NZ621314B2 - Amino quinazolines as kinase inhibitors - Google Patents
Amino quinazolines as kinase inhibitors Download PDFInfo
- Publication number
- NZ621314B2 NZ621314B2 NZ621314A NZ62131412A NZ621314B2 NZ 621314 B2 NZ621314 B2 NZ 621314B2 NZ 621314 A NZ621314 A NZ 621314A NZ 62131412 A NZ62131412 A NZ 62131412A NZ 621314 B2 NZ621314 B2 NZ 621314B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- alkoxy
- benzo
- tert
- butylsulfonyl
- Prior art date
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- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 4
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title description 3
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- -1 cyano, hydroxyl Chemical group 0.000 claims description 398
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- 125000005843 halogen group Chemical group 0.000 claims description 95
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07D471/04—Ortho-condensed systems
Abstract
Disclosed herein are 4-amino quinazoline compounds of Formula I wherein the substituents are as defined herein, and methods of making and using the same. The compounds are intended for use as RIP2 Kinase inhibitors and therefore in the treatment of conditions including dermatitis, arthritis, diabetes, ulcerative colitis and Crohn's disease. Specific examples of the compounds of formula I include: N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-4-quinazolinamine and 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol. s, ulcerative colitis and Crohn's disease. Specific examples of the compounds of formula I include: N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)sulfonyl]-4-quinazolinamine and 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol.
Description
AMINO QUINAZOLINES AS KINASE INHIBITORS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to quinazolyl amines that inhibit RIP2 kinase and methods
of making and using the same. Specifically, the present invention relates to substituted
quinazolyl amines as RIP2 kinase inhibitors.
Background of the Invention
Receptor interacting protein-2 (RIP2) kinase, which is also referred to as CARD3, RICK,
CARDIAK, or RIPK2, is a TKL family serine/threonine protein kinase involved in innate
immune signaling. RIP2 kinase is composed of an N-terminal kinase domain and a C-terminal
caspase-recruitment domain (CARD) linked via an intermediate (IM) region ((1998) J. Biol.
Chem. 273, 12296-12300; (1998) Current Biology 8, 885-889; and (1998) J. Biol. Chem. 273,
16968-16975). The CARD domain of RIP2 kinase mediates interaction with other CARD-
containing proteins, such as NOD1 and NOD2 ((2000) J. Biol. Chem. 275, 27823-27831 and
(2001) EMBO reports 2, 736-742). NOD1 and NOD2 are cytoplasmic receptors which play a
key role in innate immune surveillance. They recognize both gram positive and gram negative
bacterial pathogens and are activated by specific peptidoglycan motifs, diaminopimelic acid (i.e.,
DAP) and muramyl dipeptide (MDP), respectively ((2007) J Immunol 178, 2380-2386).
Following activation, RIP2 kinase associates with NOD1 or NOD2 and appears to
function principally as a molecular scaffold to bring together other kinases (TAK1, IKKα/β/γ)
involved in NF-κB and mitogen-activated protein kinase activation ((2006) Nature Reviews
Immunology 6, 9-20). RIP2 kinase undergoes a K63-linked polyubiquitination on lysine-209
which facilitates TAK1 recruitment ((2008) EMBO Journal 27, 373-383). This post-translational
modification is required for signaling as mutation of this residue prevents NOD1/2 mediated NF-
kB activation. RIP2 kinase also undergoes autophosphorylation on serine-176, and possibly
other residues ((2006) Cellular Signalling 18, 2223-2229). Studies using kinase dead mutants
(K47A) and non-selective small molecule inhibitors have demonstrated that RIP2 kinase activity
is important for regulating the stability of RIP2 kinase expression and signaling ((2007) Biochem
J 404, 179-190 and (2009) J. Biol. Chem. 284, 19183-19188).
Dysregulation of RIP2-dependent signaling has been linked to autoinflammatory diseases.
Gain-of-function mutations in the NACHT-domain of NOD2 cause Blau Syndrome, early-onset
sarcoidosis, a pediatric granulomateous disease characterized by uveitis, dermatitis, and arthritis
((2001) Nature Genetics 29, 19-20; (2005) Journal of Rheumatology 32, 373-375; (2005)
Current Rheumatology Reports 7, 427-433; (2005) Blood 105, 1195-1197; (2005) European
Journal of Human Genetics 13, 742-747; (2006) American Journal of Ophthalmology 142,
1089-1092; (2006) Arthritis & Rheumatism 54, 3337-3344; (2009) Arthritis & Rheumatism 60,
1797-1803; and (2010) Rheumatology 49, 194-196). Mutations in the LRR-domain of NOD2
have been strongly linked to susceptibility to Crohn’s Disease ((2002) Am. J. Hum. Genet. 70,
845-857; (2004) European Journal of Human Genetics 12, 206-212; (2008) Mucosal
Immunology (2008) 1 (Suppl 1), S5–S9. 1, S5-S9; (2008) Inflammatory Bowel Diseases 14, 295-
302; (2008) Experimental Dermatology 17, 1057-1058; (2008) British Medical Bulletin 87, 17-
; (2009) Inflammatory Bowel Diseases 15, 1145 – 1154 and (2009) Microbes and Infection
11, 912-918). Mutations in NOD1 have been associated with asthma ((2005) Hum. Mol. Genet.
14, 935-941) and early-onset and extra-intestinal inflammatory bowel disease ((2005) Hum. Mol.
Genet. 14, 1245-1250). Genetic and functional studies have also suggested a role for RIP2-
dependent signaling in a variety of other granulomateous disorders, such as sarcoidosis ((2009)
Journal of Clinical Immunology 29, 78-89 and (2006) Sarcoidosis Vasculitis and Diffuse Lung
Diseases 23, 23-29) and Wegner’s Granulomatosis ((2009) Diagnostic Pathology 4, 23).
A potent, selective, small molecule inhibitor of RIP2 kinase activity would block RIP2-
dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in
autoinflammatory diseases characterized by increased and/or dysregulated RIP2 kinase activity.
SUMMARY OF THE INVENTION
The invention is directed to quinazolyl amine compounds according to Formula (I):
wherein:
R is H, -SO (C -C )alkyl, -CO(C -C )alkyl, or (C -C )alkyl;
2 1 4 1 4 1 4
2 a a a a
R is - SR , -SOR , or -SO R , wherein R is (C -C )alkyl, halo(C -C )alkyl,
2 1 6 1 6
(C -C )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl, wherein:
said (C -C )alkyl is optionally substituted by one or two groups each independently
selected from cyano, hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy, -CO H,
1 6 1 6 2 6 2
-CO (C -C )alkyl, -SO (C -C )alkyl, (C -C )cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10
2 1 4 2 1 4 3 7
membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C -C alkyl)amino-, wherein
said (C -C )cycloalkyl, phenyl, (phenyl)(C -C alkyl)amino-, 5-6 membered heteroaryl, 9-10
3 7 1 4
membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups
each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-,
3 1 4
((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl and
1 4 1 4 1 4 1 4 1 4
(C -C )alkoxy,
said (C -C )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3
groups each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-,
3 1 4
((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl-,
1 4 1 4 1 4 1 4 1 4
oxo and (C -C )alkoxy, and
said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected
from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-, ((C -C )alkyl)((C -C )alkyl)amino-,
3 1 4 1 4 1 4
(C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and (C -C )alkoxy;
1 4 1 4 1 4 1 4
R is H, halogen, hydroxy, (C -C )alkyl-,(C -C )alkenyl-, halo(C -C )alkyl-,
1 4 2 4 1 4
(C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )alkoxy(C -C )alkyl-,
1 4 1 4 1 4 1 6
halo(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkoxy-
1 4 1 6 1 4 2 6 1 4 2 6
, hydroxy(C -C )alkyl-, hydroxy(C -C )alkoxy-, cyano(C -C )alkyl-, cyano(C -C )alkoxy-,
1 6 2 6 1 4 2 6
carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-
1 6 1 4 1 6 3 6 1 4
, (C -C )cycloalkoxy-, 4-6 membered-heterocycloalkyl(C -C )alkoxy-, or 4-6 membered-
3 6 1 4
heterocycloalkoxy-,
wherein the halo(C -C )alkyl-, halo(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkyl-, or
1 4 1 4 1 4 1 6
halo(C -C )alkoxy(C -C )alkoxy- groups contain 2 or 3 halo atoms; and
1 4 2 6
wherein the (C -C )cycloalkyl moiety of the (C -C )cycloalkyl(C -C )alkoxy- or
3 6 3 6 1 4
(C -C )cycloalkoxy-, is optionally substituted by a group selected from cyano, halo, hydroxyl,
(C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy;
1 6 1 4 2 6
wherein the 4-6 membered-heterocycloalkyl moiety of the 4-6 membered-
heterocycloalkyl(C -C )alkoxy-, or 4-6 membered-heterocycloalkoxy-, is optionally substituted
by a group selected from cyano, halo, hydroxyl, (C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy;
1 6 1 4 2 6
8 9 10
Z is phenyl or pyridyl substituted by R , R and R , wherein:
R and R are located on adjacent atoms and taken together with the atoms to which they
are attached form a 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms each
independently selected from N, O and S, which 5-membered heterocyclic group is substituted by
11
wherein one of R or R is H, halogen, cyano, (C -C )alkyl, halo(C -C )alkyl,
1 4 1 4
(C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or
1 4 1 4 1 4
aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally
substituted by 1-3 substituents each independently selected from halogen, -CF , (C -C )alkyl and
3 1 4
(C -C )alkoxy; and
11
the other of R or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl
3 1 4 1 4
or (C -C )alkoxy; or
R 14
Z is pyrazolyl, having the formula: wherein:
R is H, methyl or hydroxymethyl;
R is methyl, trifluoromethyl or hydroxymethyl;
R is H, OH, or (C -C )alkyl; or
12 13
R and R , taken together with the atoms to which they are attached, form a 6 membered
16
carbocyclic ring or heterocyclic ring substituted by R and R , wherein the heterocyclic ring
contains 1 nitrogen atom;
16
wherein R and R are each independently selected from H, halogen, cyano, (C1-C4)alkyl,
halo(C -C )alkyl, (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl,
1 4 1 4 1 4
hydroxy(C -C )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or
phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected
from halogen, -CF , (C -C )alkyl and (C -C )alkoxy;
3 1 4 1 4
or a salt thereof.
The compounds according to Formula (I), or salts, particularly pharmaceutically
acceptable salts, thereof, are inhibitors of RIP2 kinase.
Accordingly, also described herein is a method of inhibiting RIP2 kinase which method
comprises contacting a cell with a compound according to Formula (I), or a salt, particularly a
pharmaceutically acceptable salt, thereof.
Also described herein is a method of treating a RIP2 kinase-mediated disease or disorder
which comprises administering a therapeutically effective amount of a compound according to
Formula (I), or a salt, particularly a pharmaceutically acceptable salt thereof, to a patient (a
human or other mammal, particularly, a human) in need thereof. Examples of RIP2
kinase-mediated diseases or disorders include uveitis, Crohn’s disease, ulcerative colitis,
early-onset and extra-intestinal inflammatory bowel disease and granulomateous disorders, such
as sarcoidosis, Blau syndrome, early-onset sarcoidosis and Wegner’s Granulomatosis.
The present invention is further directed to a pharmaceutical composition comprising a
compound according to Formula (I), or a salt, particularly a pharmaceutically acceptable salt,
thereof and a pharmaceutically acceptable excipient. Particularly, this invention is directed to a
pharmaceutical composition for the treatment of a RIP2 kinase-mediated disease or disorder,
where the composition comprises a compound according to Formula (I), or a salt, particularly a
pharmaceutically acceptable salt, thereof and a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the combined cytokine response in rat whole blood samples obtained after
pre-dosing rats with the compound of Example 4 or prednisolone, followed by dosing
with L18-MDP.
Figure 2 shows the combined cytokine response in rat whole blood samples obtained after
pre-dosing rats with the compound of Example 6 or prednisolone, followed by dosing
with L18-MDP.
Figure 3 shows the combined cytokine response in rat whole blood samples obtained after
pre-dosing rats with the compound of Example 16 or prednisolone, followed by dosing
with L18-MDP.
Figure 4 shows the combined cytokine response in rat whole blood samples obtained after
pre-dosing rats with the compound of Example 21 or prednisolone, followed by dosing
with L18-MDP.
DETAILED DESCRIPTION OF THE INVENTION
The alternative definitions for the various groups and substituent groups of Formula (I)
provided throughout the specification are intended to particularly describe each compound
species disclosed herein, individually, as well as groups of one or more compound species. The
scope of this invention includes any combination of these group and substituent group
definitions. The compounds of the invention are only those which are contemplated to be
“chemically stable” as will be appreciated by those skilled in the art.
It will also be appreciated by those skilled in the art that when Z is pyrazolyl, the
compounds of this invention may exist as pyrazole isomers represented by Formula (I-A) and
Formula (I-B):
13 N 13 N
12 12
N R N R
(I-A) (I-B)
When R is H, the compounds of this invention may exist as tautomers. However, when
R is (C -C )alkyl, the compounds of this invention, may exist as either one of the regioisomers
represented by Formula (I-A) or Formula (I-B), or as a mixture thereof.
In addition, it will be appreciated by those skilled in the art that the compounds of this
invention, depending on further substitution, may exist in other tautomeric forms. All tautomeric
forms of the compounds described herein are intended to be encompassed within the scope of the
present invention. It is to be understood that any reference to a named compound of this
invention is intended to encompass all tautomers of the named compound and any mixtures of
tautomers of the named compound.
As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon
moiety. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl,
isopropyl, n-butyl, s-butyl, isobutyl, t-butyl and pentyl. The term "C -C alkyl" refers to an alkyl
group or moiety containing from 1 to 4 carbon atoms.
When the term "alkyl" is used in combination with other substituent groups, such as
"haloalkyl" or "hydroxyalkyl" or "arylalkyl", the term "alkyl" is intended to encompass a
divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to
mean the radical –alkylaryl, wherein the alkyl moiety thereof is a divalent straight or
branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented
by the bonding arrangement present in a benzyl group (-CH -phenyl); "halo(C -C )alkyl" or
2 1 4
"(C -C )haloalkyl" is intended to mean a radical having one or more halogen atoms, which may
be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4
carbon atoms, which a is straight or branched-chain carbon radical, and is represented by a
trifluoromethyl group (-CF ).
As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic
hydrocarbon ring. The term “(C -C )cycloalkyl” refers to a non-aromatic cyclic hydrocarbon
ring having from three to eight ring carbon atoms. Exemplary “(C -C )cycloalkyl” groups useful
in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
“Alkoxy” refers to a group containing an alkyl radical attached through an oxygen
linking atom. The term “(C -C )alkoxy” refers to a straight- or branched-chain hydrocarbon
radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
Exemplary “(C -C )alkoxy” groups useful in the present invention include, but are not limited to,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.
"Aryl" represents a group or moiety comprising an aromatic, monocyclic or bicyclic
hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be fused one or more
cycloalkyl rings. Generally, in the compounds of this invention, aryl is phenyl.
A heterocyclic group or moiety is a cyclic group or moiety having as ring members atoms
of at least two different elements (carbon and one or more of nitrogen, oxygen and/or sulfur),
which cyclic group or moiety may be saturated or partially unsaturated (non-aromatic; e.g., a
heterocycloalkyl group or moiety) or fully unsaturated (aromatic; e.g., a heteroaryl group or
moiety).
"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monocyclic
or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms,
unless otherwise specified, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen
and sulfur. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl,
oxetanyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl,
tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl,
thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,
azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and
1,5,9-triazacyclododecyl.
In some of the compounds of this invention, heterocycloalkyl groups include
4-membered heterocycloalkyl groups containing one heteroatom, such as oxetanyl, thietanyl and
azetidinyl.
In other compounds of this invention, heterocycloalkyl groups include 5-membered
heterocycloalkyl groups containing one heteroatom selected from nitrogen, oxygen and sulfur
and optionally containing one or two an additional nitrogen atoms, or optionally containing one
additional oxygen or sulfur atom, such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or
tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl, imidazolinyl,
pyrazolinyl, 1,3-dioxolanyl, and 1,3-oxathiolanon-yl.
In other compounds of this invention, heterocycloalkyl groups are 6-membered
heterocycloalkyl groups containing one heteroatom selected from nitrogen, oxygen and sulfur
and optionally containing one or two an additional nitrogen atoms or one additional oxygen or
sulfur atom, such as piperidyl (or piperidinyl), piperazinyl, morpholinyl, thiomorpholinyl,
1,1dioxoido-thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, tetrahydro-2H-1,4-thiazinyl,
1,4-dioxanyl, 1,3-oxathianyl, and 1,3-dithianyl.
"Heteroaryl" refers to a group or moiety comprising an aromatic monocyclic or bicyclic
radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen,
oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing
an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms,
including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of
heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or
furanyl), isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl),
pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl,
isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl,
indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, and isothiazolyl.
In some embodiments, the heteroaryl groups present in the compounds of this invention
are 5-membered and/or 6-membered monocyclic heteroaryl groups. Selected 5-membered
heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain
1, 2 or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, 3
or 4 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include thienyl,
pyrrolyl, imidazolyl, pyrazolyl, furyl (furanyl), isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl,
thiazolyl, triazolyl and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.
In other embodiments, the heteroaryl groups present in the compounds of this invention
are 9-membered or 10-membered monocyclic heteroaryl groups. Selected 9-10 membered
heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain
1, 2, 3 or 4 additional nitrogen ring atoms.
In some of the compounds of this invention, heteroaryl groups include a 9-membered
heteroaryl group, which includes benzothienyl, benzofuranyl, indolyl, indolinyl, isoindolyl,
isoindolinyl, indazolyl, indolizinyl, isobenzofuryl, 2,3-dihydrobenzofuryl, benzoxazolyl,
benzthiazolyl, benzimidazolyl, benzoxadiazolyl, benzthiadiazolyl, benzotriazolyl,
1,3-benzoxathiolon-yl (2-oxo-1,3-benzoxathiolyl), purinyl and imidazopyridinyl.
In some of the compounds of this invention, heteroaryl groups include a 10-membered
heteroaryl group, which includes chromenyl, chromanyl, quinolyl, isoquinolyl, phthalazinyl,
naphthridinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, tetrahydroquinolinyl, cinnolinyl, and
pteridinyl.
It is to be understood that the terms heterocyclic, heteroaryl, and heterocycloalkyl are
intended to encompass stable heterocyclic groups where a ring nitrogen heteroatom is optionally
oxidized (e.g., heterocyclic groups containing an N-oxide, such as pyridine-N-oxide) or where a
ring sulfur heteroatom is optionally oxidized (e.g., heterocyclic groups containing sulfones or
sulfoxide moieties, such as tetrahydrothienyloxide (a tetrahydrothienyl sulfoxide) or
tetrahydrothienyl-1,1-dioxide (a tetrahydrothienyl sulfone)).
“Oxo” represents a double-bonded oxygen moiety; for example, if attached directly to a
carbon atom forms a carbonyl moiety (C = O). The terms "halogen" and "halo" represent chloro,
fluoro, bromo or iodo substituents. "Hydroxy" or “hydroxyl” is intended to mean the radical
-OH.
As used herein, the terms "compound(s) of the invention" or "compound(s) of this
invention" mean a compound of Formula (I), as defined above, in any form, i.e., any salt or
non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically
acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g.,
liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific
polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi-
hydrates)), and mixtures of various forms.
As used herein, the term “optionally substituted” indicates that a group (such as an alkyl,
cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group) or ring or moiety (such as a
carbocyclic or heterocyclic ring or moiety) may be unsubstituted, or the group, ring or moiety
may be substituted with one or more substituent(s) as defined. In the case where groups may be
selected from a number of alternative groups, the selected groups may be the same or different.
The term “independently” means that where more than one substituent is selected from a
number of possible substituents, those substituents may be the same or different.
In addition, it will be appreciated by those skilled in the art that the compounds of this
invention, depending on further substitution, may exist in other tautomeric forms. All tautomeric
forms of the compounds described herein are intended to be encompassed within the scope of the
present invention. It is to be understood that any reference to a named compound of this
invention is intended to encompass all tautomers of the named compound and any mixtures of
tautomers of the named compound.
In the compounds of Formula (I) of this invention,
R is H, -SO (C -C )alkyl, -CO(C -C )alkyl, or (C -C )alkyl;
2 1 4 1 4 1 4
2 a a a a
R is - SR , -SOR , or -SO R , wherein R is (C -C )alkyl, halo(C -C )alkyl,
2 1 6 1 6
(C -C )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl, wherein:
said (C -C )alkyl is optionally substituted by one or two groups each independently
selected from cyano, hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy, -CO H,
1 6 1 6 2 6 2
-CO (C -C )alkyl, -SO (C -C )alkyl, (C -C )cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10
2 1 4 2 1 4 3 7
membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C -C alkyl)amino-, wherein
said (C -C )cycloalkyl, phenyl, (phenyl)(C -C alkyl)amino-, 5-6 membered heteroaryl, 9-10
3 7 1 4
membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups
each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-,
3 1 4
((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl and
1 4 1 4 1 4 1 4 1 4
(C -C )alkoxy,
said (C -C )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3
groups each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-,
3 1 4
((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl-,
1 4 1 4 1 4 1 4 1 4
oxo and (C -C )alkoxy, and
said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected
from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-, ((C -C )alkyl)((C -C )alkyl)amino-,
3 1 4 1 4 1 4
(C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and (C -C )alkoxy;
1 4 1 4 1 4 1 4
R is H, halogen, hydroxy, (C -C )alkyl-,(C -C )alkenyl-, halo(C -C )alkyl-,
1 4 2 4 1 4
(C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )alkoxy(C -C )alkyl-,
1 4 1 4 1 4 1 6
halo(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkoxy-
1 4 1 6 1 4 2 6 1 4 2 6
, hydroxy(C -C )alkyl-, hydroxy(C -C )alkoxy-, cyano(C -C )alkyl-, cyano(C -C )alkoxy-,
1 6 2 6 1 4 2 6
carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-
1 6 1 4 1 6 3 6 1 4
, (C -C )cycloalkoxy-, 4-6 membered-heterocycloalkyl(C -C )alkoxy-, or 4-6 membered-
3 6 1 4
heterocycloalkoxy-,
wherein the halo(C -C )alkyl-, halo(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkyl-, or
1 4 1 4 1 4 1 6
halo(C -C )alkoxy(C -C )alkoxy- groups contain 2 or 3 halo atoms; and
1 4 2 6
wherein the (C -C )cycloalkyl moiety of the (C -C )cycloalkyl(C -C )alkoxy- or
3 6 3 6 1 4
(C -C )cycloalkoxy-, is optionally substituted by a group selected from cyano, halo, hydroxyl,
(C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy;
1 6 1 4 2 6
wherein the 4-6 membered-heterocycloalkyl moiety of the 4-6 membered-
heterocycloalkyl(C -C )alkoxy-, or 4-6 membered-heterocycloalkoxy-, is optionally substituted
by a group selected from cyano, halo, hydroxyl, (C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy;
1 6 1 4 2 6
8 9 10
Z is phenyl or pyridyl substituted by R , R and R , wherein:
R and R are located on adjacent atoms and taken together with the atoms to which they
are attached form a 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms each
independently selected from N, O and S, which 5-membered heterocyclic group is substituted by
11
wherein one of R or R is H, halogen, cyano, (C -C )alkyl, halo(C -C )alkyl,
1 4 1 4
(C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or
1 4 1 4 1 4
aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally
substituted by 1-3 substituents each independently selected from halogen, -CF , (C -C )alkyl and
3 1 4
(C -C )alkoxy; and
11
the other of R or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl
3 1 4 1 4
or (C -C )alkoxy; or
R 14
Z is pyrazolyl, having the formula: wherein:
R is H, methyl or hydroxymethyl;
R is methyl, trifluoromethyl or hydroxymethyl;
R is H, OH, or (C -C )alkyl; or
12 13
R and R , taken together with the atoms to which they are attached, form a 6 membered
16
carbocyclic ring or heterocyclic ring substituted by R and R , wherein the heterocyclic ring
contains 1 nitrogen atom;
16
wherein R and R are each independently selected from H, halogen, cyano,
(C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl,
1 4 1 4 1 4 1 4
hydroxy(C -C )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or
phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected
from halogen, -CF , (C -C )alkyl and (C -C )alkoxy.
3 1 4 1 4
In another embodiment of this invention, R is H. In other embodiments, R is
(C -C )alkyl; specifically, -CH or -CH CH . Generally, in the compounds of this invention, R
1 3 3 2 3
is H.
2 a a 2 a
In one embodiment, R is -SR or -SO R . In a further embodiment, R is -SOR . In a
still further embodiment, R is -SO R .
In one embodiment of the compounds of this invention, R is an optionally substituted
(C -C )alkyl, (C -C )cycloalkyl, 4membered heterocycloalkyl, 5membered heteroaryl or
1 6 3 6
phenyl group;
wherein said (C -C )alkyl is optionally substituted by one or two groups each
independently selected from the group consisting of hydroxyl, (C -C )alkoxy, -CO (C -C )alkyl,
1 4 2 1 4
-SO (C -C )alkyl, and a (C -C )cycloalkyl, phenyl, 4membered heterocycloalkyl,
2 1 4 3 6
5membered heteroaryl, or 9membered heteroaryl, where said (C -C )cycloalkyl, phenyl,
4membered heterocycloalkyl, 5membered heteroaryl, or 9membered heteroaryl is
optionally substituted by 1-3 groups each independently selected from the group consisting of
halogen, -CF , hydroxyl, amino, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and
3 1 4 1 4 1 4
(C -C )alkoxy; and
wherein said (C -C )cycloalkyl, 4membered heterocycloalkyl, 5membered
heteroaryl or phenyl is optionally substituted by 1-3 groups each independently selected from the
group consisting of halogen, -CF , hydroxyl, amino, (C -C )alkyl, phenyl(C -C )alkyl-,
3 1 4 1 4
hydroxy(C -C )alkyl- and (C -C )alkoxy.
1 4 1 4
Suitably, R is an unsubstituted (C -C )alkyl or a (C -C )alkyl substituted by one or two
1 6 1 6
groups each independently selected from the group consisting of hydroxyl, (C -C )alkoxy,
-CO (C -C )alkyl, -SO (C -C )alkyl, and a cyclic substituent which is a (C -C )cycloalkyl,
2 1 4 2 1 4 3 6
phenyl, 4membered heterocycloalkyl, 5membered heteroaryl, or 9membered
heteroaryl, where the (C -C )cycloalkyl, phenyl, 4membered heterocycloalkyl, 5membered
heteroaryl, or 9membered heteroaryl is optionally substituted by 1-3 groups each
independently selected from the group consisting of halogen, -CF , hydroxyl, amino,
(C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and (C -C )alkoxy.
1 4 1 4 1 4 1 4
Suitably, R is an optionally substituted (C -C )cycloalkyl, 4membered
heterocycloalkyl, 5membered heteroaryl or phenyl group, wherein the (C -C )cycloalkyl,
4membered heterocycloalkyl, 5membered heteroaryl or phenyl is optionally substituted by
1-3 groups each independently selected from the group consisting of halogen, -CF , hydroxyl,
amino, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and (C -C )alkoxy.
1 4 1 4 1 4 1 4
When R is a heterocycloalkyl or heteroaryl group, it is to be understood that the
a a a
heterocycloalkyl or heteroaryl group is bonded to the sulfur atom of the -SR , -SOR or -SO R
moiety by a ring carbon atom.
In a still further embodiment, R is an optionally substituted (C -C )alkyl,
(C -C )cycloalkyl, or 4membered heterocycloalkyl group, wherein
said (C -C )alkyl is optionally substituted by a group selected from the group consisting
of hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy-, -SO (C -C )alkyl, and a group
1 2 1 2 2 3 2 1 2
selected from the group consisting of (C -C )cycloalkyl (optionally substituted by (C -C )alkyl or
3 6 1 4
hydroxy(C -C )alkyl), 4membered heterocycloalkyl (optionally substituted by (C -C )alkyl or
1 4 1 4
halogen), 5membered heteroaryl (optionally substituted by (C -C )alkyl or
hydroxy(C -C )alkyl), phenyl, and 9membered heteroaryl, and
said (C -C )cycloalkyl or 4membered heterocycloalkyl is optionally substituted by 1-3
groups each independently selected from the group consisting of halogen, (C -C )alkyl, and
hydroxy(C -C )alkyl-,
wherein any of said 5-6 membered heterocycloalkyl groups contains 1 heteroatom
selected from N, O and S. Particularly, in this embodiment, when R is an optionally substituted
(C -C )alkyl, said (C -C )alkyl is optionally substituted by a group selected from the group
1 6 1 6
consisting of hydroxyl, (C -C )alkoxy, and (C -C )alkoxy(C -C )alkoxy-.
1 2 1 2 2 3
In a still further embodiment, R is an optionally substituted (C -C )alkyl or
5membered heterocycloalkyl group, wherein:
said (C -C )alkyl is optionally substituted by a substituent selected from the group
consisting of hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy-, amino,
1 2 1 2 2 3
(C -C alkyl)amino-, (C -C alkyl)(C -C alkyl)amino-, 5membered heterocycloalkyl
1 3 1 3 1 2
(optionally substituted by (C -C )alkyl), and C -C cycloalkyl (optionally substituted by
1 4 3 6
(C -C )alkyl or hydroxy(C -C )alkyl), and
1 4 1 4
said 5-6 membered heterocycloalkyl is optionally substituted by 1 or 2 groups each
independently selected from the group consisting of halogen, (C -C )alkyl, and
hydroxy(C -C )alkyl-;
wherein any of said 5-6 membered heterocycloalkyl contains 1 heteroatom selected from
N, O and S.
In another embodiment, R is halo(C -C )alkyl containing 1-9 halogen atoms. In specific
embodiments, R is halo(C -C )alkyl, specifically a halo(C -C )alkyl containing 1-5 halogen
1 2 1 2
atoms, and more specifically a halo(C -C )alkyl containing 3 halogen atoms.
In another embodiment, R is (C -C )alkyl, optionally substituted by a substituent selected
from the group consisting of hydroxyl, (C -C )alkoxy, and (C -C )alkoxy(C -C )alkoxy-. In yet
1 2 1 2 2 3
another embodiment, R is a 5membered heterocycloalkyl group optionally substituted by 1 or
2 independently selected (C -C )alkyl groups.
In a specific embodiment, R is an unsubstituted (C -C )alkyl. In a further embodiment
of the compounds of this invention, R is an unsubstituted (C -C )alkyl group. In another
embodiment, R is a (C -C )alkyl group substituted by a hydroxyl, (C -C )alkoxy, or
1 5 1 2
(C -C )alkoxy(C -C )alkoxy- group. In another specific embodiment, R is a (C -C )alkyl
1 2 2 3 1 5
substituted by one hydroxyl group. In yet another specific embodiment, R is a tetrahydropyranyl
group.
In a specific embodiment, R is -CH , -CH(CH ) or -C(CH ) . In another specific
3 3 2, 3 3
embodiment, R is -CH CH OH or -C(CH ) CH CH OH. In yet another specific embodiment,
2 2 3 2 2 2
R is tetrahydro-2H-pyranyl.
In one embodiment of this invention, R is H.
In another embodiment of this invention, R is halogen, hydroxy, (C -C )alkyl-,
(C -C )alkenyl-, halo(C -C )alkyl-, hydroxy(C -C )alkenyl-, (C -C )alkoxy-,
2 3 1 2 2 3 1 4
(C -C )alkenyl-oxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-,
2 3 1 3 5 6 1 3
5memebered-heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-,
1 3 1 4
(C -C )alkoxy(C -C )alkoxy-, (C -C )alkyl-thio-(C -C )alkoxy-,
1 3 2 4 1 3 2 4
(C -C )alkyl-sulfonyl-(C -C )alkoxy-, carboxy-(C -C )alkoxy-, carboxy-(C -C )alkenyl-oxy-,
1 3 2 4 1 4 2 4
(C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkenyl-oxy-,
1 3 1 4 1 3 2 4
aminocarbonyl(C -C )alkoxy-, aminocarbonyl(C -C )alkenyl-oxy-, or hydroxy(C -C )alkoxy-.
1 4 2 4 2 4
In another embodiment of this invention, R is halogen, hydroxy, (C -C )alkyl-,
(C -C )alkenyl-, halo(C -C )alkyl-, hydroxy(C -C )alkenyl-, (C -C )alkoxy-,
2 3 1 2 2 3 1 4
(C -C )alkenyl-oxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-,
2 3 1 3 5 6 1 3
5memebered-heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-,
1 3 1 4
(C -C )alkoxy(C -C )alkoxy-, (C -C )alkyl-thio-(C -C )alkoxy-,
1 3 2 3 1 3 2 3
(C -C )alkyl-sulfonyl-(C -C )alkoxy-, carboxy-(C -C )alkoxy-, carboxy-(C -C )alkenyl-oxy-,
1 3 2 3 1 4 2 4
(C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkenyl-oxy-,
1 3 1 4 1 3 2 4
aminocarbonyl(C -C )alkoxy-, aminocarbonyl(C -C )alkenyl-oxy-, or hydroxy(C -C )alkoxy-.
1 3 2 3 2 4
In yet another embodiment, R is H or R is halogen, hydroxy, (C -C )alkyl-,
3 1 4
(C -C )alkenyl-, halo(C -C )alkyl-, (C -C )alkoxy-, halo(C -C )alkoxy-,
2 4 1 4 1 4 1 4
(C -C )cycloalkyl(C -C )alkoxy-, 5memebered-heterocycloalkyl-oxy-,
3 6 1 4
(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, carboxy-(C -C )alkoxy-,
1 4 1 6 1 4 2 6 1 6
(C -C )alkoxycarbonyl(C -C )alkoxy-, hydroxy(C -C )alkyl-, or hydroxy(C -C )alkoxy-.
1 4 1 6 1 6 2 6
In a further embodiment, R is H, halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-,
1 3 2 3
halo(C -C )alkyl-, (C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-,
1 2 1 4 1 3 5 6 1 3
5memebered-heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-,
1 3 1 4
(C -C )alkoxy(C -C )alkoxy-, carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, or
1 3 2 4 1 4 1 3 1 4
hydroxy(C -C )alkoxy-.
In a specific embodiment, R is chloro, -CH CH , –CH=CH , –CH=CHCH OH,
2 3 2 2
-OCH=CH , –OCH=CH-CO H, -OCH=CH-CO CH , –OCH=CH-CONH , -OH, -OCH ,
2 2 2 3 2 3
-OCF H, -OCH(CH ) , -OCH CH , -OCH CF , -OCH CH CH , -OCH CH Cl, -OCH CH Br,
2 3 2 2 3 2 3 2 2 3 2 2 2 2
-OCH CH SCH , -OCH CH SO CH , -OCH CH SO CH(CH ) , -OCH CH OH,
2 2 3 2 2 2 3 2 2 2 3 2 2 2
-OCH CH CH OH, -OCH CH OCH , -OC(CH ) CH OH, -OCH(CH )CH OH,
2 2 2 2 2 3 3 2 2 3 2
-OCH(CH )CO CH , -OCH CH(CH )OH, -OC(CH ) CO CH CH , -OCH CO H,
3 2 3 2 3 3 2 2 2 3 2 2
-OCH CONH , -OCH -cyclohexyl, or -O-tetrahydro-2H-pyranyl.
2 2 2
In a more specific embodiment, R is H, chloro,–CH CH , –CH=CH , -OH, -OCH ,
2 3 2 3
-OCF H, -OCH(CH ) , -OCH CH , -OCH CF , -OCH CH Cl, -OCH CH OH,
2 3 2 2 3 2 3 2 2 2 2
-OCH CH CH OH, -OCH CH OCH , -OC(CH ) CH OH, -OCH(CH )CH OH,
2 2 2 2 2 3 3 2 2 3 2
-OC(CH ) CO CH CH , cyclohexylmethyloxy-, or tetrahydro-2H-pyranyloxy-.
3 2 2 2 3
In a further embodiment of the compounds of Formula (I) of this invention, Z is phenyl or
8 9 10
pyridyl substituted by R , R and R , wherein:
R and R are located on adjacent atoms (carbon atoms) and taken together with the atoms
to which they are attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each
independently selected from N, O and S, which 5-membered ring is substituted by R ;
11
wherein one of R or R is H, halogen, cyano, (C -C )alkyl, halo(C -C )alkyl,
1 4 1 4
(C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or
1 4 1 4 1 4
aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally
substituted by 1-3 substituents each independently selected from the group consisting of halogen,
-CF , (C -C )alkyl and (C -C )alkoxy; and
3 1 4 1 4
11
the other of R or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl
3 1 4 1 4
or (C -C )alkoxy;
R 14
or Z is pyrazolyl, having the formula: wherein:
R is H, methyl or hydroxymethyl;
R is methyl, trifluoromethyl or hydroxymethyl;
R is H, OH, or (C -C )alkyl;
12 13
or R and R , taken together with the atoms to which they are attached, form a
16
6-membered ring substituted by R and R , wherein the 6-membered ring contains 1 nitrogen
atom;
16
wherein R and R are each independently selected from the group consisting of H,
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy,
1 4 1 4 1 4 1 4
hydroxyl, hydroxy(C -C )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy
or phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected
from the group consisting of halogen, -CF , (C -C )alkyl and (C -C )alkoxy.
3 1 4 1 4
It will be understood by one skilled in the art that the 5-membered ring formed from R
and R and the atoms to which they are attached may be non-aromatic (partially unsaturated) or
aromatic (fully unsaturated). It will be further understood by one skilled in the art that the
12 13
6-membered ring formed from R and R and the atoms to which they are attached may be non-
aromatic (partially unsaturated) or aromatic (fully unsaturated).
8 9 10 8 9
In yet another embodiment, Z is phenyl substituted by R , R and R , wherein R and R
are located on adjacent atoms and taken together with the atoms to which they are attached form
a 5-membered ring containing 1, 2 or 3 heteroatoms each independently selected from N, O and
11 10 11 10
S, which 5-membered ring is substituted by R ; wherein R and R are each H or one of R or
R is H, halogen, cyano, (C -C )alkyl, -CF , (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy,
1 4 3 1 4 1 4
hydroxyl, hydroxy(C -C )alkyl-, or aminocarbonyl, where the phenyl moiety of said phenoxy or
phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected
from the group consisting of halogen, -CF , (C -C )alkyl and (C -C )alkoxy, and the other of R
3 1 4 1 4
or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl or (C -C )alkoxy. In this
3 1 4 1 4 1 4
embodiment, Z is a 9-membered bicyclic heteroaryl group bonded to the amino (NR ) moiety of
Formula (I) via a substitutable carbon ring atom of the 6-membered, phenyl moiety of the
9-membered bicyclic heteroaryl group.
Specifically, Z is benzothiazolyl, optionally substituted by 1-3 substituents independently
selected from the group consisting of halogen, (C -C )alkyl, halo(C -C )alkyl and (C -C )alkoxy.
1 4 1 4 1 4
Accordingly, in one embodiment, Z is unsubstituted benzothiazolyl. In another embodiment, Z is
benzothiazolyl substituted by 1-3 substituents independently selected from the group consisting
of halogen, (C -C )alkyl, halo(C -C )alkyl and (C -C )alkoxy. More specifically, Z is
1 4 1 4 1 4
benzo[d]thiazolyl optionally substituted by chloro, fluoro, -CF , methyl, or methoxy. In a
specific embodiment, Z is benzo[d]thiazolyl.
8 9 10 8 9
In yet another embodiment, Z is pyridyl substituted by R , R and R , wherein R and R
are located on adjacent atoms (carbon atoms) and taken together with the atoms to which they are
attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each independently selected
11 10 11
from N, O and S, which 5-membered ring is substituted by R ; wherein one of R or R is H,
halogen, cyano, (C -C )alkyl, -CF , (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl,
1 4 3 1 4 1 4
hydroxy(C -C )alkyl-, or aminocarbonyl, where the phenyl moiety of said phenoxy or
phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected
from the group consisting of halogen, -CF , (C -C )alkyl and (C -C )alkoxy and the other of R
3 1 4 1 4
or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl or (C -C )alkoxy. In this
3 1 4 1 4 1 4
embodiment, Z is a 9-membered bicyclic heteroaryl group bonded to the amino (NR ) moiety of
Formula (I) via a substitutable carbon ring atom of the 6-membered, pyridyl moiety of the
9-membered bicyclic heteroaryl group.
12 13
In one embodiment, Z is pyrazolyl and R is H or hydroxymethyl, R is methyl or
14 12 13 14
trifluoromethyl, and R is H or methyl; or R is H or methyl, R is hydroxymethyl, and R is H
12 13
or methyl. In another embodiment, Z is pyrazolyl, R is H or methyl, R is methyl or
14 12
trifluoromethyl, and R is OH. In still another embodiment, Z is pyrazolyl, R is H or methyl,
13 14
R is methyl or trifluoromethyl, and R is H or methyl. In a further embodiment, Z is pyrazolyl,
12 13 14
R and R are both methyl, and R is H. In specific embodiments, Z is 5-(trifluoromethyl)-1H-
pyrazolyl, 1,3,4-trimethyl-1H-pyrazolyl, or 4,5-dimethyl-1H-pyrazolyl.
12 13
In a still further embodiment, Z is pyrazolyl, substituted by R and R wherein:
12 13
R and R are located on adjacent carbon atoms and taken together with the atoms to
which they are attached form a 6 membered carbocyclic ring or heterocyclic ring substituted by
16
R and R ;
wherein R is H, halogen, cyano, (C -C )alkyl, -CF , (C -C )alkoxy, phenoxy,
1 4 3 1 4
phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or aminocarbonyl, wherein the phenyl
1 4 1 4
moiety of said phenoxy or phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each
independently selected from the group consisting of halogen, -CF , (C -C )alkyl and
3 1 4
(C -C )alkoxy; and
R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl or (C -C )alkoxy.
3 1 4 1 4 1 4
In another embodiment, the invention is directed to a compound according to Formula (I),
wherein Z is a 9-membered bi-cyclic heteroaryl group, optionally substituted on either ring by
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-
1 4 1 4 1 4 1 4
or aminocarbonyl, wherein the 9-membered bi-cyclic heteroaryl group is an optionally
substituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to the amino (NR ) moiety via a
substitutable carbon ring atom of the 5-membered pyrazolyl ring moiety of the indazolyl or
pyrazolo[3,4-b]pyridinyl group, or a salt, particularly a pharmaceutically acceptable salt, thereof.
In a further embodiment, Z is an optionally substituted indazolyl or
pyrazolo[3,4-b]pyridinyl, wherein the indazolyl or pyrazolo[3,4-b]pyridinyl is optionally
substituted by hydroxyl, chloro, fluoro, -CF , cyano, hydroxymethyl-, methyl, methoxy or
aminocarbonyl. In specific embodiments, Z is 5-fluoro-1H-indazolyl, 1H-indazolyl or
3-methyl-1H-indazolyl. In selected embodiments, Z is 5-fluoro-1H-indazolyl.
In another embodiment, the invention is directed to a compound according to
Formula (II):
(II)
1 2 3 12
or a salt, particularly a pharmaceutically acceptable salt thereof, wherein R , R , R , R
and R are as defined herein.
In one embodiment, the invention is directed to a compound of Formula (I), wherein:
R is H or (C -C )alkyl;
2 a a a
R is -SR or -SO R , and R is an optionally substituted (C -C )alkyl, (C -C )cycloalkyl,
2 1 6 3 6
or 4membered heterocycloalkyl group, wherein
said (C -C )alkyl is optionally substituted by a groups selected from the group consisting
of hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy-, -SO (C -C )alkyl, and a group
1 2 1 2 2 3 2 1 2
selected from the group consisting of (C -C )cycloalkyl (optionally substituted by (C -C )alkyl or
3 6 1 4
hydroxy(C -C )alkyl), 4membered heterocycloalkyl (optionally substituted by (C -C )alkyl or
1 4 1 4
halogen), 5membered heteroaryl (optionally substituted by (C -C )alkyl or
hydroxy(C -C )alkyl), phenyl, and 9membered heteroaryl, and
said (C -C )cycloalkyl or 4membered heterocycloalkyl is optionally substituted by 1-3
groups each independently selected from the group consisting of halogen, (C -C )alkyl, and
hydroxy(C -C )alkyl-,
wherein any of said 5-6 membered heterocycloalkyl groups contains 1 heteroatom
selected from N, O and S;
R is H, halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-, halo(C -C )alkyl-,
1 4 2 4 1 4
(C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-, 5memebered-
1 4 1 4 3 6 1 4
heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, carboxy-
1 4 1 6 1 4 2 6
(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, hydroxy(C -C )alkyl-, or
1 6 1 4 1 6 1 6
hydroxy(C -C )alkoxy-;
8 9 10
Z is phenyl substituted by R , R and R , wherein:
R and R are located on adjacent atoms and taken together with the atoms to which they
are attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each independently
selected from N, O and S, which 5-membered ring is substituted by R ;
11 10 11
wherein R and R are each H or one of R or R is H, halogen, cyano, (C -C )alkyl,
-CF , (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or
3 1 4 1 4 1 4
aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally
substituted by 1-3 substituents each independently selected from the group consisting of halogen,
11
-CF , (C -C )alkyl and (C -C )alkoxy, and the other of R or R is H, hydroxyl, halogen, -CF ,
3 1 4 1 4 3
hydroxy(C -C )alkyl, (C -C )alkyl or (C -C )alkoxy,
1 4 1 4 1 4
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl,
12 13
or Z is pyrazolyl, substituted by R and R wherein:
12 13
R and R are located on adjacent carbon atoms and taken together with the atoms to
which they are attached form a 6-membered carbocyclic ring or heterocyclic ring substituted by
16
R and R ;
wherein R is H, halogen, cyano, (C -C )alkyl, -CF , (C -C )alkoxy, phenoxy,
1 4 3 1 4
phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or aminocarbonyl, wherein the phenyl
1 4 1 4
moiety of said phenoxy or phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each
independently selected from the group consisting of halogen, -CF , (C -C )alkyl and
3 1 4
(C -C )alkoxy; and
R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl or (C -C )alkoxy;
3 1 4 1 4 1 4
or a salt, particularly a pharmaceutically acceptable salt, thereof. Particularly, in this
2 a 3
embodiment, R is -SO R and/or R is halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-,
2 1 4 2 4
halo(C -C )alkyl-, (C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-, 5
1 4 1 4 1 4 3 6 1 4
memebered-heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-,
1 4 1 6 1 4 2 6
carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, hydroxy(C -C )alkyl-, or
1 6 1 4 1 6 1 6
hydroxy(C -C )alkoxy- and/or Z is other than phenyl, substituted by 1, 2 or 3 substituents each
independently selected from the group consisting of hydroxyl, halogen, hydroxy(C -C )alkyl,
(C -C )alkyl and (C -C )alkoxy.
1 4 1 4
In another embodiment, the invention is directed to a compound of Formula (I), wherein:
R is H;
2 a a a a
R is -SR , -SOR or -SO R ,wherein R is a (C -C )alkyl group, optionally substituted by
2 1 6
a substituent selected from the group consisting of hydroxyl, (C -C )alkoxy, and
(C -C )alkoxy(C -C )alkoxy-,
1 2 2 3
or R is a 5membered heterocycloalkyl group optionally substituted by 1 or 2
independently selected (C -C )alkyl groups;
R is halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-, halo(C -C )alkyl-,
1 3 2 3 1 2
hydroxy(C -C )alkenyl-, (C -C )alkoxy-, (C -C )alkenyl-oxy-, halo(C -C )alkoxy-,
2 3 1 4 2 3 1 3
(C -C )cycloalkyl(C -C )alkoxy-, 5memebered-heterocycloalkyl-oxy-,
6 1 3
(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, (C -C )alkyl-thio-(C -C )alkoxy-,
1 3 1 4 1 3 2 3 1 3 2 3
(C -C )alkyl-sulfonyl-(C -C )alkoxy-, carboxy-(C -C )alkoxy-, carboxy-(C -C )alkenyl-oxy-,
1 3 2 3 1 4 2 4
(C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkenyl-oxy-,
1 3 1 4 1 3 2 4
aminocarbonyl(C -C )alkoxy-, aminocarbonyl(C -C )alkenyl-oxy-, or hydroxy(C -C )alkoxy-;
1 3 2 3 2 4
Z is benzothiazolyl, optionally substituted by 1-3 substituents independently selected
from the group consisting of halogen, (C -C )alkyl, halo(C -C )alkyl and (C -C )alkoxy,
1 4 1 4 1 4
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl,
or Z is a 9-membered bi-cyclic heteroaryl group, optionally substituted on either ring by
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-
1 4 1 4 1 4 1 4
or aminocarbonyl, wherein the 9-membered bi-cyclic heteroaryl group is an optionally
substituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to the amino (NR ) moiety via a
substitutable carbon ring atom of the 5-membered pyrazolyl ring moiety of the indazolyl or
pyrazolo[3,4-b]pyridinyl group,
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In another embodiment, the invention is directed to a compound of Formula (I), wherein:
R is H;
2 a a a a
R is -SR , -SOR or -SO R ,wherein R is a (C -C )alkyl group, optionally substituted by
2 1 6
a substituent selected from the group consisting of hydroxyl, (C -C )alkoxy, and
(C -C )alkoxy(C -C )alkoxy-;
1 2 2 3
R is halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-, halo(C -C )alkyl-,
1 3 2 3 1 2
hydroxy(C -C )alkenyl-, (C -C )alkoxy-, (C -C )alkenyl-oxy-, halo(C -C )alkoxy-,
2 3 1 4 2 3 1 3
(C -C )cycloalkyl(C -C )alkoxy-, 5memebered-heterocycloalkyl-oxy-,
6 1 3
(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, (C -C )alkyl-thio-(C -C )alkoxy-,
1 3 1 4 1 3 2 3 1 3 2 3
(C -C )alkyl-sulfonyl-(C -C )alkoxy-, carboxy-(C -C )alkoxy-, carboxy-(C -C )alkenyl-oxy-,
1 3 2 3 1 4 2 4
(C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkenyl-oxy-,
1 3 1 4 1 3 2 4
aminocarbonyl(C -C )alkoxy-, aminocarbonyl(C -C )alkenyl-oxy-, or hydroxy(C -C )alkoxy-;
1 3 2 3 2 4
Z is benzothiazolyl, optionally substituted by 1-3 substituents independently selected
from the group consisting of halogen, (C -C )alkyl, halo(C -C )alkyl and (C -C )alkoxy,
1 4 1 4 1 4
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl,
or Z is a 9-membered bi-cyclic heteroaryl group, optionally substituted on either ring by
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-
1 4 1 4 1 4 1 4
or aminocarbonyl, wherein the 9-membered bi-cyclic heteroaryl group is an optionally
substituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to the amino (NR ) moiety via a
substitutable carbon ring atom of the 5-membered pyrazolyl ring moiety of the indazolyl or
pyrazolo[3,4-b]pyridinyl group;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In another embodiment, the invention is directed to a compound of Formula (I), wherein:
R is H or -CH CH ; particularly, R is H;
2 a a
R is -SR or -SO R ,wherein:
R is a (C -C )alkyl group, optionally substituted by a substituent selected from the group
consisting of hydroxyl, (C -C )alkoxy, and (C -C )alkoxy(C -C )alkoxy-,
1 2 1 2 2 3
or R is a 5membered heterocycloalkyl group optionally substituted by 1 or 2
independently selected (C -C )alkyl groups;
R is H, halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-, halo(C -C )alkyl-,
1 3 2 3 1 2
(C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy-, 5memebered
1 4 1 3 5 6 1 3
heterocycloalkyl-oxy-, (C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-,
1 3 1 4 1 3 2 4
carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, or hydroxy(C -C )alkoxy-;
1 4 1 3 1 4 2 4
or Z is benzothiazolyl, optionally substituted by 1-3 substituents independently selected
from the group consisting of halogen, (C -C )alkyl, halo(C -C )alkyl or (C -C )alkoxy,
1 4 1 4 1 4
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl,
or Z is a 9-membered bi-cyclic heteroaryl group, optionally substituted on either ring by
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-
1 4 1 4 1 4 1 4
or aminocarbonyl, wherein the 9-membered bi-cyclic heteroaryl group is an optionally
substituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to the amino (NH) moiety via a
substitutable carbon ring atom of the 5-membered pyrazolyl ring moiety of the indazolyl or
pyrazolo[3,4-b]pyridinyl group,
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In another embodiment, the invention is directed to a compound of Formula (I), wherein:
R is H;
2 a a a
R is -SO R ,wherein R is an unsubstituted (C -C )alkyl group or R is a (C -C )alkyl
2 1 5 1 5
group substituted by a hydroxyl, (C -C )alkoxy, or (C -C )alkoxy(C -C )alkoxy- group;
1 2 1 2 2 3
Z is benzothiazolyl, optionally substituted by a halogen, (C -C )alkyl, halo(C -C )alkyl or
1 4 1 4
(C -C )alkoxy,
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl,
or Z is a 9-membered bi-cyclic heteroaryl, optionally substituted on either ring by a
halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-
1 4 1 4 1 4 1 4
or aminocarbonyl group, wherein the 9-membered bi-cyclic heteroaryl is an optionally
substituted indazolyl or pyrazolo[3,4-b]pyridinyl, bonded to the amino (NR /NH) moiety via a
substitutable carbon ring atom of the 5-membered pyrazolyl ring moiety of the indazolyl or
pyrazolo[3,4-b]pyridinyl group;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
Specifically, the invention is directed to a compound according to Formula (I) wherein:
R is H or -CH CH ; particularly, R is H;
2 a a a
R is -SR or -SO R , and R is -CH , -CH(CH ) , -C(CH ) , -CH CH OH,
2 3 3 2 3 3 2 2
-C(CH ) CH CH OH, or tetrahydro-2H-pyranyl;
3 2 2 2
R is H, chloro,–CH CH , –CH=CH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH ,
2 3 2 3 2 3 2 2 3
-OCH CF , -OCH CH Cl, -OCH CH OH, -OCH CH CH OH, -OCH CH OCH ,
2 3 2 2 2 2 2 2 2 2 2 3
-OC(CH ) CH OH, -OCH(CH )CH OH, -OC(CH ) CO CH CH , cyclohexylmethyloxy-, or
3 2 2 3 2 3 2 2 2 3
tetrahydro-2H-pyranyloxy-; and
Z is benzo[d]thiazolyl or 5-fluoro-1H-indazolyl, or Z is pyrazolyl, wherein R is H
13 14
or methyl, R is methyl or trifluoromethyl, and R is H or methyl,
or a salt, specifically a pharmaceutically acceptable salt, thereof.
In another embodiment, the invention is directed to a compound according to Formula (I)
wherein:
R is H;
2 a a
R is -SO R , and R is -CH , -CH(CH ) , or -C(CH )
2 3 3 2 3 3;
R is H, chloro,–CH CH , –CH=CH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH ,
2 3 2 3 2 3 2 2 3
-OCH CF , -OCH CH Cl, -OCH CH OH, -OCH CH CH OH, -OCH CH OCH ,
2 3 2 2 2 2 2 2 2 2 2 3
-OC(CH ) CH OH, -OCH(CH )CH OH, -OC(CH ) CO CH CH , cyclohexylmethyloxy-, or
3 2 2 3 2 3 2 2 2 3
tetrahydro-2H-pyranyloxy-; and
Z is benzo[d]thiazolyl or 5-fluoro-1H-indazolyl,
12 13 14
or Z is pyrazolyl, wherein R is H or methyl, R is methyl or trifluoromethyl, and R is
H or methyl;
or a salt, specifically a pharmaceutically acceptable salt, thereof.
More specifically, the invention is directed to a compound according to Formula (I)
wherein:
R is H;
2 a a a
R is -SR or -SO R , and R is -CH , -CH(CH ) , -C(CH ) , -CH CH OH,
2 3 3 2 3 3 2 2
-C(CH ) CH CH OH, or tetrahydro-2H-pyranyl;
3 2 2 2
R is chloro, -CH CH , –CH=CH , –CH=CHCH OH, -OCH=CH , -OCH=CH-CO H,
2 3 2 2 2 2
-OCH=CH-CO CH , –OCH=CH-CONH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH ,
2 3 2 3 2 3 2 2 3
-OCH CF , -OCH CH CH , -OCH CH Cl, -OCH CH Br, -OCH CH SCH , -OCH CH SO CH ,
2 3 2 2 3 2 2 2 2 2 2 3 2 2 2 3
-OCH CH SO CH(CH ) , -OCH CH OH, -OCH CH CH OH, -OCH CH OCH ,
2 2 2 3 2 2 2 2 2 2 2 2 3
-OC(CH ) CH OH, -OCH(CH )CH OH, -OCH(CH )CO CH , -OCH CH(CH )OH,
3 2 2 3 2 3 2 3 2 3
-OC(CH ) CO CH CH , -OCH CO H, -OCH CONH , -OCH -cyclohexyl, or
3 2 2 2 3 2 2 2 2 2
-O-tetrahydro-2H-pyranyl; and
Z is benzo[d]thiazolyl, 5-(trifluoromethyl)-1H-pyrazolyl, 1,3,4-trimethyl-1H-
pyrazolyl, 4,5-dimethyl-1H-pyrazolyl, 5-fluoro-1H-indazolyl, 1H-indazolyl or
3-methyl-1H-indazolyl,
or a salt, specifically a pharmaceutically acceptable salt, thereof.
The invention is further directed to a compound according to Formula (I) wherein:
R is H;
R is -SO R , and
R is -CH , -CH(CH ) , or -C(CH ) , or
3 3 2 3 3
R is -CH CH OH or -C(CH ) CH CH OH;
2 2 3 2 2 2
R is chloro, -CH CH , –CH=CH , –CH=CHCH OH, -OCH=CH , -OCH=CH-CO H,
2 3 2 2 2 2
-OCH=CH-CO CH , –OCH=CH-CONH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH ,
2 3 2 3 2 3 2 2 3
-OCH CF , -OCH CH CH , -OCH CH Cl, -OCH CH Br, -OCH CH SCH , -OCH CH SO CH ,
2 3 2 2 3 2 2 2 2 2 2 3 2 2 2 3
-OCH CH SO CH(CH ) , -OCH CH OH, -OCH CH CH OH, -OCH CH OCH ,
2 2 2 3 2 2 2 2 2 2 2 2 3
-OC(CH ) CH OH, -OCH(CH )CH OH, -OCH(CH )CO CH , -OCH CH(CH )OH,
3 2 2 3 2 3 2 3 2 3
-OC(CH ) CO CH CH , -OCH CO H, -OCH CONH , -OCH -cyclohexyl, or
3 2 2 2 3 2 2 2 2 2
-O-tetrahydro-2H-pyranyl; and
Z is benzo[d]thiazolyl, 5-(trifluoromethyl)-1H-pyrazolyl, 1,3,4-trimethyl-1H-
pyrazolyl, 4,5-dimethyl-1H-pyrazolyl, 5-fluoro-1H-indazolyl, 1H-indazolyl or
3-methyl-1H-indazolyl,
or a salt, specifically a pharmaceutically acceptable salt, thereof.
Representative compounds of this invention include the compounds of Examples 3-42,
45, 47-54 and 56-80, specifically:
N-1,3-benzothiazolyl[(1,1-dimethylethyl)thio]quinazolinamine,
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]quinazolinamine,
6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazolyl)quinazolinamine,
N-1,3-benzothiazolyl[(1-methylethyl)sulfonyl]quinazolinamine,
2-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}ethanol,
N-1,3-benzothiazolyl(tetrahydro-2H-pyranylsulfonyl)quinazolinamine,
3-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}methylbutanol,
2-((4-((4,5-dimethyl-1H-pyrazolyl)amino)methoxyquinazolinyl)sulfonyl)ethanol,
N-(5-fluoro-1H-indazolyl)[(1-methylethyl)sulfonyl]quinazolinamine,
N-(4,5-dimethyl-1H-pyrazolyl)[(1-methylethyl)sulfonyl]quinazolinamine,
6-(tert-butylsulfonyl)-N-(5-(trifluoromethyl)-1H-pyrazolyl)quinazolinamine,
6-(tert-butylsulfonyl)-N-(1,3,4-trimethyl-1H-pyrazolyl)quinazolinamine,
N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)methoxyquinazolinyl)benzo[d]thiazolamine,
N-(6-(isopropylsulfonyl)methoxyquinazolinyl)benzo[d]thiazolamine,
4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol,
N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)-N-ethylbenzo[d]thiazolamine,
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)ethanol,
N-(6-(tert-butylsulfonyl)(difluoromethoxy)quinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)(2,2,2-trifluoroethoxy)quinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)(methoxymethoxy)quinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)(cyclohexylmethoxy)quinazolinyl)benzo[d]thiazolamine,
3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol,
N-(6-(tert-butylsulfonyl)((tetrahydro-2H-pyranyl)oxy)quinazolinyl)benzo[d]thiazol
amine,
N-(6-(tert-butylsulfonyl)(2-chloroethoxy)quinazolinyl)benzo[d]thiazolamine,
(R)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol,
N-(6-(tert-butylsulfonyl)propoxyquinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)(2-(methylthio)ethoxy)quinazolinyl)benzo[d]thiazolamine,
N-(7-(2-bromoethoxy)(tert-butylsulfonyl)quinazolinyl)benzo[d]thiazolamine,
4-(benzo[d]thiazolylamino)(tert-butylthio)quinazolinol,
N-(6-(tert-butylthio)isopropoxyquinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)isopropoxyquinazolinyl)benzo[d]thiazolamine,
ethyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)
methylpropanoate,
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)methylpropanol,
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethenylquinazolinamine,
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethylquinazolinamine,
N-(6-(tert-butylsulfonyl)chloroquinazolinyl)benzo[d]thiazolamine,
6-(tert-butylsulfonyl)chloro-N-(4,5-dimethyl-1H-pyrazolyl)quinazolinamine,
6-[(1,1-dimethylethyl)sulfonyl]-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridinyl)(methyloxy)
quinazolinamine,
6-(tert-butylsulfonyl)methoxy-N-(3-methyl-1H-indazolyl)quinazolinamine,
6-(tert-butylsulfonyl)-N-(1H-indazolyl)methoxyquinazolinamine,
6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazolyl)methoxyquinazolinamine,
(E)(4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)propenol,
2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)ethanol,
(R)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)propanoate,
(S)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)propanoate,
methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanoate,
(R)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol,
(S)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol,
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol,
N-(6-(tert-butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine,
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetamide,
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetic acid,
N-(6-(tert-butylsulfonyl)(2-(methylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazolamine,
N-(6-(tert-butylsulfonyl)(2-(isopropylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazolamine,
(E)-methyl 3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylate,
(E)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylamide,
(E)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylic acid,
N-(6-(tert-butylsulfonyl)(vinyloxy)quinazolinyl)benzo[d]thiazolamine,
4-(benzo[d]thiazolylamino)methoxy-N,N-dimethylquinazolinesulfonamide,
4-(benzo[d]thiazolylamino)-N-isopropylmethoxyquinazolinesulfonamide,
N-(7-methoxy(pyrrolidinylsulfonyl)quinazolinyl)benzo[d]thiazolamine,
N-(7-methoxy(morpholinosulfonyl)quinazolinyl)benzo[d]thiazolamine,
4-(benzo[d]thiazolylamino)-N-(2-hydroxyethyl)methoxyquinazolinesulfonamide,
4-(benzo[d]thiazolylamino)methoxy-N-(tetrahydro-2H-pyranyl)quinazoline
sulfonamide,
4-(benzo[d]thiazolylamino)-N-(2-hydroxymethylpropyl)methoxyquinazoline
sulfonamide,
1-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)pyrrolidinol,
4-(benzo[d]thiazolylamino)-N-(2-hydroxypropyl)methoxyquinazolinesulfonamide,
4-(benzo[d]thiazolylamino)methoxy-N-(2-methoxyethyl)quinazolinesulfonamide,
4-(benzo[d]thiazolylamino)methoxy-N-(oxetanyl)quinazolinesulfonamide,
4-(benzo[d]thiazolylamino)-N-(2-(dimethylamino)ethyl)methoxyquinazoline
sulfonamide,
1-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)pyrrolidinecarboxylic
acid,
1-(4-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)piperazin
yl)ethanone,
N-(2-(1H-tetrazolyl)ethyl)(benzo[d]thiazolylamino)methoxyquinazoline
sulfonamide,
4-(benzo[d]thiazolylamino)methoxy-N-((tetrahydro-2H-pyranyl)methyl)quinazoline
sulfonamide,
or a salt, particularly a pharmaceutically acceptable salt, thereof.
Specifically, this invention is directed to N-1,3-benzothiazolyl[(1,1-
dimethylethyl)sulfonyl]quinazolinamine or a salt, particularly a pharmaceutically acceptable
salt, thereof.
This invention is also directed to N-1,3-benzothiazolyl[(1-methylethyl)sulfonyl]
quinazolinamine, or a salt, particularly a pharmaceutically acceptable salt, thereof.
This invention is further directed to N-(6-(tert-butylsulfonyl)methoxyquinazolin
yl)benzo[d]thiazolamine or a salt, particularly a pharmaceutically acceptable salt, thereof.
Specifically, this invention is directed to 2-((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)ethanol or a salt, particularly a pharmaceutically acceptable
salt, thereof.
Accordingly, a compound of the invention includes a compound of Formula (I), or a salt
thereof, particularly a pharmaceutically acceptable salt thereof.
Accordingly, a compound of the invention includes a compound of Formula (I),
particularly the specific compounds described herein, or a salt thereof, particularly a
pharmaceutically acceptable salt thereof.
Described herein is a method of inhibiting RIP2 kinase comprising contacting a cell with
a compound of the invention. Also described herein is a method of treating a RIP2 kinase-
mediated disease or disorder comprising administering a therapeutically effective amount of a
compound of the invention to a human in need thereof. Also described herein is the use of a
compound of the invention or a pharmaceutical composition comprising a compound of the
invention to inhibit RIP2 kinase and/or treat a RIP2 kinase-mediated disease or disorder.
The compounds according to Formula (I) may contain one or more asymmetric center
(also referred to as a chiral center) and may, therefore, exist as individual enantiomers,
diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as a
chiral carbon, or particularly, a chiral –SO– moiety, may also be present in the compounds of this
invention. Where the stereochemistry of a chiral center present in a compound of this invention
(e.g., compound name) or in any chemical structure illustrated herein is not specified, the
compound, compound name, or structure is intended to encompass all individual stereoisomers
and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more
chiral center may be present as racemic mixtures, enantiomerically enriched mixtures, or as
enantiomerically pure individual stereoisomers. For example, each of (R)-N-(6-(tert-
butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine and (S)-N-(6-(tert-
butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine are encompassed by the
chemical name N-(6-(tert-butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine.
Individual stereoisomers of a compound according to Formula (I) which contain one or
more asymmetric center may be resolved by methods known to those skilled in the art. For
example, such resolution may be carried out (1) by formation of diastereoisomeric salts,
complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for
example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a
chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or
in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired
stereoisomer is converted into another chemical entity by one of the separation procedures
described above, a further step is required to liberate the desired form. Alternatively, specific
stereoisomers may be synthesized by asymmetric synthesis using optically active reagents,
substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric
transformation.
It is to be understood that a solid form of a compound of the invention may exist in
crystalline forms, non-crystalline forms or a mixture thereof. Such crystalline forms may also
exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different
crystalline forms are typically known as “polymorphs.” Polymorphs have the same chemical
composition but differ in packing, geometrical arrangement, and other descriptive properties of
the crystalline solid state. Polymorphs, therefore, may have different physical properties such as
shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs
typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns,
which may be used for identification. One of ordinary skill in the art will appreciate that
different polymorphs may be produced, for example, by changing or adjusting the conditions
used in crystallizing/recrystallizing the compound.
Because of their potential use in medicine, the salts of the compounds of Formula (I) are
preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include
those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19. Salts
encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the
compounds of this invention.
When a compound of the invention is a base (contains a basic moiety), a desired salt form
may be prepared by any suitable method known in the art, including treatment of the free base
with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid,
maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,
glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or
galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an
amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid
or cinnamic acid, or with a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid,
ethanesulfonic acid or the like.
Suitable addition salts include acetate, p-aminobenzoate, ascorbate, aspartate,
benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate,
calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate,
edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate,
gluconate, glutamate, glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate,
hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate,
lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium
maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate
(embonate), palmate, palmitate, pantothenate, phosphate/diphosphate, pyruvate,
polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate,
tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate.
Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate,
caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate,
sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate,
phenylpropionate, phenylbutrate, lactate, γ-hydroxybutyrate, mandelate, and sulfonates, such as
xylenesulfonate, propanesulfonate, naphthalenesulfonate and naphthalenesulfonate.
If an inventive basic compound is isolated as a salt, the corresponding free base form of
that compound may be prepared by any suitable method known to the art, including treatment of
the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher
pK than the free base form of the compound.
When a compound of the invention is an acid (contains an acidic moiety), a desired salt
may be prepared by any suitable method known to the art, including treatment of the free acid
with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali
metal or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts
include organic salts derived from amino acids such as glycine and arginine, ammonia, primary,
secondary, and tertiary amines, and cyclic amines, such as N-methyl-D-glucamine, diethylamine,
isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, piperidine,
morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium,
magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
Certain of the compounds of the invention may form salts with one or more equivalents
of an acid (if the compound contains a basic moiety) or a base (if the compound contains an
acidic moiety). The present invention includes within its scope all possible stoichiometric and
non-stoichiometric salt forms.
Compounds of the invention having both a basic and acidic moiety may be in the form of
zwitterions, acid-addition salt of the basic moiety or base salts of the acidic moiety.
This invention also provides for the conversion of one pharmaceutically acceptable salt of
a compound of this invention into another pharmaceutically acceptable salt of a compound of
this invention.
For solvates of the compounds of Formula (I), including solvates of salts of the
compounds of Formula (I), that are in crystalline form, the skilled artisan will appreciate that
pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated
into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such
as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they may involve
water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the
solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates."
Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of
water. The invention includes all such solvates, particularly hydrates. It is to be understood that
the term “a salt, particularly a pharmaceutically acceptable salt, thereof, or hydrate thereof”
encompasses a salt of a compound of Formula (I), a pharmaceutically acceptable salt of a
compound of Formula (I), a hydrate of a compound of Formula (I), a hydrate of a salt of a
compound of Formula (I), and a hydrate of a pharmaceutically acceptable salt of a compound of
Formula (I).
Because the compounds of Formula (I) are intended for use in pharmaceutical
compositions it will readily be understood that they are each preferably provided in substantially
pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least
85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of
the compounds may be used for preparing the more pure forms used in the pharmaceutical
compositions.
GENERAL SYNTHETIC METHODS
The compounds of Formula (I) may be obtained by using synthetic procedures illustrated
in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The
syntheses provided in these Schemes are applicable for producing compounds of the invention
having a variety of different substituent groups employing appropriate precursors, which are
suitably protected if needed, to achieve compatibility with the reactions outlined herein.
Subsequent deprotection, where needed, affords compounds of the nature generally disclosed.
While the Schemes are shown with compounds only of Formula (I), they are illustrative of
processes that may be used to make the compounds of the invention.
Intermediates (compounds used in the preparation of the compounds of the invention)
may also be present as salts. Thus, in reference to intermediates, the phrase “compound(s) of
formula (number)” means a compound having that structural formula or a pharmaceutically
acceptable salt thereof.
4-Chloroquinazoline intermediates may be from the appropriately functionalized
nitrobenzoic acid via reduction of the nitro group to an aniline followed by condensation with
formamide or formimamide and cyclization to the 4-quinazolinone. Conversion to the
chloroquinazoline could be accomplished with POCl or SOCl at elevated temperatures.
Scheme 1
Additional starting anilines may be synthesized via benzoic acids by protecting the acid
as an ester followed by halogenation. Reaction with formimamide then provides the
quinazolinone which could then be converted to the 4- chloroquinazoline as in Scheme 1.
Scheme 2
Palladium catalyzed coupling of the iodoquinazolines with thiols may provide
6-alkylthioquinazolines which could be final products, or further subjected to oxidation with
Oxone to afford the corresponding sulfone final products. Sulfoxides may also be obtained by
this route through carefully monitoring the reaction. Additionally, any sulfides at R may be
oxidized to sulfones in this manner.
Scheme 3
Substitution at C6 could also be installed prior to installation of the “A” moiety. A
palladium catalyzed coupling of a thiol with the 6-iodoquinazolinone can provide a sulfide which
can subsequently be oxidized to the sulfone. Chlorination with POCl or SOCl may provide the
4-chloroquinazoline.
Scheme 4
Anilines/amines could be reacted with 4-chloro-quinazolines under basic or acidic
conditions to afford 4-aminoquinazolines which could be final compounds or used as
intermediates for further synthesis.
Scheme 5
with
R NMP,K CO
2 2 3
3 R N
alcohol, cat.HCl
7-Hydroxyquinazolines could be synthesized by dealkylation of the
7-methoxyquinazolines with a sodium alkylthiolate.
Scheme 6
Additional alkoxy substitution at C7 can be installed by alkylation of the
7-hydroxyquinazoline. In some cases, alkylation of the secondary amine may be observed.
When Boc-protected haloalkylamines are used, a subsequent step with treatment of HCl is
necessary to remove the Boc protecting group.
Scheme 7
In select cases, the sulfide at C6 could be installed while dealkylating C7
methoxyquinazoline with the appropriate sodium alkylthiolate. Final product may be obtained
following alkylation of the resultant C7 hydroxyl and oxidation to the sulfone.
Scheme 8
Substituted hydroxyethyl chains at C7 could be accessed through reduction of an ester
that was installed as in Scheme 8.
Scheme 9
The 7-ethylquinazoline could synthesized via a Stille coupling with the C7 triflate to
provide the ethylenebenezene followed by hydrogenolysis.
Scheme 10
Alternatively, the triflate can undergo a palladium catalyzed reaction to install the allylic
alcohol.
Scheme 11
-Fluoro-1H-pyrazolo[3,4-b]pyridinamine may be synthesized from 2-chlorofluoro-
3-pyridinecarboxylic acid. Formation of the acylchloride followed by the addition of ammonia
can provide the amide which may be subsequently converted to the nitrile. Treatment with
hydrazine may provide the azaindazole.
Scheme 12
3,4-Dimethyl-1H-pyrazolamine may be synthesized by alkylation of 3-amino
methylacrylonitrile followed by a cyclization with hydrazine.
Scheme 13
The pyrazolamine can be further methylated by reaction with formic acid followed by
reduction with borohydride.
Scheme 14
“A” groups may be installed via a C4 sulfide intermediate. Treatment of the 4-chloro
methoxyquinazolines with sodium ethanethiolate provides the 4-ethylsulfide
hydroxyquinoazolines. These 4-alkythio-quinazoline intermediates may be directly treated with
an excess of amine (A-NH ) under acidic microwave conditions to provide final products.
Alternatively, the intermediates could be alkylated at R to afford the hydroxyethyl ethers before
undergoing reaction with amine (A-NH ).
Scheme 15
Hydrolysis of esters to carboxylic acids (on R side chains) may be accomplished with
LiOH (X = any alkyl chain).
Scheme 16
Direct reaction of a R phenol with acrylate provides an unsaturated ester.
Scheme 17
Elimination of an alkyl bromide under thermal conditions provides a vinyl ether.
Scheme 18
Sulfonamides may be obtained through the sulfonyl chloride. Formation of the
benzylthioether via a palladium catalyzed reaction at the 6-iodoquinazoline followed by
treatment with NCS under acidic conditions provided the sulfonyl chloride. Treatment with an
amine or ammonia affords the sulfonamide.
Scheme 19
The compounds of this invention may be particularly useful for treatment of RIP2 kinase-
mediated diseases or disorders, particularly, uveitis, interleukin-1 converting enzyme (ICE, also
known as Caspase-1) associated fever syndrome, dermatitis, acute lung injury, type 2 diabetes
mellitus, arthritis (specifically rheumatoid arthritis), inflammatory bowel disorders (such as
ulcerative colitis and Crohn’s disease), early-onset and extra-intestinal inflammatory bowel
disease, prevention of ischemia reperfusion injury in solid organs (specifically kidney) in
response ischemia induced by cardiac surgery, organ transplant, sepsis and other insults, liver
diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, and autoimmune hepatitis), allergic
diseases (such as asthma), transplant reactions (such as graft versus host disease), autoimmune
diseases (such as systemic lupus erythematosus, and multiple sclerosis), and granulomateous
disorders (such as sarcoidosis, Blau syndrome, early-onset sarcoidosis, Wegner’s granulomatosis,
and interstitial pulmonary disease).
The compounds of this invention may be particularly useful in the treatment of uveitis,
ICE fever, Blau Syndrome, early-onset sarcoidosis, ulcerative colitis, Crohn's disease, Wegener's
granulamatosis and sarcoidosis.
Treatment of RIP2 kinase-mediated diseases or disorders, or more broadly, treatment of
immune mediated diseases including, but not limited to, allergic diseases, autoimmune diseases,
prevention of transplant rejection and the like, may be achieved using a compound of this
invention as a monotherapy, or in dual or multiple combination therapy, particularly for the
treatment of refractory cases, such as in combination with other anti-inflammatory and/or anti-
TNF agents, which may be administered in therapeutically effective amounts as is known in the
art.
For example, the compounds of this invention may be administered in combination with
corticosteroids and/or anti-TNF agents to treat Blau syndrome, early-onset sarcoidosis; or in
combination with anti-TNF biologics or other anti-inflammatory biologics to treat Crohn's
Disease; or in combination with 5-ASA (mesalamine) or sulfasalazine to treat ulcerative colitis;
or in combination with low-dose corticosteroids and/or methotrexate to treat Wegener's
granulamatosis or sarcoidosis or interstitial pulmonary disease; or in combination with a biologic
(e.g. anti-TNF, anti-IL-6, etc.) to treat rheumatoid arthritis; or in combination with anti-IL6
and/or methotrexate to treat ICE fever.
Examples of suitable anti-inflammatory agents include corticosteroids, particularly low-
dose corticosteroids (such as Deltasone (prednisone)) and anti-inflammatory biologics (such as
Acterma (anti-IL6R mAb) and Rituximab (anti-CD20 mAb)). Examples of suitable anti-TNF
agents include anti-TNF biologics (such as Enbrel® (etanecerpt)), Humira (adalimumab),
Remicade (infliximab) and Simponi (golimumab)).
This invention also provides a compound of Formula (I), or a salt thereof, particularly a
pharmaceutically acceptable salt thereof, for use in therapy. Also described herein is the use of a
compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an active therapeutic
substance in the treatment of a RIP2 kinase-mediated disease or disorder, for example the
diseases and disorders recited herein; more specifically, for use in the treatment of a disease
mediated by inhibition of RIP2 kinase.
The invention also provides for the use of a compound of Formula (I), or a salt thereof,
particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
use in the treatment of a RIP2 kinase-mediated disease or disorder, for example the diseases and
disorders recited herein.
A therapeutically "effective amount" is intended to mean that amount of a compound
that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as
defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when
administered to a human in need thereof, is sufficient to modulate or inhibit the activity of RIP2
kinase such that a disease condition which is mediated by that activity is reduced, alleviated or
prevented. The amount of a given compound that will correspond to such an amount will vary
depending upon factors such as the particular compound (e.g., the potency (pIC ), efficacy
(EC ), and the biological half-life of the particular compound), disease condition and its
severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can
nevertheless be routinely determined by one skilled in the art. Likewise, the duration of
treatment and the time period of administration (time period between dosages and the timing of
the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of
the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g.,
pharmaceutical characteristics), disease or disorder and its severity and the specific composition
and method being used, but can nevertheless be determined by one of skill in the art.
"Treating" or "treatment" is intended to mean at least the mitigation of a disease or
disorder in a patient. The methods of treatment for mitigation of a disease or disorder include the
use of the compounds in this invention in any conventionally acceptable manner, for example for
prevention, retardation, prophylaxis, therapy or cure of a mediated disease or disorder. Specific
diseases and disorders that may be particularly susceptible to treatment using a compound of this
invention are described herein.
The compounds of the invention may be administered by any suitable route of
administration, including both systemic administration and topical administration. Systemic
administration includes oral administration, parenteral administration, transdermal
administration, rectal administration, and administration by inhalation. Parenteral administration
refers to routes of administration other than enteral, transdermal, or by inhalation, and is
typically by injection or infusion. Parenteral administration includes intravenous, intramuscular,
and subcutaneous injection or infusion. Inhalation refers to administration into the patient's
lungs whether inhaled through the mouth or through the nasal passages. Topical administration
includes application to the skin.
The compounds of the invention may be administered once or according to a dosing
regimen wherein a number of doses are administered at varying intervals of time for a given
period of time. For example, doses may be administered one, two, three, or four times per day.
Doses may be administered until the desired therapeutic effect is achieved or indefinitely to
maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the
invention depend on the pharmacokinetic properties of that compound, such as absorption,
distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable
dosing regimens, including the duration such regimens are administered, for a compound of the
invention depend on the disease or disorder being treated, the severity of the disease or disorder
being treated, the age and physical condition of the patient being treated, the medical history of
the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like
factors within the knowledge and expertise of the skilled artisan. It will be further understood by
such skilled artisans that suitable dosing regimens may require adjustment given an individual
patient's response to the dosing regimen or over time as individual patient needs change.
For use in therapy, the compounds of the invention will be normally, but not necessarily,
formulated into a pharmaceutical composition prior to administration to a patient. Accordingly,
the invention also is directed to pharmaceutical compositions comprising a compound of the
invention and a pharmaceutically acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk
form wherein an effective amount of a compound of the invention can be extracted and then
given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the
pharmaceutical compositions of the invention may be prepared and packaged in unit dosage
form. For oral application, for example, one or more tablets or capsules may be administered. A
dose of the pharmaceutical composition contains at least a therapeutically effective amount of a
compound of this invention (i.e., a compound of Formula (I), or a salt, particularly a
pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the
pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this
invention.
The pharmaceutical compositions of the invention typically contain one compound of the
invention. However, in certain embodiments, the pharmaceutical compositions of the invention
contain more than one compound of the invention. In addition, the pharmaceutical compositions
of the invention may optionally further comprise one or more additional pharmaceutically active
compounds.
As used herein, "pharmaceutically acceptable excipient" means a material, composition
or vehicle involved in giving form or consistency to the composition. Each excipient must be
compatible with the other ingredients of the pharmaceutical composition when commingled such
that interactions which would substantially reduce the efficacy of the compound of the invention
when administered to a patient and interactions which would result in pharmaceutical
compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient
must of course be of sufficiently high purity to render it pharmaceutically acceptable.
The compounds of the invention and the pharmaceutically acceptable excipient or
excipients will typically be formulated into a dosage form adapted for administration to the
patient by the desired route of administration. Conventional dosage forms include those adapted
for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups,
elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration
such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal
administration such as transdermal patches; (4) rectal administration such as suppositories; (5)
inhalation such as aerosols and solutions; and (6) topical administration such as creams,
ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular
dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen
for a particular function that they may serve in the composition. For example, certain
pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production
of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for
their ability to facilitate the production of stable dosage forms. Certain pharmaceutically
acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the
compound or compounds of the invention once administered to the patient from one organ, or
portion of the body, to another organ, or portion of the body. Certain pharmaceutically
acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of
excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents,
coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners,
flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants,
chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers,
surfactants, and buffering agents. The skilled artisan will appreciate that certain
pharmaceutically acceptable excipients may serve more than one function and may serve
alternative functions depending on how much of the excipient is present in the formulation and
what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select
suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
In addition, there are a number of resources that are available to the skilled artisan which
describe pharmaceutically acceptable excipients and may be useful in selecting suitable
pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences
(Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing
Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical
Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and
methods known to those skilled in the art. Some of the methods commonly used in the art are
described in Remington’s Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or
capsule comprising an effective amount of a compound of the invention and a diluent or filler.
Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.
corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.
microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid
dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch,
potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid,
tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline
cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable
disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and
sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant.
Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
EXAMPLES
The following examples illustrate the invention. Examples 3-42, 45, 47-54 and 56-80
illustrate compounds of the invention. Examples 1, 2, 43, 44, 46 and 55 are reference examples.
These examples are not intended to limit the scope of the present invention, but rather to provide
guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of
the present invention. While particular embodiments of the present invention are described, the
skilled artisan will appreciate that various changes and modifications can be made without
departing from the spirit and scope of the invention.
The invention also includes various deuterated forms of the compounds of Formula (I).
Each available hydrogen atom attached to a carbon atom may be independently replaced with a
deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated
forms of the compounds of Formula (I). For example, deuterated pyrazole alkyl groups or
deuterated alkyl-thioquinazolines or alkyl-sulfonylquinazolines may be prepared by conventional
techniques (see for example: according to the method of Preparation 7 using iodomethane-d
available from Aldrich Chemical Co., Milwaukee, WI, Cat. No. 176036, or the method of
Scheme 13 using methane-d -thiol, Cat. No. 614904, respectively). Employing such compounds
will allow for the preparation of compounds of Formula (I) in which various hydrogen atoms are
replaced with deuterium atoms. Halogen substitution on the quinazoline core may also be
converted the deuterated form via a lithium halogen exchange followed by a quench with MeOH-
Names for the intermediate and final compounds described herein were generated using
the software naming program ACD/Name Pro V6.02 available from Advanced Chemistry
Development, Inc., 110 Yonge Street, 14 Floor, Toronto, Ontario, Canada, M5C 1T4
(http://www.acdlabs.com/) or the naming program in ChemDraw, Struct=Name Pro 12.0, as part
of ChemBioDraw Ultra, available from CambridgeSoft. 100 CambridgePark Drive, Cambridge,
MA 02140 USA (www.cambridgesoft.com). It will be appreciated by those skilled in the art that
each naming program may generate a different name for the same structurally depicted chemical
group/moiety, e.g., may be named as a tert-butylsulfonyl or as a (1,1-
dimethylethyl)sulfonyl group/moiety. In addition, it will be appreciated by those skilled in the
art that in certain instances this program will name a structurally depicted compound as a
tautomer of that compound. It is to be understood that any reference to a named compound or a
structurally depicted compound is intended to encompass all tautomers of such compounds and
any mixtures of tautomers thereof.
In the following experimental descriptions, the following abbreviations may be used:
Abbreviation Meaning
AcOH acetic acid
aq aqueous
brine saturated aqueous sodium chloride
CH2Cl2 or DCM methylene chloride
CH3CN or MeCN acetonitrile
CH3NH2 methylamine
d day
DCE 1,2-dichloroethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EDC 1-ethyl(3-dimethylaminopropyl) carbodiimide
equiv equivalents
Et ethyl
Et3N or TEA triethylamine
Et2O diethyl ether
EtOAc ethyl acetate
h, hr hour(s)
HATU O-(7-Azabenzotriazol-1yl)-N,N,N’,N’-tetramethylyronium hexafluorophosphate
HCl hydrochloric acid
ICl iodine monochloride
i-Pr2NEt N’,N’-diisopropylethylamine
KOt-Bu potassium tert-butoxide
LCMS liquid chromatography-mass spectroscopy
LiHDMS lithium hexamethyldisilazide
Me methyl
MeOH or CH3OH methanol
MgSO4 magnesium sulfate
min minute(s)
MS mass spectrum
µw microwave
NaBH4 sodium borohydride
Na2CO3 sodium carbonate
NaHCO3 sodium bicarbonate
NaOH sodium hydroxide
Na2SO4 sodium sulfate
N2H2 hydrazine
NH4Cl ammonium chloride
NiCl •6H O nickel (II) chloride hexahydrate
NMP N-methylpyrrolidone
Ph phenyl
POCl phosphoryl chloride
rt room temperature
satd. saturated
SPE solid phase extraction
TFA trifluoroacetic acid
THF tetrahydrofuran
t retention time
Preparation 1
6-(methylthio)-4(1H)-quinazolinone
-(Methylthio)nitrobenzoic acid (1.0 g, 4.7 mmol), zinc (1.8 g, 28 mmol), and MeOH
(38 mL) were purged with nitrogen for 10 min and cooled to 0°C. Ammonium formate (2.96 g,
46.9 mmol) was added in several portions and the reaction was left to stir at rt overnight. After
18 h, the milky-white reaction was diluted with acetone and filtered. The solid was collected and
placed in a round bottom flask with formamide (9.35 mL, 235 mmol). The reaction was heated
to 150°C for 30 min. After cooling to rt, the mixture was partitioned between satd. NaHCO and
Et O. The aqueous layer was extracted with Et O (5x). The combined organic portions were
dried over MgSO and concentrated to yield 350 mg of crude product which was dry-loaded onto
silica and purified via column chromatography (Biotage SP-1, 100% EtOAc) to afford 120 mg of
pure material. The aqueous layer was extracted again with 15% MeOH/EtOAc (3x). The
combined organic portions were dried over MgSO and concentrated to yield 4 g of formamide
and desired product. The crude product was dry-loaded onto silica and purified via column
chromatography (Biotage SP-1, 100% EtOAc) which removed the ~35% of the formamide.
Chromatography was repeated (2x) to yield pure product (100 mg) which was combined with the
earlier 120 mg to provide 6-(methylthio)-4(1H)-quinazolinone (215 mg, 1.12 mmol, 23.9%
yield). MS (m/z) 193 (M+H ); H NMR (400 MHz, DMSO-d ) δ 12.29 (br. s., 1H), 8.05 (s, 1H),
7.85 (d, J = 2.3 Hz, 1H), 7.67 - 7.74 (m, 1H), 7.56 - 7.63 (m, 1H), 2.57 (s, 3H)
Preparation 2
N-1,3-benzothiazolyliodoquinazolinamine
Step 1. 4-chloroiodoquinazoline: 6-iodo-4(1H)-quinazolinone (10 g, 37 mmol) was
weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5 mL, 6.5
mmol) were added to give a grey suspension. The mixture was heated to reflux. Heating was
continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid
precipitated and was collected by filtration to afford 8.6 g (77%) of the title compound.
Step 2. N-1,3-benzothiazolyliodoquinazolinamine: To a solution of 4-chloro
iodoquinazoline (2.60 g, 8.95 mmol) in isopropanol (60 mL) was added 1,3-benzothiazol
amine (1.479 g, 9.85 mmol). The mixture was then placed in oil bath preheated to 90°C. The
reaction was complete in 30 min., and the solution was allowed to cool to room temperature. A
yellow solid precipitated and was filtered and dried to provide 3.6 g (91%) of the title compound.
The following intermediate, N-(5-fluoro-1H-indazolyl)iodoquinazolinamine, was
made in the same manner:
Preparation 3
4-chloro[(1-methylethyl)sulfonyl]quinazoline
Step 1. 6-[(1-methylethyl)thio]-4(1H)-quinazolinone: To a solution of 6-iodo-4(1H)-
quinazolinone (3.0 g, 11.0 mmol), 2-propanethiol (1.1 mL, 12.1 mmol) and Et N (4.6 mL, 33.1
mmol) in DMF (40 mL) was added Pd(Ph P) (1.27 g, 1.10 mmol) under nitrogen. The solution
was stirred at 90 ºC for 1 h. The reaction mixture was allowed to cool to rt and DMF was
removed in vacuo. The crude material was purified by column chromatography (0 to 5%
MeOH/CH Cl ) to provide 6-[(1-methylethyl)thio]-4(1H)-quinazolinone (1.8 g, 7.4 mmol, 67%
yield). MS (m/z): 221(M+H).
Step 2. 6-[(1-methylethyl)sulfonyl]-4(1H)-quinazolinone: 6-[(1-Methylethyl)thio]-
4(1H)-quinazolinone (500 mg, 2.27 mmol) was dissolved in MeOH and water. Oxone (2.8 g, 4.5
mmol) was then added and the mixture stirred for 1 h. The reaction mixture was filtered. The
solution was concentrated and crude material was purified by column chromatography (starting
with 100% EtOAc to a mixture of 20% EtOAc with 80% of 10% NH OH in IPA). The
collection was triturated with Et O to provide 700 mg product with 70% purity. MS (m/z): 253
(M+H).
Step 3. 4-chloro[(1-methylethyl)sulfonyl]quinazoline: 6-[(1-Methylethyl)thio]-4(1H)-
quinazolinone (0.20 g, 0.91 mmol), DMF (0.1 mL) and thionyl chloride (5 mL) were place in a
sealed tube and heated at 85 C for 5 h. LCMS showed 85% of starting material was converted to
product. The solvent was removed in vacuo to provide the title compound (0.20 g crude
material). MS (m/z): 271 (M+H).
Preparation 4
-fluoro-1H-pyrazolo[3,4-b]pyridinamine
Step 1. 2-chlorofluoropyridinecarboxamide: 2-Chlorofluoro
pyridinecarboxylic acid (20 g, 110 mmol) was dissolved in CH Cl (400 mL), and then DMF (88
μL, 1.1 mmol) was added at 0°C. After the DMF addition, oxalyl chloride (26 mL, 300 mmol)
was added dropwise at 0°C. The reaction mixture was stirred at rt for 16 h, and concentrated in
vacuo. The resulting yellow liquid was dissolved in 1,4-dioxane (400 mL), cooled to 0°C and
NH (gas) (19.4 g, 1140 mmol) was bubbled through the solution for 30 min. The mixture was
stirred at rt for 16 h. The resulting white mixture was filtered and the filtrate was concentrated to
give the desired product as a white solid (18 g, 89% yield). MS (m/z) 175 (M+H ); H NMR
(400 MHz, DMSO-d ) δ ppm 8.53 (d, 1 H), 8.10 (s, 1 H), 8.00 (dd, 1 H), 7.88 (s, 1 H).
Step 2. 2-chlorofluoropyridinecarbonitrile: 2-Chlorofluoro
pyridinecarboxamide (18 g, 102 mmol) was suspended in CH Cl (500 mL), and then Et N (31
2 2 3
mL, 220 mmol) was added at 0°C. Trifluoroacetic anhydride (TFAA) (16 mL, 110 mmol) was
added dropwise to the reaction mixture at 0°C. The white carboxamide starting material
disappeared after 20 min at 0°C, indicating the completion of the reaction. The reaction mixture
was stirred at 0°C for 1 h. The reaction mixture was diluted with CH Cl , and then washed with
satd. NaHCO (aq). The organic layer was washed with brine, dried over MgSO , filtered and the
filtrate was concentrated to a brown residue. The residue was purified by column
chromatography (8%-20% EtOAc/hexanes; 330g column). Collected fractions were combined
and concentrated to give the desired product as a white solid (15 g, 96% yield). MS (m/z) 157
(M+H ). H NMR (400 MHz, DMSO-d ) δ ppm 8.68 (dd, 1 H), 8.83 (d, 1 H).
Step 3. 5-fluoro-1H-pyrazolo[3,4-b]pyridinamine: 2-Chlorofluoro
pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in 1-butanol (300 mL), and then hydrazine
monohydrate (16.82 mL, 293 mmol) was added, followed by hydrochloric acid (4N in 1,4-
dioxane) (0.244 mL, 0.977 mmol). The reaction mixture was maintained at 70°C for 4 h, and the
resulting yellow crystalline solid was collected by filtration (12.5 g, 84% yield). MS (m/z) 153
(M+H ). H NMR (400 MHz, DMSO-d ) δ ppm 5.56 (s, 2 H), 7.97 (dd, 1 H), 8.39 (m, 1 H),
12.07 (s, 1 H).
Preparation 5
6-(tert-butylsulfonyl)-4,7-dichloroquinazoline
Step 1. 7-chloroiodo-4(1H)-quinazolinone: A solution of methyl 2-aminochloro
iodobenzoate (3.4 g, 10.9 mmol) and imidoformamide (3.4 g, 32.7 mmol) in 2-methoxyethanol
(15 mL) was stirred at 125°C for 7 h. The reaction mixture was allowed to cool to rt and the
residue suspended in water. The solid was collected by filtration, washed with water and dried
under vacuum (50 ºC) to give 3.2 g of the title compound (96%). MS: m/z: 307 [M+H] .
Step 2. 7-chloro[(1,1-dimethylethyl)thio]-4(1H)-quinazolinone: To a solution of 6,7-
bis[(1,1-dimethylethyl)thio]-4(1H)-quinazolinone (500 mg, 1.6 mmol), 2-methylpropanethiol
(162 mg, 1.8 mmol), Et N (0.68 mL, 4.9 mmol) in DMF (5 mL) was added Pd(Ph P) (189 mg,
3 3 4
0.16 mmol). The reaction mixture was stirred at 90°C for 1 h. Solvent was removed in vacuo.
The crude material was purified by column chromatography (0 to 5% MeOH/CH Cl ) to provide
0.37 g of the title compound (84%). MS: m/z: 269 [M+H] .
Step 3. 7-chloro[(1,1-dimethylethyl)sulfonyl]-4(1H)-quinazolinone: To a solution of
7-chloro[(1,1-dimethylethyl)thio]-4(1H)-quinazolinone (370 mg, 1.4 mmol) in THF (8 mL)
and water (2 mL) was added oxone (1.9 g, 3.0 mmol) and stirred overnight. Aq. NaHCO was
added to neutralize the solution to pH=7. The solution was extracted with EtOAc, dried over
Na SO , filtered, and evaporated. Crude material was purified by column chromatography (0 to
8% MeOH/CH Cl ) to give 0.30 g product (yield 64%). MS: m/z: 301 [M+H] .
Step 4. 4,7-dichloro[(1,1-dimethylethyl)sulfonyl]quinazoline: To a solution of 7-
chloro[(1,1-dimethylethyl)sulfonyl]-4(1H)-quinazolinone (180 mg, 0.60 mmol), POCl (0.22
mL, 2.39 mmol) in 1,2-dichloroethane (5 mL) was added DIPEA (0.52 mL, 3.0 mmol). The
reaction mixture was heated at 80°C for 4 h and then cooled to rt. The solvent was removed
under high vacuum. The residue was treated with satd. aq. NaHCO and extracted with CH Cl .
3 2 2
The organic extract was dried over Na SO . The organic extract was filtered and concentrated
for use in the next step (166 mg of title compound). MS: m/z: 319 [M+H] .
Preparation 6
6-(tert-butylsulfonyl)chloromethoxyquinazoline
Step 1. 6-[(1,1-dimethylethyl)thio](methyloxy)-4(1H)-quinazolinone: To a solution of
6-iodo(methyloxy)-4(1H)-quinazolinone(1.0 g, 3.3 mmol), 2-methylpropanethiol (0.36 g,
4.0 mmol), Et N (1.4 mL, 9.9 mmol) in DMF (5 mL) was added Pd(Ph P) (0.38 g, 0.33 mmol).
3 3 4
The reaction mixture was stirred at 90 C for 1 h. Solvent was removed in vacuo. The crude
material was purified by column chromatography (0 to 5% MeOH/CH Cl ) to provide 0.90 g of
the title compound (93%). MS:m/z: 265 [M+H] .
Step 2. 6-[(1,1-dimethylethyl)sulfonyl](methyloxy)-4(1H)-quinazolinone: 6-[(1,1-
dimethylethyl)thio](methyloxy)-4(1H)-quinazolinone (900 mg, 3.4 mmol) was dissolved in
MeOH (10 mL), THF (10 mL) and water (0.4 mL). Oxone (4.2 g, 6.8 mmol) was added and
reaction mixture was stirred at rt overnight. The solution was filtered, and the solid was washed
with CH Cl and MeOH. The solvent was evaporated. The crude material was purified by
column chromatography (0 to 10% MeOH/CH Cl ). 1.1 g of the title compound as collected with
a purity of 74%. MS:m/z: 297.2 [M+H] .
Step 3. 4-chloro[(1,1-dimethylethyl)sulfonyl](methyloxy)quinazoline: 6-[(1,1-
Dimethylethyl)sulfonyl](methyloxy)-4(1H)-quinazolinone (60 mg, 0.20 mmol) and POCl (2
mL, 21.5 mmol) and the reaction mixture was heated at 80°C for 4h. The solution was allowed
to cool to rt. POCl was removed under high vacuum. The residue was treated with satd. aqueous
NaHCO and extracted with CH Cl . The organic extract was dried over Na SO , filtered, and
3 2 2 2 4
concentrated. MS:m/z: 315, 317 [M+H] .
Preparation 7
3,4-Dimethyl-1H-pyrazolamine
Step1. 3-aminomethylbutenenitrile: To a suspension of NaH (11.7 g, 292 mmol) in
toluene (100 mL) at 30°C was added a solution of (2Z)aminobutenenitrile (20 g, 244
mmol) in toluene (400 mL) and the reaction mixture was stirred for 10 min. Iodomethane (15.23
mL, 244 mmol) was added and the reaction was cooled with cold water to maintain a
temperature of 40 ºC. The reaction was then cooled to 30°C and stirred overnight. An orange
solid formed and was collected via filtration washing with toluene. The solid was suspended in
water (400 mL) and stirred for 1 h. The solid was then filtered washing with water and air dried
for 15 min, then placed under vacuum overnight (6.7 g, 29%). The mother liquor was
concentrated under vacuum and the resulting residue dissolved in EtOAc to give a biphasic
solution with mineral oil. The layers were separated and the EtOAc was removed under vacuum;
the resulting solid was recrystallized from benzene to give the title compound (2.8 g, 12%). H
NMR (400 MHz, DMSO-d ) δ ppm 1.57 (s, 3 H) 1.92 (s, 3 H) 6.12 (br. s., 2 H); MS (m/z) 97
(M+H ).
Step 2. 3,4-dimethyl-1H-pyrazolamine: To a solution of 3-aminomethyl
butenenitrile (1.0 g, 10.4 mmol) in ethanol (10.4 mL) was added hydrazine (0.60 mL, 10.4
mmol). The resulting mixture was heated to 75°C for 16 h open to atmosphere. The reaction
was concentrated onto silica gel and purified via flash chromatography eluting with 0-10%
MeOH in CH Cl to give the title compound as a yellow oil (710 mg, 61%). H NMR (400
MHz, DMSO-d ) δ ppm 1.72 (s, 3 H) 1.99 (s, 3 H) 3.99 - 4.50 (m, 2 H) 10.72 - 11.07 (m, 1 H);
MS (m/z) 112 (M+H ).
Preparation 8
N,4,5-trimethyl-1H-pyrazolamine
Step 1. (4,5-dimethyl-1H-pyrazolyl)formamide. A mixture of 4,5-dimethyl-1H-
pyrazolamine (1.92 g, 17.3 mmol) in formic acid (10 mL) was stirred under nitrogen at reflux
for 2 h. The reaction mixture was cooled to rt and concentrated to yield the title compound as a
solid. LCMS (m/z): 140 (M+H ).
Step 2. N,4,5-trimethyl-1H-pyrazolamine. A mixture of (4,5-dimethyl-1H-pyrazol
yl)formamide (2.47 g, 17.7 mmol) and BH •THF (53.1 mL of a 1.0 M solution in THF, 53.1
mmol) was stirred under nitrogen at rt for 3 h. The mixture was then cooled to 0°C and quenched
with MeOH (dropwise addition). The crude product was purified via column chromatography
using 0-7% MeOH:CH Cl gradient, 80 g column to yield 0.70 g of the title compound as a
colorless viscous oil. H NMR (400 MHz, DMSO-d ) δ 10.27 - 11.36 (m, 1H), 4.56 (br. s., 1H),
2.64 (s, 3H), 2.00 (s, 3H), 1.71 (s, 3H); LCMS (m/z): 126 (M+H ).
Example 1
4-methyl{[6-(methylthio)quinazolinyl]amino}phenol
A mixture of 6-(methylthio)-4(1H)-quinazolinone (200 mg, 1.1 mmol) and phosphorus
oxychloride (5.0 mL, 53 mmol) was heated at 110°C for 3 h. Toluene was added and the
reaction was concentrated to dryness. To the crude 4-chloro(methylthio)quinazoline (249 mg,
1.18 mmol) in NMP (9.6 mL) were added potassium carbonate (490 mg, 3.5 mmol) and 3-amino-
4-methylphenol (145 mg, 1.18 mmol). The reaction was heated at 100°C for 30 min, cooled to rt,
and partitioned between EtOAc and satd. NaHCO . The aqueous layer was extracted with
EtOAc (3x) and the combined organic layers were washed with brine (3x), dried over MgSO ,
dry-loaded onto silica and chromatographed (Biotage SP-1, 25%-100% EtOAc/hexane) to yield
4-methyl{[6-(methylthio)quinazolinyl]amino}phenol (140 mg, 0.471 mmol, 39.9% yield).
MS (m/z) 298 (M+H ); H NMR (400 MHz, DMSO-d ) δ 9.60 (s, 1H), 9.30 (s, 1H), 8.35 (s, 1H),
8.19 (d, J = 2.0 Hz, 1H), 7.62 - 7.78 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H),
6.65 (dd, J = 8.1, 2.5 Hz, 1H), 2.63 (s, 3H), 2.05 (s, 3H).
Example 2
4-methyl{[6-(methylsulfonyl)quinazolinyl]amino}phenol
To a suspension of 4-methyl{[6-(methylthio)quinazolinyl]amino}phenol (130 mg,
0.44 mmol) in MeOH (2.5 mL) and water (2.5 mL) was added Oxone (322 mg, 0.525 mmol).
The reaction was stirred at rt for 30 min and concentrated to near dryness under a stream of
nitrogen. The residue was partitioned between EtOAc and satd. NaHCO3. The aqueous layer
was extracted with EtOAc (2x) and the combined organic extracts were washed with brine (1x),
dried over MgSO and concentrated to dryness to yield pure 4-methyl{[6-(methylsulfonyl)
quinazolinyl]amino}phenol (110 mg, 0.334 mmol, 76% yield). MS (m/z) 330 (M+H ); H NMR
(400 MHz, DMSO-d ) δ 10.18 (s, 1H), 9.33 (s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.27
(dd, J = 8.7, 1.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 2.5 Hz,
1H), 6.66 (dd, J = 8.2, 2.4 Hz, 1H), 3.34 (s, 3H), 2.06 (s, 3H).
Example 3
N-1,3-benzothiazolyl[(1,1-dimethylethyl)thio]quinazolinamine
A 20 mL microwave vial was charged with N-1,3-benzothiazolyliodo
quinazolinamine (182 mg, 0.270 mmol), Pd(Ph P) (31.2 mg, 0.027 mmol) and 2-methyl
propanethiol (0.032 mL, 0.284 mmol). The flask was then evacuated and backfilled with
nitrogen three times. 1,4-Dioxane (10 mL) was then added followed by Et N (0.25 mL, 1.794
mmol). The yellow suspension was sparged with argon for 5 min, then sealed and heated to
60°C in a heating block. After 18 hr the reaction was cooled to rt and concentrated directly to
afford a dark red oil. The crude material was purified via column chromatography (25 g SNAP
column, 0-15% MeOH/CH Cl ). The combined fractions containing the desired product
appeared to be ~ 80% pure.
Example 4
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]quinazolinamine
A 20 mL microwave vial was charged with N-1,3-benzothiazolyliodo
quinazolinamine (182 mg, 0.270 mmol), Pd(Ph P) (31.2 mg, 0.027 mmol) and 2-methyl
propanethiol (0.032 mL, 0.284 mmol). The flask was then evacuated and backfilled with
nitrogen three times. 1,4-Dioxane (10 mL) was then added followed by Et N (0.25 mL, 1.794
mmol). The yellow suspension was sparged with argon for 5 min, then sealed and heated to
60°C in a heating block. After 18 hr the reaction was cooled to rt and concentrated directly to
afford a dark red oil. The crude material was purified via column chromatography (25 g SNAP
column, 0-15% MeOH/CH Cl ). The combined fractions containing the desired product
appeared to be ~ 80% pure.
Alternatively, this reaction can be run in solvents other than 1,4-dioxane, including DMF,
and at temperatures other than 60 C as appropriate for each substrate.
N-1,3-benzothiazolyl[(1,1-dimethylethyl)thio]quinazolinamine (150 mg, 0.327
mmol) was dissolved in MeOH (10 mL) in a 20 mL scintillation vial. To this deep red solution
was added oxone (300 mg, 0.488 mmol) and the reaction was stirred at rt. After 1 hr the reaction
was treated with 5 mL of (5:1 Na S O /NaHCO ) for 5 min then poured into 50mL sat. aq.
2 2 3 3
bicarbonate solution. The mixture was diluted with 50mL H O and then extracted with CH Cl
2 2 2
(50 mL x 3) and EtOAc (50mL). The combined organics were concentrated and the crude
material was purified via column chromatography (25g SNAP column, 0 - 8% MeOH/CH Cl ) to
afford 37 mg (26%) of the title compound. MS (m/z) 399.1 (M+H ). H NMR (DMSO-d ) δ:
.65 (br. s., 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.10 - 8.28 (m, 2H), 7.99
(d, J = 8.6 Hz, 1H), 7.89 - 7.96 (m, 1H), 1.33 (s, 9H).
Select compounds were purified by reverse phase HPLC.
The following examples were prepared in the same manner:
Ex. Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-d )
δ 1.34 (s, 9 H), 7.28 (td, J =
9.03, 2.15 Hz, 1 H), 7.41 (d, J =
8.84 Hz, 1 H), 7.57 (dd, J = 8.97,
401 4.17 Hz, 1 H), 7.91 (d, J = 8.08 as Ex. 4
Hz, 1 H), 8.12 (d, J = 8.34 Hz, 1
H), 8.53 (s, 1 H), 9.15 ( s., 1 H),
6-(tert-butylsulfonyl)-N-(5-fluoro-1H-
12.25(br. S. 1 H)
indazolyl)quinazolinamine
H NMR (DMSO-d ) δ: 10.64
(br. s., 1H), 9.44 (s, 1H), 9.27 (s,
1H), 8.75 (s, 1H), 8.66 (s, 1H),
6 385.1 8.14 - 8.29 (m, 2H), 8.00 (d, J = as Ex. 4
8.8 Hz, 1H), 7.87 - 7.96 (m, 1H),
3.49 - 3.65 (m, 1H), 1.24 (d, J =
N-1,3-benzothiazolyl[(1-
6.8 Hz, 6H).
methylethyl)sulfonyl]
quinazolinamine
H NMR (DMSO-d ) δ: 9.23 (s,
1H), 8.73 (br. s., 1H), 8.06 (br.
s., 1H), 7.85 (d, J = 8.3 Hz, 1H),
7.75 - 7.83 (m, 1H), 7.61 - 7.75
7 387 as Ex. 4
(m, 2H), 7.39 (br. s., 2H), 4.27
(t, J = 6.9 Hz, 1H), 4.15 (dd, J =
.4, 3.4 Hz, 2H), 3.70 (t, 2H).
2-{[4-(1,3-benzothiazolylamino)
quinazolinyl]sulfonyl}ethanol
H NMR (DMSO-d ) δ: 10.62
(br. s., 1H), 9.44 (s, 1H), 9.26 (s,
1H), 8.77 (s, 1H), 8.67 (s, 1H),
8.15 - 8.27 (m, 2H), 7.89 - 8.07
8 427 as Ex. 4
(m, 2H), 4.94 - 5.07 (m, 1H),
4.09 (q, J = 5.2 Hz, 1H), 3.94
(dd, J = 11.2, 3.9 Hz, 2H), 3.58 -
N-1,3-benzothiazolyl
3.74 (m, 1H), 3.18 (d, J = 5.3
(tetrahydro-2H-pyranylsulfonyl)
Hz, 4H).
quinazolinamine
Example 9
3-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}methylbutanol
Step 1. 3-{[4-(1,3-benzothiazolylamino)quinazolinyl]thio}methylbutanol: To
a solution of N-1,3-benzothiazolyliodoquinazolinamine (202 mg, 0.500 mmol), 3-
mercaptomethylbutanol (60 mg, 0.50 mmol), potassium tert-butoxide (168 mg, 1.50 mmol)
and (oxydi-2,1-phenylene)bis(diphenyl phosphine) (27 mg, 0.05 mmol) in dioxane (4 mL) was
added Pd dba (46 mg, 0.05 mmol) and the mixture was sparged with N for 10 min. The
2 3 2
reaction was complete in 2 h. Solvent was removed and the crude material was purified via
column chromatography (0 to 5% MeOH/CH Cl ) to afford 142 mg of the title compound (72%).
MS: m/z: 397 [M+H]
Cesium carbonate may also be used as the base in these coupling reactions. An
equivalent of triethamine may also be added when the starting quinazoline is an HCl salt.
Step 2. 3-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}methyl
butanol: 3-{[4-(1,3-benzothiazolylamino)quinazolinyl]thio}methylbutanol (140 mg,
0.35 mmol) and oxone (434 mg, 0.71 mmol) were suspended in MeOH (2 mL) and the mixture
was stirred at rt for 5 h. Upon filtration the cake was washed with MeOH and the filtrate was
concentrated. The crude material was purified via column chromatography (0 to 8%
MeOH/CH Cl ) to afford 3-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}
methylbutanol (67 mg, 0.15 mmol, 42% yield). MS: m/z: 429 [M+H] ; H NMR (DMSO-d )
δ: 10.66 (s, 1H), 9.44 (s, 1H), 9.25 (d, J = 1.5 Hz, 1H), 8.76 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.13
- 8.30 (m, 2H), 7.89 - 8.07 (m, 2H), 4.58 (t, J = 4.8 Hz, 1H), 3.58 (d, J = 5.3 Hz, 2H), 1.86 (t, J =
6.9 Hz, 2H), 1.34 (s, 6H).
EtOH and water (1:1) may also be used as the solvent mixture.
The following example was prepared in a similar manner:
Ex. Structure/Name MS (M+H) NMR Method
H NMR (400 MHz,
Cs CO
METHANOL-d4) ppm 1.95 (s, as base
3 H), 2.31 (s, 3 H), 3.73 (t, in step
378 J=5.68 Hz, 2 H), 3.93 - 3.97 (m, 1; EtOH
2 H), 4.22 (s, 3 H), 7.38 (s, 1 H), / H 0 as
8.72 (s, 1 H), 9.15 (br.s., 1 H) solvent
in step 2
Example 11
N-(5-fluoro-1H-indazolyl)[(1-methylethyl)sulfonyl]quinazolinamine
To a solution of 4-chloro[(1-methylethyl)sulfonyl]quinazoline (100 mg, 0.37 mmol) in
isopropanol (1 mL) was added 5-fluoro-1H-indazolamine (56 mg, 0.37 mmol). The reaction
mixture was stirred at 90°C for 1 h. The solvent was removed in vacuo and the crude material
was purified by HPLC to give 23 mg of the title compound. MS (m/z): 386 (M+H). H NMR
(DMSO-d ) δ: 13.01 (br. s., 1H), 9.19 (br. s., 1H), 8.54 (br. s., 1H), 8.17 (br. s., 1H), 7.95 (br. s.,
1H), 7.58 (dd, J = 9.1, 4.3 Hz, 1H), 7.44 (br. s., 1H), 7.29 (td, J = 9.1, 2.3 Hz, 1H), 3.48 - 3.65
(m, 1H), 1.25 (d, J = 6.8 Hz, 6H).
The following compounds were prepared using procedures analogous to those described
above using the appropriate commercial amine. Examples 11 and 12 were neutralized with Et N
before being concentrated for purification. Some reactions varied in temperature and solvent.
Ex. Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-
d ): δ = 12.31 (s, 1 H), 9.40 (s,
1 H), 9.06 (s, 1 H), 8.53 (d,
12 346 as Ex. 11
J=5.3 Hz, 1 H), 7.90 (m, 1 H),
6.60 (d, J=5.3 Hz, 1 H), 2.22
(s, 3 H), 1.81 ppm (s, 3 H),
N-(4,5-dimethyl-1H-pyrazolyl)
1.25 (d, J = 6.8 Hz, 6H).
[(1-methylethyl)sulfonyl]
quinazolinamine
H NMR (400 MHz, DMSO-
as Ex. 11
d ) δ 13.65 (br. s., 1H), 11.70
(br. s., 1H), 8.42 - 9.17 (m, using 1,4-
13 400
dioxane as
2H), 8.14 (d, J = 8.08 Hz, 1H),
7.89 (br. s., 1H), 6.79 (br. s., solvent
6-(tert-butylsulfonyl)-N-(5-
1H), 1.30 (s, 9H)
(trifluoromethyl)-1H-pyrazol
yl)quinazolinamine
H NMR (400 MHz, DMSO-
d ) δ 10.38 (br. s., 1H), 9.10 as Ex. 11
using 1,4-
(br. s., 1H), 8.63 (br. s., 1H),
14 374 8.17 (d, J = 8.34 Hz, 1H), 7.99 dioxane as
(d, J = 8.34 Hz, 1H), 3.54 (s, solvent at
3H), 2.11 (s, 3H), 1.79 (s, 3H), 150°C
1.32 (s, 9H)
6-(tert-butylsulfonyl)-N-(1,3,4-
trimethyl-1H-pyrazol
yl)quinazolinamine
Example 15
N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine
Step 1. Methyl 2-aminomethoxybenzoate: To a solution of 2-amino(methyloxy)
benzoic acid (5 g, 30 mmol) in MeOH (30 mL) and toluene (60 mL) was added
trimethylsilyldiazomethane (30 mL, 60 mmol). The reaction mixture was stirred at 0°C for 1 h.
The reaction mixture was allowed to warm to rt and solvent was removed in vacuo. The crude
material was purified by column chromatography (0 to 15% EtOAC/hexanes) to provide 4.2 g of
the title compound (74%). MS: m/z: 182 [M+H] .
Step 2. Methyl 2-aminoiodomethoxybenzoate: Methyl 2-amino(methyloxy)
benzoate (3.78 g, 20.86 mmol) was dissolved in 25 mL of water, 15 mL of ethanol and 2.2 mL of
concentrated HCl. A solution of ICl (1.1 mL, 21.9 mmol) in 3.8 mL concentrated HCl and 14
mL of water at 5 ºC was added to the aniline solution. The reaction was stirred overnight and
was then filtered to obtain 6.9 g of a light brown solid. MS: m/z: 308 [M+H]
Step 3. 6-iodomethoxyquinazolin-4(1H)-one: A solution of methyl 2-aminoiodo
(methyloxy)benzoate (2 g, 6.5 mmol) and imidoformamide (2.0 g, 19.5 mmol) in 2-
methoxyethanol (15 mL) was stirred at 125°C for 6 h. The solvent was removed in vacuo, and
the residue was suspended in water and the solid was collected by filtration, washed with water
and dried under vacuum (50 ºC) to afford 2.1 g of the title compound (96% pure). MS: m/z: 303
[M+H] .
Step 4. 4-chloroiodo(methyloxy)quinazoline: 6-Iodo(methyloxy)-4(1H)-
quinazolinone (2.0 g, 6.6 mmol), POCl (3.1 mL, 33.1 mmol) and DIPEA (6.9 mL, 40 mmol)
were combined in DCE (50 mL) a round bottom flask. The reaction mixture was heated at 80°C
for 5 h, followed by heating at 70°C for 10 h. The reaction mixture was allowed to cool to rt. A
yellow solid was precipitated out. The solid was filtered. The solution was concentrated and
neutralized with satd. NaHCO , extracted with CH Cl and dried over Na SO . The mixture was
3 2 2 2 4
filtered, and the solvent was removed in vacuo. Solid portions were combined to obtain 2.0 g of
the title compound (88%). MS: m/z: 321 [M+H] .
Step 5. N-1,3-benzothiazolyliodo(methyloxy)quinazolinamine: To a solution
of 4-chloroiodo(methyloxy)quinazoline (2.0 g, 5.4 mmol) in isopropanol (30 mL) was
added 1,3-benzothiazolamine (1.2 g, 8.1 mmol). The suspension was heated in oil bath at
90°C (preheated). The reaction mixture stirred at this temperature for 30 min. A yellow solid
precipitated out as the reaction mixture was allowed to cool to rt. The solid was filtered to
provide 2.1 g of the title compound (77%, 93% pure). MS: m/z: 471 [M+H] .
Step 6. N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine: To a
solution of N-1,3-benzothiazolyliodo(methyloxy)quinazolinamine (2.1 g, 4.5 mmol),
2-methylpropanethiol (483 mg, 5.35 mmol), Et N (1.9 mL, 13.4 mmol) in DMF (5 mL) was
added Pd(Ph P) (516 mg, 0.45 mmol). The reaction mixture was stirred at 90°C for 1 h. Most
of DMF was removed in vacuo. The crude material was triturated with MeOH. The red solid
was filtered and washed with Et O to provide 1.7 g of the title compound as an off white solid
(96%). MS: m/z: 397 [M+H] .
The following compound, N-(6-(isopropylthio)methoxyquinazolin
yl)benzo[d]thiazolamine (used only as an intermediate and not submitted for testing against
RIP2 kinase), was made in a similar manner:
Example 16
N-(6-(tert-butylsulfonyl)methoxyquinazolinyl)benzo[d]thiazolamine
To a solution of N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine
(1.2 g, 2.5 mmol) in THF (20 mL) and water (2 mL) was added oxone (3.1 g, 5.0 mmol). The
reaction mixture was stirred at rt for 8 h. Satd. aq. NaHCO was added to the reaction mixture to
adjust to pH~7. The mixture was extracted with EtOAc (100 mL x 2) and CH Cl (100 mL x 2),
dried over Na SO , and filtered. The solvent was removed in vacuo and crude material was
purified by column chromatography (0 to 8% MeOH/CH Cl ) to provide 530 mg of the title
compound (19%). MS: m/z: 429 [M+H] ; H NMR (400 MHz, DMSO-d6) δ 1.34 (s, 9 H), 4.01
(s, 3 H), 7.40 (s, 1 H), 7.89 (dd, J = 8.80, 1.78 Hz, 1 H), 8.17 (d, J = 8.80 Hz, 1 H), 8.59 (d, J =
1.78 Hz, 1 H), 8.64 (s, 1 H), 9.14 (s, 1 H), 9.42 (s, 1 H), 10.55 (s, 1 H).
The following example was prepared in a similar manner:
Ex. Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-d )
δ 1.23 (d, J = 6.82 Hz, 6 H), 3.79
(dt, J = 13.71, 6.66 Hz, 1 H),
4.08 (s, 3 H), 7.43 (s, 1 H), 7.89
17 415 as Ex. 16
(d, J = 8.84 Hz, 1 H), 8.16 (d, J =
8.84 Hz, 1 H), 8.63 (d, J = 13.39
N-(6-(isopropylsulfonyl) Hz, 2 H), 9.14 (s, 1 H), 9.42 (s, 1
methoxyquinazolin H), 10.56 (br. s., 1 H).
yl)benzo[d]thiazolamine
Example 18
4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol
To a solution of N-(6-(tert-butylsulfonyl)methoxyquinazolinyl)benzo[d]thiazol
amine (2.0 g, 4.7 mmol) in DMF (30 mL) was added sodium isopropylthiolate (2.7 g, 28.0
mmol), and the solution was stirred at 150°C for 1 h. Solvent was removed in vacuo. 1 N aq.
HCl was added to reaction mixture to neutralize to pH =6. A yellow solid precipitated out, which
was filtered and purified by column chromatography (0 to 5% MeOH/CH Cl ) to provide 1.5 g of
the title compound (65%). MS: m/z: 415 [M+H] ; H NMR (400 MHz, DMSO-d ) δ 1.15 - 1.46
(s, 9 H), 7.21 (s, 1 H), 7.89 (dd, J = 8.72, 1.78 Hz, 1 H), 8.16 (d, J = 8.72 Hz, 1 H), 8.55 (s, 1 H),
8.58 (d, J = 1.78 Hz, 1 H), 9.07 (s, 1 H), 9.42 (s, 1 H), 10.47 (s, 1 H), 11.45 (br. s., 1 H).
Examples 19 and 20
N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)benzo[d]thiazolamine and N-(6-(tert-
butylsulfonyl)ethoxyquinazolinyl)-N-ethylbenzo[d]thiazolamine
To a solution of 4-(1,3-benzothiazolylamino)[(1,1-dimethylethyl)sulfonyl]
quinazolinol (66 mg, 0.15 mmol) in DMF (1 mL) was added K CO (62 mg, 0.45 mmol). The
solution was stirred at rt for 10 min. Iodoethane (35 mg, 0.23 mmol) was then added, and the
reaction mixture was stirred at rt for 30 min. Solid precipitate was filtered out, and solution was
concentrated for purification. The crude material was purified by HPLC. The two products were
not separable. The TFA salts were neutralized by passing the material through a carbonate
cartridge. The mixture was repurified by column chromatography (0 to 4% MeOH/CH Cl ) to
isolate 13 mg of N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)benzo[d]thiazolamine
+ 1
(20%). MS: m/z: 443 [M+H] ; H NMR (400 MHz, DMSO-d ) δ 1.35 (s, 9 H), 1.42 (t, J = 6.96
Hz, 3 H), 4.30 (q, J = 6.96 Hz, 2 H), 7.36 (s, 1 H), 7.89 (d, J = 8.84 Hz, 1 H), 8.16 (d, J = 8.84
Hz, 1 H), 8.58 (. s., 1 H), 8.62 ( s., 1 H), 9.13 (s, 1 H), 9.42 (s, 1 H), 10.54 (s, 1 H). In addition,
7% of the over alkylation product N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)-N-
ethylbenzo[d]thiazolamine was obtained and isolated. MS:m/z: 471 [M+H] ; H NMR (400
MHz, DMSO-d ) δ 1.18 - 1.38 (m, 12 H), 1.41 (t, J = 6.95 Hz, 3 H), 4.15 (q, J = 7.07 Hz, 2 H),
4.33 (q, J = 7.07 Hz, 2 H), 6.99 (s, 1 H), 7.15 (dd, J = 8.34, 1.77 Hz, 1 H), 7.67 (d, J = 1.52 Hz, 1
H), 7.98 (d, J = 8.59 Hz, 1 H), 8.04 (s, 1 H), 8.66 (s, 1 H), 9.30 (s, 1 H).
Example 21
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)ethanol
N HN
HN Br(CH ) OH
2 2 O O
K CO
HO N
4-(Benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol (8.0 g, 19.3 mmol)
and K CO (5.9 g, 42.5 mmol) were dissolved in 98 ml DMF and stirred 2 min before adding 2-
bromoethanol (5.1 mL, 72.4 mmol). The mixture was heated for 3 h at 70 C, and then cooled to
rt and stirred for 18 h. Water (300 mL) was added, and the resulting solid was filtered and
washed with water. The wet cake was slurried again in water and filtered to give a tan solid. The
solid was dissolved in hot EtOAc/MeOH (150 mL/50 mL) and cooled to rt to give a white solid
precipitate which was filtered and dried under vacuum to give the product as a white solid (2.4
g). The resulting filtrate was evaporated to dryness, triturated with EtOAc, filtered, and dried to
give a light brown solid (3.1 g). The solids were combined (5.5 g, 62% yield). Several batches
of this material were combined to give 15 g of input material. To this solid was added water (150
mL). The mixture was sonicated, and stirred for 15 min at rt. The solid was filtered and dried
under vacuum at 70 C for 3 days to give the title compound as a solid (14.8 g, 98% recovery).
+ 1
MS: m/z: 459 [M+H] ; H NMR (400 MHz, DMSO-d ) δ 1.36 (s, 9 H), 3.81 (q, J = 4.80 Hz, 2
H), 4.28 (t, J = 4.80 Hz, 2 H), 4.81 (t, J = 4.80 Hz, 1 H), 7.41 (s, 1 H), 7.89 (d, J = 8.40 Hz, 1 H),
8.17 (d, J = 8.40 Hz, 1 H), 8.58 (s, 1 H), 8.63 (s, 1 H), 9.14 (s, 1 H), 9.42 (s, 1 H), 10.55 (s, 1 H).
The following compounds were prepared using procedures analogous to those described
above using the appropriate alkylating agent. Isolation and purification methods vary depending
upon the substrate.
Ex. Structure/Name MS (M+H) NMR Method
H NMR (400 MHz,
DMSO-d ) δ 1.37 (s, 9 H),
3.17(s, 1H), 7.59 (s, 1 H),
22 465 as Ex. 21
7.88 (s, 1 H), 8.17 (s, 1 H),
8.56 (s, 1 H), 8.70 (s, 1 H),
9.27 (s, 1 H), 9.43 (s, 1 H),
.76 (s, 1 H)
N-(6-(tert-butylsulfonyl)
(difluoromethoxy)quinazolin
yl)benzo[d]thiazolamine
H NMR (400 MHz,
DMSO-d ) δ 1.35 (s, 9 H),
.08 (d, J = 8.59 Hz, 2 H),
7.51 (br. s., 1 H), 7.87 (br.
23 497 as Ex. 21
s., 1 H), 8.16 (d, J = 7.83
Hz, 1 H), 8.56 (br. s., 2 H),
N-(6-(tert-butylsulfonyl)(2,2,2-
9.17 (br. s., 1 H), 9.42 (s, 1
trifluoroethoxy)quinazolin
H), 10.63 (br. s., 1 H)
yl)benzo[d]thiazolamine
H NMR (400 MHz,
DMSO-d ) δ 1.35 (s, 9 H),
3.35 (s, 3 H), 3.67 - 3.84 (m,
2 H), 4.28 - 4.53 (m, 2 H),
24 473 7.39 (br, 1 H), 7.88 (s, 1 H), as Ex. 21
N-(6-(tert-butylsulfonyl) 8.16 (d, J = 8.59 Hz, 1 H),
8.57 (s, 2 H), 9.13 (s, 1 H),
(methoxymethoxy)quinazolin
yl)benzo[d]thiazolamine 9.41 (s, 1 H), 10.55 (br s, 1
H NMR (400 MHz,
DMSO-d ) δ 0.98 - 1.31 (m,
6 H), 1.35 (s, 9 H), 1.59 -
2.03 (m, 5 H), 4.04 (d, J =
6.32 Hz, 2 H), 7.36 (s, 1 H),
511 7.89 (dd, J = 8.72, 1.64 Hz, as Ex. 21
1 H), 8.16 (d, J = 8.84 Hz, 1
H), 8.58 (d, J = 1.52 Hz, 1
H), 8.62 (s, 1 H), 9.13 (s, 1
N-(6-(tert-butylsulfonyl)
H), 9.42 (s, 1 H), 10.54 (s, 1
(cyclohexylmethoxy)quinazolin
yl)benzo[d]thiazolamine
H NMR (DMSO-d ) δ:
.54 (s, 1H), 9.42 (s, 1H),
9.14 (s, 1H), 8.56 - 8.65 (m,
2H), 8.17 (d, J = 8.6 Hz,
1H), 7.88 (s, 1H), 7.37 (s,
26 473 as Ex. 21
1H), 4.57 (t, J = 5.3 Hz,
1H), 4.30 (t, J = 6.1 Hz,
2H), 3.60 - 3.71 (m, 2H),
1.95 (quin, J = 6.2 Hz, 2H),
3-((4-(benzo[d]thiazolylamino)
1.35 (s, 9H)
(tert-butylsulfonyl)quinazolin
yl)oxy)propanol
H NMR (DMSO-d ) δ:
11.16 (s, 1H), 9.45 (s, 1H),
9.23 (s, 1H), 8.74 (s, 1H),
8.52 (s, 1H), 8.22 (d, J = 8.6
Hz, 1H), 7.80 - 7.87 (m,
27 499 as Ex. 21
1H), 7.48 (s, 1H), 5.03 -
.12 (m, 1H), 3.87 - 3.98
(m, 2H), 3.54 - 3.64 (m,
2H), 2.04 (br. s., 2H), 1.75
N-(6-(tert-butylsulfonyl)((tetrahydro-
(br. s., 2H), 1.38 (s, 9H)
2H-pyranyl)oxy)quinazolin
yl)benzo[d]thiazolamine
H NMR (DMSO-d ) δ:
11.44 (br. s., 1H), 9.47 (s,
1H), 9.26 (s, 1H), 8.82 (s,
1H), 8.49 (d, J = 1.8 Hz,
1H), 8.25 (d, J = 8.8 Hz,
28 477, 479 as Ex. 21
1H), 7.82 (dd, J = 8.7, 1.9
Hz, 1H), 7.43 (s, 1H), 4.55 -
4.63 (m, 2H), 4.00 - 4.09
(m, 2H), 1.38 (s, 9H)
N-(6-(tert-butylsulfonyl)(2-
chloroethoxy)quinazolin
yl)benzo[d]thiazolamine
H NMR (400 MHz,
DMSO-d6) δ ppm 10.56 (s,
1 H), 9.43 (s, 1 H), 9.15 (s,
1 H), 8.64 (s, 1 H), 8.59 (d,
J=2.0 Hz, 1 H), 8.17 (d,
29 473 J=8.7 Hz, 1 H), 7.89 (dd, as Ex. 21
J=8.7, 2.0 Hz, 1 H), 7.38 (s,
1 H), 4.81 (d, J=4.0 Hz, 1
H), 4.0 - 4.18 (m, 2 H), 3.17
(d, J=5.5 Hz, 1 H), 1.36 (s, 9
H), 1.26 (d, J=5.5 Hz, 3 H)
H NMR (400 MHz,
DMSO-d6) δ ppm 10.51 -
.62 (m, 1 H), 9.38 - 9.47
(m, 1 H), 9.07 - 9.20 (m, 1
H), 8.62 - 8.68 (m, 1 H),
457 8.53 - 8.61 (m, 1 H), 8.09 - as Ex. 21
8.23 (m, 1 H), 7.86 - 7.94
(m, 1 H), 7.31 - 7.41 (m, 1
H), 4.13 - 4.24 (m, 2 H),
1.75 - 1.89 (m, 2 H), 1.07 (t,
J=7.45 Hz, 3 H)
H NMR (400 MHz,
CHLOROFORM-d) δ ppm
9.07 (s, 1 H), 8.76 (s, 1 H),
8.58 - 8.69 (m, 1 H), 8.14 (s,
1 H), 8.00 (d, J=8.6 Hz, 1
31 488 H), 7.77 (dd, J=8.6, 2.0 Hz, as Ex. 21
1 H), 7.35 (s, 1 H), 7.28 (s,
1 H), 4.36 (t, J=7.2 Hz, 2
H), 3.02 (t, J=7.2 Hz, 2 H),
2.24 (s, 3 H), 1.45 (s, 9 H)
H NMR (400 MHz,
DMSO-d6) δ ppm 10.58 (s,
S 1 H), 9.42 (s, 1 H), 9.16 (s,
1 H), 8.64 (s, 1 H), 8.59 (s,
1 H), 8.17 (d, J=8.7 Hz, 1
32 O N 521 as Ex. 21
H), 7.89 (d, J=8.7 Hz, 1 H),
7.43 (s, 1 H), 4.64 (t, J=5.31
Hz, 2 H), 3.76 - 3.90 (m, 2
H), 1.36 (m, 9 H)
N-(7-(2-bromoethoxy)(tert-
butylsulfonyl)quinazolin
yl)benzo[d]thiazolamine
Example 33
4-(benzo[d]thiazolylamino)(tert-butylthio)quinazolinol
To a solution of N-1,3-benzothiazolyliodo(methyloxy)quinazolinamine (100
mg, 0.23 mmol) in DMF (2 mL) was added sodium 2-methylpropanethiolate (258 mg, 2.30
mmol). The reaction mixture was stirred at 150 ºC for 3 days. The solvent was evaporated under
vacuum and crude material was purified by column chromatography to provide 45 mg of the title
compound (49%). MS: m/z: 383 [M+H] .
Example 34
N-(6-(tert-butylthio)isopropoxyquinazolinyl)benzo[d]thiazolamine
To a solution of 4-(1,3-benzothiazolylamino)[(1,1-dimethylethyl)thio]
quinazolinol (25 mg, 0.065 mmol) and Cs CO (63.9 mg, 0.20 mmol) in DMF (1 mL) was added
2-iodopropane (22 mg, 0.13 mmol). The solution was stirred at rt for 2 h. Solvent was removed
in vacuo and the crude material was purified by column chromatography (0 to 10%
MeOH/CH Cl ) to provide 14 mg of the title compound (48%). MS: m/z: 425 [M+H] . H NMR
(DMSO-d ) δ: 10.04 (s, 1H), 9.41 (s, 1H), 8.84 (s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 8.58 (s, 1H),
8.14 (d, J = 8.6 Hz, 1H), 7.94 (dd, J = 8.7, 1.9 Hz, 1H), 7.23 (s, 1H), 4.90 (dt, J = 12.1, 6.1 Hz,
1H), 1.38 (d, J = 6.1 Hz, 6H), 1.31 (s, 9H).
Example 35
N-(6-(tert-butylsulfonyl)isopropoxyquinazolinyl)benzo[d]thiazolamine
To a solution of N-1,3-benzothiazolyl[(1,1-dimethylethyl)thio][(1-
methylethyl)oxy]quinazolinamine (100 mg, 0.24 mmol) in MeOH (2 mL) and water (0.4 mL)
was added oxone (290 mg, 0.47 mmol), and the reaction mixture was stirred at rt for one h. Solid
was filtered out. The remaining solution was concentrated and residue was purified by HPLC
and basified by carbonate cartridge to give 25 mg of the title compound 22%). MS: m/z: 457
[M+H] ; H NMR (400 MHz, DMSO-d ) δ 1.31 (s, 9 H), 1.38 (d, J = 6.06 Hz, 6 H), 4.90 (dt, J =
12.13, 6.06 Hz, 1 H), 7.23 (s, 1 H), 7.94 (dd, J = 8.72, 1.89 Hz, 1 H), 8.14 (d, J = 8.59 Hz, 1 H),
8.58 (s, 1 H), 8.70 (d, J = 1.77 Hz, 1 H), 8.84 (s, 1 H), 9.41 (s, 1 H), 10.04 (s, 1 H)
Example 36
Ethyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)
methylpropanoate
A suspension of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol (250
mg, 0.60 mmol) and potassium carbonate (250 mg, 1.81 mmol) in DMF (3 mL) was stirred at rt
for 2 min before ethyl 2-bromomethylpropanoate (99 µl, 0.66 mmol) was added, then stirred
at 60°C for 1 h. The reaction mixture was partitioned between EtOAc and water, the organic
washed with satd. NH Cl and dried over MgSO and concentrated to an oil. The residue was
purified via column chromatography (30% to 100% in EtOAc in hexanes; 40g silica gel cartridge
column). The pooled fractions were concentrated in vacuo to give a white solid, ethyl 2-((4-
(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)methylpropanoate (101
mg, 32% yield). H NMR (CHLOROFORM-d) δ: 9.06 (s, 1 H), 8.68 - 8.79 (m, 2 H), 8.51 - 8.63
(m, 1 H), 7.99 (d, J = 8.6 Hz, 1 H), 7.76 (dd, J = 8.6, 2.0 Hz, 1 H), 7.28 (s, 1 H), 7.15 (br. s., 1
H), 4.31 (q, J = 7.1 Hz, 2 H), 1.79 (s, 6 H), 1.47 (s, 9 H), 1.28 (t, J = 7.1 Hz, 3 H). MS (m/z):
529.0 (M+H ).
Example 37
2-((4-(Benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)-
2-methylpropanol
To a solution of ethyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin-
7-yl)oxy)methylpropanoate (134 mg, 0.25 mmol) in THF (2.4 mL) at rt was slowly added
LAH (127 µl, 0.13 mmol). After stirring for 30m, the reaction mixture was concentrated to an
oil, and preabsorbed on silica. The residue was purified via column chromatography (EtOAc to a
3:5 mixture of a 10% NH OH in IPA solution:EtOAc; 40g silica gel cartridge column). The
pooled fractions were concentrated in vacuo to give a white solid, 2-((4-(benzo[d]thiazol
ylamino)(tert-butylsulfonyl)quinazolinyl)oxy)methylpropanol (43 mg, 35% yield).
H NMR (CHLOROFORM-d) δ: 9.07 (s, 1 H), 8.67 - 8.78 (m, 2 H), 8.52 - 8.63 (m, 1 H), 7.97
(d, J = 8.6 Hz, 1 H), 7.77 (dd, J = 8.6, 1.8 Hz, 1 H), 7.59 (br. s., 1 H), 7.28 (s, 1 H), 4.04 (m, 1
H), 3.58 - 3.76 (m, 2 H), 1.64 (s, 6 H), 1.43 (s, 9 H). MS (m/z) 487.1 (M+H ).
Example 38
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethenylquinazolinamine
Step 1. 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl
trifluoromethanesulfonate: To an ice cooled solution of 4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinol (346 mg, 0.83 mmol) in pyridine (6 mL) was slowly added triflic
anhydride (421 µl, 2.50 mmol). The reaction was warmed to rt over 5 min. The reaction mixture
was triturated from CH Cl . The solid residue was purified via column chromatography (10% to
100% in EtOAc in hexanes; 40 g silica gel cartridge column). The fractions were pooled and
concentrated in vacuo to provide 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin-
7-yl trifluoromethanesulfonate as a yellow solid (72 mg, 18% yield). H NMR
(CHLOROFORM-d) δ: 9.02 - 9.13 (m, 1H), 8.90 (d, J = 5.3 Hz, 1H), 8.77 - 8.85 (m, 1H), 8.58 -
8.66 (m, 1H), 8.15 - 8.25 (br. s., 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.95 (t, J = 6.6 Hz, 1H), 7.80 (d, J
= 8.7 Hz, 1H), 1.44 (s, 9H). MS (m/z) 546.9 (M+H ).
Step 2. N-(6-(tert-butylsulfonyl)vinylquinazolinyl)benzo[d]thiazolamine: To a
solution of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl
trifluoromethanesulfonate (60.0 mg, 0.091 mmol) and vinyltri-n-butyltin (37.1 µl, 0.126 mmol)
in DMF (1.01 mL) was added PdCl (dppf)-CH Cl adduct (18 mg, 0.02 mmol). The reaction
2 2 2
was heated at 150°C for 20 min in a microwave reactor. The residue was purified via column
chromatography (10% to 100% in EtOAc in hexanes; 40 g silica gel cartridge column). The
fractions were pooled and concentrated in vacuo to provide N-(6-(tert-butylsulfonyl)
vinylquinazolinyl)benzo[d]thiazolamine (40 mg, 86% yield) as an oil. H NMR (DMSO-
d ) δ: 10.64 - 10.78 (m, 1H), 9.45 (s, 1H), 9.21 (s, 1H), 8.76 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H),
8.21 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.6, 2.0 Hz, 1H), 7.69 - 7.83 (m, 1H), 7.46 - 7.68 (m, 1H),
6.05 (d, J = 17.2 Hz, 1H), 5.58 (d, J = 11.9 Hz, 1H), 1.32 (s, 9H). MS (m/z) 425.0 (M+H ).
Example 39
N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethylquinazolinamine
To a solution of N-(6-(tert-butylsulfonyl)vinylquinazolinyl)benzo[d]thiazolamine
(40 mg, 0.094 mmol) in EtOH/THF (9.4 mL) was added 10% Pd/C (15 mg). The solution was
purged with nitrogen then hydrogenated at atmospheric pressure with a hydrogen balloon for 21
h, when another 20 mg of Pd/C was added. The reaction was hydrogenated another 4h. Some
olefin was still present in the reaction mixture. The mixture was filtered through glass filter
paper and the residue was subjected to the original reaction conditions and continued
hydrogenation until complete in 18h. The reaction mixture was filtered through glass filter paper
and concentrated in vacuo. The residue was purified via reverse phase chromatography (6% to
75% 0.1% TFA in MeCN in 0.1% TFA in water; 5um 30x150 mm Waters Sunfire column, 15
min gradient). The pure fraction was partitioned between EtOAc and satd. NaHCO , the organic
layer was washed with brine, then dried over MgSO and concentrated in vacuo to obtain N-(6-
(tert-butylsulfonyl)ethylquinazolinyl)benzo[d]thiazolamine (7.5 mg, 19% yield). H
NMR (DMSO-d ) δ: 10.67 (s, 1H), 9.42 (s, 1H), 9.18 (s, 1H), 8.69 (s, 1H), 8.57 (d, J = 2.0 Hz,
1H), 8.17 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 8.7, 2.0 Hz, 1H), 7.82 (s, 1H), 3.20 (td, J = 7.3 Hz,
2H), 1.33 (s, 9H), 1.16 (t, J = 7.3 Hz, 3H). MS (m/z) 427.1 (M+H ).
Example 40
N-(6-(tert-butylsulfonyl)chloroquinazolinyl)benzo[d]thiazolamine
To a solution of 4,7-dichloro[(1,1-dimethylethyl)sulfonyl]quinazoline (60 mg, 0.15
mmol) in N-methylpyrrolidone (1 mL) was added 1,3-benzothiazolamine (27 mg, 0.18
mmol). The reaction mixture was heated at 90°C for 20 min. The solution was allowed to cool
to rt. The reaction mixture was filtered and the filtrate was purified by HPLC and free based
with a carbonate SPE cartridge to provide 21 mg of the title compound (32%). MS: m/z: 433.1
[M+H] . H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 9 H), 7.87 - 8.07 (m, 2 H), 8.14 - 8.31 (m, 2
H), 8.66 (d, J = 1.77 Hz, 1 H), 8.77 (s, 1 H), 9.27 (d, J = 1.52 Hz, 1 H), 9.44 (s, 1 H), 10.63 (s, 1
The following compound was prepared using procedures analogous to those described
above using the appropriate amine.
Example Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-
d ) δ 1.37 (s, 9 H), 2.18 (s, 6
as Ex. 40
41 394 H), 7.97 (s, 1 H), 8.57 (s, 1 H),
9.21 (s, 1 H), 10.72 (br. s., 1
H), 12.26 (br. s., 1 H)
6-(tert-butylsulfonyl)chloro-N-
(4,5-dimethyl-1H-pyrazol
yl)quinazolinamine
Example 42
6-[(1,1-dimethylethyl)sulfonyl]-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridinyl)(methyloxy)
quinazolinamine
In a flask was combined 4-chloro[(1,1-dimethylethyl)sulfonyl]
(methyloxy)quinazoline (100 mg, 0.32 mmol), 5-fluoro-1H-pyrazolo[3,4-b]pyridinamine (58
mg, 0.38 mmol) in NMP (1 mL). The reaction mixture was heated at 80°C for 1h. The solution
was allowed to cool to rt. The solid was filtered out and remaining solution was concentrated
and residue was purified by HPLC to provide 20 mg of the title compound. MS:m/z: 431
[M+H] ; H NMR (400 MHz, DMSO-d6) δ 1.24 - 1.36 (s, 9 H), 3.98 (s, 3 H), 7.27 ( s., 1 H), 8.02
(s, J = 8.72, 2.65 Hz, 1 H), 8.42 (s, 1 H), 8.54 (s, 2 H), 9.04 (s, 1 H).
Alternatively, these reactions can be performed in EtOH with a catalytic amount of HCl.
The following compounds were prepared using procedures analogous to those described.
Example Structure/Name MS (M+H) NMR Method
H NMR (DMSO-d6) δ: 10.38
(s, 1H), 9.08 (s, 1H), 8.64 (s,
1H), 7.62 (d, J = 2.0 Hz, 1H),
43 436 HCl/EtOH
7.46 - 7.52 (m, 1H), 7.38 -
7.46 (m, 2H), 4.01 (s, 3H),
3.89 (s, 3H), 1.33 (s, 9H)
H NMR (DMSO-d6) δ: 10.30
(br. s., 1H), 9.07 (s, 1H), 8.61
(s, 1H), 7.55 (d, J = 2.0 Hz,
44 422 HCl/EtOH
1H), 7.38 (s, 1H), 7.32 (d, J =
8.5 Hz, 1H), 7.22 (dd, J = 8.7,
2.1 Hz, 1H), 4.00 (s, 3H), 3.17
(s, 1H), 1.32 (s, 9H)
H NMR (DMSO-d6) δ: 9.23
(s, 1H), 8.82 (s, 1H), 7.91 (s,
1H), 7.76 (d, J = 8.5 Hz, 1H),
HCl/EtOH
45 426
7.44 (s, 1H), 7.38 (dd, J = 8.8,
1.5 Hz, 1H), 4.05 (s, 3H), 2.51
(s, 3H), 1.34 (s, 9H)
H NMR (DMSO-d6) δ: 10.74
(br. s., 1H), 9.05 (s, 1H), 8.58
46 424 HCl/EtOH
(br. s., 1H), 7.52 - 7.65 (m,
2H), 7.34 - 7.45 (m, 2H), 4.02
(s, 3H), 1.33 (s, 9H)
H NMR (DMSO-d6) δ: 13.03
(br. s., 1H), 10.51 (br. s., 1H),
9.14 (s, 1H), 8.65 (s, 1H), 8.14
47 412 HCl/EtOH
(s, 1H), 8.05 (s, 1H), 7.76 (d, J
= 8.6 Hz, 1H), 7.48 (dd, J =
8.6, 1.3 Hz, 1H), 7.39 (s, 1H),
4.01 (s, 3H), 1.33 (s, 9H)
Example 48
6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazolyl)methoxyquinazolinamine
In a flask was combined 6-[(1,1-dimethylethyl)sulfonyl](methyloxy)-4(1H)-
quinazolinone (60 mg, 0.20 mmol) and POCl (2 mL, 21.5 mmol), and the reaction mixture was
heated at 80°C for 4h. The solution was allowed to cool to rt. POCl was removed under high
vacuum. The residue was treated with satd. aq. NaHCO and extracted with CH Cl . The
3 2 2
organic extract was dried over Na SO . The solvent was removed and crude material was
dissolved in NMP (1 mL) followed by addition of 4,5-dimethyl-1H-pyrazolamine(27 mg, 0.24
mmol). The reaction mixture was heated at 80°C for 1 h. The solution was allowed to cool to rt.
The solid was filtered out and the remaining solution was concentrated and residue was purified
by HPLC to provide 6.0 mg of the title compound. MS (m/z): 390 (M+H); H NMR (400 MHz,
DMSO-d ) δ 1.30 (s, 9 H), 2.21 (s, 6 H), 4.00(s, 3 H), 7.91 (s, 1 H), 8.65 (s, 1 H), 9.11 (s, 1 H),
.19 (br. s., 1 H), 12.32 (br. s., 1 H).
Example 49
(E)(4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)propenol
To a vial was added 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl
trifluoromethanesulfonate (820 mg, 1.50 mmol), Pd dba (137 mg, 0.15 mmol), tri-tert-
butylphosphine, tetrafluoroborate (87 mg, 0.30 mmol), and sodium carbonate (318 mg, 3.00
mmol). The vial was evacuated and backfilled with nitrogen three times before 1,4-dioxane (15
mL) and allyl acetate (0.24 mL, 2.25 mmol) were added. The reaction was heated to 90°C for
three days. Upon completion, it was cooled to rt and concentrated. The residue was then passed
through a C13 SPE cartridge but no separation was observed. Fractions collected were
combined, concentrated, and purified by RP HPLC to afford the desired product (78 mg, 10 %).
H NMR (DMSO-d6) d 9.35 (s, 1H), 8.61 (br. s., 1H), 8.10 - 8.22 (m, 1H), 8.04 (d, J = 8.3 Hz,
1H), 7.85 - 7.96 (m, 1H), 7.35 (br. s., 1H), 6.20 (s, 1H), 5.86 - 6.07 (m, 1H), 5.28 (s, 1H), 5.25 (d,
J = 5.0 Hz, 1H), 4.63 (br. s., 1H), 1.32 (s, 9H); MS (m/z) 455.1 (M+H ).
Example 50
2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)ethanol
Step 1. 2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)thio)ethanol: To a
flask was added N-(6-iodomethoxyquinazolinyl)benzo[d]thiazolamine (1 g, 2.30 mmol),
Pd dba (0.21 g, 0.23 mmol), and Xantphos (0.13 g, 0.23 mmol) which was then evacuated and
backfilled with nitrogen three times before DMF (15 ml), TEA (0.96 ml, 6.91 mmol), and
mercaptoethanol (0.17 ml, 2.42 mmol) were added. The reaction was heated to 100°C overnight.
It was then cooled to rt and partially concentrated. The resulting residue was titurated with
MeOH. A minimal amount of solid precipitated which was filtered to give a dark green residue.
The filtrate was then diluted with ether (100 mL) but no solid formed. The solution sat for three
days at rt. A suspension was observed which was filtered and the cake was washed with ether to
give the desired product as a yellow solid (603 mg, 65 %). MS (m/z) 385.1 (M+H ).
Step 2. 2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)ethanol:
2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)thio)ethanol (603 mg, 1.57 mmol)
was taken up in acetonitrile (10 mL), ethanol (10 mL), and water (10 mL) before oxone (2.89 g,
4.71 mmol) was added. The reaction was stirred at rt for 6 hours. It was then diluted with sat aq
NaHCO (100 mL), and extracted using DCM (2 x 200 mL). The combined organics were dried
over sodium sulfate, filtered through celite, and concentrated. The aqueous layer was a
suspension so it was filtered to give a second crop of material which was more pure than the
material from the concentrated organics. The second crop of material was dissolved in 1 mL of
DMSO and purified by RP HPLC (10 -> 50 % MeCN in water with 0.1 % TFA) on a 5 μM C18
OBD Sunfire 30 x 100 mm. Desired fractions were combined and concentrated to afford the
product as a yellowish solid (33 mg, 17 %). 1H NMR (DMSO-d6) δ 11.27 (br. s., 1H), 9.45 (s,
1H), 9.21 (s, 1H), 8.80 (s, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.84 (dd, J =
8.7, 1.9 Hz, 1H), 7.45 (s, 1H), 4.12 (s, 3H), 3.63 - 3.84 (m, 4H), 2.55 (s, 1H); MS (m/z) 417.1
(M+H ).
Example 51
(R)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)propanoate and (S)-Methyl 2-((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)propanoate
A suspension of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol
(0.50 g, 1.21 mmol) and potassium carbonate (0.50 g, 3.62 mmol) in N,N-Dimethylformamide
(DMF) (6.3 ml) was stirred for 2 minutes before methyl 2-bromopropanoate (0.15 ml, 1.57
mmol) was added. The reaction was heated for 1h at 70°C. The reaction was cooled and water
(20 mL) was added. The product was filtered out as a yellow solid and let dry, then triturated
with 5mL MeOH. Methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)propanoate (350 mg, 58% yield) was filtered out. The racemic mixture was resolved
(Chiralpak AD-H column, 60% EtOH in hexanes with 0.1% DIEA), separating a faster eluting
isomer (R =8.6 min) and a slower eluting isomer (R =13.5 min).
Each enantiomer was isolated by evaporation of solvent (R and S)-methyl 2-((4-
(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanoate (115 mg each,
combined yield: 38%). H NMR (400 MHz, DMSO-d ) δ ppm 10.58 (s, 1 H), 9.42 (s, 1 H), 9.18
(s, 1 H), 8.62 (s, 1 H), 8.58 (d, J=1.77 Hz, 1 H), 8.17 (d, J=8.59 Hz, 1 H), 7.77 - 7.97 (m, 1 H),
7.14 (s, 1 H), 5.32 - 5.50 (m, 1 H), 3.74 (s, 3 H), 1.61 (d, J=6.57 Hz, 3 H), 1.40 (s, 9 H). LC/MS:
M+H 501.2
The racemate was made in an analogous method without the resolution.
Example Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-
d ) δ ppm 10.58 (s, 1 H), 9.42
(s, 1 H), 9.18 (s, 1 H), 8.62 (s,
1 H), 8.58 (d, J=1.77 Hz, 1 H),
As Ex.
52 501 8.17 (d, J=8.59 Hz, 1 H), 7.77
- 7.97 (m, 1 H), 7.14 (s, 1 H),
.32 - 5.50 (m, 1 H), 3.74 (s, 3
H), 1.61 (d, J=6.57 Hz, 3 H),
1.40 (s, 9 H)
Example 53
(R)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol
(depicted) and (S)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)propanol
HN HN
O N O N
O OH
To a solution of (R or S)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)propanoate (110 mg, 0.22 mmol) in THF (2mL) was added
lithium aluminum hydride (220 µl, 0.22 mmol, 1M in THF; or 110 µl, 0.11 mmol, 1M in THF).
The reaction was stirred at 25°C. An orange precipitate was immediately formed and the product
was filtered. The solid was dissolved in 1.5 mL DMSO. The solution was filtered and the
product was purified via Gilson reverse phase chromatography (8% to 70% 0.1% TFA in MeCN
in 0.1% TFA in water or 8% to 60% 0.1% TFA in MeCN in 0.1% TFA in water; 5um 30x150
mm Waters Sunfire column). Pure fractions were collected and partitioned between EtOAc and
water/saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate,
and evaporated in vacuo to give (R or S)((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)propanol as a white solid.
Enantiomer 1 (prepared from the slower eluting isomer of Example 51): H NMR (400
MHz, CHLOROFORM-d) δ ppm 9.08 (s, 1 H), 8.77 (s, 1 H), 8.64 (m, 2 H), 8.06 (br. s., 1 H),
8.02 (d, J=8.6 Hz, 1 H), 7.78 (dd, J=8.6, 2.0 Hz, 1 H), 7.43 (s, 1 H), 4.73 (d, J=4.0 Hz, 2 H), 3.79
(t, J=4.4 Hz, 3 H), 3.61 - 3.72 (m, 1 H), 1.49 (s, 9 H). LC/MS: 473.2
Enantiomer 2(prepared from the faster eluting isomer of Example 51): H NMR (400
MHz, CHLOROFORM-d) δ ppm 9.08 (s, 1 H), 8.77 (s, 1 H), 8.64 (s, 1 H), 8.48 (s, 1 H), 8.13
(br. s., 1 H), 8.02 (d, J=8.6 Hz, 1 H), 7.78 (dd, J=8.6, 2.0 Hz, 1 H), 7.43 (s, 1 H), 4.73 (d, J=4.0
Hz, 2 H), 3.79 (t, J=4.4 Hz, 3 H), 3.61 - 3.72 (m, 1 H), 1.49 (s, 9 H). LC/MS: 473.2
The racemate was made in an analogous fashion.
Example Structure/Name MS (M+H) NMR Method
H NMR (METHANOL-d ) δ:
9.31 (s, 1 H), 9.11 (s, 1 H),
8.60 (s, 1 H), 8.57 (d, J = 1.8
Hz, 1 H), 8.12 (d, J = 8.7 Hz, As Ex.
54 473
1 H), 7.90 (dd, J = 8.7, 1.8 Hz,
1 H), 7.44 (s, 1 H), 3.75 - 3.84
(m, 2 H), 2.70 (m, 3 H), 2.16 -
2.22 (m, 1 H), 1.48 (s, 9 H)
Example 55
6-(tert-butylsulfonyl)((4-chlorofluorophenyl)amino)quinazolinol
6-(tert-Butylsulfonyl)(ethylthio)quinazolinol (144 mg, 0.44 mmol) and 4-chloro
fluoroaniline (0.49 mL, 4.4 mmol) were combined with one drop of HCl and heated to 150 ºC in
the microwave for 20 minutes. After cooling to rt, the mixture was diluted with ether and filtered.
The solid ppt was taken up in MeOH (5 mL) and treated with MP carbonate resin (400 mg, 3 eq.
@ 3.28 mmol/gram loading). The beads were filtered and the mother liquor concentrated and
purified on silica gel (0 to 100% EtOAc followed by 0 to 10% MeOH/DCM). Fractions
containing product were combined and concentrated to provide 2 mg of the desired product
(1.1%). H NMR (DMSO-d6) δ: 10.37 (s, 1H), 8.96 (s, 1H), 8.43 (s, 1H), 7.49 - 7.61 (m, 2H),
7.35 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 1.34 (s, 9H); MS (m/z) 410.2, 412.0 (M+H ).
Example 56
N-(6-(tert-butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine
A mixture of N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine (106 mg,
0.27 mmol) and oxone (36 mg, 0.06 mmol) was stirred for 15 min in 1:1 THF:water (2.6 mL)
The reaction was quenched with saturated sodium bicarbonate. The resulting orange solid was
filtered, dissolved in 30 mL of 1:1 DCM:MeOH and preabsorbed onto silica gel. The product
was purified by column chromatography (Isco CombiFlash, 75% to 100% EtOAc/Hexanes to
% NH OH in MeOH). The pure fractions were concentrated in vacuo and the residue was
purified via Gilson reverse phase chromatography (10% to 75% of 0.1% TFA in MeCN in 0.1%
TFA in water; 5um 30x150 mm Waters Sunfire column). The pure fractions were partitioned
between EtOAc and aqueous saturated sodium bicarbonate. The organic layer was separated,
dried over sodium sulfate, and concentrated in vacuo to give N-(6-(tert-butylsulfinyl)
methoxyquinazolinyl)benzo[d]thiazolamine as a white solid (40 mg, 36% yield). H NMR
(400 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H) 9.41 (s, 1 H) 8.88 (s, 1 H) 8.62 (d, J=2.0 Hz, 1 H)
8.61 (s, 1 H) 8.15 (d, J=8.6 Hz, 1 H) 7.92 (dd, J=8.34, 2.53 Hz, 1 H) 7.33 (s, 1 H) 3.99 (s, 3 H)
1.19 (s, 9 H). MS (m/z) 413.2 (M+H ).
Example 57
2-((4-(Benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetamide
A solution of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol (50.0
mg, 0.121 mmol) and triethylamine (12 mg, 0.12 mmol) in DMF (0.63 mL)) was stirred 2
minutes before 2-bromoacetamide (17 mg, 0.12 mmol) was added. Little reaction occurred after
heating to 70°C. Solid NaH (15 mg, 0.63 mmol) was added and the reaction was heated at 100°C
for 18h. The reaction mixture was filtered and the filtrate was purified via Gilson reverse phase
chromatography (6% to 75% of 0.1% TFA in MeCN in 0.1% TFA in water; 5um 30x150 mm
Waters Sunfire column). The pure fractions were combined and evaporated to dryness, to yield
2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetamide (13 mg,
23% yield) as a yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.38 (s, 1 H), 9.27
(s, 1 H), 8.80 (s, 1 H), 8.43 (d, J=1.8 Hz, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.81 (dd, J=8.6, 1.77 Hz,
1 H), 7.21 (s, 1 H), 5.26 (s, 2 H), 1.48 (s, 9 H); MS (m/z) 471.9 (M+H ).
Example 58
2-((4-(Benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetic acid
Step 1. Methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)acetate: A suspension of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin-
7-ol (350 mg, 0.84 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (4.4 mL) was
stirred 2 minutes before adding methyl 2-bromoacetate (108 µl, 1.14 mmol). The reaction was
heated at 25°C for 6 h. The mixture was added to 15 mL water, and a yellow solid was collected
by filtration and triturated with 6 mL MeOH to a thick white precipitate. The solid was filtered
out to give methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)acetate (200 mg, 49% yield). H NMR (400 MHz, DMSO-d ) δ ppm 10.56 - 10.61 (m, 1
H), 9.43 (s, 1 H), 9.17 (s, 1 H), 8.63 (s, 1 H), 8.57 (d, J=1.8 Hz, 1 H), 8.16 (d, J=8.6 Hz, 1 H),
7.88 (dd, J=8.6, 1.8 Hz, 1 H), 3.75 (s, 2 H), 1.38 (s, 9 H), 1.34 (s, 3 H); MS (m/z) 487.2 (M+H ).
Step 2. 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin
yl)oxy)acetic acid: To a solution of methyl 2-((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)acetate (115 mg, 0.24 mmol) in THF (3.5 mL) was added
LiOH (11 mg, 0.47 mmol) in water (1.2 mL) at 25°C. After 1 h, the reaction was concentrated to
remove the THF. The residue was purified via Gilson reverse phase chromatography (10% to
60% of 0.1% TFA in MeCN in 0.1% TFA in water; 5um 30x150 mm Waters Sunfire column).
The pooled fractions were concentrated to dryness in vacuo to provide 2-((4-(benzo[d]thiazol
ylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetic acid (29 mg, 26% yield) as a white
solid. H NMR (400 MHz, DMSO-d6) δ ppm 9.46 (s, 1 H), 9.22 - 9.27 (m, 1 H), 8.72 - 8.79 (m,
1 H), 8.47 - 8.56 (m, 1 H), 8.23 (d, J=8.3 Hz, 1 H), 7.83 (d, J=9.8 Hz, 1 H), 7.26 (s, 1 H), 5.08 (s,
2 H), 1.39 (s, 9 H); MS (m/z) 473.2 (M+H ).
Example 59
N-(6-(tert-butylsulfonyl)(2-(methylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazolamine
A solution of N-(6-(tert-butylsulfonyl)(2-(methylthio)ethoxy)quinazolin
yl)benzo[d]thiazolamine (30 mg, 0.061 mmol) in 1:1 THF: H O (0.6 mL) was stirred 25
minutes with oxone (113 mg, 0.18 mmol) at 25°C. The reaction mixture was partitioned between
EtOAc and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over
sodium sulfate and evaporated in vacuo to yield N-(6-(tert-butylsulfonyl)(2-
(methylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazolamine (12.4, 39% yield). H NMR
(400 MHz, DMSO-d6) δ ppm 10.57 - 10.65 (m, 1 H), 9.38 - 9.51 (m, 1 H), 9.09 - 9.24 (m, 1 H),
8.65 - 8.74 (m, 1 H), 8.54 - 8.62 (m, 1 H), 8.09 - 8.22 (m, 1 H), 7.81 - 7.95 (m, 1 H), 7.46 - 7.56
(m, 1 H), 4.56 - 4.71 (m, 2 H), 3.64 - 3.75 (m, 2 H), 3.21 (s, 3 H), 1.29 - 1.40 (m, 9 H); MS (m/z)
521.1 (M+H ).
The following compounds were prepared using procedures analogous to those described
in examples 21 and 60 using the appropriate thiol.
Example
Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-
S d6) δ ppm 10.60 (s, 1 H), 9.43
(s, 1 H), 9.16 (s, 1 H), 8.66 (s,
1 H), 8.59 (d, J=2.0 Hz, 1 H),
8.18 (d, J=8.6 Hz, 1 H), 7.86 -
60 549 As ex. 90
7.93 (m, 1 H), 7.52 (s, 1 H),
4.64 (t, J=5.6 Hz, 2 H), 3.63 -
3.73 (m, 2 H), 3.63 (m, 1 H),
N-(6-(tert-butylsulfonyl)(2- 1.40 (s, 9 H), 1.30 (dd, J=7.1
(isopropylsulfonyl)ethoxy)quinazolin-
Hz, 6 H)
yl)benzo[d]thiazolamine
Example 61
(E)-methyl 3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylate
A suspension of 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol (200
mg, 0.48 mmol) and DABCO (5 mg, 0.05 mmol) in THF (4.8 mL) was stirred 2 minutes at 25°C
before adding methyl propiolate (41 mg, 0.48 mmol). After 10 minutes, the reaction mixture was
partitioned between EtOAc and aqueous saturated sodium bicarbonate and back extracted with
DCM. The combined organics were dried over sodium sulfate and evaporated in vacuo. The
residue was purified via column chromatography (Isco CombiFlash 50% to 100% in EtOAc in
Hexanes; 40g silica gel cartridge column). The pure fractions were concentrated in vacuo to give
(E)-methyl 3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylate
(115 mg, 48% yield) as a white solid. H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.09 (s, 1
H), 8.83 (s, 1 H), 8.69 (s, 1 H), 8.64 (d, J=2.0 Hz, 1 H), 8.04 (d, J=8.6 Hz, 1 H), 7.87 (d, J=12.1
Hz, 1 H), 7.78 (dd, J=8.7, 2.2 Hz, 1 H), 7.62 (s, 1 H), 5.91 (d, J=12.1 Hz, 1 H), 5.32 (s, 1 H), 1.68
(s, 3 H), 1.47 (s, 9 H); MS (m/z) 499.1 (M+H ).
The following compounds were prepared using procedures analogous to those described
above using the appropriate alkyne.
Example Structure/Name MS (M+H) NMR Method
H NMR (400 MHz, DMSO-
d6) δ ppm 10.71 (s, 1 H), 9.44
(s, 1 H), 9.24 (s, 1 H), 8.70 (s,
1 H), 8.58 (d, J=1.8 Hz, 1 H),
62 484 as Ex. 92
8.19 (d, J=8.8 Hz, 1 H), 7.74 -
7.95 (m, 1 H), 7.61 (s, 1 H),
7.01 - 7.15 (m, 1 H), 5.91 (d,
J=11.87 Hz, 1 H), 1.24 - 1.44
(m, 9 H)
Example 63
(E)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylic acid
A suspension of (E)-methyl 3-((4-(benzo[d]thiazolylamino)(tert-
butylsulfonyl)quinazolinyl)oxy)acrylate (115 mg, 0.23 mmol) in THF (1.2 mL) and water (1.2
mL) was stirred with LiOH (11 mg, 0.46 mmol) for 2 h at 50°C. Water and 10% citric acid (10
mL) were added and the mixture was extracted with EtOAc and DCM/20% EtOH (2x each). The
combined organics were washed with brine and the organics concentrated to dryness. The residue
was purified via Gilson reverse phase chromatography (10% to 75% of 0.1% TFA in MeCN in
0.1% TFA in water; 5um 30x150 mm Waters Sunfire column). Pure fractions were partitioned
between EtOAc and saturated sodium bicarbonate followed by brine. The organic layer was dried
over magnesium sulfate and concentrated in vacuo to provide (E)((4-(benzo[d]thiazol
ylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylic acid (10.5 mg, 9% yield). H NMR
(400 MHz, DMSO-d6) δ ppm 11.01 - 11.17 (m, 1 H), 9.45 (s, 1 H), 9.29 (s, 1 H), 8.72 - 8.84 (m,
1 H), 8.49 - 8.60 (m, 1 H), 8.24 (d, J=8.6 Hz, 1 H), 7.97 (d, J=12.0 Hz, 1 H), 7.81 - 7.84 (m, 1 H),
7.68 (s, 1 H), 5.73 (d, J=12.0 Hz, 1 H), 1.37 (s, 9 H); MS (m/z) 484.9 (M+H ).
Example 64
N-(6-(tert-butylsulfonyl)(vinyloxy)quinazolinyl)benzo[d]thiazolamine
A solution of N-(7-(2-bromoethoxy)(tert-butylsulfonyl)quinazolin
yl)benzo[d]thiazolamine (25 mg, 0.05 mmol) and 2-(pyridinyl)ethanol (15 mg, 0.12 mmol)
was heated in DMF (939 µl) at 70°C. After 10 minutes, 60% NaH (10 mg, 0.25 mmol) was
added and heated 1 min. The residue was filtered, then purified via Gilson reverse phase
chromatography (10% to 75% of 0.1% TFA in MeCN in 0.1% TFA in water; 5um 30x100 mm
Waters Sunfire column). Pure fractions were partitioned between EtOAc and sat'd sodium
bicarbonate, then washed with brine. The organic layer was dried over magnesium sulfate and
concentrated in vacuo to provide N-(6-(tert-butylsulfonyl)(vinyloxy)quinazolin
yl)benzo[d]thiazolamine (7.5 mg, 36% yield).
H NMR (400 MHz, DMSO-d6) δ ppm 10.63 - 10.69 (m, 1 H), 9.43 (s, 1 H), 9.17 - 9.33 (m, 1
H), 8.65 - 8.70 (m, 1 H), 8.50 - 8.63 (m, 1 H), 8.18 (d, J=8.8 Hz, 1 H), 7.89 (d, J=9.1 Hz, 1 H),
7.48 (s, 1 H), 7.17 (dd, J=13.3, 5.8 Hz, 1 H), 5.02 (dd, J=13.3, 2.0 Hz, 1 H), 4.81 (dd, J=5.8, 2.0
Hz, 1 H), 1.37 (s, 9 H); MS (m/z) 441.0 (M+H ).
Example 65
4-(benzo[d]thiazolylamino)methoxy-N,N-dimethylquinazolinesulfonamide
To a vial was added DMAP (3.75 mg, 0.03 mmol) followed by a suspension of 4-
(benzo[d]thiazolylamino)methoxyquinazolinesulfonyl chloride (125 mg, 0.31 mmol) in
THF (2 mL), then TEA (0.17 mL, 1.23 mmol), and finally dimethylamine (2.0 M in THF, 0.30
mL). The reaction was stirred at rt overnight. It was then concentrated and the crude material
was dissolved in 1:1 DMSO:MeOH and purified by RP HPLC (10 -> 50 % MeCN in water with
0.1 % TFA) on a 5 μM C18 OBD Sunfire 30 x 100 mm. Desired fractions were combined,
concentrated, and the residue was redissolved in MeOH and treated with MP-carbonate resin.
The solution was pipetted off the resin and concentrated to afford the title compound (19 mg, 14
%). H NMR (DMSO-d6) d 11.05 (br. s., 1H), 9.45 (s, 1H), 9.18 (s, 1H), 8.76 (s, 1H), 8.55 (d, J
= 1.5 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.41 (s, 1H), 4.08 (s, 3H),
2.83 (s, 6H); MS (m/z) 416.1 (M+H ).
The following compound was prepared using procedures analogous to those described
above using the appropriate amine.
Example Structure/Name MS (M+H) NMR Method
H NMR (DMSO-d6) δ 11.29
(br. s., 1H), 9.46 (s, 1H), 9.21
(s, 1H), 8.81 (s, 1H), 8.53 (d, J
= 1.8 Hz, 1H), 8.23 (d, J = 8.8
as in Ex.
66 430
Hz, 1H), 7.83 (dd, J = 8.8, 1.8
Hz, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.39 (s, 1H), 4.10 (s, 3H),
3.28 - 3.43 (m, 1H), 1.00 (d, J
= 6.6 Hz, 6H)
H NMR (DMSO-d6) δ 10.97
(br. s., 1H), 9.44 (s, 1H), 9.19
(s, 1H), 8.74 (s, 1H), 8.57 (s,
1H), 8.20 (d, J = 8.8 Hz, 1H),
as in Ex.
67 442
7.86 (d, J = 8.6 Hz, 1H), 7.40
(s, 1H), 4.09 (s, 3H), 3.33 (t, J
= 6.4 Hz, 4H), 1.73 - 1.86 (m,
H NMR (DMSO-d6) δ 10.73
(br. s., 1H), 9.43 (s, 1H), 9.14
(s, 1H), 8.70 (s, 1H), 8.58 (s,
1H), 8.19 (d, J = 8.6 Hz, 1H), as in Ex.
68 458
7.87 (d, J = 8.6 Hz, 1H), 7.40
(s, 1H), 4.07 (s, 3H), 3.58 -
3.67 (m, 4H), 3.18 - 3.24 (m,
H NMR (DMSO-d6) δ 11.34
(br. s., 1H), 9.47 (s, 1H), 9.20
(s, 1H), 8.83 (s, 1H), 8.52 (d, J
= 2.0 Hz, 1H), 8.24 (d, J = 8.5
as in Ex.
69 432 Hz, 1H), 7.83 (dd, J = 8.5, 2.0
Hz, 1H), 7.52 (t, J = 5.8 Hz,
1H), 7.41 (s, 1H), 4.09 (s, 3H),
3.38 (t, J = 6.4 Hz, 2H), 2.87 -
2.97 (m, 2H)
H NMR (DMSO-d6) δ 11.52
(br. s., 1H), 9.48 (s, 1H), 9.24
(s, 1H), 8.87 (s, 1H), 8.51 (s,
1H), 8.26 (d, J = 8.8 Hz, 1H),
7.87 (d, J = 7.8 Hz, 1H), 7.82 as in Ex.
70 472
(dd, J = 8.7, 1.4 Hz, 1H), 7.41
(s, 1H), 4.12 (s, 3H), 3.74 (d, J
= 11.5 Hz, 2H), 3.27 - 3.34
(m, 1H), 3.14 - 3.28 (m, 2H),
1.40 - 1.60 (m, 4H)
H NMR (DMSO-d6) δ 10.84
(br. s., 1H), 9.44 (s, 1H), 9.14
(s, 1H), 8.72 (s, 1H), 8.59 (s,
1H), 8.19 (d, J = 8.5 Hz, 1H), as in Ex.
71 460
7.87 (d, J = 8.5 Hz, 1H), 7.40
(s, 1H), 7.13 (t, J = 6.1 Hz,
1H), 4.08 (s, 3H), 2.72 (d, J =
6.0 Hz, 2H), 1.07 (s, 6H)
H NMR (DMSO-d6) δ 10.46
(s, 1H), 9.42 (s, 1H), 9.12 (s,
1H), 8.64 (d, J = 4.3 Hz, 2H),
8.16 (d, J = 8.5 Hz, 1H), 7.91
(d, J = 8.5 Hz, 1H), 7.38 (s, as in Ex.
72 458
1H), 5.00 (d, J = 2.8 Hz, 1H),
4.26 (br. s., 1H), 4.04 (s, 3H),
3.46 (dd, J = 8.5, 5.3 Hz, 3H),
3.18 (d, J = 9.5 Hz, 1H), 1.69 -
1.93 (m, 2H)
H NMR (DMSO-d6) δ 10.49
(br. s., 1H), 9.42 (s, 1H), 9.10
(s, 1H), 8.64 (d, J = 5.5 Hz,
2H), 8.16 (d, J = 8.8 Hz, 1H),
7.91 (d, J = 8.5 Hz, 1H), 7.38 as in Ex.
73 446
(s, 1H), 7.27 (t, J = 6.0 Hz,
1H), 4.68 (br. s., 1H), 4.06 (s,
3H), 3.59 (d, 1H), 2.64 - 2.87
(m, 2H), 1.00 (d, J = 6.3 Hz,
3H), 1.01 (d, J = 6.3 Hz, 3H)
H NMR (DMSO-d6) δ 10.48
(br. s., 1H), 9.42 (s, 1H), 9.09
(s, 1H), 8.64 (br. s., 2H), 8.16
(d, J = 8.8 Hz, 1H), 7.91 (d, J as in Ex.
74 446
= 8.5 Hz, 1H), 7.47 (t, J = 5.9
Hz, 1H), 7.38 (s, 1H), 4.06 (s,
3H), 3.28 (t, J = 5.8 Hz, 2H),
3.09 (s, 3H), 3.03 (q, 2H)
H NMR (DMSO-d6) δ10.60
(br. s., 1H), 9.43 (s, 1H), 9.12
(s, 1H), 8.64 (d, J = 17.8 Hz,
2H), 8.56 (d, J = 7.5 Hz, 1H), as in Ex.
75 444.1
8.17 (d, J = 8.5 Hz, 1H), 7.90
(d, J = 8.5 Hz, 1H), 7.37 (s,
1H), 4.37 - 4.63 (m, 5H), 4.09
(s, 3H)
H NMR (DMSO-d6) δ 11.30
(br. s., 1H), 10.07 (br. s., 1H),
9.46 (s, 1H), 9.24 (s, 1H), 8.82
(s, 1H), 8.54 (s, 1H), 8.23 (d, J
as in Ex.
76 459
= 8.8 Hz, 1H), 7.92 - 8.02 (m,
1H), 7.85 (d, J = 8.5 Hz, 1H),
7.46 - 7.53 (m, 1H), 4.12 (s,
3H), 3.15 - 3.29 (m, 4H), 2.80
(br. s., 6H)
H NMR (DMSO-d6) δ 9.47
(s, 1H), 9.25 (s, 1H), 8.83 (s,
1H), 8.52 (s, 1H), 8.24 (d, J =
8.5 Hz, 1H), 7.95 (d, J = 7.3
Hz, 1H), 7.83 (d, J = 8.8 Hz, as in Ex.
77 486
1H), 7.47 - 7.58 (m, 2H), 4.48
(dd, J = 8.7, 3.1 Hz, 1H), 3.39
- 3.52 (m, 1H), 3.20 - 3.33 (m,
1H), 2.10 - 2.21 (m, 1H), 1.72
- 2.04 (m, 3H)
H NMR (DMSO-d6) δ 11.62
(br. s., 1H), 9.48 (s, 1H), 9.26
(s, 1H), 8.87 (s, 1H), 8.50 (s,
1H), 8.26 (d, J = 8.8 Hz, 1H), as in Ex.
78 499
7.95 (d, J = 7.3 Hz, 1H), 7.82
(d, J = 8.5 Hz, 1H), 7.45 - 7.59
(m, 1H), 4.09 (s, 3H), 3.16 -
3.31 (m, 4H), 1.99 (s, 3H)
H NMR (DMSO-d6) δ 11.38
(br. s., 1H), 9.47 (s, 1H), 9.21
(s, 1H), 8.84 (s, 1H), 8.53 (s,
1H), 8.24 (d, J = 8.5 Hz, 1H), as in Ex.
79 484
7.91 (t, J = 5.6 Hz, 1H), 7.84
(d, J = 8.8 Hz, 1H), 7.42 (s,
1H), 4.05 (s, 3H), 3.32 (q, J =
6.7 Hz, 2H), 3.04 (t, 2H)
H NMR (DMSO-d6) δ 9.47
(s, 1H), 9.22 (s, 1H), 8.85 (s,
1H), 8.52 (s, 1H), 8.25 (d, J =
8.8 Hz, 1H), 7.95 (d, J = 7.0
Hz, 1H), 7.80 - 7.86 (m, 1H),
as in Ex.
80 486
7.74 (t, J = 5.8 Hz, 1H), 7.47
(s, 1H), 4.09 (s, 3H), 3.81 (dd,
J = 11.3, 2.8 Hz, 2H), 3.19 -
3.27 (m, 2H), 2.72 (t, J = 6.3
Hz, 2H), 1.51 - 1.71 (m, 3H),
1.00 - 1.16 (m, 2H)
Pharmaceutical Compositions
Example A
Tablets are prepared using conventional methods and are formulated as follows:
Ingredient Amount per tablet
Compound 5mg
Microcrystalline cellulose 100mg
Lactose 100mg
Sodium starch glycollate 30mg
Magnesium stearate 2mg
Total 237mg
Example B
Capsules are prepared using conventional methods and are formulated as follows:
Ingredient Amount per tablet
Compound 15mg
Dried starch 178mg
Magnesium stearate 2mg
Total 195mg
Biological Assay:
A fluorescent polarization based binding assay was developed to quantitate interaction of
novel test compounds at the ATP binding pocket of RIPK2, by competition with a fluorescently
labeled ATP competitive ligand. Full length FLAG His tagged RIPK2 was purified from a
Baculovirus expression system and was used at a final assay concentration of twice the
KDapparent. A fluorescent labeled ligand (5-({[2-({[3-({4-[(5-hydroxymethylphenyl)amino]-
2-pyrimidinyl}amino)phenyl]carbonyl}amino)ethyl] amino}carbonyl)(6-hydroxyoxo-3H-
xanthenyl)benzoic acid, prepared as described in WO2011/120025) was used at a final assay
concentration of 5nM. Both the enzyme and ligand were prepared in solutions in 50mM HEPES
pH7.5, 150mM NaCl, 10mM MgCl , 1mM DTT, and 1mM CHAPS. Test compounds were
prepared in 100% DMSO and 100nL was dispensed to individual wells of a multiwell plate.
Next, 5ul RIPK2 was added to the test compounds at twice the final assay concentration, and
incubated at rt for 10 min. Following the incubation, 5ul of the fluorescent labeled ligand
solution, was added to each reaction, at twice the final assay concentration, and incubated at rt
for at least 10 min. Finally, samples were read on an instrument capable of measuring
fluorescent polarization. Test compound inhibition was expressed as percent (%) inhibition of
internal assay controls.
For concentration/dose response experiments, normalized data were fit and pIC s
determined using conventional techniques. The pIC s are averaged to determine a mean value,
for a minimum of 2 experiments.
As determined using the above method, the compounds of Examples 1-80 exhibited a
pIC between approximately 5.0 and 9.0. For instance, the compounds of Examples 4 and 16
inhibited RIP2 kinase in the above method with a mean pIC of approximately 7.5 and 8.5,
respectively. The compounds of Examples 4, 6, 16, 21, and 23 inhibited RIP2 kinase in the
above method with a mean pIC in the range of approximately 7.0-9.0.
FLAG His tagged RIPK2 Preparation:
Full-length human RIPK2 (receptor-interacting serine-threonine kinase 2) cDNA was
purchased from Invitrogen (Carlsbad, California, USA, Clone ID:IOH6368, RIPK2-pENTR
221). Gateway LR cloning was used to site-specifically recombine RIPK2 downstream to an N-
terminal FLAG-6His contained within the destination vector pDEST8-FLAG-His6 according to
the protocol described by Invitrogen. Transfection into Spodoptera frugiperda(Sf9) insect cells
was performed using Cellfectin® (Invitrogen), according to the manufacturer’s protocol.
Sf9 cells were grown in Excell 420 (SAFC Biosciences, Lenexa, Kansas, US; Andover,
Hampshire UK) growth media at 27°C, 80 rpm in shake flask until of a sufficient volume to
inoculate a bioreactor. The cells were grown in a 50 litre working volume bioreactor (Applikon,
Foster City, California, US; Schiedam, Netherlands) at 27°C, 30% dissolved oxygen and an
agitation rate of 60-140 rpm until the required volume was achieved with a cell concentration of
approximately 3.7xe6 cells/mL. The insect cells were infected with Baculovirus at a multiplicity
of infection (MOI) of 12.7. The cultivation was continued for a 43 hour expression phase. The
infected cells were removed from the growth media by centrifugation at 2500 g using a Viafuge
(Carr) continuous centrifuge at a flow rate of 80 litres/hour. The cell pellet was immediately
frozen and subsequently supplied for purification.
Purification Procedure I: 9.83 x 10 Insect cells were re-suspended in 1.4 L lysis buffer
(50mM Tris (pH 8.0), 150mM NaCl, 0.5mM NaF, 0.1% Triton X-100, 1mL/litre Protease
Inhibitor Cocktail Set III (available from EMD Group; CalBiochem/Merck Biosciences,
Gibbstown, New Jersey, US; Damstadt, Germany) and processed by dounce homogenization on
ice. The suspension was then clarified by centrifugation at 47,900g for 2 h, at 4°C. The lysate
was decanted from the insoluble pellet and loaded at a linear flow rate of 16 cm/h onto a 55 mL
FLAG-M2 affinity column (2.6 x 10.4 cm) that had been pre-equilibrated with 10 column
volumes buffer A (50mM Tris (pH 8.0), 150mM NaCl, 0.5mM NaF, 1mL/litre Protease Inhibitor
Cocktail Set III). The column was then washed with 15 column volumes buffer A, and eluted
with 6 column volumes buffer B (buffer A + 150µg/mL 3X FLAG peptide) at a linear flow rate
of 57 cm/h. Fractions identified by SDS-PAGE as containing protein of interest were dialyzed to
remove the 3X FLAG peptide from the preparation against 5 L of Buffer A (not containing the
Protease Inhibitor Cocktail) overnight, using 10 kDa MWCO SnakeSkin Pleated Dialysis
Tubing. The purification process yielded 11.3 mg of total protein, with the RIPK2 present at
40% purity by gel densitometry scanning, and identity confirmed by peptide mass fingerprinting.
The main contaminating proteins in the preparation were identified as lower molecular weight
degraded species of RIPK2.
Purification Procedure II: 100g cells (10 liter scale fermentation) were frozen, thawed,
and re-suspended in 1L lysis buffer (50mM Tris HCL pH7.5, 250 mM NaCl, 0.1mM TCEP, 3ml
Protease inhibitor cocktail) and lysed by high pressure homogenization at 10,000 psi once
(Avestin). The suspension was then clarified by centrifugation at 35,000g for 45 minutes at 4°C.
The supernatant was collected by centrifugation and incubated with 5 ml anti-FLAG-M2 resin
which was pre-equilibrated with buffer A (50mM Tris HCL pH7.5, 250 mM NaCl, 0.1mM
TCEP). After protein binding at 4 C degree for 1 hour, the resin was packed into two 25ml
disposable columns. Each column was washed with 25ml buffer A and eluted with 10ml (buffer
A + 200ug/ml Flag peptide). The elution pool was concentrated to 1ml and applied to a superdex
200 (16/60) sizing column. Fractions containing full length RIPK2 were collected according to
SDS-PAGE analysis results. The purification process yielded 1.36mg/L 80% pure RIPK2
protein and identity was confirmed by peptide mass fingerprinting.
Biological in vivo Assay
The efficacy of RIP2 inhibitors may also be evaluated in vivo in rodents. Intraperitoneal
(i.p.) or intravenous (i.v.) administration of L18-MDP in mice has been shown to induce an
inflammatory response through activation of the NOD2 signaling pathway (Rosenweig, H. L., et
al. 2008. Journal of Leukocyte Biology 84:529-536). The level of the inflammatory response in
the L18-MDP treated mice/rats is monitored using conventional techniques by measuring
increases in cytokine levels (IL8, TNFα, IL6 and IL-1β) in serum and/or peritoneal lavage fluid
and by measuring neutrophil influx into the peritoneal space (when L18-MDP is dosed i.p.).
Inhibition of the L18-MDP induced inflammatory response in treated rodents may be shown by
orally pre-dosing with selected compounds of this invention, then measuring and comparing
cytokine levels (IL8, TNFα, IL6 and IL-1β) in serum and/or peritoneal lavage fluid and
neutrophil influx into the peritoneal space (when L18-MDP is dosed i.p.) using conventional
techniques.
For example, rats were orally pre-dosed with a compound of Example 4, 6, 16, or 21, at a
dose of 2 mg/kg or 10 mg/kg (8 rats) and with prednisolone (8 rats, used as a positive control),
followed by dosing with L18-MDP (50 µg/rat) 0.25 h/min after pre-dosing. Combined cytokine
levels (IL8, TNFα, IL6 and IL-1β) in whole blood samples taken from the rats in this study were
measured using an antibody based detection (Meso-Scale Discovery platform). The combined
cytokine response was calculated as the averaged response for the 4 cytokines measured relative
to the response observed in the vehicle-treated mice, and are depicted in the figures as the mean ±
standard error of the mean (n=8 rats /group).
References:
WO2011/011522, WO2009080200, WO2008/33747, WO2008/33749, US6,046,206,
WO96/09294, CA2086968, WO93/07124, EP1199070, CAS Registry No. 13474608, J.
Med. Chem. (2010), 53(3) 2000-2009.
Claims (22)
1. A compound according to Formula (I): wherein: R is H, -SO (C -C )alkyl, -CO(C -C )alkyl, or (C -C )alkyl; 2 1 4 1 4 1 4 2 a a a a R is - SR , -SOR , or -SO R , wherein R is (C -C )alkyl, halo(C -C )alkyl, 2 1 6 1 6 (C -C )cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl, wherein: said (C1-C6)alkyl is optionally substituted by one or two groups each independently selected from cyano, hydroxyl, (C -C )alkoxy, (C -C )alkoxy(C -C )alkoxy, -CO H, 1 6 1 6 2 6 2 -CO (C -C )alkyl, -SO (C -C )alkyl, (C -C )cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 2 1 4 2 1 4 3 7 membered heteroaryl, 4-7 membered heterocycloalkyl and (phenyl)(C -C alkyl)amino-, wherein said (C -C )cycloalkyl, phenyl, (phenyl)(C -C alkyl)amino-, 5-6 membered heteroaryl, 9-10 3 7 1 4 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-, 3 1 4 ((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl and 1 4 1 4 1 4 1 4 1 4 (C -C )alkoxy, said (C -C )cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted by 1-3 groups each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-, 3 1 4 ((C -C )alkyl)((C -C )alkyl)amino-, (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl-, 1 4 1 4 1 4 1 4 1 4 oxo and (C -C )alkoxy, and said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from halogen, -CF , hydroxyl, amino, ((C -C )alkyl)amino-, ((C -C )alkyl)((C -C )alkyl)amino-, 3 1 4 1 4 1 4 (C -C )alkyl, phenyl(C -C )alkyl-, hydroxy(C -C )alkyl- and (C -C )alkoxy; 1 4 1 4 1 4 1 4 R is H, halogen, hydroxy, (C -C )alkyl-,(C -C )alkenyl-, halo(C -C )alkyl-, 1 4 2 4 1 4 (C -C )alkoxy-, halo(C -C )alkoxy-, (C -C )alkoxy(C -C )alkyl-, 1 4 1 4 1 4 1 6 halo(C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkoxy- 1 4 1 6 1 4 2 6 1 4 2 6 , hydroxy(C -C )alkyl-, hydroxy(C -C )alkoxy-, cyano(C -C )alkyl-, cyano(C -C )alkoxy-, 1 6 2 6 1 4 2 6 carboxy-(C -C )alkoxy-, (C -C )alkoxycarbonyl(C -C )alkoxy-, (C -C )cycloalkyl(C -C )alkoxy- 1 6 1 4 1 6 3 6 1 4 , (C -C )cycloalkoxy-, 4-6 membered-heterocycloalkyl(C -C )alkoxy-, or 4-6 membered- 3 6 1 4 heterocycloalkoxy-, wherein the halo(C -C )alkyl-, halo(C -C )alkoxy-, halo(C -C )alkoxy(C -C )alkyl-, or 1 4 1 4 1 4 1 6 halo(C -C )alkoxy(C -C )alkoxy- groups contain 2 or 3 halo atoms; and 1 4 2 6 wherein the (C -C )cycloalkyl moiety of the (C -C )cycloalkyl(C -C )alkoxy- or 3 6 3 6 1 4 (C -C )cycloalkoxy-, is optionally substituted by a group selected from cyano, halo, hydroxyl, (C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy; 1 6 1 4 2 6 wherein the 4-6 membered-heterocycloalkyl moiety of the 4-6 membered- heterocycloalkyl(C -C )alkoxy-, or 4-6 membered-heterocycloalkoxy-, is optionally substituted by a group selected from cyano, halo, hydroxyl, (C -C )alkoxy and (C -C )alkoxy(C -C )alkoxy; 1 6 1 4 2 6 8 9 10 Z is phenyl or pyridyl substituted by R , R and R , wherein: R and R are located on adjacent atoms and taken together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, which 5-membered heterocyclic group is substituted by 10 11 wherein one of R or R is H, halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, 1 4 1 4 (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, hydroxy(C -C )alkyl-, or 1 4 1 4 1 4 aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected from halogen, -CF , (C -C )alkyl and 3 1 4 (C -C )alkoxy; and 10 11 the other of R or R is H, hydroxyl, halogen, -CF , hydroxy(C -C )alkyl, (C -C )alkyl 3 1 4 1 4 or (C -C )alkoxy; or Z is pyrazolyl, having the formula: wherein: R is H, methyl or hydroxymethyl; R is methyl, trifluoromethyl or hydroxymethyl; R is H, OH, or (C -C )alkyl; or 12 13 R and R , taken together with the atoms to which they are attached, form a 6 membered 15 16 carbocyclic ring or heterocyclic ring substituted by R and R , wherein the heterocyclic ring contains 1 nitrogen atom; 15 16 wherein R and R are each independently selected from H, halogen, cyano, (C -C )alkyl, halo(C -C )alkyl, (C -C )alkoxy, phenoxy, phenyl(C -C )alkoxy, hydroxyl, 1 4 1 4 1 4 hydroxy(C -C )alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(C -C )alkoxy is optionally substituted by 1-3 substituents each independently selected from halogen, -CF , (C -C )alkyl and (C -C )alkoxy; 3 1 4 1 4 or a salt thereof.
2. The compound or salt according to claim 1, wherein R is H.
3. The compound or salt according to claim 1 or claim 2, wherein R is -SO R .
4. The compound or salt according to any one of claims 1-3, wherein R is a (C -C )alkyl group optionally substituted by a substituent selected from the group consisting of hydroxyl, (C -C )alkoxy, and (C -C )alkoxy(C -C )alkoxy- or R is a 5membered heterocycloalkyl 1 2 1 2 2 3 group optionally substituted by 1 or 2 independently selected (C -C )alkyl groups.
5. The compound or salt according to any one of claims 1-3, wherein R is -CH , -CH(CH ) , -C(CH ) , -CH CH OH, -C(CH ) CH CH OH, or tetrahydro-2H-pyranyl. 3 2 3 3 2 2 3 2 2 2
6. The compound or salt according to any one of claims 1-5, wherein R is halogen, hydroxy, (C -C )alkyl-, (C -C )alkenyl-, halo(C -C )alkyl-, (C -C )alkoxy-, halo(C -C )alkoxy-, 1 3 2 3 1 2 1 4 1 3 (C -C )cycloalkyl(C -C )alkoxy-, 5memebered-heterocycloalkyl-oxy-, 5 6 1 3 (C -C )alkoxy(C -C )alkyl-, (C -C )alkoxy(C -C )alkoxy-, carboxy-(C -C )alkoxy-, 1 3 1 4 1 3 2 4 1 4 (C -C )alkoxycarbonyl(C -C )alkoxy-, or hydroxy(C -C )alkoxy-. 1 3 1 4 2 4
7. The compound or salt according to any one of claims 1-5, wherein R is H, chloro, -CH CH , –CH=CH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH , -OCH CF , 2 3 2 3 2 3 2 2 3 2 3 -OCH CH Cl, -OCH CH OH, -OCH CH CH OH, -OCH CH OCH , -OC(CH ) CH OH, 2 2 2 2 2 2 2 2 2 3 3 2 2 -OCH(CH )CH OH, -OC(CH ) CO CH CH , cyclohexylmethyloxy-, or 3 2 3 2 2 2 3 tetrahydro-2H-pyranyloxy-.
8. The compound or salt according to any one of claims 1-7, wherein Z is benzothiazolyl, optionally substituted by 1-3 substituents independently selected from halogen, (C -C )alkyl, halo(C -C )alkyl or (C -C )alkoxy. 1 4 1 4 1 4
9. The compound or salt according to any one of claims 1-7, wherein Z is benzo[d]thiazolyl.
10. The compound or salt according to any one of claims 1-7, wherein Z is pyrazolyl, R 13 14 is H or methyl, R is methyl or trifluoromethyl, and R is H or methyl.
11. The compound or salt according to any one of claims 1-7, wherein Z is pyrazolyl, R 13 14 and R are each methyl, and R is H.
12. The compound or salt according to claim 1, wherein: R is H; 2 a a a R is -SR or -SO R , and R is -CH , -CH(CH ) , -C(CH ) , -CH CH OH, 2 3 3 2 3 3 2 2 -C(CH ) CH CH OH, or tetrahydro-2H-pyranyl; 3 2 2 2 R is H, chloro,–CH CH , –CH=CH , -OH, -OCH , -OCF H, -OCH(CH ) , -OCH CH , 2 3 2 3 2 3 2 2 3 -OCH CF , -OCH CH Cl, -OCH CH OH, -OCH CH CH OH, -OCH CH OCH , 2 3 2 2 2 2 2 2 2 2 2 3 -OC(CH ) CH OH, -OCH(CH )CH OH, -OC(CH ) CO CH CH , cyclohexylmethyloxy-, or 3 2 2 3 2 3 2 2 2 3 tetrahydro-2H-pyranyloxy-; and Z is benzo[d]thiazolyl or 5-fluoro-1H-indazolyl, or Z is pyrazolyl, wherein R is H 13 14 or methyl, R is methyl or trifluoromethyl, and R is H or methyl.
13. A compound which is N-1,3-benzothiazolyl[(1,1-dimethylethyl)thio]quinazolinamine, N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]quinazolinamine, 6-(tert-butylsulfonyl)-N-(5-fluoro-1H-indazolyl)quinazolinamine, N-1,3-benzothiazolyl[(1-methylethyl)sulfonyl]quinazolinamine, 2-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}ethanol, N-1,3-benzothiazolyl(tetrahydro-2H-pyranylsulfonyl)quinazolinamine, 3-{[4-(1,3-benzothiazolylamino)quinazolinyl]sulfonyl}methylbutanol, N-(5-fluoro-1H-indazolyl)[(1-methylethyl)sulfonyl]quinazolinamine, N-(4,5-dimethyl-1H-pyrazolyl)[(1-methylethyl)sulfonyl]quinazolinamine, 6-(tert-butylsulfonyl)-N-(5-(trifluoromethyl)-1H-pyrazolyl)quinazolinamine, 6-(tert-butylsulfonyl)-N-(1,3,4-trimethyl-1H-pyrazolyl)quinazolinamine, N-(6-(tert-butylthio)methoxyquinazolinyl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)methoxyquinazolinyl)benzo[d]thiazolamine, N-(6-(isopropylsulfonyl)methoxyquinazolinyl)benzo[d]thiazolamine, 4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinol, N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)ethoxyquinazolinyl)-N-ethylbenzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)(difluoromethoxy)quinazolinyl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)(2,2,2-trifluoroethoxy)quinazolinyl)benzo[d]thiazol amine, N-(6-(tert-butylsulfonyl)(methoxymethoxy)quinazolinyl)benzo[d]thiazolamine, 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol, N-(6-(tert-butylsulfonyl)(cyclohexylmethoxy)quinazolinyl)benzo[d]thiazol amine, 3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol, N-(6-(tert-butylsulfonyl)((tetrahydro-2H-pyranyl)oxy)quinazolin yl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)(2-chloroethoxy)quinazolinyl)benzo[d]thiazolamine, 4-(benzo[d]thiazolylamino)(tert-butylthio)quinazolinol, N-(6-(tert-butylthio)isopropoxyquinazolinyl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)isopropoxyquinazolinyl)benzo[d]thiazolamine, ethyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy) methylpropanoate, 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy) methylpropanol, N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethenylquinazolinamine, N-1,3-benzothiazolyl[(1,1-dimethylethyl)sulfonyl]ethylquinazolinamine, N-(6-(tert-butylsulfonyl)chloroquinazolinyl)benzo[d]thiazolamine, 6-(tert-butylsulfonyl)chloro-N-(4,5-dimethyl-1H-pyrazolyl)quinazolinamine, 6-[(1,1-dimethylethyl)sulfonyl]-N-(5-fluoro-1H-pyrazolo[3,4-b]pyridinyl) (methyloxy)quinazolinamine, 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-1H-pyrazolyl)methoxyquinazolinamine, or a salt thereof.
14. A compound which is 2-((4-((4,5-dimethyl-1H-pyrazolyl)amino)methoxyquinazolinyl)sulfonyl)ethanol, (R)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propan N-(6-(tert-butylsulfonyl)propoxyquinazolinyl)benzo[d]thiazolamine, N-(6-(tert-butylsulfonyl)(2-(methylthio)ethoxy)quinazolinyl)benzo[d]thiazolamine, N-(7-(2-bromoethoxy)(tert-butylsulfonyl)quinazolinyl)benzo[d]thiazolamine, 6-(tert-butylsulfonyl)methoxy-N-(3-methyl-1H-indazolyl)quinazolinamine, 6-(tert-butylsulfonyl)-N-(1H-indazolyl)methoxyquinazolinamine, (E)(4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)propenol, 2-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)ethanol, (R)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin yl)oxy)propanoate, (S)-methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin yl)oxy)propanoate, methyl 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin yl)oxy)propanoate, (R)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propan (S)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propan 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)propanol, N-(6-(tert-butylsulfinyl)methoxyquinazolinyl)benzo[d]thiazolamine, 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetamide, 2-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acetic acid, N-(6-(tert-butylsulfonyl)(2-(methylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazol amine, N-(6-(tert-butylsulfonyl)(2-(isopropylsulfonyl)ethoxy)quinazolinyl)benzo[d]thiazol amine, (E)-methyl 3-((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin yl)oxy)acrylate, (E)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolin yl)oxy)acrylamide, (E)((4-(benzo[d]thiazolylamino)(tert-butylsulfonyl)quinazolinyl)oxy)acrylic acid, N-(6-(tert-butylsulfonyl)(vinyloxy)quinazolinyl)benzo[d]thiazolamine, 4-(benzo[d]thiazolylamino)methoxy-N,N-dimethylquinazolinesulfonamide, 4-(benzo[d]thiazolylamino)-N-isopropylmethoxyquinazolinesulfonamide, N-(7-methoxy(pyrrolidinylsulfonyl)quinazolinyl)benzo[d]thiazolamine, N-(7-methoxy(morpholinosulfonyl)quinazolinyl)benzo[d]thiazolamine, 4-(benzo[d]thiazolylamino)-N-(2-hydroxyethyl)methoxyquinazolinesulfonamide, 4-(benzo[d]thiazolylamino)methoxy-N-(tetrahydro-2H-pyranyl)quinazoline sulfonamide, 4-(benzo[d]thiazolylamino)-N-(2-hydroxymethylpropyl)methoxyquinazoline sulfonamide, 1-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)pyrrolidinol, 4-(benzo[d]thiazolylamino)-N-(2-hydroxypropyl)methoxyquinazoline sulfonamide, 4-(benzo[d]thiazolylamino)methoxy-N-(2-methoxyethyl)quinazoline sulfonamide, 4-(benzo[d]thiazolylamino)methoxy-N-(oxetanyl)quinazolinesulfonamide, 4-(benzo[d]thiazolylamino)-N-(2-(dimethylamino)ethyl)methoxyquinazoline sulfonamide, 1-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)pyrrolidine carboxylic acid, 1-(4-((4-(benzo[d]thiazolylamino)methoxyquinazolinyl)sulfonyl)piperazin yl)ethanone, N-(2-(1H-tetrazolyl)ethyl)(benzo[d]thiazolylamino)methoxyquinazoline sulfonamide, 4-(benzo[d]thiazolylamino)methoxy-N-((tetrahydro-2H-pyran yl)methyl)quinazolinesulfonamide, or a salt thereof.
15. A compound which is 2-((4-(benzo[d]thiazolylamino)(tert- butylsulfonyl)quinazolinyl)oxy)ethanol, or a salt thereof.
16. The compound or salt according to any one of claims 1-15, wherein the salt is a pharmaceutically acceptable salt of said compound.
17. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to claim 16, and one or more pharmaceutically acceptable excipients.
18. A pharmaceutical composition according to claim 16, which further comprises one or more additional pharmaceutically active compounds.
19. The use of a compound or pharmaceutically acceptable salt thereof according to claim 16 in the preparation of a medicament for use in the treatment of a disease mediated by inhibition of RIP2 kinase.
20. The use of the compound, or pharmaceutically acceptable salt thereof, according to claim 16 in the preparation of a medicament for use in the treatment of a disease mediated by inhibition of RIP2 kinase.
21. The use according to claim 19 or claim 20, wherein the disease mediated by inhibition of RIP2 kinase is selected from uveitis, interleukin-1 converting enzyme associated fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoid arthritis, an inflammatory bowel disorder, ulcerative colitis, Crohn’s disease, early-onset and extra-intestinal inflammatory bowel disease, prevention of ischemia reperfusion injury in solid organ transplant, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, asthma, graft versus host disease, systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner’s granulomatosis, and interstitial pulmonary disease.
22. A pharmaceutical composition according to claim 17 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
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US201161524925P | 2011-08-18 | 2011-08-18 | |
US61/524,925 | 2011-08-18 | ||
PCT/US2012/051247 WO2013025958A1 (en) | 2011-08-18 | 2012-08-17 | Amino quinazolines as kinase inhibitors |
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NZ621314B2 true NZ621314B2 (en) | 2016-05-27 |
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