Download Protein kinase inhibitors and methods of treatment

US008962830B2
(12) United States Patent
(10) Patent N0.:
(45) Date of Patent:
Lessene et a].
(56)
(54)
PROTEIN KINASE INHIBITORS AND
METHODS OF TREATMENT
(75)
Inventors: Guillaume Laurent Lessene, Parkville
US 8,962,830 B2
Feb. 24, 2015
References Cited
U.S. PATENT DOCUMENTS
(AU); Jonathan Bayldon Baell,
Parkville (AU); Antony Wilks Burgess,
Camberwell (AU); Hiroshi Maruta,
Brunswick West (AU)
(73) Assignee:
The Walter and Eliza Hall Institute of
Medical Research, Parkville (AU)
(*)
Notice:
2007/0293516 A1
12/2007 Knight et al.
FOREIGN PATENT DOCUMENTS
W0
W0
W0
W0
W0
Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
W0 02/076986
W0 02/080926
WO 2008/039218
WO 2010/009342
WO 2011/046964
A1
A1
A2
A2
A2
10/2002
10/2002
4/2008
1/2010
4/2011
OTHER PUBLICATIONS
(21) Appl. No.:
13/809,369
(22)
PCT Filed:
Jul. 8, 2011
(86)
PCT No.:
PCT/AU2011/000858
International Search Report and Written Opinion for PCT/AU2011/
000858, mailed on Aug. 24, 2011 (11 pages).
International Preliminary Report on Patentability for PCT/AU2011/
000858, mailed Jan. 15, 2013 (6 pages).
Apsel, B. et a1., “Targeted polypharmacology: discovery of dual
inhibitors of tyrosine and phosphoinositide kinases,” Nature Chemi
cal Biology 4(1 l):69 l -699, 2008.
(2), (4) Date:
Mar. 29, 2013
Primary Examiner * Nyeemah A GraZier
(74) Attorney, Agent, or Firm * Cooley LLP
U.S.C. 154(b) by 0 days.
(87)
PCT Pub. No.: WO2012/003544
(57)
PCT Pub. Date: Jan. 12, 2012
The present invention relates to chemical compounds of for
mula (I) and methods for their use and preparation. In par
(65)
Prior Publication Data
US 2013/0184274 A1
ABSTRACT
ticular, the invention relates to substituted pyrazolo[3,4-d]
pyrimidine based compounds which can be used in treating
proliferative disorders, use of these compounds in methods of
Jul. 18,2013
therapy and the manufacture of medicaments as well as com
positions containing these compounds.
Related US. Application Data
(60)
Provisional application No. 61/362,739, ?led on Jul. 9,
2010.
(51)
Int. Cl.
C07D 48 7/00
A61K 31/519
C07D 487/04
(52)
(2006.01)
(2006.01)
(2006.01)
US. Cl.
CPC .......... .. C07D 487/04 (2013.01); A61K31/519
(2013.01)
USPC
(58)
...................................... .. 544/262; 514/262.1
Field of Classi?cation Search
None
See application ?le for complete search history.
22 Claims, No Drawings
US 8,962,830 B2
1
2
PROTEIN KINASE INHIBITORS AND
METHODS OF TREATMENT
FIELD OF THE INVENTION
O/
5
(\N/
Cl
O\/\/N\)
H
N
The present invention relates generally to chemical com
pounds and methods for their use and preparation. In particu
lar, the invention relates to substituted pyrazolo[3,4-d]pyri
midine based compounds which can be used in treating
proliferative disorders, use of these compounds in methods of
N
Cl
NC
/
10
/O
therapy and the manufacture of medicaments as well as com
Bosutinib
positions containing these compounds.
Cl
O
15
BACKGROUND OF THE INVENTION
o
of the larger protein kinase class of enzymes. The enzymes’
ability to phosphorylate is an important mechanism in signal
transduction for the regulation of cellular activity. Cellular
proliferation in thought to rely (at least to some extent) on
TKRs. Mutations can cause some TPKs to become constitu
20
\N/w
.5
2
IN\
N/
N
H
ders such as cancer. Accordingly, in relation to the treatment
\
l \>\
N
S
N/\\
NH
\\/N
30
of cells the TPK subgroup of enzymes represents an attractive
O
target.
HO
Cl
A family of proto-oncogenic TPKs referred to herein as
better understanding of the mechanism of cancer as a disease
N
AZOSBO
contribute to initiation or progression of proliferative disor
SFKs (Src family kinases) have provided researchers with a
\N
K/N \/\O
tively active, and this aberrant activity has been thought to
of diseases and conditions characterised by the proliferation
O
O\/
Tyrosine protein kinases (TPKs) are able to catalyse the
transfer of the terminal phosphate of adenosine triphosphate
to tyrosine residues in protein substrates. TPK are a subgroup
HN
Desatinib
35
state where normally healthy cellular signalling is disrupted.
SUMMARY OF INVENTION
SFKs have been observed to play a critical role in cell adhe
sion, invasion, proliferation, survival and angiogenesis dur
40
ing tumour development.
SFKs comprise nine family members that share similar
In one aspect the invention provides compounds of formula
(I) or salts thereof,
structure and function. The nine members are c-Src, Yrk, Yes,
Fyn, F gr, Lyn, Lck, Hck, and Blk. The overexpres sion or high
Formula (I)
activation of these SFKs has been observed in many tumours.
SFKs can interact with tyrosine kinase receptors, such as
the EGFR and the VEGF receptor. SFKs are thought to affect
HZN
45
cell proliferation through the Ras/ERK/MAPK pathway and
may regulate gene expression via transcription factors such as
R5—
\N
/ \ N2
N\
STAT molecules. SFKs like some other TPKs can also affect 50
cell adhesion and migration. The SFKs are thought to act via
interaction with integrins, actins, GTPase-activating proteins,
N
R1
2V /
N
R3 R4
\ R2
scaffold proteins, such as pl3OCAS and paxillin, and kinases
such as focal adhesion kinases. Furthermore, SFKs have also
been shown to regulate angiogenesis via gene expression of 55 wherein:
angiogenic growth factors, such as VEGF, interleukin 8, and
R1 is selected from hydrogen, optionally substituted alkyl,
?broblast growth factor.
i(SOq)-optionallv substituted arvl. i(SO¢)-option
Due to this recognition and better understanding as to role
being played by TPKs in general and SFKs in particular,
small-molecule SFK inhibitors are being developed for the 60
treatment of hyperproliferative disorders such as cancer. At
this stage however of a number of promising SFK inhibitors
(e.g., Bosutinib, AZ0530, and Desatinib as shown below)
only Desatinib is approved whereas the others are presently
still undergoing clinical trials and as such there is no guaran 65
tee that any further acceptable SFK inhibitor (based on the
currently recognised compounds) will reach the market.
ally substituted heteroaryl, optionally substituted het
eroaryl, optionally substituted heterocyclyl, optionally
substituted aryl, and C(:X)iR6;
R2 is selected from hydrogen and C l-C3 alkyl;
R3 and R4 are independently C l-C3 alkyl;
L is selected from a bond, iOi, iSi, iN(R9)i,
optionally substituted alkylene, iN(R9)C(X')iN
(R9,)i, where each of R9 and R9! is independently
hydrogen or C l-C4 alkyl;
US 8,962,830 B2
4
3
R5 is selected from optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocy
clyl, and optionally substituted cycloalkyl;
atoms and have at least 1 and preferably from 1-2, carbon to
carbon,
double
bonds.
Examples
include
ethenyl
(iCH:CH2), n-propenyl (4CH2CH:CH2), iso-propenyl
X and X' are independently selected from O, S and NR7;
(iC(CH3):CH2), but-2-enyl (iCHZCH:CHCH3), and
R6 is selected from optionally substituted C l-C6 alkyl,
the like.
The term “alkynyl” as used herein refers to monovalent
alkynyl groups Which may be straight chained or branched
and preferably have from 2 to 10 carbon atoms, more prefer
ably 2 to 6 carbon atoms and most preferably 2 to 4 carbon
atoms and have at least 1, and preferably from 1-2, carbon to
optionally substituted Cl-C6 alkoxy, optionally substi
tuted C2-C6alkenyl, optionally substituted C2-C6 alky
nyl, optionally substituted heteroaryl, optionally substi
tuted heterocyclyl, optionally substituted aryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted amino, optionally
substituted acylamino, optionally substituted arylacyl,
optionally substituted heteroarylacyl, optionally substi
tuted heterocyclylacyl, optionally substituted
cycloalkylacyl, and trihalomethyl;
carbon, triple bonds. Examples of alkynyl groups include
ethynyl (iCECH), propargyl (4CH2CECH), pent-2-ynyl
(iCHZCECCHziCHQ, and the like.
The term “amino” as used herein refers to the group
iNR*R* Where each R* is independently hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, and heterocyclyl and Where each
of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as
R7 is selected from hydrogen, cyano, optionally substituted
Cl-C6 alkyl, optionally substituted aryl, S(O)2R8, and
optionally substituted aminoacyl; and
R8 is selected from optionally substituted C l-C6 alkyl and
optionally substituted aryl.
described herein.
The term “aminoacyl” as used herein refers to the group
20
In a further aspect the invention provides pharmaceutical
compositions comprising a compound of formula (I) or a salt
thereof, together With at least one pharmaceutically accept
able adjuvant, carrier or diluent.
In a further aspect the invention provides a method of
treating a disease or condition characterised by cell prolifera
tion including the step of administering an effective amount
of a compound of formula (I) or a salt thereof to a patient in
need thereof.
In still a further aspect the invention provides the use of a
compound of formula (I) or a salt thereof in the manufacture
cycloalkyl, is as described herein.
“Acylamino” refers to the group iNR*C(O)R* Where
each R* is independently hydrogen, alkyl, cycloalkyl, aryl,
25
heteroaryl and heterocyclyl and Where each of alkyl,
cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described
herein, and preferably hydrogen and C l-C4 alkyl.
“Oxyacylamino” refers to the group iNR*C(O)OR*
30
Where each R* is independently hydrogen, alkyl, cycloalkyl,
aryl, heteroaryl and heterocyclyl and Where each of alkyl,
cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described
herein, and preferably hydrogen and C l-C4 alkyl.
of a medicament for the treatment of a disease or condition
The term “cycloalkyl” as used herein refers to cyclic alkyl
characterised by cell proliferation, including cell hyperpro
liferation.
In yet a further aspect the invention also provides the use of
a compound of formula (I) or a salt thereof for the treatment
of a disease or condition characterised by cell proliferation,
4C(O)NR*R* Where each R* is independently hydrogen,
alkyl, cycloalkyl and aryl, and Where each of alkyl, aryl, and
35
groups having a single cyclic ring or multiple condensed
rings, preferably incorporating 3 to 8 carbon atoms. Such
cycloalkyl groups include, by way of example, single ring
structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclooctyl, and the like, or multiple ring struc
including cell hyperproliferation.
tures such as adamantanyl, and the like.
DETAILED DESCRIPTION OF THE INVENTION
40
The term “alkyl” as used herein refers to monovalent alkyl
groups Which may be straight chained or branched and pref
erably have from 1 to 10 carbon atoms, more preferably 1 to
6 carbon atoms and most preferably 1 to 4 carbon atoms.
cyclobut-2-enyl,
45
Examples of such alkyl groups include methyl, ethyl, n-pro
pyl, iso-propyl, n-butyl, iso-butyl, and the like.
“Heteroaryl” refers to a monovalent aromatic carbocyclic
group, preferably of from 2 to 10 carbon atoms and l to 4
50
mers (e.g., 4CH2CH2CH2i and iCH(CH3)CH2i), and
the like.
55
erably having from 6 to 14 carbon atoms. Examples of aryl
groups include phenyl, naphthyl and the like.
The term “acyl” refers to groups H4C(O)i, alkyl-C
“Heteroarylacyl” refers to the group iC(O)heteroaryl
Where heteroaryl is given the meaning referred to above.
“Heteroarylthio” as used herein refers to the group *8
heteroaryl Wherein the heteroaryl group is as described
above.
(O)i, cycloalkyl-C(O)i, aryl-C(O)i, heteroaryl-C(O)i
60
eroaryl and heterocyclyl are as described herein.
The term “arylacyl” as used herein refers to the group
iC(O)aryl Where the aryl group is as described above.
The term “alkenyl” as used herein refers to a monovalent
alkenyl groups Which may be straight chained or branched
and preferably have from 2 to 10 carbon atoms, more prefer
ably 2 to 6 carbon atoms and most preferably 2 to 4 carbon
heteroatoms selected from oxygen, nitrogen and sulfur Within
the ring. The most preferred heteroatoms are nitrogen, oxy
gen, and sulfur. Such heteroaryl groups can have a single ring
(e.g., pyridyl, pyrrolyl, imididazolyl, thienyl, or furanyl) or
multiple condensed rings (e.g., indoliZinyl or benzothienyl).
The term “aryl” as used herein refers to an unsaturated
and heterocyclyl-C(O)i, Where alkyl, cycloalkyl, aryl, het
cyclohex-4-enyl,
The term “halo” or “halogen” as used herein refers to
The term “alkylene” as used herein refers to divalent alkyl
aromatic carbocyclic group having a single ring (eg., phenyl)
or multiple condensed rings (eg., naphthyl or anthryl), pref
cyclopent-3-enyl,
cyclooct-3-enyl and the like.
?uoro, chloro, bromo and iodo.
groups. Examples of such alkylene groups include methylene
(4CH2i), ethylene (4CH2CH2i), and the propylene iso
“Cycloalkenyl” refers to cyclic alkenyl groups having a
single cyclic ring and at least one point of internal unsatura
tion, preferably incorporating 4 to 8 carbon atoms. Examples
of suitable cycloalkenyl groups include, for instance,
65
“Heterocyclyl” as used herein refers to a monovalent satu
rated or unsaturated group having a single ring or multiple
condensed rings, preferably from 1 to 8 carbon atoms and
from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxy
gen, selenium or phosphorous Within the ring. The most pre
ferred heteroatoms are nitrogen and oxygen. Examples of
heterocyclyl groups include morpholinyl, piperidinyl and
piperaZinyl.
US 8,962,830 B2
6
5
“Heterocyclylacyl” as used herein refers to the group
In an embodiment L is a bond and R5 is a phenyl group
iC(O)heterocyclyl Where heterocyclyl is given the meaning
substituted With halo and hydroxy.
referred to above.
In an embodiment -LR5 is
In this speci?cation the term “optionally substituted” is
taken to mean that a group may or may not be further substi
tuted or fused (so as to form a condensed polycyclic group)
Br
With one or more groups. Substituents may be selected from
hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
alkynyloxy, amino, aminoacyl, oxyacylamino, thio, aryla
lkyl, arylalkoxy, aryl, aryloxy, carboxyl, cycloalkyl, cyano,
halogen, nitro, sulphate, phosphate, heterocyclyl, heteroaryl,
heterocyclyloxy, heteroaryloxy, trihalomethyl, and trialkylsi
lyl.
OH.
In an embodiment L is a bond and R5 is a heteroaryl group.
In an embodiment -LR5 is
In an embodiment L is 40*, iSi, iN(R9)i, option
ally substituted alkylene (preferably Cl-C3 alkylene), or
iN(R9)CQ(')iN(R9)i, Where each of R9 and R9! is inde
pendently hydrogen or C l-C4 alkyl.
In an embodiment L is a bond.
In an embodiment L is a bond and R5 is selected from
20
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, and optionally substi
tuted cycloalkyl.
In an embodiment L is a bond and R5 is an optionally
substituted aryl or optionally substituted heteroaryl.
In an embodiment L is a bond and R5 is a phenyl group
25
substituted With aryloxy.
In an embodiment L is a bond and R5 is an optionally
substituted phenyl.
In an embodiment -LR5 is
In an embodiment L is a bond and R5 is a phenyl group
substituted one to three times With substitutent groups inde
pendently selected from halo, hydroxyl, acyl, Cl-C8 alkyl,
C2-C6 alkenyl, C2-C6 alkenyloxy, amino, oxyacylamino,
Cl-C8 alkoxy, aryl, aryloxy, carboxyl, cycloalkyl, cycloalky
loxy, cyano, sulphate, phosphate, heterocyclyl, heterocycly
loxy, heteroaryl, heteroaryloxy, trihalomethyl, and trialkylsi
lyl.
30
g
35
In an embodiment L is a bond and R5 is a phenyl group
substituted one or two times With substituent groups indepen
In an embodiment L is 4CH2i and R5 is a phenyl group
dently selected from halo, hydroxyl, acyl, C l-C8 alkyl, C2-C6
alkenyl, C2-C6 alkenyloxy, amino, oxyacylamino, Cl-C8
alkoxy, aryl, aryloxy, carboxyl, cycloalkyl, cycloalkyloxy,
0
substituted With halo, hydroxy, and C l-C3 alkyl.
In an embodiment L is 4CH2i and R5 is a phenyl group
40
cyano, sulphate, phosphate, heterocyclyl, heterocyclyloxy,
heteroaryl, heteroaryloxy, trihalomethyl, and trialkylsilyl,
and preferably Cl-C4 alkyl, hydroxy, oxyacylamino, het
substituted With hydroxy.
In an embodiment -LR5 is
eroaryl, aryloxy, and halo.
In an embodiment L is a bond and R5 is a phenyl group
45
substituted With hydroxyl.
In an embodiment -LR5 is
OH
OH.
In an embodiment L is 4CH2i and R5 is a phenyl group
substituted With C l-C3 alkyl.
In an embodiment L is a bond and R5 is a phenyl group
In an embodiment -LR5 is
substituted With C l-C4 alkoxy and iNHC(O)OCl-C4 alkyl.
In an embodiment -LR5 is
60
HTO+ I
DCQiT O
65
In an embodiment, L is 4CH2i and R5 is a phenyl group
substituted With chloro and C l-C4 alkyl.
US 8,962,830 B2
8
7
With reference to compounds of formula (I) and (Ia), pref
erably R10 is Cl-C4 alkyl or halo.
In an embodiment -LR5 is
In a further preferred embodiment and With reference to
Cl
compounds of formula (I) and (Ia), R3 and R4 are indepen
dently Cl-C3 alkyl, and R10 is Cl-C4 alkyl or halo.
In a further aspect the invention provides compounds of
formula (lb) or salts thereof,
In an embodiment -LR5 is phenyl.
10
In an embodiment L is a bond and R5 is a phenyl group
substituted With a substituent group selected from halo,
hydroxyl, acyl, Cl-C8 alkyl, C2-C6 alkenyl, C2-C6 alkeny-
Formula (1b)
loxy, amino, Cl-C8 alkoxy, aryl, aryloxy, carboxyl, i 5
cycloalkyl, cycloalkyloxy, cyano, sulphate, phosphate, het
erocyclyl, trihalomethyl, and trialkylsilyl.
R10
HZN
In a preferred embodiment, Where L is a bond and R5 is a
phenyl group, the substituent group, if present, is in the para
\N
position.
20
Accordingly, in a further aspect the invention provides
/ \
N
compounds of formula (Ia) or salts thereof,
\N
>
/
NR
JVN/\R21
Formula (Ia) 25
R3 R4
30
wherein:
R1 is selected from hydrogen, optionally substituted alkyl,
i(SOZ)-optionally substituted aryl, i(SOZ)-option
35
ally substituted heteroaryl, optionally substituted het
eroaryl, optionally substituted heterocyclyl, optionally
h
W
_
substituted aryl, and C(:X)iR6;
erem:
-
R1 is selected from hydrogen, optionally substituted alkyl,
i(SO2)-optionally substituted aryl, i(SOZ)-option- 40
ally substituted heteroaryl, optionally substituted hetero
l, o tionall
substituted heteroc cl 1, o tionall
subguteg aryl, aid C(IX)iR6; y y p
y
R215 selected from hydrogen and C1_C3 alkyl;
R3 and R4 are independently Cl-C3 alkyl;
45
R10 is selected from hydrogen, halo, Cl-C4 alkyl, C2-C4
alkynyl, C2-C4 alkenyl, arylalkyl, ORl (where R1 is H,
C l-C3 alkyl or aryl), COOR2 (Where R2 is H, C l-C3 alkyl
or aryl), nitro, cyano, amino, trihalomethyl, thio, and
thio C1-C3 alkyl;
50
R2 ls seleCted from hydmgen and C1-C3 alkyl’
R3 and R4 are independently C1-C3 alkyl;
R10 is C1_C4a1ky1 or halo;
.
_
X is selected from O, S and NR7,
R6 is selected from optionally substituted Cl-C6 alkyl,
optionally substituted Cl-C6 alkoxy, optionally substi
tuted C2-C6 alkenyl, optionally substituted C2-C6 alky
nyl, optionally substituted heteroaryl, optionally substi
tuted heterocyclyl, optionally substituted aryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted amino, optionally
X is seleCted from O: S and NR7;
substituted acylamino, optionally substituted arylacyl,
R6 is_se1e0ted from Optionally SUbStimte‘l Cl'C6 alky_1>
optionally substituted heteroarylacyl, optionally substi
optionally substituted C1 -C6 alkoxy,'optionally subst1-
tuted
tuted Cg-C6 alkenyl,'optionally substituted C2-C6 alky-
cycloalkylacyla and trihalomethyl;
nyl, optionally substituted heteroaryl, optionally subst1- 55
tuted
heterocyclyl,
Optionally
substituted
aryl,
_
Optionally
substituted
_
R7 is selected from hydrogen, cyano, acyl, optionally sub
optionally substituted cycloalkyl, optionally substituted
smuted C1—C6 alkyl: Optionally SPbSIimted ary 1: 8(0)
cycloalkenyl, optionally substituted ammo, optionally
substituted acylamino, optionally substituted arylacyl,
optionally substituted heteroarylacyl, optionally substi- 60
tuted heterocyclylacyl, optionally substituted
cycloalkylacyl, and trihalomethyl;
ZRS’ 411d UPUUIMHY W‘meut‘? 4111111U4W1, 411d
R8 is selected from Optionally substituted C1-C6 alkyl, and
Optionally substituted ary1_
In an embodiment and With reference to formula (Ia) or
(Ib), R10 is methyl or chloro.
R7 is selected from hydrogen, cyano, optionally substituted
In a further embodiment and With reference to formula (Ia)
Cl-C6 alkyl, optionally substituted aryl, S(O)2R8, and
optionally substituted aminoacyl; and
R8 is selected from optionally substituted C l-C6 alkyl and
optionally substituted aryl.
heterocyclylacyl,
65
or (Ib), R10 is methyl.
Accordingly, in a further aspect the invention provides
compounds of formula (Ic) or salts thereof,
US 8,962,830 B2
10
R2 is selected from hydrogen and C l-C3 alkyl;
X is selected from O, S and NR7;
Formula (Ic)
R6 is selected from optionally substituted Cl-C6 alkyl,
optionally substituted Cl-C6 alkoxy, optionally substi
tuted C2-C6 alkenyl, optionally substituted C2-C6 alky
nyl, optionally substituted heteroaryl, optionally substi
tuted heterocyclyl, optionally substituted aryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted amino, optionally
substituted acylamino, optionally substituted arylacyl,
optionally substituted heteroarylacyl, optionally substi
tuted heterocyclylacyl, optionally substituted
cycloalkylacyl, and trihalomethyl;
R7 is selected from hydrogen, cyano, optionally substituted
wherein:
Cl-C6 alkyl, optionally substituted aryl, S(O)2R8, and
optionally substituted aminoacyl; and
R1 is selected from hydrogen, optionally substituted alkyl,
i(SO2)-optionally substituted aryl, i(SOZ)-option
R8 is selected from optionally substituted C l-C6 alkyl and
ally substituted heteroaryl, optionally substituted het
optionally substituted aryl.
eroaryl, optionally substituted heterocyclyl, optionally
In an embodiment and With reference to formula (I), (Ia),
substituted aryl, and C(:X)iR6;
R2 is selected from hydrogen and C l-C3 alkyl;
R3 and R4 are independently C l-C3 alkyl;
(Ib), (Ic) or (Id), R2 is hydrogen or methyl.
In a further embodiment and With reference to formula (I),
(Ia), (Ib), (Ic) or (Id), R2 is hydrogen.
X is selected from O, S and NR7;
Accordingly in a further aspect the invention provides
compounds of formula (Ie), or salts thereof,
R6 is selected from optionally substituted Cl-C6 alkyl,
optionally substituted Cl-C6 alkoxy, optionally substi
tuted C2-C6 alkenyl, optionally substituted C2-C6 alky
nyl, optionally substituted heteroaryl, optionally substi
tuted heterocyclyl, optionally substituted aryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted amino, optionally
substituted acylamino, optionally substituted arylacyl,
optionally substituted heteroarylacyl, optionally substi
tuted heterocyclylacyl, optionally substituted
cycloalkylacyl, and trihalomethyl;
R7 is selected from hydrogen, cyano, optionally substituted
Formula (Ie)
30
35
Cl-C6 alkyl, optionally substituted aryl, S(O)2R8, and
optionally substituted aminoacyl; and
R8 is selected from optionally substituted C l-C6 alkyl and
optionally substituted aryl.
In an embodiment and With reference to formula (I), (Ia),
40
wherein:
(lb) or (Ic), R3 and R4 are independently selected from C l-C2
R1 is selected from hydrogen, optionally substituted alkyl,
alkyl.
i(SOZ)-optionally substituted aryl, i(SOZ)-option
In a further embodiment and With reference to formula (I),
(Ia), (lb) or (Ic), R3 and R4 are methyl.
Accordingly, in a further aspect the invention provides
compounds of formula (Id) or salts thereof,
ally substituted heteroaryl, optionally substituted het
45
eroaryl, optionally substituted heterocyclyl, optionally
substituted aryl, and C(:X)iR6;
X is selected from O, S and NR7;
R6 is selected from optionally substituted Cl-C6 alkyl,
optionally substituted Cl-C6 alkoxy, optionally substi
Formula (Id)
50
55
tuted C2-C6 alkenyl, optionally substituted C2-C6 alky
nyl, optionally substituted heteroaryl, optionally substi
tuted heterocyclyl, optionally substituted aryl,
optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted amino, optionally
substituted acylamino, optionally substituted arylacyl,
optionally substituted heteroarylacyl, optionally substi
tuted heterocyclylacyl, optionally substituted
cycloalkylacyl, and trihalomethyl;
R7 is selected from hydrogen, cyano, optionally substituted
Cl-C6 alkyl, optionally substituted aryl, S(O)2R8, and
optionally substituted aminoacyl; and
wherein:
R8 is selected from optionally substituted C l-C6 alkyl and
R1 is selected from hydrogen, optionally substituted alkyl,
optionally substituted aryl.
i(SO2)-optionally substituted aryl, i(SOZ)-option
ally substituted heteroaryl, optionally substituted het
eroaryl, optionally substituted heterocyclyl, optionally
substituted aryl, and C(:X)iR6;
65
In still a further embodiment and With reference to formula
(I), (Ia), (Ib), (Ic), (Id) or (Ie) R1 is selected from the following
preferred groups:
US 8,962,830 B2
11
12
a) hydrogen;
(ii) a 6-membered heteroaryl group selected from pyridine,
pyrimidine, pyraZine, and 1,3,5-triaZine;
Wherein heterocyclyl preferably represents:
b) optionally substituted C l-C6 alkyl, and more preferably
C l-C6 alkyl;
c) i(SOZ)i optionally substituted aryl or i(SOZ)i
optionally substituted heteroaryl;
(i) a 5-membered heterocyclyl group selected from l-pyr
5
roline, 2-pyrroline, 3-pyrroline, pyrrolidine, tetrahydro
furan, tetrahydrothiophene, 2-pyrazoline, 3-pyrazoline,
d) C(:X)iR6 Where X is O, S and NR7, Wherein R6 is
selected from optionally substituted alkyl, optionally
2-imidazoline, pyrazolidine, imidazolidine, 3-diox
substituted aryl, optionally substituted heteroaryl,
optionally substituted aryl-Cl_3alkyl, optionally substi
tuted heteroaryl-Cl_3alkyl, optionally substituted aryl
Cl_3alkoxy, optionally substituted heteroaryl-CL3
olane, thiazolidine, and isoxazolidine; or
(ii) a 6-membered heterocyclyl group selected from
2H-pyran, 4H-pyran, 3,4-dihydro-2H-pyran, piperidine,
l,4-ovaine, l,4-dioxine, piperaZine, morpholine,
lH-dioxane, l,4-thaZine, thiomorpholine, l,4-oxathane,
alkoxy, tri?uoroalkyl, NR'R" (Where R' is hydrogen or
Cl_3 alkyl, and R" is hydrogen, optionally substituted
alkyl, or optionally substituted arylacyl) and R7 is hydro
gen, optionally substituted aryl, or optionally substi
15
tuted Cl_3alkyl.
l,4-dithane, 1,3,5-trioxane, 6H-l ,2,5-thiadiaZine, 2H-l,
5,2-dithiaZine, and 1,3,5-trithiane;
and Wherein preferably aryl is selected from phenyl,
napthyl and anthracenyl;
and Where the heteroaryl, heterocyclyl or aryl group may be
substituted from 1 to 4 times by the group consisting of
In still a further embodiment and With reference to formula
(I), (Ia), (Ib), (Ic), (Id) or (Ie) R1 is selected from the following
preferred groups:
hydroxyl, acyl, Cl-C4 alkyl, Cl-C4 alkoxy, C2-C6 alkenyl,
C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, iOi
20 (CH2)H>H, *O*(CH2)M%)C1-C3 alkyl, *(CHzp
amino, i(CH2)n-diCl-C3 alkyl amino, i(CH2)n-aminoa
cyl, i(CH2)n-thio, arylalkyl, i(CH2)n-arylalkoxy,
i<CH2)n-ary1, i<CH2):-aryloxy, *(CHZL-carboxyl,
0
— C — optionally substituted heteroaryl/hetero cyclyl
i(CH2)n-cycloalkyl, cyano, halogen, nitro, sulphate, phos
25 phate,
i(CH2)n-heterocyclyl,
i(CH2)n-heteroaryl,
i(CH2)n-trihalomethyl, and i(CH2)n-trialkylsilyl, Wherein
O
— C — optionally substituted aryl
O
n is an integer from 0-6.
In an embodiment, 4C(O)-optionally substituted Cl-C6
— C —O — CH2 — optionally substituted aryl
alkyl includes:
4C(O)i(CH2)n-substituent,
— C — optionally substituted C 1—C6 alkyl
Where n is an integer from 1 to 6
and the substituent group is selected from:
a) iNC(O)O-optionally substituted phenyl;
— C — O — CH2 — optionally substituted heteroaryl/heterocyclyl
b) %(O)Cl-C3 alkyl;
c) 4OCl-C3 alkyl;
35
e) -optionally substituted phenyl;
f) %N;
g) 404C1-C3 alkylene-optionally substituted phenyl;
— C — optionally substituted heteroaryl/hetero cyclyl
i
S
— C — optionally substituted aryl
d) 4O-optionally substituted phenyl;
40
S
and
h) -amino.
In a further embodiment and With reference to formula (I),
(Ia), (Ib), (Ic), or (Ie), R1 is C(O)R6 Where R6 is de?ned above.
In a further embodiment the invention provides com
— C —O — CH2 — optionally substituted aryl
pounds of formula (If):
45
(If)
50
HZN
\N
/ \ 2
— S — optionally substituted aryl/heteroaryl
N
S
55
\
N
N
N\"/ optionally substituted heteroaryl
— C — NH — optionally substituted aryl
S
H
O
— C — NH — C — optionally substituted aryl
60
Wherein heteroaryl preferably represents:
(i) a 5-membered heteroaryl group selected from pyrrole,
Preferably, and With reference to formula (If) compounds,
the optionally substituted heteroaryl group is selected from
optionally substituted pyridyl or optionally substituted thia
Zolyl. Preferred substituents, When present, include
2H-pyrrole, furan, pyrazole, thiophene, isothiazole,
thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 65 i(CH2)n-heterocyclyl, optionally substituted Cl-C4 alkoxy
and optionally substituted phenyl, Where n is an integer from
1,2,5-oxadiazole, 1,3,4-thiadiazole, tetrazole, imida
Zole, oxazole, and isoxazole; or
0-4.
US 8,962,830 B2
33
34
-continued
-continued
HZN
%
HN
NBoc
NHBoc
20
25
30
35
45
50
55
60
65
US 8,962,830 B2
35
36
-continued
-continued
HZN
\N» S
4HN
/
\Nl
HN
NH2
TFA
65
O
US 8,962,830 B2
37
-continued
-continued
N
\
\N
NH;
R3
R4
NH
(3)
iStepF
HZN
R5/L
The compounds of the present invention may be prepared
by the following general reaction sequence depicted in the
HZN
Step
N/\
2 LG
\N
N
Schemes beloW:
G)
Scheme 1
R3
N NH3 A 9
N/\\ N)
Wm
R4
25
(10)
(1)
RS/L
\N
(9)
Wherein
(2)
30
and
R4 H
N
R3
represent nitrogen protecting groups, and variables R3-R5 and
L are as de?ned above.
N02
Preferred conditions for the steps outlined in Scheme 1
include:
(3)
lStep B
40
Step A: Addition of the 2,2-disubstituted nitroethene (1) to
protected carbazate (2) may be facilitated by mixing the
starting materials (in preferably equimolar amounts) in an
aqueous solvent system. Preferably the solvent system is
1:1 water/acetonitrile. Preferably the reaction is conducted
R3
R4 H
N
R
\ NH
Stgp
R4 §
3
at room temperature. The reaction progress can be moni
\ NH
tored by layer chromatography (TLC) [e.g., CH2Cl2/
MeOH 90: 10].
Step B: The reduction of (3) to primary amine (4) may be
facilitated by any suitable reducing agent known in the art
4—
NH
NH;
(4)
(5)
50
lStep D
55
N\
(9
NH3
Step E
Xe
or Raney nickel as catalysts. More preferably the reduction
process is catalysed by 10% Pd/C in the presence of ammo
nium forrnate in a polar protic solvent such as methanol.
This reaction is preferably conducted at room temperature
and the reaction progress may be monitored by TLC (e. g.,
CH2C12/MeOH 95:5). The crude reaction product may be
separated from the catalyst by ?ltration and used in the next
step Without any further puri?cation.
Step C: Involves the protection of the primary amine group.
Suitable nitrogen protecting groups for
R4 H
R3
such as FeCl3, and sodium dithionite. The reduction may
also be facilitated by hydrogenation using pallasium (Pd)
R5\L
NH
NC
OMe
(6)
CN
(7)
and