Substituted 3-amino-thieno [2, 3-b] pyridine-2-carboxylic acid amide compounds and processes for ...

88 Pages·2013·3.81 MB·English

US 20040053957A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2004/0053957 A1
Cywin et al. (43) Pub. Date: Mar. 18, 2004
(54) SUBSTITUTED 3-AMINO-THIENO Related US. Application Data
[2,3-B]PYRIDINE-2-CARBOXYLIC ACID
AMIDE COMPOUNDS AND PROCESSES (60) Provisional application No. 60/386,312, ?led on Jun.
FOR PREPARING AND THEIR USES 6, 2002. Provisional application No. 60/457,867, ?led
on Mar. 26, 2003.
(75) Inventors: Charles L. Cywin, Bethel, CT (US);
Zhidong Chen, New Milford, CT (US); Publication Classi?cation
Roman Wolfgang Fleck, Greenwich,
CT (US); Ming-Hong Hao, Ridge?eld, (51) Int. Cl.7 .................. .. C07D 498/02; A61K 31/4743
CT (US); Eugene Hickey, Danbury, CT (52) US. Cl. .......................................... .. 514/301; 546/114
(US); Weimin Liu, Sandy Hook, CT
(US); Daniel Richard Marshall, (57) ABSTRACT
Norwalk, CT (US); Peter Nemoto,
Southbury, CT (US); Ronald John Disclosed are compounds of formula (I):
Sorcek, Bethel, CT (US); SanXing Sun,
Danbury, CT (US); J iang-Ping Wu,
Danbury, CT (US); Tina Morwick,
New Milford, CT (US); Jonathan
Emeigh, Gilbertsville, PA (US)
Correspondence Address:
BOEHRINGER INGELHEIM CORPORATION
5 NH2
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD, CT 06877 (US)
wherein R1 and R2 are de?ned herein, which are useful as
(73) Assignee: Boehringer Ingelheim Pharmaceuti inhibitors of the kinase activity of the IKB kinase (IKK)
cals, Inc., Ridge?eld, CT (US) complex. The compounds are therefore useful in the treat
ment of IKK mediated diseases including autoimmune dis
(21) Appl. No.: 10/453,175 eases in?ammatory diseases and cancer. Also disclosed are
pharmaceutical compositions comprising these compounds
(22) Filed: Jun. 3, 2003 and processes for preparing these compounds.
US 2004/0053957 A1 Mar. 18, 2004
SUBSTITUTED 3-AMINO-THIENO phosphorylated on serine residues, S177 and S181 of the
[2,3-B]PYRIDINE-Z-CARBOXYLIC ACID AMIDE activation loop in the case of IKKB, and S176 and S180 of
COMPOUNDS AND PROCESSES FOR PREPARING the activation loop for IKKot. An IKKB mutant having
AND THEIR USES alanines in place of serines at 177 and 181 prevented IKKB
phosphorylation and subsequent activation of the IKK com
APPLICATION DATA plex by TNFot, IL-1 and other upstream activators. These
[0001] This application claims bene?t to US. provisional results support a key role for IKK, in phosphorylation of IKB
folloWing proin?ammatory stimulation.
application No. 60/386,312 ?led Jun. 6, 2002 and US.
provisional application No. 60/457,867, ?led Mar. 26, 2003
[0006] Studies in Which the NF-KB pathWay has been
and are hereby claimed and said applications are herein
inhibited in cells and animals support the concept that
incorporated by reference.
inhibition of the phosphorylation of IKB is a viable approach
to treatment of in?ammatory, autoimmune and other dis
TECHNICAL FIELD OF THE INVENTION
eases. In these studies, NF-KB activation Was prevented by
[0002] This invention relates to substituted 3-amino expression of a non-degradable version of the IKB protein.
thieno[2,3-b]pyridine-2-carboxylic acid amide compounds Expression of this inhibitor in synovial cells derived from
useful as inhibitors of the kinase activity of the IKB kinase rheumatoid arthritis patients reduced the expression of
(IKK) complex. The compounds are therefore useful in the TNFot, IL-6, IL-1[3 and IL-8 While the anti-in?ammatory
treatment of IKK-mediated diseases including autoimmune molecules IL-10, IL-1ra and IL-11 Were not affected. Matrix
diseases, in?ammatory diseases and cancer. The invention metalloproteinases (MMP1 and MMP3) Were also doWn
also relates to processes for preparing such compounds and regulated (J. Bonderson et al., Proc. Natl. Acad. Sci. U.S.A.,
pharmaceutical compositions comprising them. 1999, 96, 5668). Transgenic expression of the IKB inhibitor
in T cells caused a signi?cant reduction in the severity and
BACKGROUND OF THE INVENTION
onset of collagen—induced arthritis in mice (R. Seethara
[0003] NF-KB or nuclear factor KB is a transcription factor man et al.,]. Immunol. 1999, 163, 1577). These experiments
that induces the expression of a large number of pro indicate that suppression of NF-KB in the diseased joint
in?ammatory and anti-apoptotic genes. These include cytok could reduce both the severity and progression of RA. In
ines such as IL-1, IL-2, TNFO. and IL-6, chemokines includ primary intestinal epithelial cells, the NF-KB inhibitor
ing IL-8 and RANTES, as Well as other pro-in?ammatory blocked the expression of IL-1, IL-8, iNOS and COX-2,
molecules including COX-2 and cell adhesion molecules mediators that are up-regulated during the course of in?am
such as ICAM-l, VCAM-l, and E-selectin. The NF-KB matory boWel disease (C. Jubin et al., J. Immunol, 1998,
family includes homo- and heterodimeric transcription fac 160, 410). Expression of this inhibitor in certain tumor cells
tors composed of members of the Rel family (see for enhances killing of these cells by chemotherapeutic reagents
example P. A. Baeurle and D. Baltimore, Cell, 1996, 87, 13). (A. A. Beg and D. Baltimore, Science, 1996, 274, 782).
Under resting conditions, NF-KB is present in the cytosol of
[0007] Analysis of biopsies from lungs of patients With
cells as a complex With IKB. The IKB family of proteins
chronic obstructive pulmonary disease (COPD) found an
serve as inhibitors of NF-KB, interfering With the function of
its nuclear localiZation signal (see for example U. Siebenlist increased expression of NF-KB that correlated With disease
et al.,Ann. Rev. Cell Biol., 1994, 10, 405). Upon disruption severity (A. Di Stefano et al., Eur. Resp. J ., 2002, 1, 437).
of the IKB-NF-KB complex folloWing cell activation, NF-KB Inhibition of NF-KB activation With inhibitors of IKK-B Was
among the anti-in?ammatory approaches reported to be
translocates to the nucleus and activates gene transcription.
Disruption of the IKB-NF-KB complex and subsequent acti potentially useful in the treatment of COPD (P. J. Barnes,
vation of NF-KB is initiated by degradation of IKB. Nature Rev. Drug Disc., 2002, 1, 437). LikeWise, inhibition
of NF-KB activity has been mentioned as a therapeutic
[0004] Upon cellular activation by a variety of pro-in?am approach for asthma (A. Pahl and I. SZelenyi, In?. Res.,
matory stimuli including IL-1, TNF-ot and LPS (bacterial 2002, 51, 273).
lipopolysaccharide), tWo speci?c serine residues of IKB are
phosphorylated. Upon phosphorylation, IKB undergoes [0008] A recent revieW describes the essential role of
polyubiquination and subsequent degradation by the 26S in?ammatory mediators in the development cardiovascular
proteasome (see for example V. J. Palombella et al., Cell, disease. The in?ammatory mediators and the cells that they
1994, 78, 773), freeing NF-KB to translocate to the nucleus. recruit are reported to play a key role in the development of
The phosphorylation of IKB is carried out by the IKB kinases fatty streaks and plaques that lead to atherosclerosis. In
(see for example a revieW by M. Karin and M. Delhase, addition they are reported to play a key role in subsequent
Seminars in Immunology, 2000, 12, 85). The traditional IKK degradation of the ?brous cap that forms over the plaque,
complex includes at least three subunits, IKKO. (also called leading to rupture and clot formation. If the clot groWs large
IKK-l), IKKB (or IKK-2) and IKKY (or NEMO), although enough it can lead to myocardial infarction or stroke. Thus,
other relevant complexes involving IKKO. and IKKB may anti-in?ammatory drugs that can inhibit the production of
exist. IKKO. and IKKB are both catalytic subunits While these mediators and subsequent recruitment and activation
IKKY is believed to be a regulatory subunit. Both IKKO. and of these cells may be bene?cial in treatment of these diseases
IKKB can phosphorylate IKB. For the purposes of this (P. Libby, Scienti?c American, 2002, 46).
document, the terms IKK or IKK complex refers to any
[0009] A number of studies indicate that activation of
complex that has kinase activity derived from IKKO. and/or
NF-KB also plays a key role in the pathogenesis and devel
IKKB subunits.
opment of cancer (see for example revieWs by B. Haefner,
[0005] In vivo, activation of IKK occurs upon phospho DrugDisc. Today, 2002, 7, 653 and M. Karin et al., Nat. Rev.
rylation of its catalytic subunit. Both IKKO. and IKKB can be Cancer, 2002, 2, 301). Studies have shoWn that cells in
US 2004/0053957 A1 Mar. 18, 2004
Which NF-KB is constitutively active are resistant to apop With inappropriate B cell activation such as lupus (O. T.
tosis. This can contribute to carcinogenesis by preventing Chan et al., Immunological Rev., 1999, 169, 107) and
cell death in cells that have undergone chromosomal rheumatoid arthritis (A. Gause and C. Borek, Biodrugs,
changes or damage. In addition tumor cells With constitu 2001, 15, 73). In addition, an inhibitor of IKKO. may be
tively active NF-KB are resistant to anti-cancer therapies useful in the treatment of breast cancer since NF-KB is
including chemotherapy and radiation. Further studies have constitutively active in a number of breast tumors and many
linked activated NF-KB to a variety of lymphoid-, myeloid of these tumors depend on Cyclin D1 for proliferation.
and epithelial-derived malignancies including leukemia,
lymphomas and breast, gastric, colorectal, lung, and pan [0015] Some inhibitors of IKKB have been reported. WO
01/58890 and WO 03/037886 describes heteoaromatic car
creatic cancers. Thus it is suggested that inhibitors of
NF-KB, including inhibitors of IKKO. and IKKB, may be boXamide derivatives as inhibitors of IKKB. WO 01/68648
describes substituted [3-carbolines having IKKB inhibiting
useful either alone or in combination With other anti-cancer
activity. Substituted indoles having IKKB inhibitory activity
therapies in treating cancer.
are reported in WO 01/30774. WO 01/00610 describes
[0010] Collectively, the studies described above provide substituted benZimidaZoles having NF-KB inhibitory activ
support that inhibition of NF-KB function through inhibition ity. Aspirin and salicylate have been reported to bind to and
of IKK may be a useful therapeutic approach to treatment of inhibit IKKB (M. Yin et al., Nature, 1998, 396, 77).
autoimmune and in?ammatory disease, cardiovascular dis
[0016] Substituted thienopyridines having cell adhesion
ease and cancer.
inhibiting activity are reported in US. 2001/0020030 A1 and
[0011] Studies have also been done in mice With targeted
A. O. SteWart et al., J. Med. Chem., 2001, 44, 988.
disruption of the IKKB gene. Knockout of the IKKB gene Thienopyridines eXhibiting gonadotropin releasing hormone
resulted in embryonic lethality due to apoptosis of hepato
antagoniZing activity are reported in US. Pat. No. 6,313,
cytes. HoWever, ?broblasts from the IKKB knockouts did
301. Substituted thienopyridines described as telomerase
not undergo IKK and NF-KB activation upon stimulation
inhibitors are disclosed in US. Pat. No. 5,656,638.
With IL-1 or TNFO. (Q. Li et al., Science, 1999, 284, 321),
supporting a key role for IKKB in and NF-KB activation [0017] A number of 4,6-disubstituted thieno[2,3-b]pyri
folloWing in?ammatory stimuli. dine-2-carboXylic acid amides have been described in the
chemical literature. Examples include 3-amino-4,6-dim
[0012] A conditional knockout Was generated by eXpress
ethyl-thieno[2,3-b]pyridine-2-carboXylic acid amide,
ing a liver-speci?c inducible dominant negative IKBO. trans 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboXylic
gene (I. Lavon et al., Nature Medicine, 2000, 6, 573). These
acid diamide, 3-amino-4-methyl-6-phenyl-thieno[2,3-b]-py
mice Were viable With no signs of liver dysfunction even ridine-2-carboXamide, 3-amino-6-methyl-4-phenyl-thieno
after one year but they did have impaired immune function.
[2,3-b]pyridine-2-carboXylic acid amide, 3-amino-6-(4
This study supports the idea that inhibition of IKKB can bromo-phenyl)-4-methyl-thieno[2,3-b]pyridine-2
result in immune suppression Without damage to the liver.
carboXylic acid amide, 3-amino-4-(4-bromo-phenyl)-6
[0013] IKKO. knock-out mice died shortly after birth and methyl-thieno[2,3-b]pyridine-2-carboXylic acid amide,
3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboXylic
displayed a variety of skeletal defects and skin abnormali
ties. Fibroblast and thymocytes from these mice shoWed acid 2-amide 4-butylamide, 3-amino-6-furan-2-yl-4-phenyl
normal IKK activation and IKB degradation in response to thieno[2,3-b]pyridine-2-carboXylic acid amide, 3-amino-6
furan-2-yl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboXy
TNFot, IL-1 or LPS Hu et al., Science, 1999, 284, 316;
K. Takeda et al., Science, 1999, 284, 313). Recent studies lic acid amide, 3-amino-4-(4-chloro-phenyl)-6-phenyl
With knock-out and knock-in mice have revealed distinct thieno[2,3-b]pyridine-2-carboXylic acid amide, 3-amino-4
(4-?uoro-phenyl)-6-furan-2-yl-thieno[2,3-b]pyridine-2
roles for IKKO. in development and cell signaling. In con
trast to the studies With IKKO. knock-out mice, mice having carboXylic acid amide, 3-amino-4-(4-chloro-phenyl)-6
a kinase inactive version of IKKO. knocked in are viable and furan-2-yl-thieno[2,3-b]pyridine-2-carboXylic acid amide,
fertile, indicating that the perinatal lethality and abnormali 3-amino-4-(4-bromo-phenyl)-6-furan-2-yl-thieno[2,3-b]py
ties seen in the IKKO. knock-out mice are not due to the lack ridine-2-carboXylic acid amide, 3-amino-4,6-bis-(4-chloro
of kinase activity. HoWever, these mice do have defects in B phenyl)-thieno[2,3-b]pyridine-2-carboXylic acid amide,
cell maturation and development of secondary lymphoid 3-amino-6-naphth-2-yl-4-pyridin-3-yl-thieno[2,3-b]pyri
organs (U. Senftleben et al., Science, 2001, 293, 1495). This dine-2-carboXylic acid amide, 3-amino-6-methyl-thieno[2,
phenotype appears to be due to a defect in processing of the 3-b]pyridine-2,4-dicarboXylic acid 2-amide 4-(2-hydroXy
NF-KB2/p100 protein to p52, the DNA binding form of this ethyl)amide, 3-amino-6-methyl-4-piperidin-1-yl-thieno[2,3
member of the Rel family of transcription factors. In turn, b]-pyridine-2-carboXamide and 3-amino-4-methyl-6
this leads to a defect in the activation of a subset of NF-KB hydroXy-thieno[2,3-b]-pyridine-2-carboXamide reported as
target genes in B cells. In addition, other studies With these intermediates for synthesis of tricyclic heterocycles and
same mice have shoWn that IKKO. kinase activity is required evaluated for anti-allergic activity (G. Wagner et al., Phar
for NF-KB activation in the mammary epithelium during mazie, 1990, 45, 102).
pregnancy (Cao, Y., et. al., Cell, 2001, 107,763). This
[0018] Other examples includes 3-amino-4,6-diphenyl
pathWay is speci?cally activated through the TNF receptor
thieno[2,3-b]pyridine-2-carboXylic acid amide (A. M.
family member RANK, requires phosphorylation of the
Shestopalov et al., J. Org. Chem. USSR, (Engl. Transl.)
canonical IKK substrate lKBot, and culminates in induction
1984, 20, 1382), 3-amino-6-methyl-4-pyridin-4-yl-thieno[2,
of the cell cycle regulatory gene Cyclin D1.
3-b]pyridine-2-carboXylic acid amide and 3-amino-6-me
[0014] These studies indicate that an inhibitor of IKKO. thyl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboXylic acid
kinase activity may be useful in treating diseases associated amide (G. Wagner et al., Pharmazie, 1993, 48, 514),
US 2004/0053957 A1 Mar. 18, 2004
3-amino-4-methoXymethyl-6-methyl-thieno[2,3-b]pyridine [0026] (b) heterocyclyl selected from l-piperidi
2-carboXylic acid amide I. Kaigorodova et a1., Chem. nyl, 1-piperaZinyl, l-pyrrolidinyl and 4-morpholi
Heterocycl. Compd. (Engl. Transl), 1996, 32, 1234), nyl, optionally substituted With one to tWo groups
3-amino-6-phenyl-4-thiophen-2-yl-thieno[2,3-b]pyridine-2 selected from C1_6alkyl, —CO2C1_5alkyl, phenyl,
carboXylic acid amide, 3-amino-4-furan-2-yl-6-methyl benZyl, —OH and —C(O)heteroaryl, Wherein the
thieno[2,3-b]pyridine-2-carboXylic acid amide, 3-amino-4 heteroaryl is selected from furanyl, thienyl,
(4-chloro-phenyl)-6-methyl-thieno[2,3-b]pyridine-2 pyridyl and pyrrolyl,
carboXylic acid amide and 3-amino-4-furan-2-yl-6-phenyl
[0027] (c) R6(CH2)mO—,
thieno[2,3-b]pyridine-2-carboXylic acid amide A. Attaby,
Phosphorus, Sulfur; Silicon Relat. Elem, 1998, 139, 1), [0028] (d) R6OCH2—,
3-amino-6-(4-chloro-phenyl)-4-thiophen-2-yl-thieno[2,3-b]
pyridine-2-carboXylic acid amide (Y. Sharanin et al., J. Org.
Chem. USSR, (Engl. Transl.) 1996, 32, 1207), 3-amino-6
phenyl-4-pyridin-3-yl-thieno[2,3-b]pyridine-2-carboXylic
[0031] (g) C1_6alkyl, optionally partially of fully
acid amide (A. KrauZe, Eur. J. Med. Chem. Chim Ther.,
halogenated and optionally substituted With one to
1999, 34, 301) and 3-amino-6-thiophen-2-yl-4-tri?uorom
tWo R9,
ethyl-thieno[2,3-b]pyridine-2-carboXylic acid amide (M. I.
Abdel-Monem et a1., Pharinazie, 2001, 56, 41). [0032] (h) C1_8alkoXy, optionally partially of fully
halogenated and optionally substituted With one to
[0019] In no case are these compounds described as hav
ing the ability to inhibit IKKO. or IKKB. tWo R9,
[0033] C1_8alkylS(O)n—, optionally partially of
SUMMARY OF THE INVENTION
fully halogenated and optionally substituted With
[0020] It is therefore an object of this invention to provide
novel compounds according to the following formula (I): one to tWo R9,
[0034] (j) —N(R4)(R5), Or
[0035] (k) —C(O)NHR‘, Wherein R‘ is R6, pyridyl
(1)
or —CH3;
[0036] R2 is
[0037] (a) C1_6alkyl, optionally partially or fully
halogenated and optionally substituted With one to
R2 N S NHZ tWo R10,
[0038] (b) C1_6alkoXy, optionally partially or fully
halogenated and optionally substituted With one to
[0021] Wherein the variables R1 and R2 are described
herein Which inhibit IKK. It is a further object of the tWo R10,
invention to provide methods for treating diseases and [0039] (c) C1_6alkylamino, optionally partially or
pathological conditions exacerbated by IKK such as, but not fully halogenated and optionally substituted With
limited to autoimmune diseases, in?ammatory diseases and
one to tWo R10,
cancer. It is yet a further object of the invention to provide
[0040] (d) C1_6alkylthio, optionally partially or
novel processes for preparation of the above-mentioned
fully halogenated and optionally substituted With
novel compounds.
one to tWo R10,
DETAILED DESCRIPTION OF THE
[0041] (e) heterocyclyl(CH2)m— Wherein said het
INVENTION
erocycle is selected from piperidinyl, piperaZinyl,
[0022] A ?rst aspect of the invention comprises a method morpholinyl, aZepanyl, pyrrolidinyl, 1,4-diaZacy
of treating an in?ammatory or autoimmune condition by cloheptanyl, aZepanyl, 2,5-diaZabicyclo[2.2.1]
administration of certain novel and knoWn molecules of the
heptanyl, oXaZepanyl and thiomorpholino and is
formula (I):
optionally substituted With one or three R7,
(1) [0042] heterocyclylCH2O— Wherein the het
NH; erocyclyl is selected from l-piperidinyl, l-piper
aZinyl, 4-morpholinyl and l-pyrrolidinyl, option
ally substituted With C1_6alkyl,
[0043] (g) phenyl, optionally substituted With one
R2 N S NHZ
or three R3,
[0044] (h) —N(R4)(R5),
[0023] Wherein:
[0045] heteroaryl selected from furanyl, thienyl,
[0024] R1 is imidaZolyl, pyridyl and pyrrolyl, or
[0025] (a) phenyl or heteroaryl selected from fura
[0046] —H;
nyl, thienyl, pyridyl, pyrrolyl, imidaZolyl and ben
Zofuranyl, optionally substituted With one to tWo [0047] R3 is chosen from C1_6alkyl, C1_6alkoXy,
R3, hydroXyC1_6alkyl, halogen, —CN, —COZH,
US 2004/0053957 A1 Mar. 18, 2004
[0059] Wherein:
[0060] R1 is
[0061] (a) phenyl or heteroaryl selected from fura
nyl, thienyl, pyridyl, pyrrolyl, irnidaZolyl and ben
[0048] R4 and R5 are independently selected from H,
Zofuranyl, optionally substituted With one to tWo
C1_6alkyl, —C(O)C1_6alkyl, —SO2C1_6alkyl, phe
R3,
nyl, pyridyl, benZyl, piperidinyl, phenylethyl and
(CH3)3COC(O)—; [0062] (b) heterocyclyl selected from 1-piperidi
nyl, 1-piperaZinyl, 1-pyrrolidinyl and 4-rnorpholi
[0049] R6 is a phenyl group optionally substituted nyl, optionally substituted With one to tWo groups
With one or tWo groups selected from halogen, selected from C1_6alkyl, —CO2C1_5alkyl, phenyl,
C1_6alkyl, —CN, —CO2C1_6alkyl, —C(O)NR4R5, benZyl, —OH and —C(O)heteroaryl, Wherein the
—SO2NH2, —NO2, —OH, —NH2, —CF3 and heteroaryl is selected from furanyl, thienyl,
C1_6alkoXy, or R6 is C3_6cycloalkyl, —CHZOH, pyridyl and pyrrolyl,
naphthalene-2-yl, naphthalene-l-yl or 2-thienyl;
[0063] (c) R6(CH2)mO—,
[0050] R7 is selected from —OH, —CN, OX0,
[0064] (d) R6OCH2—,
[0067] (g) C1_6alkyl, optionally partially of fully
halogenated and optionally substituted With one to
tWo R9,
HO(CH2)mCH2CH(NH2)C(O)—, [0068] (h) C1_8alkoXy, optionally partially of fully
HOCH(R6)CH2NH—R6CH2CH(OH)CH2NH—,
halogenated and optionally substituted With one to
R6OCH2CH(OH)CH2NH— and —C(O)heterocy
tWo R9,
clyl, Wherein said heterocyclyl is selected from pip
[0069] C1_8alkylS(O)n—, optionally partially of
eridinyl, piperaZinyl, rnorpholinyl and pyrrolidinyl,
fully halogenated and optionally substituted With
or R7 is 2-hydroXyethylarnino, rnethylcarbarnirn
idoyl, hydroXyirnino, hydroZinocarbonyl, sulfarnoyl, one to tWo R9,
rnethanesulfonylarnino, rnethylsulfonylhydraZino,
2-hydroXypropylarnino, 2,3-dihydroXypropylarnino,
2-hydroXy-l-rnethylethylarnino, carbarnoylrnethy [0071] (k) —C(O)NHR‘, Wherein R‘ is R6, pyridyl
larnino, N‘-phenylhydraZinocarbonyl or toluene-4 or —CH3;
sulfonylarnino; [0072] R2 is
[0051] R8 is selected from C1_6alkyl, —(CH2)1_ [0073] (a) C1_6alkyl, optionally partially or fully
4NH2, phenyl or benZyl; halogenated and optionally substituted With one to
tWo R10,
[0052] R9 is selected from OX0, —OH, —NR4R5,
[0074] (b) C1_6alkoXy, optionally partially or fully
—CO2H and C1_6alkoXy;
halogenated and optionally substituted With one to
tWo R10,
[0075] (c) C1_6alkylarnino, optionally partially or
[0054] R6, and heteroaryl selected from furanyl, thie fully halogenated and optionally substituted With
nyl, irnidaZolyl, pyridyl, indolyl and pyrrolyl; one to tWo R10,
[0076] (d) C1_6alkylthio, optionally partially or
[0055] In is 0 or 1;
fully halogenated and optionally substituted With
[0056] n is 0, 1 or 2; and one to tWo R10,
[0077] (e) heterocyclyl(CH2)m— Wherein said het
[0057] p is 0, 1, 2 or 3.
erocycle is selected from piperidinyl, piperaZinyl,
[0058] In its second aspect, the invention provides novel rnorpholinyl, aZepanyl, pyrrolidinyl, 1,4-diaZacy
compounds of formula (I): cloheptanyl, aZepanyl, 2,5-diaZabicyclo[2.2.1]
heptanyl, oXaZepanyl and thiornorpholino and is
optionally substituted With one to three R7,
R (I) [0078] heterocyclylCH2O— Wherein the het
1 NH2 erocyclyl is selected from 1-piperidinyl, 1-piper
aZinyl, 4-rnorpholinyl and 1-pyrrolidinyl, option
/ I \ 0
ally substituted With C1_6alkyl,
[0079] (g) phenyl, optionally substituted With one
R; \N S NH2
to three R3,
[0080] (h) —N(R4)(R5),
US 2004/0053957 A1 Mar. 18, 2004
[0081] heteroaryl selected from furanyl, thienyl, [0096] R1 is
imidaZolyl, pyridyl and pyrrolyl, or
[0097] (a) phenyl or heteroaryl selected from fura
[00821 0)—H; nyl, thienyl, pyridyl, pyrrolyl, imidaZolyl and ben
Zofuranyl optionally substituted With one to tWo
[0083] R3 is chosen from C1_6alkyl, C1_6alkoXy, R3,
hydroXyC1_6alkyl, halogen, —CN, —COZH,
—CO2C1_6alkyl, —S(O)nC1_6alkyl, —NO2, —OH,
—CF3, —N(R4)(R5), —NHC(O)NHC1_6alkyl,
—C(O)N(R4)(R5) and phenyl optionally substituted
With halogen, C1_6alkyl, —CN or C1_6alkoXy;
[0084] R4 and R5 are independently selected from H,
C1_6alkyl, —C(O)C1_6alkyl, —SO2C1_6alkyl, phe [0102] C1_6alkyl, optionally partially of fully
nyl, pyridyl, benZyl, piperidinyl, phenylethyl and halogenated and optionally substituted With one to
(CH3)3COC(O)—; tWo R9,
[0103] (g) C1_8alkoXy, optionally partially of fully
[0085] R6 is a phenyl group optionally substituted
halogenated and optionally substituted With one to
With one or tWo groups selected from halogen,
tWo R9,
C1_6alkyl, —CN, —CO2C1_6alkyl, —C(O)NR4R5,
—SO2NH2, —NO2, —OH, —NH2, —CF3 and
C1_6alkoXy, or R6 is C3_6cycloalkyl, —CHZOH,
napbthalene-2-yl, naphthalene-l-yl or 2-thienyl;
[0106] —C(O)NHR‘, Wherein R‘ is R6, pyridyl
[0086] R7 is selected from —OH, —CN, OX0,
or —CH3,
[0107] R2 is
[0108] (a) C1_6alkyl, optionally substituted With
10’
[0109] (b) C1_6alkoXy, optionally substituted With
10’
HO(CH2)mCH2CH(NH2)C(O)—, [0110] (c) C1_6alkylamino, optionally substituted
HOCH(R6)CH2NH—, R6CH2CH(OH)CH2NH—, With R10,
R6OCH2CH(OH)CH2NH— and —C(O)heterocy
[0111] (d) heterocyclyl selected from from 1-pip
clyl, Wherein said heterocyclyl is selected from pip eridinyl, 1-piperaZinyl, 4-morpholinyl, 1-aZepa
eridinyl, piperaZinyl, morpholinyl and pyrrolidinyl,
nyl, l-pyrrolidinyl, 1,4-diaZacycloheptan-1-yl,
or R7 is 2-hydroXyethylamino, methylcarbamim 1-aZepanyl, 2,5-diaZabicyclo[2.2.1]heptan-2-yl,
idoyl, hydroXyimino, hydroZinocarbonyl, sulfamoyl,
oXaZepan-4-yl and 4-thiomorpholino and is
methanesulfonylamino, methylsulfonylhydraZino,
optionally substituted With one to three R7,
2-hydroXypropylamino, 2,3-dihydroXypropylamino,
2-hydroXy-l-methylethylamino, carbamoylmethy [0112] (e) heterocyclylCH2O— Wherein the het
lamino, N‘-phenylhydraZinocarbonyl or toluene-4 erocyclyl is selected from l-piperidinyl, 1-piper
sulfonylamino; aZinyl, 4-morpholinyl and l-pyrrolidinyl, option
ally substituted With C1_6alkyl, or
[0087] R8 is selected from C1_6alkyl, —(CH2)1_
[0113] (f) —N(R4)(R5);
4NH2, phenyl or benZyl;
[0114] R3 is chosen from C1_6alkyl, C1_6alkoXy,
[0088] R9 is selected from OX0, —OH, —NR4R5, hydroXyC1_6alkyl, halogen, —CN, —COZH,
—CO2H and C1_6alkoXy; —CO2C1_6alkyl, —S(O)nC1_6alkyl, —NO2, —OH,
—CF3, —N(R4)(R5), —NHC(O)NHC1_6alkyl,
—C(O)N(R4)(R5) and phenyl optionally substituted
With halogen, C1_6alkyl, —CN or C1_6alkoXy;
[0090] R6, and heteroaryl selected from furanyl, thie
[0115] R4 and R5 are independently selected from H,
nyl, imidaZolyl, pyridyl, indolyl and pyrrolyl;
C1_6alkyl, —C(O)C1_6alkyl, pyridyl, benZyl, pip
eridinyl and phenylethyl;
[0091] m is 0 or 1;
[0116] R6 is a phenyl group optionally substituted
[0092] n is 0, 1 or 2;
With one or tWo groups selected from C1, F, C1_6akyl,
—CN, —CO2C1_6alkyl, —C(O)NR4R5, —SO2NH2,
[0093] p is 0, 1, 2 or 3;
—NO2, —OH, —NH2, —CF3 and C1_6alkoXy or R6
[0094] and pharmaceutically acceptable salts, esters, tau is C3_6cycloalkyl, —CHZOH, naphthalene-2-yl,
tomers, individual isomers, and miXtures of isomers thereof. naphthalene-l-yl or 2-thienyl;
[0095] In another embodiment, there are provided novel
compounds of the formula (I) as described above and
Wherein:
US 2004/0053957 A1 Mar. 18, 2004
—CO2C1_6alkyl, —S(O)nC1_6alkyl, —NO2, —OH,
—CF3, —N(R4)(R5), —NHC(O)NHC1_6alkyl,
—C(O)N(R4)(R5) and phenyl optionally substituted
With halogen, C1_6alkyl, —CN or C1_6alkoXy;
wherein said heterocyclyl is selected from piperidi
nyl, piperaZinyl, morpholinyl and pyrrolidinyl, or R7 [0142] R4 and R5 are independently selected from H,
is 2-hydroXyethylamino, methylcarbamimidoyl, C1_6alkyl, —C(O)C1_6alkyl, pyridyl, benZyl, pip
hydroXyimino, hydroZinocarbonyl, sulfamoyl, meth eridinyl and phenylethyl;
anesulfonylamino, methylsulfonylhydraZino, 2-hy
droXypropylamino, 2,3-dihydroXypropylamino, [0143] R6 is a phenyl group optionally substituted
2-hydroXy-l-methylethylamino, carbamoylmethy With one or tWo groups selected from Cl, F,
lamino, N‘-phenylhydraZinocarbonyl or toluene-4 C1_6alkyl, —CN, —CO2C1_6alkyl, —C(O)NR4R5,
sulfonylamino; —SO2NH2, —NO2, —OH, —NH2, —CF3 and
C1_6alkoXy, or R6 is C3_6cycloalkyl, —CHZOH,
[0118] R8 is selected from C1_6alkyl, —(CH2)1_4NH2,
naphthalene-2-yl, naphthalene-l-yl or 2-thienyl;
phenyl or benZyl;
[0119] R9 is —OH;
[0120] R10 is selected from —OH, —N(R4)(R5),
C1_6alkoXy and beteroaryl selected from furanyl,
thienyl and pyridyl;
[0121] m is 0 or 1;
[0122] n is 0, 1 or 2;
[0123] p is 0, 1, 2 or 3; R6OCH2CH(OH)CH2NH— and —C(O)heterocy
clyl, Wherein said heterocyclyl is selected from pip
[0124] and pharmaceutically acceptable salts, esters, tau
eridinyl, piperaZinyl, morpholinyl and pyrrolidinyl,
tomers, individual isomers, and mixtures of isomers thereof.
or R7 is 2-hydroXyethylamino, methylcarbamim
[0125] In yet another embodiment of the invention there idoyl, 25 hydroXyimino, hydroZinocarbonyl, sulfa
are provided novel compounds of the formula (I) as moyl, methanesulfonylamino, methylsulfonylhy
described above and Wherein:
draZino, 2-hydroXypropylamino, 2,3
[0126] R1 is dihydroXypropylamino, 2-hydroXy-1
methylethylamino, carbamoylmethylamino,
[0127] (a) phenyl or heteroaryl selected from fura
nyl, thienyl and pyridyl, optionally substituted N‘-phenylhydraZinocarbonyl or toluene-4-sulfony
lamino;
With one to tWo R3,
[0128] (b) R6(CH2)mO—, [0145] R8 is selected from C1_6alkyl, —(CH2)1_
4NH2, phenyl or benZyl;
[0129] (c) R6OCH2—,
[0146] mis0or1;
[0147] n is 0, 1 or 2;
[0148] p is 0, 1, 2 or 3;
[0133] (g) C1_6alkylOH, [0149] and pharmaceutically acceptable salts, esters, tau
tomers, individual isomers, and mixtures of isomers thereof.
[0134] (h) —CF3,
[0135] (i) C1-6a1kOXy> [0150] In still another embodiment of the invention there
are provided novel compounds of the formula (I) as
[0136] described above and Wherein:
[0137] (k) C1_8alkylthio,
[0151] R1 is
[01381 (1) —N(R4)(R5>, or
[0152] (a) phenyl, optionally substituted With one
[0139] —C(O)NHR‘, Wherein R‘ is R6, pyridyl to tWo R3,
or —CH3;
[0153] (b) R6CH=CH—
[0140] R2 is heterocyclyl Wherein said heterocycle is
[0154] (c) C1_6alkyl,
selected from 1-piperidinyl, 1-piperaZinyl, 4-mor
pholinyl, 1-aZepanyl, l-pyrrolidinyl, 1,4-diaZacyclo
[0155] (d) —C2_3alkylOH,
heptan-1-yl, 1-aZepanyl 2,5-diaZabicyclo[2.2.1]hep
tan-2-yl, oXaZepan-4-yl and 4-thiomorpholino and is [0156] (e) —CF3,
optionally substituted With one to three R7,
[0157] —C1_6alkoXy,
[0141] R3 is chosen from C1_6alkyl, C1_6alkoXy,
hydroXyC1_6alkyl, halogen, —CN, —COZH, [0158] (g) —OC2_3alkylOH,
US 2004/0053957 A1 Mar. 18, 2004
[0159] (h) —C1_6aMkylthio, or [0170] R1 is
[0171] (a) —CH2CH2CH3,
[0172] (b) —OCH2CH3,
[0161] R2 is
[0162] heterocyclyl wherein said heterocycle is [0173] (c) —SCH3,
selected from l-piperidinyl, 1-piperaZinyl,
[0174] (d) —C(O)NHR‘, Where R‘ is 3-pyridyl, or
1-aZepanyl, 1,4-diaZacycloheptan-1-yl and
phenyl substituted in the 4-position With —OH,
1-aZepanyl and is optionally substituted With one
—C(O)NH2, or —SO2NH2;
to three R7;
[0163] R3 is chosen from —CH3, —OCH3, F, Cl, [0175] R2 is heterocyclyl Wherein said heterocycle is
—CO2CH3, —SO2CH3 and —NO2; selected from l-piperidinyl and 1-piperaZinyl and is
optionally substituted With one to three R7;
[0164] R4 and R5 are independently selected from H,
—CH3 and benZyl; [0176] R4 and R5 are independently selected from H,
—CH3 and benZyl;
[0165] R6 is a phenyl group optionally substituted
With one or tWo groups selected from Cl, F, [0177] R6 is a phenyl group optionally substituted
C1_6alkyl, —CN, CO2C1_6alkyl, C(O)NR4R5,
With one or tWo groups selected from Cl, F, —CH3,
—SO2NH2, —NO2, —OH, —NH2, —CF3 and
—CN, —CO2CH3, —C(O)NR4R5, —NO2, —OH,
C1_6alkoXy or R6 is C3_6cycloalkyl, —CHZOH,
—NH2, —CF3 and —CH3, or R6 is naphthalene-2
naphthalene-2-yl, naphthalene-l-yl or 2-thienyl;
yl, naphthalene-l-yl or 2-thienyl;
[0178] R7 is selected from —OH, —CN, OX0,
—C(O)NH2, —NH2, —CH2NH2, —CH3, —NH
C(O)NH2, H2NCH(R8)C(O)—,
HOCH(R6)CH2NH—, R6CH2CH(OH)CH2NH—
and R6OCH2CH(OH)CH2NH—, or R7 is 2-hydroXy
ethylamino, methylcarbamimidoyl, methanesulfony
lamino, methylsulfonylhydraZino, 2-hydroXypropy
R6OCH2CH(OH)CH2NH— and —C(O)heterocy
lamino, 2,3-dihydroxypropylamino,
clyl, Wherein said heterocyclyl is selected from pip
eridinyl, piperaZinyl, morpholinyl and pyrrolidinyl, carbamoylmethylamino or N‘-phenylhydraZinocar
bonyl;
or R7 is 2-hydroXyethylamino, methylcarbamim
idoyl, hydroXyimino, hydroZinocarbonyl, sulfamoyl,
methanesulfonylamino, methylsulfonylhydraZino,
2-hydroXypropylamino, 2,3-dihydroXypropylamino, [0180] and pharmaceutically acceptable salts, esters, tau
2-hydroXy-l-methylethylamino, carbamoylmethy
tomers, individual isomers, and miXtures of isomers thereof;
lamino, N‘-phenylhydraZinocarbonyl or toluene-4
sulfonylamino; [0181] With the proviso that in each of the above embodi
ments of novel compounds, if R1 is phenyl or heteroaryl,
[0167] R8 is selected from C1_6alkyl, —(CH2)1_
C1_6alkyl, —CF3, —C(O)NR4R5 or heterocyclyl, then R2 is
4NH2, phenyl or benZyl;
not C1_6alkyl, phenyl, heteroaryl, —CF3, or H. In the ?rst
[0168] and pharmaceutically acceptable salts, esters, tau aspect of the invention related to a method of treating an
tomers, individual isomers, and miXtures of isomers thereof. in?ammatory or autoimmune condition With compounds of
formula (I), this proviso does not apply.
[0169] In a further embodiment of the invention there are
provided novel compounds of the formula (I) as described [0182] In a further embodiment of the invention, there are
above and Wherein: provided the folloWing compounds:
Name Structure
3-Amino-6-(4-hydroxy-piperidin-1—yl)—
4—propyl—thieno[2,3—b]pyridine—2—
carboXylic acid amide
HO
US 2004/0053957 A1 Mar. 18, 2004
-c0ntinued
Name Structure
3-Amin0-6-(4-carbamoy1-piperidin-1— CH3
y1)—4-propyl-thieno[2,3—b]pyridine-2—
carboxylic acid amide
O
NH2
3-Amino-6-(4-methy1-piperazin-1—y1)—
4-propy1-thieno[2,3—b]pyridine—2—
carboxylic acid amide
3-Amino- 6-piperazin-1-y1-4-propy1
thieno[2,3—b]pyridine—2—carboxylic
acid amide
3-Amino- 6- (4-methanesu1fony1
piperazin-1—y1)-4—propy1—thieno[2,3—b]pyri—
dine-Z-carboxylic acid amide