U.S. patent application number 16/886437 was filed with the patent office on 2021-04-22 for pyridyl benzothiophenes as kinase inhibitors.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Sougato Boral, Thomas C. Malone, Shimiao Wang.
Application Number | 20210115029 16/886437 |
Document ID | / |
Family ID | 1000005305488 |
Filed Date | 2021-04-22 |
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United States Patent
Application |
20210115029 |
Kind Code |
A1 |
Boral; Sougato ; et
al. |
April 22, 2021 |
PYRIDYL BENZOTHIOPHENES AS KINASE INHIBITORS
Abstract
This invention is directed to compounds, which are useful as
protein kinase (PK) inhibitors and can be used to treat such
diseases as cancer, blood vessel proliferative disorders, fibrotic
disorders, mesangial cell proliferative disorders, metabolic
diseases inflammatory disorders and neurodegenerative
disorders.
Inventors: |
Boral; Sougato; (Irvine,
CA) ; Malone; Thomas C.; (Irvine, CA) ; Wang;
Shimiao; (Tustin, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005305488 |
Appl. No.: |
16/886437 |
Filed: |
May 28, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15843945 |
Dec 15, 2017 |
10669265 |
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16886437 |
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15162172 |
May 23, 2016 |
9868726 |
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15843945 |
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14511112 |
Oct 9, 2014 |
9371314 |
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15162172 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 409/14 20130101;
C07D 409/12 20130101; C07D 409/04 20130101; C07D 213/81 20130101;
C07D 213/79 20130101; C07F 9/58 20130101 |
International
Class: |
C07D 409/12 20060101
C07D409/12; C07D 409/04 20060101 C07D409/04; C07D 409/14 20060101
C07D409/14; C07D 213/81 20060101 C07D213/81; C07D 213/79 20060101
C07D213/79; C07F 9/58 20060101 C07F009/58 |
Claims
1. A compound represented by Formula I or a pharmaceutically
acceptable salt thereof or stereoisomeric forms thereof, or the
enantiomers, diastereoisomers, and pharmaceutically acceptable
salts thereof: ##STR00287## wherein: W is S; R.sup.1 is hydrogen;
R.sup.2 is hydrogen; R.sup.3 is hydrogen; X is
--C(O)N(R.sup.4R.sup.5); R.sup.4 is hydrogen; R.sup.5 is
substituted heterocycle or substituted alkyl; Y is hydrogen; Z is
--NHR.sup.11; and R.sup.11 is hydrogen.
2. The compound of claim 1, wherein R.sup.5 is substituted aromatic
heterocycle or substituted alkyl.
3. The compound of claim 1, wherein R.sup.5 is an aromatic
heterocycle substituted with --C.sub.1-8 alkyl group or R.sup.5 is
an alkyl group substituted with a methylphenyl group.
4. The compound of claim 3, wherein the --C.sub.1-8 alkyl group is
tert-butyl.
5. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00288## and pharmaceutically salts
thereof.
6. A pharmaceutical composition comprising as active ingredient a
therapeutically effective amount of a compound according to claim 1
and a pharmaceutically acceptable adjuvant, diluent or carrier.
Description
CROSS-RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/843,945, filed Dec. 15, 2017, which is a
divisional of U.S. patent application Ser. No. 15/162,172, filed
May 23, 2016, now U.S. Pat. No. 9,868,726, issued Jan. 16, 2018,
which is a continuation of U.S. patent application Ser. No.
14/511,112, filed Oct. 9, 2014, now U.S. Pat. No. 9,371,314, issued
Jun. 21, 2016, the disclosures of which are hereby incorporated by
reference in their entireties and serve as the basis of a priority
and/or benefit claim for the present application.
FIELD OF THE INVENTION
[0002] The invention relates to inhibitors of VEGFR2 kinase or
VEGFR, PDGFR kinases or PDGFR and Protein Kinase R (EIF2AK2), and
methods of using such compounds. The present invention is also
directed to methods of regulating, modulating or inhibiting protein
kinases, whether of the receptor or non-receptor class, for the
prevention and/or treatment of disorders related to unregulated
protein kinase signal transduction, including cell growth,
metabolic, and blood vessel proliferative disorders.
DESCRIPTION OF THE RELATED ART
[0003] Protein kinases (PKs) comprise a large and diverse class of
proteins having enzymatic activity which catalyzes the transfer of
the terminal phosphate of ATP to the hydroxyl group of a serine,
threonine or tyrosine group in a protein. Protein kinases (PKs) are
involved in numerous diseases which result from dysregulation of
their normal function.
[0004] There are numerous examples where protein kinases, have been
found to be involved in cellular signaling pathways leading to
pathological conditions. In the VEGFR2 kinase protein kinase, which
is a receptor tyrosine kinase, pathological conditions involving
aberrant angiogenesis include cancer, wet age-related macular
degeneration (Ni et al. Ophthalmologica 2009 223 401-410; Chappelow
et al. Drugs 2008 68 1029-1036), diabetic retinopathy (Zhang et al
Int. J. Biochem. Cell Biol. 2009 41 2368-2371), cancer (Aora et al.
J. Path. Exp. Ther. 2006, 315, 971), psoriasis (Heidenreich et al
Drug News Perspective 2008 21 97-105) and hyper immune response. In
ophthalmic diseases, such as neovascular age-related macular
degeneration and diabetic retinopathy aberrant activation of VEGF
receptors can lead to abnormal blood vessel growth. The importance
of VEGFR signaling in the neovascular age-related macular
degeneration disease process is evident by the clinical success of
multiple anti-VEGF targeting agents including Lucentis.RTM.,
Avastin.RTM., and EYLEA.TM. (Barakat et al. Expert Opin. Investig.
Drugs 2009, 18, 637). Recently it has been suggested that
inhibition of multiple protein kinase signaling pathways may
provide a greater therapeutic effect than targeting a single
signaling pathway. For example, in neovascular ocular disorders
such as neovascular age-related macular degeneration and diabetic
retinopathy the inhibition of both VEGFR and PDGFR.beta. may
provide a greater therapeutic effect in by causing regression of
existing neovascular blood vessels present in the disease (Adamis
et al. Am. J. Pathol. 2006 168 2036-2053). In cancer inhibition of
multiple PK signaling pathways has been suggested to have a greater
effect than inhibiting a single PK pathway (DePinho et al. Science
2007 318 287-290; Bergers et al. J. Clin Invest. 2003 111
1287-1295).
[0005] It has also been suggested that misregulated protein kinases
are involved in neurodegenerative disease. In particular Protein
Kinase R has been implicated in neurodegenerative disease. Protein
Kinase R (PKR, also known as interferon-induced, double-stranded
RNA-activated protein kinase, or eukaryotic translation initiation
factor 2-alpha kinase 2) is one of four known mammalian kinases
that phosphorylate eukaryotic translation initiation factor 2-alpha
(eIF-2.alpha.) in response to a variety of stress conditions
(Donnelly et al., Cell. Mol. Life Sci. 2013, 70, 3493-3511). PKR
plays a central role in the innate immune system and serves to
prevent viral replication and viral infection (for a detailed
review see Garcia et al., Microbiol. and Mol. Bio. Rev. 2006, 70,
1032-1060). It is proposed that in chronic conditions like AMD,
innate immune players respond to modified host derived elements
(ROS/Alu) and external particulate matter(drusen) by activation of
inflammasome complex. Emerging evidence indicates that PKR has a
key role in NLRP3 inflammasome activation (Yim & Williams; J of
Interferon & Cytokine Res, 2014, Campbell & Doyle, J Mol
Med, 2013, Lu et. al; Nature, 2012).
[0006] The binding of double stranded RNA to the double stranded
RNA regulatory domains of PKR induces dimerization and
autophosphorylation which leads to activation of the kinase (Dever
et al., Cell 2005, 122, 901-913). Once activated by dimerization
PKR can suppress protein synthesis by phosphorylation of serine-51
on eukaryotic translation initiation factor 2-alpha (eIF-2.alpha.).
In its phosphorylated form eIF2alpha increases its affinity for
eIF-2B by 100-fold effectively converting it into a competitive
inhibitor of eIF-2B. By this mechanism, a small amount of
phosphorylated eIF2alpha can effectively inhibit the guanine
nucleotide exchange activity of eIF-2B and shut down protein
translation (Ramaiah et al., Biochemistry 2000, 39,
12929-12938).
[0007] In addition to PKR's role in regulation of protein synthesis
it also plays an important role in signal transduction linked to
apoptotic cell death. PKR has been shown to be activated by dsRNA,
number of growth factors and cytokines including INF, PDGF,
TNF-alpha, and IL-1 and by the activation of Toll receptors. PKR
has also been shown to be phosphorylated by JAK1 and Tyk2 kinases
(Su et al., EMBO Reports 2007, 3, 265). Activation of PKR leads to
the activation of multiple signaling pathways that are involved in
inflammation and cell death. PKR is required for phosphorylation of
MKK6 (Williams et al., J. Biol. Chem. 2004, 279, 37670-37676) and
subsequent p38 MAPK signaling (Williams et al., The EMBO Journal
2000, 19, 4292-4297). PKR induces the expression of the pro
apoptotic factor CHOP and has been shown to induce apoptosis by the
FADD/Caspase 8 pathway (Barber, G. et al, The EMBO Journal 1998,
17, 6888-6902).
[0008] Due to its key role in regulation of apoptotic cell death
PKR inhibition may be useful in prevention of the rod and cone
photoreceptor cell death and ganglion cell death associated with
the atrophic form of macular degeneration (Shimazawa et al, IVOS
2007, 48, 3729-3736).
[0009] The identification of effective small compounds which
specifically inhibit signal transduction by modulating the activity
of receptor and non-receptor protein kinases to regulate and
modulate abnormal or inappropriate cell proliferation is therefore
desirable and one object of this invention.
[0010] Certain small compounds are disclosed in PCT publication No.
WO/1999/062890, PCT publication No. WO/2005/082001 and PCT
publication No. WO/2006/026034 as useful for the treatment of
diseases related to unregulated TKS transduction. These patents
disclose starting materials and methods for the preparation
thereof, screens and assays to determine a claimed compound's
ability to modulate, regulate and/or inhibit cell proliferation,
indications which are treatable with said compounds, formulations
and routes of administration, effective dosages, etc.
US2009/0163545 refers to methods of using lifespan-altering
compounds for altering the lifespan of eukaryotic organisms and
screening for such compounds. WO2009/019504 refers to the
preparation of benzoxazoles, benzimidazoles, indoles and their
analogs for the treatment of muscular dystrophy and cachexia.
WO2007/091106 refers to the preparation of benzoxazoles,
benzimidazoles, indoles and their analogs for the treatment of
muscular dystrophy and cachexia. KR 2011033395 refers to the
preparation of benzoxazolyl-pyridine derivatives as protein kinase
inhibitors. WO2009/075874 refers to the preparation of
N-[4-pyridin-4-yl)phenyl] amides as gamma-secretase modulators.
SUMMARY OF THE INVENTION
[0011] The present invention relates to organic molecules capable
of modulating, regulating and/or inhibiting protein kinase signal
transduction, useful for treating diseases related to protein
kinase signal transduction, for example, cancer, blood vessel
proliferative disorders, fibrotic disorders, and neurodegenerative
diseases. In particular, the compounds of the present invention are
useful for treatment of mesangial cell proliferative disorders and
metabolic diseases, lung carcinomas, breast carcinomas, Non
Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer,
malignant pleural mesothelioma, melanoma, arthritis, restenosis,
hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetic
mellitus, wound healing, inflammation and neurodegenerative
diseases and preferably ophthalmic diseases, i.e. diabetic
retinopathy, retinopathy of prematurity, macular edema, retinal
vein occlusion, exudative or neovascular age-related macular
degeneration, high-risk eyes (i.e. fellow eyes have neovascular
age-related macular degeneration) with dry age-related macular
degeneration, neovascular disease associated with retinal vein
occlusion, neovascular disease (including choroidal
neovascularization) associated with the following: pathologic
myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic
choroidal rupture, atrophic macular degeneration, geographic
atrophy, central serous retinopathy, cystoid macular edema,
diabetic retinopathy, proliferative diabetic retinopathy, diabetic
macular edema, rubeosis iridis, retinopathy of prematurity, Central
and branch retinal vein occlusions, inflammatory/infectious
retinal, neovascularization/edema, corneal neovascularization,
hyperemia related to an actively inflamed pterygia, recurrent
pterygia following excisional surgery, post-excision, progressive
pterygia approaching the visual axis, prophylactic therapy to
prevent recurrent pterygia, of post-excision, progressive pterygia
approaching the visual axis, chronic low grade hyperemia associated
with pterygia, neovascular glaucoma, iris neovascularization,
idiopathic etiologies, presumed ocular histoplasmosis syndrome,
retinopathy of prematurity, chronic allergic conjunctivitis, ocular
rosacea, blepharoconjunctivitis, recurrent episcleritis,
keratoconjunctivitis sicca, ocular graft vs host disease, etc.
[0012] In one aspect, the invention provides a compound represented
by Formula I or a pharmaceutically acceptable salt thereof or
stereoisomeric forms thereof, or the enantiomers, diastereoisomers,
tautomers, zwitterions and pharmaceutically acceptable salts
thereof:
##STR00001##
wherein: W is O, S, N(CO)R.sup.14, CF.sub.2, C(CH.sub.3).sub.2,
N(CO)(NH)R.sup.14 or NR.sup.14;
[0013] R.sup.1 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl; R.sup.2 is
--N(R.sup.4)C(O)N(R.sup.4R.sup.5), --N(R.sup.4)C(O)R.sup.5,
--C(O)N(R.sup.4R.sup.5), hydrogen, substituted or unsubstituted
C.sub.1-8 alkyl, halo or haloalkyl;
[0014] R.sup.3 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl; X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5),
--N(R.sup.4)C(O)R.sup.5, --C(O)N(R.sup.4R.sup.5), hydrogen,
substituted or unsubstituted C.sub.1-8 alkyl, halo or
haloalkyl;
[0015] R.sup.4 is hydrogen or substituted or unsubstituted alkyl;
R.sup.5 is substituted or unsubstituted alkyl, substituted or
unsubstituted heterocycle or substituted or unsubstituted aryl;
[0016] Y is hydrogen, --C(O)--N.dbd.S(O)R.sup.7R.sup.6,
--N(R.sup.4)C(O)R.sup.8, --COOR.sup.9, --C(O)NHR.sup.10,
--B(OH).sub.2, --B(OR.sup.12)(OR.sup.13) or
##STR00002##
[0017] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0018] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0019] R.sup.8 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0020] R.sup.9 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0021] R.sup.10 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0022] Z is --NHR.sup.11;
[0023] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0024] R.sup.12 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0025] R.sup.13 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0026] R.sup.14 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl; and
[0027] with the proviso that the compound of Formula I is not
##STR00003##
[0028] In another aspect, the invention provides a compound
represented by Formula I wherein:
[0029] W is O, S, N(CO)R.sup.14, CF.sub.2, C(CH.sub.3).sub.2,
N(CO)(NH)R.sup.14 or NR.sup.14;
[0030] R.sup.1 is hydrogen;
[0031] R.sup.2 is hydrogen;
[0032] R.sup.3 is hydrogen;
[0033] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5),
--N(R.sup.4)C(O)R.sup.5, or --C(O)N(R.sup.4R.sup.5);
[0034] R.sup.4 is hydrogen or substituted or unsubstituted
alkyl;
[0035] R.sup.5 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0036] Y is hydrogen, --C(O)--N.dbd.S(O)R.sup.7R.sup.6,
--COOR.sup.9, --C(O)NHR.sup.10, --B(OH).sub.2, or
##STR00004##
[0037] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0038] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0039] R.sup.9 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0040] R.sup.10 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0041] Z is --NHR.sup.11; and
[0042] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0043] R.sup.14 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl; and
[0044] with the proviso that the compound of Formula I is not
##STR00005##
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0045] W is S;
[0046] R.sup.1 is hydrogen;
[0047] R.sup.2 is hydrogen;
[0048] R.sup.3 is hydrogen;
[0049] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0050] R.sup.4 is hydrogen or substituted or unsubstituted
alkyl;
[0051] R.sup.5 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0052] Y is hydrogen, --C(O)--N.dbd.S(O)R.sup.7R.sup.6,
--COOR.sup.9, --C(O)NHR.sup.10, --B(OH).sub.2, or
##STR00006##
[0053] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0054] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0055] R.sup.9 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0056] R.sup.10 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0057] Z is --NHR.sup.11; and
[0058] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0059] W is S;
[0060] R.sup.1 is hydrogen;
[0061] R.sup.2 is hydrogen;
[0062] R.sup.3 is hydrogen;
[0063] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0064] R.sup.4 is hydrogen or substituted or unsubstituted
alkyl;
[0065] R.sup.5 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0066] Y is --C(O)--N.dbd.S(O)R.sup.7R.sup.6;
[0067] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0068] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0069] Z is --NHR.sup.11; and
[0070] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0071] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0072] W is S;
[0073] R.sup.1 is hydrogen;
[0074] R.sup.2 is hydrogen;
[0075] R.sup.3 is hydrogen;
[0076] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0077] R.sup.4 is hydrogen or substituted or unsubstituted
alkyl;
[0078] R.sup.5 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0079] Y is --C(O)--N.dbd.S(O)R.sup.7R.sup.6;
[0080] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0081] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0082] Z is --NHR.sup.11; and
[0083] R.sup.11 is hydrogen.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0084] W is S;
[0085] R.sup.1 is hydrogen;
[0086] R.sup.2 is hydrogen;
[0087] R.sup.3 is hydrogen;
[0088] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0089] R.sup.4 is hydrogen;
[0090] R.sup.5 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0091] Y is --C(O)--N.dbd.S(O)R.sup.7R.sup.6;
[0092] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0093] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0094] Z is --NHR.sup.11; and
[0095] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0096] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0097] W is S;
[0098] R.sup.1 is hydrogen;
[0099] R.sup.2 is hydrogen;
[0100] R.sup.3 is hydrogen;
[0101] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0102] R.sup.4 is hydrogen;
[0103] R.sup.5 is substituted or unsubstituted aryl;
[0104] Y is --C(O)--N.dbd.S(O)R.sup.7R.sup.6;
[0105] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0106] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0107] Z is --NHR.sup.11; and
[0108] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0109] W is S;
[0110] R.sup.1 is hydrogen;
[0111] R.sup.2 is hydrogen;
[0112] R.sup.3 is hydrogen;
[0113] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0114] R.sup.4 is hydrogen;
[0115] R.sup.5 is substituted or unsubstituted heterocycle;
[0116] Y is --C(O)--N.dbd.S(O)R.sup.7R.sup.6;
[0117] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0118] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0119] Z is --NHR.sup.11; and
[0120] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0121] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0122] W is S;
[0123] R.sup.1 is hydrogen;
[0124] R.sup.2 is hydrogen;
[0125] R.sup.3 is hydrogen;
[0126] X is --N(R.sup.4)C(O)R.sup.5;
[0127] R.sup.4 is hydrogen;
[0128] R.sup.5 is substituted or unsubstituted heterocycle or
substituted or unsubstituted aryl;
[0129] Y is hydrogen, --C(O)--N.dbd.S(O)R.sup.7R.sup.6,
--COOR.sup.9, --C(O)NHR.sup.10, --B(OH).sub.2, or
##STR00007##
[0130] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0131] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0132] R.sup.9 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0133] R.sup.10 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0134] Z is --NHR.sup.11; and
[0135] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0136] W is S;
[0137] R.sup.1 is hydrogen;
[0138] R.sup.2 is hydrogen;
[0139] R.sup.3 is hydrogen;
[0140] X is --N(R.sup.4)C(O)R.sup.5;
[0141] R.sup.4 is hydrogen;
[0142] R.sup.5 is substituted or unsubstituted aryl;
[0143] Y is hydrogen, --C(O)--N.dbd.S(O)R.sup.7R.sup.6,
--COOR.sup.9, --C(O)NHR.sup.10, --B(OH).sub.2, or
##STR00008##
[0144] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl;
[0145] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl;
[0146] R.sup.9 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0147] R.sup.10 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0148] Z is --NHR.sup.11; and
[0149] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0150] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0151] W is S;
[0152] R.sup.1 is hydrogen;
[0153] R.sup.2 is hydrogen;
[0154] R.sup.3 is hydrogen;
[0155] X is --C(O)N(R.sup.4R.sup.5);
[0156] R.sup.4 is hydrogen;
[0157] R.sup.5 is substituted or unsubstituted aryl;
[0158] Y is --COOR.sup.9;
[0159] R.sup.7 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0160] R.sup.6 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0161] R.sup.9 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0162] Z is --NHR.sup.11; and
[0163] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0164] W is S;
[0165] R.sup.1 is hydrogen;
[0166] R.sup.2 is hydrogen;
[0167] R.sup.3 is hydrogen;
[0168] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0169] R.sup.4 is hydrogen;
[0170] R.sup.5 is substituted or unsubstituted aryl;
[0171] Y is --C(O)NHR.sup.10;
[0172] R.sup.10 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0173] Z is --NHR.sup.11; and
[0174] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0175] W is S;
[0176] R.sup.1 is hydrogen;
[0177] R.sup.2 is hydrogen;
[0178] R.sup.3 is hydrogen;
[0179] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0180] R.sup.4 is hydrogen;
[0181] R.sup.5 is substituted or unsubstituted aryl;
[0182] Y is
##STR00009##
[0183] Z is --NHR.sup.11; and
[0184] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
In another aspect, the invention provides a compound represented by
Formula I wherein:
[0185] W is S;
[0186] R.sup.1 is hydrogen;
[0187] R.sup.2 is hydrogen;
[0188] R.sup.3 is hydrogen;
[0189] X is --N(R.sup.4)C(O)N(R.sup.4R.sup.5);
[0190] R.sup.4 is hydrogen;
[0191] R.sup.5 is substituted or unsubstituted aryl;
[0192] Y is --B(OH).sub.2;
[0193] Z is --NHR.sup.11; and
[0194] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0195] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0196] W is S;
[0197] R.sup.1 is hydrogen;
[0198] R.sup.2 is hydrogen;
[0199] R.sup.3 is hydrogen;
[0200] X is --N(R.sup.4)C(O)R.sup.5;
[0201] R.sup.4 is hydrogen;
[0202] R.sup.5 is substituted or unsubstituted aryl;
[0203] Y is hydrogen;
[0204] Z is --NHR.sup.11; and
[0205] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0206] In another aspect, the invention provides a compound
represented by Formula I
wherein:
[0207] W is S;
[0208] R.sup.1 is hydrogen;
[0209] R.sup.2 is hydrogen;
[0210] R.sup.3 is hydrogen;
[0211] X is --C(O)N(R.sup.4R.sup.5);
[0212] R.sup.4 is hydrogen or substituted or unsubstituted
alkyl;
[0213] R.sup.5 is substituted or unsubstituted alkyl or substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0214] Y is hydrogen;
[0215] Z is --NHR.sup.11; and
[0216] R.sup.11 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0217] In one aspect, the invention provides a compound represented
by Formula II or a pharmaceutically acceptable salt thereof or
stereoisomeric forms thereof, or the enantiomers, diastereoisomers,
tautomers, zwitterions and pharmaceutically acceptable salts
thereof:
##STR00010##
wherein:
[0218] R.sup.15 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl;
[0219] R.sup.16 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl;
[0220] R.sup.17 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl;
[0221] X.sup.a is --N(R.sup.19)C(O)N(R.sup.19 R.sup.20);
[0222] R.sup.18 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, halo or haloalkyl;
[0223] R.sup.19 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0224] R.sup.20 is substituted or unsubstituted alkyl, substituted
or unsubstituted heterocycle or substituted or unsubstituted
aryl;
[0225] Y.sup.a is hydrogen, --C(O)--N.dbd.S(O)R.sup.21R.sup.22,
--N(R.sup.23)C(O)R.sup.24, --COOR.sup.25, --C(O)NHR.sup.27,
--B(OH).sub.2, --B(OR.sup.28)(OR.sup.29) or
##STR00011##
[0226] R.sup.21 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0227] R.sup.22 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0228] R.sup.23 is substituted or unsubstituted C.sub.1-8 alkyl,
substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0229] R.sup.24 is hydrogen, substituted or unsubstituted C.sub.1-8
alkyl, substituted or unsubstituted heterocycle or substituted or
unsubstituted aryl;
[0230] Z.sup.a is --NHR.sup.26;
[0231] R.sup.25 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0232] R.sup.26 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0233] R.sup.27 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl;
[0234] R.sup.28 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl; and
[0235] R.sup.29 is hydrogen or substituted or unsubstituted
C.sub.1-8 alkyl.
[0236] The term "alkyl", as used herein, refers to saturated,
monovalent or divalent hydrocarbon moieties having linear or
branched moieties or combinations thereof and containing 1 to 12
carbon atoms. One methylene (--CH.sub.2--) group, of the alkyl
group can be replaced by oxygen, sulfur, sulfoxide, nitrogen,
carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide,
sulfonamide, by a divalent C.sub.3-8 cycloalkyl, by a divalent
heterocycle, or by a divalent aryl group. Alkyl groups can have one
or more chiral centers. Alkyl groups can be independently
substituted by halogen atoms, hydroxyl groups, cycloalkyl groups,
amino groups, heterocyclic groups, aryl groups, carboxylic acid
groups, phosphonic acid groups, sulphonic acid groups, phosphoric
acid groups, nitro groups, amide groups, sulfonamide groups, ester
groups, ketone groups.
[0237] The term "cycloalkyl", as used herein, refers to a
monovalent or divalent group of 3 to 8 carbon atoms derived from a
saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic
or polycyclic. Cycloalkyl can be independently substituted by
halogen atoms, sulfonyl C.sub.1-8 alkyl groups, sulfoxide C.sub.1-8
alkyl groups, sulfonamide groups, nitro groups, cyano groups,
--OC.sub.1-8 alkyl groups, --SC.sub.1-8 alkyl groups, --C.sub.1-8
alkyl groups, --C.sub.2-6 alkenyl groups, --C.sub.2-6 alkynyl
groups, ketone groups, alkylamino groups, amino groups, aryl
groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups.
[0238] The term "cycloalkenyl", as used herein, refers to a
monovalent or divalent group of 3 to 8 carbon atoms derived from a
saturated cycloalkyl having at least one double bond. Cycloalkenyl
groups can be monocyclic or polycyclic. Cycloalkenyl groups can be
independently substituted by halogen atoms, sulfonyl groups,
sulfoxide groups, nitro groups, cyano groups, --OC.sub.1-6 alkyl
groups, --SC.sub.1-6 alkyl groups, --C.sub.1-6 alkyl groups,
--C.sub.2-6 alkenyl groups, --C.sub.2-6 alkynyl groups, ketone
groups, alkylamino groups, amino groups, aryl groups, C.sub.3-8
cycloalkyl groups or hydroxyl groups.
[0239] The term "halogen", as used herein, refers to an atom of
chlorine, bromine, fluorine, iodine.
[0240] The term "alkenyl", as used herein, refers to a monovalent
or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived
from a saturated alkyl, having at least one double bond. One
methylene (--CH.sub.2--) group, of the alkenyl can be replaced by
oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl,
sulfate, sulfonate, amide, sulfonamide, by a divalent C.sub.3-8
cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
C.sub.2-6 alkenyl can be in the E or Z configuration. Alkenyl
groups can be substituted by alkyl groups, as defined above or by
halogen atoms.
[0241] The term "alkynyl", as used herein, refers to a monovalent
or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived
from a saturated alkyl, having at least one triple bond. One
methylene (--CH.sub.2--) group, of the alkynyl can be replaced by
oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl,
sulfate, sulfonate, amide, sulfonamide, by a divalent C.sub.3-8
cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
Alkynyl groups can be substituted by alkyl groups, as defined
above, or by halogen atoms.
[0242] The term "heterocycle" as used herein, refers to a 3 to 10
membered ring, which can be aromatic or non-aromatic, saturated or
unsaturated, containing at least one heteroatom selected form
oxygen, nitrogen, sulfur, or combinations of at least two thereof,
interrupting the carbocyclic ring structure. The heterocyclic ring
can be interrupted by a C.dbd.O; the S and N heteroatoms can be
oxidized. Heterocycles can be monocyclic or polycyclic.
Heterocyclic ring moieties can be substituted by halogen atoms,
sulfonyl groups, sulfoxide groups, nitro groups, cyano groups,
--OC.sub.1-6 alkyl groups, --SC.sub.1-6 alkyl groups, --C.sub.1-8
alkyl groups, --C.sub.2-6 alkenyl groups, --C.sub.2-6 alkynyl
groups, ketone groups, alkylamino groups, amino groups, aryl
groups, C.sub.3-8 cycloalkyl groups or hydroxyl groups.
[0243] The term "aryl" as used herein, refers to an organic moiety
derived from an aromatic hydrocarbon consisting of a ring
containing 6 to 10 carbon atoms, by removal of one hydrogen atom.
Aryl can be substituted by halogen atoms, sulfonyl C.sub.1-6 alkyl
groups, sulfoxide C.sub.1-6 alkyl groups, sulfonamide groups,
carboxyclic acid groups, C.sub.1-6 alkyl carboxylates (ester)
groups, amide groups, nitro groups, cyano groups, --OC.sub.1-6
alkyl groups, --SC.sub.1-6 alkyl groups, --C.sub.1-6 alkyl groups,
--C.sub.2-6 alkenyl groups, --C.sub.2-6 alkynyl groups, ketone
groups, aldehydes, alkylamino groups, amino groups, aryl groups,
C.sub.3-8 cycloalkyl groups or hydroxyl groups. Aryls can be
monocyclic or polycyclic.
[0244] The term "hydroxyl" as used herein, represents a group of
formula "--OH".
[0245] The term "carbonyl" as used herein, represents a group of
formula "--C(O)--".
[0246] The term "ketone" as used herein, represents an organic
compound having a carbonyl group linked to a carbon atom such as
--C(O)R.sup.x wherein R.sup.x can be alkyl, aryl, cycloalkyl,
cycloalkenyl, heterocycle as defined above.
[0247] The term "ester" as used herein, represents an organic
compound having a carbonyl group linked to a carbon atom such as
--C(O)OR.sup.x wherein R.sup.x can be alkyl, aryl, cycloalkyl,
cycloalkenyl, heterocycle as defined above.
[0248] The term "amine" as used herein, represents a group of
formula "--NR.sup.xR.sup.y", wherein R.sup.x and R.sup.y can be the
same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl,
heterocycle as defined above.
[0249] The term "carboxyl" as used herein, represents a group of
formula "--C(O)O--".
[0250] The term "sulfonyl" as used herein, represents a group of
formula "--SO.sub.2.sup.-".
[0251] The term "sulfate" as used herein, represents a group of
formula "--O--S(O).sub.2--O--".
[0252] The term "sulfonate" as used herein, represents a group of
the formula "--S(O).sub.2--O--".
[0253] The term "carboxylic acid" as used herein, represents a
group of formula "--C(O)OH".
[0254] The term "nitro" as used herein, represents a group of
formula "--NO.sub.2".
[0255] The term "cyano" as used herein, represents a group of
formula "--CN".
[0256] The term "amide" as used herein, represents a group of
formula "--C(O)NR.sup.xR.sup.y," wherein R.sup.x and R.sup.y can be
the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl,
heterocycle as defined above.
[0257] The term "sulfonamide" as used herein, represents a group of
formula "--S(O).sub.2NR.sup.xR.sup.y" wherein R.sup.x and R.sup.y
can be the same or independently H, alkyl, aryl, cycloalkyl,
cycloalkenyl, heterocycle as defined above.
[0258] The term "sulfoxide" as used herein, represents a group of
formula "--S(O)--".
[0259] The term "phosphonic acid" as used herein, represents a
group of formula "--P(O)(OH).sub.2".
[0260] The term "phosphoric acid" as used herein, represents a
group of formula "--OP(O)(OH).sub.2".
[0261] The term "sulphonic acid" as used herein, represents a group
of formula "--S(O).sub.2OH".
[0262] The formula "H", as used herein, represents a hydrogen
atom.
[0263] The formula "O", as used herein, represents an oxygen
atom.
[0264] The formula "N", as used herein, represents a nitrogen
atom.
[0265] The formula "S", as used herein, represents a sulfur
atom.
Other defined terms are used throughout this specification: "Ac"
refers to acetyl "DCE" refers to dichloroethane "DCM" refers to
dichloromethane "DMAP" refers to dimethylaminopyridine "EDCI"
refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide "Et" refers
to ethyl "iPr" refers to i-propyl "Me" refers to methyl "MeOH"
refers to methanol "PDGF" refers to platelet derived growth factor
"Ph" refers to phenyl "PKs" refers to protein kinase "RTKs" refers
to receptor tyrosine kinase "rt" refers to room temperature "tBu"
refers to t-butyl. "THF" refers to tetrahydrofuran "VEGF" refers to
vascular endothelial growth factor "VEGFR" refers to vascular
endothelial growth factor receptor Compounds of the invention are
tabulated in Table 1:
TABLE-US-00001 TABLE 1 List of compound names and structures Ex-
am- ple Structure Compound Name 1 ##STR00012##
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-[5-({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]nicotinamide 2 ##STR00013##
6-amino-5-[5-({[(3-chloro-4- fluorophenyl)amino]carbonyl}a-
mino)-1-benzothien-2-yl]-N- [dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]nicotinamide 3 ##STR00014##
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-[5-({[(2-fluoro-2- 5-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2-
yl]nicotinamide 4 ##STR00015## 6-amino-5-{5-
[(anilinocarbonyl)amino]-1- benzothien-2-yl}-N-
[dimethyl(oxido)-.lamda..sup.4- sulfanylidene]nicotinamide 5
##STR00016## 6-amino-5-{5-[({[4-chloro-3-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}-N-[dimethyl(oxido)-.lamda..sup.4- sulfanylidene]nicotinamide 6
##STR00017## 6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-{5-[({[2-fluoro- 5-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}nicotinamide 7 ##STR00018## methyl 6-amino-5-{5-[({[3-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}nicotinate 8 ##STR00019## methyl 6-amino-5-{5-[({[2- fluoro-4-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}nicotinate 9 ##STR00020## methyl 6-amino-5-{5-[({[4- chloro-3-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}nicotinate 10 ##STR00021## methyl 6-amino-5-[5-({[(2- fluoro-5-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]nicotinate
11 ##STR00022## methyl 6-amino-5-[5-({[(3-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]nicotinate
12 ##STR00023## methyl 6-amino-5-[5-({[(3- chloro-4-
fluorophenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]nicotinate
13 ##STR00024## methyl 6-amino-5-[5-({[(4-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]nicotinate
14 ##STR00025## methyl 6-amino-5-[5-({[(2-
fluorophenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]nicotinate
15 ##STR00026## methyl 6-amino-5-{5- [(anilinocarbonyl)amino]-1-
benzothien-2-yl}nicotinate 16 ##STR00027## methyl
6-amino-5-[5-({[(2,4- difluorophenyl)amino]carbonyl}
amino)-1-benzothien-2- yl]nicotinate 17 ##STR00028##
6-amino-5-[5-({[(3-chloro-4- fluorophenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]nicotinic acid 18 ##STR00029##
6-amino-5-[5-({[(2-fluoro-5- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]nicotinic acid 19 ##STR00030##
6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]nicotinic acid 20 ##STR00031##
6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]nicotinamide 21 ##STR00032## methyl
4-[({6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]pyridin-3- yl}carbonyl)amino]butanoate 22
##STR00033## methyl 6-[({6-amino-5-[5-({[(3-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2- yl]pyridin-3-
yl}carbonyl)amino]hexanaote 23 ##STR00034##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-[2-fluoro-5-
(trifluoromethyl)phenyl]urea 24 ##STR00035##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-[3-
(trifluoromethyl)phenyl]urea 25 ##STR00036##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-[4-chloro-3-
(trifluoromethyl)phenyl]urea 26 ##STR00037##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-(2-fluoro-5-
methylphenyl)urea 27 ##STR00038## 1-{2-[2-amino-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-3-yl]-1-benzothien-
5-yl}-3-(3-chloro-4- fluorophenyl)urea 28 ##STR00039##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-(3-ethylphenyl)urea 29
##STR00040## 1-{2-[2-amino-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-3-yl]-1-benzothien-
5-yl}-3-(3-methylphenyl)urea 30 ##STR00041##
1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]-1-benzothien- 5-yl}-3-phenylurea 31 ##STR00042##
{6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]pyridin-3-yl}boronic acid 32 ##STR00043##
(6-amino-5-{5- [(anilinocarbonyl)amino]-1-
benzothien-2-yl}pyridin-3- yl)boronic acid 33 ##STR00044##
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-{5-[(3-methyl- 2-furoyl)amino]-1-benzothien-2-
yl}nicotinamide 34 ##STR00045## 6-amino-5-(5-{[4-chloro-3-
(trifluoromethyl)benzoyl]amino}- 1-benzothien-2-yl)-N-
[dimethyl(oxido)-.lamda..sup.4- sulfanylidene]nicotinamide 35
##STR00046## 6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-{5-[(2-fluoro-5- methylbenzoyl)amino]-1-
benzothien-2-yl}nicotinamide 36 ##STR00047##
6-amino-5-[5-(benzoylamino)-1- benzothien-2-yl]-N-
[dimethyl(oxido)-.lamda..sup.4- sulfanylidene]nicotinamide 37
##STR00048## 6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-{5-[(3- methylbenzoyl)amino]-1-
benzothien-2-yl}nicotinamide 38 ##STR00049##
6-amino-N-[(dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-(5-{[2-fluoro-5- (trifluoromethyl)benzoyl]amino}-
1-benzothien-2-yl)nicotinamide 39 ##STR00050## methyl
6-amino-5-{5-[(3- methyl-2-furoyl)amino]-1-
benzothien-2-yl}nicotinate 40 ##STR00051## methyl 6-amino-5-{5-[(3-
methylbenzoyl)amino]-1- benzothien-2-yl}nicotinate 41 ##STR00052##
methyl 6-amino-5-{5-[(2-fluoro- 5-methylbenzoyl)amino]-1-
benzothien-2-yl}nicotinate 42 ##STR00053## methyl 6-amino-5-[5-
(benzoylamino)-1-benzothien-2- yl]nicotinate 43 ##STR00054## methyl
6-amino-5-{5-[(3-chloro- 4-fluorobenzoyl)amino]-1-
benzothien-2-yl}nicotinate 44 ##STR00055## methyl
6-amino-5-(5-{[2-fluoro- 5- (trifluoromethyl)benzoyl]amino}-
1-benzothien-2-yl)nicotinate 45 ##STR00056## methyl
6-amino-5-{5-[(1- benzofuran-2- ylcarbonyl)amino]-1-
benzothien-2-yl}nicotinate 46 ##STR00057##
N-[2-(2-aminopyridin-3-yl)-1- benzothien-5-yl]-3- methylbenzamide
47 ##STR00058## N-[2-(2-aminopyridin-3-yl)-1-
benzothien-5-yl]benzamide 48 ##STR00059##
2-(2-aminopyridin-3-yl)-N-(3- methylphenyl)-1-
benzothiophen-5-carboxamide 49 ##STR00060##
2-(2-aminopyridin-3-yl)-N-(5- tert-butylisoxazol-3-yl)-1-
benzothiophene-5-carboxamide 50 ##STR00061##
2-(2-aminopyridin-3-yl)-N-(3- methylbenzyl)-1-
benzothiophene-5-carboxamide 51 ##STR00062##
2-(2-aminopyridin-3-yl)-N-(2- fluoro-5-methylphenyl)-1-
benzothiophene-5-carboxamide 52 ##STR00063##
2-(2-aminopyridin-3-yl)-N-(3- chloro-4-fluorophenyl)-1-
benzothiophene-5-carboxamide 53 ##STR00064## methyl
5-[N-({6-amino-5-[5- ({[(3- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-
methylsulfonimidoyl]pentanoate 54 ##STR00065## methyl
5-[N-({6-amino-5-[5- ({[(2-fluoro-5- methylphenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-
methylsulfonimidoyl]pentanoate 55 ##STR00066## methyl
5-[N-({6-amino-5-[5- ({[(3-chloro-4- fluorophenyl)amino]carbonyl}a-
mino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-
methylsulfonimidoyl]pentanoate 56 ##STR00067## 6-amino-N-[bis(3-
hydroxypropyl)(oxido)-.lamda..sup.4- sulfanylidene]-5-[5-({[(3-
methylphenyl)amino]carbonyl}a- mino)-1-benzothien-2-
yl]nicotinamide 57 ##STR00068## N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-{5-[({[2-fluoro- 5-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}nicotinamide 58 ##STR00069## 5-{5-[({[4-chloro-3-
(trifluoromethyl)phenyl]amino}car- bonyl)amino]-1-benzothien-2-
yl}-N-[dimethyl(oxido)-.lamda..sup.4- sulfanylidene]nicotinamide 59
##STR00070## 6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-[4-({[(2-fluoro- 5-methylphenyl)
amino]carbonyl}amino)phenyl]ni- cotinamide 60 ##STR00071##
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-
sulfanylidene]-5-[4-({[(2-fluoro- 5- methylphenyl)amino]carbonyl}a-
mino)phenyl]nicotinamide 61 ##STR00072##
[6-amino-5-(4-{[(2-fluoro-5- methylphenyl)carbamoyl]amino}
phenyl)pyridin-3-yl]boronic acid 62 ##STR00073##
1-{4-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2-yl)pyridin-3-yl]phenyl}-3-(2- fluoro-5-methylphenyl)urea 63
##STR00074## 1-{4-[2-amino-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-3-yl]phenyl}-3-
phenylurea 64 ##STR00075## dimethyl {6-amino-5-[4-({[3-
(trifluoromethyl)phenyl]carba- moyl}amino)phenyl]pyridin-3-
yl}phosphonate 65 ##STR00076## diethyl [6-amino-5-(4-{[(2-
fluoro-5- methylphenyl)carbamoyl]amino} phenyl)pyridin-3-
yl]phosphonate 66 ##STR00077## dimethyl {6-amino-5-[4-({[2-
fluoro-5- (trifluoromethyl)phenyl]carba-
moyl}amino)phenyl]pyridin-3- yl}phosphonate 67 ##STR00078##
dimethyl [6-amino-5-(4-{[(2- fluoro-5-
methylphenyl)carbamoyl]amino} phenyl)pyridin-3- yl]phosphonate 68
##STR00079## dimethyl (6-amino-5-{4-
[(phenylcarbamoyl)amino]phenyl} pyridin-3-yl)phosphonate 69
##STR00080## 6-amino-N-[bis(3- hydroxypropyl)(oxido)-.lamda..sup.6-
sulfanylidene]-5-(4-{5[(3- methylphenyl)carbamoyl]amino}
phenyl)pyridine-3-carboxamide 70 ##STR00081## dimethyl
5,5'-(N-{[6-amino-5- (4-{[(3-
methylphenyl)carbamoyl]amino} phenyl)pyridin-3-
yl]carbonyl}sulfonimidoyl)di- pentanoate 71 ##STR00082## dimethyl
5,5'-(N-{[6-amino-5- (4-{[(2-fluoro-5-
methylphenyl)carbamoyl]amino} phenyl)pyridin-3-
yl]carbonyl}sulfonimidoyl)di- pentanoate 72 ##STR00083## dimethyl
5,5'-[N-({6-amino-5- [4-({[3- (trifluoromethyl)phenyl]carba-
moyl}amino)phenyl]pyridin-3- yl}carbonyl)sulfonimidoyl]di-
pentanoate 73 ##STR00084## methyl 6-amino-5-(4-{[(2- fluoro-5-
methylphenyl)carbamoyl]amino} phenyl)pyridine-3-carboxylate 74
##STR00085## methyl 6-amino-5-[4-({[2- fluoro-5-
(trifluoromethyl)phenyl]carba- moyl}amino)phenyl]pyridine-3-
carboxylate 75 ##STR00086## methyl 6-amino-5-[4-({[4- chloro-3-
(trifluoromethyl)phenyl]carba- moyl}amino)phenyl]pyridine-3-
carboxylate 76 ##STR00087## methyl 6-amino-5-{4-
[(phenylcarbamoyl)amino]phenyl} pyridine-3-carboxylate
[0266] Compounds of formula I and of formula II are useful as
protein kinase inhibitors. As such, compounds of formula I and of
formula II will be useful for treating diseases related to
unregulated protein kinase signal transduction, for example,
cancer, blood vessel proliferative disorders, fibrotic disorders,
inflammatory disorders and neurodegenerative diseases. In
particular, the compounds of the present invention are useful for
treatment of mesangial cell proliferative disorders and metabolic
diseases, lung carcinomas, breast carcinomas, Non Hodgkin's
lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural
mesothelioma, melanoma, arthritis, restenosis, hepatic cirrhosis,
atherosclerosis, psoriasis, rosacea, diabetic mellitus, wound
healing, inflammation and neurodegenerative diseases and preferably
ophthalmic diseases, i.e. diabetic retinopathy, retinopathy of
prematurity, macular edema, retinal vein occlusion, exudative or
neovascular age-related macular degeneration, high-risk eyes (i.e.
fellow eyes have neovascular age-related macular degeneration) with
dry age-related macular degeneration, neovascular disease
associated with retinal vein occlusion, neovascular disease
(including choroidal neovascularization) associated with the
following: pathologic myopia, pseudoxanthoma elasticum, optic nerve
drusen, traumatic choroidal rupture, atrophic macular degeneration,
geographic atrophy, central serous retinopathy, cystoid macular
edema, diabetic retinopathy, proliferative diabetic retinopathy,
diabetic macular edema, rubeosis iridis, retinopathy of
prematurity, Central and branch retinal vein occlusions,
inflammatory/infectious retinal, neovascularization/edema, corneal
neovascularization, hyperemia related to an actively inflamed
pterygia, recurrent pterygia following excisional surgery,
post-excision, progressive pterygia approaching the visual axis,
prophylactic therapy to prevent recurrent pterygia, of
post-excision, progressive pterygia approaching the visual axis,
chronic low grade hyperemia associated with pterygia, neovascular
glaucoma, iris neovascularization, idiopathic etiologies, presumed
ocular histoplasmosis syndrome, retinopathy of prematurity, chronic
allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis,
recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs
host disease, etc.
[0267] Some compounds of Formula I and of Formula II and some of
their intermediates may have at least one asymmetric center in
their structure. This asymmetric center may be present in an R or S
configuration, said R and S notation is used in correspondence with
the rules described in Pure Appli. Chem. (1976), 45, 11-13.
[0268] The term "pharmaceutically acceptable salts" refers to salts
or complexes that retain the desired biological activity of the
above identified compounds and exhibit minimal or no undesired
toxicological effects. The "pharmaceutically acceptable salts"
according to the invention include therapeutically active,
non-toxic base or acid salt forms, which the compounds of Formula I
and of Formula II are able to form.
[0269] The acid addition salt form of a compound of Formula I and
of Formula II that occurs in its free form as a base can be
obtained by treating the free base with an appropriate acid such as
an inorganic acid, for example, hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, nitric acid and the like; or
an organic acid such as for example, acetic acid, hydroxyacetic
acid, propanoic acid, lactic acid, pyruvic acid, malonic acid,
fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic
acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic
acid, citric acid, methylsulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, formic and the like (Handbook of
Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth
(Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).
[0270] The base addition salt form of a compound of Formula I and
of Formula II that occurs in its acid form can be obtained by
treating the acid with an appropriate base such as an inorganic
base, for example, sodium hydroxide, magnesium hydroxide, potassium
hydroxide, calcium hydroxide, ammonia and the like; or an organic
base such as for example, L-Arginine, ethanolamine, betaine,
benzathine, morpholine and the like. (Handbook of Pharmaceutical
Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag
Helvetica Chimica Acta-Zurich, 2002, 329-345).
[0271] Compounds of Formula I and of Formula II and their salts can
be in the form of a solvate, which is included within the scope of
the present invention. Such solvates include for example hydrates,
alcoholates and the like.
[0272] With respect to the present invention reference to a
compound or compounds, is intended to encompass that compound in
each of its possible isomeric forms and mixtures thereof unless the
particular isomeric form is referred to specifically.
[0273] Compounds according to the present invention may exist in
different polymorphic forms. Although not explicitly indicated in
the above formula, such forms are intended to be included within
the scope of the present invention.
[0274] The actual amount of the compound to be administered in any
given case will be determined by a physician taking into account
the relevant circumstances, such as the severity of the condition,
the age and weight of the patient, the patient's general physical
condition, the cause of the condition, and the route of
administration.
[0275] The patient will be administered the compound orally in any
acceptable form, such as a tablet, liquid, capsule, powder and the
like, or other routes may be desirable or necessary, particularly
if the patient suffers from nausea. Such other routes may include,
without exception, transdermal, parenteral, subcutaneous,
intranasal, via an implant stent, intrathecal, intravitreal,
topical to the eye, back to the eye, intramuscular, intravenous,
and intrarectal modes of delivery. Additionally, the formulations
may be designed to delay release of the active compound over a
given period of time, or to carefully control the amount of drug
released at a given time during the course of therapy.
[0276] In another embodiment of the invention, there are provided
pharmaceutical compositions including at least one compound of the
invention in a pharmaceutically acceptable carrier thereof. The
phrase "pharmaceutically acceptable" means the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0277] Pharmaceutical compositions of the present invention can be
used in the form of a solid, a solution, an emulsion, a dispersion,
a patch, a micelle, a liposome, and the like, wherein the resulting
composition contains one or more compounds of the present
invention, as an active ingredient, in admixture with an organic or
inorganic carrier or excipient suitable for enteral or parenteral
applications. Invention compounds may be combined, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The carriers
which can be used include glucose, lactose, gum acacia, gelatin,
mannitol, starch paste, magnesium trisilicate, talc, corn starch,
keratin, colloidal silica, potato starch, urea, medium chain length
triglycerides, dextrans, and other carriers suitable for use in
manufacturing preparations, in solid, semisolid, or liquid form. In
addition auxiliary, stabilizing, thickening and coloring agents and
perfumes may be used. Invention compounds are included in the
pharmaceutical composition in an amount sufficient to produce the
desired effect upon the process or disease condition.
[0278] Pharmaceutical compositions containing invention compounds
may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, or syrups or
elixirs. Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of a sweetening
agent such as sucrose, lactose, or saccharin, flavoring agents such
as peppermint, oil of wintergreen or cherry, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets containing invention compounds in
admixture with non-toxic pharmaceutically acceptable excipients may
also be manufactured by known methods. The excipients used may be,
for example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, potato starch or alginic
acid; (3) binding agents such as gum tragacanth, corn starch,
gelatin or acacia, and (4) lubricating agents such as magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed.
[0279] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the invention compounds are mixed
with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin. They may also be in the form of soft
gelatin capsules wherein the invention compounds are mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
[0280] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0281] Pharmaceutical compositions containing invention compounds
may be in a form suitable for topical use, for example, as oily
suspensions, as solutions or suspensions in aqueous liquids or
nonaqueous liquids, or as oil-in-water or water-in-oil liquid
emulsions. Pharmaceutical compositions may be prepared by combining
a therapeutically effective amount of at least one compound
according to the present invention, or a pharmaceutically
acceptable salt thereof, as an active ingredient with conventional
ophthalmically acceptable pharmaceutical excipients and by
preparation of unit dosage suitable for topical ocular use. The
therapeutically efficient amount typically is between about 0.0001
and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in
liquid formulations.
[0282] For ophthalmic application, preferably solutions are
prepared using a physiological saline solution as a major vehicle.
The pH of such ophthalmic solutions should preferably be maintained
between 4.5 and 8.0 with an appropriate buffer system, a neutral pH
being preferred but not essential. The formulations may also
contain conventional pharmaceutically acceptable preservatives,
stabilizers and surfactants. Preferred preservatives that may be
used in the pharmaceutical compositions of the present invention
include, but are not limited to, benzalkonium chloride,
chlorobutanol, thimerosal, phenylmercuric acetate and
phenylmercuric nitrate. A preferred surfactant is, for example,
Tween 80. Likewise, various preferred vehicles may be used in the
ophthalmic preparations of the present invention. These vehicles
include, but are not limited to, polyvinyl alcohol, povidone,
hydroxypropyl methyl cellulose, poloxamers, carboxymethyl
cellulose, hydroxyethyl cellulose cyclodextrin and purified
water.
[0283] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0284] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
[0285] In a similar manner an ophthalmically acceptable antioxidant
for use in the present invention includes, but is not limited to,
sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole and butylated hydroxytoluene.
[0286] Other excipient components which may be included in the
ophthalmic preparations are chelating agents. The preferred
chelating agent is edentate disodium, although other chelating
agents may also be used in place of or in conjunction with it.
[0287] The ingredients are usually used in the following
amounts:
TABLE-US-00002 Ingredient Amount (% w/v) active ingredient about
0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10
buffer 0.01-10 pH adjustor q.s. pH 4.5-7.8 antioxidant as needed
surfactant as needed purified water to make 100%
[0288] The actual dose of the active compounds of the present
invention depends on the specific compound, and on the condition to
be treated; the selection of the appropriate dose is well within
the knowledge of the skilled artisan.
[0289] The ophthalmic formulations of the present invention are
conveniently packaged in forms suitable for metered application,
such as in containers equipped with a dropper, to facilitate
application to the eye. Containers suitable for dropwise
application are usually made of suitable inert, non-toxic plastic
material, and generally contain between about 0.5 and about 15 ml
solution. One package may contain one or more unit doses.
Especially preservative-free solutions are often formulated in
non-resealable containers containing up to about ten, preferably up
to about five units doses, where a typical unit dose is from one to
about 8 drops, preferably one to about 3 drops. The volume of one
drop usually is about 20-35 .mu.l.
[0290] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0291] The compounds of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions may be prepared by mixing the invention
compounds with a suitable non-irritating excipient, such as cocoa
butter, synthetic glyceride esters of polyethylene glycols, which
are solid at ordinary temperatures, but liquefy and/or dissolve in
the rectal cavity to release the drug.
[0292] Since individual subjects may present a wide variation in
severity of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner.
The present invention is further directed to pharmaceutical
compositions comprising a pharmaceutically effective amount of one
or more of the above-described compounds and a pharmaceutically
acceptable carrier or excipient, wherein said compositions are
effective for treating the above diseases and conditions;
especially ophthalmic diseases and conditions. Such a composition
is believed to modulate signal transduction by a protein kinase,
either by inhibition of catalytic activity, affinity to ATP or
ability to interact with a substrate.
[0293] More particularly, the compositions of the present invention
may be included in methods for treating diseases comprising
proliferation, fibrotic or metabolic disorders, for example cancer,
fibrosis, psoriasis, rosacea, atherosclerosis, arthritis, and other
disorders related to abnormal vasculogenesis and/or angiogenesis,
such as exudative age related macular degeneration and diabetic
retinopathy.
[0294] The present invention is further directed to pharmaceutical
compositions comprising a pharmaceutically effective amount of the
above-described compounds and a pharmaceutically acceptable carrier
or excipient. Such a composition is believed to modulate signal
transduction by a protein kinase, tyrosine kinase, or serine
threonine kinase either by inhibition of catalytic activity,
affinity to ATP or ability to interact with a substrate.
[0295] The present invention relates to compounds capable of
regulating and/or modulating protein kinase signal transduction and
more particularly receptor and non-receptor protein kinase signal
transduction.
[0296] Receptor tyrosine kinase mediated signal transduction is
initiated by extracellular interaction with a specific growth
factor (ligand), followed by receptor dimerization, transient
stimulation of the intrinsic protein tyrosine kinase activity and
phosphorylation. Binding sites are thereby created for
intracellular signal transduction molecules and lead to the
formation of complexes with a spectrum of cytoplasmic signaling
molecules that facilitate the appropriate cellular response (e.g.,
cell division, metabolic effects and responses to the extracellular
microenvironment).
[0297] It has been shown that tyrosine phosphorylation sites in
growth factor receptors function as high-affinity binding sites for
SH2 (src homology) domains of signaling molecules. Several
intracellular substrate proteins that associate with receptor
tyrosine kinases have been identified. They may be divided into two
principal groups: (1) substrates which have a catalytic domain; and
(2) substrates which lack such domain but serve as adapters and
associate with catalytically active molecules. The specificity of
the interactions between receptors and SH2 domains of their
substrates is determined by the amino acid residues immediately
surrounding the phosphorylated tyrosine residue. Differences in the
binding affinities between SH2 domains and the amino acid sequences
surrounding the phosphotyrosine residues on particular receptors
are consistent with the observed differences in their substrate
phosphorylation profiles. These observations suggest that the
function of each receptor tyrosine kinase is determined not only by
its pattern of expression and ligand availability but also by the
array of downstream signal transduction pathways that are activated
by a particular receptor. Thus, phosphorylation provides an
important regulatory step which determines the selectivity of
signaling pathways recruited by specific growth factor receptors,
as well as differentiation factor receptors.
[0298] Protein kinase signal transduction results in, among other
responses, cell proliferation, differentiation and metabolism.
Abnormal cell proliferation may result in a wide array of disorders
and diseases, including the development of neoplasia such as
carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis,
arteriosclerosis, arthritis and diabetic retinopathy (or other
disorders related to uncontrolled angiogenesisand/or
vasculogenesis, e.g. macular degeneration).
[0299] This invention is therefore directed to compounds which
regulate, modulate and/or inhibit protein kinase signal
transduction by affecting the enzymatic activity of the PKs and
interfering with the signal transduced by such proteins. More
particularly, the present invention is directed to compounds which
regulate, modulate and/or inhibit the protein kinase mediated
signal transduction pathways as a therapeutic approach to cure many
kinds of solid tumors, including but not limited to carcinoma,
sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma,
astrocytoma, melanoma and myoblastoma. Indications may include, but
are not limited to brain cancers, bladder cancers, ovarian cancers,
gastric cancers, pancreas cancers, colon cancers, blood cancers,
lung cancers and bone cancers.
[0300] The present invention concerns also processes for preparing
the compounds of Formula I and of Formula II. The compounds of
formula I and of formula II according to the invention can be
prepared analogously to conventional methods as understood by the
person skilled in the art of synthetic organic chemistry. The
following Synthetic Schemes set forth below, illustrate how the
compounds according to the invention can be made.
##STR00088##
##STR00089##
##STR00090##
##STR00091##
##STR00092##
##STR00093##
##STR00094##
##STR00095##
##STR00096##
##STR00097##
[0301] At this stage, those skilled in the art will appreciate that
many additional compounds that fall under the scope of the
invention may be prepared by performing various common chemical
reactions. Details of certain specific chemical transformations are
provided in the examples.
[0302] Those skilled in the art will be able to routinely modify
and/or adapt the following scheme to synthesize any compounds of
the invention covered by Formula I and of Formula II. The present
invention is not to be limited in scope by the exemplified
embodiments which are intended as illustrations of single aspects
of the invention only. Indeed, various modifications of the
invention in addition to those described herein will become
apparent to those skilled in the art from the foregoing
description.
DETAILED DESCRIPTION OF THE INVENTION
[0303] The present invention relates to a method of regulating,
modulating or inhibiting protein kinases, whether of the receptor
or non-receptor class, for the prevention and/or treatment of
disorders related to unregulated protein kinase signal
transduction, including cell growth, metabolic, and blood vessel
proliferative disorders, which comprises administering a
pharmaceutical composition comprising a therapeutically effective
amount of at least one kinase inhibitor as described herein.
[0304] In another aspect, the invention provides the use of at
least one kinase inhibitor for the manufacture of a medicament for
the treatment of a disease or a condition mediated by tyrosine
kinases in a mammal.
[0305] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. As used herein, the use of the singular includes the
plural unless specifically stated otherwise.
[0306] It will be readily apparent to those skilled in the art that
some of the compounds of the invention may contain one or more
asymmetric centers, such that the compounds may exist in
enantiomeric as well as in diastereomeric forms. Unless it is
specifically noted otherwise, the scope of the present invention
includes all enantiomers, diastereomers and racemic mixtures. Some
of the compounds of the invention may form salts with
pharmaceutically acceptable acids or bases, and such
pharmaceutically acceptable salts of the compounds described herein
are also within the scope of the invention.
[0307] The present invention includes all pharmaceutically
acceptable isotopically enriched compounds. Any compound of the
invention may contain one or more isotopic atoms enriched or
different than the natural ratio such as deuterium .sup.2H (or D)
in place of hydrogen .sup.1H (or H) or use of .sup.13C enriched
material in place of .sup.12C and the like. Similar substitutions
can be employed for N, O and S. The use of isotopes may assist in
analytical as well as therapeutic aspects of the invention. For
example, use of deuterium may increase the in vivo half-life by
altering the metabolism (rate) of the compounds of the invention.
These compounds can be prepared in accord with the preparations
described by use of isotopically enriched reagents.
[0308] The following examples are for illustrative purposes only
and are not intended, nor should they be construed as limiting the
invention in any manner. Those skilled in the art will appreciate
that variations and modifications of the following examples can be
made without exceeding the spirit or scope of the invention.
[0309] As will be evident to those skilled in the art, individual
isomeric forms can be obtained by separation of mixtures thereof in
conventional manner. For example, in the case of diasteroisomeric
isomers, chromatographic separation may be employed.
[0310] Compound names were generated with ACDLabs version 12.5.
Some of the intermediate and reagent names used in the examples
were generated with software such as Chem Bio Draw Ultra version
12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.
[0311] In general, characterization of the compounds is performed
according to the following methods; NMR spectra are recorded on 300
or 600 MHz Varian and acquired at room temperature. Chemical shifts
are given in ppm referenced either to internal TMS or to the
solvent signal.
[0312] All the reagents, solvents, catalysts for which the
synthesis is not described are purchased from chemical vendors such
as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR,
Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge,
Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle,
Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some
known intermediates, were prepared according to published
procedures.
[0313] Usually the compounds of the invention were purified by
medium pressure liquid chromatography, unless noted otherwise.
Preparation 1
##STR00098##
[0314] tert-butyl
{2-[2-amino-5-({[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]amino}carbon-
yl)pyridin-3-yl]-1-benzothien-5-yl}carbamate
[0315] To the degassed mixture of
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-iodonicotinamid-
e (1.19 g, 3.51 mmol, 1 eq),
5-tert-butoxycarbonylaminobenzothiophene-2-boronic acid (1.52 g,
1.15 eq), and aq sodium carbonate (2M, 5.27 mL, 3 eq) in dioxane
(7.5 mL) was added Ph.sub.3P (184 mg, 0.2 eq) and Pd(OAc).sub.2 (79
mg, 0.1 eq). The mixture was heated to 50.degree. C. with vigorous
stirring for 30 minutes. The reaction mixture was then partitioned
between aq NH.sub.4Cl and EtOAc. The organic layer was isolated,
washed with sat aq NaHCO.sub.3, brine, and finally dried with
anhydrous sodium sulfate.
[0316] The upper solution was decanted, concentrated, and the foamy
oily residue was subject to a gradient column chromatography
(EtOAc-Hex 3:1 to 6:1) yielding tert-butyl
{2-[2-amino-5-({[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]amino}carbon-
yl)pyridin-3-yl]-1-benzothien-5-yl}carbamate as a white solid in
amount of 1.274 g (79%).
Preparation 2
##STR00099##
[0317]
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..su-
p.4-sulfanylidene]nicotinamide
[0318] To the mixture of tert-butyl
{2-[2-amino-5-({[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]amino}carbon-
yl)pyridin-3-yl]-1-benzothien-5-yl}carbamate (1.23 g, 2.67 mmol, 1
eq) in dichloromethane (6 mL) at 0.degree. C. was added dropwise
trifluoroacetic acid (5.16 mL, 20 eq). During this process the
reaction mixture became a brown solution. The reaction was stirred
at 0.degree. C. for 15 minutes and then at room temperature for 3
hours. The reaction was partitioned between DCM and cold saturated
aq NaHCO.sub.3. The organic layer was isolated, washed with brine
and dried with anhydrous sodium sulfate. The clear layer was
decanted, concentrated, and the brown solid residue was treated
with EtOAc. An orange colored solid was obtained upon filtration
giving
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..s-
up.4-sulfanylidene]nicotinamide in amount of 0.837 g (87%).
Example 1
##STR00100##
[0319]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-[5-({[(3--
methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide
[0320] To the solution of
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide (72 mg, 0.2 mmol. 1 eq) in anhydrous DMF
(2 mL) at room temperature was added dropwise m-tolylisocyanate
(0.03 mL, 1.2 eq). After the reaction solution was stirred at rt
for 2 hours, it was diluted with EtOAc, washed sequentially with
saturated aq NaHCO.sub.3, aq NH.sub.4Cl, brine, and finally dried
with anhydrous sodium sulfate. The organic layer was decanted,
concentrated, and the solid residue was triturated with DCM with
stirring. A lightly pink solid was obtained upon filtration to
yield
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-[5-({[(3-methyl-
phenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide in
amount of 91 mg (92%).
[0321] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.78 (s, 1H), 8.61 (s,
1H), 8.61 (d, J=2.1 Hz, 1H), 8.10 (dd, J=2.1, 0.3 Hz, 1H), 8.02 (d,
J=2.1 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.59 (s, 1H), 7.37 (dd,
J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.16 (t,
J=7.8 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.76 (s, 2H), 3.44 (s, 6H),
2.29 (s, 3H).
Example 2
##STR00101##
[0322]
6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-be-
nzothien-2-yl]-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]nicotinamide
[0323] In a manner similar to that described in Example 1,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 2-chloro-1-fluoro-4-isocyanatobenzene
were converted to the title compound.
[0324] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.91 (d, J=4.7 Hz, 2H),
8.61 (d, J=2.3 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.3 Hz,
1H), 7.88 (d, J=8.5 Hz, 1H), 7.83 (dd, J=6.7, 2.1 Hz, 1H), 7.59 (s,
1H), 7.38 (dd, J=8.8, 2.1 Hz, 1H), 7.32-7.35 (m, 2H), 6.75 (s, 2H),
3.44 (s, 6H).
Example 3
##STR00102##
[0325]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-[5-({[(2--
fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide
[0326] In a manner similar to that described in Example 1,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 1-fluoro-2-isocyanato-4-methylbenzene
were converted to the title compound.
[0327] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.18 (s, 1H), 8.61 (d,
J=2.1 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H),
8.01-8.04 (m, 2H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.35 (dd,
J=8.5, 2.1 Hz, 1H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 6.79-6.82 (m,
1H), 6.75 (s, 2H), 3.44 (s, 6H), 2.28 (s, 3H).
Example 4
##STR00103##
[0328]
6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}-N-[dimethy-
l(oxido)-.lamda..sup.4-sulfanylidene]nicotinamide
[0329] In a manner similar to that described in Example 1,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and isocyanatobenzene were converted to
the title compound.
[0330] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.80 (s, 1H), 8.69 (s,
1H), 8.60 (d, J=2.3 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.3
Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.48 (dd, J=8.5, 0.9
Hz, 2H), 7.37 (dd, J=8.5, 2.1 Hz, 1H), 7.29 (dd, J=8.2, 7.6 Hz,
2H), 6.96-6.99 (m, 1H), 6.75 (s, 2H), 3.44 (s, 6H)
Example 5
##STR00104##
[0331]
6-amino-5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-
amino]-1-benzothien-2-yl}-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]n-
icotinamide
[0332] In a manner similar to that described in Example 1,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and
1-chloro-4-isocyanato-2-(trifluoromethyl)benzene were converted to
the title compound.
[0333] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.30 (br. s., 1H), 9.08
(br. s., 1H), 8.61 (d, J=2.1 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.11
(d, J=1.8 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),
7.60-7.67 (m, 3H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 6.76 (s, 2H), 3.44
(s, 6H).
Example 6
##STR00105##
[0334]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[({[2--
fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}n-
icotinamide
[0335] In a manner similar to that described in Example 1,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene were converted to
the title compound.
[0336] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.31 (s, 1H), 8.93 (d,
J=2.6 Hz, 1H), 8.67 (dd, J=7.3, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz,
1H), 8.15 (d, J=2.1 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.91 (d, J=8.5
Hz, 1H), 7.62 (s, 1H), 7.51 (dd, J=10.6, 8.8 Hz, 1H), 7.38-7.41 (m,
1H), 7.36 (dd, J=8.5, 2.1 Hz, 1H), 6.77 (s, 2H), 3.44 (s, 6H).
Example 7
##STR00106##
[0337] methyl
6-amino-5-{5-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzot-
hien-2-yl}nicotinate
[0338] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-isocyanato-3-(trifluoromethyl)benzene were converted to the title
compound.
[0339] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.08 (s, 1H), 8.94 (s,
1H), 8.57 (d, J=2.3 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.06 (t, J=1.5
Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.63 (s,
1H), 7.59 (d, J=8.8 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.40 (dd,
J=8.5, 2.1 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.01 (br. s., 2H), 3.81
(s, 3H).
Example 8
##STR00107##
[0340] methyl
6-amino-5-{5-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-
-1-benzothien-2-yl}nicotinate
[0341] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene were converted to
the title compound.
[0342] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.31 (s, 1H), 8.93 (d,
J=2.6 Hz, 1H), 8.67 (dd, J=7.3, 2.1 Hz, 1H), 8.58 (d, J=2.1 Hz,
1H), 8.16 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.91 (d, J=8.8
Hz, 1H), 7.65 (s, 1H), 7.51 (dd, J=10.7, 8.9 Hz, 1H), 7.38-7.42 (m,
1H), 7.37 (dd, J=8.7, 2.2 Hz, 1H), 7.02 (br. s., 2H), 3.81 (s,
3H).
Example 9
##STR00108##
[0343] methyl
6-amino-5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-
-1-benzothien-2-yl}nicotinate
[0344] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-chloro-4-isocyanato-2-(trifluoromethyl)benzene were converted to
the title compound.
[0345] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.20 (s, 1H), 9.00 (s,
1H), 8.57 (d, J=2.3 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.12 (d, J=2.1
Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.61-7.67
(m, 3H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (br. s., 2H), 3.81 (s,
3H).
##STR00109##
Example 10
methyl
6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-be-
nzothien-2-yl]nicotinate
[0346] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-fluoro-2-isocyanato-4-methylbenzene were converted to the title
compound.
[0347] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.19 (s, 1H), 8.57 (d,
J=2.1 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.03
(dd, J=7.9, 1.8 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.89 (d, J=8.8 Hz,
1H), 7.62 (s, 1H), 7.36 (dd, J=8.5, 2.1 Hz, 1H), 7.11 (dd, J=11.3,
8.4 Hz, 1H), 7.01 (br. s., 2H), 6.79-6.82 (m, 1H), 3.81 (s, 3H),
2.28 (s, 3H)
Preparation 3
##STR00110##
[0348] methyl
6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate
[0349] To the degassed mixture of methyl 6-amino-5-iodonicotinate
(4.17 g, 15 mmol, 1 eq),
{[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-5-yl]-
-carbamic acid tert-butyl ester} (6.47 g, 1.15 eq), and aq sodium
carbonate (2M, 22.5 mL, 3 eq) in dioxane (30 mL) was added
Ph.sub.3P (393 mg, 0.1 eq) and Pd(OAc).sub.2 (340 mg, 0.1 eq). The
mixture was heated to 50.degree. C. with vigorous stirring for 45
minutes. The reaction mixture was then partitioned between aq
NH.sub.4Cl and EtOAc. The organic layer was isolated, washed with
sat aq NaHCO.sub.3, brine, and finally dried with anhydrous sodium
sulfate. The upper solution-layer was decanted, concentrated, and
the solid residue was treated with EtOAc-Hex (1:4) with stirring at
room temperature for 3 hours. methyl
6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate
was obtained upon filtration as a slightly green-yellowish
solid.
[0350] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.48 (br. s., 1H), 8.56
(d, J=2.1 Hz, 1H), 8.08 (br. s., 1H), 7.93 (d, J=2.3 Hz, 1H), 7.84
(d, J=8.5 Hz, 1H), 7.59 (s, 1H), 7.41 (dd, J=8.8, 2.1 Hz, 1H), 7.00
(br. s., 2H), 3.81 (s, 3H), 1.50 (s, 9H)
Preparation 4
##STR00111##
[0351] methyl 6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate
[0352] To the above obtained crude solid of methyl
6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate
(15 mmol, 1 eq) in dichloromethane (25 mL) at 0.degree. C. was
added dropwise trifluoroacetic acid (11.7 mL, 10 eq). During this
process the reaction mixture became a brown solution. After the
reaction was stirred at 0.degree. C. for 10 minutes and at room
temperature for 5 hours, it was slowly poured into an ice-cooled
saturated aqueous sodium bicarbonate solution with stirring. When
all the bubbling ceased, the mixture was extracted with
dichloromethane, which was washed with brine and dried with
anhydrous sodium sulfate. The upper brown solution was decanted,
concentrated to a lesser amount, and the occurring solid mixture
was treated with EtOAc-Hex (1:1). A green-yellowish solid was
obtained upon filtration which was further subject to
chromatography (MeOH-DCM 1:100 to 1:20). The corresponding product
fractions were collected, concentrated, and triturated with
EtOAc-Hex (1:4) giving methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate as a slightly
yellow solid in amount of 3.48 g upon filtration with a yield of
78% for two steps.
[0353] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.54 (d, J=2.1 Hz, 1H),
7.91 (d, J=2.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 6.97
(d, J=2.1 Hz, 1H), 6.94 (br. s., 2H), 6.74 (dd, J=8.5, 2.1 Hz, 1H),
5.13 (s, 2H), 3.80 (s, 3H)
Example 11
##STR00112##
[0354] methyl
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinate
[0355] To the solution of methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate (120 mg, 0.4 mmol.
1 eq) in anhydrous THF (4 mL) at room temperature was added
dropwise m-tolylisocyanate (0.051 mL, 1 eq). After the reaction was
stirred at room temperature for 4 hours, the solid appeared in the
reaction was directly filtered to give methyl
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinate as a white solid in amount of 84 mg.
[0356] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.78 (s, 1H), 8.61 (s,
1H), 8.57 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3
Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.61 (s, 1H), 7.38 (dd, J=8.7, 2.2
Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.16 (t, J=7.8 Hz,
1H), 7.01 (br. s., 2H), 6.80 (d, J=7.3 Hz, 1H), 3.81 (s, 3H), 2.29
(s, 3H).
Example 12
##STR00113##
[0357] methyl
6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothi-
en-2-yl]nicotinate
[0358] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
2-chloro-1-fluoro-4-isocyanatobenzene are converted to the title
compound.
[0359] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.90 (s, 1H), 8.90 (s,
1H), 8.57 (d, J=2.3 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.1
Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.83 (dd, J=6.9, 1.9 Hz, 1H), 7.62
(s, 1H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 7.31-7.35 (m, 2H), 7.01 (br.
s., 2H), 3.81 (s, 3H).
Example 13
##STR00114##
[0360] methyl
6-amino-5-[5-({[(4-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinate
[0361] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-isocyanato-4-methylbenzene are converted to the title
compound.
[0362] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.75 (s, 1H), 8.57 (d,
J=2.1 Hz, 2H), 8.09 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.87
(d, J=8.8 Hz, 1H), 7.61 (s, 1H), 7.34-7.39 (m, 3H), 7.09 (d, J=8.2
Hz, 2H), 7.01 (br. s., 2H), 3.81 (s, 3H), 2.25 (s, 3H).
Example 14
##STR00115##
[0363] methyl
6-amino-5-[5-({[(2-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinate
[0364] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
1-fluoro-2-isocyanatobenzene are converted to the title
compound.
[0365] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.21 (s, 1H), 8.57-8.59
(m, 2H), 8.19 (td, J=8.3, 1.6 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.94
(d, J=2.1 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.37 (dd,
J=8.8, 2.1 Hz, 1H), 7.25 (ddd, J=11.7, 8.1, 1.3 Hz, 1H), 7.15 (t,
J=7.8 Hz, 1H), 6.99-7.04 (m, 3H), 3.81 (s, 3H).
Example 15
##STR00116##
[0366] methyl
6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}nicotinate
[0367] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
isocyanatobenzene are converted to the title compound.
[0368] .sup.1H NMR (DMSO-d.sub.6) .quadrature.: 8.81 (s, 1H), 8.69
(s, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.94 (d,
J=2.3 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.46-7.49 (m,
2H), 7.38 (dd, J=8.5, 2.1 Hz, 1H), 7.27-7.31 (m, 2H), 7.01 (br. s.,
2H), 6.98 (tt, J=7.3, 1.0 Hz, 1H), 3.81 (s, 3H).
Example 16
##STR00117##
[0369] methyl
6-amino-5-[5-({[(2,4-difluorophenyl)amino]carbonyl}amino)-1-benzothien-2--
yl]nicotinate
[0370] In a manner similar to that described in Example 11, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
2,4-difluoro-1-isocyanatobenzene are converted to the title
compound.
[0371] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.15 (s, 1H), 8.57 (d,
J=2.3 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.09-8.14 (m, 2H), 7.94 (d,
J=2.1 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.37 (dd,
J=8.5, 2.1 Hz, 1H), 7.32 (ddd, J=11.5, 8.7, 2.9 Hz, 1H), 7.04-7.08
(m, 1H), 7.01 (br. s., 2H), 3.81 (s, 3H).
Example 17
##STR00118##
[0372]
6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-be-
nzothien-2-yl]nicotinic acid
[0373] In a manner similar to that described in Example 19, methyl
6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothi-
en-2-yl]nicotinate was converted to the title compound.
[0374] .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.65 (br. s., 1H), 8.96
(d, J=3.5 Hz, 2H), 8.55 (d, J=2.3 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H),
7.95 (d, J=2.3 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.80-7.86 (m, 1H),
7.62 (s, 1H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 7.30-7.36 (m, 2H), 6.99
(br. s., 2H).
Example 18
##STR00119##
[0375]
6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-be-
nzothien-2-yl]nicotinic acid
[0376] In a manner similar to that described in Example 19, methyl
6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothi-
en-2-yl]nicotinate was converted to the title compound.
[0377] .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.73 (br. s., 1H), 9.27
(s, 1H), 8.51-8.58 (m, 2H), 8.14 (d, J=2.1 Hz, 1H), 8.02 (dd,
J=7.9, 1.8 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H),
7.63 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.04-7.20 (m, 3H), 6.80
(ddd, J=7.7, 5.2, 2.1 Hz, 1H), 2.28 (s, 3H)
Example 19
##STR00120##
[0378]
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien--
2-yl]nicotinic acid
[0379] To the stirring mixture of methyl
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinate (420 mg, 0.972 mmol, 1 eq) in MeOH--H.sub.2O (3:1, 20 mL)
at room temperature was added potassium hydroxide pellets (272 mg,
5 eq) and the reaction mixture was stirred at 65.degree. C. for
total of two hours, at which time the reaction mixture became a
clear yellow solution. The solution was concentrated under reduced
pressure to remove most part of methanol. The mixture was then
cooled in an ice-bath, concentrated hydrochloride was added
dropwise, and the pH was adjusted to about 3. After the mixture was
stirred for about another 30 minutes, it was filtered through a
Buchner funnel, rinsed with water, and
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinic acid was obtained as a yellow solid in quantitative
yield.
[0380] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.09 (s, 1H), 8.88 (s,
1H), 8.55 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.1
Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.29-7.45 (m, 4H),
7.26 (d, J=8.2 Hz, 1H), 7.12-7.19 (m, 1H), 6.79 (d, J=7.3 Hz, 1H),
2.28 (s, 3H)
Example 20
##STR00121##
[0381]
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien--
2-yl]nicotinamide
[0382] To a seal tube containing
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinic (84 mg, 0.2 mmol, 1 eq), DMAP (5 mg, 0.2 eq), and EDCI
(46.1 mg, 1.2 eq) in anhydrous THF (3 mL) at room temperature,
gaseous ammonia was bubbled through for about 5 minutes. The tube
was quickly capped and the reaction was heated at 60.degree. C. for
one hour. TLC indicated the reaction did not proceed.
[0383] After the reaction was cooled to room temperature, to the
reaction mixture was added anhydrous DMF (3 mL),
diisopropylethylamine (0.2 mL, 5 eq), ammonium chloride (32.1 mg, 3
eq), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (97.3 mg, 1.1 eq). After the reaction was
stirred at 60.degree. C. for 30 minutes, it was partitioned between
ethyl acetate and aqueous ammonium chloride. The organic layer was
isolated, washed with saturated aqueous sodium bicarbonate, brine,
and dried with anhydrous sodium sulfate. The clear solution was
decanted, concentrated, the solid residue was subject to a gradient
column chromatography (from DCM to MeOH-DCM 1:1).
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinamide was obtained as white solid in two portions, 38 mg from
the chromatography fractions and 16 mg from a remainder on top of
the syringe column. Both were confirmed by proton NMR.
[0384] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.81 (s, 1H), 8.63 (s,
1H), 8.55 (d, J=2.1 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.3
Hz, 1H), 7.95-6.88 (br. s., 2H), 7.86 (d, J=8.5 Hz, 1H), 7.59 (s,
1H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 1H),
7.13-7.19 (m, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.48 (s, 2H), 2.29 (s,
3H).
Example 21
##STR00122##
[0385] methyl
4-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-
-yl]pyridin-3-yl}carbonyl)amino]butanoate
[0386] In a manner similar to that described in Example 22,
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinic acid was converted to the title compound.
[0387] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.80 (s, 1H), 8.62 (s,
1H), 8.52 (d, J=2.3 Hz, 1H), 8.33 (t, J=5.6 Hz, 1H), 8.10 (d, J=2.1
Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.60 (s,
1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.22-7.28 (m, 1H),
7.13-7.20 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.61 (s, 2H), 3.58 (s,
3H), 3.21-3.30 (m, 2H), 2.37 (t, J=7.3 Hz, 2H), 2.29 (s, 3H), 1.77
(quin, J=7.1 Hz, 2H)
Example 22
##STR00123##
[0388] methyl
6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-
-yl]pyridin-3-yl}carbonyl)amino]hexanoate
[0389] The reaction mixture of
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinic acid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate
hydrochloride (43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI
(46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (3 mL) was
stirred and heated at 50.degree. C. for 2 hours. It was then
diluted with ethyl acetate, washed sequentially with aqueous
NH.sub.4Cl, saturated aqueous NaHCO.sub.3, and brine, and dried
with anhydrous sodium sulfate. The upper clear solution was
decanted, concentrated, and the solid residue was triturated with
EtOAc-Hex (3:1) yielding methyl
6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-
-yl]pyridin-3-yl}carbonyl)amino]hexanoate as a white solid in
amount of 83 mg.
[0390] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.79 (s, 1H), 8.62 (s,
1H), 8.51 (d, J=2.3 Hz, 1H), 8.29 (t, J=5.6 Hz, 1H), 8.10 (d, J=1.8
Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.60 (s,
1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.22-7.28 (m, 1H),
7.13-7.20 (m, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.60 (s, 2H), 3.57 (s,
3H), 3.22 (q, J=6.4 Hz, 2H), 2.26-2.35 (m, 5H), 1.53 (tt, J=14.5,
7.3 Hz, 4H), 1.26-1.36 (m, 2H).
Example 23
##STR00124##
[0391]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea
[0392] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene are converted to
the title compound.
[0393] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.30 (s, 1H), 8.92 (d,
J=2.6 Hz, 1H), 8.67 (dd, J=7.3, 2.1 Hz, 1H), 8.24 (d, J=1.8 Hz,
1H), 8.12 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.8
Hz, 1H), 7.61 (s, 1H), 7.46-7.55 (m, 1H), 7.33-7.43 (m, 2H), 6.53
(s, 2H), 1.28 (s, 12H).
Example 24
##STR00125##
[0394]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-[3-(trifluoromethyl)phenyl]urea
[0395] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and 1-isocyanato-3-(trifluoromethyl)benzene are
converted to the title compound.
[0396] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.07 (s, 1H), 8.92 (s,
1H), 8.24 (d, J=1.8 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.06 (s, 1H),
7.87 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.56-7.62 (m, 2H),
7.48-7.55 (m, 1H), 7.39 (dd, J=8.6, 2.2 Hz, 1H), 7.31 (d, J=7.6 Hz,
1H), 6.53 (s, 2H), 1.28 (s, 12H)
Example 25
##STR00126##
[0397]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-[4-chloro-3-(trifluoromethyl)phenyl]urea
[0398] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and
1-chloro-4-isocyanato-2-(trifluoromethyl)benzene are converted to
the title compound.
[0399] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.19 (s, 1H), 8.98 (s,
1H), 8.24 (d, J=1.8 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.1
Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.62-7.66
(m, 2H), 7.59 (s, 1H), 7.39 (dd, J=8.5, 2.1 Hz, 1H), 6.53 (s, 2H),
1.28 (s, 12H)
Example 26
##STR00127##
[0400]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-(2-fluoro-5-methylphenyl)urea
[0401] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and 1-fluoro-2-isocyanato-4-methylbenzene are
converted to the title compound.
[0402] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.18 (s, 1H), 8.50 (d,
J=2.6 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.03
(dd, J=7.9, 1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz,
1H), 7.58 (s, 1H), 7.36 (dd, J=8.8, 2.1 Hz, 1H), 7.11 (dd, J=11.4,
8.2 Hz, 1H), 6.77-6.84 (m, 1H), 6.53 (s, 2H), 2.28 (s, 3H), 1.28
(s, 12H)
Example 27
##STR00128##
[0403]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-(3-chloro-4-fluorophenyl)urea
[0404] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and 2-chloro-1-fluoro-4-isocyanatobenzene are
converted to the title compound.
[0405] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.89 (s, 1H), 8.88 (s,
1H), 8.24 (d, J=1.8 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.81-7.89 (m,
2H), 7.69 (d, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.31-7.41 (m, 3H), 6.52
(s, 2H), 1.28 (s, 12H)
Example 28
##STR00129##
[0406]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-(3-ethylphenyl)urea
[0407] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and 1-ethyl-3-isocyanatobenzene are converted
to the title compound.
[0408] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.76 (s, 1H), 8.62 (s,
1H), 8.24 (d, J=1.8 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.8
Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.34-7.39 (m, 2H),
7.23-7.30 (m, 1H), 7.15-7.23 (m, 1H), 6.83 (d, J=7.3 Hz, 1H), 6.52
(s, 2H), 2.58 (q, J=7.5 Hz, 2H), 1.28 (s, 12H), 1.19 (t, J=7.6 Hz,
3H)
Example 29
##STR00130##
[0409]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea
[0410] To the solution of
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine (734.6 mg, 2 mmol. 1 eq) in anhydrous THF (10
mL) at room temperature was added dropwise m-tolylisocyanate (0.251
mL, 1 eq). After the reaction was stirred at room temperature for 4
hours, it was partitioned between ethyl acetate and aqueous
ammonium chloride. The organic layer was isolated, washed with
saturated aqueous sodium bicarbonate, brine, and dried with
anhydrous sodium sulfate. The upper solution layer was decanted,
concentrated, and the solid residue was subject to a gradient
column chromatography (DCM to MeOH-DCM 1:5). The products'
fractions were collected, concentrated, the solid was triturated
with EtOAc-Hex (1:7) yielding
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl-
]-1-benzothien-5-yl}-3-(3-methylphenyl)urea as a white powder upon
filtration in amount of 407 mg.
[0411] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.77 (s, 1H), 8.60 (s,
1H), 8.24 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.85 (d, J=8.5
Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.37 (dd, J=8.6, 2.2
Hz, 1H), 7.32 (s, 1H), 7.22-7.28 (m, 1H), 7.13-7.20 (m, 1H), 6.79
(d, J=7.3 Hz, 1H), 6.52 (s, 2H), 2.29 (s, 3H), 1.28 (s, 12H).
Example 30
##STR00131##
[0412]
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]-1-benzothien-5-yl}-3-phenylurea
[0413] In a manner similar to that described in Example 29,
3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)pyridin-2-amine and isocyanatobenzene are converted to the
title compound.
[0414] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.78 (s, 1H), 8.68 (s,
1H), 8.24 (d, J=1.5 Hz, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.85 (d, J=8.8
Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=7.6 Hz,
2H), 7.38 (dd, J=8.8, 1.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 2H),
6.94-7.01 (m, 1H), 6.53 (s, 2H), 1.28 (s, 12H).
Example 31
##STR00132##
[0415]
{6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-
-2-yl]pyridin-3-yl}boronic acid
[0416] To the solution of
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl-
]-1-benzothien-5-yl}-3-(3-methylphenyl)urea (500 mg, 1 mmol, 1 eq)
in tetrahydrofuran (6 mL) at room temperature was added dropwise
aqueous HCl (3 N, 6 mL) and the reaction was stirred at room
temperature for 4 hours. The reaction mixture was filtered directly
through a Buchner funnel, rinsed with isopropanol, followed by
i-PrOH--H.sub.2O (1:1) to give
{6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]-
pyridin-3-yl}boronic acid as a white solid in amount of 384 mg.
[0417] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.26 (s, 1H), 9.02 (s,
1H), 8.54 (br. s., 2H), 8.27 (dd, J=12.0, 1.5 Hz, 2H), 8.20 (d,
J=2.1 Hz, 1H), 8.16 (br. s., 2H), 7.94 (d, J=8.8 Hz, 1H), 7.65 (s,
1H), 7.42 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=8.5 Hz,
1H), 7.12-7.19 (m, 1H), 6.79 (d, J=7.3 Hz, 1H), 2.28 (s, 3H).
Example 32
##STR00133##
[0418]
(6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}pyridin-3--
yl)boronic acid
[0419] In a manner similar to that described in Example 31,
1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl-
]-1-benzothien-5-yl}-3-phenylurea was converted to the title
compound.
[0420] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.13 (s, 1H), 8.97 (s,
1H), 8.52 (br. s., 2H), 8.26 (dd, J=6.4, 1.5 Hz, 2H), 8.19 (d,
J=1.8 Hz, 1H), 8.04 (br. s., 2H), 7.94 (d, J=8.8 Hz, 1H), 7.65 (s,
1H), 7.48 (d, J=7.3 Hz, 2H), 7.41 (dd, J=8.8, 2.1 Hz, 1H), 7.29 (t,
J=8.1 Hz, 2H), 6.94-7.01 (m, 1H)
Example 33
##STR00134##
[0421]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[(3-me-
thyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinamide
[0422] To the mixture of
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide (72 mg, 0.2 mmol, 1 eq) and
3-methylfuranylcarboxylic acid (25.2 mg, 1 eq) in dichloroethane (2
mL) at 50.degree. C. was added catalytic amount of DMAP and EDCI
(46.1 mg, 1.2 eq). The reaction was stirred at that temperature for
1 h and then at room temperature for 20 h. It was then partitioned
between EtOAc and saturated aq NaHCO.sub.3. The organic layer was
further washed with brine and then dried with anhydrous sodium
sulfate. The organic layer was decanted, concentrated, and the
residue was subject to a gradient column chromatography (EtOAc-Hex
2:1 to neat EtOAc) rendering
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[(3-methyl-2-
-furoyl)amino]-1-benzothien-2-yl}nicotinamide as white solid in
amount of 90 mg (96%).
[0423] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.17 (s, 1H), 8.61 (d,
J=2.1 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.92
(d, J=8.8 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.71 (dd, J=8.8, 2.1 Hz,
1H), 7.62 (s, 1H), 6.76 (s, 2H), 6.61 (d, J=1.5 Hz, 1H), 3.44 (s,
6H), 2.37 (s, 3H)
Example 34
##STR00135##
[0424]
6-amino-5-(5-{[4-chloro-3-(trifluoromethyl)benzoyl]amino}-1-benzoth-
ien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]nicotinamide
[0425] In a manner similar to that described in Example 33,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 4-chloro-3-(trifluoromethyl)benzoic
acid were converted to the title compound.
[0426] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.66 (s, 1H), 8.62 (d,
J=2.1 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.31
(dd, J=8.2, 1.8 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.8 Hz,
1H), 7.95 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.5, 2.1 Hz, 1H), 7.68 (s,
1H), 6.79 (s, 2H), 3.44 (s, 6H)
Example 35
##STR00136##
[0427]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[(2-fl-
uoro-5-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinamide
[0428] In a manner similar to that described in Example 33,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 2-fluoro-5-methylbenzoic acid were
converted to the title compound.
[0429] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.50 (s, 1H), 8.61 (d,
J=2.3 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.95
(d, J=8.8 Hz, 1H), 7.66 (s, 1H), 7.62 (dd, J=8.7, 1.9 Hz, 1H), 7.50
(dd, J=6.5, 1.8 Hz, 1H), 7.36-7.40 (m, 1H), 7.22-7.26 (m, 1H), 6.78
(s, 2H), 3.44 (s, 6H), 2.36 (s, 3H)
Example 36
##STR00137##
[0430]
6-amino-5-[5-(benzoylamino)-1-benzothien-2-yl]-N-[dimethyl(oxido)-.-
lamda..sup.4-sulfanylidene]nicotinamide
[0431] In a manner similar to that described in Example 33,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and benzoic acid were converted to the
title compound.
[0432] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.39 (s, 1H), 8.61 (d,
J=2.1 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 8.00
(d, J=7.0 Hz, 2H), 7.95 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.7, 1.9 Hz,
1H), 7.66 (s, 1H), 7.59-7.63 (m, 1H), 7.53-7.57 (m, 2H), 6.78 (s,
2H), 3.44 (s, 6H)
Example 37
##STR00138##
[0433]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[(3-me-
thylbenzoyl)amino]-1-benzothien-2-yl}nicotinamide
[0434] In a manner similar to that described in Example 33,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 3-methylbenzoic acid were converted to
the title compound.
[0435] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.34 (s, 1H), 8.61 (d,
J=2.1 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.95
(d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J=6.7 Hz, 1H), 7.71 (dd,
J=8.5, 1.8 Hz, 1H), 7.65 (s, 1H), 7.40-7.44 (m, 2H), 6.78 (s, 2H),
3.44 (s, 6H), 2.42 (s, 3H)
Example 38
##STR00139##
[0436]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-(5-{[2-fl-
uoro-5-(trifluoromethyl)benzoyl]amino}-1-benzothien-2-yl)nicotinamide
[0437] In a manner similar to that described in Example 33,
6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide and 2-fluoro-5-(trifluoromethyl)benzoic
acid were converted to the title compound.
[0438] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.73 (s, 1H), 8.61 (d,
J=2.3 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.10 (dd, J=6.2, 2.1 Hz,
1H), 8.04 (d, J=2.1 Hz, 1H), 7.99-8.02 (m, 1H), 7.98 (d, J=8.8 Hz,
1H), 7.68 (s, 1H), 7.64 (t, J=9.1 Hz, 1H), 7.61 (dd, J=8.8, 2.1 Hz,
1H), 6.79 (s, 2H), 3.44 (s, 6H)
Example 39
##STR00140##
[0439] methyl
6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate
[0440] To the mixture of methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate (120 mg, 0.4 mmol,
1 eq) and 3-methylfuranylcarboxylic acid (50.4 mg, 1 eq) in
1,2-dichloroethane (3 mL) at 60.degree. C. was added catalytic
amount of DMAP (10 mg, 0.2 eq) and EDCI (92.2 mg, 1.2 eq). The
reaction was stirred at that temperature for 2 h and then
partitioned between EtOAc and saturated aq NaHCO.sub.3. The organic
layer was further washed with brine and then dried with anhydrous
sodium sulfate. The organic layer was decanted, concentrated, and
the solid residue which was treated with ethyl acetate with
stirring at room temperature for an hour. Methyl
6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate
was obtained upon filtration as a white solid in amount of 128
mg.
[0441] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.18 (s, 1H), 8.58 (d,
J=2.3 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.92
(d, J=8.8 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz,
1H), 7.64 (s, 1H), 7.02 (br. s., 2H), 6.61 (d, J=1.5 Hz, 1H), 3.81
(s, 3H), 2.37 (s, 3H)
Example 40
##STR00141##
[0442] methyl
6-amino-5-{5-[(3-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinate
[0443] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and 3-methylbenzoic
acid were converted to the title compound.
[0444] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.34 (s, 1H), 8.58 (d,
J=2.1 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 7.94-7.97 (m, 2H), 7.81 (s,
1H), 7.78 (d, J=6.7 Hz, 1H), 7.72 (dd, J=8.7, 1.9 Hz, 1H), 7.68 (s,
1H), 7.40-7.45 (m, 2H), 7.03 (br. s., 2H), 3.81 (s, 3H), 2.42 (s,
3H)
Example 41
##STR00142##
[0445] methyl
6-amino-5-{5-[(2-fluoro-5-methylbenzoyl)amino]-1-benzothien-2-yl}nicotina-
te
[0446] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
2-fluoro-5-methylbenzoic acid were converted to the title
compound.
[0447] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.51 (s, 1H), 8.58 (d,
J=2.1 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 7.94-7.97 (m, 2H), 7.68 (s,
1H), 7.63 (dd, J=8.7, 1.9 Hz, 1H), 7.50 (dd, J=6.5, 1.5 Hz, 1H),
7.36-7.40 (m, 1H), 7.24 (t, J=9.2 Hz, 1H), 7.03 (br. s., 2H), 3.81
(s, 3H), 2.36 (s, 3H)
Example 42
##STR00143##
[0448] methyl
6-amino-5-[5-(benzoylamino)-1-benzothien-2-yl]nicotinate
[0449] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and benzoic acid
were converted to the title compound.
[0450] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.39 (s, 1H), 8.58 (d,
J=2.3 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.96
(dd, J=5.6, 3.2 Hz, 2H), 7.73 (dd, J=8.8, 2.1 Hz, 1H), 7.68 (s,
1H), 7.59-7.63 (m, 1H), 7.53-7.58 (m, 2H), 7.04 (br. s., 2H), 3.81
(s, 3H)
Example 43
##STR00144##
[0451] methyl
6-amino-5-{5-[(3-chloro-4-fluorobenzoyl)amino]-1-benzothien-2-yl}nicotina-
te
[0452] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
3-chloro-4-fluorobenzoic acid were converted to the title
compound.
[0453] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.49 (s, 1H), 8.58 (d,
J=2.1 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.25 (dd, J=7.2, 2.2 Hz,
1H), 8.04 (ddd, J=8.7, 4.7, 2.2 Hz, 1H), 7.95-7.99 (m, 2H),
7.68-7.72 (m, 2H), 7.62 (t, J=9.0 Hz, 1H), 7.04 (br. s., 2H), 3.81
(s, 3H)
Example 44
##STR00145##
[0454] methyl
6-amino-5-(5-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}-1-benzothien-2--
yl)nicotinate
[0455] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
2-fluoro-5-(trifluoromethyl)benzoic acid were converted to the
title compound.
[0456] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.74 (s, 1H), 8.58 (d,
J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.10 (dd, J=6.2, 2.1 Hz,
1H), 7.99-8.02 (m, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.96 (d, J=2.1 Hz,
1H), 7.70 (s, 1H), 7.64-7.67 (m, 1H), 7.62 (dd, J=8.7, 1.9 Hz, 1H),
7.04 (br. s., 2H), 3.81 (s, 3H)
Example 45
##STR00146##
[0457] methyl
6-amino-5-{5-[(1-benzofuran-2-ylcarbonyl)amino]-1-benzothien-2-yl}nicotin-
ate
[0458] In a manner similar to that described in Example 39, methyl
6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and
benzofuran-2-carboxylic acid were converted to the title
compound.
[0459] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.68 (s, 1H), 8.58 (d,
J=2.3 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.96
(d, J=2.3 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.81 (d, J=0.6 Hz, 1H),
7.78 (dd, J=8.7, 1.9 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.70 (s, 1H),
7.50-7.54 (m, 1H), 7.37-7.40 (m, 1H), 7.05 (br. s., 2H), 3.81 (s,
3H)
Example 46
##STR00147##
[0460]
N-[2-(2-aminopyridin-3-yl)-1-benzothien-5-yl]-3-methylbenzamide
[0461] In a manner similar to that described in Example 39,
3-(5-aminobenzo[b]thiophen-2-yl)pyridin-2-amine and 3-methylbenzoic
acid were converted to the title compound.
[0462] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.33 (s, 1H), 8.40 (d,
J=1.8 Hz, 1H), 8.02 (dd, J=4.7, 1.8 Hz, 1H), 7.93 (d, J=8.8 Hz,
1H), 7.81 (s, 1H), 7.78 (d, J=6.7 Hz, 1H), 7.69 (dd, J=8.7, 1.9 Hz,
1H), 7.64 (s, 1H), 7.60 (dd, J=7.3, 1.8 Hz, 1H), 7.40-7.45 (m, 2H),
6.70 (dd, J=7.3, 5.0 Hz, 1H), 6.06 (s, 2H), 2.42 (s, 3H)
Example 47
##STR00148##
[0463] N-[2-(2-aminopyridin-3-yl)-1-benzothien-5-yl]benzamide
[0464] In a manner similar to that described in Example 39,
3-(5-aminobenzo[b]thiophen-2-yl)pyridin-2-amine and benzoic acid
were converted to the title compound.
[0465] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.38 (s, 1H), 8.40 (d,
J=1.8 Hz, 1H), 7.90-8.04 (m, 4H), 7.70 (dd, J=8.8, 1.8 Hz, 1H),
7.52-7.66 (m, 5H), 6.70 (dd, J=7.5, 4.8 Hz, 1H), 6.07 (s, 2H)
Example 48
##STR00149##
[0466]
2-(2-aminopyridin-3-yl)-N-(3-methylphenyl)-1-benzothiophene-5-carbo-
xamide
[0467] In a manner similar to that described in Example 51,
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and
m-toluidine were converted to the title compound.
[0468] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.27 (s, 1H), 8.48 (s,
1H), 8.13 (d, J=8.2 Hz, 1H), 8.04 (d, J=4.7 Hz, 1H), 7.95 (d, J=8.5
Hz, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.62 (t, J=8.2 Hz, 2H), 7.25
(t, J=7.8 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.72 (dd, J=7.2, 5.1 Hz,
1H), 6.10 (s, 2H), 2.33 (s, 3H)
Example 49
##STR00150##
[0469]
2-(2-aminopyridin-3-yl)-N-(5-tert-butylisoxazol-3-yl)-1-benzothioph-
ene-5-carboxamide
[0470] In a manner similar to that described in Example 51,
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and
5-(tert-butyl)isoxazol-3-amine were converted to the title
compound.
[0471] .sup.1H NMR (DMSO-d.sub.6) .delta.: 11.43 (s, 1H), 8.54 (s,
1H), 8.13 (d, J=8.5 Hz, 1H), 8.04 (dd, J=4.7, 1.5 Hz, 1H), 7.98
(dd, J=8.5, 1.5 Hz, 1H), 7.75 (s, 1H), 7.62 (dd, J=7.3, 1.5 Hz,
1H), 6.77 (s, 1H), 6.71 (dd, J=7.3, 4.7 Hz, 1H), 6.10 (s, 2H), 1.34
(s, 9H).
Example 50
##STR00151##
[0472]
2-(2-aminopyridin-3-yl)-N-(3-methylbenzyl)-1-benzothiophene-5-carbo-
xamide
[0473] In a manner similar to that described in Example 51,
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and
m-tolylmethanamine were converted to the title compound. .sup.1H
NMR (DMSO-d.sub.6) .delta.: 9.11 (t, J=5.9 Hz, 1H), 8.41 (s, 1H),
8.07 (d, J=8.2 Hz, 1H), 8.03 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd,
J=8.5, 1.2 Hz, 1H), 7.72 (s, 1H), 7.60 (dd, J=7.6, 1.5 Hz, 1H),
7.20-7.24 (m, 1H), 7.12-7.17 (m, 2H), 7.06 (d, J=7.6 Hz, 1H), 6.70
(dd, J=7.3, 5.0 Hz, 1H), 6.08 (s, 2H), 4.49 (d, J=5.9 Hz, 2H), 2.29
(s, 3H)
Preparation 5
##STR00152##
[0474] 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid
[0475] Benzothiophene-5-carboxylic acid (2 g, 11.2 mmol, 1 eq) was
dissolved in anhydrous THF (50 mL). To the solution was added
dropwise tert-BuLi pentane solution (1.7 M, 20 mL, 3 eq) at
-78.degree. C. for 5 minutes under nitrogen atmosphere. The
reaction mixture was allowed to warm to room temperature, stirred
for 30 minutes, and cooled to -78.degree. C. again, followed by an
addition of triisopropyl borate (3.97 mL, 1.5 eq). The reaction was
then allowed to warm to room temperature and stirred at that
temperature for one hour. To the reaction mixture was added
saturated aqueous ammonium chloride (50 mL) and 10% aqueous
potassium hydrogensulfate solution (50 mL) to adjust pH to 2. After
the mixture was stirred at room temperature for 30 minutes, it was
extracted with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. The upper
solution was decanted, concentrated, and the residue was suspended
in Hexane/CHCl.sub.3/MeOH (40:4:1). The solid was filtered, rinsed
with hexane. 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid
was obtained as a grayish solid in amount of 1.325 g (53%).
[0476] .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.94 (br. s., 1H), 8.57
(br. s., 2H), 8.49 (s, 1H), 8.05-8.09 (m, 2H), 7.90 (d, J=8.5 Hz,
1H).
Preparation 6
##STR00153##
[0477] 2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic
acid
[0478] To the degassed mixture of 2-amino-3-iodpyridine (1.12 g,
5.09 mmol, 1 eq), 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic
acid, [2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid (1.3
g, 1.15 eq)], and aqueous sodium carbonate (2M, 7.6 mL, 3 eq) in
dioxane (10 mL) was added Ph.sub.3P (267 mg, 0.2 eq) and
Pd(OAc).sub.2 (114.3 mg, 0.1 eq). The mixture was heated to
50.degree. C. with vigorous stirring for 30 minutes. The yellow
mixture was then partitioned between aq NH.sub.4Cl and
MeOH--CHCl.sub.3 (1:5). Some solids precipitation was observed.
After the pH was carefully adjusted to around 6, the whole mixture
was filtered through a Buchner funnel to obtain a yellow solid. The
solid was further triturated with MeOH/H.sub.2O to give
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid as a
white-off solid in amount of 1.18 g after dried in vacuo (86%).
[0479] .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.97 (br. s., 1H), 8.46
(s, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.03 (d, J=3.5 Hz, 1H), 7.90 (dd,
J=8.4, 1.3 Hz, 1H), 7.77 (s, 1H), 7.60 (dd, J=7.3, 1.2 Hz, 1H),
6.70 (dd, J=7.3, 5.0 Hz, 1H), 6.09 (br. s., 2H)
Example 51
##STR00154##
[0480]
2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophen-
e-5-carboxamide
[0481] The reaction mixture of
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid (54 mg,
0.2 mmol, 1 eq), 2-fluoro-5-methylaniline (0.048 mL, 2.1 eq), DMAP
(5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous
1,2-dichloroethane (2 mL) and anhydrous DMF (0.5 mL) was stirred
and heated at 60.degree. C. for 1 hour. It was then diluted with
ethyl acetate, washed sequentially with aqueous NH.sub.4Cl,
saturated aqueous NaHCO.sub.3, and brine, and finally dried with
anhydrous sodium sulfate. The upper, clear solution-layer was
decanted, concentrated, and the solid residue was subject to a
gradient column chromatography (EtOAc-Hex 1:4 to 1:1) to yield
2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophene-5-ca-
rboxamide as a white solid in amount of 39.8 mg.
[0482] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.14 (s, 1H), 8.49 (s,
1H), 8.13 (d, J=8.5 Hz, 1H), 8.04 (dd, J=4.7, 1.2 Hz, 1H), 7.95
(dd, J=8.5, 0.9 Hz, 1H), 7.77 (s, 1H), 7.62 (dd, J=7.3, 1.2 Hz,
1H), 7.45 (d, J=6.2 Hz, 1H), 7.18 (dd, J=10.0, 8.8 Hz, 1H),
7.06-7.09 (m, 1H), 6.71 (dd, J=7.3, 5.0 Hz, 1H), 6.10 (s, 2H), 2.32
(s, 3H).
Example 52
##STR00155##
[0483]
2-(2-aminopyridin-3-yl)-N-(3-chloro-4-fluorophenyl)-1-benzothiophen-
e-5-carboxamide
[0484] In a manner similar to that described in Example 51,
2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and
3-chloro-4-fluoroaniline were converted to the title compound.
[0485] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.54 (s, 1H), 8.47 (s,
1H), 8.16 (d, J=8.5 Hz, 1H), 8.13 (dd, J=6.7, 2.6 Hz, 1H), 8.04
(dd, J=4.7, 1.5 Hz, 1H), 7.94 (dd, J=8.5, 1.2 Hz, 1H), 7.76-7.79
(m, 2H), 7.62 (dd, J=7.3, 1.5 Hz, 1H), 7.44 (t, J=9.1 Hz, 1H), 6.71
(dd, J=7.3, 5.0 Hz, 1H), 6.10 (s, 2H)
Example 53
##STR00156##
[0486] methyl
5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-
-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate
[0487] To
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothi-
en-2-yl]nicotinic acid (418 mg, 1 mmol, 1 equiv.) and (S)-methyl
5-(S-methylsulfonimidoyl)pentanoate (232 mg, 1.2 equiv.) in
anhydrous DMF (6 mL) under nitrogen atmosphere was added
diisopropylethylamine (0.348 mL, 2.0 equiv.) and
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (486.5 mg, 1.1 equiv.). The reaction mixture
was heated to 60.degree. C. and stirred for 2 hours. After the
reaction was cooled to room temperature, it was diluted with EtOAc
and washed sequentially with saturated aqueous NaHCO.sub.3, brine,
aqueous NH.sub.4Cl, and brine. After the organic layer was dried
(anhydrous Na.sub.2SO.sub.4), it was decanted, concentrated, and
the brown oily residue was subject to a column chromatography
(EtOAc-Hex 1:4 to 6:1). methyl
5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-ben-
zothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate
was obtained as a yellow foam in amount of 394 mg (66%).
[0488] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.78 (s, 1H), 8.61 (s,
1H), 8.60 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H),
7.87 (d, J=8.5 Hz, 1H), 7.59 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H),
7.33 (s, 1H), 7.22-7.28 (m, 1H), 7.13-7.20 (m, 1H), 6.80 (d, J=7.6
Hz, 1H), 6.75 (s, 2H), 3.55-3.63 (m, 5H), 3.41 (s, 3H), 2.39 (t,
J=7.2 Hz, 2H), 2.29 (s, 3H), 1.76-1.87 (m, 2H), 1.63-1.74 (m,
2H)
Example 54
##STR00157##
[0489] methyl
5-[N-({6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-b-
enzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate
[0490] In a manner similar to that described in Example 53,
6-amino-5-(5-(3-(2-fluoro-5-methylphenyl)ureido)benzo[b]thiophen-2-yl)nic-
otinic acid and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate were
converted to the title compound.
[0491] .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.19 (s, 1H), 8.61 (d,
J=2.1 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H),
8.00-8.05 (m, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.36 (dd,
J=8.8, 2.1 Hz, 1H), 7.11 (dd, J=11.4, 8.2 Hz, 1H), 6.77-6.84 (m,
1H), 6.76 (s, 2H), 3.53-3.65 (m, 5H), 3.41 (s, 3H), 2.40 (t, J=7.0
Hz, 2H), 2.28 (s, 3H), 1.75-1.88 (m, 2H), 1.64-1.74 (m, 2H)
Example 55
##STR00158##
[0492] methyl
5-[N-({6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-b-
enzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate
[0493] In a manner similar to that described in Example 53,
6-amino-5-(5-(3-(3-chloro-4-fluorophenyl)ureido)benzo[b]thiophen-2-yl)nic-
otinic acid and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate were
converted to the title compound.
[0494] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.90 (s, 1H), 8.90 (s,
1H), 8.61 (d, J=2.3 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.3
Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.81-7.86 (m, 1H), 7.60 (s, 1H),
7.31-7.41 (m, 3H), 6.76 (s, 2H), 3.54-3.63 (m, 5H), 3.41 (s, 3H),
2.39 (t, J=7.2 Hz, 2H), 1.75-1.88 (m, 2H), 1.63-1.74 (m, 2H)
Preparation 7
[0495] S(CH.sub.2CH.sub.2CH.sub.2OTBDMS).sub.2
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane
[0496] To the solution of 3,3'-thiodipropanol (5 g, 32.6 mmol, 1
eq) and tert-butyldimethylsilyl chloride (13.18 g, 2.6 eq) in
anhydrous DMF (25 mL) at 0.degree. C. was added imidazole (11.21 g,
5 eq). After the reaction was stirred at room temperature for one
hour, it was partitioned between ethyl acetate and water. The
organic layer was isolated, washed once more with water, then
brine, and lastly dried with anhydrous sodium sulfate. The upper
clear solution was decanted, concentrated, and the oily residue was
subject to a column chromatography (EtOC-Hex: from 1:9 to 4:1).
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapent-
adecane, was obtained as clear oil in 12.32 g.
[0497] .sup.1H NMR (DMSO-d.sub.6) .delta.: 3.64 (t, J=6.2 Hz, 4H),
2.49-2.53 (m, 4H), 1.65-1.71 (m, 4H), 0.86 (s, 18H), 0.03 (s,
12H)
Preparation 8
[0498] O.dbd.S(CH.sub.2CH.sub.2CH.sub.2OTBDMS).sub.2
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane
8-oxide
[0499] A solution of sodium (meta)periodate (7.751 g, 1.1 eq) in
water (40 mL) was slowly poured into a solution of
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane,
(12.32 g, 1 eq) in methanol (150 mL) at 0.degree. C. and the
reaction mixture was stirred at room temperature for 2 hours. The
reaction mixture was then filtered through a pad of celite and
silica gel which was washed with methanol. The filtrate was
concentrated under reduced pressure at a temperature below
25.degree. C. The residue was diluted with brine and extracted a
couple of times with chloroform. All organic solvents were
combined, dried with anhydrous sodium sulfate, and concentrated to
give a clear oil as crude
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane
8-oxide, in amount of 12.84 g.
[0500] .sup.1H NMR (DMSO-d.sub.6) .delta.: 3.69 (t, J=6.2 Hz, 4H),
2.59-2.83 (m, 4H), 1.80 (tdd, J=6.8, 6.7, 6.4 Hz, 4H), 0.86 (s,
18H), 0.04 (s, 12H)
Preparation 9
##STR00159##
[0501]
8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8.lamda..sup.4-th-
ia-3,13-disilapentadecane 8-oxide
[0502] To the solution of above obtained crude oil
2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane
8-oxide, in anhydrous dichloromethane (150 mL) was added
trifluoroacetamide (7.60 g, 2 eq), magnesium oxide (5.256 g. 4 eq),
rhodium acetate dimer (432 mg, 0.03 eq), and (diacetoxyiodo)benzene
(15.75 g, 1.5 eq) under nitrogen atmosphere at room temperature.
The greenish reaction mixture was stirred at room temperature for
18 hours. Then additional amount of trifluoroacetamide (3.0 g),
rhodium acetate dimer (300 mg), (diacetoxyiodo)benzene (5.0 g), and
anhydrous dichloromethane (100 mL) was added. The mixture was
continued being stirred at room temperature for another 3 hours and
then filtered through a pad of celite and silica gel. The pad was
washed first with dichloromethane followed by MeOH-DCM (1:5). The
filtrate was concentrated and the brown oil was taken up into
methanol (200 mL). Potassium carbonate (22.53 g, 5 eq) was added to
the newly formed solution. After the mixture was stirred at room
temp for 2 hours, it was filtered through a pad of celite and
silica gel. The pad was washed first with DCM-EtOAC (1:1) followed
by a later 10% (v/v) addition of MeOH with stirring of the sediment
on top of the pad. The filtrate was concentrated and the residue
mixture was treated with DCM-EtOAc (2:3) with stirring at room temp
for 30 minutes. The mixture was filtered again through a pad of
celite and silica gel. This filtration and concentration circle may
be repeated a couple of times such that most of the solid
by-product was removed and a reddish oil was obtained. Upon a
gradient column chromatography (EtOAc-HEX 1:20 to 1:1)
8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-W-thia-3,13-disilapenta-
decane 8-oxide, was obtained as a reddish oil in amount of 9.538 g
with a total yield of 72% for 4 steps.
[0503] .sup.1H NMR (DMSO-d.sub.6) .delta.: 3.67 (t, J=6.3 Hz, 4H),
3.65 (s, 1H), 2.99 (t, J=7.9 Hz, 4H), 1.82-1.88 (m, 4H), 0.86 (s,
18H), 0.04 (s, 12H)
Example 56
##STR00160##
[0504]
6-amino-N-[bis(3-hydroxypropyl)(oxido)-.lamda..sup.4-sulfanylidene]-
-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinam-
ide
[0505] The reaction mixture of
8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8.lamda..sup.4-thia-3,1-
3-disilapentadecane 8-oxide, (102.25 mg, 0.25 mmol, 1 eq),
6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]n-
icotinic acid (89 mg, 1 eq), DMAP (6.125 mg, 0.2 eq), and EDCI
(57.6 mg, 1.2 eq) in anhydrous DCE (2.5 mL) was heated at
70.degree. C. for 2 hours. It was then diluted with DCM, washed
sequentially with aqueous NH.sub.4Cl, saturated aqueous
NaHCO.sub.3, and brine, and dried with anhydrous sodium sulfate.
The upper clear solution was decanted, concentrated, and the oily
residue was subject to gradient column chromatography (EtOAc-Hex
1:30 to 2:1) yielding
6-amino-N-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)-.lamda..s-
up.4-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzot-
hien-2-yl]nicotinamide as a white foam in amount of 70 mg.
[0506] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.77 (s, 1H), 8.59-8.61
(m, 2H), 8.10 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.85 (d,
J=8.8 Hz, 1H), 7.57 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.33 (s,
1H), 7.25 (d, J=8.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.80 (d, J=7.6
Hz, 1H), 6.76 (br. s., 2H), 3.71 (t, J=6.2 Hz, 4H), 3.62-3.70 (m,
4H), 2.29 (s, 3H), 1.89-1.98 (m, 4H), 0.85 (s, 18H), 0.03 (s,
12H)
[0507] To the solution of
6-amino-N-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)-.lamda..s-
up.4-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzot-
hien-2-yl]nicotinamide (70 mg, 0.086 mmol, 1 eq) in anhydrous THF
(2 mL) at 0.degree. C. was added dropwise tetrabutylammonium
fluoride (0.355 mL, 1.0 M in anhyd. THF, 4.1 eq) and the reaction
was stirred at that temp for 2 hours. The reaction was then
partitioned between saturated aqueous NaHCO.sub.3 and ethyl
acetate. The organic layer was further washed with aqueous
NH.sub.4Cl, brine, lastly dried with anhydrous Na.sub.2SO.sub.4.
The upper solution was decanted, concentrated, and the solid
residue was wrapped with silica gel which was subject to a gradient
column chromatography (EtOAc-Hex 6:1 to MeOH-EtOAc 1:9) to give
6-amino-N-[bis(3-hydroxypropyl)(oxido)-.lamda..sup.4-sulfanylidene]-5-[5--
({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide
as a slightly brown solid in amount of 42 mg.
[0508] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.84 (s, 1H), 8.67 (s,
1H), 8.62 (d, J=2.3 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 8.01 (d, J=2.1
Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.37 (dd, J=8.5, 2.1
Hz, 1H), 7.33 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.16 (t, J=7.8 Hz,
1H), 6.79 (d, J=7.3 Hz, 1H), 6.76 (s, 2H), 4.74 (t, J=5.3 Hz, 2H),
3.62-3.68 (m, 2H), 3.55-3.60 (m, 2H), 3.52 (q, J=6.1 Hz, 4H), 2.29
(s, 3H), 1.84-1.96 (m, 4H)
Example 57
##STR00161##
[0509]
N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-{5-[({[2-fluoro-5-
-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinam-
ide
[0510] Synthesized using a procedure similar to Example 1.
[0511] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.35 (s, 1H)
9.18 (d, J=2.35 Hz, 1H) 9.09 (d, J=2.05 Hz, 1H) 8.94 (d, J=2.93 Hz,
1H) 8.66 (dd, J=7.19, 2.20 Hz, 1H) 8.51 (t, J=2.05 Hz, 1H) 8.19 (d,
J=1.76 Hz, 1H) 8.08 (s, 1H) 7.96 (d, J=8.80 Hz, 1H) 7.51 (dd,
J=10.56, 8.80 Hz, 1H) 7.38-7.42 (m, 2H) 3.54 (s, 6H)
Example 58
##STR00162##
[0512]
5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-
-benzothien-2-yl}-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]nicotinam-
ide
[0513] Synthesized using a procedure similar to Example 1.
[0514] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.22 (s, 1H)
9.18 (d, J=2.35 Hz, 1H) 9.08 (d, J=1.76 Hz, 1H) 9.03 (s, 1H) 8.51
(t, J=2.20 Hz, 1H) 8.15 (dd, J=4.70, 2.35 Hz, 2H) 8.07 (s, 1H) 7.94
(d, J=8.51 Hz, 1H) 7.65-7.68 (m, 1H) 7.61-7.64 (m, 1H) 7.42 (dd,
J=8.51, 2.05 Hz, 1H) 3.54 (s, 6H)
[0515] The compounds represented by Formula II can be synthesized
according to the following example.
Example 60
##STR00163##
[0516]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-[4-({[(2--
fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide
[0517]
1-(2-fluoro-5-methylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)urea (212 mg, 0.6 mmoles) and
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-iodonicotinamid-
e (170 mg, 0.5 mmoles) was added to a mixture of 6 ml of dioxane
and 2 ml of 2M aqueous Sodium Carbonate. Next, Palladium(II)
Acetate (.about.5 mol %, 6 mg) and Triphenylphosphene (.about.20
mol %, 27 mg) was added, followed by 2 ml of dioxane. Dry nitrogen
was bubbled through the resulting solution for 15 minutes.
Following this, the reaction mixture was set up with a reflux
condenser, under nitrogen atmosphere, and heated at 95 C for 2
hours. The reaction was then cooled to room temperature and 40 ml
of ethyl acetate was added. The mixture was transferred to a
separatory funnel and extracted with saturated Sodium Bicarbonate
(3.times.40 ml) followed by saturated NaCl (3.times.40 ml). The
organic layer was dried with anhydrous Sodium Sulfate, loaded onto
silica and columned using ethyl acetate/hexanes, to give 120 mg of
the product.
[0518] .sup.1H NMR (dmso) .delta.: 9.18 (s, 1H), 8.55 (d, J=2.0 Hz,
1H), 8.50 (d, J=2.6 Hz, 1H), 8.00 (dd, J=7.8, 1.9 Hz, 1H), 7.75 (d,
J=2.3 Hz, 1H), 7.52-7.59 (m, 2H), 7.30-7.38 (m, 2H), 7.10 (dd,
J=11.4, 8.2 Hz, 1H), 6.79 (s, 1H), 6.24 (s, 2H), 3.41 (s, 6H), 2.27
(s, 3H)
##STR00164##
Example 64
dimethyl
(6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-
-3-yl)phosphonate
[0519] The reaction mixture of dimethyl
(6-amino-5-(4-aminophenyl)pyridin-3-yl)phosphonate (30 mg, 0.10
mmol, 1 eq) and 1-isocyanato-3-(trifluoromethyl)benzene (0.018 mL,
1.2 eq) in anhydrous DMF (0.5 mL) under anhydrous nitrogen
atmosphere was stirred at room temperature for an hour. It was then
diluted with ethyl acetate, washed sequentially with aqueous
ammonium chloride, saturated aqueous sodium bicarbonate, brine, and
lastly dried with anhydrous sodium sulfate. The upper clear
solution was decanted, concentrated, and the solid residue was
subject to a gradient column chromatography (EtOAc-Hex 2:1 to
MeOH-EtOAc 1:20) to yield dimethyl
(6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)
phenyl)pyridin-3-yl)phosphonate as a white solid in amount of 41
mg.
[0520] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 9.12 (s, 1H)
9.01 (s, 1H) 8.19 (dd, J=6.37, 2.12 Hz, 1H) 8.03 (s, 1H) 7.56-7.64
(m, 3H) 7.49-7.55 (m, 1H) 7.29-7.42 (m, 4H) 6.44 (br. s., 2H) 3.65
(s, 3H) 3.62 (s, 3H).
Example 65
##STR00165##
[0521] diethyl
[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-
-yl]phosphonate
[0522] Synthesized using a procedure similar to Example 64.
[0523] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 9.22 (s, 1H)
8.51 (d, J=2.49 Hz, 1H) 8.19 (dd, J=6.37, 2.12 Hz, 1H) 8.00 (dd,
J=7.84, 1.83 Hz, 1H) 7.57 (d, J=8.64 Hz, 2H) 7.33-7.42 (m, 3H) 7.11
(dd, J=11.28, 8.35 Hz, 1H) 6.77-6.85 (m, 1H) 6.40 (br. s., 2H)
3.93-4.05 (m, 4H) 2.28 (s, 3H) 1.23 (t, J=7.03 Hz, 6H)
Example 66
##STR00166##
[0524] dimethyl
{6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)pheny-
l]pyridin-3-yl}phosphonate
[0525] Synthesized using a procedure similar to Example 64.
[0526] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 9.36 (br.
s., 1H) 8.95 (br. s., 1H) 8.63 (dd, J=7.33, 2.20 Hz, 1H) 8.19 (dd,
J=6.37, 2.12 Hz, 1H) 7.55-7.61 (m, 2H) 7.51 (dd, J=10.99, 8.94 Hz,
1H) 7.36-7.44 (m, 4H) 6.45 (br. s., 2H) 3.66 (s, 3H) 3.62 (s,
3H)
Example 67
##STR00167##
[0527] dimethyl
[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-
-yl]phosphonate
[0528] Synthesized using a procedure similar to Example 64.
[0529] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 9.23 (s, 1H)
8.53 (d, J=1.90 Hz, 1H) 8.19 (dd, J=6.30, 2.05 Hz, 1H) 7.97-8.02
(m, 1H) 7.56 (d, J=8.50 Hz, 2H) 7.34-7.42 (m, 3H) 7.11 (dd,
J=11.28, 8.50 Hz, 1H) 6.77-6.84 (m, 1H) 6.44 (br. s., 2H) 3.65 (s,
3H) 3.62 (s, 3H) 2.28 (s, 3H)
Example 63
##STR00168##
[0530]
1-{4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl]phenyl}-3-phenylurea
[0531] Synthesized using a procedure similar to Example 62.
[0532] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 8.81 (br.
s., 1H) 8.71 (br. s., 1H) 8.18 (d, J=1.76 Hz, 1H) 7.91-7.97 (m, 1H)
7.53-7.57 (m, 2H) 7.47 (d, J=7.92 Hz, 2H) 7.32-7.37 (m, 2H)
7.26-7.31 (m, 2H) 6.97 (t, J=7.34 Hz, 1H) 5.98 (br. s., 2H) 1.27
(s, 12H)
Example 59
##STR00169##
[0533]
6-amino-N-[dimethyl(oxido)-.lamda..sup.4-sulfanylidene]-5-[4-({[(2--
fluoro-5-methylphenyl) amino]carbonyl}amino)phenyl]nicotinamide
[0534] Synthesized using a procedure similar to Example 69.
[0535] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.22 (s, 1H)
8.56 (d, J=2.20 Hz, 1H) 8.53 (d, J=2.05 Hz, 1H) 8.00 (dd, J=7.78,
1.61 Hz, 1H) 7.74 (d, J=2.05 Hz, 1H) 7.56 (d, J=8.51 Hz, 2H) 7.36
(d, J=8.51 Hz, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.79-6.83 (m,
1H) 6.24 (br. s., 2H) 4.73 (t, J=5.36 Hz, 2H) 3.54-3.66 (m, 4H)
3.51 (q, J=6.02 Hz, 4H) 2.28 (s, 3H) 1.83-1.95 (m, 4H)
Example 70
##STR00170##
[0536] dimethyl
5,5'-(N-{[6-amino-5-(4-{[(3-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-
-yl]carbonyl}sulfonimidoyl)dipentanoate
[0537] Synthesized using a procedure similar to Example 69.
[0538] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 8.79 (s, 1H)
8.61 (s, 1H) 8.55 (d, J=2.20 Hz, 1H) 7.73 (d, J=2.05 Hz, 1H) 7.56
(d, J=8.66 Hz, 2H) 7.34 (d, J=8.51 Hz, 2H) 7.31 (s, 1H) 7.24 (d,
J=8.36 Hz, 1H) 7.16 (t, J=7.78 Hz, 1H) 6.80 (d, J=7.34 Hz, 1H) 6.23
(br. s., 2H) 3.49-3.63 (m, 10H) 2.38 (t, J=7.26 Hz, 4H) 2.28 (s,
3H) 1.62-1.85 (m, 8H)
Example 71
##STR00171##
[0539] dimethyl
5,5'-(N-{[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)-
pyridin-3-yl]carbonyl}sulfonimidoyl)dipentanoate
[0540] Synthesized using a procedure similar to Example 69.
[0541] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.19 (s, 1H)
8.55 (d, J=2.20 Hz, 1H) 8.50 (d, J=2.35 Hz, 1H) 8.00 (dd, J=7.92,
1.76 Hz, 1H) 7.74 (d, J=2.05 Hz, 1H) 7.56 (d, J=8.66 Hz, 2H) 7.35
(d, J=8.51 Hz, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.79-6.83 (m,
1H) 6.24 (br. s., 2H) 3.50-3.62 (m, 10H) 2.38 (t, J=7.26 Hz, 4H)
2.28 (s, 3H) 1.63-1.84 (m, 8H)
Example 72
##STR00172##
[0542] dimethyl
5,5'-[N-({6-amino-5-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)pheny-
l]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate
[0543] Synthesized using a procedure similar to Example 69.
[0544] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.08 (s, 1H)
8.95 (s, 1H) 8.55 (d, J=2.20 Hz, 1H) 8.03 (s, 1H) 7.74 (d, J=2.20
Hz, 1H) 7.56-7.61 (m, 3H) 7.52 (t, J=8.00 Hz, 1H) 7.36 (d, J=8.51
Hz, 2H) 7.32 (d, J=7.63 Hz, 1H) 6.24 (br. s., 2H) 3.50-3.62 (m,
10H) 2.38 (t, J=7.34 Hz, 4H) 1.72-1.84 (m, 4H) 1.64-1.70 (m,
4H)
Example 68
##STR00173##
[0545] dimethyl
(6-amino-5-{4-[(phenylcarbamoyl)amino]phenyl}pyridin-3-yl)phosphonate
[0546] Synthesized using a procedure similar to Example 64.
[0547] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.85 (s, 1H)
8.71 (s, 1H) 8.19 (dd, J=6.37, 2.12 Hz, 1H) 7.54-7.60 (m, 2H)
7.44-7.49 (m, 2H) 7.33-7.41 (m, 3H) 7.29 (t, J=7.91 Hz, 2H)
6.94-7.01 (m, 1H) 6.43 (br. s., 2H) 3.65 (s, 3H) 3.62 (s, 3H)
Example 62
##STR00174##
[0548]
1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
n-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea
[0549] To the nitrogen bubbled mixture of
1-(4-(2-amino-5-bromopyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea
(487 mg, 1.17 mmol, 1 eq), bis(pinacolato)diboron (0.36 g, 1.2 eq),
and potassium acetate (0.46 g, 4 eq) in anhydrous 1,4-dioxane (6
mL) was added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (0.14 g, 0.15 eq) and the mixture was
heated at 120.degree. C. for one and half hours. After the reaction
was cooled to room temperature, it was filtered through a celite
pad and washed with ethyl acetate. The filtrate was collected,
washed sequentially with aqueous ammonium chloride, saturated
aqueous sodium bicarbonate, brine, and lastly dried with anhydrous
sodium sulfate. The upper clear solution was decanted,
concentrated, and the brown oily residue was subject to a gradient
column chromatography (EtOAc-Hex 1:4 to 4:1) to yield
1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl-
)phenyl)-3-(2-fluoro-5-methylphenyl)urea as a brown oil which
solidified in vacuo in amount of 101 mg.
[0550] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.17 (s, 1H)
8.49 (br. s., 1H) 8.18 (d, J=1.76 Hz, 1H) 8.00 (d, J=7.92 Hz, 1H)
7.51-7.57 (m, 2H) 7.42 (d, J=1.76 Hz, 1H) 7.33-7.37 (m, 2H) 7.11
(dd, J=11.30, 8.36 Hz, 1H) 6.78-6.84 (m, 1H) 5.99 (s, 2H) 2.28 (s,
3H) 1.27 (s, 12H).
Example 61
##STR00175##
[0551]
(6-amino-5-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)pyridin-3-y-
l)boronic acid
[0552] To the solution of
1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl-
)phenyl)-3-(2-fluoro-5-methylphenyl)urea (AGN-227971, 108 mg, 0.234
mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added aq HCl (3
N, 2 mL) and the reaction was first stirred at room temperature for
two hours. Additional conc. HCl (0.5 mL) was dropwise added to the
reaction and the mixture was stirred at 50.degree. C. for further
four hours. The reaction was then poured into saturated aqueous
sodium bicarbonate and extracted with ethyl acetate. The organic
layer was isolated, washed with brine, and dried with anhydrous
sodium sulfate. The upper clear solution was decanted, concentrated
to lesser amount, and the solid crashed-out was filtered. This
solid was further purified by a reversed phase chromatography (from
WATER-CH.sub.3CN 9:1 to CH.sub.3CN) to give
(6-amino-5-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)pyridin-3-yl)boro-
nic acid as a grey solid in amount of 7 mg.
[0553] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 9.15 (s, 1H)
8.48 (d, J=2.49 Hz, 1H) 8.31 (d, J=1.76 Hz, 1H) 8.00 (dd, J=7.85,
1.83 Hz, 1H) 7.80 (s, 2H) 7.68 (d, J=1.91 Hz, 1H) 7.52-7.56 (m, 2H)
7.34-7.38 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.78-6.83 (m, 1H)
5.71 (s, 2H) 2.28 (s, 3H)
Example 69
##STR00176##
[0554]
6-amino-N-[bis(3-hydroxypropyl)(oxido)-.lamda..sup.4-sulfanylidene]-
-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide
[0555] To the solution of
6-amino-5-(4-aminophenyl)-N-[bis(3-hydroxypropyl)(oxido)-.lamda..sup.4-su-
lfanylidene]nicotinamide (39 mg, 0.1 mmol, 1.0 eq) in anhydrous THF
(1 mL) was added 1-isocyanato-3-methylbenzene (0.013 mL, 1.0 eq)
dropwise. The reaction was stirred at room temperature for 1 hour
and then diluted with EtOAc. The organic layer was washed
sequentially with saturated aq NaHCO.sub.3, aq NH.sub.4Cl, brine,
and finally dried with anhydrous Na.sub.2SO.sub.4. The supernatant
liquid was decanted, concentrated, and the oily residue was subject
to a gradient column chromatography (EtOAc-Hex 7:1 to MeOH-EtOAc
1:9) yielding
6-amino-N-[bis(3-hydroxypropyl)(oxido)-.lamda..sup.4-sulfanylidene]-5-[4--
({[(3-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide as a
white solid in amount of 30 mg.
[0556] .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 8.82 (br.
s., 1H) 8.64 (br. s., 1H) 8.56 (d, J=2.05 Hz, 1H) 7.74 (d, J=2.05
Hz, 1H) 7.56 (d, J=8.51 Hz, 2H) 7.34 (d, J=8.22 Hz, 2H) 7.31 (s,
1H) 7.24 (d, J=7.63 Hz, 1H) 7.16 (t, J=7.78 Hz, 1H) 6.80 (d, J=7.34
Hz, 1H) 6.23 (br. s., 2H) 4.72 (t, J=5.28 Hz, 2H) 3.49-3.66 (m, 8H)
2.28 (s, 3H) 1.82-1.95 (m, 4H)
Example 74
##STR00177##
[0557] methyl
6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl-
]pyridine-3-carboxylate
[0558] To methyl 6-amino-5-(4-aminophenyl)nicotinate (0.18 mmoles)
in 3 ml of tetrahydrofuran (THF) under nitrogen atmosphere was
added a solution of
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.22 mmoles, 1.2
equivalents) in 1 ml THF. The reaction was stirred at room
temperature under nitrogen atmosphere for 30 minutes. Following
this, the reaction was loaded onto silica and columned using ethyl
acetate-hexanes, to give 25 mg of the product.
[0559] .sup.1H NMR (dmso-d.sup.6) .delta.: 9.29-9.34 (m, 1H), 8.92
(br. s., 1H), 8.60-8.65 (m, 1H), 8.51 (d, J=2.4 Hz, 1H), 7.68 (d,
J=2.2 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.46-7.52 (m, 1H), 7.38 (d,
J=8.6 Hz, 3H), 6.52 (br. s., 2H), 3.78 (s, 3H)
Example 75
##STR00178##
[0560] methyl
6-amino-5-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl-
]pyridine-3-carboxylate
[0561] Synthesized using a procedure similar to methyl
6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl-
]pyridine-3-carboxylate.
[0562] .sup.1H NMR (dmso-d.sup.6) .delta.: 9.20-9.25 (m, 1H), 9.04
(s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.59-7.68
(m, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 6.51 (br.
s., 2H), 3.77 (s, 3H)
Example 73
##STR00179##
[0563] methyl
6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridine-3-
-carboxylate
[0564] Synthesized using a procedure similar to methyl
6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl-
]pyridine-3-carboxylate.
[0565] .sup.1H NMR (dmso-d.sup.6) .delta.: 9.21 (s, 1H), 8.50 (d,
J=2.2 Hz, 2H), 7.97-8.01 (m, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.54-7.57
(m, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.10 (dd, J=11.5, 8.3 Hz, 1H),
6.77-6.82 (m, 1H), 6.51 (br. s., 2H), 3.78 (s, 3H), 2.27 (s,
3H).
Example 76
##STR00180##
[0566] methyl
6-amino-5-{4-[(phenylcarbamoyl)amino]phenyl}pyridine-3-carboxylate
[0567] Synthesized using a procedure similar to methyl
6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl-
]pyridine-3-carboxylate.
[0568] .sup.1H NMR (dmso-d.sup.6) .delta.: 8.81 (s, 1H), 8.68 (s,
1H), 8.50 (d, J=2.2 Hz, 1H), 7.66-7.68 (m, 1H), 7.54-7.57 (m, J=8.6
Hz, 2H), 7.46 (dd, J=8.6, 1.0 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.28
(t, J=7.9 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 6.51 (br. s., 2H), 3.77
(s, 3H).
[0569] Biological data for the compounds of the present invention
was generated by use of the following assays.
[0570] VEGFR2 Kinase Assay
[0571] Biochemical KDR kinase assays were performed in 96 well
microtiter plates that were coated overnight with 75 .mu.g/well of
poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH
7.4. The coated plates were washed with 2 mls per well PBS+0.05%
Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA,
then washed with 2 mls per well PBS-T prior to starting the
reaction. Reactions were carried out in 100 .mu.L reaction volumes
containing 2.7 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH
7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM
Na.sub.3VO.sub.4). Test compounds were reconstituted in 100% DMSO
and added to the reaction to give a final DMSO concentration of 5%.
Reactions were initiated by the addition 20 ul per well of kinase
buffer containing 200-300 ng purified cytoplasmic domain KDR
protein (BPS Bioscience, San Diego, Calif.). Following a 15 minute
incubation at 30.degree. C., the reactions were washed 2 mls per
well PBS-T. 100 .mu.l of a monoclonal anti-phosphotyrosine
antibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added
to the wells for 30 minutes. Following a 2 mls per well wash with
PBS-Tween-20, 100 .mu.l of 0-Phenylenediamine Dihydrochloride in
phosphate-citrate buffer, containing urea hydrogen peroxide, was
added to the wells for 7-10 minutes as a colorimetric substrate for
the peroxidase. The reaction was terminated by the addition of 100
.mu.l of 2.5N H.sub.2SO.sub.4 to each well and read using a
microplate ELISA reader set at 492 nm. IC.sub.50 values for
compound inhibition were calculated directly from graphs of optical
density (arbitrary units) versus compound concentration following
subtraction of blank values.
VEGFR2 Cellular Assay
[0572] Automated FLIPR (Fluorometric Imaging Plate Reader)
technology was used to screen for inhibitors of VEGF induced
increases in intracellular calcium levels in fluorescent dye loaded
endothelial cells. HUVEC (human umbilical vein endothelial cells)
(Clonetics) were seeded in 384-well fibronectin coated black-walled
plates overnight @ 37.degree. C./5% CO2. Cells were loaded with
calcium indicator Fluo-4 for 45 minutes at 37.degree. C. Cells were
washed 2 times (Elx405, Biotek Instruments) to remove extracellular
dye. For screening, cells were pre-incubated with test agents for
30 minutes, at a single concentration (10 uM) or at concentrations
ranging from 0.0001 to 10.0 uM followed by VEGF.sub.165 stimulation
(10 ng/mL). Changes in fluorescence at 516 nm were measured
simultaneously in all 384 wells using a cooled CCD camera. Data
were generated by determining max-min fluorescence levels for
unstimulated, stimulated, and drug treated samples. IC.sub.50
values for test compounds were calculated from % inhibition of VEGF
stimulated responses in the absence of inhibitor.
PDGFR.beta. Kinase Assay
[0573] Biochemical PDGFR.beta. kinase assays were performed in 96
well microtiter plates that were coated overnight with 75 .mu.g of
poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH
7.4. The coated plates were washed with 2 mls per well PBS+0.05%
Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA,
then washed with 2 mls per well PBS-T prior to starting the
reaction. Reactions were carried out in 100 .mu.L reaction volumes
containing 36 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH
7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM
Na.sub.3VO.sub.4). Test compounds were reconstituted in 100% DMSO
and added to the reaction to give a final DMSO concentration of 5%.
Reactions were initiated by the addition 20 ul per well of kinase
buffer containing 200-300 ng purified cytoplasmic domain PDGFR-b
protein (Millipore). Following a 60 minute incubation at 30.degree.
C., the reactions were washed 2 mls per well PBS-T. 100 .mu.l of a
monoclonal anti-phosphotyrosine antibody-peroxidase conjugate
diluted 1:10,000 in PBS-T was added to the wells for 30 minutes.
Following a 2 mls per well wash with PBS-Tween-20, 100 .mu.l of
0-Phenylenediamine Dihydrochloride in phosphate-citrate buffer,
containing urea hydrogen peroxide, was added to the wells for 7-10
minutes as a colorimetric substrate for the peroxidase. The
reaction was terminated by the addition of 100 .mu.l of 2.5N
H.sub.2SO.sub.4 to each well and read using a microplate ELISA
reader set at 492 nm. IC.sub.50 values for compound inhibition were
calculated directly from graphs of optical density (arbitrary
units) versus compound concentration following subtraction of blank
values.
PDGFR.beta. Cellular Assay
[0574] Automated FLIPR (Fluorometric Imaging Plate Reader)
technology was used to screen for inhibitors of PDGF-induced
increases in intracellular calcium levels in fluorescent dye loaded
endothelial cells. NHDF-Ad (Normal Human Dermal Fibroblasts, Adult;
Lonza) were seeded in 384-well fibronectin coated black-walled
plates overnight @ 37.degree. C./5% CO2. Cells were loaded with
calcium indicator Fluo-4 for 45 minutes at 37.degree. C. Cells were
washed 2 times (Elx405, Biotek Instruments) to remove extracellular
dye. For screening, cells were pre-incubated with test agents for
30 minutes, at a single concentration (10 uM) or at concentrations
ranging from 0.0001 to 10.0 uM followed by PDGF-BB stimulation (30
ng/mL). Changes in fluorescence at 516 nm were measured
simultaneously in all 384 wells using a cooled CCD camera. Data
were generated by determining max-min fluorescence levels for
unstimulated, stimulated, and drug treated samples. IC.sub.50
values for test compounds were calculated from % inhibition of
PDGF-BB stimulated responses in the absence of inhibitor.
PKR KinaseGlo Assay
[0575] Commercially available recombinant human GST-PKR
(SignalChem, Canada; 1.5 uM-2 uM stock) is diluted to 500 nM in
assay buffer (20 mM Tris-HCl, pH 7.2, 10 mM KCl, 10 mM MgCl2, 10%
glycerol). Preactivated PKR is dispensed to 384/96-well black
plates at 3.125/12.5 uls/well using the liquid handler Janus.
Appropriate dilutions of inhibitors are added to 384/96-well plate
followed by 6.6 uM ATP (final) and incubated for 10 minutes at room
temperature. The remaining ATP/well is determined by adding 6.25/25
uls/well Kinase-Glo assay mix (Promega) and luminescence is
measured on EnVision luminescence plate reader (integration time,
0.2 sec; Perkin-Elmer, Massachusetts, USA). The % inhibition for
the compounds is calculated using ATP only (100% inhibition) and
PKR+ATP (0% inhibition). IC50 values are determined by plotting %
activity versus inhibitor concentration. Curves are fitted using
Activity base XLfit (IDBS, UK) using the formula--
fit=(A+((B-A)/(1+(10{circumflex over ( )}((C-x)*D)))))
inv=(C-(log(((B-A)/(y-A))-1)/D))
res=(y-fit) 4 Parameter Logistic Model
[0576] The biological results for the various compounds are shown
in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 below.
[0577] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0578] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0579] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0580] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0581] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0582] The compounds of this invention may also be delivered
orally, subcutaneously, intravenously, intrathecally or some
suitable combination(s) thereof.
[0583] In addition to the common dosage forms set out above, the
compounds of this invention may also be administered by controlled
release means and/or delivery devices such as those described in
U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;
3,630,200; 4,008,719; and 5,366,738.
[0584] For use where a composition for intravenous administration
is employed, a suitable daily dosage range for anti-inflammatory,
anti-atherosclerotic or anti-allergic use is from about 0.001 mg to
about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound
of this invention per kg of body weight per day and for
cytoprotective use from about 0.1 mg to about 100 mg (preferably
from about 1 mg to about 100 mg and more preferably from about 1 mg
to about 10 mg) of a compound of this invention per kg of body
weight per day. For the treatment of diseases of the eye,
ophthalmic preparations for ocular administration comprising
0.001-1% by weight solutions or suspensions of the compounds of
this invention in an acceptable ophthalmic formulation may be
used.
[0585] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0586] The magnitude of prophylactic or therapeutic dose of a
compound of this invention will, of course, vary with the nature of
the severity of the condition to be treated and with the particular
compound and its route of administration. It will also vary
according to the age, weight and response of the individual
patient. It is understood that a specific daily dosage amount can
simultaneously be both a therapeutically effective amount, e.g.,
for treatment to slow progression of an existing condition, and a
prophylactically effective amount, e.g., for prevention of
condition.
[0587] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.001 mg to about
500 mg. In one embodiment, the quantity of active compound in a
unit dose of preparation is from about 0.01 mg to about 250 mg. In
another embodiment, the quantity of active compound in a unit dose
of preparation is from about 0.1 mg to about 100 mg. In another
embodiment, the quantity of active compound in a unit dose of
preparation is from about 1.0 mg to about 100 mg. In another
embodiment, the quantity of active compound in a unit dose of
preparation is from about 1.0 mg to about 50 mg. In still another
embodiment, the quantity of active compound in a unit dose of
preparation is from about 1.0 mg to about 25 mg.
[0588] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0589] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 0.01 mg/day to about 2000
mg/day of the compounds of the present invention. In one
embodiment, a daily dosage regimen for oral administration is from
about 1 mg/day to 1000 mg/day. In another embodiment, a daily
dosage regimen for oral administration is from about 1 mg/day to
500 mg/day. In another embodiment, a daily dosage regimen for oral
administration is from about 100 mg/day to 500 mg/day. In another
embodiment, a daily dosage regimen for oral administration is from
about 1 mg/day to 250 mg/day. In another embodiment, a daily dosage
regimen for oral administration is from about 100 mg/day to 250
mg/day. In still another embodiment, a daily dosage regimen for
oral administration is from about 1 mg/day to 100 mg/day. In still
another embodiment, a daily dosage regimen for oral administration
is from about 50 mg/day to 100 mg/day. In a further embodiment, a
daily dosage regimen for oral administration is from about 1 mg/day
to 50 mg/day. In another embodiment, a daily dosage regimen for
oral administration is from about 25 mg/day to 50 mg/day. In a
further embodiment, a daily dosage regimen for oral administration
is from about 1 mg/day to 25 mg/day. The daily dosage may be
administered in a single dosage or can be divided into from two to
four divided doses.
[0590] In one aspect, the present invention provides a kit
comprising a therapeutically effective amount of at least one
compound of the present invention, or a pharmaceutically acceptable
salt of said compound and a pharmaceutically acceptable carrier,
vehicle or diluents, and directions for the use of said kit.
[0591] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the relevant art and are intended to
fall within the scope of the appended claims.
TABLE-US-00003 TABLE 2 Sulfoximine/Urea ##STR00181## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example A
(IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 1 ##STR00182## 8 20 20
2 ##STR00183## 3 25 17 3 ##STR00184## 8 3 17 4 ##STR00185## 42 68
73 5 ##STR00186## 6 11 21 6 ##STR00187## 6 5 27
TABLE-US-00004 TABLE 3 Ester/Urea ##STR00188## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example A
(IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 7 ##STR00189## 7 22 11
8 ##STR00190## 10 12 24 9 ##STR00191## 15 63 45 10 ##STR00192## 17
27 15 11 ##STR00193## 20 328 18 12 ##STR00194## 21 355 26 13
##STR00195## 45 941 12 14 ##STR00196## 81 1595 10 15 ##STR00197##
137 1352 28 16 ##STR00198## NA NA 9
TABLE-US-00005 TABLE 4 Acid or Amide/Urea ##STR00199## VEGFR2
VEGFR2 PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example
Y Z A (IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 17 ##STR00200##
##STR00201## ##STR00202## 41 N/A N/A 18 ##STR00203## ##STR00204##
##STR00205## 38 N/A N/A 19 ##STR00206## ##STR00207## ##STR00208##
120 N/A 431 20 ##STR00209## ##STR00210## ##STR00211## 35 N/A N/A 21
##STR00212## ##STR00213## ##STR00214## 118 N/A N/A 22 ##STR00215##
##STR00216## ##STR00217## 132 N/A N/A
TABLE-US-00006 TABLE 5 Boronate Ester/Urea ##STR00218## VEGFR2
VEGFR2 PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example
A (IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 23 ##STR00219## 10
N/A 17 24 ##STR00220## 13 N/A N/A 25 ##STR00221## 16 N/A 21 26
##STR00222## 25 N/A 10 27 ##STR00223## 37 N/A N/A 28 ##STR00224##
42 N/A 18 29 ##STR00225## 54 N/A 20 30 ##STR00226## 301 N/A 130
TABLE-US-00007 TABLE 6 Boronic Acid/Urea ##STR00227## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example A
(IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 31 ##STR00228## 93 N/A
42 32 ##STR00229## 378 N/A 138
TABLE-US-00008 TABLE 7 Sulfoximine/Amide ##STR00230## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example Q
(IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 33 ##STR00231## 17 6
457 34 ##STR00232## 32 277 36 35 ##STR00233## 50 45 258 36
##STR00234## 51 N/A N/A 37 ##STR00235## 53 N/A 131 38 ##STR00236##
178 1023 128
TABLE-US-00009 TABLE 8 Ester/Amide ##STR00237## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay (IC.sub.50 Assay
(IC.sub.50 Assay (IC.sub.50 Example Y Q nM) nM) nM) 39 ##STR00238##
##STR00239## 31 75 61 40 ##STR00240## ##STR00241## 57 145 25 41
##STR00242## ##STR00243## 199 1102 38 42 ##STR00244## ##STR00245##
224 3945 503 43 ##STR00246## ##STR00247## 264 2488 25 44
##STR00248## ##STR00249## 930 8722 29 45 ##STR00250## ##STR00251##
N/A N/A 936 46 H ##STR00252## 1171 5110 1278 47 H ##STR00253## 1488
1815 N/A
TABLE-US-00010 TABLE 9 Reverse Amides ##STR00254## VEGFR2 VEGFR2
PDGFR.beta. Enzyme Cellular Enzyme Assay Assay Assay Example T
(IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50 nM) 48 ##STR00255## 3570
N/A >10,000
TABLE-US-00011 TABLE 10 Other Sulfoximine substituents/Ureas
##STR00256## VEGFR2 VEGFR2 PDGFR.beta. Enzyme Cellular Enzyme Assay
Assay Assay Example Y A (IC.sub.50 nM) (IC.sub.50 nM) (IC.sub.50
nM) 53 ##STR00257## ##STR00258## 5 N/A 16 54 ##STR00259##
##STR00260## 3 N/A N/A 55 ##STR00261## ##STR00262## 4 N/A N/A 56
##STR00263## ##STR00264## 8 N/A 8
TABLE-US-00012 TABLE 11 PKR data for Pyridyl Benzothiophenes PKR
KINASEGLO Enzyme Assay IC50 Example Structure (nM) 5 ##STR00265##
69 6 ##STR00266## 167
TABLE-US-00013 TABLE 12 VEGFR2 PKR Enzyme KINASEGLO Assay Enzyme
Assay Example Structure (IC.sub.50 nM) IC50 (nM) 57 ##STR00267## 7
551 58 ##STR00268## 14 390
TABLE-US-00014 TABLE 13 VEGFR2 VEGFR2 PDGFR.beta. PDGFR.beta.
Example Kinase Cellular Kinase Cellular Number Structure IC.sub.50
nM IC.sub.50 nM IC.sub.50 nM IC.sub.50 nM 59 ##STR00269## 26 na 100
na 60 ##STR00270## 6 12 na na 61 ##STR00271## 25 na 58 150 62
##STR00272## 53 na 24 na 63 ##STR00273## 206 na na na 64
##STR00274## 57 10 na 66 65 ##STR00275## 95 35 82 118 66
##STR00276## 115 25 na na 67 ##STR00277## 133 30 na na 68
##STR00278## 891 na na na 69 ##STR00279## 13 na 83 na 70
##STR00280## 14 3 138 173 71 ##STR00281## 33 13 88 141 72
##STR00282## 42 11 13 192 73 ##STR00283## 9 14 na na 74
##STR00284## 7 41 na na 75 ##STR00285## 7 74 na na 76 ##STR00286##
29 115 na na
* * * * *