
effect on the symptoms of the viral infection and/or a reduction in
viral load.
[0126] As used herein, a therapeutic that "prevents" a disorder or
condition refers to a compound that, in a statistical sample,
reduces the occurrence of the disorder or condition in the treated
sample relative to an untreated control sample, or delays the onset
or reduces the severity of one or more symptoms of the disorder or
condition relative to the untreated control sample.
[0127] The term "treating" includes prophylactic and/or therapeutic
treatments. The term "prophylactic or therapeutic" treatment is
art-recognized and includes administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic (i.e., it protects the host against developing the
unwanted condition), whereas if it is administered after
manifestation of the unwanted condition, the treatment is
therapeutic, (i.e., it is intended to diminish, ameliorate, or
stabilize the existing unwanted condition or side effects thereof).
For example, treating a viral infection encompasses alleviating,
reducing the frequency of, or eliminating one or more symptoms of
the infection and/or a reducing the viral load.
Exemplary Compounds
[0128] One aspect of the invention relates to a compound
represented by formula (I):
##STR00012##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein
[0129] A is N or CR.sup.8;
[0130] Z is
##STR00013##
[0131] E is selected from optionally substituted alkyl, cycloalkyl,
arylalkyl cycloalkyl alkyl, amino, alkoxy, cycloalkyloxy, and
cycloalkylamino;
[0132] R.sup.1 is selected from optionally substituted aryl and
heteroaryl,
[0133] R.sup.2 and R.sup.3 are independently selected from H,
deutero, optionally substituted alkyl, haloalkyl, or R.sup.2 and
R.sup.3, together with the carbon to which they are bound, combine
to form a carbonyl; and
[0134] R.sup.8 is selected from H, deutero, halo, hydroxyl, cyano,
amino, alkyl, alkoxy, carboxy, alkoxycarbonyl, and
aminocarbonyl;
provided that E is not
##STR00014##
[0135] In some embodiments, A is N.
[0136] In some embodiments, E is
##STR00015##
R.sup.10, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each
independently H or halo; or R.sup.10 and R.sup.12 combine to form a
3-, 4-, or 5-membered ring. and R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are each independently H, halo, or alkyl; or
R.sup.23 and R.sup.24 combine to form a 3-, 4-, or 5-membered
ring.
[0137] In some embodiments, R.sup.23 and R.sup.24 combine to form a
3-membered ring. In some embodiments, R.sup.20 and R.sup.21 are
each halo, e.g., F.
[0138] In some embodiments, E is
##STR00016##
[0139] In some embodiments, E is
##STR00017##
and Y.sup.1 is selected from O, NR.sup.27, and CR.sup.28R.sup.29;
Y.sup.2 is selected from O, NR.sup.30, and CR.sup.31R.sup.32;
R.sup.26, R.sup.28, R.sup.29, R.sup.31, and R.sup.32 are each
independently H, halo, optionally substituted alkyl or haloalkyl;
R.sup.27 is selected from H and alkyl; R.sup.30 is selected from
H,
##STR00018##
R.sup.d is selected from alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl; or R.sup.26 and R.sup.29 combine to form a 3-, 4-, or
5-membered ring.
[0140] In some embodiments, R.sup.d is methyl. In some embodiments,
R.sup.26 and R.sup.29 combine to form a 3-membered ring. In some
embodiments, R.sup.3'1 and R.sup.32 are each halo. In some
embodiments, R.sup.31 and R.sup.32 are each F.
[0141] In some embodiments, E is
##STR00019##
[0142] In some embodiments, E is
##STR00020##
and R.sup.33, R.sup.34, and R.sup.35 are each independently H,
halo, optionally substituted alkyl, haloalkyl or optionally
substituted aryl; or R.sup.33 and R.sup.34 combine to form a an
optionally substituted 3-, 4-, 5-, or 6-membered ring.
[0143] In some embodiments, the 3-, 4-. 5-, or 6-membered ring is
substituted with one to four substitutents selected from halo,
alkyl, and haloalkyl.
[0144] In some embodiments, R.sup.33 and R.sup.34 combine to form a
4- or 5-membered ring. In some embodiments, R.sup.33 and R.sup.34
are each halo (e.g., F).
[0145] In some embodiments, E is
##STR00021##
[0146] In some embodiments, E is
##STR00022##
and R.sup.36, R.sup.37, R.sup.38, R.sup.39, and R.sup.40 are each
independently H, halo, alkyl, haloalkyl, or aryl; or R.sup.37 and
R.sup.38 combine to form an optionally substituted 3-, 4-, 5-, or
6-membered ring.
[0147] In some embodiments, said 3-, 4-, 5-, or 6-membered ring is
substituted with one to four substitutents selected from halo,
alkyl, and haloalkyl. In some embodiments, R.sup.38 and R.sup.39
are each alkyl. In some embodiments, R.sup.38 and R.sup.39 are each
methyl.
[0148] In some embodiments, E is
##STR00023##
[0149] In some embodiments, E is
##STR00024##
and R.sup.41 is H, halo, or alkyl.
[0150] In some embodiments, R.sup.1 is substituted with one or more
groups selected from halo, hydroxyl, amino, amino, nitro, carboxy,
aminocarbonyl, cyano, azido, aminosulfonyl, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkoxy, haloalkoxy, optionally substituted alkynyl, optionally
substituted cycloalkyloxy, optionally substituted aryl and
optionally substituted heteroaryl.
[0151] In some embodiments, R.sup.1 is
##STR00025##
and Y.sup.3 is N or CH and R.sup.50 is H, halo, or alkyl.
[0152] In some embodiments, R.sup.1 is
##STR00026##
[0153] In some embodiments, R.sup.50 is halo.
[0154] In some embodiments, Z is
##STR00027##
[0155] In some embodiments, R.sup.1 is
##STR00028##
R.sup.51 is H, deutero, halo, cyano, azido, alkyl, haloalkyl,
fluoroalkyl, cycloalkyl, hydroxyl, alkoxy, haloalkoxy,
carbocyclyloxy, heterocyclylalkoxy, aryloxy, heteroaryloxy, amino,
alkylamino, carbocyclylamino, heterocyclylamino, arylamino,
heteroarylamino, amido, alkenyl, alkynyl, carbocyclyl, aryl,
heteroaryl, or carbocyclylalkoxy;
Y.sup.4 is N or CH; and
[0156] n is an integer selected from 1, 2, or 3.
[0157] In some embodiments, R.sup.1 is phenyl, pyridin-1-yl,
pyridin-2-yl, or pyridin-3-yl, optionally substituted with one,
two, or three substituents selected from H, deutero, halo, cyano,
azido, alkyl, haloalkyl, fluoroalkyl, cycloalkyl, hydroxyl, alkoxy,
haloalkoxy, carbocyclylalkoxy, heterocyclylalkoxy, aryloxy,
heteroaryloxy, amino, alkylamino, carbocyclylamino,
heterocyclylamino, arylamino, heteroarylamino, amido, alkenyl,
alkynyl, carbocyclyl, aryl, heteroaryl, and carbocyclylalkoxy.
[0158] In some embodiments, n is 2 or 3.
[0159] In some embodiments, R.sup.1 is
##STR00029##
R.sup.51a is H, deutero, halo, cyano, azido, alkyl, haloalkyl,
fluoroalkyl, cycloalkyl, hydroxyl, alkoxy, haloalkoxy,
carbocyclylalkoxy, heterocyclylalkoxy, aryloxy, heteroaryloxy,
amino, alkylamino, carbocyclylamino, heterocyclylamino, arylamino,
heteroarylamino, amido, alkenyl, alkynyl, carbocyclyl, aryl,
heteroaryl, or carbocyclylalkoxy; and n is an integer selected from
0, 1 or 2.
[0160] In some embodiments, R.sup.1 is
##STR00030##
R.sup.51b is H, deutero, halo, cyano, azido, alkyl, haloalkyl,
fluoroalkyl, cycloalkyl, hydroxyl, alkoxy, haloalkoxy,
carbocyclylalkoxy, heterocyclylalkoxy, aryloxy, heteroaryloxy,
amino, alkylamino, carbocyclylamino, heterocyclylamino, arylamino,
heteroarylamino, amido, alkenyl, alkynyl, carbocyclyl, aryl,
heteroaryl, or carbocyclylalkoxy; and n is an integer selected from
0, 1, or 2.
[0161] In some embodiments, R.sup.1 is
##STR00031##
L is
##STR00032##
[0162] R.sup.f are each independently selected from H, alkyl, and
cycloalkyl. R.sup.9 is selected from H, optionally substituted
alkyl, amino, cycloamino, cycloalkyl, heterocyclyl, aryl, and
heteroaryl; and n is an integer selected from 0, 1 or 2.
[0163] In some embodiments, R.sup.9 is phenyl or pyridinyl
optionally substituted with deutero, alkenyl, alkynyl, halo,
haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, haloalkoxy, hydroxyalkyl,
aminoalkyl fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkenylthio, alkynylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl,
fluoroalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
alkoxysulfonyl, haloalkoxysulfonyl, fluoroalkoxysulfonyl,
alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl
N-aralkyl-N-alkylamino sulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluroralkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluroralkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfinyl,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, alkylsulfonylamino,
arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino,
alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino,
aralkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl,
arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl,
N-alkyl-N-arylaminocarbonyl, N-aralkyl-N-alkylamino carbonyl cyano,
nitro, azido, phosphinyl, phosphoryl including phosphine oxide and
phosphonate, silyl, silyloxy cyclic acetal, aryl, heteroaryl.
[0164] In some embodiments, R.sup.9 is phenyl or pyridinyl
optionally substituted with halo, amino, amide, cyano, carboxy,
alkoxycarbonyl, lower cycloalkyl, sulfonamide, phosphine oxide,
phosphoryl, sulfoxide, sulfone, alkyl, or lower cycloalkyl. In some
embodiments, wherein R.sup.9 is phenyl.
[0165] In some embodiments, R.sup.9 is
##STR00033## ##STR00034##
[0166] In some embodiments, Z is
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050##
[0167] In certain other aspects the invention relates to compounds
represented by formula (II)
##STR00051##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
chemically-protected form, enantiomer or stereoisomer thereof;
wherein, independently for each occurrence, wherein
[0168] R.sup.a, R.sup.b, and R.sup.c are independently selected
from H, halo, hydroxy, optionally substituted alkyl, optionally
substituted alkoxy, optionally substituted aryl, and optionally
substituted heteroaryl;
[0169] R.sup.5 and R.sup.6 are independently selected from H,
deutero, and alkyl, or R.sup.5 and R.sup.6, together with the
carbon to which they are bound, combine to form a carbonyl; and
[0170] R.sup.7 is
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057##
[0171] In some embodiments, R.sup.a, R.sup.b, and R.sup.c are each
halo. In some embodiments, R.sup.b and R.sup.c are each H. In some
embodiments. one of R.sup.a, R.sup.b, and R.sup.c is
##STR00058##
[0172] Exemplary compounds of Formula I and Formula II are depicted
in the examples and Table 1. The compounds disclosed in the
examples and Table 1 are understood to encompass both the free base
and the conjugate acid. For example, the compounds in the examples
and Table 1 may be depicted as complexes or salts with
trifluoroacetic acid or hydrochloric acid, but the compounds in
their corresponding free base forms or as salts with other acids
are equally within the scope of the invention. Compounds may be
isolated in either the free base form, as a salt (e.g., a
hydrochloride salt) or in both forms. In the chemical structures
shown below, standard chemical abbreviations are sometimes
used.
TABLE-US-00001 TABLE 1 Expemplary compounds of Formula I and
Formula II. Compound number Structure IC50(uM) 1433 ##STR00059##
>5 1429 ##STR00060## 0.95 1427 ##STR00061## 2.45 1428
##STR00062## >5 1424 ##STR00063## 2.8 1422 ##STR00064## 0.36
1421 ##STR00065## >5 1420 ##STR00066## 0.49 1406 ##STR00067##
0.46 1405 ##STR00068## 0.07-0.26 1431 ##STR00069## 0.55 1425
##STR00070## 3.4 1372 ##STR00071## >2 1384 ##STR00072## 0.33
1404 ##STR00073## 0.63 1403 ##STR00074## 0.19-0.73 1402
##STR00075## 2.9 1401 ##STR00076## 3.7 1400 ##STR00077## 0.67 1399
##STR00078## 0.22 1398 ##STR00079## 0.075-0.32 1397 ##STR00080##
2.4-4.2 1413 ##STR00081## 0.068 1412 ##STR00082## 0.13 1391
##STR00083## 0.08-0.26 1411 ##STR00084## 0.14 1410 ##STR00085##
0.22-0.49 1409 ##STR00086## 2.9 1474 ##STR00087## 1407 ##STR00088##
0.23-0.5 1390 ##STR00089## 1.1 1388 ##STR00090## 0.5 1387
##STR00091## >5 1386 ##STR00092## 4.4 1385 ##STR00093## 2.2 1381
##STR00094## >2 1359 ##STR00095## >2 1373 ##STR00096## 0.1
1408 ##STR00097## 4 1383 ##STR00098## >2 1382 ##STR00099## >2
1374 ##STR00100## >2 1371 ##STR00101## >2 1370 ##STR00102##
~2.2 1369 ##STR00103## >2 1368 ##STR00104## >2 1367
##STR00105## >2 1366 ##STR00106## >2 1358 ##STR00107## 0.2
1357 ##STR00108## 0.5 1356 ##STR00109## >2 1346 ##STR00110## 0.2
1344 ##STR00111## 0.17 1328 ##STR00112## 0.25 1298 ##STR00113## 1.5
1362 ##STR00114## >2 1355 ##STR00115## 1.74 1343 ##STR00116##
0.32 1336 ##STR00117## 0.051 1335 ##STR00118## 0.018 1334
##STR00119## 0.019 1333 ##STR00120## 0.015 1320 ##STR00121## >2
1319 ##STR00122## 0.31 1317 ##STR00123## 0.4 1376 ##STR00124##
>2 1316 ##STR00125## 0.07 1315 ##STR00126## 0.4 1311
##STR00127## 0.08 1142 ##STR00128## 0.52 1275 ##STR00129## 0.05
1138 ##STR00130## >2 1279 ##STR00131## 1.5 1278 ##STR00132##
>2 1312 ##STR00133## 0.6 1136 ##STR00134## >2 1277
##STR00135## >2 1246 ##STR00136## <2 1141 ##STR00137## 0.7
1245 ##STR00138## 0.6 1244 ##STR00139## 0.5 1243 ##STR00140## 0.5
1255 ##STR00141## 0.4 1254 ##STR00142## 0.2 1253 ##STR00143## 1.5
1123 ##STR00144## 0.02 1112 ##STR00145## <2 1118 ##STR00146##
0.001 1111 ##STR00147## 0.013 1114 ##STR00148## <2 1115
##STR00149## 1.4 1117 ##STR00150## 0.05 1113 ##STR00151## <2
1310 ##STR00152## 0.31 1325 ##STR00153## 1 1324 ##STR00154## 1.5
1349 ##STR00155## 0.5 1321 ##STR00156## 0.09 1342 ##STR00157## 1.1
1341 ##STR00158## 0.32 1340 ##STR00159## 1.27 1026 ##STR00160##
0.3-0.5 1249 ##STR00161## 0.2 1304 ##STR00162## >1.5 1252
##STR00163## 0.8 1251 ##STR00164## 1.7 1250 ##STR00165## 0.8 1122
##STR00166## ~2 1260 ##STR00167## 0.7 1259 ##STR00168## 0.7 1258
##STR00169## 0.4 1257 ##STR00170## 0.3 1256 ##STR00171## 1444
##STR00172## 0.025 1443 ##STR00173## 0.0045 1441 ##STR00174## 0.248
1445 ##STR00175## 0.71 1323 ##STR00176## 0.015 1322 ##STR00177##
0.011 1301 ##STR00178## 0.4 1303 ##STR00179## ~2 1302 ##STR00180##
>2
1354 ##STR00181## >2 1330 ##STR00182## 1.51 1309 ##STR00183##
0.42 1352 ##STR00184## 1.7 1332 ##STR00185## 0.9 1329 ##STR00186##
0.31 1327 ##STR00187## 0.67 1326 ##STR00188## 0.92 1363
##STR00189## 1.0 1353 ##STR00190## 1.5 1351 ##STR00191## 1.1 1350
##STR00192## 0.8 1348 ##STR00193## 1.3 1339 ##STR00194## 1.4 1338
##STR00195## 0.082 1337 ##STR00196## 1.2 1308 ##STR00197## >2
1307 ##STR00198## 0.37 1306 ##STR00199## 1.35 1305 ##STR00200##
0.36 1364 ##STR00201## 1.9 1512 ##STR00202## 1511 ##STR00203## 1508
##STR00204## 1507 ##STR00205## 1506 ##STR00206## 1503 ##STR00207##
1496 ##STR00208## 1488 ##STR00209## 1478 ##STR00210## 1477
##STR00211## 1476 ##STR00212## 1475 ##STR00213## 1473 ##STR00214##
1472 ##STR00215## 1471 ##STR00216## 1470 ##STR00217## 1465
##STR00218## 1462 ##STR00219## >1 1461 ##STR00220## 0.15 1460
##STR00221## >1 1459 ##STR00222## 0.2 1365 ##STR00223## 1.6 1432
##STR00224## 0.185 1458 ##STR00225## 0.009 1456 ##STR00226## 0.19
1455 ##STR00227## 0.04 1453 ##STR00228## >5 1451 ##STR00229##
>5 1442 ##STR00230## 0.6 1505 ##STR00231## 1504 ##STR00232##
1393 ##STR00233## >5 1392 ##STR00234## 1 1389 ##STR00235## 1361
##STR00236## >2 1360 ##STR00237## >2 1379 ##STR00238## ~2.2
1378 ##STR00239## >2 1375 ##STR00240## >2 1440 ##STR00241##
1439 ##STR00242## 1518 ##STR00243## 1517 ##STR00244## 1516
##STR00245## 1515 ##STR00246## 1530 ##STR00247## 1529 ##STR00248##
1528 ##STR00249## 1527 ##STR00250## 1526 ##STR00251## 1525
##STR00252## 1524 ##STR00253## 1523 ##STR00254## 1522 ##STR00255##
1521 ##STR00256## 1520 ##STR00257## 1622 ##STR00258## 0.019 1621
##STR00259## 0.030 1586 ##STR00260## 0.045 1584 ##STR00261## 0.03
1582 ##STR00262## 0.24 1549 ##STR00263## 0.05 1548 ##STR00264##
0.007 1580 ##STR00265## 0.70 1587 ##STR00266## 0.13 1585
##STR00267## 1.3 1583 ##STR00268## 0.15 1581 ##STR00269## 0.47 1560
##STR00270## 0.04 1562 ##STR00271## 0.013 1561 ##STR00272## 0.008
1539 ##STR00273## 0.1 1534 ##STR00274## 0.2 1801 ##STR00275## 2.1
1802 ##STR00276## 3.3 1803 ##STR00277## 0.27 1804 ##STR00278## 1.9
1805 ##STR00279## 0.6 1806 ##STR00280## 0.24 1807 ##STR00281## 2.5
1808 ##STR00282##
[0173] Compounds of the invention may be provided as salts with
pharmaceutically compatible counterions (i.e., pharmaceutically
acceptable salts). A "pharmaceutically acceptable salt" means any
non-toxic salt that, upon administration to a recipient, is capable
of providing, either directly or indirectly, a compound or a
prodrug of a compound of this invention. A "pharmaceutically
acceptable counterion" is an ionic portion of a salt that is not
toxic when released from the salt upon administration to a
recipient. Pharmaceutically compatible salts may be formed with
many acids, including but not limited to hydrochloric, sulfuric,
acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be
more soluble in aqueous or other protonic solvents than are the
corresponding free base forms.
[0174] Acids commonly employed to form pharmaceutically acceptable
salts include inorganic acids such as hydrogen bisulfide,
hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric
acid, as well as organic acids such as para-toluenesulfonic,
salicylic, tartaric, bitartaric, ascorbic, maleic, besylic,
fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic,
ethanesulfonic, benzenesulfonic, lactic, oxalic,
para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and
acetic acid, and related inorganic and organic acids. Such
pharmaceutically acceptable salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caprate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexene-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, terephthalate,
sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate,
glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like salts. Preferred pharmaceutically acceptable acid addition
salts include those formed with mineral acids such as hydrochloric
acid and hydrobromic acid, and especially those formed with organic
acids such as maleic acid.
[0175] Suitable bases for forming pharmaceutically acceptable salts
with acidic functional groups include, but are not limited to,
hydroxides of alkali metals such as sodium, potassium, and lithium;
hydroxides of alkaline earth metal such as calcium and magnesium;
hydroxides of other metals, such as aluminum and zinc; ammonia, and
organic amines, such as unsubstituted or hydroxy-substituted mono-,
di-, or trialkylamines; dicyclohexylamine; tributyl amine;
pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine;
mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-,
bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like.
[0176] Certain compounds of the invention and their salts may exist
in more thin one crystal form and the present invention includes
each crystal form and mixtures thereof.
[0177] Certain compounds of the invention and their salts may also
exist in the form of solvates, for example hydrates, and the
present invention includes each solvate and mixtures thereof.
[0178] Certain compounds of the invention may contain one or more
chiral centers, and exist in different optically active forms. When
compounds of the invention contain one chiral center, the compounds
exist in two enantiomeric forms and the present invention includes
both enantiomers and mixtures of enantiomers, such as racemic
mixtures. The enantiomers may be resolved by methods known to those
skilled in the art, for example by formation of diastereoisomeric
salts which may be separated, for example, by crystallization;
formation of diastereoisomeric derivatives or complexes which may
be separated, for example, by crystallization, gas-liquid or liquid
chromatography; selective reaction of one enantiomer with an
enantiomer-specific reagent, for example enzymatic esterification;
or gas-liquid or liquid chromatography in a chiral environment, for
example on a chiral support for example silica with a bound chiral
ligand or in the presence of a chiral solvent, it will be
appreciated that where the desired enantiomer is converted into
another chemical entity by one of the separation procedures
described above, a further step may be used to liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0179] When a compound of the invention contains more than one
chiral center, it may exist in diastereoisomeric forms. The
diastereoisomeric compounds may be separated by methods known to
those skilled in the art, for example chromatography or
crystallization and the individual enantiomers may be separated as
described above. The present invention includes each
diastereoisomer of compounds of the invention and mixtures
thereof.
[0180] Certain compounds of the invention may exist in different
tautomeric forms or as different geometric isomers, and the present
invention includes each tautomer and/or geometric isomer of
compounds of the invention and mixtures thereof.
[0181] Certain compounds of the invention may exist in different
stable conformational forms which may be separable. Torsional
asymmetry due to restricted rotation about an asymmetric single
bond, for example because of steric hindrance or ring strain, may
permit separation of different conformers. The present invention
includes each conformational isomer of compounds of the invention
and mixtures thereof.
[0182] Certain compounds of the invention may exist in zwitterionic
form and the present invention includes each zwitterionic form of
compounds of the invention and mixtures thereof.
[0183] The present invention also includes pro-drugs. As used
herein the term "pro-drug" refers to an agent that is converted
into the parent drug in vivo by some physiological chemical process
(e.g., a prodrug on being brought to the physiological pH is
converted to the desired drug form). Pro-drugs are often useful
because, in some situations, they may be easier to administer than
the parent drug. They may, for instance, be bioavailable by oral
administration whereas the parent drug is not. The prodrug may also
have improved solubility in pharmacological compositions over the
parent drug. An example, without limitation, of a pro-drug would be
a compound of the present invention wherein it is administered as
an ester (the "pro-drug") to facilitate transmittal across a cell
membrane where water solubility is not beneficial, but then it is
metabolically hydrolyzed to the carboxylic acid once inside the
cell where water solubility is beneficial. Pro-drugs have many
useful properties. For example, a pro-drug may be more water
soluble than the ultimate drug, thereby facilitating intravenous
administration of the drug. A pro-drug may also have a higher level
of oral bioavailability than the ultimate drug. After
administration, the prodrug is enzymatically or chemically cleaved
to deliver the ultimate drug in the blood or tissue.
[0184] Exemplary pro-drugs upon cleavage release the corresponding
free acid, and such hydrolyzable ester-forming residues of the
compounds of this invention include but are not limited to
carboxylic acid substituents (e.g., --C(O).sub.2H or a moiety that
contains a carboxylic acid) wherein the free hydrogen is replaced
by (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.12)alkanoyloxymethyl,
(C.sub.4-C.sub.9)1-(alkanoyloxy)ethyl,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxy
carbonyl oxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)-alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidine-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0185] Other exemplary pro-drugs release an alcohol or amine of a
compound of the invention wherein the free hydrogen of a hydroxyl
or amine substituent is replaced by (C1-C6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyl-oxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylamino-methyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl wherein said .alpha.-aminoacyl
moieties are independently any of the naturally occurring L-amino
acids found in proteins, --P(O)(OH).sub.2,
--P(O)(O(C1-C6)alkyl).sub.2 or glycosyl (the radical resulting from
detachment of the hydroxyl of the hemiacetal of a
carbohydrate).
[0186] The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Examples of such
protecting groups include esters of carboxylic acids, silyl ethers
of alcohols, and acetals and ketals of aldehydes and ketones,
respectively. The field of protecting group chemistry has been
reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991). Protected
forms of the inventive compounds are included within the scope of
this invention.
[0187] The term "chemically protected form," as used herein,
pertains to a compound in which one or more reactive functional
groups are protected from undesirable chemical reactions, that is,
are in the form of a protected or protecting group (also known as a
masked or masking group). It may be convenient or desirable to
prepare, purify, and/or handle the active compound in a chemically
protected form.
[0188] By protecting a reactive functional group reactions
involving other unprotected reactive functional groups can be
performed, without affecting the protected group; the protecting
group may be removed, usually in a subsequent step, without
substantially affecting the remainder of the molecule. See, for
example, Protective Groups in Organic Synthesis (T. Green and P.
Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T.
Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
[0189] For example, a hydroxy group may be protected as an ether
(--OR) or an ester (--OC(.dbd.O)R), for example, as: a t-butyl
ether; a benzyl, benzhydryl (diphenylmethyl), or trityl
(triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl
ether; or an acetyl ester (--OC(.dbd.O)CH.sub.3, --OAc).
[0190] For example, an aldehyde or ketone group may be protected as
an acetal or ketal, respectively, in which the carbonyl group
(C(.dbd.O)) is converted to a diether (C(OR).sub.2), by reaction
with, for example, a primary alcohol. The aldehyde or ketone group
is readily regenerated by hydrolysis using a large excess of water
in the presence of acid.
[0191] For example, an amine group may be protected for example, as
an amide (--NRC(.dbd.O)R) or a urethane (--NRC(.dbd.O)OR), for
example, as: a methyl amide (--NHC(.dbd.O)CH.sub.3); a benzyloxy
amide (--NHC(.dbd.O)OCH.sub.2C.sub.6H.sub.5NHCbz), as a t-butoxy
amide (--NHC.dbd.(.dbd.O)OC(CH.sub.3).sub.3, --NHBoc); a
2-biphenyl-2-propoxy amide
(--NHC(.dbd.O)OC(CH.sub.3).sub.2C.sub.6H.sub.4C.sub.6H.sub.5NHBoc),
as a 9-fluorenylmethoxy amide (--NHFmoc), as a 6-nitroveratryloxy
amide (--NHNvoc), as a 2-trimethylsilylethyloxy amide (--NHTeoc),
as a 2,2,2-trichloroethyloxy amide (--NHTroc), as an allyloxy amide
(--NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (--NHPsec); or,
in suitable cases (e.g., cyclic amines), as a nitroxide
radical.
[0192] For example, a carboxylic acid group may be protected as an
ester or an amide, for example, as: a benzyl ester; a t-butyl
ester; a methyl ester; or a methyl amide.
[0193] For example, a thiol group may be protected as a thioether
(--SR), for example, as: a benzyl thioether; or an acetamidomethyl
ether (--SCH.sub.2NHC(.dbd.O)CH.sub.3).
[0194] The compounds described herein are isolated molecules. An
isolated molecule is a molecule that is substantially pure and is
free of other substances with which it is ordinarily found in
nature or in vivo systems to an extent practical and appropriate
for its intended use. In particular, the molecular species are
sufficiently pure and are sufficiently free from other biological
constituents of host cells so as to be useful in, for example,
producing pharmaceutical preparations or sequencing if the
molecular species is a nucleic acid, peptide, or polysaccharide.
Because an isolated molecular species of the invention may be
admixed with a pharmaceutically-acceptable carrier in a
pharmaceutical preparation or be mixed with some of the components
with which it is associated in nature, the molecular species may
comprise only a small percentage by weight of the preparation. The
molecular species is nonetheless substantially pure in that it has
been substantially separated from the substances with which it may
be associated in living systems.
Methods
[0195] In certain aspects, the invention provides methods of
treating a disease or infection in a subject, comprising
administering to a subject a compound of Formula I or Formula II,
e.g., in a therapeutically effective amount.
[0196] In some embodiments, the disease or infection is cancer,
obesity, HIV/AIDS, a viral infection (e.g, by Ebola, Lassa fever,
Marburg, Nipah, Hendra, and avian-derived influenza viruses),
hemorrhagic fever, Ebola Hemorrhagic Fever (EHF).
[0197] In some embodiments, the invention provides for methods of
inhibiting Niemann-Pick C1 (NPC1) activity.
[0198] Several viruses produce a syndrome referred to as
hemorrhagic fever following infection of humans. Although the
viruses are not structurally similar, they produce this syndrome in
humans, which is characterized by an exaggerated immune response.
Often the viruses which produce this type of systemic inflammatory
response resulting in hemorrhagic fever have transferred from a
different species to humans. Examples of viruses that fall into
this category include Ebola, Lassa fever, Marburg, Nipah, Hendra,
and avian-derived influenza. The methods of the invention are
particularly useful for treating Ebola viruses.
[0199] The methods of the invention are useful for treating a
subject in need thereof. A subject in need thereof is a subject
having or at risk of having an enveloped virus infection. In its
broadest sense, the terms "treatment" or "to treat" refer to both
therapeutic and prophylactic treatments. If the subject in need of
treatment is experiencing a condition (i.e., has or is having a
particular condition), then "treating the condition" refers to
ameliorating, reducing or eliminating one or more symptoms arising
from the condition. If the subject in need of treatment is one who
is at risk of having a condition, then treating the subject refers
to reducing the risk of the subject having the condition or, in
other words, decreasing the likelihood that the subject will
develop an infectious disease to the virus, as well as to a
treatment after the subject has been infected in order to fight the
infectious disease, e.g., reduce or eliminate it altogether or
prevent it from becoming worse.
[0200] Thus the invention encompasses the use of the inhibitors
described herein alone or in combination with other therapeutics
for the treatment of a subject having or at risk of having a viral
infection, e.g., an enveloped viral infection. A. "subject having
an enveloped viral infection" is a subject that has had contact
with a virus. Thus the virus has invaded the body of the subject.
The word "invade" as used herein refers to contact by the virus
with an external surface of the subject, e.g., skin or mucosal
membranes and/or refers to the penetration of the external surface
of the subject by the virus. A subject at risk of having an
enveloped virus infection is one that has been exposed to or may
become exposed to an enveloped virus or a geographical area in
which an enveloped viral infection has been reported. Further risks
include close contact with a human or non-human primate or their
tissues infected with the virus. Such persons include laboratory or
quarantine facility workers who handle non-human primates that have
been associated with the disease. In addition, hospital staff and
family members who care for patients with the disease are at risk
if they do not use proper barrier nursing techniques.
[0201] As used herein, a subject includes humans and non-human
animals such as non-human primates, dogs, cats, sheep, goats, cows,
pigs, horses and rodents.
[0202] The compositions are delivered in effective amounts. The
term "effective amount" refers to the amount necessary or
sufficient to realize a desired biologic effect. Combined with the
teachings provided herein, by choosing among the various active
compounds and weighing factors such as potency, relative
bioavailability, patient body weight, severity of adverse
side-effects and preferred mode of administration, an effective
prophylactic or therapeutic treatment regimen can be planned which
does not cause substantial toxicity and yet is effective to treat
the particular subject. In addition, based on testing, toxicity of
the inhibitor is expected to be low. The effective amount for any
particular application can vary depending on such factors as the
disease or condition being treated, the particular inhibitor being
administered, the size of the subject, or the severity of the
disease or condition. One of ordinary skill in the art can
empirically determine the effective amount of a particular
inhibitor and/or other therapeutic agent without necessitating
undue experimentation. It is preferred generally that a maximum
dose be used, that is, the highest safe dose according to some
medical judgment. Multiple doses per day may be contemplated to
achieve appropriate systemic levels of compounds. Appropriate
systemic levels can be determined by, for example, measurement of
the patient's peak or sustained plasma level of the drug. "Dose"
and "dosage" are used interchangeably herein.
[0203] For any compound described herein, the therapeutically
effective amount can be initially determined from preliminary in
vitro studies and/or animal models. A therapeutically effective
dose can also be determined from human data for inhibitors which
have been tested in humans and for compounds which are known to
exhibit similar pharmacological activities, such as other related
active agents. The applied dose can be adjusted based on the
relative bioavailability and potency of the administered compound.
Adjusting the dose to achieve maximal efficacy based on the methods
described above and other methods well-known in the art, is well
within the capabilities of the ordinarily skilled artisan.
[0204] In certain embodiments, the methods of the invention are
useful for treating infection with enveloped viruses. Viruses are
small infectious agents which contain a nucleic acid core and a
protein coat, but are not independently living organisms. A virus
cannot multiply in the absence of a living cell within which it can
replicate. Viruses enter specific living cells either by transfer
across a membrane or direct injection and multiply, causing
disease. The multiplied virus can then be released and infect
additional cells. Some viruses are DNA-containing viruses and
others are RNA-containing viruses. The genomic size, composition
and organization of viruses show tremendous diversity.
[0205] As used herein, an "enveloped" virus is a virus which
possesses a membrane or `envelope`, which is a lipid bilayer
containing viral proteins. The envelope proteins of a virus play a
pivotal role in its lifecycle. They participate in the assembly of
the infectious particle and also play a crucial role in virus entry
by binding to a receptor present on the host cell and inducing
fusion between the viral envelope and a membrane of the host cell.
Enveloped viruses can be either spherical or filamentous
(rod-shaped) and include but are not limited to filoviruses, such
as Ebola virus or Marburg virus, Lassa virus, Arboroviruses such as
Togaviruses, flaviviruses (such as hepatitis-C virus),
bunyaviruses, and Arenaviruses, Orthomyxoviridae, Paramyxoviridae,
poxvirus, herpesvirus, hepadnavirus, Rhabdovirus, Bornavirus, and
Arterivirus.
[0206] In some embodiments, the invention provides for methods of
treating infection by Ebola virus. Five species of Ebola virus have
been identified: Cote d'Ivoire (CI), Sudan (S), Zaire (Z), and
Reston (R), Bundibugyo (B), The Reston subtype is the only known
filovirus that is not known to cause fatal disease in humans;
however, it can be fatal in monkeys. In some embodiments, the
compounds of the invention may selectively inhibit Ebola
infection.
[0207] Infection by Ebola virus leads to Ebola. Hemorrhagic Fever
(EHF), the clinical manifestations of which are severe. The
incubation period varies between four and sixteen days. The initial
symptoms are generally a severe frontal and temporal headache,
generalized aches and pains, malaise, and by the second day the
victim will often have a fever, Later symptoms include watery
diarrhea, abdominal pain, nausea, vomiting, a dry sore throat, and
anorexia. By day seven of the symptoms, the patient will often have
a maculopapular (small slightly raised spots) rash. At the same
time the person may develop thrombocytopenia and hemorrhagic
manifestations, particularly in the gastrointestinal tract, and the
lungs, hut it can occur from any orifice, mucous membrane or skin
site. Ebola causes lesions in almost every organ, although the
liver and spleen are the most noticeably affected. Both are
darkened and enlarged with signs of necrosis. The cause of death
(>75% in most outbreaks) is normally shock, associated with
fluid and blood loss into the tissues. The hemorrhagic and
connective tissue complications of the disease are not well
understood, but may be related to onset of disseminated
intravascular coagulation.
[0208] As used herein, the term "Marburg virus" refers to the
filovirus that causes Marburg hemorrhagic fever. Marburg
hemorrhagic fever is a rare, severe type of hemorrhagic fever which
affects both humans and non-human primates. The case-fatality rate
for Marburg hemorrhagic fever is 70% in recent Angola outbreak.
After an incubation period of 5-10 days, the onset of the disease
is sudden and is marked by fever, chills, headache, and myalgia.
Around the fifth day after the onset of symptoms, a maculopapular
rash, most prominent on the trunk (chest, back, stomach), may
occur. Nausea, vomiting, chest pain, a sore throat, abdominal pain,
and diarrhea then may appear. Symptoms become increasingly severe
and may include jaundice, inflammation of the pancreas, severe
weight loss, delirium, shock, liver failure, massive hemorrhaging,
and multi-organ dysfunction.
[0209] The family Orthomyxoviridae includes, without limitation,
influenza A virus, influenza B virus, influenza C virus,
Thogotovirus, Dhori virus, and infectious salmon anemia virus.
[0210] Influenza type A viruses are divided into subtypes based on
two proteins on the surface of the virus. These proteins are called
hemagglutinin (HA) and neuraminidase (NA). There are 15 different
HA subtypes and 9 different NA subtypes. Subtypes of influenza A
virus are named according to their HA and NA surface proteins, and
many different combinations of HA and NA proteins are possible. For
example, an "H7N2 virus" designates an influenza A subtype that has
an HA 7 protein and an NA 2 protein. Similarly an "H5N1" virus has
an HA 5 protein and an NA 1 protein. Only some influenza A subtypes
(i.e., H1N1, H2N2, and H3N2) are currently in general circulation
among people. Other subtypes such as H5 N1 are found most commonly
in other animal species and in a small number of humans, where it
is highly pathogenic. For example, H7N7 and H3N8 viruses cause
illness in horses. Humans can be infected with influenza types A,
B, and C. However, the only subtypes of influenza A virus that
normally infect people are influenza A subtypes H1N1, H2N2, and
H3N2 and recently, H5N1.
[0211] The family Paramyxoviridae includes, without limitation,
human parainfluenza virus, human respiratory syncytial virus (RSV),
Sendai virus, Newcastle disease virus, mumps virus, rubeola
(measles) virus, Hendra virus, Nipah virus, avian pneumovirus, and
canine distemper virus. The family Filoviridae includes, without
limitation, Marburg virus and Ebola virus. The family Rhabdoviridae
includes, without limitation, rabies virus, vesicular stomatitis
virus (VSV), Mokola virus, Duvenhage virus, European bat virus,
salmon infectious hematopoietic necrosis virus, viral hemorrhagic
septicaemia virus, spring viremia of carp virus, and snakehead
rhabdovirus. The family Bornaviridae includes, without limitation,
Borna disease virus. The family Bunyaviridae includes, without
limitation, Bunyamwera virus, Hantaan virus, Crimean Congo virus,
California encephalitis virus, Rift Valley fever virus, and sandfly
fever virus. The family Arenaviridae includes, without limitation,
Old World. Arenaviruses, such as Lassa virus (Lassa fever), Ippy
virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, and
Mopeia virus and New World Arenaviruses, such as Junin virus
(Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever),
Amapari virus, Flexal virus, Guanarito virus (Venezuela hemorrhagic
fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus,
Boliveros virus, Parana virus, Pichinde virus, Pirital virus,
Tacaribe virus, Tatniami virus, and Whitewater Arroyo virus. The
Arenaviridae associated with specific diseases include Lymphocytic
choriomeningitis virus (meningitis), Lassa virus (hemorrhagic
fever), Junin Virus (Argentine hemorrhagic fever), Machupo Virus
(Bolivian hemorrhagic fever), Sabia virus (Brazilian hemorrhagic
fever), and Guanarito (Venezuelan Hemorrhagic fever).
[0212] The arboviruses are a large group (more than 400) of
enveloped RNA viruses that are transmitted primarily (but not
exclusively) by arthropod vectors (mosquitoes, sand-flies, fleas,
ticks, lice, etc). More recently, the designated Arborviruses have
been split into four virus families, including the togaviruses,
flaviviruses, arenaviruses and bunyaviruses.
[0213] As used herein, the term "togavirus" refers to members of
the family Togaviridae, which includes the genuses Alphavirus (e.g.
Venezuela equine encephalitis virus, Sindbis virus, which causes a
self-limiting febrile viral disease characterized by sudden onset
of fever, rash, arthralgia or arthritis, lassitude, headache and
myalgia) and Rubivirus (e.g. Rubella virus, which causes Rubella in
vertebrates).
[0214] Rubella virus infections in adults are frequently
sub-clinical. A characteristic pink, continuous maculopapular rash
appears in 95% of adolescent patients 14-25 days after infection,
and the patient is infectious for most of this time. After early
viremia, rubella virus multiplies in many organs, particularly
lymph nodes (lymphadenopathy), including the placenta, but symptoms
in adults are rare. In children Rubella virus causes a mild febrile
illness. The virus crosses placenta and multiplies in the fetus. Up
to 85% of infants infected in the first trimester of pregnancy get
congenital rubella syndrome (CRS), characterized by low birth
weight, deafness, CNS involvement, and possibly abortion, with
symptoms worse the earlier in pregnancy they occur.
[0215] Flaviviridae is a member of the family of (+)-sense RNA
enveloped viruses. Flaviviridae includes flavivirus, Pestivirus,
and Hepacivirus. Flavivirus genus including yellow fever virus,
dengue fever virus, and Japanese encaphilitis (JE) virus. The
Pestivirus genus includes the three serotypes of bovine viral
diarrhea, but no known human pathogens. Genus Hepacivirus consists
of hepatitis C virus and hepatitis C-like viruses.
[0216] A yellow fever virus infection is characterized by an
incubation period of 3 to 6 days, during which 5% to 50% of
infected people develop disease. Yellow fever begins with a
nonspecific 1- to 3-day febrile illness, followed by a brief
remission, and then by a life-threatening toxic syndrome
accompanied by epistaxis, other hemorrhagic phenomena, jaundice,
and disseminated intravascular coagulation. Mortality rates for
yellow fever are approximately 20%.
[0217] There are four serotypes of dengue fever virus, all
transmitted by mosquitos. Dengue fever virus infection may be
asymptomatic or may result in dengue fever. This is generally a
self-limiting febrile illness which occurs after a 4-8 day
incubation period. It has symptoms such as fever, aches and
arthralgia (pain in the joints) which can progress to arthritis
(inflammation of the joints), myositis (inflammation of muscle
tissue) and a discrete macular or maculopapular rash. In this
situation clinical differentiation from other viral illnesses may
not be possible, recovery is rapid, and need for supportive
treatment is minimal. Dengue haemorrhagic fever (DHF) is a
potentially deadly complication. Dengue hemorrhagic fever commences
with high fever and many of the symptoms of dengue fever, but with
extreme lethargy and drowsiness. The patient has increased vascular
permeability and abnormal homeostasis that can lead to hypovolemia
and hypotension, and in severe cases, result in hypovolemic shock
often complicated by severe internal bleeding.
[0218] The Japanese encephalitis antigenic complex includes Alfuy,
Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley
encephalitis, St. Louis encephalitis, Stratford, Usutu, and West
Nile viruses. These viruses are transmissible by mosquitoes and
many of them can cause febrile, sometimes fatal, illnesses in
humans, West Nile virus is the most widespread of the flaviviruses,
with geographic distribution including Africa and Eurasia, West
Nile virus RNA has been detected in overwintering mosquitoes in New
York City & the geographic range of the virus is increasing in
the USA.
[0219] The genus Pestivirus has been divided into bovine viral
diarrhea virus (BVDV), classical swine fever virus (CSFV), and
border disease virus (BDV). Infection with BVDV results in a
variety of diseases ranging from subclinical to highly fatal. Many
BVDV viruses cause only clinically mild disease in nonpregnant
adult cattle. Prenatal infection can cause congenital malformations
and/or fetal death.
[0220] The Hepacivirus genus includes the hepatitis C virus (HCV).
The majority of cases of HCV infection give rise to an acute
illness, where up to 85% of infections may develop into chronic
hepatitis. Almost all patients develop a vigorous antibody and
cell-mediated immune response which fails to clear the infection
but may contribute towards liver damage.
[0221] Arenaviridae is a member of the family of (-) sense RNA
viruses. As used herein, the term "Arenavirus" refers to members of
the genus Arenavirius, a family of viruses whose members are
generally associated with rodent-transmitted disease in humans,
including Lymphocytic choriomeningitis virus (LCMV), Lassa virus,
Junin virus, which causes Argentine hemorrhagic fever, Machupo
virus, which causes Bolivian hemorrhagic fever, Guanarito virus,
which causes Venezuelan hemorrhagic fever, and Sabia, which causes
Brazilian hemorrhagic fever. LCMV causes which causes lymphocytic
choriomeningitis, a mild disease that is occasionally severe with
hemorrhaging. Infection by LCMV is rare in humans. Lassa virus
causes Lassa fever in humans. Signs and symptoms of Lassa fever
typically occur 1-3 weeks after the patient comes into contact with
the virus. These include fever, retrosternal pain, sore throat,
back pain, cough, abdominal pain, vomiting, diarrhea,
conjunctivitis, facial swelling, proteinuria, and mucosal bleeding.
Neurological problems have also been described, including hearing
loss, tremors, and encephalitis.
[0222] Bunyaviridae is a family of (-)-sense RNA viruses. As used
herein, "bunyavirus" refers to members of the Bunyaviridae family
and includes the genuses Orthobunyavirus, Hantavirus, Phlebovirus,
and Nairovirus.
[0223] Hantavirus infection is spread from rodents (reservoir) to
man by aerosolized feces, not insect vector, causing hantavirus
pulmonary syndrome (HPS). Patients with HPS typically present in
with a relatively short febrile prodrome lasting 3-5 days. In
addition to fever and myalgias, early symptoms include headache,
chills, dizziness, non-productive cough, nausea, vomiting, and
other gastrointestinal symptoms. Malaise, diarrhea, and
lightheadedness are reported by approximately half of all patients,
with less frequent reports of arthralgias, back pain, and abdominal
pain. Patients may report shortness of breath, (respiratory rate
usually 26-30 times per minute). Typical findings on initial
presentation include fever, tachypnea and tachycardia. The physical
examination is usually otherwise normal.
[0224] In man the Phlebovirus Rift valley fever virus produces an
acute, flu-like illness and is transmitted by mosquitoes from
animal reservoirs (e.g. sheep) to man. Sand fly fever is
transmitted to man by Phlebotomous flies (sand-flies) and causes an
acute, febrile illness characterized by fever, malaise, eye pain,
and headache.
[0225] Hendra and Nipah virus in the Henipavirus genus of the
subfamily Paramyxovirinae are distinguished by fatal disease in
both animal and human hosts. In particular, the high mortality and
person-to-person transmission associated with the most recent Nipah
virus outbreak.
Combination Therapy
[0226] The compounds of the invention may be used in combination
with other therapeutic agents to treat a disease or infection
disclosed herein. The compound and other therapeutic agent may be
administered simultaneously or sequentially. When the other
therapeutic agents are administered simultaneously they can be
administered in the same or separate formulations, but are
administered at the same time. The other therapeutic agents are
administered sequentially with one another and with the inhibitors,
when the administration of the other therapeutic agents and the
inhibitors is temporally separated. The separation in time between
the administration of these compounds may be a matter of minutes or
it may be longer. Other therapeutic agents include but are not
limited to anti-viral vaccines and anti-viral agents, inhibitors of
metabolizing enzymes, e.g., liver enzymes, that normally metabolize
said anti-viral agents and/or compounds of the invention. In some
instances the inhibitors are administered with multiple therapeutic
agents, e.g., 2, 3, 4 or even more different anti-viral agents.
[0227] An anti-viral vaccine is a formulation composed of one or
more viral antigens and one or more adjuvants. The viral antigens
include proteins or fragments thereof as well as whole killed
virus. Adjuvants are well known to those of skill in the art.
[0228] Antiviral agents are compounds which prevent infection of
cells by viruses or replication of the virus within the cell. There
are many fewer antiviral drugs than antibacterial drugs because
viruses are more dependent on host cell factors than bacteria.
There are several stages within the process of viral infection
which can be blocked or inhibited by antiviral agents. These stages
include, attachment of the virus to the host cell (immunoglobulin
or binding peptides), membrane penetration inhibitors, e.g. T-20,
uncoating of the virus (e.g. amantadine), synthesis or translation
of viral mRNA (e.g. interferon), replication of viral RNA or DNA
(e.g. nucleotide analogues), maturation of new virus proteins (e.g.
protease inhibitors), and budding and release of the virus.
[0229] Nucleotide analogues are synthetic compounds which are
similar to nucleotides, but which have an incomplete or abnormal
deoxyribose or ribose group. Once the nucleotide analogues are in
the cell, they are phosphorylated, producing the triphosphate
formed which competes with normal nucleotides for incorporation
into the viral DNA or RNA. Once the triphosphate form of the
nucleotide analogue is incorporated into the growing nucleic acid
chain, it causes irreversible association with the viral polymerase
and thus chain termination. Nucleotide analogues include, but are
not limited to, acyclovir (used for the treatment of herpes simplex
virus and varicella-zoster virus), gancyclovir (useful for the
treatment of cytomegalovirus), idoxuridine, ribavirin (useful for
the treatment of respiratory syncitial virus), dideoxyinosine,
dideoxycytidine, zidovudine (azidothymidine), imiquimod, and
resimiquimod.
[0230] The interferons are cytokines which are secreted by
virus-infected cells as well as immune cells. The interferons
function by binding to specific receptors on cells adjacent to the
infected cells, causing the change in the cell which protects it
from infection by the virus. .alpha.- and .beta.-interferon also
induce the expression of Class I and Class II MHC molecules on the
surface of infected cells, resulting in increased antigen
presentation for host immune cell recognition. .alpha.- and
.beta.-interferons are available as recombinant forms and have been
used for the treatment of chronic hepatitis B and C infection. At
the dosages which are effective for anti-viral therapy, interferons
have severe side effects such as fever, malaise and weight
loss.
[0231] Anti-viral agents which may be useful in combination with
the inhibitors of the invention include but are not limited to
immunoglobulins, amantadine, interferons, nucleotide analogues, and
other protease inhibitors (other than the papain-like cysteine
protease inhibitors--although combinations of papain-like cysteine
protease inhibitors are also useful). Specific examples of
anti-viral agents include but are not limited to Acemannan;
Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept
Sudotox; Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine
Mesylate; Avridine; Cidofovir; Cipamfylline; Cytarabine
Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine;
Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine
Hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet
Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium;
Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine
Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir;
Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate;
Somantadine Hydrochloride; Sorivudine; Statolon; Stavudine;
Tilorone Hydrochloride; Trifluridine; Valacyclovir Hydrochloride;
Vidarabine; Vidarabine Phosphate; Vidarabine Sodium Phosphate;
Viroxime; Zalcitabine; Zidovudine; and Zinviroxime.
[0232] Immunoglobulin therapy is used for the prevention of viral
infection. Immunoglobulin therapy for viral infections is different
than bacterial infections, because rather than being
antigen-specific, the immunoglobulin therapy functions by binding
to extracellular virions and preventing them from attaching to and
entering cells which are susceptible to the viral infection. The
therapy is useful for the prevention of viral infection for the
period of time that the antibodies are present in the host. In
general there are two types of immunoglobulin therapies, normal
immunoglobulin therapy and hyper-immunoglobulin therapy. Normal
immune globulin therapy utilizes a antibody product which is
prepared from the serum of normal blood donors and pooled. This
pooled product contains low titers of antibody to a wide range of
human viruses, such as hepatitis A, parvovirus, enterovirus
(especially in neonates). Hyper-immune globulin therapy utilizes
antibodies which are prepared from the serum of individuals who
have high titers of an antibody to a particular virus. Those
antibodies are then used against a specific virus. Another type of
immunoglobulin therapy is active immunization. This involves the
administration of antibodies or antibody fragments to viral surface
proteins.
Pharmaceutical Compositions
[0233] In certain embodiments, the present invention provides
pharmaceutical compositions comprising a compound of Formula I or
II and a pharmaceutically acceptable carrier.
[0234] The formulations of the invention are administered in
pharmaceutically acceptable solutions, which may routinely contain
pharmaceutically acceptable concentrations of salt, buffering
agents, preservatives, compatible carriers, adjuvants, and
optionally other therapeutic ingredients.
[0235] For use in therapy, an effective amount of the inhibitor can
be administered to a subject by any mode that delivers the
inhibitor to the desired surface. Administering the pharmaceutical
composition of the present invention may be accomplished by any
means known to the skilled artisan. Preferred routes of
administration include but are not limited to oral, intrathecal,
intra-arterial, direct bronchial application, parenteral (e.g.
intravenous), intramuscular, intranasal, sublingual, intratracheal,
inhalation, ocular, vaginal, and rectal, e.g., using a
suppository.
[0236] For oral administration, the compounds (i.e., inhibitors,
and other therapeutic agents) can be formulated readily by
combining the active compound(s) with pharmaceutically acceptable
carriers well known in the art. Such carriers enable the compounds
of the invention to be formulated as tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions and the
like, for oral ingestion by a subject to be treated. Pharmaceutical
preparations for oral use can be obtained as solid excipient,
optionally grinding a resulting mixture, and processing the mixture
of granules, after adding suitable auxiliaries, if desired, to
obtain tablets or dragee cores. Suitable excipients are, in
particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations such as, for example,
maize starch, wheat starch, rice starch, potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
If desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Optionally the oral formulations
may also be formulated in saline or buffers, i.e. EDTA for
neutralizing internal acid conditions or may be administered
without any carriers.
[0237] Also specifically contemplated are oral dosage forms of the
above component or components. The component or components may be
chemically modified or mixed with other components so that oral
delivery of the derivative is efficacious. Generally, the chemical
modification or mixture contemplated permits (a) longer half-lives;
and (b) uptake into the blood stream from the stomach or intestine.
Also desired is the increase in overall stability of the component
or components and increase in circulation time in the body.
Examples of such moieties or other compounds include: polyethylene
glycol, copolymers of ethylene glycol and propylene glycol,
carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl
pyrrolidone and polyproline. Abuchowski and Davis, 1981, "Soluble
Polymer-Enzyme Adducts" In: Enzymes as Drugs, Hocenberg and
Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383;
Newmark, et al., 1982, J. Appl. Biochem. 4:185-189. Other polymers
that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.
Preferred for pharmaceutical usage, as indicated above, are
polyethylene glycol moieties.
[0238] For the component (or derivative) the location of release
may be the stomach, the small intestine (the duodenum, the jejunum,
or the ileum), or the large intestine. One skilled in the art has
available formulations which will not dissolve in the stomach, yet
will release the material in the duodenum or elsewhere in the
intestine. Preferably, the release will avoid the deleterious
effects of the stomach environment, either by protection of the
inhibitor (or derivative) or by release of the biologically active
material beyond the stomach environment, such as in the
intestine.
[0239] To ensure full gastric resistance a coating impermeable to
at least pH 5.0 is essential. Examples of the more common inert
ingredients that are used as enteric coatings are cellulose acetate
trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP),
HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit
L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L,
Eudragit 5, and Shellac. These coatings may be used as mixed
films.
[0240] A coating or mixture of coatings can also be used on
tablets, which are not intended for protection against the stomach.
This can include sugar coatings, or coatings which make the tablet
easier to swallow. Capsules may consist of a hard shell (such as
gelatin) for delivery of dry therapeutic i.e. powder; for liquid
forms, a soft gelatin shell may be used. The shell material of
cachets could be thick starch or other edible paper. For pills,
lozenges, molded tablets or tablet triturates, moist massing
techniques can be used.
[0241] The therapeutic can be included in the formulation as fine
multi-particulates in the form of granules or pellets of particle
size about 1 mm. The formulation of the material for capsule
administration could also be as a powder, lightly compressed plugs
or even as tablets. The therapeutic could be prepared by
compression.
[0242] Colorants and flavoring agents may all be included. For
example, the inhibitor (or derivative) may be formulated (such as
by liposome or microsphere encapsulation) and then further
contained within an edible product, such as a refrigerated beverage
containing colorants and flavoring agents.
[0243] One may dilute or increase the volume of the therapeutic
with an inert material. These diluents could include carbohydrates,
especially mannitol, .alpha.-lactose, anhydrous lactose, cellulose,
sucrose, modified dextrans and starch. Certain inorganic salts may
be also be used as tillers including calcium triphosphate,
magnesium carbonate and sodium chloride. Some commercially
available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and
Avicell.
[0244] Disintegrants may be included in the formulation of the
therapeutic into a solid dosage form. Materials used as
disintegrates include but are not limited to starch, including the
commercial disintegrant based on starch, Explotab. Sodium starch
glycolate, Amberlite, sodium carboxymethylcellulose,
ultramylopectin, sodium alginate, gelatin, orange peel, acid
carboxymethyl cellulose, natural sponge and bentonite may all be
used. Another form of the disintegrants are the insoluble cationic
exchange resins. Powdered gums may be used as disintegrants and as
binders and these can include powdered gums such as agar, Karaya or
tragacanth. Alginic acid and its sodium salt are also useful as
disintegrants.
[0245] Binders may be used to hold the therapeutic agent together
to form a hard tablet and include materials from natural products
such as acacia, tragacanth, starch and gelatin. Others include
methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl
cellulose (CMC). Polyvinyl pyrrolidone (PVP) and
hydroxypropylmethyl cellulose (HPMC) could both be used in
alcoholic solutions to granulate the therapeutic.
[0246] An anti-frictional agent may be included in the formulation
of the therapeutic to prevent sticking during the formulation
process. Lubricants may be used as a layer between the therapeutic
and the die wall, and these can include but are not limited to;
stearic acid including its magnesium and calcium salts,
polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and
waxes. Soluble lubricants may also be used such as sodium lauryl
sulfate, magnesium lauryl sulfate, polyethylene glycol of various
molecular weights, Carbowax 4000 and 6000.
[0247] Glidants that might improve the flow properties of the drug
during formulation and to aid rearrangement during compression
might be added. The glidants may include starch, talc, pyrogenic
silica and hydrated silicoaluminate.
[0248] To aid dissolution of the therapeutic into the aqueous
environment a surfactant might be added as a wetting agent.
Surfactants may include anionic detergents such as sodium lauryl
sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium
sulfonate. Cationic detergents might be used and could include
benzalkonium chloride or benzethonium chloride. The list of
potential non-ionic detergents that could be included in the
formulation as surfactants are lauromacrogol 400, polyoxyl 40
stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60,
glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty
acid ester, methyl cellulose and carboxymethyl cellulose. These
surfactants could be present in the formulation of the inhibitor or
derivative either alone or as a mixture in different ratios.
[0249] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. Microspheres formulated for oral
administration may also be used. Such microspheres have been well
defined in the art. All formulations for oral administration should
be in dosages suitable for such administration.
Kits
[0250] The invention also includes kits. The kit has a container
housing an inhibitor of the invention and optionally additional
containers with other therapeutics such as anti-viral agents or
viral vaccines. The kit also includes instructions for
administering the component(s) to a subject who has or is at risk
of having an enveloped viral infection.
[0251] In some aspects of the invention, the kit can include a
pharmaceutical preparation vial, a pharmaceutical preparation
diluent vial, and inhibitor. The vial containing the diluent for
the pharmaceutical preparation is optional. The diluent vial
contains a diluent such as physiological saline for diluting what
could be a concentrated solution or lyophilized powder of
inhibitor. The instructions can include instructions for mixing a
particular amount of the diluent with a particular amount of the
concentrated pharmaceutical preparation, whereby a final
formulation for injection or infusion is prepared. The instructions
may include instructions for use in an oral formulation, inhaler,
intravenous injection or any other device useful according to the
invention. The instructions can include instructions for treating a
patient with an effective amount of inhibitor. It also will be
understood that the containers containing the preparations, whether
the container is a bottle, a vial with a septum, an ampoule with a
septum, an infusion bag, and the like, can contain indicia such as
conventional markings which change color when the preparation has
been autoclaved or otherwise sterilized.
EXAMPLES
Example 1: Syntheses of Exemplary Compounds of the Invention
[0252] The compounds of the invention can be synthesized according
to the following representative procedures (Methods A, B, C),
wherein the substituents are as defined above, except where further
noted.
[0253] .sup.1H NMR spectra were recorded on a Varian Inova 600 MHz
spectrometer with chemical shifts reported in parts per million
(ppm) relative to an internal standard (trimethylsilane). Coupling
constants (J) are reported in hertz (Hz). Standard resolution mass
spectra were obtained on an Agilent 1200 Series HPLC (4.6.times.100
mm, 5 .mu.m Phenomenex C18 reverse-phase column) and a 6130 Series
mass spectrometer system all mass spectra were obtained using
electrospray ionization (EI) in positive ion mode. Standard
reverse-phase HPLC conditions were as follows: mobile phase A=0.1%
formic acid in water; mobile phase B=0.1% formic acid in
acetonitrile. Solvents for synthesis were purchased as anhydrous
grade and used without further purification. Reagents were
purchased from commercial sources and used as received.
##STR00283## ##STR00284## ##STR00285## ##STR00286##
##STR00287## ##STR00288##
##STR00289## ##STR00290##
##STR00291##
tert-Butyl 4-(2-amino-5-chlorobenzoyl)piperazine-1-carboxylate
[0254] To the proper amount of DCM solution Boc-piperazine (1 eq)
and 2-amino-5-chlorobenzoic acid (1.2 eq), under the nitrogen
flushing, minimum amount of DCM solution of NaBH(Ac).sub.3 (3 eq)
was added dropwise. Then the mixture was stirred at room
temperature overnight. After the reaction, the solvent was removed
by GeneVec. Saturated Na.sub.2CO.sub.3 aq was added into the
mixture, after sonication and centrifugation, the clear water phase
was removed and the residues was dissolved in EtOAc and dried by
MgSO4. Then the mixture was directly loaded onto a solid phase
extraction (SPE) cartridge containing strong ion exchanger (SCX, 1
g; UCT, CUBCX1M15). The cartridge was first washed with EtOAc:MeOH
(10:1, 12 mL), which was discarded, and then the product was eluted
with EtOAc-MeOH-Et3N (20:2:1, 6 mL) and obtained by concentration.
MS m/z: 440.20 (M+1), calc'd for C.sub.16H.sub.22ClN.sub.3O.sub.3:
339.13.
(2-Amino-5-chlorophenyl)(piperazin-1-yl)methanone
[0255] In a glass vial, the Boc protected piperazine derivative was
dissolved in 1 mL of EtOAc and then 1 mL of 4N HCl in Dioxane was
added to the solution. Under N.sub.2 protection, the mixture was
stirred at room temperature overnight. After the reaction the
mixture was then concentrated by GeneVec. The pure product was
obtained as a solid. MS m/z: 240.10 (M+1), calc'd for
C.sub.11H.sub.14ClN.sub.3O: 239.08.
4-Chloro-2-(piperazin-1-ylmethyl-d2)aniline
[0256] (2-Amino-5-chlorophenyl)(piperazin-1-yl)methanone and
lithium aluminium hydride (6 eq) was dissolved separated in
unhydrous THF and was degassed and refilled with N.sub.2. Then the
solution of amide was added to a stirred suspension of lithium
aluminium hydride in unhydrous THF. The reaction was heated to
50.degree. C. for 4 hours and then cooled. The reaction was
quenched by adding 6 eq of Sodium sulfate decahydrate portion-wise
and stirred at rt for overnight. Then the mixture was filtered and
the filtrate was concentrated to afford the product. MS m/z: 228.20
(M+1), calc'd for C.sub.11H.sub.14D.sub.2ClN.sub.3: 227.12.
N-(2-(4-((2-amino-5-chlorophenyl)methyl-d2)piperazin-1-yl)-2-oxoethyl)-2-(-
4,4-difluorocyclohexyl)acetamide 1412
[0257] (2-(4,4-difluorocyclohexyl)acetyl)glycine (1 eq), amine (1
eq), EDCI (1.2 eq) and HOBt (1.5 eq) were dissolved in proper
amount of DCM and then DIEA (12 eq) was added to the solution.
Under N.sub.2 protection, the mixture was stirred at room
temperature overnight. After the reaction, the DIEA was evaporated
by GeneVec. Water was added into the residue, and some oily or
solid substance was appeared. After sonication and centrifugation,
the water phase was removed and the residue was dissolved in EtOAc,
dried by MgSO4, filtered and concentrated. Pure product was then
obtained by productive thin layer chromatography (MeOH:DCM 1:20).
.sup.1H NMR (400 MHz, CDCl.sub.3, ppm): .delta. 7.06 (dd, J1=2.5,
J2=8.4, 1H), 6.95 (d, J=2.5, 1H), 6.58 (d, J=8.4, 1H), 6.55 (br,
1H), 4.05 (d, J=4.0, 2H), 3.63 (t, J=5.0, 2H), 3.39 (t, J=5.0, 2H),
2.43 (t, J=5.0, 4H), 2.18 (d, =7.0, 2H), 2.10-1.74 (m, 6H), 1.33
(m, 3H). MS m/z: 445.2 (M+1), calc'd for
C.sub.21H.sub.27D.sub.2ClF.sub.2N.sub.4O.sub.2: 444.21. Compound
N-(2-(4-((2-amino-5-chlorophenyl)methyl-d2)piperazin-1-yl)-2-oxoethyl)-6,-
6-difluorospiro[2.5]octane-1-carboxamide 1413 was prepared from
(6,6-difluorospiro[2.5]octane-1-carbonyl)glycine in a manner
similar to that described for compound 1412MS m/z: 457.20 (M+1),
calc'd for C.sub.22H.sub.27D.sub.2ClF.sub.2N.sub.4O.sub.2:
456.21,
General Procedures for Certain Compounds
##STR00292##
[0258] Method A1
[0259] To a mixture of the appropriate acid (1, 1 mmol, 1 eq), HATU
(1.5 mmol, 1.5 eq), under nitrogen was added 1.4 mL of anhydrous
DMF. Under stirring, N, N-diisopropylethylamine (2, 0.3 mL) was
added and the reaction stirred for 1 hr, then tert-butyl glycinate
hydrochloride (1.2 mmol, 1.2 eq) added in one portion. The reaction
was then stirred for overnight at room temperature. The reaction
was concentrated in genevec to remove iPr2NEt, water added, and
deep brown color precipitation, spinned, washed with water
2.times.6 mL to afford crude product 3 which were used for next
step without further purification. In a 5 mL glass vial, 3 was
dissolved in 1 mL of EtOAc and then 1 mL of 4N HCl in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction the
mixture was then concentrated by GeneVec. The pure product acid 4
was obtained as a solid.
[0260] In a vial was placed Boc-piperizine (6, 2 mmol, 1.1-3 eq) in
5 mL of anhydrous DME or DCM. Aldehyde 5 (1.85 mmol, 1 eq) was then
added, followed by NaBH(OAc).sub.3 (3.7 mmol, 2-4 eq). The reaction
stirred for overnight and then was dried to afford an oily crude
mixture. To this crude was added sat. aq. Na.sub.2CO.sub.3,
sonicated for 10 minutes, to get a sticky brown color wax/oil.
Washed, sonicated with water 2.times.10 mL. The residue was dried
to afford the 7.
[0261] In a 5 mL glass vial, the Boc-protected amine 7 was
dissolved in 2 mL of EtOAc and then 2 mL of 4N FICA in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction the
mixture was then concentrated by GeneVec. The HCl salt of amine 8
was obtained as a solid.
[0262] In a glass vial, the appropriate acid (4, 1 eq), amine (8, 1
eq) and HATU (1.2 eq), were dissolved in minimum amount of DMF and
then the same amount of DIEA was added to the solution (Method
A1a). [Alternative method: Appropriate acid (4, 1 eq), amine (8, 1
eq), EDCI (1.2 eq) and HOBt (1.5 eq) were dissolved in proper
amount of DCM and then DIEA (12 eq) was added to the solution
(Method A1b).] Under N.sub.2 protection, the mixture was stirred at
room temperature for overnight. After the reaction, the DIEA was
evaporated by GeneVec. Water was added into the residue, and some
oily or solid substance was appeared. After sonication and
centrifugation, the water phase was removed and the residue was
dissolved in EtOAc, dried by MgSO4, filtered and concentrated. Pure
product 9 was then obtained by productive thin layer chromatography
(5% MeOH/CH.sub.2Cl.sub.2).
##STR00293##
Method A2
[0263] To a mixture of the appropriate acid (1, 3.2 mmol, 1 eq),
ethyl glycinate hydrochloride (2, 3.9 mmol, 1.2 eq), HATU (4.8
mmol, 1.5 eq), under nitrogen was added 6 mL of anhydrous DME Under
stirring, N, N-diisopropylethylamine (0.3 mL) was added and the
reaction then stirred for overnight at room temperature. To the
mixture was added water (30 mL), white wax type precipitation
formed. The water was decanted, and the wax washed with 3.times.30
mL water under sonication to afford 3.
[0264] To the wax 3 was added 15 mL of EtOH, and 15 mL of 1N NaOH,
stirred at rt for over night. After the MeOH was removed, the
mixture was extracted by EtOAc. The water layer is acidified to
pH=5 by 1N HCl, and white solid formed, filtered to get 4.
[0265] In a vial was placed Boc-piperizine (6, 2 mmol, 1.1-3 eq) in
5 mL of anhydrous DME or DCM. Aldehyde 5 (1.85 mmol, 1 eq) was then
added, followed by NaBH(OAc).sub.3 (3.7 mmol, 2-4 eq). The reaction
stirred for overnight and then was dried to afford an oily crude
mixture.
[0266] To this crude was added sat. aq. Na.sub.2CO.sub.3, sonicated
for 10 minutes, to get a sticky brown color wax/oil. Washed,
sonicated with water 2.times.10 mL. The residue was dried to afford
the 7.
[0267] In a 5 mL glass vial, the Boc-protected piperazine 7 was
dissolved in 2 mL of EtOAc and then 2 mL of 4N HCl in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction the
mixture was then concentrated by GeneVec. The HCl salt of
piperazine 8 was obtained as a solid.
[0268] In a glass vial, the appropriate acid (4, 1 eq), amine (8, 1
eq) and HATU (1.2 eq), were dissolved in minimum amount of DMF and
then the same amount of DIEA was added to the solution (Method
A2a). [Alternative method: Appropriate acid (4, 1 eq), amine (8, 1
eq), EDCI (1.2 eq) and HOBt (1.5 eq) were dissolved in proper
amount of DCM and then DIEA (12 eq) was added to the solution
(Method A2b).] Under N.sub.2 protection, the mixture was stirred at
room temperature for overnight. After the reaction, the DIEA was
evaporated by GeneVec. Water was added into the residue, and some
oily or solid substance was appeared. After sonication and
centrifugation, the water phase was removed and the residue was
dissolved in EtOAc, dried by MgSO4, filtered and concentrated. Pure
product 9 was then obtained by productive thin layer chromatography
(5% MeOH/CH.sub.2Cl.sub.2).
##STR00294##
Method B1
[0269] To a mixture of proper aldehyde (1, 3.8 mmol, 1 eq) and
potassium carbonate (11 mmol, 4 eq) in DMF (5 mL) was added methyl
4-(bromomethyl)benzoate (2, 4.0 mmol, 1.05 eq) and the resulting
mixture was stirred for 16 h at room temperature. The solvent was
removed under reduced pressure and the residue was partitioned
between HBO (20 mL) and EtOAc (15 mL). The organic layer was washed
with brine, dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (gradient: 20-100% EtOAc/hexanes) to give 3 as a
white solid.
[0270] In a vial was placed Boc-piperizine (4, 2 mmol 1.1-3 eq) in
5 mL of anhydrous DME or DCM. Aldehyde 3 (1.85 mmol. 1 eq) was then
added, followed by NaBH(OAc).sub.3 (3.7 mmol, 2-4 eq). The reaction
stirred for overnight and then was dried to afford an oily crude
mixture. To this crude was added sat. aq. Na.sub.2CO.sub.3,
sonicated for 10 minutes, to get a sticky brown color wax/oil.
Washed, sonicated with water 2.times.10 mL. The residue was dried
to afford the 5.
[0271] In a 5 mL glass vial, the Boc-protected piperazine 5 (2
mmol) was dissolved in 2 mL of EtOAc and then 2 mL of 4N HCl in
Dioxane was added to the solution. Under nitrogen protection, the
mixture was stirred at room temperature overnight. After the
reaction, the mixture was then concentrated by GeneVec. The HCl
salt of piperazine 6 was obtained as a solid.
[0272] To a mixture of the (tert-butoxycarbonyl)glycine (7, 1.2
mmol, 1.2 eq), piperazine (1 mmol, 1 eq), HATU (1.5 mmol, 1.5 eq),
under nitrogen was added 3 mL of anhydrous DMF. Under stirring, N,
N-diisopropylethylamine (0.2 mL) was added and the reaction then
stirred for overnight at room temperature. To the mixture was added
water (10 mL), white precipitation formed. After sonication and
centrifugation, the water was decanted, and the residue was washed
with 10 nit water under sonication one more time to afford 8.
[0273] In a 5 mL glass vial, the Boc-protected amine 8 (1 mmol) was
dissolved in 1 mL of EtOAc and then 1 mL of 4N HCl in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction, the
mixture was then concentrated by GeneVec. The HCl salt of amine 9
was obtained as a solid.
[0274] In a glass vial, the appropriate acid (10, 1 eq), amine (9,
1 eq) and HATU (1.2 eq), were dissolved in minimum amount of DMF
and then the same amount of DIEA was added to the solution. Under
N.sub.2 protection, the mixture was stirred at room temperature for
overnight. After the reaction, the DIEA was evaporated by GeneVec.
Water was added into the residue, and some oily or solid substance
was appeared. After sonication and centrifugation, the water phase
was removed and the residue was dissolved in EtOAc, dried by MgSO4,
filtered and concentrated. Pure product 11 was then obtained by
productive thin layer chromatography (5%
MeOH/CH.sub.2Cl.sub.2).
##STR00295##
Method B2
[0275] In a sealed vial under nitrogen was placed the acid 2 (1.1
eq) in 1 mL of anhydrous DME, DIEA (1.6 eq) added, followed by DPPA
(1.2 eq). The reaction was shaken for 2 hrs at rt and then was
heated up to 78.degree. C. on a shaker for another 2 h, and then
cooled to rt, methyl
4-((2-(piperazin-1-ylmethyl)phenoxy)methyl)benzoate hydrochloride 1
in 0.5 mL of anhydrous DMF added, followed by another 3 eq of DIEA.
The mixture shaken for overnight. A mixture of amide and urea were
obtained and the pure product of these two derivatives were
separated by PTLC (5% MeOH/CH.sub.2Cl.sub.2).
##STR00296##
[0276] In a vial was placed test-butyl
(2-oxo-2-(piperazin-1-yl)ethyl)carbamate (2, 2 mmol, 1.1-3 eq) in 5
mL of anhydrous DCM. Aldehyde 1 (1.85 mmol, 1 eq) was then added,
followed by NaBH(OAc).sub.3 (3.7 mmol, 2-4 eq). The reaction
stirred for overnight and then was dried to afford an oily crude
mixture. To this crude was added sat. aq. Na.sub.2CO.sub.3,
sonicated for 10 minutes, to get a sticky brown color wax/oil.
Washed, sonicated with water 2.times.10 mL. The residue was dried
to afford the 3.
[0277] In a 5 mL glass vial, the Boc-protected amine 3 (2 mmol) was
dissolved in 2 mL of EtOAc and then 2 mL of 4N HCl in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction, the
mixture was then concentrated by GeneVec. The HCl salt of amine 4
was obtained as a solid.
[0278] In a glass vial, appropriate acid (5, 1 eq), amine (4, 1
eq), EDCI (1.2 eq) and HOBt (1.5 eq) were dissolved in proper
amount of DCM and then DIEA (12 eq) was added to the solution.
[0279] Under N.sub.2 protection, the mixture was stirred at room
temperature for overnight. After the reaction, the DIEA was
evaporated by GeneVec. Water was added into the residue, and some
oily or solid substance was appeared. After sonication and
centrifugation, the water phase was removed and the residue was
dissolved in EtOAc, dried by MgSO4, filtered and concentrated. Pure
product 6 was then obtained by productive thin layer chromatography
(5% MeOH/CH.sub.2Cl.sub.2).
##STR00297##
Method B4
[0280] In a glass vial, (tert-butoxycarbonyl)glycine (2, 2.2 mmol,
1.1 eq), proper piperidine (1, 2 mmol, 1 eq) and HATU (2.%1 mmol,
1.2 eq), were dissolved in minimum amount of DMF and then the same
amount of DIEA was added to the solution. Under N.sub.2 protection,
the mixture was stirred at room temperature for overnight. After
the reaction, the DIEA was evaporated by GeneVec. Water was added
into the residue, and some oily or solid substance was appeared.
After sonication and centrifugation, the water phase was removed
and the residue was dissolved in EtOAc, dried by MgSO4, filtered
and concentrated to afford crude 3.
[0281] In a 5 mL glass vial, the Boc-protected amine 3 (1 mmol) was
dissolved in 1 mL of EtOAc and then 1 mL of 4N HCl in Dioxane was
added to the solution. Under nitrogen protection, the mixture was
stirred at room temperature overnight. After the reaction, the
mixture was then concentrated by GeneVec. The HCl salt of amine 4
was obtained as a solid.
[0282] In a glass vial, (tert-butoxycarbonyl)glycine (5, 1.2 eq),
proper amine (4, 1 eq) and HATU (0.08 mmol, 1.5 eq), were dissolved
in minimum amount of DMF and then the same amount of DIEA was added
to the solution. Under N.sub.2 protection, the mixture was stirred
at room temperature for overnight. After the reaction, the DIEA was
evaporated by GeneVec. Water was added into the residue, and some
oily or solid substance was appeared. After sonication and
centrifugation, the water phase was removed and the residue was
dissolved in EtOAc, dried by MgSO4, filtered and concentrated to
afford crude. Pure product 6 was then obtained h productive thin
layer chromatography (5% MeOH/CH.sub.2Cl.sub.2).
##STR00298##
Method C1
[0283] To a mixture of the appropriate acid (1, 2.4 mmol, 1.2 eq),
tert-butyl 4-glycylpiperazine-1-carboxylate (2, 2 mmol, 1 eq), HATU
(3 mmol, 1.5 eq), under nitrogen was added 4 mL of anhydrous DMF.
Under stirring, N, N-diisopropylethylamine (0.3 mL) was added and
the reaction then stirred for overnight at room temperature. To the
mixture was added water (30 mL), white wax type precipitation
formed. The water was decanted, and the residue washed with
3.times.30 mL water under sonication to afford 3.
[0284] In a 5 mL glass vial, the Boc-protected piperazine 3 (1
mmol) was dissolved in 1 mL of EtOAc and then 1 mL of 4N HCl in
Dioxane was added to the solution. Under nitrogen protection, the
mixture was stirred at room temperature overnight. After the
reaction, the mixture was then concentrated by GeneVec. The HCl
salt of piperazine 4 was obtained as a solid.
[0285] In a vial was placed piperizine (4, 0.06-0.15 mmol, 1.1-3
eq) in 2 mL of anhydrous DME or DCM. Aldehyde 5 (0.05 mmol, 1 eq)
was then added, followed by NaBH(OAc).sub.3 (0.1-0.2 mmol, 2-4 eq).
The reaction stirred for overnight and then was dried to afford an
oily crude mixture. To this crude was added sat. aq.
Na.sub.2CO.sub.3, sonicated for 10 minutes, to get a sticky brown
color wax/oil. Washed, sonicated with water 2.times.10 mL. The
residue was dried to afford the crude. Pure product 6 was then
obtained by productive thin layer chromatography (5%
MeOH/CH.sub.2Cl.sub.2).
1311 105
##STR00299##
Methyl
4-((4-chloro-2-((4-((2-(4,4-difluorocyclohexyl)(acetyl)glycyl)pipe-
razin-1-yl)methyl)phenoxy)methyl)benzoate
[0286] This compound was prepared according to Method B1 using
5-chloro-2-hydroxybenzaldehyde and 2-(4,4-difluorocyclohexyl)acetic
acid. MS m/z: 592.3 (M+1), calc'd for
C.sub.30H.sub.36ClF.sub.2N.sub.3O.sub.5: 591.23.
1334 106
##STR00300##
Methyl
4-((4-chloro-2-((4-((2-(1-methylcyclohexyl)acetyl)glycyl)piperazin-
-1-yl)methyl)phenoxy)methyl)benzoate
[0287] This compound was prepared according to Method B1 using
5-chloro-2-hydroxybenzaldehyde and 2-(1-methylcyclohexyl)acetic
acid. MS m/z: 570.3 (M+1), calc'd for
C.sub.31H.sub.40ClN.sub.3O.sub.5: 569.27.
1335 109
##STR00301##
Methyl
4-((2-((4-((2-(4,4-difluorocyclohexyl)acetyl)glycyl)piperazin-1-yl-
)methyl-4-fluorophenoxy)methyl)benzoate
[0288] This compound was prepared according to Method 131 using
5-fluoro-2-hydroxybenzaldehyde and 2-(4,4-difluorocyclohexyl)acetic
acid. MS m/z: 554.3 (M+1), calc'd for
C.sub.30H.sub.36F.sub.3N.sub.3O.sub.5: 553.30.
1336 110
##STR00302##
Methyl
4-((4-fluoro-2-((4-((2-(1-methylcyclohexyl)acetyl)glycyl)piperazin-
-1-yl)methyl)phenoxy)methyl)benzoate
[0289] This compound was prepared according to Method B1 using
5-fluoro-2-hydroxybenzaldehyde and 2-(1-methylcyclohexyl)acetic
acid. MS m/z: 576.3 (M+1), calc'd for
C.sub.31H.sub.40FN.sub.3O.sub.5: 575.26.
1342
##STR00303##
N-(2-(4-(2-Acetamido-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-((3s)-a-
damantan-1-yl)acetamide
[0290] This compound was prepared according to Method A2a using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-amino-5-chlorobenzaldehyde with an additional step shown as
following. MS: m/z 501.3 (M+1), calc'd for
C.sub.27H.sub.37ClN.sub.4O.sub.3: 500.26.
##STR00304##
In a glass vial, A (1 eq), B (1.3 eq) were dissolved in 2 mL
anhydrous DCM. The reaction was stirred at II for overnight. Then
the mixture was concentrated and the pure product C was obtained by
PTCL (5% MeOH/DCM). 13432-120/173
##STR00305##
N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluo-
rocyclohexyl)acetamide
[0291] This compound was prepared according to Method A1b using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-chlorobenzaldehyde, MS m/z: 443.2 (M+1), calc'd for
C.sub.21H.sub.29ClF.sub.2N.sub.4O.sub.2: 442.19
1344 119d
##STR00306##
Methyl
4-((2-((4-((3,3-difluorobicyclo[3.1.0]hexane-6-carbonyl)glycyl)-pi-
perazin-1-yl)methy)phenoxy)methyl)benzoate
[0292] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid. MS m/z: 542.3
(M+1), calc'd for C.sub.29H.sub.33F.sub.2N.sub.3O.sub.5:
541.24.
1346 123
##STR00307##
Methyl
4-((4-chloro-2-((4-((3,3-difluorobicyclo[3.1.0]hexane-6-carbonyl)g-
lycyl)piperazin-1-yl)methyl)phenoxy)methyl)benzoate
[0293] This compound was prepared according to Method B1 using
5-chloro-2-hydroxybenzaldehyde and
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid. MS m/z: 576.2
(M+1), calc'd for C.sub.29H.sub.32ClF.sub.2N.sub.3O.sub.5:
575.20.
1347 124
##STR00308##
Methyl
4-((2-((4-((3,3-difluorobicyclo[3.1.0]hexane-6-carbonyl)glycyl)pip-
erazin-1-yl)methyl)-4-fluorophenoxy)methyl)benzoate
[0294] This compound was prepared according to Method B1 using
5-fluoro-2-hydroxybenzaldehyde and
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid. MS m/z: 560.3
(M+1), calc'd for C.sub.29H.sub.32F.sub.3N.sub.3O.sub.5:
559.23.
1355 131m
##STR00309##
N-(2-(4-(2-Amino-5-bromobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluor-
ocyclohexyl)acetamide
[0295] This compound was prepared according to Method A1b using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-bromobenzaldehyde MS m/z: 487.2 (M+1), calc'd for
C.sub.21H.sub.29BrF.sub.2N.sub.4O.sub.2: 486.14.
1356 133
##STR00310##
N-(2-(4-(5-bromo-2-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-3,3-difluorob-
icyclo[3.1.0]hexane-6-carboxamide
[0296] This compound was prepared according to Method A1a using
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid and
5-bromo-2-chlorobenzaldehyde MS m/z: 490.1 (M+1), calc'd for
C.sub.20H.sub.23BrClF.sub.2N.sub.3O.sub.2: 489.06.
1357 134
##STR00311##
Methyl
4-((4-chloro-2-((4-((2,2-difluorocyclopropane-1-carbonyl)glycyl)pi-
perazin-1-yl)methyl)phenoxy)methyl)benzoate
[0297] This compound was prepared according to Method B1 using
5-chloro-2-hydroxybenzaldehyde and
2,2-difluorocyclopropane-1-carboxylic acid. MS m/z: 536.2 (M+1),
calc'd for C.sub.26H.sub.28ClF.sub.2N.sub.3O.sub.5: 535.17.
1358 135
##STR00312##
Methyl
4-((4-chloro-2-((4-((2,2,3,3-tetrafluoropropanoyl)glycyl)piperazin-
-1-yl)methyl)phenoxy)methyl)benzoate
[0298] This compound was prepared according to Method B1 using
5-chloro-2-hydroxybenzaldehyde and 2,2,3,3-tetrafluoropropanoic
acid. MS m/z: 560.2 (M+1), calc'd for
C.sub.25H.sub.26ClF.sub.4N.sub.3O.sub.5: 559.15.
1359 143
##STR00313##
N-(2-(4-((4-Amino-4'-fluoro-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)-2-
-oxoethyl)-2-(4,4-difluorocyclohexyl)acetamide
[0299] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-bromobenzaldehyde with an additional step as following.
MS m/z: 503.3 (M+1), calc'd for
C.sub.27H.sub.33F.sub.3N.sub.4O.sub.2: 502.26.
##STR00314##
[0300] In a glass vial, A (0.2 mmol), B (0.24 mmol), C (0.6 mmol)
and D (0.02 mmol) were dissolved in 2 mL of E in a 10 mL pressure
vessel. The mixture was stirred, degassed by replacing the air with
N.sub.2, and placed in an 80.degree. C. oil bath for 18 h. After
the reaction, the solvent was removed by reduced pressure
evaporation. Then the residue was diluted by water and EtOAc. The
organic phase was washed and dried by MgSO4, filtered and loaded
onto a solid phase extraction (SPE) cartridge containing strong ion
exchanger (SCX, 1 g; UCT, CUBCX1M15), The cartridge was first
washed with EtOAc:MeOH (10:1, 12 mL), which was discarded, and then
the product was eluted with EtOAc-MeOH-Et3N (20:2:1, 6 mL). The
eluent was concentrated in vacuo to yield F as an orange oil.
1360 147
##STR00315##
N-(2-(4-(5-Bromo-2-ureidobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluo-
rocyclohexyl)acetamide
[0301] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-bromobenzaldehyde with an additional step as following.
MS m/z: 530.2 (M+1), calc'd for
C.sub.22H.sub.30BrF.sub.2N.sub.5O.sub.3: 529.15.
##STR00316##
[0302] 74 mg A was dissolved in 2 ml, of AcOH and then 1 mL of B
(17 mg) in water was added to the solution, Under N.sub.2
protection, the mixture was stirred at room temperature overnight.
Then the mixture was concentrated by GeneVec. Product C was
purified by PTLC (5% MeOH/CH2Cl.sub.2).
1361 148
##STR00317##
N-(2-(4-(5-Chloro-2-ureidobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-diflu-
orocyclohexyl)acetamide
[0303] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-chlorobenzaldehyde with an additional step as following.
MS m/z: 486.20 Calc'd for C22H30ClF2N5O3: 485.20.
##STR00318##
[0304] 65 mg of A was dissolved in 2 mL of AcOH and then 1 mL of B
(17 mg) in water was added to the solution, Under N.sub.2
protection, the mixture was stirred at room temperature overnight.
Then the mixture was concentrated by GeneVec. Product C was
purified by PTLC (5% MeOH/CH2Cl.sub.2).
1362 152
N-(2-(4-(2-Amino-5-bromobenzyl)piperazin-1-yl)-2-oxoethyl)-3,3-difluorobic-
yclo[3.1.0]hexane-6-carboxamide
##STR00319##
[0306] This compound was prepared according to Method A1a using
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid and
2-amino-5-bromobenzaldehyde. MS m/z: 471.2 (M+1), calc'd for
C.sub.20H.sub.25BrF.sub.2N.sub.4O.sub.2: 470.11.
1373 153
##STR00320##
N-(4-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluoros-
piro[2.5]octane-1-carboxamide
[0307] This compound was prepared according to Method 1Ab using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-5-chlorobenzaldehyde. MS m/z: 455.2 (M+1), calc'd for
C.sub.22H.sub.29ClF.sub.2N.sub.4O.sub.2: 454.19.
1374 156
##STR00321##
N-(2-(4-(5-Bromo-2-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-(diflu-
orocyclohexyl)acetamide
[0308] This compound was prepared according to Method A1b using
4,4-difluorocyclohexyl)acetic acid and
5-bromo-2-chlorobenzaldehyde. MS m/z: 506.2 (M+1), calc'd for
C.sub.21H.sub.27BrClF.sub.2N.sub.3O.sub.2: 505.09.
1375 157
##STR00322##
N-(4-Bromo-2-((4-((2-(4,4-difluorocyclohexyl)acetyl)glycyl)piperazin-1-yl-
)methyl)phenyl)cyclopropanecarboxamide
[0309] This compound was prepared according to Method A1b using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-bromobenzaldehyde with an additional step as following.
MS m/z: 555.2 (M+1), calc'd for
C.sub.25H.sub.33BrF.sub.2N.sub.4O.sub.3: 554.17.
##STR00323##
[0310] In a glass vial, A (1 eq), B (1.1 eq) were dissolved in 2 mL
anhydrous DCM followed by 3 eq of Et.sub.3N. The reaction was
stirred at rt for overnight. Then the mixture was concentrated and
the pure product C was obtained by PTCL (5% MeOH/DCM).
1376 158
##STR00324##
Methyl
4-((2-((4-((1-fluorocyclopropane-1-carbonyl)glycyl)piperazin-1-yl)-
methyl)phenoxy)methyl)benzoate
[0311] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 1-fluorocyclopropane-1-carboxylic acid.
MS m/z: 484.3 (M+1), calc'd for C.sub.26H.sub.30FN.sub.3O.sub.5:
483.22.
1377 163
##STR00325##
N-(3-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-3-oxopropyl)-3,3-difluoro-
bicyclo[3.1.0]hexane-6-carboxamide
[0312] This compound was prepared according to Method A2b using
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid, methyl
3-aminopropanoate hydrochloride instead of ethyl glycinate
hydrochloride and 2-amino-5-chlorobenzaldehyde. MS m/z: 441.2
(M+1), calc'd for C.sub.21H.sub.27ClF.sub.2N.sub.4O.sub.2:
440.18.
1378 164
##STR00326##
N-(4-Chloro-2-((4-((2-(4,4-difluorocyclohexyl)acetyl)glycyl)piperazin-1-y-
l)methyl)phenyl)cyclopropanecarboxamide
[0313] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-chlorobenzaldehyde with an additional step as following.
MS m/z: 511.3 (M+1), calc'd for
C.sub.25H.sub.33ClF.sub.2N.sub.4O.sub.3: 510.22.
##STR00327##
[0314] In a glass vial, A (1 eq), B (1.1 eq) were dissolved in 2 mL
anhydrous DCM followed by 3 eq of Et.sub.3N. The reaction was
stirred at rt for overnight. Then the mixture was concentrated and
the pure product C was obtained by PTCL (5% MeOH/DCM).
1379 165
##STR00328##
N-(2-(4-(5-Chloro-2-(cyclopropanesulfonamido)benzyl)piperazin-1-yl)-2-oxo-
ethyl)-2-(4,4-difluorocyclohexyl)acetamide
[0315] This compound was prepared according to Method A1b using
2-(4,4-difluorocyclohexyl)acetic acid and
2-amino-5-chlorobenzaldehyde with an additional step as following.
MS m/z: 547.3 (M+1), calc'd for
C.sub.24H.sub.33ClF.sub.2N.sub.4O.sub.4S: 546.19.
##STR00329##
[0316] In a glass vial, A (65 mg), B (28 mg) were dissolved in a
mixture of 300 uL DCM and 300 uL pyridine. The reaction was stirred
at rt for overnight. Then the mixture was concentrated and the pure
product C was obtained by PTCL (5% MeOH/DCM).
1385 171
##STR00330##
N-(2-(4-(3-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluo-
rocyclohexyl)acetamide
[0317] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
3-chloro-5-nitrobenzaldehyde with an additional step as following.
MS m/z: 443.3 (M+1), calc'd for
C.sub.21H.sub.29ClF.sub.2N.sub.4O.sub.2: 442.19.
##STR00331##
A, B and C were dissolved in 2 mL of EtOH/H2O (1:1). Then the
mixture was stirred at 70.degree. C. for overnight. After reaction,
the EtOH was removed by GeneVec. The residue was extracted by ETOAc
twice. The organic phase was combined, dried by MgSO.sub.4, The
solution was concentrated and dissolved again in a few amount of
DCM which was loaded to the PTLC and eluted by DCM/MeOH (15:1) to
afford the product F. 186 172
##STR00332##
(1R,5S,6r)-N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-3,-
3-difluorobicyclo[3.1.0]hexane-6-carboxamide
[0318] This compound was prepared according to Method A1a using
3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid and
2-amino-5-chlorobenzaldehyde. MS m/z: 427.2 (M+1), calc'd for
C.sub.20H.sub.25ClF.sub.2N.sub.4O.sub.2: 426.16.
1387 176
##STR00333##
N-(2-(4-(4-Amino-3-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluo-
rocyclohexyl)acetamide
[0319] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
4-amino-3-chlorobenzaldehyde. MS m/z: 443.2 (M+1), calc'd for
C.sub.21F.sub.29ClF.sub.2N.sub.4O.sub.2: 442.19.
1388 180
##STR00334##
N-(2-(4-(3-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluoros-
piro[2.5]octane-1-carboxamide
[0320] This compound was prepared according to Method Aa using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
3-chloro-5-nitrobenzaldehyde with an additional step as following.
MS m/z: 455.2 (M+1), calc'd for
C.sub.22H.sub.29ClF.sub.2N.sub.4O.sub.2: 454.19.
##STR00335##
[0321] In a glass vial, A (40 mg), B (48 mg) and C (45 mg) were
dissolved in 2 mL of EtOH/H2O (1:1). Then the mixture was stirred
at 70.degree. C. for overnight. After reaction, the EtOH was
removed by GeneVec. The residue was extracted by EtOAc twice. The
organic phase was combined, dried by MgSO.sub.4. The solution was
concentrated and dissolved again in a few amount of DCM which was
loaded to the PTLC and eluted by DCM/MeOH (15:1) to afford the
product D.
1389 181
##STR00336##
4-(3-Chloro-5-(cyclopropanesulfonamido)benzyl)-N-(3-(4,4-difluorocyclohex-
yl)-2-oxopropyl)piperazine-1-carboxamide
[0322] This compound was prepared using
N-(2-(4-(3-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difluo-
rocyclohexyl)acetamide by one step as following. MS m/z: 547.2
(M+1). Calc'd for C.sub.24H.sub.33ClF.sub.2N.sub.4O.sub.4S,
546.19.
##STR00337##
[0323] In a glass vial, A (8 mg), B (12.5 mg) were dissolved in a
mixture of 300 uL DCM and 300 uL pyridine. The reaction was stirred
at rt for overnight. Then the mixture was concentrated and the pure
product C was obtained by PTCL (5% MeOH/DCM).
1390 183
##STR00338##
N-(2-(4-(4-Amino-3-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluoros-
piro[2.5]octane-1-carboxamide
[0324] This compound was prepared according to Method B3 using
4-amino-3-chlorobenzaldehyde and
6,6-difluorospiro[2.5]octane-1-carboxylic acid. MS m/z: 455.2
(M+1), calc'd for C.sub.22H.sub.29ClF.sub.2N.sub.4O.sub.2:
454.19.
1394 194
N-(2-(4-(2-Amino-5-cyclopropylbenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-diflu-
orospiro[2.5]octane-1-carboxamide
[0325] This compound was prepared according to Method A1b using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-5-chlorobenzaldehyde with an additional step as following.
MS m/z: 461.3 (M+1), calc'd for C25H34F2N4O2: 460.26
##STR00339##
[0326] In a glass vial, A (0.2 mmol), B (0.26 mmol), C (0.7 mmol),
D (0.2 mmol) and E (0.02 mmol) were dissolved in 2 mL of E (with
0.04 mL water) in a 10 mL pressure vessel. The mixture was stirred,
degassed by replacing the air with N.sub.2, and placed in an
80.degree. C. oil bath for 18 h. After the reaction, the solvent
was removed by reduced pressure evaporation. Then the residue was
diluted by water and EtOAc. The organic phase was washed and dried
by MgSO4, filtered and loaded onto a solid phase extraction (SPE)
cartridge containing strong ion exchanger (SCX, 1 g; UCT,
CUBCX1M15). The cartridge was first washed with EtOAc:MeOH (10:1,
12 mL), which was discarded, and then the product was eluted with
EtOAc-MeOH-Et3N (20:2:1, 6 mL). The eluent was concentrated in
vacuo to yield F as an orange oil.
1398 198
##STR00340##
N-(2-(4-(5-Chloro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluor-
ospiro[2.5]octane-1-carboxamide
[0327] This compound was prepared according to Method B3 using
5-chloro-2-hydroxybenzaldehyde and
6,6-difluorospiro[2.5]octane-1-carboxylic acid. MS m/z: 456.2
(M+1), Calc'd for C.sub.22H.sub.28ClF.sub.2N.sub.3O.sub.3:
455.18.
1399 200
##STR00341##
N-(2-(4-(5-Chloro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2,2-diethyl-
cyclopropane-1-carboxamide
[0328] This compound was prepared according to Method B3 using
5-chloro-2-hydroxybenzaldehyde and
2,2-diethylcyclopropane-1-carboxylic acid. MS m/z: 408.2 (M+1),
calc'd for C.sub.21H.sub.30ClN.sub.3O.sub.3: 407.20
1400 202
##STR00342##
N-(2-(4-(5-Bromo-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-diflu-
orocyclohexyl)acetamide
[0329] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-bromo-2-hydroxybenzaldehyde. MS m/z: 488.2 (M+1), calc'd for
C.sub.21H.sub.28BrF.sub.2N.sub.3O.sub.3: 487.13.
1401 218
##STR00343##
N-(2-(4-(3,5-Dichloro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4--
difluorocyclohexyl)acetamide
[0330] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
3,5-dichloro-2-hydroxybenzaldehyde. MS m/z: 478.2 (M+1), calc'd for
C.sub.21H.sub.27Cl.sub.2F.sub.2N.sub.3O.sub.3: 477.14.
1402 219
##STR00344##
N-(2-(4-(5-Chloro-3-fluoro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2--
(4,4-difluorocyclohexyl)acetamide
[0331] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-3-fluoro-2-hydroxybenzaldehyde. MS m/z: 462.2 (M+1),
calc'd for C.sub.21H.sub.27ClF.sub.3N.sub.3O.sub.3: 461.17.
1403 220
##STR00345##
N-(2-(4-(5-Chloro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difl-
uorocyclohexyl)acetamide
[0332] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-2-hydroxybenzaldehyde. .sup.1H NMR (400 MHz, CDCl.sub.3,
ppm): .delta. 7.15 (dd, J1=2.5, J2=8.4, 1H), 6.95 (d, J=2.5, 1H),
6.77 (d, J=8.4, 1H), 6.53 (br, 1H), 4.05 (d, J=4.0, 2H), 3.68 (s,
4H), 3.48 (t, J=5.0, 2H), 2.57 (s, 4H), 2.18 (d, =7.0, 2H),
2.10-1.74 (m, 6H), 1.33 (m, 3H). MS m/z: 444.2 (M+1), calc'd for
C.sub.21H.sub.28ClF.sub.2N.sub.3O.sub.3: 443.18.
1404 221
##STR00346##
N-(2-(4-(5-chloro-3-fluoro-2-hydroxybenzyl)piperazin-1-yl-2-oxoethyl)-6,6-
-difluorospiro[2.5]octane-1-carboxamide
[0333] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
5-chloro-3-fluoro-2-hydroxybenzaldehyde. MS m/z: 474.2 (M+1),
calc'd for C.sub.22H.sub.27ClF.sub.3N.sub.3O.sub.3: 473.17.
1409 226
##STR00347##
N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)spiro[2.3]hexa-
ne-1-carboxamide
[0334] This compound was prepared according to Method B3 using
2-amino-5-chlorobenzaldehyde and spiro[2.3]hexane-1-carboxylic
acid. MS m/z: 391.2 (M+1), calc'd for
C.sub.20H.sub.27ClN.sub.4O.sub.2: 390.18.
1410 227
##STR00348##
N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)spiro[2.4]hept-
ane-1-carboxamide
[0335] This compound was prepared according to Method B3 using
2-amino-5-chlorobenzaldehyde and spiro[2.4]heptane-1-carboxylic
acid. MS m/z: 405.2 (M+1), calc'd for
C.sub.21H.sub.29ClN.sub.4O.sub.2: 404.20.
1411 228
##STR00349##
N-(2-(4-(2-amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2,2-diethylcy-
clopropane-1-carboxamide
[0336] This compound was prepared according to Method B3 using
2-amino-5-chlorobenzaldehyde and
2,2-diethylcyclopropane-1-carboxylic acid. MS m/z: 407.2 (M+1),
calc'd for C.sub.21H.sub.31ClN.sub.4O.sub.2: 406.21.
1412 236
N-(2-(4-((2-amino-5-chlorophenyl)methyl-d2)piperazin-1-yl)-2-oxoethyl)-2-(-
4,4-difluorocyclohexyl)acetamide
[0337] See Example: Synthesis of 1412 and 1413
[0338] .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): .delta. 7.06 (dd,
J1=2.5, J2=8.4, 1H), 6.95 (d, J=2.5, 1H), 6.58 (d, J=8.4, 1H), 6.55
(br, 1H), 4.05 (d, J=4.0, 2H), 3.63 (t, J=5.0, 2H), 3.39 (t, J=5.0,
2H), 2.43 (t, J=5.0, 4H), 2.18 (d, J=7.0, 2H), 2.10-1.74 (m, 6H),
1.33 (m, 3H). MS m/z: 445.2 (M+1), calc'd for
C.sub.21H.sub.27D.sub.2ClF.sub.2N.sub.4O.sub.2: 444.21.
1413 237
N-(2-(4-((2-amino-5-chlorophenyl)methyl-d2)piperazin-1-yl)-2-oxoethyl)-6,6-
-difluorospiro[2.5]octane-1-carboxamide
[0339] See Example: Synthesis of 1412 and 1413
[0340] MS m/z: 457.2 (M+1), calc'd for
C.sub.22H.sub.27D.sub.2ClF.sub.2N.sub.4O.sub.2: 456.21.
1420 239
##STR00350##
6,6-Difluoro-N-(2-oxo-2-(4-(quinolin-8-ylmethyl)piperazin-1-yl)ethyl)spir-
o[2.5]octane-1-carboxamide
[0341] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
quinoline-8-carbaldehyde. MS m/z: 457.3 (M+1), calc'd for
C.sub.25H.sub.30F.sub.2N.sub.4O.sub.2: 456.23.
1421 240
##STR00351##
N-(2-(4-((5-Chloro-1H-indazol-7-yl)methyl)piperazin-1-yl)-2-oxoethyl)-6,6-
-difluorospiro[2.5]octane-1-carboxamide
[0342] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
5-chloro-1H-indazole-7-carbaldehyde. MS m/z: 480.2 (M+1), calc'd
for C.sub.23H.sub.28ClF.sub.2N.sub.5O.sub.2: 479.19.
1422 245
##STR00352##
N-(2-(4-((6-Chloroquinolin-8-yl)methyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-
-difluorocyclohexyl)acetamide
[0343] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
6-chloroquinoline-8-carbaldehyde. .sup.1H NMR (400 MHz, CDCl.sub.3,
ppm): .delta. 8.90 (dd, J1=1.7, J2=4.2, 1H), 8.09 (dd, J1=1.7,
J2=8.3, 1H), 7.83 (d, J=2.2, 1H), 7.73 (d, 0.1=2.2, 1H), 7.44 (dd,
J1=4.2, J2=8.3, 1H), 6.58 (br, 1H), 4.28 (s, 2H), 4.05 (d, J=4.0,
2H), 3.72=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.62 (t, J=5.0, 4H), 2.18
(d, J=7.0, 2H), 2.10-174 (m, 6H), 1.33 (m, 3H). MS m/z: 479.2
(M+1), calc'd for C.sub.24H.sub.29ClF.sub.2N.sub.4O.sub.2:
478.19.
1423 246
##STR00353##
N-(2-(4-((6-Chloroquinolin-8-yl)methyl)piperazin-1-yl)-2-oxoethyl)-2-(4-m-
ethyltetrahydro-2H-pyran-4-yl)acetamide
[0344] This compound was prepared according to Method B3 using
6-chloroquinoline-8-carbaldehyde and
2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid. .sup.1H NMR (400
MHz, CDCl.sub.3, ppm): .delta. 8.90 (dd, J1=1.8, J2=4.2, 1H), 8.08
(dd, J1=1.8, J2=8.3, 1H), 7.82 (d, J=2.4, 1H), 7.73 (d, J=2.4, 1H),
7.44 (dd, J1=4.2, J2=8.3, 1H), 6.54 (br, 1H), 4.28 (s, 2H), 4.05
(d, J=4.0, 2H), 3.67 (m, 6H), 3.47 (t, J=5.0, 2H), 2.63 (t, J=4.9,
4H), 2.23 (s, 2H), 1.66 (m, 2H), 1.45 (m, 2H) 1.15 (s, 3H). MS m/z:
459.2 (M+1), calc'd for C24H31ClN4O3: 458.21.
1425 250
##STR00354##
N-(2-(4-(5-Chloro-2-hydroxybenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4-fluoro-
phenyl)cyclopropane-1-carboxamide
[0345] This compound was prepared according to Method B3 using
5-chloro-2-hydroxybenzaldehyde and
2-(4-fluorophenyl)cyclopropane-1-carboxylic acid. MS m/z: 446.2
(M+1), calc'd for C.sub.23H.sub.25ClFN.sub.3O.sub.3: 445.16.
[0346] .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): .delta. 7.50 (m,
6H), 7.68 (d, J=8.7, 7.73 (br, 1H), 4.11 (d, J=4.0, 2H), 3.69 (s,
4H), 3.49 (s, 2H), 2.60 (s, 4H).
1426 251
##STR00355##
2-(4,4-Difluorocyclohexyl)-N-(2-(4-(isoquinolin-8-ylmethyl)piperazin-1-yl-
)-2-oxoethyl)acetamide
[0347] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
isoquinoline-8-carbaldehyde, .sup.1H NMR (400 MHz, CDCl.sub.3,
ppm): .delta. 8.94 (dd, J1=1.7, J2=4.2, 1H), 8.66 (d, J=5.7, 1H),
7.78 (d, J=8.3, 1H), 7.67 (d, J=5.8, 1H), 7.61 (dd, J1=7, J2=8.3,
1H), 7.46 (d, J=7, 1H), 6.59 (br, 1H), 4.04 (d, =4.0, 2H), 3.99 (s,
2H), 3.62 (t, J=5.0, 2H), 3.37 (t, J=5.0, 2H), 2.52 (q, J=5.0, 4H),
2.18 (d, J=7.0, 2H), 2.10-1.74 (m, 6H), 1.33 (m, 3H). MS m/z: 445.2
(M+1), calc'd for C.sub.24H.sub.30F.sub.2N.sub.4O.sub.2:
444.23.
1428 255
##STR00356##
2-(4,4-Difluorocyclohexyl)-N-(2-oxo-2-(4-(quinolin-5-ylmethyl)piperazin-1-
-yl)ethyl)acetamide
[0348] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and quinoline-5-carbaldehyde.
.sup.1H NMR (400 MHz, CDCl.sub.3, ppm): .delta. 8.94 (dd, J1=1.7,
J2=4.2, 1H), 8.66 (d, J=8.8, 1H), 8.09 (d, J=8.4, 1H), 7.65 (m,
1H), 7.44 (m, 2H), 6.56 (br, 1H), 4.04 (d, =4.0, 2H), 3.93 (s, 2H),
3.64 (s, 2H), 3.37 (t, 5, 2H), 2.64 (q, J=5, 4H), 2.18 (d/=7.0,
2H). 2.10-1.74 (m, 6H), 1.33 (m, 3H). MS m/z: 445.3 (M+1), calc'd
for C.sub.24H.sub.30F.sub.2N.sub.4O.sub.2: 444.23.
1429 256
##STR00357##
2-(4,4-Difluorocyclohexyl)-N-(2-(4-((6-fluoroquinolin-8-yl)methyl)piperaz-
in-1-yl)-2-oxoethyl)acetamide
[0349] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
6-fluoroquinoline-8-carbaldehyde. NMR (400 MHz, CDCl.sub.3, ppm):
.delta. 8.86 (dd, J1=1.7, J2=4.3, 1H), 8.12 (dd, J=1.8, J=8.3, 1H),
7.70 (d, J=9.1, 1H), 7.43 (dd, J1=4.1, J2=8.3, 1H), 7.35 (m, 1H),
6.58 (br, 1H), 4.30 (s, 2H), 4.05 (d, =4.0, 2H), 3.73 (s, 2H), 3.49
(s, 2H), 2.64 (s, 4H), 2.21 (d, =7.0, 2H), 2.10-1.74 (m, 6H), 1.33
(m, 3H). MS m/z: 463.3 (M+1), calc'd for
C.sub.24H.sub.29F.sub.3N.sub.4O.sub.2: 462.22.
1430 257
##STR00358##
6,6-Difluoro-N-(2-(4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)pipe-
razin-1-yl)-2-oxoethyl)spiro[2.5]octane-1-carboxamide
[0350] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
1-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde. MS m/z: 437.3
(M+1), calc'd for C.sub.22H.sub.30F.sub.2N.sub.4O.sub.3: 43623.
1431 258
##STR00359##
N-(2-(4-(5-Chloro-2-methylbenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluoro-
spiro[2.5]octane-1-carboxamide
[0351] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
5-chloro-2-methylbenzaldehyde, MS m/z: 454.2 (M+1), calc'd for
C.sub.23H.sub.30ClF.sub.2N.sub.3O.sub.2: 453.20.
1432 270
##STR00360##
N-(2-(4-(3-Chloro-5-(pyridin-4-yloxy)benzyl)piperazin-1-yl)-2-oxoethyl)-2-
-(4,4-difluorocyclohexyl)acetamide
[0352] This compound was prepared according to Method A1b using
2-(4,4-difluorocyclohexyl)acetic acid and
3-chloro-5-hydroxybenzaldehyde with an additional step as
following. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): .delta. 8.51
(dd, J1=1.7, J2=4.8, 1H), 7.22 (t, =1.8, 1H), 6.98 (m, 3H), 6.85
(dd, J1=1.6, J2=4.8, 1H), 6.56 (br, 1H), 4.05 (d, J=4.0, 2H), 3.65
(t, J=5.4, 2H), 3.50 (s, 1H), 3.47 (s, 1H). 3.42 (t, J=5.0, 2H),
2.45 (m, 4H), 2.21 (d, J=7.0, 2H), 2.10-1.74 (m, 6H), 1.33 (m, 3H).
MS m/z: 521.2 (M+1), calc'd for
C.sub.26H.sub.31ClF.sub.2N.sub.4O.sub.3: 520.21.
##STR00361##
[0353] In a glass vial, A (1 eq), B (1.2 eq) and eq of
K.sub.2CO.sub.3 were dissolved in 2 mL anhydrous NMP. The reaction
was stirred at 120.degree. C. for overnight. After reaction, water
was added into the residue. After sonication and centrifugation,
the water phase was removed and the residue was dissolved in EtOAc,
dried by MgSO4, filtered and concentrated to afford the crude
product C.
1433 271
##STR00362##
N-(2-(4-(5-Chloro-1H-indol-7-yl)methyl-d2)piperazin-1-yl)-2-oxoethyl)-2-(-
4,4-difluorocyclohexyl)acetamide
[0354] This compound was prepared by a similar method of 1412 using
5-chloro-1H-indole-7-carboxylic acid. NMR (400 MHz, CDCl.sub.3,
ppm): .delta. 9.41 (s, 1H), 7.55 (d, J=2, 1H), 7.24 (t, J=2.8, 1H),
6.96 (d, J=1.9, 1H), 654 (br, 1H), 6.50 (dd, J1=2.0, J2=3.0, 1H),
4.05 (d, J=4.0, 2H), 3.68 (t, J=5.4, 2H), 3.44 (t, J=5.4, 2H), 2.50
(m, 4H), 2.19 (d, J=2H), 2.10-1.74 (m, 3H). MS: m/z 469.2 (M+1),
calc'd for C.sub.23H.sub.27D.sub.2ClF.sub.2N.sub.4O.sub.2:
468.21.
1416 HL-01-091-002
##STR00363##
[0355] Ethyl
4-benzyl-1-((6,6-difluorospiro[2.5]octane-1-carbonyl)glycyl)piperidine-4--
carboxylate
[0356] This compound was prepared according to Method B4 using
ethyl 4-benzylpiperidine-4-carboxylate and
6,6-difluorospiro[2.5]octane-1-carboxylic acid. MS: m/z 477.3
(M+1), calc'd for C.sub.26H.sub.34F.sub.2N.sub.2O.sub.4:
476.25.
1415 HL-01-091-001
##STR00364##
[0357]
N-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)-6,6-difluorospiro[2.5]oct-
ane-1-carboxamide
[0358] This compound was prepared according to Method B4 using
4-benzylpiperidine and 6,6-difluorospiro[2.5]octane-1-carboxylic
acid. MS: m/z 405.3 (M+1), calc'd for
C.sub.23H.sub.30F.sub.2N.sub.2O.sub.2: 404.23.
1414 HL-01-087-001
##STR00365##
[0359]
N-(2-(4-(3-Chloro-2,4-difluorobenzyl)piperazin-1-yl)-2-oxoethyl)-2--
(4,4-difluorocyclohexyl)acetamide
[0360] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
3-chloro-2,4-difluorobenzaldehyde MS: m/z 464.2 (M+1), calc'd for
C.sub.21H.sub.26ClF.sub.4N.sub.3O.sub.2: 463.16.
1407 HL-01-085-H
##STR00366##
[0361]
N-(2-(4-(2-Amino-3-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)-6,6-dif-
luorospiro[2.5]octane-1-carboxamide
[0362] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-3-chlorobenzaldehyde. MS: m/z 455.2 (M+1), calc'd for
C.sub.22H.sub.29ClF.sub.2N.sub.4O.sub.2: 454.19.
1406 HL-01-085-C
##STR00367##
[0363]
N-(2-(4-((5-Chloro-1H-indazol-7-yl)methyl)piperazin-1-yl)-2-oxoethy-
l)-2-(4,4-difluorocyclohexyl)acetamide
[0364] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-1H-indazole-7-carbaldehyde. MS: m/z 468.2 (M+1), calc'd
for C.sub.22H.sub.28ClF.sub.2N.sub.5O.sub.2: 467.19.
[0365] 5-chloro-1H-indazole-7-carbaldehyde was prepared by the
following procedures:
##STR00368##
[0366] In a flask under nitrogen was placed acid in 2 mL of
anhy-THF. Cooled to 0.degree. C., LiAH4 added slowly. The ice bath
was then removed, and reaction allowed to warm to rt. Stirred for 6
hrs, after which. Na.sub.2SO.sub.4-10 H.sub.2O added. The mixture
stirred for overnight. The solid was spinned down, washed with
EtOAc, and the organic layers concentrated under vacuum.
[0367] In a vial under nitrogen was placed alcohol B (17 mg), Hess
Martin reagent (47 mg) in 2 mL of anhydrous CH.sub.2Cl.sub.2. The
reaction stirred for overnight. To the mixture was added 2 drops of
MeOH, stirred for 2 more hours, then diluted with EtOAc, filtered,
concentrated to afford the crude C.
1405 HL-01-085-B
##STR00369##
[0368]
N-(2-(4-((6-Chloroquinolin-8-yl)methyl)piperazin-1-yl)-2-oxoethyl)--
6,6-difluorospiro[2.5]octane-1-carboxamide
[0369] This compound was prepared according to Method C1 using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
6-chloroquinoline-8-carbaldehyde. MS: m/z 491.2 (M+1), calc'd for
C.sub.25H.sub.29ClF.sub.2N.sub.4O.sub.2: 490.19.
1393 HL-01-078-003
##STR00370##
[0370]
N-(2-(4-((5-Chloro-2-(3-cyclopropylureido)pyridin-3-yl)methyl)piper-
azin-1-yl)-2-oxoethyl)-6,6-difluorospiro[2.5]octane-1-carboxamide
[0371] This compound was prepared according to Method A1a using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-5-chloronicotinaldehyde with two additional steps as
following. MS: m/z 539.3 (M+1), calc'd for
C.sub.25H.sub.33ClF.sub.2N.sub.6O.sub.3: 538.23.
##STR00371##
[0372] In a glass vial, A (200 mg) was dissolved in tetrahydrofuran
(2 ml) under a nitrogen atmosphere. Pyridine (97 mg) was added.
Then phenyl chloroformate (191 mg) was added at room temperature,
and the cloudy mixture was stirred for 60 minutes. A saturated
aqueous solution of sodium hydrogencarbonate (6 ml) was added to
the mixture. The mixture was extracted with EtOAc, and combined
organic layers dried. The residue was washed with water 2.times.5
mL, and dried. The crude intermediate was taken to next step
directly.
[0373] In a microwave vial was placed C (1 eq), D (57 mg, 10 eq) in
2 mL of anhyd. DME, iPr2Net (5 eq) added, and heated to 80.degree.
C. for 2 hrs. Cooled to rt, concentrated. The residue was dissolved
by minimal amount of MeOH, added with water, and the precipitation
spinned, washed, to afford the crude E.
1392 HL-01-078-002
##STR00372##
[0374]
N-(2-(4-((5-Chloro-2-(3-phenylureido)pyridin-3-yl)methyl)piperazin--
1-yl)-2-oxoethyl)-6,6-difluorospiro[2.5]octane-1-carboxamide
[0375] This compound was prepared according to Method A1a using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-5-chloronicotinaldehyde with two additional steps as
following. MS: m/z 575.3 (M+1), calc'd for
C.sub.28H.sub.33ClF.sub.2N.sub.6O.sub.3: 574.23.
##STR00373##
[0376] In a glass vial, A (200 mg) was dissolved in tetrahydrofuran
(2 ml) under a nitrogen atmosphere. Pyridine (97 mg) was added.
Then phenyl chloroformate (191 mg) was added at room temperature,
and the cloudy mixture was stirred for 60 minutes. A saturated
aqueous solution of sodium hydrogencarbonate (6 ml) was added to
the mixture. The mixture was extracted with EtOAc, and combined
organic layers dried. The residue was washed with water 2.times.5
mL, and dried. The crude intermediate was taken to next step
directly.
[0377] In a microwave vial was placed C (1 eq), D (33 mg, 5 eq) in
2 mL of anhyd. DME, iPr2Net (5 eq) added, and heated to 80.degree.
C. for 2 hrs. Cooled to rt, concentrated. The residue was dissolved
by minimal amount of MeOH, added with water, and the precipitation
spinned, washed, to afford the crude E.
1391 HL-01-078-001
##STR00374##
[0378]
N-(2-(4-(5-Chloro-2-(methylamino)benzyl)piperazin-1-yl)-2-oxoethyl)-
-6,6-difluorospiro[2.5]octane-1-carboxamide
[0379] This compound was prepared according to Method A1a using
6,6-difluorospiro[2.5]octane-1-carboxylic acid and
2-amino-5-chlorobenzaldehyde with two additional steps as
following. MS: m/z 469.2 (M+1), calc'd for
C.sub.23H.sub.31ClF.sub.2N.sub.4O2: 468.21.
##STR00375##
[0380] In a vial was placed aniline-A (60 mg), B (50 mg) in 2 ml,
of anhy DME, iPr2Net (1 eq) was added, and the reaction stirred for
overnight. To the reaction was added water, extracted with EtOAc,
and the combined organic phases concentrated, taken to the next
step directly.
[0381] In a uwave vial wider nitrogen was placed C (36 mg, 0.077
mmol) in 2 mL of anhyd THF. Cooled to 0.degree. C., and NaHMDS
(0.085 mmol) added slowly. After 15 minutes, MeI (0.092 mmol) added
slowly, and reaction stirred for 4 more hours, allowed to warm to
rt slowly. The reaction was then quenched with sat aq NH.sub.4Cl,
extraction with EtOAc. The combined organic layers concentrated,
taken to the next step directly.
1384 HL-01-074-E
##STR00376##
[0382]
N-(2-(4-(5-Chloro-2-methoxybenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,-
4-difluorocyclohexyl)acetamide
[0383] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-2-methoxybenzaldehyde. MS: m/z 458.2 (M+1), calc'd for
C.sub.22H.sub.30ClF.sub.2N.sub.3O.sub.3: 457.19.
1383 HL-01-074-D
##STR00377##
[0384]
N-(2-(4-(3,5-dichlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difl-
uorocyclohexyl)acetamide
[0385] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and 3,5-dichlorobenzaldehyde.
MS: m/z 462.2 (M+1), calc'd for
C.sub.21H.sub.27Cl.sub.2F.sub.2N.sub.3O.sub.2: 461.14.
1382 HL-01-074-C
##STR00378##
[0386]
N-(2-(4-(2,3-Dichlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difl-
uorocyclohexyl)acetamide
[0387] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and 2,3-dichlorobenzaldehyde.
MS: m/z 462.2 (M+1), calc'd for
C.sub.21H.sub.27Cl.sub.2F.sub.2N.sub.3O.sub.2: 461.14.
1381 HL-01-074-B
##STR00379##
[0388]
N-(2-(4-(2-Amino-3,5-dichlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(-
4,4-difluorocyclohexyl)acetamide
[0389] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
3,5-dichloro-2-nitrobenzaldehyde with an additional step as
following. MS: m/z 477.2 (M+1), calc'd for
C.sub.21H.sub.28Cl.sub.2F.sub.2N.sub.4O.sub.2: 476.16.
##STR00380##
[0390] In a sealed tube was placed. A, 25 mg of Indium q), 50 mg
(10 eq) of NH.sub.4Cl, in 1.5 mL EtOH, 1.5 mL of water, heated to
75.degree. C. for 8 hrs. The solid was filtered, and the filtrate
was concentrated, diluted with water, extracted with EtOAc. The
organic phases concentrated, purified by TLC (3%
MeOH/CH.sub.2Cl.sub.2) to afford B.
1380 HL-01-073-001
##STR00381##
[0391]
N-(2-(4-(5-Chloro-2-(trifluoromethoxy)benzyl)piperazin-1-yl)-2-oxoe-
thyl)-2-(4,4-difluorocyclohexyl)acetamide
[0392] This compound was prepared according to Method C1 using
difluorocyclohexyl)acetic acid and
5-chloro-2-(trifluoromethoxy)benzaldehyde. MS: m/z 512.2 (M+1),
calc'd for C.sub.22H.sub.27ClF.sub.5N.sub.3O.sub.3: 511.17.
1371 L-01-070-I
##STR00382##
[0393]
N-(2-(4-(5-Bronco-2-cyanobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4--
difluorocyclohexyl)acetamide
[0394] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
4-bromo-2-formylbenzonitrile. MS: m/z 497.2 (M+1), calc'd for
C.sub.22H.sub.27BrF.sub.2N.sub.4O.sub.2: 496.13.
1370 L-01-070-H
##STR00383##
[0395]
N-(2-(4-(5-Bromo-2-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4--
difluorocyclohexyl)acetamide
[0396] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-bromo-2-fluorobenzaldehyde. MS: m/z 490.2 (M+1), calc'd for
C.sub.21H.sub.27BrF.sub.3N.sub.3O.sub.2: 489.12.
1369 L-01-070-G
##STR00384##
[0397]
N-(2-(4-(5-Chloro-2,3-difluorobenzyl)piperazin-1-yl)-2-oxoethyl)-2--
(4,4-difluorocyclohexyl)acetamide
[0398] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-2,3-difluorobenzaldehyde. MS: m/z 464.2 (M+1), calc'd for
C.sub.21H.sub.26ClF.sub.4N.sub.3O.sub.2: 463.16.
1368 L-01-070-F
##STR00385##
[0399]
N-(2-(4-(5-chloro-2,4-difluorobenzyl)piperazin-1-yl)-2-oxoethyl)-2--
(4,4-difluorocyclohexyl)acetamide
[0400] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and 2,4-difluorobenzaldehyde.
MS: m/z 464.2 (M+1), calc'd for
C.sub.21H.sub.26ClF.sub.4N.sub.3O.sub.2: 463.16.
1367 L-01-070-D
##STR00386##
[0401]
N-(2-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-
-difluorocyclohexyl)acetamide
[0402] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and
5-chloro-2-fluorobenzaldehyde. MS: m/z 446.2 (M+1), calc'd for
C.sub.21H.sub.27ClF.sub.3N.sub.3O.sub.2: 445.17.
1366 L-01-070-C
##STR00387##
[0403]
N-(2-(4-(2,5-Dichlorobenzyl)piperazin-1-yl)-2-oxoethyl)-2-(4,4-difl-
uorocyclohexyl)acetamide
[0404] This compound was prepared according to Method C1 using
2-(4,4-difluorocyclohexyl)acetic acid and 2,5-dichlorobenzaldehyde.
MS: m/z 462.2 (M+1), calc'd for
C.sub.21H.sub.27Cl.sub.2F.sub.2N.sub.3O.sub.2: 461.14.
1365 HL-01-067-F
##STR00388##
[0405]
N-(2-(4-(3-Chloro-5-cyclopropoxybenzyl)piperazin-1-yl)-2-oxoethyl)--
2-(4,4-difluorocyclohexyl)acetamide
[0406] This compound was prepared according to Method A1a using
2-(4,4-difluorocyclohexyl)acetic acid and
3-chloro-5-hydroxybenzaldehyde with an additional step as
following. MS: m/z 484.2 (M+1), calc'd for
C.sub.24H.sub.32ClF.sub.2N.sub.3O.sub.3: 483.21.
##STR00389##
[0407] In a sealed tube was placed A, Cs.sub.2CO.sub.3 (3 eq) in
1.5 mL of Anhyd NMP. 4 eq of B added, heated at 110.degree. C. for
6 hrs, after which, another 4 eq of B added, heated for O.N.
Reaction cooled to rt, diluted with water, extracted with EtOAc.
The EtOAc was removed, to the residue (with NMP) was added water,
off white precipitation formed. The residue was spinned (emulsion),
washed with water, 2.times.3 mL. get HL-01-067-C as an off-white
solid.
1364HL-01-064-003
##STR00390##
[0408]
2-((4-((2-((1R,3R,5S)-Adamantan-1-yl)acetyl)glycyl)piperazin-1-yl)m-
ethyl)-4-bromobenzamide
[0409] This compound was prepared according to Method Ata using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
4-bromo-2-formylbenzonitrile with an additional step as following.
MS: m/z, 531.2 (M+1), calc'd for C.sub.26H.sub.35BrN.sub.4O.sub.3:
530.19.
##STR00391##
[0410] In a vial was placed the cyano compound in 2.5 mL of DMSO.
NaOH (2 M) added, followed by H.sub.2O.sub.2 (50% w/w, diluted by
3.times.volume of water). The reaction became cloudy at beginning,
and sonicated. Stirred at rt for 1 hr, the reaction was diluted
with water (8 mL), extracted with EtOAc, concentrated. The DMSO was
removed by Genevec to get a white solid.
1363 HL-01-063-C
##STR00392##
[0411]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(2,6-dichlorobenzyl)piperazin-
-1-yl)-2-oxoethyl)acetamide
[0412] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2,6-dichlorobenzaldehyde. MS: m/z 478.2 (M+1), calc'd for
C.sub.25H.sub.33Cl.sub.2N.sub.3O.sub.2: 477.19.
1354 HL-01-062-F
##STR00393##
[0413]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-cyclopropoxy-2-fluorobenzy-
l)piperazin-1-yl)-2-oxoethyl)acetamide
[0414] This compound was prepared according to Method Ata using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-fluoro-5-hydroxybenzaldehyde with an additional step as
following. MS: m/z 484.3 (M+1), calc'd for
C.sub.28H.sub.38FN.sub.3O.sub.3: 483.29,
##STR00394##
[0415] In a sealed tube was placed A, Cs.sub.2CO.sub.3 in 1.5 mL of
Anhyd NMP. 4 eq of B added, heated at 110.degree. C. for 6 hrs,
after which, another 4 eq of B added, heated for O.N. Reaction
cooled to rt, diluted with water, extracted with EtOAc. The EtOAc
was removed, to the residue (with NMP) was added water, yellow
precipitation formed. The residue was spinned, washed with water,
2.times.3 mL, get crude product as a brown solid.
1353HL-01-063-B
##STR00395##
[0416]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(2-chloro-4,5-difluorobenzyl)-
piperazin-1-yl)-2-oxoethyl)acetamide
[0417] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-chloro-4,5-difluorobenzaldehyde. MS: m/z 480.3 (M+1), calc'd for
C.sub.25H.sub.32ClF.sub.2N.sub.3O.sub.2: 479.22.
1352 HL-01-063-A
##STR00396##
[0418]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-ethynyl-2-fluorobenzyl)pip-
erazin-1-yl)-2-oxoethyl)acetamide
[0419] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-ethynyl-2-fluorobenzaldehyde. MS: m/z 452.3 (M+1), calc'd for
C.sub.27H.sub.34FN.sub.3O.sub.2: 451.26.
1351 HL-01-060-007
##STR00397##
[0420]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(2-bromo-5-chlorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0421] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-bromo-5-chlorobenzaldehyde. MS: m/z 522.2 (M+1), calc'd for
C.sub.25H.sub.33BrClN.sub.3O.sub.2: 521.14.
1350 HL-01-060-006
##STR00398##
[0422]
2-((1R,3R,5S)-adamantan-1-yl)-N-(2-oxo-2-(4-(2,3,5-trifluorobenzyl)-
piperazin-1-yl)ethyl)acetamide
[0423] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2,3,5-trichlorobenzaldehyde. MS: m/z 512.2 (M+1), calc'd for
C.sub.25H.sub.32Cl.sub.3N.sub.3O.sub.2: 511.16.
1349 HL-01-060-005
##STR00399##
[0424]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(2-amino-3,5-dichlorobenzyl)p-
iperazin-1-yl)-2-oxoethyl)acetamide
[0425] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3,5-dichloro-2-nitrobenzaldehyde with an additional step shown as
following. MS: m/z 493.2 (M+1), calc'd for
C.sub.25H.sub.34Cl.sub.2N.sub.4O.sub.2: 492.21.
##STR00400##
[0426] In a sealed tube was placed A, 25 mg of Indium (5 eq), 50 mg
of NH.sub.4Cl (10 eq), in 1.5 mL EtOH, 1.5 mL of water, heated to
75.degree. C. for 8 hrs. The solid was filtered, and the filtrate
was concentered, diluted with water, extracted with EtOAc. The
organic phases concentrated, purified by TLC (3%
MeOH/CH.sub.2Cl.sub.2) to afford B.
1348 HL-01-055-F
##STR00401##
[0427]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-bromo-5-cyanobenzyl)pipera-
zin-1-yl)-2-oxoethyl)acetamide
[0428] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-bromo-5-formylbenzonitrile. MS: m/z 513.2 (M+1), calc'd for
C.sub.26H.sub.33BrN.sub.4O.sub.2: 512.18.
1341 HL-01-055-002
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-amino-5-bromobenzyl)-piperazin-1--
yl)-2-oxoethyl)acetamide
[0429] This compound was prepared from
2-((1R,3R,5S)-adamantan-1-yl)-N-(2-(4-(3-bromo-5-nitrobenzyl)piperazin-1--
yl)-2-oxoethyl)acetamide by following procedures. MS: m/z 503.2
(M+1), calc'd for C.sub.25H.sub.35BrN.sub.4O.sub.2: 502.19.
##STR00402##
[0430] In a sealed tube was placed A, 25 mg of Indium (5 eq), 50 mg
(10 eq) of NH.sub.4Cl, in 1.5 mL EtOH, 1.5 mL of water, heated to
75.degree. C. for 8 hrs. The solid was filtered, and the filtrate
was concentrated, diluted with water, extracted with EtOAc. The
organic phases concentrated, purified by TLC (3% MeOH/CH2Cl.sub.2)
to afford B.
1340 HL-01-055-G
##STR00403##
[0431]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-bromo-5-nitrobenzyl)pipera-
zin-1-yl)-2-oxoethyl)acetamide
[0432] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-bromo-5-nitrobenzaldehyde. MS: m/z 533.2 (M+1), calc'd for
C.sub.25H.sub.33BrN.sub.4O.sub.4: 532.17.
1339 HL-01-055-E
##STR00404##
[0433]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-bromo-5-fluorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0434] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-bromo-5-fluorobenzaldehyde. MS: m/z 506.2 (M+1), calc'd for
C.sub.25H.sub.33BrFN.sub.3O.sub.2: 505.17.
13381HL-01-055-D
##STR00405##
[0435]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-bromo-2-chlorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0436] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-promo-2-chlorobenzaldehyde. MS: m/z 522.2 (M+1), calc'd for
C.sub.25H.sub.33BrClN.sub.3O.sub.2: 521.14.
1337 HL-01-055-C
##STR00406##
[0437]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-bromo-2-fluorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0438] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-bromo-2-fluorobenzaldehyde. MS: m/z 506.2 (M+1), calc'd for
C.sub.25H.sub.33BrFN.sub.3O.sub.2: 505.17.
1332 HL-01-050-G
##STR00407##
[0439]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-bromo-5-chlorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0440] This compound was prepared according to Method Ata using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-bromo-5-chlorobenzaldehyde. MS: m/z 522.2 (M+1), calc'd for
C.sub.25H.sub.33BrClN.sub.3O.sub.2: 521.14.
1331 HL-01-051-1
##STR00408##
[0441] 2-(1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-chloro-.
5-(trifluoromethoxy)benzyl)piperazin-1-yl)-2-oxoethyl)acetamide
[0442] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-chloro-5-(trifluoromethoxy)benzaldehyde. MS: m/z 528.3 (M+1),
calc'd for C.sub.26H.sub.33ClF.sub.3N.sub.3O.sub.3: 527.22.
1329 HL-01-051-B
##STR00409##
[0443]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-bromo-2-cyanobenzyl)pipera-
zin-1-yl)-2-oxoethyl)acetamide
[0444] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
4-bromo-2-formylbenzonitrile. MS: m/z 513.2 (M+1), calc'd for
C.sub.26H.sub.33BrN.sub.4O.sub.2: 512.18.
##STR00410##
Methyl
4-((2-((4-((4,4-difluoro-1-methylcyclohexane-1-carbonyl)glycyl)pip-
erazin-1-yl)methyl)phenoxy)methyl)benzoate
[0445] This compound was prepared by a similar manner to Method B1
using 4,4-difluoro-1-methylcyclohexane-1-carbonyl chloride as
following. MS: m/z 558.3.2 (M+1), calc'd for
C.sub.30H.sub.37F.sub.2N.sub.3O.sub.5: 557.27.
##STR00411##
1327 HL-01-051-G
##STR00412##
[0446]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2,3-difluorobenzyl)-
piperazin-1-yl)-2-oxoethyl)acetamide
[0447] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-Chloro-2,3-difluorobenzaldehyde. MS: m/z 480.3 (M+1), calc'd for
C.sub.25H.sub.32ClF.sub.2N.sub.3O.sub.2: 479.22.
1326 HL-01-051-F
##STR00413##
[0448]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-chloro-5-(trifluoromethyl)-
benzyl)piperazin-1-yl)-2-oxoethyl)acetamide
[0449] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-chloro-5-(trifluoromethyl)benzaldehyde. MS: m/z 512.3 (M+1),
calc'd for C.sub.26H.sub.33ClF.sub.3N.sub.3O.sub.2: 511.22.
1325 HL-01-051-E
##STR00414##
[0450]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3,5-difluoro-2-hydroxybenzyl-
)piperazin-1-yl)-2-oxoethyl)acetamide
[0451] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3,5-difluoro-2-hydroxybenzaldehyde. MS: m/z 462.3 (M+1), calc'd for
C.sub.24H.sub.33F.sub.2N.sub.3O.sub.3: 461.25.
1324 HL-01-051-C
##STR00415##
[0452]
2-((1R,3R,8S)-Adamantan-1-yl)-N-(2-(4-(4,5-difluoro-2-hydroxybenz)p-
iperazin-1-yl)-2-oxoethyl)acetamide
[0453] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
4,5-difluoro-2-hydroxybenzaldehyde. MS: m/z 462.3 (M+1), calc'd for
C.sub.25H.sub.33F.sub.2N.sub.3O.sub.3: 461.25.
1323 HL-01-050-I
##STR00416##
[0454] Methyl
4-(3-((4-((2-((1R,3R,5S)-adamantan-1-yl)acetyl)glycyl)piperazin-1-yl)meth-
yl)-5-chlorophenoxy)benzoate
[0455] This compound was prepared according to Method A2a using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-chloro-5-hydroxybenzaldehyde with an additional step shown as
following. MS: m/z 594.3 (M+1), calc'd for C33H40ClN3O5:
593.27.
##STR00417##
[0456] A microwave vial under nitrogen is charged with phenol A (1
eq), Cu(OAc).sub.2 (2 eq), boronic acid eq) in CH.sub.2Cl.sub.2 (2
mL), followed by pyridine (6 eq). The reaction mixture was stirred
at room temperature for overnight. The stirring was stopped, and
the blue color suspension is allowed to settle, and then the clear
solution transferred by an syringe to a uWave vial under nitrogen,
and contains an additional 2 eq of boronic acid, 2 eq Cu(OAc)2. The
mixture was stirred at room temperature for another 48 hrs,
Reaction diluted with water, extracted with EtOAc. The organic
phases dried, and loaded onto Silica bound PhSO3H, basic eluent
(EtOAc/MeOH, 10:1, Et3N), get product with reasonable purity.
1322 HL-01-050-H
##STR00418##
[0457] Methyl
3-(3-((4-((2-((1R,3R,5S)-adamantan-1-yl)acetyl)glycyl)piperazin-1-yl)meth-
yl)-5-chlorophenoxy)benzoate
[0458] This compound was prepared according to Method A2a using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-chloro-5-hydroxybenzaldehyde with an additional step shown as
following. MS: m/z 594.3 (M+1), calc'd for
C.sub.33H.sub.40ClN.sub.3O.sub.5: 593.27.
##STR00419##
[0459] A microwave vial under nitrogen is charged with phenol A (1
eq), Cu(OAc).sub.2 (2 eq), boronic acid (2 eq) in CH.sub.2Cl.sub.2
(2 mL), followed by pyridine (6 eq). The reaction mixture was
stirred at room temperature for overnight. The stirring was
stopped, and the blue color suspension is allowed to settle, and
then the clear solution transferred by an syringe to a uWave vial
under nitrogen, and contains an additional 2 eq of boronic acid, 2
eq Cu(OAc)2. The mixture was stirred at room temperature for
another 48 hrs, Reaction diluted with water, extracted with EtOAc.
The organic phases dried, and loaded onto Silica bound. PhSO3H,
basic eluent (EtOAc/MeOH, 10:1, Et.sub.3N), get product with
reasonable purity.
1321 HL-01-050-F
##STR00420##
[0460]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(2-amino-5-chlorobenzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide
[0461] This compound was prepared according to Method A2a using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-amino-5-chlorobenzaldehyde. MS: m/z 459.3 (M+1), calc'd for
C.sub.25H.sub.35ClN.sub.4O.sub.2: 458.24.
1320 HL-01-049-002
##STR00421##
[0462] Methyl
4-((2-((4-(((4,4-difluorocyclohexyl)carbamoyl)glycyl)piperazin-1-yl)methy-
l)phenoxy)methyl)benzoate
[0463] This compound was prepared from 4,4-difluorocyclohexan-1-ol
by following procedures. MS: m/z 559.3 (M+1), calc'd for
C.sub.29H.sub.36F.sub.2N.sub.4O.sub.5: 558.27.
##STR00422##
[0464] In a vial under nitrogen was placed A (43 mg 1 eq), CDI (43
mg, 1.05 eq) in 2 mL of anhyd DMF, iPr2NEt added slowly. The
reaction was stirred for 2 hrs, and then added to a solution of C
(1.2 eq) in anhyd. DMF. followed by additional iPr2NEt Reaction
stirred for ON. Reaction was precipitated with water, the white
solid formed was dried, and purified by Benzene-sulfonic acid
silica gel column to afford product D.
1319 HL-01-049-001
##STR00423##
[0465] Methyl
4-((2-((4-(((((4,4-difluorocyclohexyl)oxy)carbonyl)glycyl)piperazin-1-yl)-
methyl)phenoxy)methyl)benzoate
[0466] This compound was prepared from 4,4-difluorocyclohexan-1-ol
by following procedures. MS: m/z 560.3 (M+1), calc'd for
C.sub.29H.sub.35F.sub.2N.sub.3O.sub.6: 559.25.
##STR00424##
[0467] In a vial under nitrogen was placed triphosgene (34 mg, 0.35
eq) in 1 mL of any and A (45 mg, 1 eq) and iPr2NEt in 1 ml, of THF
added slowly. The reaction was stirred for 2 hrs, and then was
added to a solution of C (1.2 eq) in anhyd. DME, followed by
additional iPr2NEt. Reaction stirred for ON. Reaction was dried,
sonicated with water, the white solid formed was dried, and pun
tied by Benzene-sulfonic acid silica gel column to afford. Product
D.
1317 HL-01-041-G
##STR00425##
[0468] Methyl
4-((2-((4-((2,2-dimethylcyclopropane-1-carbonyl)glycyl)piperazin-1-yl)met-
hyl)phenoxy)methyl)benzoate
[0469] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 2,2-dimethylcyclopropane-1-carboxylic
acid. MS: m/z 494.3 (M+1), calc'd for
C.sub.28H.sub.35N.sub.3O.sub.5: 493.26.
1316 HL-01-041-F
##STR00426##
[0470] Methyl
4-((2-((4-((spiro[2.5]octane-1-carbonyl)glycyl)piperazin-1-yl)methyl)phen-
oxy)methyl)benzoate
[0471] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and spiro[2.5]octane-1-carboxylic acid. MS:
m/z 534.3 (M+1), calc'd for C.sub.31H.sub.39N.sub.3O.sub.5:
533.29.
1315 HL-01-041-E
##STR00427##
[0472] Methyl
4-((2-((4-((2-(3,3-difluorocyclobutyl)acetyl)glycyl)piperazin-1-yl)methyl-
)phenoxy)methyl)benzoate
[0473] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 2-(3,3-difluorocyclobutyl)acetic acid.
MS: m/z 530.3 (M+1), calc'd for
C.sub.28H.sub.33F.sub.2N.sub.3O.sub.5: 529.24
1312 HL-01-041-D
##STR00428##
[0474] Methyl
4-((2-((4-((2-(4-fluorophenyl)acetyl)glycyl)piperazin-1-yl)methyl)phenoxy-
)methyl)benzoate
[0475] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 2-(4-fluorophenyl)acetic acid. MS: m/z
534.3 (M+1), calc'd for C.sub.30H.sub.32FN.sub.3O.sub.5:
533.23.
1311 HL-01-041-B
Methyl
4-((2-((4-((2-(1-methylcyclohexyl)acetyl)glycyl)piperidin-1-yl)meth-
yl)phenoxy)methyl)benzoate
##STR00429##
[0477] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 2-(1-methylcyclohexyl)acetic acid. MS:
m/z 536.3 (M+1), calc'd for C.sub.31H.sub.41N.sub.3O.sub.5:
535.30.
1310 HL-01-044-001
##STR00430##
[0478] Methyl
3'-((4-((2-((1R,3R,5S)-adamantan-1-yl)acetyl)glycyl)piperazin-1-yl)methyl-
)-4'-hydroxy-[1,1'-biphenyl]-3-carboxylate
[0479] This compound was prepared according to Method A2a using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2-hydroxybenzaldehyde with an additional step shown as
following. MS: m/z 560.3 (M+1) calc'd for
C.sub.33H.sub.41N.sub.3O.sub.5: 559.30.
##STR00431##
[0480] An microwave vial under N.sub.2, was loaded with A (1.5 eq),
B (1 eq), KF (3 eq), Pd(OAc).sub.2 (0.1 eq), and RuPhos (0.2 eq).
The system was then evacuated and backfilled twice with N2. 1.5 mL
of anhydrous DME added, and the suspension was bubbled with N2,
vacuumed, and filled with N2; the process was repeated one more
time. The vessel was placed in an oil bath at 65.degree. C., and
heated overnight. The dark brown suspension was cooled and
filtered. The crude mixture was concentrated, and purified by TLC
(4% MeOH/CH.sub.2Cl.sub.2) to afford the product C.
1309 HL-01-030-I
##STR00432##
[0481]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-(trifluoromethyl)-
benzyl)piperazin-1-yl)-2-oxoethyl)acetamide
[0482] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2-(trifluoromethoxy)benzaldehyde. MS: m/z 528.3 (M+1),
calc'd for C.sub.26H.sub.33ClF.sub.3N.sub.3O.sub.3: 527.22.
1308 HL-01-030-H
##STR00433##
[0483]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-(trifluoromethyl)-
benzyl)piperazin-1-yl)-2-oxoethyl)acetamide
[0484] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2-(trifluoromethyl)benzaldehyde. MS: m/z 512.3 (M+1),
calc'd for C.sub.26H.sub.33ClF.sub.3N.sub.3O.sub.2: 511.22.
1307 HL-01-030-F
##STR00434##
[0485]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2,4-difluorobenzyl)-
piperazin-1-yl)-2-oxoethyl)acetamide
[0486] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2,4-difluorobenzaldhyde. MS: m/z 480.3 (M+1), calc'd for
C.sub.25H.sub.32ClF.sub.2N.sub.3O.sub.2: 479.22.
1306 HL-01-030-E
##STR00435##
[0487]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(3-chloro-2,6-difluorobenzyl)-
piperazin-1-yl)-2-oxoethyl)acetamide
[0488] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
3-chloro-2,6-difluorobenzaldhyde. MS: m/z 480.3 (M+1), calc'd for
C.sub.25H.sub.32ClF.sub.2N.sub.3O.sub.2: 479.22.
1305 HL-01-030-D
##STR00436##
[0489]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-fluorobenzyl)pipe-
razin-1-yl)-2-oxoethyl)acetamide
[0490] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2-fluorobenzaldehyde. MS: m/z 462.3 (M+1), calc'd for
C.sub.25H.sub.33ClFN.sub.3O.sub.2: 461.22.
1304 HL-01-030-C
##STR00437##
[0491]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-((2-amino-5-chloropyridin-3-y-
l)methyl)piperazin-1-yl)-2-oxoethyl)acetamide
[0492] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
2-amino-5-chloronicotinaldehyde. MS: m/z 460.3 (M+1), calc'd for
C.sub.24H.sub.34ClN.sub.5O.sub.2: 459.24.
1303 HL-01-038-B
##STR00438##
[0493]
4-(2-((4-((2-(1R,3R,5S)-Adamantan-1-yl)acetyl)glycyl)piperazin-1-yl-
)methyl)-4-chlorophenoxy)butanoate
[0494] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and methyl
4-(4-chloro-2-formylphenoxy)butanoate. MS: m/z 560.3 (M+1), calc'd
for C.sub.30H.sub.42ClN.sub.3O.sub.5: 559.28.
[0495] Methyl 4-(4-chloro-2-formylphenoxy)butanoate was prepared by
following procedures:
##STR00439##
[0496] In a sealed vial under N.sub.2 was placed the A (103 mg), B
(101 in 1.5 mL of anhyd. DMF. Stirred at rt for overnight; diluted
with water, extracted with CH.sub.2Cl.sub.2, and the organic phase
washed with sat Na.sub.2CO.sub.3 (2.times.2 mL), The organic phases
were then dried with MgSO4, filtered and concentrated to afford the
crude product C.
1302 HL-01-032-D
##STR00440##
[0497] Methyl
2-(2-((4-((2-((1R,3R,5S)-adamantan-1-yl)acetyl)glycyl)piperazin-1-yl)meth-
yl)-4-chlorophenoxy)acetate
[0498] This compound was prepared from
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-hydroxybenzyl)piperazin-
-1-yl)-2-oxoethyl)acetamide by the following procedures. MS: m/z
532.3 (M+1), calc'd for C.sub.28H.sub.38ClN.sub.3O.sub.5:
531.25.
##STR00441##
[0499] In a sealed vial under N.sub.2 was placed the starting
materials in 1.5 mL of anhyd, DMF. Stirred at rt for overnight. The
reaction was diluted with water, extracted with EtOAc, dried,
filtered concentrated and purified by TLC (3%
MeOH/CH.sub.2Cl.sub.2) to afford B.
1301HL-01-033-001
##STR00442##
[0500]
N-(2-(4-(2-((1-acetylpiperidin-4-yl)methoxy)-5-chlorobenzyl)piperaz-
in-1-yl)-2-oxoethyl)-2-((3r,5r,7r)-adamantan-1-yl)acetamide
[0501] This compound was prepared from
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-hydroxybenzyl)piperazin-
-1-yl)-2-oxoethyl)acetamide by the following procedures. MS: m/z
599.4 (M+1), calc'd for C.sub.33H.sub.47ClN.sub.4O.sub.4:
598.33,
##STR00443##
[0502] In a sealed vial under N.sub.2 was placed the A (56 mg, 1
eq), B (60 mg, 1.4 eq), K.sub.2CO.sub.3 (3 eq) in 1.5 mL of anhyd.
DMF. Stirred at 60.degree. C. for 6 hrs. The reaction was diluted
with water, extracted with EtOAc.C was purified by TLC (3%
MeOH/CH.sub.2Cl.sub.2);
[0503] The Boc of C was removed under standard conditions mentioned
in Method C1, and the HCl/dioxane and EtOAc was removed under
vacuum to afford D.
[0504] In a vial under nitrogen was placed the D (1 eq) in 1 mL of
anhydrous DME. Acetic anhydride (3 eq) added followed by DIEA (8
eq), and the reaction was stirred for overnight. The residue was
then concentrated to dryness, E was purified by TLC (6%
MeOH/CH.sub.2Cl.sub.2).
1300 HL-01-034-C
##STR00444##
[0505] Methyl
4-((2-((4-((4,4-difluorocyclohexane-1-carbonyl)glycyl)piperazin-.
1-yl)methyl)phenoxy)methyl)benzoate
[0506] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 4,4-difluorocyclohexane-1-carboxylic
acid. MS: m/z 544.3 (M+1), calc'd for
C.sub.29H.sub.35F.sub.2N.sub.3O.sub.5: 543.25.
1297 HL-01-035-D
##STR00445##
[0507] Methyl
4-((2-((4-(2-(4,4-difluorocyclohexyl)acetyl)piperazin-1-yl)methyl)phenoxy-
)methyl)benzoate
[0508] This compound was prepared according to Method B2 using
2-(4,4-difluorocyclohexyl)acetic acid. MS: m/z 501.3 (M+1), calc'd
for C.sub.28H.sub.34F.sub.2N.sub.2O.sub.4: 500.25.
1296 HL-01-035-C
##STR00446##
[0509] Methyl
4-((2-((4-((3-methyl-3-phenylbutanoyl)glycyl)piperazin-1-yl)methyl)phenox-
y)methyl)benzoate
[0510] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 3-methyl-3-phenylbutanoic acid. MS: m/z
558.3 (M+1), calc'd for C33H39N3O5: 557.29.
1278 HL-01-019-002
##STR00447##
[0511] Methyl
4-((4-((4-((4,4,4-trifluoro-3,3-dimethylbutanoyl)glycyl)piperazin-1-yl)me-
thyl)phenoxy)methyl)benzoate
[0512] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 4,4,4-trifluoro-3,3-dimethylbutanoic
acid. MS: m/z 550.3 (M+1), calc'd for
C.sub.28H.sub.34F.sub.3N.sub.3O.sub.5: 549.25.
1277 HL-01-019-001
##STR00448##
[0513]
(1s,3r,5R,7S)-3-(2-((2-(4-(2-((4-(Methoxycarbonyl)benzyl)oxy)benzyl-
)piperazin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)adamantane-1-carboxylic
Acid
[0514] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and
(1s,3r,5R,7S)-3-(carboxymethyl)adamantane-1-carboxylic acid. MS:
m/z 618.3 (M+1), calc'd for C.sub.35H.sub.43N.sub.3O.sub.7:
617.31.
1275HL-01-017-002
##STR00449##
[0515] Methyl
4-((2-((4-((2-(4,4-difluorocyclohexyl)acetyl)glycyl)piperazin-1-yl)methyl-
)phenoxy)methyl)benzoate
[0516] This compound was prepared according to Method B1 using
2-hydroxybenzaldehyde and 2-(4,4-difluorocyclohexyl)acetic acid.
MS: m/z 558.3 (M+1), calc'd for
C.sub.30H.sub.37F.sub.2N.sub.3O.sub.5: 557.27.
1249 YT-A-1/HL-01-031-001
##STR00450##
[0517]
2-((1R,3R,5S)-Adamantan-1-yl)-N-(2-(4-(5-chloro-2-hydroxybenzyl)pip-
erazin-1-yl)-2-oxoethyl)acetamide
[0518] This compound was prepared according to Method C1 using
2-((1R,3R,5S)-adamantan-1-yl)acetic acid and
5-chloro-2-hydroxybenzaldehyde. MS: m/z 460.3 (M+1), calc'd for
C.sub.25H.sub.34ClN.sub.3O.sub.3: 459.23.
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
(2-{4-[5-chloro-2-(5-cyano-pyridin-2-ylmethoxy)-benzyl]-piperazin-1-yl}-2-
-oxo-ethyl)-amide (1622)
[0519] This compound was prepared according to Method B1. MS m/z:
572.2 (M+1), calc'd: 571.22 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic acid
(2-{4-[5-chloro-2-(5-methanesulfonyl-pyridin-2-ylmethoxy)-benzyl]-piperaz-
in-1-yl}-2-oxo-ethyl)-amide (1621)
[0520] This compound was prepared according to Method B1. MS m/z:
625.2 (M+1) calc'd: 624.20 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic acid
[2-(4-{5-chloro-2-[(5-methanesulfonyl-pyridin-2-ylmethyl)-amino]-phenyl}--
di-deutero-methyl}-piperazin-1-yl)-2-oxa-ethyl]-amide (1586)
[0521] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 626.2 (M+1), calc'd: 625.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(5-cyano-pyridin-2-ylmethyl)-amino]-phenyl}-di-deutero-
-methyl}-piperazin-1-yl)-2-oxo-ethyl]-amide (1584)
[0522] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 573.2 (M+1) calc'd: 572.24 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-phenyl}-di-dentar-
y-methyl}-piperazin-1-yl)-2-oxo-ethyl]-amide (1582)
[0523] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 566.2 (M+1), calc'd: 565.24 (M).
5-{[4-Chloro-2-(4-{2-[(6,6-difluoro-spiro[2.5]octane-1-carbonyl)-amino]-ac-
etyl}-piperazin-1-yl-di-deutero-methyl)-phenylamino]-methyl}-pyridine-2-ca-
rboxylic Acid Methyl Ester (1549)
[0524] This compound was prepared from 1413 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 606.2 (M+1) 605.25 (M).
6-{[4-Chloro-2-(4-{2-[(6,6-difluoro-spiro[2.5]octane-1-carbonyl)-amino]-ac-
etyl}-piperazin-1-yl-di-deutero-methyl)-phenylamino]-methyl}-nicotinic
Acid Methyl Ester (1548)
[0525] This compound was prepared from 1413 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 606.2 (M+1), calc'd: 605.25 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(pyrimidin-2-ylmethyl)-amino]-phenyl}-di-deutero-methy-
l}-piperazin-1-yl)-2-oxo-ethyl]-amide (1580)
[0526] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 549.2 (M+1), calc'd: 548.24 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(oxazol-5-ylmethyl)-amino]-phenyl}-di-deutero-methyl}--
piperazin-1-yl)-2-oxy-ethyl]-amide (1587)
[0527] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 538.2 (M+1), calc'd: 537.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(oxazol-2-ylmethyl)-amino]-phenyl}-di-deutero-methyl}--
piperazin-1-yl)-2-oxo-ethyl]amide (1585)
[0528] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 538.2 (M+1), calc'd: 537.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(oxazol-4-ylmethyl)-amino]-phenyl}-di-deutero-methyl}--
piperazin-1-yl)-2-oxo-ethyl]-amide (1583)
[0529] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 538.2 (M+1), calc'd: 537.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic acid
[2-(4-{5-chloro-2-[(isoxazol-3-ylmethyl)-amino]-phenyl}-di-deutero-methyl-
}-piperazin-1-yl)-2-oxo-ethyl]-amide (1581)
[0530] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 538.2 (M+1), calc'd: 537.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
[2-(4-{5-chloro-2-[(oxazol-5-ylmethyl)-amino]-phenyl}-di-deutero-methyl}--
piperazin-1-yl)-2-oxo-ethyl]-amide (1560)
[0531] This compound was prepared from 1413 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 5382 (M+1), calc'd: 537.23 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic acid
(2-{4-[5-chloro-2-(2-fluoro-4-methanesulfonyl-benzylamino)-phenyl}-di-deu-
tero-methyl]-piperazin-1-yl}-2-oxo-amide (1562)
[0532] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 643.2 (M+1), calc'd: 642.22 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
(2-{4-[5-chloro-2-(3-fluoro-4-methanesulfonyl-benzylamino)-phenyl}-di-deu-
tero-methyl]-piperazin-1-yl}-2-oxo-ethyl)-amide (1561)
[0533] This compound was prepared from 1466 and the corresponding
aldehyde using the reductive amination conditions described in
Method A1. MS m/z: 643.2 (M+1), calc'd: 642.22 (M).
[0534] Spiro[2.5]octane-1-carboxylic Acid
(2-{4-[5-chloro-2-(4-ethanesulfonyl-benzyloxy)-benzyl]-piperazin-1-yl}-2--
oxo-ethyl)-amide (1539)
[0535] This compound was prepared according to Method B1. MS m/z:
588.2 (M+1), calc'd: 587.22 (M).
6,6-Difluoro-spiro[2.5]octane-1-carboxylic Acid
{2-[4-(5-chloro-2-ethylamino-phenyl}-di-deutero-methyl)-piperazin-1-yl]-2-
-oxo-ethyl}-amide (1534)
[0536] This compound was prepared similarly as 1391, MS m/z: 485.2
(M+1) calc'd: 484.24 (M).
2-((3r,5r,7r)-Adamantan-1-yl)-N-(2-(4-(oxazol-2-yl)benzyl)oxy)benzyl)piper-
azin-1-yl)-2-oxoethyl)acetamide (1803)
[0537] Yield: 42.1%. .sup.1H NMR (400 MHz, Chloroform-d, ppm)
.delta.:8.08 (s, 7.79-7.21 (m, 7H), 7.00-6.92 (m, 2H). 6.50 (d,
J=3.8 Hz, 1H), 5.17 (s, 2H), 4.02 (d, J=4.0 Hz, 2H), 3.62 (s, 4H),
3.40 (t, J=4.9 Hz, 2H), 2.47-2.42 (m, 4H), 2.01 (s, 2H), 1.97 (s,
3H), 1.74-1.60 (m, 12H). MS: m/z 583.30 [M+H].sup.+, calc'd for
C.sub.35H.sub.43N.sub.4O.sub.4: 583.33.
(1s,3r,5R,7S)--N-(2-((4-(2-((4-bromobenzyl)oxy)benzyl)piperazin-1-yl)-2-ox-
oethyl)-3-(4-hydroxy-3-nitrophenyl)adamantane-1-carboxamide
(1805)
[0538] Yield: 42.3%. .sup.1H NMR (400 MHz, Chloroform-d, ppm)
.delta.: 10.47 (s, 1H), 8.03 (t, J=2.2 Hz, 1H), 7.63 (dt, J1=8.8
Hz/2=2.1 Hz, 1H), 7.51 (d, 6.8 Hz, 2H), 7.37-7.22 (m, 4H),
7.12-7.09 (d, J=8.8 Hz, 1H), 6.97 (t, J=7.2 Hz, 1H), 6.91 (d, J=8.0
Hz, 1H), 6.84 (s, 1H), 5.03 (s, 2H), 4.02 (dd, J=4.1, 1.6 Hz, 2H),
3.64 (d, J=5.6 Hz, 4H), 3.41 (s, 2H), 2.49 (d, 0.1=5.2 Hz, 4H),
2.30 (s, 2H), 1.99-1.87 (m, 9H), 1.27 (s, 2H). MS m/z: 717.30
[M+H].sup.+, calc'd for C.sub.37H.sub.42BrN.sub.4O.sub.6:
717.23.
N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)spiro[2.4]hepta-
ne-1-carboxamide (1806)
[0539] Yield: 10.4%. .sup.1H NMR (400 MHz, Chloroform-d, ppm)
.delta.: 7.06 (dd, J=8.4, 2.5 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.61
(s, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.60 (br, 2H), 4.07 (d, =4.1 Hz,
2H), 3.63 (t, J=5.1 Hz, 2H), 3.48 (s, 2H), 3.39 (t, J=5.1 Hz, 2H),
2.43 (t, J=5.1 Hz, 4H), 1.65-1.51 (m, 8H), 1.35 (t, J=7.3 Hz, 1H),
1.24-1.21 (m, 1H), 0.93 (dd, J1=8.2 Hz, J2=4.2 Hz, 1H), MS m/z:
405.20 [M H].sup.+, calc'd for C.sub.21H.sub.30ClN.sub.4O.sub.2:
405.21.
N-(2-(4-(2-Amino-5-chlorobenzyl)piperazin-1-yl)-2-oxoethyl)spiro[23]hexane-
-1-carboxamide (1807)
[0540] Yield: 119%. .sup.1H NMR (400 J, Chloroform-d, ppm) .delta.:
7.06 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.96 (d, J=2.5 Hz, 6.58 (d,
J=8.4 Hz, 1), 4.62 (hr, 2H), 4.10-4.05 (m, 2H), 3.64 (t, J=5.1 Hz,
2H), 3.48 (s, 2H), 3.39 (t, J=5.1 Hz, 2H). 2.43 (t, 0.1=5.1 Hz,
4H), 2.23-1.98 (m, 4H), 1.45 (dd, =8.4, 5.3 Hz, 1H), 1.38 (t, J=7.3
Hz, 1H), 1.23-1.09 (m, 1H),0.97-0.84 (m, 2H). MS m/z: 391.20
[M+H].sup.+, calc'd for C.sub.20H.sub.28ClN.sub.4O.sub.2:
391.19.
N-(2-(4-(2-Amino-5-chlorobenzoyl)piperazin-1-yl)-2-oxoethyl)-6,6-difluoros-
piro[2.5]octane-1-carboxamide (1808)
[0541] Yield: 38.4%. .sup.1H NMR (400 MHz, Chloroform-d, ppm)
.delta.: 7.15 (dd, J=8.6, 2.4 Hz, 1H), 7.04 (d1=2.4 Hz, 1H), 6.67
(d, J=8.6 Hz, 2H), 4.32 (s, 2H), 4.10 (dd, J=7.4, 3.5 Hz, 2H),
3.75-3.58 (m, 6H), 3.50-3.42 (m, 2H), 2.02-1.80 (m, 6H), 1.57-1.43
(m, 3H), 1.21 (t, J=4.9 Hz, 1H), 0.86 (dd, =8.0, 4.5 Hz, 1H). MS
m/z: 469.20 [M+H].sup.+, calc'd for
C.sub.22H.sub.28ClF.sub.2N.sub.4O.sub.3: 469.18.
Example 2: Biological Assays
[0542] The following assay methods were used to identify and
evaluate compounds of Formula (I) and Formula (II).
[0543] Solubility.
[0544] Kinetic solubility was tested from a 10 mM DMSO stock
solution by spiking into pre-warmed pH 7.4 phosphate buffered
saline in a 96-well plate. The final concentration was 100 .mu.M
(1% DMSO). The plate was maintained at ambient temperature for 24
hours on an orbital shaker. Samples were centrifuged through a
Millipore Multiscreen Solvinter 0.45 micron low binding PTFE
hydrophilic filter plate and were analyzed by HPLC or LC-MS/MS if
additional sensitivity was required. Peak area was compared to
standards of known concentration.
[0545] Plasma Protein Binding.
[0546] Plasma protein binding was determined using equilibrium
dialysis using ThermoScientific.TM. RED Device. The plate was
incubated with shaking at 37.degree. C. For 6 hours. The
concentration of drug in the plasma vs buffer compartments were
determined by LC-MS/MS. The fraction bound was calculated as
([plasma]-[buffer])/[plasma].
[0547] Plasma Stability.
[0548] Plasma stability was evaluated by incubating 10 .mu.M test
compound with undiluted plasma at 37.degree. C. With aliquots
removed at multiple time points out to four hours. Aliquots were
added to acetonitrile (5.times., v:v) to stop any enzymatic
activity and held on ice. Samples were centrifuged through a
Millipore Multiscreen Solvinter 0.45 micron low binding PTFE.
Hydrophilic filter plate and analyzed by LC-MS/MS.
[0549] Hepatic Microsomal Stability.
[0550] Microsome stability was evaluated by incubating 1 .mu.M test
compound with 1 mg/mL hepatic microsomes in 100 mM KPi, at pH 7.4.
The reaction was initiated by adding NADPH (1 mM final
concentration). Aliquots were removed at 0, 5, 10, 20, 40, and 60
minutes and added to acetonitrile (5.times., v:v) to stop the
reaction and precipitate the protein. NADPH dependence of the
reaction was evaluated by setting up incubations without NADPH. At
the end of the assay, the samples were centrifuged through a
Millipore Multiscreen Solvinter 0.45 micron low binding PTFE
hydrophilic filter plate and analyzed by LC-MS/MS. Data were log
transformed and represented as half-life.
[0551] Pharmacokinetics.
[0552] Pharmacokinetics of the compounds were assessed in C57Bl/6
or BALB/cmice. Blood was collected at representative time points
e.g. 0.08, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours and
pharmacokinetic parameters were calculated using Phoenix
WinNonlin.RTM. to determine peak plasma concentration (Cmax), oral
bioavailability (% F), exposure (AUC), half-life (t1/2), clearance
(CL), and volume of distribution (Vd). Compounds were dosed
intravenously via the tail vein or by oral gavage. In some cases,
co-formulation with Ritonavir was used as a boosting strategy. All
procedures are approved by the Scripps Florida IACUC and Scripps
vivarium is fully AAALAC accredited.
[0553] Cell Lines
[0554] Vero, 293T, HeLa (ATCC) and human fibroblasts (Coriell) were
maintained in DMEM (Invitrogen) supplemented with 5% FetalPlex, 5%
FBS (Gemini) or 10% FBS (HeLa, human fibroblasts). All CHO derived
cell lines were grown as previously described. Millard, E. Eel al.
J. Biol. Chem. 280, 28581-28590 (2005); Millard, E. E. et al., J.
Biol. Chem. 275, 38445-38451 (2000).
Production and Purification of Pseudotyped Virions
[0555] VSV-.DELTA.G pseudotyped viruses were created as described
previously. Chandran, K. et al., Science 308, 1643-1645 (2005).
LacZ-encoding retroviral pseudotypes bearing the designated
envelope glycoproteins were prepared as previously described.
Soneoka, Y. et al. Nucleic Acids Res. 23, 628-633 (1995).
Infection Assays with Pseudotyped Virus
[0556] VSV pseudotyped viruses expressing GFP were added to cells
in serial tenfold dilutions and assayed using fluorescence
microscopy. An infectious unit (i.u.) is defined as one
GFP-expressing cell within a range where the change in GFP-positive
cells is directly proportional to the virus dilution. For VSV
expressing the luciferase reporter, pseudotyped virus was added to
cells and luciferase activity was assayed 6-20 h post-infection
using the firefly luciferase kit (Promega). Signal was measured in
relative luminescence units (RLU) using an EnVison plate reader
(Perkin Elmer). In experiments involving inhibitors, stock
solutions of the compounds of the invention in DMSO were diluted to
a final concentration of 1% DMSO in media. Inhibitory activity was
stable in the media of cultured cells for more than 72 h as
assessed using a single cycle entry assay.
Ebola Virus Infections Under BSL-4 Conditions
[0557] Vero cells or CHO cells were seeded to 96-well plates and
exposed to EboV-GFP. Vero cells were incubated with the compounds
of the invention, ??E-64-d (150 .mu.N) or 1% DMSO 90 Mill before
the addition of virus (m.o.i.=0.1). Virus was added to CHO cells at
m.o.i. Of 1 as measured on Vero cells. Virus-encoded GFP
fluorescence was determined using a SpectraMax M5 plate reader
(Molecular Devices) at excitation 485 nm, emission 515 nm, cutoff
495 nm at 22.5, 42, 71 and 97 h post-infection. An additional
inhibitor experiment was performed using the compounds of the
invention. Vero cells were treated with the compounds of the
invention (20 .mu.M) or 1% DMSO alone for 4 h, and then infected
with EBOV Zaire-1995 (m.o.i.=0.1). After 1 h, the virus inoculum
was removed, cells were washed, and fresh media containing the
compounds of the invention or DMSO was added. Cell supernatant was
collected at 0, 24, 48, 72, or 91 h post-infection. RNA was
isolated. From the supernatant using Virus RNA Extraction kits
(Qiagen) and EboV NP RNA was measured using a real-time RT-PCR
assay. Virus titre was calculated using
TABLE-US-00002 TABLE 3 Data for Compound 1466 EBOV G-A82 (Hela)
EC.sub.50: 0.37 .mu.M EBOV Kikwit(Hela) EC.sub.50: 2.49 .mu.M EBOV
Makona (Hela) EC.sub.50: 2.19 .mu.M EBOV Maiynga) (Hela) EC.sub.50:
4.28 .mu.M Molecular Weight: 457 cLogP: 287 m-.mu.some T.sub.1/2: 3
min m-.mu.some T.sub.1/2 (with 3 .mu.M of Ritonavir) 91 min
m-plasma stability stable m-plasma protein binding: 88% m-PK P.O.
dose: 50 mpk of 1466 and 50 mpk of Ritonavir AUC: 121 .mu.M*hr
C.sub.max 19.5 .mu.M C.sub.@12 hr 2 .mu.M T.sub.1/2: 3.2 h
TABLE-US-00003 TABLE 4 Data for Compound 1476 EBOV G-A82 (Hela)
EC.sub.50: <0.08 .mu.M EBOV Kikwit(Hela) EC.sub.50: 0.21 .mu.M
EBOV Makona (Hela) EC.sub.50: 0.14 .mu.M EBOV Maiynga) (Hela)
EC.sub.50: 0.42 .mu.M Molecular Weight: 623 cLogP: 3.82 m-.mu.some
T.sub.1/2 (with 3 .mu.M of Ritonavir) 170 min m-plasma stability
stable m-plasma protein binding: 98.7% m-PK P.O. dose: 75 mpk of
1476 and 50 mpk of Ritonavir AUC: 314 .mu.M*hr C.sub.max 23 .mu.M
C.sub.@12 hr 14 .mu.M T.sub.1/2: 6.1 h
TABLE-US-00004 TABLE 5 Data for Compound 1477 EBOV Kikwit(Hela)
EC.sub.50: 0.012 .mu.M EBOV Makona (Hela) EC.sub.50: 0.052 .mu.M
EBOV Maiynga) (Hela) EC.sub.50: 0.033 .mu.M Molecular Weight: 610
cLogP: 3.55 m-.mu.some T.sub.1/2 (with 3 .mu.M of Ritonavir) 90 min
m-plasma stability stable m-plasma protein binding: 99.9%
TABLE-US-00005 TABLE6 Data for Compound 1478 EBOV Kikwit(Hela)
EC.sub.50: 0.009 .mu.M EBOV Makona (Hela) EC.sub.50: 0.017 .mu.M
EBOV Maiynga) (Hela) EC.sub.50: 0.035 .mu.M Molecular Weight: 622
cLogP: 3.24 m-.mu.someT.sub.1/2 (with 3 .mu.M of Ritonavir) 128 min
m-plasma stability stable m-plasma protein binding: 99.9%
Pharmacokinetic Properties of Certain Compounds of the
Invention
[0558] The effect of structure changes on the pharmacokinetic
properties of certain compounds is highlighted in FIG. 8 and Table
7.
TABLE-US-00006 TABLE 7 Effect changes on PK properties. Cpd:
IC.sub.50(mM) MW clogP Sol(mM) T.sub.1/2(min) 1343 0.25 442.9 2.94
>100 8.7 1373 0.12 454.9 3.15 1.3 1412 0.13 444.9 2.94 >100
13 1413 0.068 456.9 3.15 2.0
[0559] Additionally, FIG. 9 illustrates that CYP3A4 inhibition
(e.g., Ritonavir, Ketoconazole, Sulphaenazole, Quidine) improves
the half-life of compound 1412.
TABLE-US-00007 TABLE 8 Improved T1/2 with ritonavir IC50 T.sub.1/2
-/+- Compound (nM) ritonavir (min) PPB % 1412 68 1.4/144 94 1413
130 13/215 86
[0560] Additional pharmacokinetic properties of certain compounds
disclosed herein are highlighted in Tables 9 and 10.
TABLE-US-00008 TABLE 9 PK properties of compound 1412 IC.sub.50:
130 nM MW: 444.95 daltons CLogP: 2.94 Kinetic solubility: >100
.mu.M Plasma protein binding: 86% Plasma stability: Stable
Microsome T.sub.1/2: 8.7-13 min - with ritonavir: 215 min
TABLE-US-00009 TABLE 10 PK properties of compound 1413 IC.sub.50:
68 nM MW: 456.96 daltons CLogP: 3.15 Kinetic solubility: >100
.mu.M Plasma protein binding: 94% Plasma stability: Stable
Microsome T.sub.1/2: 1.4-2.0 min - with ritonavir: 144 min
Example 3: Comparison of In Vitro ADME Properties
[0561] The impact of replacement of the adamantane and other
changes that decreased hydrophobicity on the in vitro ADME
(absorption, distribution, metabolism, and excretion) properties of
1343 (c log P=2.94), 1412 (c log P=2.94), the (-)-enantiomer of
1413 (also referred to herein as compound 14199) (c log P=2.87),
1458 (c log P=4.10), the (-)-entantiomer of 1476 (c log P=3.82) and
the (-)-entantiomer of 1503 (c log P=3.24) was examined (Table 11).
Although inhibitors (-)-1476 and (-)-1503 are very potent, they are
less soluble and bind more extensively to mouse plasma proteins
(plasma protein binding, PPB 97.6% and 99.8%, respectively) than
smaller compounds such as 1343, and (-)-1413 (PPB=86.9% and 87.9%,
respectively). The stability of each compound in plasma is
determined by factors such as the molecular weight and steric
hindrance around the amide bond. Lower molecular weight compounds,
such as 1343, 1412 and (+1413, are stable in mouse plasma (>86%
remained after four hours) regardless of the left hand acetamide
structures. However, the larger compound 1458, which has the less
sterically hindered di-fluorocyclohexane acetamide, was unstable in
mouse plasma (30% remained after four hours). By comparison,
compound (-)-1476, in which the .alpha.-carbon of the acetamide is
blocked by the methylene of the cyclopropane ring, is more stable
(69% remained after four hours).
[0562] The stability of these compounds in mouse liver microsomes
(MLM) remained suboptimal and in particular, deuteride blocking at
the benzylic position of 1343 (T.sub.1/22==99 min) had minimal
impact on the microsomal stability (1412, T.sub.11/22==1111 min).
To better understand the oxidative metabolic pathways in mice, we
carried out additional studies of mouse liver microsomes that
revealed 3A4 as the major P450 cytochrome isoform responsible for
metabolism of these compounds (data not shown). Consistent with
this finding, the presence of the CYP3A4 inhibitor ritonavir (3
.mu.M), which is approved for clinical use as a booster of anti-HIV
drugs,.sup.22 increased the stabilities of 1412 (T.sub.1/2>120
min) and (-)-1413 (T.sub.1/2=91 min) in mouse liver microsomes by
10- to 30-fold. The salutary effect of ritonavir was also conferred
on derivatives such as (-)-1476 and (-)-1503 that contain the
benzyl moiety. Ritonavir does not inhibit VSV EBOV infection
(IC.sub.50>25 .mu.M), and thus is not expected to confound the
evaluation of lead NPC1 inhibitors as anti-EBOV agents. As with
3.47, (racemic)-1476, 1477 and (racemic)-1503, the concentration of
each of these inhibitors required to reduce cell viability by 50%
exceeded 10 .mu.M.
TABLE-US-00010 TABLE 11 In vitro ADME properties of selected
compounds. Mouse MLM, Mouse plasma T1/2 Kinetic PPB stability MLM
(min) HLM solubility (% (% at T1/2 (ritonavir T1/2 No. (.mu.M)
bound) 4 hours) (min) 3 .mu.M) (min) 1803 5 99.7 37 1 -- -- 1254 --
-- -- 1 -- -- 1343 >100 86.9 94 9 -- 27 1412 93 -- 86 11 >120
32 (-)-1413 78 87.9 88 3 91 16 1458 -- -- 30 -- >120 -- (-)-1476
10 97.6 69 -- >120 -- (-)-1503 4 99.8 72 2 87 1
Example 4--Pharmacokinetic Profile of Exemplary Compounds
[0563] At this stage, whether the in vitro optimization of 3.47
along with the protective effect of ritonavir would translate into
an acceptable pharmacokinetic profile in vivo was investigated.
Oral pharmacokinetic properties for selected compounds were
obtained in mice (Table 12).
TABLE-US-00011 TABLE 12 Oral pharmacokinetic parameters for
selected compounds in mice. T.sub.max C.sub.max C@12 hr
AUC.sub.last T.sub.1/2 Cl_obs No. Dose (hr) (.mu.M) (.mu.M) (.mu.M
hr) (hr) (mL/min/Kg) 1412 25 mg/kg 0.6 7.2 0.2 19.9 2.3 49.0 1412/
25 mg/kg/ 1.3 12.0 1.7 76.8 2.3 12.3 ritonavir 20 mg/kg (-)-1413/
50 mg/kg/ 1.7 19.5 2.0 120.9 3.2 15.5 ritonavir 50 mg/kg (-)-1476/
50 mg/kg/ 4.0 10.4 4.7 116.4 2.2 11.9 ritonavir 50 mg/kg (-)-1503/
50 mg/kg/ 7.3 7.4 5.7 107.5 1.7 12.5 ritonavir 50 mg/kg
[0564] After administration to mice by gavage, the inhibitor 1412
was rapidly absorbed and reached a C.sub.max of 7.2 .mu.M but was
nearly completely cleared in 12 hours. Co-administration of
ritonavir (20 mpk) increased the AUC and decreased the clearance of
1412 by nearly 4-fold. As a result, the plasma concentration of
1412 after 12 hours increased to 1.7 .mu.M. The pharmacokinetics of
a single 50 mpk dose of (+1413, (+1476 and (+1503 co-administered
with ritonavir (50 mpk) was also studied. The plasma concentrations
of (-)-1476 (4.7 .mu.M) and (-)-1503 (5.7 .mu.M) after 12 hours
were 50-fold greater than the in vitro IC.sub.50s of these
compounds measured against rVSV EBOV infection in 50% human serum.
When the concentration of ritonavir decreased after 12 hours, the
plasma concentration of the inhibitors declined more rapidly. These
findings suggest that an oral b.i.d dosing regimen that delivers an
effective concentration of EBOV inhibitors (-)-1476 and (-)-1503
can be achieved in mice.
INCORPORATION BY REFERENCE
[0565] All publications and patents mentioned herein are hereby
incorporated by reference in their entirety as if each individual
publication or patent was specifically and individually indicated
to be incorporated by reference. In case of conflict, the present
application, including any definitions herein, will control.
EQUIVALENTS
[0566] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
appended claims are not intended to claim all such embodiments and
variations, and the full scope of the invention should be
determined by reference to the claims, along with their full scope
of equivalents, and the specification, along with such
variations.
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