The present invention relates to small molecule antagonists of the Stimulator of
Interferon Genes (STING) protein. Accordingly, the small molecule antagonists may be
5 of use in the treatment of various inflammatory diseases such as fatty liver disease,
pulmonary fibrosis, pancreatitis, lupus, and so on. The invention extends to the
pharmaceutical compositions of the compounds per se, methods of making the
compounds and methods of modulating the STING protein using these compounds.
10 STING (STimulator of INterferon Genes) is an innate signalling molecule that plays a
crucial role in mediating an immune response to cytosolic DNA.
The human immune system has evolved to recognize and respond to different types of
threats and pathogens to maintain a healthy host. The innate arm of the immune
15 system is mainly responsible for a rapid initial inflammatory response to danger signals
associated with cellular or tissue damage from bacteria, viruses and other infectious
threats. The innate immune system responds to these damage-associated molecular
patterns (DAMPs) or microbial product pathogen-associated molecular patterns
(PAMPs) through an array of sentinel proteins called pattern recognition receptors
20 (PRRs) to provide broad and lasting protection to the host against a wide range of
threats (P. Broz et. al., Nat. Revs Immunol., 2013, 13, 551).
The P AMPs and DAMPs are often constituents or replication intermediates of
intracellular pathogens. PRRs include Toll-like receptors (TLRs; activated by
25 endosomal nucleic acids), C-type lectin receptors, retinoic acid inducible gene I (RIGIlike
receptors; activated by cytosolic RNA), NOD-like receptors (NLRs) and also double
stranded DNA sensors (Diebold et. al., Science, 2004, 3Q3, 1529-1531; 0. Takeuchi et.
al., Cell, 2010, 140, 8os; Pichlmair et. al., 2006, 3!4, 997). PRRs respond to DAMPs
and PAMPs by up-regulating type-1 interferons and cytokines. Free cytosolic nucleic
30 acids (DNA and RNA) are known P AMPs/DAMPs. The main sensor for cytosolic DNA
is cGAS (cyclic GMP-AMP synthase). Upon recognition of cytosolic dsDNA, cGAS
triggers formation of one specific isomer of the cyclic dinucleotide (CDN) cGAMP,
c[G(2',5')pA(3',s')p] (Gao et. al., Cell, 2013,153, 1094).
2
CDNs are second messenger signalling molecules produced by diverse bacteria and
consist of two ribonucleotides that are connected via phosphodiester bonds to make a
cyclic structure. CDNs cyclo-di(GMP) (c-diGMP), cyclo-di(AMP) (c-diAMP) and hybrid
cyclo-(AMP jGMP) (cGAMP) derivatives (A. Ablasser et. al., Nature, 2013, .4.9..8., 380)
5 all bind strongly to the ER-transmembrane adaptor protein STING (D.L. Burdette et.
al., Nature, 2011, .4.ZB., 515; H. Ishikawa, Nature, 2008, 455, 674).
STING recognises CDNs through its cytosolic carboxy-terminal domain, which forms a
homodimer and adopts a V-shaped binding pocket to bind CDNs (Zhang et. al., Mol.
10 Cell, 2013,51, 226; G. N. Barber et. al., Nat. Immunol., 2011, 12, 929). Ligand-induced
activation of STING triggers its relocation to the Golgi and a conformational change to
facilitate binding to TBK1. TBK1 in turn signals through the transcription factors IRF -3,
STAT6 and NFKB to induce type-I interferons and other cytokines and interferonstimulated
genes (C. Greenhill, Nat. Revs., Endocrinol., 2018, !4, 192; Y. Li, H.L.
15 Wilson, and E. Kiss-Toth, J. Inflamm., 2017, !4, 11). Following its activation, STING is
rapidly degraded in the normal response.
Excessive activation of STING is associated with a range of monogenic
autoinflammatory disorders referred to as interferonopathies (Y.J. Crow and N. Manel,
20 Nat. Revs. Immunol., 2015,15, 429-440). Loss offunction mutations in the human
DNAse Trex1 are associated with elevated levels of cGAMP and autoimmune diseases
such as the rare but severe inflammatory disease Aicardi-Goutieres syndrome (AGS),
familial chilblain lupus (FCL), systemic lupus erythematosus (SLE) and retinal
vasculopathy (Y. Crow et. al., Hum. Mol. Gen., 2009, 18, R130).
25
Inhalation of silica particles can result in lung inflammation and pulmonary fibrosis,
triggered by lung cell death and release of dsDNA products. Benmerzoug et. al. have
reported that this increase in circulating dsDNA activates STING and via increased
levels of CXCL10 and IFN signalling produces lung inflammation (S. Benmerzoug et.
30 al., Nat. Comm., 2018, .9, 5226).
Increased cytosolic dsDNA was detected in fibroblast-like synoviocytes (FLS) taken
from rheumatoid arthritis (RA) patients with the levels of dsDNA correlating with the
severity of rheumatoid synovitis (J. Wang et. al., Int. Immunopharm., 2019, .zQ,
35 105791). These findings indicated that increased dsDNA promoted an inflammatory
3
response via the STING pathway in RA FLS and led to increased expression of STING,
suggesting that cytosolic DNA accumulation is an important factor in RA-related
inflammation.
5 Patients with autosomal dominant gain of function mutations in STING have a
pediatric autoinflammatory condition called SA VI (STING-associated vasculopathy
with onset in infancy), manifest clinically as skin rash, vasculopathy, lupus-like
syndromes and pulmonary fibrosis characterised by aberrant IFN production and
systemic inflammation that are associated with high morbidity and mortality (N. Konig,
10 et. al.,Ann. Rheum., Dis., 2017, .zQ, 468). Characterised mutations in humans include
V147L, N154S, V155M and G166E which are all located at the interfacial region between
the trans-membrane domain and the ligand binding domain and result in ligandindependent
constitutively activated protein. More recently, three other gain of
function STING mutations C2o6Y, R281Q and R284S have been identified at a cluster
15 region that is proposed to promote STING aggregation and disfavour complexation to
the C-terminal tail region (H. Konno, et. al., Cell Rep. 2018, 23, 1112 and I. Melki, et.
al., J Allergy Clin Immunol. 2017, 140(2), 543·
A recent report by Habtezion et al. has shown that in mice with acute pancreatitis,
20 STING responds to acinar cell death by detecting DNA from necrotic cells and
promotes acute pancreatic inflammation (A. Habtezion et. al., Gastroenterology, 2018,
154, 1822). STING-knockout mice had less severe acute pancreatitis (less edema, less
inflammation) while administering a STING agonist resulted in more severe
pancreatitis.
25
Luo et al. have also shown recently that levels of STING were increased in liver tissues
from patients with non-alcoholic fatty liver disease and in mice with a high-fat diet
induced hepatic steatosis. Once again, STING-knockout mice developed less severe
liver fibrosis and a less acute inflammatory response (X. Luo et.al., Gastroenterology,
30 2018, 155, 1971).
Elevated cGAMP levels in the peripheral blood mononuclear cells of SLE patients was
associated with higher disease scores (J. An et. al., Arthritis Rheum., 2017, .6..9., 8oo)
suggesting a link between disease severity in lupus and activation of the STING
35 pathway.
4
The kidney tubule cells of subjects with fibrosis have been shown to lack mitochondrial
transcription factor A (TF AM). Mice lacking tubule TF AM developed severe
mitochondrial loss and energy deficit caused by aberrant packaging of mitochondrial
5 DNA and its translocation to the cytosol, where the STING pathway was activated
(K.W. Chung, Cell Metab., 2019, 3Q, 1). The ensuing cytokine expression and
inflammation led to renal fibrosis.
Bennion et. al. have demonstrated that the gain of function mutation N 153S knock-in
10 mice showed enhanced susceptibility to viral infection and responded to infection by a
murine gamma herpesvirus yHV68 with severe autoinflammation and pulmonary
fibrosis (B. Bennion et. al., J. Virol., 2019, .93, e018o6).
Other conditions where excessive immune system activation may be linked to STING
15 pathway activation include systemic inflammatory response syndrome (R.K. Boyapati
et. al., F1ooo Res., 2017, .Q, 169), cardiovascular disease (K.R. King et. al., Nat. Med.,
2017,£3, 1481), stroke (A.M. Jeffries et. al., Neurosci. Lett., 2017, 6s8, 53) and agerelated
macular degeneration (N. Kerur et. al., Nat. Med., 2018, £.4, so).
20 There is therefore a compelling body of evidence that blocking, inhibiting or
antagonising the STING pathway could have therapeutic benefit in a number of
conditions and disease states. There is therefore a pressing need for improved small
molecule blockers of the STING pathway, and in particular for small molecule direct
antagonists of the STING protein.
25
30
The present invention has arisen from the inventors work in attempting to identify
STING protein modulators.
In a first aspect of the invention, there is provided a compound of formula (I):
R4 Rs x3¢cN,xs II I
X2 -0 X~Z)n
R1
(I)
, wherein X2 is CR2 or N;
5
X3 is CR3 or N;
X6 is C=O, C=S or CR7Rs;
the or each Z is independently CR9R10 or NR9;
X7 isS, SO, S02, 0, NR11 or CR11R12;
5 n is o, 1 or 2;
R\ R4, Rs, R9, R10, R11 and R12 are each independently selected from the group
consisting ofH, halogen, OH, CN, COOR13, CONR13R14, NR13R14, NR13CQR14, optionally
substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted
mono or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally
10 substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted ClC6
alkoxycarbonyl group, mono or bicyclic optionally substituted C6-C12 aryl, mono or
bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted
mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy,
optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy;
15 one of R2 and R3 is -U-U-L3-L4-R1s and, when X2 is CR2 and X3 is CR3, the other of R2
and R3 is selected from the group consisting of H, halogen, OH, CN, COOR13,
CONR13R14, NR13R14, NR13CQR14, optionally substituted C1-C6 alkyl, optionally
substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
20 substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, mono or
bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to
10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered
heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and
optionally substituted heterocyclyloxy;
25 Rs and R7 are each independently selected from the group consisting of H, halogen, OH,
CN, COOR13, CONR13R14, NR13R14, NR13CQR14, optionally substituted C1-C6 alkyl,
optionally substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6
cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,
optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group,
30 mono or bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally
substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8
membered heterocycle, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted heterocyclyloxy and L5-L6-R16; wherein a
maximum of one ofRs and R7 is -LS-L6-R16;
6
R13 and R14 are each independently selected from the group consisting of H, halogen,
OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl, optionally
substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
5 substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, mono or
bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to
10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered
heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and
optionally substituted heterocyclyloxy;
10 U is absent or is NR17, 0, an optionally substituted C1-C6 alkylene, an optionally
substituted C2-C6 alkenylene, an optionally substituted C2-C6 alkynylene, an optionally
substituted C3-C6 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally
substituted 5 to 10 membered heteroarylene or an optionally substituted 3 to 8
membered heterocyclylene;
15 U is absent or is C=O, C=8, C=NR19 or 802;
L3 is absent or is NR18, 0, an optionally substituted C1-C6 alkylene, an optionally
substituted C2-C6 alkenylene, an optionally substituted C2-C6 alkynylene, an optionally
substituted C3-C6 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally
substituted 5 to 10 membered heteroarylene or an optionally substituted 3 to 8
20 membered heterocyclylene;
L4 is absent or is an optionally substituted C1-C6 alkylene, an optionally substituted C2-
C6 alkenylene, an optionally substituted C2-C6 alkynylene, an optionally substituted C3-
C6 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally substituted 5 to
10 membered heteroarylene or an optionally substituted 3 to 8 membered
25 heterocyclylene;
L5 is absent or an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6
alkenylene, an optionally substituted C2-C6 alkynylene, 0, 8, 8=0, 802 or NR19;
L6 is absent or an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6
alkenylene, an optionally substituted C2-C6 alkynylene, 0, 8, 8=0, 802 or NR19;
30 R1s isH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
optionally substituted C2-C6 alkynyl, optionally substituted mono or bicyclic C3-C6
cycloalkyl, mono or bicyclic optionally substituted C6-C12 aryl, mono or bicyclic
optionally substituted 5 to 10 membered heteroaryl or optionally substituted mono or
bicyclic 3 to 8 membered heterocycle;
7
R16 isH, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,
optionally substituted mono or bicyclic C3-C6 cycloalkyl, mono or bicyclic optionally
substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to 10 membered
heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and
5 R17 to R19 are independently H, an optionally substituted C1-C6 alkyl, an optionally
substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl or CN;
wherein, when X2 is N, X3 is CR3; and
when U is absent and U is C=O, L3 is not NR1s;
or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or
10 polymorphic form thereof.
The compounds of formula (I) may be used as medicaments.
Hence, in a second aspect, there is provided a compound of formula (I), or a
15 pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic
form thereof, for use as a medicament.
20
25
The inventors have found that compounds of formula (I) are useful in modulating the
STimulator of INterferon Genes (STING) protein.
Hence, in a third aspect, there is provided a compound of formula (I), or a
pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic
form thereof, for use in modulating the STimulator of INterferon Genes (STING)
protein.
Preferably, the compound of formula (I) is for use in inhibiting, or inactivating, the
STING protein. The compound of formula (I) may be for use in inhibiting, or
inactivating, STING functional activity as evidenced by a reduction of one or more
biological effects selected from the group consisting of cellular interferon ~ production,
30 cellular levels of interferon-stimulated genes, production of cytokines and
phosphorylation of the transcription factors IRF-3 and NF-KB.
By inhibiting the STING protein, it is possible to treat, ameliorate or prevent liver
fibrosis, fatty liver disease, pulmonary fibrosis, lupus, rheumatoid arthritis (RA),
8
STING-associated vasculopathy with onset in infancy (SAVI), pancreatitis,
cardiovascular disease, non-alcoholic fatty liver disease and renal fibrosis.
By inhibiting the STING protein, it is possible to treat, ameliorate or prevent liver
5 fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis,
lupus, rheumatoid arthritis (RA), STING-associated vasculopathy with onset in infancy
(SAVI), Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic
lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic
inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis,
10 stroke and age-related macular degeneration (AMD).
Accordingly, in a fourth aspect there is provided a compound of formula (I), or a
pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic
form thereof, for use in treating, ameliorating or preventing a disease selected from
15 liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary
fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated
vasculopathywith onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), familial
chilblain lupus (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy,
neuroinflammation, systemic inflammatory response syndrome, pancreatitis,
20 cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration
(AMD).
In a fifth aspect, there is provided a method of modulating the STING protein in a
subject, the method comprising administering, to a subject in need of such treatment, a
25 therapeutically effective amount of a compound of formula (I), or a pharmaceutically
acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
Preferably, the method comprises inhibiting the STING protein.
30
Preferably, the method is a method of inhibiting, or inactivating, the STING protein.
In a sixth aspect, there is provided a method of treating, ameliorating or preventing a
disease selected from liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis
(NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes,
STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres
35 syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE),
9
retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome,
pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular
degeneration (AMD); the method comprising administering, to a subject in need of
such treatment, a therapeutically effective amount of a compound of formula (I), or a
5 pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic
form thereof.
It may be appreciated that the term "preventing" can mean "reducing the likelihood of'.
10 In one preferred embodiment, the disease is fibrosis. The fibrosis may be selected from
the group consisting of liver fibrosis, pulmonary fibrosis or renal fibrosis. In some
embodiments, the fibrosis patient may have up regulated STING expression and j or
STING activity in a tissue compared to that of a healthy subject.
15 In an alternative preferred embodiment, the disease is fatty liver disease. The fatty
liver disease may be non-alcoholic (or simple) fatty liver or non-alcoholic
steatohepatitis (NASH).
The following definitions are used in connection with the compounds of the present
20 invention unless the context indicates otherwise.
Throughout the description and the claims of this specification the word "comprise"
and other forms of the word, such as "comprising" and "comprises," means including
but not limited to, and is not intended to exclude for example, other additives,
25 components, integers, or steps.
As used in the description and the appended claims, the singular forms "a," "an," and
"the" include plural referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a composition" includes mixtures of two or more such
30 compositions.
35
"Optional" or "optionally" means that the subsequently described event, operation or
circumstances can or cannot occur, and that the description includes instances where
the event, operation or circumstance occurs and instances where it does not.
10
The term "alkyl" as used herein, unless otherwise specified, refers to a saturated
straight or branched hydrocarbon. In certain embodiments, the alkyl group is a
primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group
includes one to six carbon atoms, i.e. C1-C6 alkyl. C1-C6 alkyl includes for example
5 methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl,
pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and isohexyl. An alkyl
group can be unsubstituted or substituted with one or more of halogen, OH, optionally
substituted C1-C6 alkoxy, CN, oxo, C(O)R20, COOR20, OC(O)R2o, CONR2oR2\ NR2oR2NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21),
10 optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl,
optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered
heterocycle. Accordingly, it will be appreciated that an optionally substituted C1-C6
alkyl may be an optionally substituted C1-C6 haloalkyl, i.e. a C1-C6 alkyl substituted with
at least one halogen, and optionally further substituted with one or more of OH,
15 optionally substituted C1-C6 alkoxy, CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR2oR2NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally substituted 5 to 10
membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted
3 to 8 membered heterocycle. The optionally substituted C1-C6 alkyl may be a
20 polyfluoroalkyl, preferably a C1-C3 polyfluoroalkyl.
R20 and R21 may each independently be selected from the group consisting of H,
halogen, OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl,
optionally substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6
25 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,
optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group,
mono or bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally
substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8
membered heterocycle, optionally substituted aryloxy, optionally substituted
30 heteroaryloxy and optionally substituted heterocyclyloxy. R20 and R21 may each
independently be selected from the group consisting of H and halogen.
The term "alkylene", as used herein, unless otherwise specified, refers to a bivalent
saturated straight or branched hydrocarbon. In certain embodiments, the alkylene
35 group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the
11
alkylene group includes one to six carbon atoms, i.e. C1-C6 alkylene. C1-C6 alkylene
includes for example methylene, ethylene, n-propylene and isopropylene, butylene,
pentylene, hexylene, isobutylene, sec-butylene, tert-butylene, isopentylene,
neopentylene, and isohexylene. An alkylene group can be unsubstituted or substituted
5 with one or more of optionally substituted C1-C6 alkyl, halogen, OH, optionally
substituted C1-C6 alkoxy, CN, oxo, C(O)R20, COOR20, OC(O)R2o, CONR2oR2\ NR2oR2NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21),
optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl,
optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered
10 heterocycle. Accordingly, it will be appreciated that an optionally substituted C1-C6
alkylene may be an optionally substituted C1-C6 haloalkylene, i.e. a C1-C6 alkylene
substituted with at least one halogen, and optionally further substituted with one or
more of optionally substituted C1-C6 alkyl, OH, optionally substituted C1-C6 alkoxy, CN,
oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20,
15 S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl,
optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
cycloalkyl and optionally substituted 3 to 8 membered heterocycle. It will be
appreciated that an optionally substituted C1-C6 alkylene may be an optionally
substituted polyfluoroalkylene, preferably a C1-C3 polyfluoroalkylene. R20 and R21 may
20 be as defined above. R20 and R21 may each independently be selected from the group
consisting of H, halogen and optionally substituted C1-C6 alkyl.
25
The term "halo" or "halogen" includes flu oro (-F), chloro ( -Cl), bromo (-Br) and iodo (I).
The term "polyfluoroalkyl" may denote a C1-C3 alkyl group in which two or more
hydrogen atoms are replaced by fluorine atoms. The term may include perfluoroalkyl
groups, i.e. a C1-C3 alkyl group in which all the hydrogen atoms are replaced by fluorine
atoms. Accordingly, the term C1-C3 polyfluoroalkyl includes, but is not limited to,
30 difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-
trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-1-
( trifl uoromethyl )ethyl.
"Alkoxy" refers to the group R22-0-, where R22 is an optionally substituted C1-C6 alkyl
35 group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C2-
12
C6 alkenyl or an optionally substituted C2-C6 alkynyl. Exemplary C1-C6 alkoxy groups
include but are not limited to methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy and
tert-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of
halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R25 NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21),
optionally substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl,
optionally substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered
heterocycle. R20 and R21 may be as defined above. R20 and R21 may each
independently be selected from the group consisting of H, halogen and optionally
10 substituted C1-C6 alkyl.
"Aryl" refers to an aromatic 6 to 12 membered hydrocarbon group. The term includes
bicyclic groups where one of the rings is aromatic and the other is not. Examples of a
C6-C12 aryl group include, but are not limited to, phenyl, a-naphthyl, ~-naphthyl,
15 biphenyl, tetrahydronaphthyl and indanyl. An aryl group can be unsubstituted or
substituted with one or more of optionally substituted C1-C6 alkyl, optionally
substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,optionally substituted
C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R2o, CONR2oR2NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R220 OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally substituted 5 to 10
membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally
substituted 3 to 8 membered heterocycle. R20 and R21 may be as defined above. R20
and R21 may each independently be selected from the group consisting of H, halogen
and optionally substituted C1-C6 alkyl.
25
"Arylene" refers to a bivalent aromatic 6 to 10 membered hydrocarbon group. An
arylene group may be as defined above in relation the aryl group, but with a hydrogen
atom removed therefrom to cause the group to be bivalent.
30 The term "bicycle" or "bicyclic" as used herein refers to a molecule that features two
fused rings, which rings are a cycloalkyl, heterocyclyl, or heteroaryl. In one
embodiment, the rings are fused across a bond between two atoms. The bicyclic
moiety formed therefrom shares a bond between the rings. In another embodiment,
the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of
35 the rings to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or
13
more atoms connecting two bridgeheads in a polycyclic compound. In another
embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" moiety. The spirocyclic
group may be a C3-C6 cycloalkyl or a mono or bicyclic 3 to 8 membered heterocycle
which is bound through a single carbon atom of the spirocyclic moiety to a single
5 carbon atom of a carbocyclic or heterocyclic moiety. In one embodiment, the
spirocyclic group is a cycloalkyl and is bound to another cycloalkyl. In another
embodiment, the spirocyclic group is a cycloalkyl and is bound to a heterocyclyl. In a
further embodiment, the spirocyclic group is a heterocyclyl and is bound to another
heterocyclyl. In still another embodiment, the spirocyclic group is a heterocyclyl and is
10 bound to a cycloalkyl. A spirocyclic group can be unsubstituted or substituted with
one or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH,
CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20,
SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12
15 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R20 and R21 may
be as defined above. R20 and R21 may each independently be selected from the group
consisting of H, halogen and optionally substituted C1-C6 alkyl.
20 "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic,
bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. Representative
examples of a C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl. A cycloalkyl group can be unsubstituted or substituted with one
or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
25 optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH,
CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20,
SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12
aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R20 and R21 may be
30 as defined above. R20 and R21 may each independently be selected from the group
consisting of H, halogen and optionally substituted C1-C6 alkyl.
"Cycloalkylene" refers to a bivalent non-aromatic, saturated, partially saturated,
monocyclic, bicyclic or polycyclic hydrocarbon 3 to 6 membered ring system. A
14
cycloalkylene group may be as defined above in relation to the cycloalkyl group, but
with a hydrogen atom removed therefrom to cause the group to be bivalent.
"Heteroaryl" refers to a monocyclic or bicyclic aromatic 5 to 10 membered ring system
5 in which at least one ring atom is a heteroatom. The term includes bicyclic groups
where one of the rings is aromatic and the other is not. The or each heteroatom may be
independently selected from the group consisting of oxygen, sulfur and nitrogen.
Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole,
azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N -methylimidazole,
10 pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole,
1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-1,2,4-triazole, 1H -tetrazole, 1-methyltetrazole,
benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, Nmethylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, and
isoquinoline. Bicyclic 5 to 10 membered heteroaryl groups include those where a
15 phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6-membered
monocyclic heteroaryl ring. A heteroaryl group can be unsubstituted or substituted with
one or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH,
CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20,
20 SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12
aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R20 and R21 may be
as defined above. R20 and R21 may each independently be selected from the group
consisting of H, halogen and optionally substituted C1-C6 alkyl.
25
30
"Heteroarylene" refers to a bivalent monocyclic or bicyclic aromatic 5 to 10 membered
ring system in which at least one ring atom is a heteroatom. A heteroarylene group may
be as defined above in relation to the heteroaryl group, but with a hydrogen atom
removed therefrom to cause the group to be bivalent.
"Heterocycle" or "heterocyclyl" refers to 3 to 8 membered monocyclic, bicyclic or
bridged molecules in which at least one ring atom is a heteroatom. The or each
heteroatom may be independently selected from the group consisting of oxygen, sulfur
and nitrogen. A heterocycle may be saturated or partially saturated. Exemplary 3 to 8
35 membered heterocycle groups include but are not limited to aziridine, oxirane, oxirene,
15
thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene,
tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl,
tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane,
diazepane and oxazine. A heterocycle group can be unsubstituted or substituted with
5 one or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH,
CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20,
SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12
aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
10 cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R20 and R21 may be
as defined above. R20 and R21 may each independently be selected from the group
consisting of H, halogen and optionally substituted C1-C6 alkyl.
"Heterocyclylene" refers to a bivalent 3 to 8 membered monocyclic, bicyclic or bridged
15 molecules in which at least one ring atom is a heteroatom. A heterocyclylene group may
be as defined above in relation to the heterocycle group, but with a hydrogen atom
removed therefrom to cause the group to be bivalent.
"Alkenyl" refers to an olefinically unsaturated hydrocarbon groups which can be
20 unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6
carbons, i.e. it is a C2-C6 alkenyl. C2-C6 alkenyl includes for example vinyl, allyl,
propenyl, butenyl, pentenyl and hexenyl. An alkenyl group can be unsubstituted or
substituted with one or more of optionally substituted C2-C6 alkynyl, optionally
substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R20,
25 CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally substituted 5 to 10
membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted
3 to 8 membered heterocycle. R20 and R21 may be as defined above. R20 and R21 may
each independently be selected from the group consisting of H, halogen and optionally
30 substituted C1-C6 alkyl.
"Alkynyl" refers to an acetylenically unsaturated hydrocarbon groups which can be
unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6
carbons, i.e. it is a C2-C6 alkynyl. C2-C6 alkynyl includes for example propargyl,
35 propynyl, butynyl, pentynyl and hexynyl. An alkynyl group can be unsubstituted or
16
substituted with one or more of optionally substituted C2-C6 alkenyl, optionally
substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R20,
CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R2OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally substituted 5 to 10
5 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted
3 to 8 membered heterocycle. R20 and R21 may be as defined above. R20 and R21 may
each independently be selected from the group consisting of H, halogen and optionally
substituted C1-C6 alkyl.
10 The term "alkenylene", as used herein, unless otherwise specified, refers to a bivalent
olefinically unsaturated straight or branched hydrocarbon. An alkenylene group may
be as defined above in relation the alkenyl group, but with a hydrogen atom removed
therefrom to cause the group to be bivalent.
15 The term "alkynylene", as used herein, unless otherwise specified, refers to a bivalent
acetylenically unsaturated straight or branched hydrocarbon. An alkynylene group may
be as defined above in relation the alkynyl group, but with a hydrogen atom removed
therefrom to cause the group to be bivalent.
20 "Alkylsulfonyl" refers to the group alkyl-S02- where alkyl is an optionally substituted
C1-C6 alkyl, and is as defined as above.
"Alkoxycarbonyl" refers to the group alkyl-0-C(O)-, where alkyl is an optionally
substituted C1-C6 alkyl. An alkoxycarbonyl group can be unsubstituted or substituted
25 with one or more of optionally substituted C2-C6 alkenyl, optionally substituted C2-C6
alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R20, COOR20,
OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20,
S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally
substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl and
30 optionally substituted 3 to 8 membered heterocycle.
"Aryloxy" refers to the group Ar-0- where Ar is a mono or bicyclic optionally
substituted C6-C12 aryl group, as defined above.
17
"Heteroaryloxy" refers to the group heteroaryl-0- where the heteroaryl is a mono or
bicyclic optionally substituted 5 to 10 membered heteroaryl, and is as defined above.
"Heterocyclyloxy" refers to the group heterocycle-0- where heterocycle is an
5 optionally substituted mono or bicyclic 3 to 8 membered heterocycle, and is as defined
as above.
A complex of the compound of formula (I) may be understood to be a multi -component
complex, wherein the drug and at least one other component are present in
10 stoichiometric or non-stoichiometric amounts. The complex may be other than a salt
or solvate. Complexes of this type include clathrates (drug-host inclusion complexes)
and co-crystals. The latter are typically defined as crystalline complexes of neutral
molecular constituents which are bound together through non-covalent interactions,
but could also be a complex of a neutral molecule with a salt. Co-crystals may be
15 prepared by melt crystallisation, by recrystallisation from solvents, or by physically
grinding the components together- see Chem Commun, 17, 1889-1896, by 0.
Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a
general review of multi-component complexes, see J Pharm Sci, .6.4 (8), 1269-1288, by
Haleblian (August 1975), incorporated herein by reference.
20
The term "pharmaceutically acceptable salt" may be understood to refer to any salt of a
compound provided herein which retains its biological properties and which is not toxic
or otherwise undesirable for pharmaceutical use. Such salts may be derived from a
variety of organic and inorganic counter-ions well known in the art. Such salts include,
25 but are not limited to: (1) acid addition salts formed with organic or inorganic acids
such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, adepic,
aspartic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic,
glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic,
fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic,
30 mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-
hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-
naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-
methylbicyclo[2.2.2]-oct -2-ene-1-carboxylic, glucoheptonic, 3-phenyl propionic,
trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic,
35 hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the
18
like acids; or (2) base addition salts formed when an acidic proton present in the parent
compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline
earth ion or an aluminium ion, or alkali metal or alkaline earth metal hydroxides, such
as sodium, potassium, calcium, magnesium, aluminium, lithium, zinc, and barium
5 hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic,
alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine,
diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine,
ethylenediamine, lysine, arginine, ornithine, choline, N ,N' -dibenzylethylene-diamine,
chloroprocaine, diethanolamine, procaine, N -benzylphenethylamine, N-
10 methylglucamine piperazine, tris(hydroxymethyl)-aminomethane,
tetramethylammonium hydroxide, and the like.
Pharmaceutically acceptable salts may include, sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium and the like, and when the compound
15 contains a basic functionality, salts of non-toxic organic or inorganic acids, such as
hydrohalides, e.g. hydrochloride, hydrobromide and hydroiodide, carbonate or
bicarbonate, sulfate or bisulfate, borate, phosphate, hydrogen phosphate, dihydrogen
phosphate, pyroglutamate, saccharate, stearate, sulfamate, nitrate, orotate, oxalate,
palmitate, pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate,
20 cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate,
tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartarate,
camsylate, citrate, cyclamate, benzoate, isethionate, esylate, formate, 3-(4-
hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate,
methanesulfonate (mesylate), methylsulphate, naphthylate, 2-napsylate, nicotinate,
25 ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate
(besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate,
camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct -2-ene-1-carboxylate,
glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate,
gluceptate, gluconate, glucoronate, hexafluorophosphate, hibenzate, benzoate,
30 glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate,
muconate, xinofoate and the like.
Hemisalts of acids and bases may also be formed, for example, hemisulphate salts.
19
The skilled person will appreciate that the aforementioned salts include ones wherein
the counterion is optically active, for exampleD-lactate, or racemic, for example DLtartrate.
5 For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties,
Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one
or more of three methods:
(i) by reacting the compound of formula (I) with the desired acid or base;
10 (ii) by removing an acid- or base-labile protecting group from a suitable precursor
of the compound of formula (I) using the desired acid or base; or
(iii) by converting one salt of the compound of formula (I) to another by reaction
with an appropriate acid or base or by means of a suitable ion exchange column.
15 All three reactions are typically carried out in solution. The resulting salt may
precipitate out and be collected by filtration or may be recovered by evaporation of the
solvent. The degree of ionisation in the resulting salt may vary from completely ionised
to almost non-ionised.
20 The term "solvate" may be understood to refer to a compound provided herein or a salt
thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent
bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is
a hydrate. Pharmaceutically acceptable solvates in accordance with the invention
include those wherein the solvent of crystallization may be isotopically substituted, e.g.
25 D20, d6-acetone and d6-DMSO.
A currently accepted classification system for organic hydrates is one that defines
isolated site, channel, or metal-ion coordinated hydrates- see Polymorphism in
Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995),
30 incorporated herein by reference. Isolated site hydrates are ones in which the water
molecules are isolated from direct contact with each other by intervening organic
molecules. In channel hydrates, the water molecules lie in lattice channels where they
are next to other water molecules. In metal-ion coordinated hydrates, the water
molecules are bonded to the metal ion.
35
20
When the solvent or water is tightly bound, the complex will have a well-defined
stoichiometry independent of humidity. When, however, the solvent or water is weakly
bound, as in channel solvates and hygroscopic compounds, the water/solvent content
will be dependent on humidity and drying conditions. In such cases, non-stoichiometry
5 will be the norm.
The compounds of the invention may exist in a continuum of solid states ranging from
fully amorphous to fully crystalline, including polymorphs of said crystalline material.
The term 'amorphous' refers to a state in which the material lacks long range order at
10 the molecular level and, depending upon temperature, may exhibit the physical
properties of a solid or a liquid. Typically such materials do not give distinctive X-ray
diffraction patterns and, while exhibiting the properties of a solid, are more formally
described as a liquid. Upon heating, a change from solid to liquid properties occurs
which is characterised by a change of state, typically second order ('glass transition').
15 The term 'crystalline' refers to a solid phase in which the material has a regular ordered
internal structure at the molecular level and gives a distinctive X-ray diffraction pattern
with defined peaks. Such materials when heated sufficiently will also exhibit the
properties of a liquid, but the change from solid to liquid is characterised by a phase
change, typically first order ('melting point').
20
The compounds of the invention may also exist in a mesomorphic state (mesophase or
liquid crystal) when subjected to suitable conditions. The mesomorphic state is
intermediate between the true crystalline state and the true liquid state (either melt or
solution). Mesomorphism arising as the result of a change in temperature is described
25 as 'thermotropic' and that resulting from the addition of a second component, such as
water or another solvent, is described as 'lyotropic'. Compounds that have the potential
to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules
which possess an ionic (such as -COO-N a+, -COO-K+, or -S03-Na+) or non-ionic (such as
-N-N+(CH3) 3) polar head group. For more information, see Crystals and the Polarizing
30 Microscope by N.H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970),
incorporated herein by reference.
Compounds of formula (I) may include one or more stereogenic centers and so may
exist as optical isomers, such as enantiomers and diastereomers. All such isomers and
35 mixtures thereof are included within the scope of the present invention.
5
10
21
It will be understood that the above compounds may exist as enantiomers and as
diastereoisomeric pairs. These isomers also represent further embodiments of the
invention.
Conventional techniques for the preparation/isolation of individual enantiomers
include chiral synthesis from a suitable optically pure precursor or resolution of the
racemate (or the racemate of a salt or derivative) using, for example, chiral high
pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable
optically active compound, for example, an alcohol, or, in the case where the compound
of formula (I) contains an acidic or basic moiety, a base or acid such as 1-
phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be
15 separated by chromatography and/ or fractional crystallization and one or both of the
diastereoisomers converted to the corresponding pure enantiomer(s) by means well
known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in
20 enantiomerically-enriched form using chromatography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or
hexane, containing from o to so% by volume of isopropanol, typically from 2% to 20%,
and from o to 5% by volume of an alkylamine, typically 0.1% diethylamine.
Concentration of the eluate affords the enriched mixture.
25
Mixtures of stereoisomers may be separated by conventional techniques known to
those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by
E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
30 R1 may be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted
C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. R1 may be H, halogen, OH, CN,
C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Preferably, R1 is H.
X2 may be CR2.
35
22
X3 may be CR3.
In one embodiment X2 is Nand X3 is CR3. In this embodiment, R3 is -U-U-L3-L4-R1s.
5 In an alternative embodiment, X2 is CR2 and X3 is N. In this embodiment, R2 is -U-UL3-
L4-Rls.
However, in a preferred embodiment, X2 is CR2 and X3 is CR3. In some embodiments,
R2 is -U-U-L3-L4-R1s. In alternative embodiments, R3 is -U-U-L3-L4-R1s. Accordingly,
10 the compound may be a compound of Formula (Ia) or Formula (lb ):
(Ia) (lb)
Preferably, one ofR2 and R3 is -U-U-L3-L4-R1s and the other ofR2 and R3 isH, halogen,
OH, CN, COOR13, CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl,
optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, and R13 and
15 R14 are each independently selected from the group consisting of H, optionally
substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl and optionally substituted
C2-C alkynyl. More preferably, one ofR2 and R3 is -U-U-L3-L4-R1s and the other ofR2
and R3 isH, halogen, OH, CN, CONR13R14, NR13R14, C1-C3 alkyl, C2-C3 alkenyl or C2-C3
alkynyl, and R13 and R14 are each independently selected from the group consisting of
20 H, C1-C3 alkyl, C2-C3 alkenyl and C2-C alkynyl. Preferably, one of R2 and R3 is -U-U-L3-
L4-R1s and the other of R2 and R3 is H, bromine or CONH2. In a preferred embodiment,
one ofR2 and R3 is -U-U-L3-L4-R1s and the other ofR2 and R3 is H.
Preferably at least one of U to L4 is present.
25
In some embodiments, U is absent or is NR17. U may be C=O, C=S, C=NR19 or S02. L3
23
R1a
~f:b~t'i· , w h ere an asten.s k m. d"1 cates t h e po.m t of b on d"m g to L4 or, m. emb o d"1 ments
where L4 is absent, R1s.
R17 and R18 may independently be H, optionally substituted C1-C6 alkyl, optionally
5 substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. R17 and R18 may
independently be H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Preferably, R17 and R18
are H or methyl.
R19 may be H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or CN. R19 may be H, methyl or
10 CN. Preferably, R19 isH or CN.
In an alternative embodiment, U is absent or is an optionally substituted C1-C6
alkylene, an optionally substituted C2-C6 alkenylene or an optionally substituted C2-C6
alkynylene. Preferably, U is absent or a C1-C3 alkylene. U may be absent or CH2. U
15 may be absent. L3 may be 0. Accordingly, in some embodiments, -U-U-L3- may be
-0-* or -CH20-*, where an asterisk indicates the point of bonding to L4 or, in
embodiments where L4 is absent, R1s.
In a further alternative embodiment, U may be an optionally substituted C3-C6
20 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally substituted 5 to 10
membered heteroarylene or an optionally substituted 3 to 8 membered heterocyclylene.
U may be an optionally substituted C3-C6 cycloalkylene, an optionally substituted C6
arylene, an optionally substituted 5 or 6 membered heteroarylene or an optionally
substituted 3 to 6 membered heterocyclylene. U may be a C5-C6 cycloalkylene, a C6
25 arylene, a 5 or 6 membered heteroarylene or a 5 to 6 membered heterocyclylene. The
cycloalkylene may be cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
U may be a 5 membered heteroarylene. The heteroarylene may be pyrrolylene,
pyrazolylene, imidazolylene, 1,2,4-triazolylene, 1,2,3-triazolylene, furanylene,
thiophenylene, oxazolylene, isoxazolylene, thiazolylene or isothiazolylene. U may be a
30 6 membered heterocyclylene. The heterocyclylene may be pyrrolidinylene,
pyrazolidinylene, imidazolidinylene, tetrahydrofuranylene, a,3-dioxolanylene,
tetrahydrothiophenylene, piperidinylene, piperazinylene, tetrahydropyranylene,
thianylene, morpholinylene or thiomorpholinylene. U may be absent. L3 may be
24
~-:>-!* absent. Accordingly, in some embodiments, -U-U-L3- may be H
H N-N
~-N '; }I ~c-' 0\\ 1~ ~c-' ''1"'-N f' * ~.~r-' -~-N N-~-·
N f' * H N S" * or \__/ where an asterisk
' ' '
indicates the point of bonding to L4 or, in embodiments where L4 is absent, R1s.
5 In some embodiments, L4 is absent, an optionally substituted C1-C6 alkylene, an
optionally substituted C2-C6 alkenylene or an optionally substituted C2-C6 alkynylene.
Preferably, L4 is absent or a C1-C3 alkenylene. More preferably, L4 is absent or is CH2,
CH2CH2 or CH2CH2CH2.
10 In alternative embodiments, L4 is an optionally substituted C3-C6 cycloalkylene, an
optionally substituted C6-C12 arylene, an optionally substituted 5 to 10 membered
heteroarylene or an optionally substituted 3 to 8 membered heterocyclylene.
Preferably, L4 is an optionally substituted C3-C6 cycloalkylene, an optionally substituted
C6 arylene, an optionally substituted 5 to 6 membered heteroarylene or an optionally
15 substituted 3 to 6 membered heterocyclylene. More preferably, L4 is a C5-C6
cycloalkylene, a C6 arylene, a 5 to 6 membered heteroarylene or a 5 to 6 membered
heterocyclylene. The cycloalkylene may be cyclopropylene, cyclobutylene,
cyclopentylene or cyclohexylene. L4 may be a 5 membered heteroarylene. The
heteroarylene may be pyrrolylene, pyrazolylene, imidazolylene, 1,2,4-triazolylene, 1,2,3-
20 triazolylene, furanylene, thiophenylene, oxazolylene, isoxazolylene, thiazolylene or
isothiazolylene. The heterocyclylene may be pyrrolidinylene, pyrazolidinylene,
imidazolidinylene, tetrahydrofuranylene, a,3-dioxolanylene, tetrahydrothiophenylene,
piperidinylene, piperazinylene, tetrahydropyranylene, thianylene, morpholinylene or
H p
thiomorpholinylene. Accordingly, in some embodiments, L4 may be ' ~,
25
/-?N'w'\. ~-o-~·
\=.! or - where an asterisk indicates the point of bonding to R1s.
25
Accordingly, in some embodiments, -U-U-L3-L4- may be -OCH2CH2-*, -CH20CH2-*,
N~ H N-N ~*
1 \ N-N I \ /I., 0 ~N I* ? }I ~~ ~N;)--/ '-, }~~~
H ''""r'N S"' * H ~N S" * or
' ' '
1-~-N N-~-·
5 \__/ , where an asterisk indicates the point of bonding to R1s. Preferably, R17
and R18 are independently H or CH3•
In one embodiment, R1s is a mono or bicyclic optionally substituted C6-C12 aryL The
optionally substituted C6-C12 aryl may be an optionally substituted phenyl, 5,6,7,8-
10 tetrahydronaphthalenyl or 2,3-dihydro-1H-indenyL The aryl may be unsubstituted or
substituted with one or more substituents selected from the group consisting of
optionally substituted C1-C6 alkyl, halogen, OH, oxo, OP(O)(OR20)(0R21), optionally
substituted C1-C6 alkoxy, NR20R2\ CONR20R2\ CN, C(O)R20, COOR20, N02, azido,
S02R20, C(O)R20 and NR2°COR21. When the aryl is substituted with an optionally
15 substituted alkyl, the alkyl may be unsubstituted or substituted with one or more
substituents selected from the group consisting of halogen, OH, C1-C6 alkoxy, NR20R2C(O)R20, CN, oxo, OP(O)(OR20)(0R21), OC(O)R20, COOR20, C1-C6 alkenyl, C1-C6 alkynyl,
=NOR20, NR2°C(O)R2\ S02R20 and S02NR20R21. Halogen may be F. R20 and R21 may
independently be H or methyL Accordingly, the aryl may be substituted with one or
20 more substituents selected from the group consisting ofF, CN, NH2, C(O)CH3, CONH2,
CH3 and CH2COOH.
In an alternative embodiment, R1s is a mono or bicyclic optionally substituted 5 to 10
membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally
25 substituted 3 to 8 membered heterocycle. The optionally substituted 5 to 10 membered
heteroaryl may be optionally substituted pyrrolyl, optionally substituted furanyl,
optionally substituted thiophenyl, optionally substituted oxazolyl, optionally
26
substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted
isothiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl,
optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally
substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted
5 indolinyl, optionally substituted indolinyl, optionally substituted 1H -indolyl, optionally
substituted 7-azaindolyl, optionally substituted 1H-pyrrolo[3,2-b]pyridinyl, optionally
substituted benzofuranyl, optionally substituted azaindolyl, optionally substituted
benzisoxazolyl, optionally substituted azabenzimidazolyl, optionally substituted
indazolyl, optionally substituted benzo[b]thiophenyl, optionally substituted
10 benzimidazolyl, optionally substituted, benzo[d]oxazolyl, optionally substituted
benzo[d]thiazolyl, optionally substituted 1,4-benzodioxanyl, optionally substituted
1,2,3,4-tetrahydroquinolinyl, optionally substituted quinazolinyl, optionally substituted
quinolinyl, optionally substituted isoquinolinyl, optionally substituted 1,2,3,4-
tetrahydroisoquinolinyl, optionally substituted 3,4-dihydro-2H -1,4-benzoxazyl or
15 optionally substituted 7,8-dihydropyrido[4,3-d]pyrimidinyl. The optionally substituted
3 to 8 membered heterocycle may be optionally substituted tetrahydrofuranyl,
optionally substituted tetrahydrothiophenyl, optionally substituted pyrrolidinyl,
optionally substituted piperidinyl, optionally substituted piperazinyl, optionally
substituted tetrahydropyranyl, optionally substituted thianyl, optionally substituted
20 morpholinyl, optionally substituted thiomorpholinyl, optionally substituted 1,2-
oxazinyl, optionally substituted 1,3-oxazinyl, optionally substituted 1,4-oxazinyl,
optionally substituted azepanyl, optionally substituted 1,2-diazepinyl, optionally
substituted 1,3-diazepinyl, optionally substituted 1,4-diazepinyl or optionally
substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine. The heteroaryl, cycloalkyl or
25 heterocycle may be unsubstituted or substituted with one or more substituents selected
from the group consisting of optionally substituted C1-C6 alkyl, halogen, OH, oxo,
OP(O)(OR20)(0R21), optionally substituted C1-C6 alkoxy, NR20R2\ CONR20R2\ CN,
C(O)R20, COOR20, N02, azido, S02R20, C(O)R20 and NR2°COR21. When the heteroaryl,
cycloalkyl or heterocycle is substituted with an optionally substituted alkyl, the alkyl
30 may be unsubstituted or substituted with one or more substituents selected from the
group consisting of halogen, OH, C1-C6 alkoxy, NR20R2\ C(O)R20, CN, oxo,
OP(O)(OR20)(0R21), OC(O)R20, COOR20, CONR20R2\ C1-C6 alkenyl, C1-C6 alkynyl,
=NOR20, NR2°C(O)R2\ S02R20 and S02NR20R21. Halogen may be For Cl. Preferably,
halogen is F. R20 and R21 may independently be H or methyl. Accordingly, the
35 heteroaryl, cycloalkyl or heterocycle may be substituted with one or more substituents
27
selected from the group consisting ofF, oxo, CN, NH2, C(O)CH3, CONH2, CH3 and
CH2COOH. For instance, the optionally substituted 5 to 10 membered heteroaryl may
be optionally substituted with a methyl group, and optionally one or more further
substituents. Accordingly, the optionally substituted 5 to 10 membered heteroaryl may
5 be an optionally substituted 1-methylindolyl, an optionally substituted 2-methyl-lHindolyl,
an optionally substituted 5-methyl-1H-indolyl, optionally substituted Nmethylimidazolyl,
optionally substituted N-methylpyrazolyl or optionally substituted
N-methylbenzimidazolyl.
10
15
~ Accordingly, R1s may be phenyl, F,
~~ ~
~CI ~CN
'
~NH, ~NH, f_y;O';, j~ ~ ~ lJ 0 u \L_N~ N ~~
' ' ' ' ' '
In some embodiments, R1s is 1H-indolyl or a phenyl substituted with NR20R21.
Preferably, R1s is 1H -indolyl or a phenyl substituted with NH2.
10
28
R4 may be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally
substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. R4 may be H, halogen,
OH, CN, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Preferably, R4 is H.
Preferably, Ls is an optionally substituted C1-C3 alkylene, an optionally substituted C2-
C3 alkenylene or an optionally substituted C2-C3 alkynylene. The alkylene, alkenylene
or alkynylene may be unsubstituted or substituted with one or more of halogen, OH,
CN, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20,
S02R20, OS02R20, S02NR20R21 and oxo. R20 and R21 may be independently be H,
optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally
substituted C2-C3 alkynyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or
optionally substituted mono or bicyclic 3 to 8 membered heterocycle. Preferably, R 20
15 and R21 are independently H, methyl or cyclopropyl. Preferably, Ls is CH2, CH2CH2,
Alternatively, Ls may be absent.
20 In some embodiments, L6 is absent.
25
Alternatively, L6 may be 0, S, S=O, S02 or NR19. R19 may be H, an optionally
substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl or an optionally
substituted C2-C3 alkynyl. Preferably, L6 is 0 or S, and most preferably is 0.
R16 may be optionally substituted mono or bicyclic C3-C6 cycloalkyl, mono or bicyclic
optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to 10
membered heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered
heterocycle. Preferably, R16 is a mono or bicyclic optionally substituted C6-C12 aryl, a
30 mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or optionally
substituted mono or bicyclic 3 to 8 membered heterocycle. Mono or bicyclic optionally
substituted C6-C12 aryl may be optionally substituted phenyl. Optionally substituted
mono or bicyclic C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or
29
cyclohexyl. Mono or bicyclic optionally substituted 5 to 10 membered heteroaryl may
be optionally substituted oxazolyl, optionally substituted thiazolyl, optionally
substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted
imidazolyl, optionally substituted pyrazolyl, optionally substituted 1,2,3-oxadiazolyl,
5 optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,2,5-oxadiazolyl,
optionally substituted 1,3,4-oxadiazolyl, optionally substituted pyridinyl, optionally
substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted
pyrazinyl, optionally substituted 1H -indolyl, optionally substituted azaindolyl,
optionally substituted benzisoxazolyl, optionally substituted 4-azabenzimidazolyl,
10 optionally substituted 5-benzimidazolyl, optionally substituted indazolyl, optionally
substituted benzimidazolyl, optionally substituted benzofuranyl, optionally substituted
benzo[b]thiophenyl, optionally substituted benzo[d]isoxazolyl, optionally substituted
benzo[d]isothiazolyl, optionally substituted imidazo[1,2-a]pyridinyl, optionally
substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted
15 isoquinolinyl, optionally substituted benzothiazole, optionally substituted 1,3-
benzodioxolyl, optionally substituted benzofuranyl, optionally substituted 2,1,3-
benzothiadiazolyl, optionally substituted 3,4-dihydro-2H,1,4-benzoxazinyl, or
optionally substituted benzo-1,4-dioxanyl. Mono or bicyclic 3 to 8 membered
heterocycle may be an optionally substituted pyrrolidinyl, optionally substituted
20 tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted
piperidinyl, an optionally substituted piperazinyl, an optionally substituted
tetrahydropyranyl, an optionally substituted dioxanyl, an optionally substituted thianyl,
an optionally substituted dithianyl or an optionally substituted morpholinyl.
25 When R16 is an aryl, the aryl may be unsubstituted or substituted with one or more
substituents selected from the group consisting of optionally substituted C1-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R20,
CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20, SR20, S02R20, OS02R20, S02NR20R230 OP(O)(OR20)(0R21), optionally substituted C6-C12 aryl, optionally substituted 5 to 10
membered heteroaryl, optionally substituted C3-C6 cycloalkyl and optionally substituted
3 to 8 membered heterocycle. Halogen may be For Cl. When R16 is a cycloalkyl,
heteroaryl or heterocycle, the cycloalkyl, heteroaryl or heterocycle may be
unsubstituted or substituted with one or more substituents selected from the group
35 consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
30
optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH,
CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR20R2\ NR20R2\ NR2°C(O)R2\ =NOR20,
SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally substituted C6-C12
aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6
5 cycloalkyl and optionally substituted 3 to 8 membered heterocycle. Halogen may be F
or Cl. When the cycloalkyl, aryl, heteroaryl or heterocycle is substituted, directly or
indirectly, with an optionally substituted alkyl, alkenyl, alkynyl or alkoxy, the alkyl,
alkenyl, alkynyl or alkoxy may be unsubstituted or substituted with one or more
substituents selected from the group consisting of halogen, OH, C1-C6 alkoxy, NR20R210 CONR20R2\ C(O)R20, CN, oxo, OP(O)(OR20)(0R21), OC(O)R20, COOR20, C1-C6 alkenyl,
C1-C6 alkynyl, =NOR20, NR2°C(O)R2\ S02R20 and S02NR20R21. Preferably, when the
cycloalkyl, aryl, heteroaryl or heterocycle is substituted, directly or indirectly, with an
optionally substituted alkyl, alkenyl, alkynyl or alkoxy, the alkyl, alkenyl, alkynyl or
alkoxy is unsubstituted or substituted with one or more of halogen and OH. When the
15 cycloalkyl, aryl, heteroaryl or heterocycle is substituted with an optionally substituted
aryl or optionally substituted heteroaryl it may be substituted with an optionally
substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl. R20 and
R21 may independently be H, optionally substituted C1-C3 alkyl, optionally substituted
C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Preferably, R20 and R21 are
20 independently H and optionally substituted methyl, and more preferably are H, CH3 or
CF3• Accordingly, the cycloalkyl, aryl, heteroaryl or heterocycle may be unsubstituted
or substituted with one or more ofF, Cl, oxo, OH, CN, NH2, methyl, t-butyl, CF3,
CH20H, OCH3, OCHF2, OCF3, SCF3, COCH3, COOH, COOCH3, CONH2, S02CH3, 1,2,4-
triazolyl and phenyl. For instance, the optionally substituted 5 to 10 membered
25 heteroaryl may be optionally substituted with a methyl group, and optionally one or
more further substituents. Accordingly, the optionally substituted 5 to 10 membered
heteroaryl may be optionally substituted 1-methylindolyl, optionally substituted Nmethylimidazolyl,
optionally substituted N-methylpyrazolyl or optionally substituted
N-methylbenzimidazolyl. The aryl, heteroaryl or heterocycle is preferably
30 unsubstituted or substituted with 1 or 2 substituents.

Claims
1. A compound of formula (I):
, wherein X2 is CR2 or N;
X3 is CR3 orN;
X6 is C=O, or CR7Rs;
(I)
10 the or each Z is independently CR9R10 or NR9;
X7 isS, SO, S02, 0, NR11 or CR11R12;
n is o, 1 or 2;
wherein, when n is 1 and Z is CR9R10; then X7 is S, SO, S02, 0 or NR11
; and
when n is 1 and Z is NR9 then X7 is CR11R12;
15 R\ R4, and R8 are each independently selected from the group consisting of H, halogen,
OH, CN, COOR13, CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl,
optionally substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6
cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,
optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group,
20 mono or bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally
substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8
membered heterocycle, optionally substituted aryloxy, optionally substituted
heteroaryloxy and optionally substituted heterocyclyloxy;
R9, R10, R11 andR12 are each independently selected from the group consisting ofH,
25 halogen, OH, CN, COOR13, CONR13R14, NR13R14, NR13COR14, optionally substituted ClC6
alkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl;
one of R2 and R3 is -U-U-L3-L4-R1s and, when X2 is CR2 and X3 is CR3, the other of R2
and R3 is selected from the group consisting ofH, halogen, OH, CN, COOR13,
CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl, optionally
30 substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, mono or
AMENDED SHEET (ARTICLE 19)
2
bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to
10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered
heterocycle, optionally substituted aryloxy and optionally substituted heteroaryloxy,
optionally substituted heterocyclyloxy;
5 Rs and R7 are selected from the group consisting of H, halogen, OH, CN, COOR13,
CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl, optionally
substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, mono or
10 bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to
10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered
heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocyclyloxy and Ls-L6-R16; wherein a maximum of one of Rs
and R7 is -Ls-L6-R16;
15 R13 and R14 are each independently selected from the group consisting of H, halogen,
OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl, optionally
substituted C1-C6 alkylsulfonyl, optionally substituted mono or bicyclic C3-C6 cycloalkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally
substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, mono or
20 bicyclic optionally substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to
10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered
heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and
optionally substituted heterocyclyloxy;
a) U is NR17 or 0, U is C=O, C=8, C=NR19 or 802, and L3 is absent, NR18 or 0;
25 b) U is absent, U is C=O, C=8, C=NR19 or 802, and L3 is NR18 or 0 and when U is C=O,
L3 is not NR1s;
c) U is absent or is a C1-C3 alkylene; U is absent; and L3 is 0; or
d) U is a C5-C6 cycloalkylene, a C6 arylene, a 5 membered heteroarylene or a 5 to 6
membered heterocyclylene; U is absent and L3 is absent;
30 L4 is absent or is an optionally substituted C1-C6 alkylene, an optionally substituted C2-
C6 alkenylene, an optionally substituted C2-C6 alkynylene, an optionally substituted C3-
C6 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally substituted 5 to
10 membered heteroarylene or an optionally substituted 3 to 8 membered
heterocyclylene;
35 L5 is absent or an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6
alkenylene, an optionally substituted C2-C6 alkynylene, 0, 8, 8=0, 802 or NR19;
AMENDED SHEET (ARTICLE 19)
3
L6 is absent or an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6
alkenylene, an optionally substituted C2-C6 alkynylene, 0, S, S=O, S02 or NR19;
R1s is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,
optionally substituted C2-C6 alkynyl, optionally substituted mono or bicyclic C3-C6
5 cycloalkyl, mono or bicyclic optionally substituted C6-C12 aryl, mono or bicyclic
optionally substituted 5 to 10 membered heteroaryl or optionally substituted mono or
bicyclic 3 to 8 membered heterocycle, wherein when R1s is an optionally substituted
aryl the aryl is unsubstituted or substituted with one or more substituents selected from
the group consisting of optionally substituted C1-C6 alkyl, halogen, OH, oxo,
10 OP(O)(OR20)(0R21), optionally substituted C1-C6 alkoxy, NR20R2\ CONR20R2\ CN,
C(O)R20, COOR20, N02, azido, S02R20, C(O)R20 and NR2°COR21 and when R1s is an
optionally substituted heteroaryl, an optionally cycloalkyl or an optionally substituted
heterocycle the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with
one or more substituents selected from the group consisting of optionally substituted
15 C1-C6 alkyl, halogen, OH, oxo, OP(O)(OR20)(0R21), optionally substituted C1-C6 alkoxy,
NR20R2\ CONR20R2\ CN, C(O)R20, COOR20, N02, azido, S02R20, C(O)R20 and
NR2oCOR21;
R16 is H, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl,
optionally substituted mono or bicyclic C3-C6 cycloalkyl, mono or bicyclic optionally
20 substituted C6-C12 aryl, mono or bicyclic optionally substituted 5 to 10 membered
heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and
R17 to R19 are independently H, an optionally substituted C1-C6 alkyl, an optionally
substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl or CN;
or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or
25 polymorphic form thereof.
2. The compound of claim 1, wherein X2 is CR2 and X3 is CR3.
3. The compound of either claim 1 or claim 2, wherein R1 and R4 are independently
30 H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6
alkenyl or optionally substituted C2-C6 alkynyl.
4. The compound of any preceding claim, wherein X2 is CR2 and X3 is CR3, and one
ofR2 and R3 is -U-U-L3-L4-R1s and the other ofR2 and R3 isH, halogen, OH, CN,
35 optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally
substituted C2-C6 alkynyl.
AMENDED SHEET (ARTICLE 19)
5
4
5. The compound of any preceding claim, wherein;
U is NR17, U is C=O, C=8, C=NR19 or 802 and L3 is absent or is NR1s; or
U is absent, U is C=8, C=NR19 or 802 and L3 is NR1s.
6. The compound of any one of claims 1 to 4, wherein U is absent or a C1-C3
alkylene, U is absent and L3 is 0.
10 7· The compound of any one of claims 1 to 4, wherein U is an optionally
substituted C5-C6 cycloalkylene, an optionally substituted C6 arylene, an optionally
substituted 5 membered heteroarylene or an optionally substituted 5 or 6 membered
heterocyclylene, U is absent and L3 is absent.
15
N H N-N
'J }I\\ N-N '-, }I ~~ 0\>r'-N/-/* ~ ~~ 'L"N f'* '; j~-~~
-CH 0-* H N f' * H -~N f' * or
2 ' ' ' '
1-~-N N-~-·
\__/ where an asterisk indicates the point of bonding to L4 or, when L4 is
absent, R1s.
20 g. The compound of any preceding claim, wherein L4 is absent, an optionally
substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene or an optionally
substituted C2-C6 alkynylene.
10. The compound of any one of claims 1 to 9, wherein L4 is an optionally
25 substituted C3-C6 cycloalkylene, an optionally substituted C6-C12 arylene, an optionally
substituted 5 to 10 membered heteroarylene or an optionally substituted 3 to 8
membered heterocyclylene.
AMENDED SHEET (ARTICLE 19)
5
11. The compound of any preceding claim, wherein -V-U-L3-L4- is -OCH2CH2-*,
R17 R1a
I I
\"N'-t(N'/*
~ ~ j~~ N-~ ~ }~-~~ 0\~ ''"L"N/-/* '; j I ~ c-' ''"L"N '; j ~ -~ ~
~ N H ''"'t'N ) * H '~N .\ * or
' ' '
1-~-N N-~-·
5 \__/ , where an asterisk indicates the point of bonding to R1s.
10
12. The compound of any preceding claim, wherein R17 and R1s are independently
H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally
substituted C2-C6 alkynyl and R19 is H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl.
13. The compound of any preceding claim, wherein R1s is a mono or bicyclic C6-C12
aryl and the aryl is unsubstituted or substituted with one or more substituents selected
from the group consisting of optionally substituted C1-C6 alkyl, halogen, OH, oxo,
OP(O)(OR20)(0R21), optionally substituted C1-C6 alkoxy, NR20R2\ CONR20R2\ CN,
15 C(O)R20, COOR20, N02, azido, S02R20, C(O)R20 and NR2°COR21.
14. The compound of any one of claims 1 to 12, wherein R1s is a mono or bicyclic
optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6
cycloalkyl or an optionally substituted 3 to 8 membered heterocycle, and the heteroaryl,
20 cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents
selected from the group consisting of optionally substituted C1-C6 alkyl, halogen, OH,
oxo, OP(O)(OR20)(0R21), optionally substituted C1-C6 alkoxy, NR20R2\ CONR20R2\ CN,
C(O)R20, COOR20, N02, azido, S02R20, C(O)R20 and NR2°COR21.
25 15- The compound of any preceding claim, wherein R1s is
AMENDED SHEET (ARTICLE 19)
6
~ /0 ~ ~NH2 ~NH2
phenyl, F, Cl, CN, u , 0 ,
~
. H . H H H
-...;:: N -...;:: N J- N N /--?" N ~N ~~) '()) '():)
' ' ' ' '
5
16. The compound of any preceding claim, wherein Rs is -Ls-L6-R16.
10 17. The compound of claim 16, wherein Ls is absent, an optionally substituted C1-C3
alkylene, an optionally substituted C2-C3 alkenylene or an optionally substituted C2-C3
alkynylene.
18.
H2Ny~
The compound of claim 17, wherein Ls is CH2, CH2CH2, CO, '0 ,
15
AMENDED SHEET (ARTICLE 19)
7
19. The compound of any one of claims 16 to 18, wherein L6 is absent, 0, S, S=O,
S02 orNR19.
20. The compound of any one of claims 16 to 19, wherein R16 is optionally
5 substituted mono or bicyclic C3-C6 cycloalkyl, mono or bicyclic optionally substituted
C6-C12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or
optionally substituted mono or bicyclic 3 to 8 membered heterocycle.
21. The compound of claim 20, wherein the cycloalkyl, aryl, heteroaryl or
10 heterocycle is unsubstituted or substituted with one or more substituents selected from
the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6
alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy,
halogen, OH, CN, oxo, C(O)R20, COOR20, OC(O)R20, CONR2oR2\ NR2oR2\ NR2oC(O)R2=NOR20, SR20, S02R20, OS02R20, S02NR20R2\ OP(O)(OR20)(0R21), optionally
15 substituted C6-C12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally
substituted C3-C6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle.
22. The compound of claim 20 or 21, wherein R16 is cyclopropyl, cyclopentyl,
ClyyF
\N
;l ('YF
\)lAc1 \~c1
' '
CF3X) ~OH ~
\1#\N \~oH
' ' ' 20
):: ;c: ('YF ~OH ~
\)lAF \jlAc1 \~ \A) \~oH
' ' ' ' '
JX~ O CF3 \F ;"y"'-OI H \F "";'-y F;yO..I. ...._ F~I I OH \ ""'- \ ""'- ()"
\ Cl F Cl F Cl
' ' ' ' '
AMENDED SHEET (ARTICLE 19)
5
8
0 0.::::. /;
ITYSCF3 0 ~CN FyyCN ;SyYCI
\~ \~eN \~) \N \~
' ' ' ' '
1 o\ o]
yAJ \~0 or .
10 23. The compound of any one of claims 1 to 15, wherein Rs is H, optionally
substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted
C2-C6 alkynyl.
AMENDED SHEET (ARTICLE 19)
5
9
24. The compound of any preceding claim, wherein R7 and R8 are independently H,
halogen, OH, CN, COOR13, CONR13R14, NR13R14, NR13CQR14, optionally substituted C1-
C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl.
25. The compound of any preceding claim, wherein n is 1.
26. The compound of claim 25, wherein Z is CR9R10 and X7 isS, SO, S02, 0 or NR11
•
10 27. The compound of claim 26, wherein R9 and R10 are H, halogen, OH, CN,
COOR13, CONR13R14, NR13R14, NR13CQR14, optionally substituted C1-C6 alkyl, optionally
substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl and R13 and R14 are H,
optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally
substituted C2-C3 alkynyl.
15
28. The compound of either claims 26 or claim 27, wherein X7 is S or 0.
29. The compound of claim 25, wherein Z is NR9 and X7 is CR11R12.
20 30. The compound of claim 29, wherein R9 isH, optionally substituted C1-C6 alkyl,
optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl and R11 and
R12 are independently H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally
substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl.
25 31. The compound of any one of claims 1 to 24, wherein n is o.
32. The compound of any preceding claim, wherein the compound is a compound of
formula (II) or (III):
(II) (III)
30 33· The compound of any preceding claim 32, wherein the compound is a
compound of formula (IIa), (lib), (Ilia) or (IIIb):
AMENDED SHEET (ARTICLE 19)
10
(II a) (Ilia)
(IIIb)
34. The compound of claim 1, wherein the compound is:
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-phenyl urea;
5 1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(4-fluorophenyl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(pyridin-3-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(pyridin-4-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-s-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(4-cyanobenzyl)urea;
1 o 1-( 4-Fl uorop henyl )-3 -(3-oxo-4 -(pyridin -3-ylmethyl )-3,4 -dihydro-2Hbenzo[
b] [1,4 ]thiazin-6-yl)urea;
1-( 4-Fl uorop henyl )-3 -(3-oxo-4 -(pyridin -4-ylmethyl )-3,4 -dihydro-2Hbenzo[
b] [1,4 ]thiazin-6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-3-yl)urea;
15 1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-7-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-7-yl)-3-(1H -indol-6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(2,3-
dihydrobenzo[b] [1,4 ]dioxin-6-yl)urea;
1-(4-(Benzo[d]isoxazol-3-ylmethyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-
20 3-(1H-indol-6-yl)urea;
1-(3-Aminophenyl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea;
1-( 4-Fl uorop henyl )-3 -( 4 -(imidazo [ 1,2-a]pyridin -2-ylmethyl )-3-oxo-3,4 -dihydro-2Hbenzo[
b] [1,4 ]thiazin-6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1-methyl-1H-indol-6-
25 yl)urea;
AMENDED SHEET (ARTICLE 19)
11
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indazol-6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(2-oxo-1,2,3,4-
tetrahydroquinolin-7-yl)urea;
1-(1H-Benzo[d]imidazol-6-yl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-
5 6-yl)urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-6-yl)-1-
methylurea;
1-(4-Benzyl-2-methyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-phenylurea;
4 -(3 -( 4-Benzyl-3-oxo-3 ,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )ureido) benzamide;
10 (S)-1-(1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-
fluorophenyl)urea;
1-( 1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin -7-yl )-3 -( 4-fl uorophenyl )urea;
1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-?-yl)-3-(1H-indol-6-yl)urea
ex40;
15 4-(2-Chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazin-3(4H)-
one;
4-(2-Chloro-6-fluorobenzyl)-6-(((4-fluorobenzyl)oxy)methyl)-2H-benzo[b][1,4]thiazin-
3(4H)-one;
4-(2-Chloro-6-fluorobenzyl)-6-(s-phenyl-1H-imidazol-2-yl)-2H-benzo[b][1,4]thiazin-
2o 3(4H)-one;
4-(2-Chloro-6-fluorobenzyl)-6-(s-phenyl-1H-1,2,4-triazol-3-yl)-2Hbenzo[
b][1,4]thiazin-3(4H)-one;
6-(5-Benzyl-4H -1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl)-2Hbenzo[
b][1,4]thiazin-3(4H)-one;
25 4-(2-Chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-
one;
N-(4-Benzyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indol-6-
yl)acetamide;
N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(furan-2-
30 yl)acetamide;
4-Benzoyl-N -(fur an -2-ylmethyl )-3 ,4 -dihydro-2H-benzo[b] [ 1,4 ]thiazine-6-sulfonamide;
1-( 4-Benzyl-3,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-3 -( 1H-indol-6-yl )urea;
1-(4-Benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
1-( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo[b] [ 1,4 ]thiazin -6-yl )-3-(3 ,4 -dihydro-2H-
35 benzo[b][1,4]oxazin-6-yl)urea;
1-(4-benzyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(4-fluorophenyl)urea;
AMENDED SHEET (ARTICLE 19)
12
1-( 4 -(3 -amino benzyl )-3 -oxo-3 ,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-3 -( 1H-indol-6-
yl)urea;
3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b] [1,4 ]thiazin -6-yl)-1-(1H -indol-6-yl)-1-
methylurea;
5 1-( 1H-indol-6-yl )-3-( 4 -( (2-methyl pyridin -4-yl )methyl )-3-oxo-3,4 -dihydro-2Hbenzo[
b] [1,4 ]thiazin-6-yl)urea;
1-(1H-indol-6-yl)-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea;
1-(1H -indol-6-yl)-3-(3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)urea;
1-(4-(2-chloro-6-fluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-
10 (1H-indol-6-yl)urea;
1-(4-benzyl-2,2-dimethyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo[b] [ 1,4 ]oxazin -7-yl )-3-(5-methyl-1H-indol-6-
yl)urea;
15 1-( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo[b] [ 1,4 ]oxazin -7-yl )-3-( 2-methyl-1H-indol-6-
yl)urea;
1-(4-(2-chloro-6-fluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(4-(2-chloro-4-fluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-
20 indol-6-yl)urea;
1-(4-(2,3-difluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(4-(2,6-difluorobenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
25 1-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-oxo-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
3 -( (7-(3 -( 1H-indol-6-yl )ureido )-3 -oxo-2,3-dihydro-4H-benzo [b] [ 1,4 ]oxazin -4-
yl)methyl)benzamide;
1-(4-(3-chloro-s-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4 ]oxazin-
30 7-yl)-3-(1H-indol-6-yl)urea;
1-(4-(2-(2-chlorophenoxy)ethyl)-3-0x0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
1-(4-([1,1' -biphenyl]-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4 ]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
35 1-(4-(3-chloro-s-fluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
AMENDED SHEET (ARTICLE 19)
13
1-(4-( ( 6-chlorobenzo[ d] [1,3]dioxol-s-yl)methyl)-3-oxo-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
1-(1H-indol-6-yl)-3-(3-0X0-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydro-
2H-benzo[b][1,4]oxazin-7-yl)urea;
5 1-(4-(3,s-difluorobenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(1H-indol-6-yl)-3-(3-0X0-4-(4-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-( 4 -(3 -chloro-4 -(trifl uoromethoxy) benzyl )-3-oxo-3,4 -dihydro-2H-
10 benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
1-(4-(4-fluoro-3-methylbenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
1-(4-( 4-( difluoromethoxy)benzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
15 1-(4-(2-chlorophenethyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -7-yl)-3-(1Hindol-
6-yl)urea;
1-(4-(3-chloro-4-fluorobenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(4-(3-fluoro-s-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-
20 7-yl)-3-(1H-indol-6-yl)urea;
1-(1H -indol-6-yl)-3-(3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-(4-(benzo[ d] [1,3]dioxol-s-ylmethyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -7-
yl)-3-(1H-indol-6-yl)urea;
25 1-(4-(2,5-dimethoxybenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(4-(3-cyanobenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-
yl)urea;
1-(4-(benzo[ d]thiazol-2-ylmethyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-
30 (1H-indol-6-yl)urea;
6-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-
yl)methyl)nicotinic acid;
1-(4-(benzo[ c] [1,2,5]thiadiazol-s-ylmethyl)-3-oxo-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
35 1-(4-(4-cyano-2-fluorobenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
AMENDED SHEET (ARTICLE 19)
14
1-(1H-indol-6-yl)-3-(3-oxo-4-((3-phenyl-1,2,4-oxadiazol-s-yl)methyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-(4-( 4-chloro-2-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4 ]oxazin-
7-yl)-3-(1H-indol-6-yl)urea;
5 1-(4-( 4-cyanobenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -7-yl)-3-(1H -indol-6-
yl)urea;
1-( 4 -(2-chloro-6-fl uoro-3-methoxybenzyl )-3 -oxo-3,4 -dihydro-2H-benzo[b] [ 1,4 ]thiazin-
7-yl)-3-(1H-indol-6-yl)urea;
1-(4-(2-chloro-6-fluoro-3-hydroxybenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazinw
7-yl)-3-(1H-indol-6-yl)urea;
1-( 4 -(2,6-difl uoro-4-methoxybenzyl )-3-oxo-3 ,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -7-yl )-
3-(1H-indol-6-yl)urea;
1-(4-(2,6-difluoro-4-hydroxybenzyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-
3-(1H-indol-6-yl)urea;
15 1-(4-( 4-(1H -1,2,4-triazol-1-yl)benzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-
3-(1H-indol-6-yl)urea;
1-(4-(benzo[ c] [1,2,S]oxadiazol-s-ylmethyl)-3-0X0-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-
7-yl)-3-(1H-indol-6-yl)urea;
1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(furan-2-
20 ylmethyl)urea;
1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(3-(4-chlorophenyl)-
1H-pyrazol-4-yl)urea;
1-( (1H-pyrrol-3-yl)methyl)-3-( 4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-
yl)urea;
25 1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(5,6,7,8-
tetrahydronaphthalen-2-yl)urea;
1-(4-((s-(tert-butyl)-1,2,4-oxadiazol-3-yl)methyl)-3-oxo-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1,2,3,4-
30 tetrahydronaphthalen-2-yl)urea;
1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(2,3-dihydro-1H -inden-
2-yl)urea;
1-(4-benzyl-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-( 4-
phenylcyclohexyl)urea;
35 1-(4-benzyl-3-0x0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1-phenyl-1H-pyrazol-
3-yl)urea;
AMENDED SHEET (ARTICLE 19)
15
1-(4-( 4-hydroxybenzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-
6-yl)urea;
methyl2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-
yl )methyl) benzoate;
5 N -( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazin -7-yl )-3 ,4 -dihydroisoquinoline-
2(1H)-carboxamide;
1-( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo[b] [ 1,4 ]oxazin -7-yl )-3-(indolin -6-yl )urea;
2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-
yl)methyl)benzoic acid;
10 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-
yl)methyl)benzamide;
1-(4-( (1,4-dioxan-2-yl)methyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1Hindol-
6-yl)urea;
1-(1H -indol-6-yl)-3-(3-oxo-4-( (tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-
15 benzo[b][1,4]oxazin-7-yl)urea;
1-( 1H-indol-6-yl )-3-(3-oxo-4 -(pyridin -4-ylmethyl )-3 ,4 -dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-(1H -indol-6-yl)-3-(3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
20 1-(1H -indol-6-yl)-3-(3-oxo-4-(pyridin-2-ylmethyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-( 1H-indol-6-yl )-3-(3-oxo-4 -( (tetrahydrofuran -3-yl )methyl )-3 ,4 -dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-
25 (1H-indol-6-yl)urea;
1-(4-(3-hydroxybenzyl)-3-0x0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-
6-yl)urea;
1-(4-( 4-(hydroxymethyl)benzyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -7-yl)-3-
(1H -indol-6-yl)urea;
30 1-(1H -indol-6-yl)-3-(3-oxo-4-(pyrazin-2-ylmethyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
3 -( (7-(3 -( 1H-indol-6-yl )ureido )-3 -oxo-2,3-dihydro-4H-benzo [b] [ 1,4 ]oxazin -4-
yl)methyl)benzamide;
1-( 4 -(3 -(hydroxymethyl) benzyl )-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazin -7-yl )-3-
35 (1H-indol-6-yl)urea;
AMENDED SHEET (ARTICLE 19)
16
1-(4-( cyanomethyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-
yl)urea;
1-(1H -indol-6-yl)-3-(3-oxo-4-( (2-oxo-1,2-dihydropyridin -3-yl)methyl)-3,4-dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
5 1-(4-(2-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-
6-yl)urea;
1-( 1H-indol-6-yl )-3-(3-oxo-4 -(pyrimidin -4-ylmethyl )-3,4 -dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
1-(4-((1H-pyrazol-s-yl)methyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-
10 (1H-indol-6-yl)urea;
1-(4-( (1H -imidazol-s-yl)methyl)-3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
1-(4-((1,2,4-oxadiazol-s-yl)methyl)-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-
(1H -indol-6-yl)urea;
15 1-( 1H-indol-6-yl )-3-( 4 -(isoxazol-3-ylmethyl )-3 -oxo-3 ,4 -dihydro-2Hbenzo[
b] [1,4 ]oxazin-7-yl)urea;
7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-
carboxamide;
1-( 4-benzyl-6-bromo-3 -oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazin -7-yl )-3-( 1H-indol-6-
20 yl)urea;
1-(4-fluorophenyl)-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea;
2-amino-N -( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-7 ,8-
dihydropyrido[4,3-d]pyrimidine-6(sH)-carboxamide;
1-(1H -indol-6-yl)-3-(3-oxo-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)urea;
25 N -( 4-benzyl-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-1H-indole-6-
carboxamide;
1-(4-Benzyl-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-6-yl)urea;
1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea;
1-(4-benzoyl-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-6-yl)urea;
30 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea;
1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea;
1-(4-( cyclopropylmethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin -6-yl)-3-(1H -indol-6-
yl)urea;
1-(1H -indol-6-yl)-3-( 4-(pyridin-4-ylmethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin -6-
35 yl)urea;
AMENDED SHEET (ARTICLE 19)
17
1-(4-( cyclopentylmethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-6-yl)-3-(1H -indol-6-
yl)urea;
1-(1H -indol-6-yl)-3-( 4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-
6-yl)urea;
5 1-(4-benzyl-1-oxido-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin -6-yl)-3-(1H -indol-6-yl)urea;
1-(1H-indol-6-yl)-3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea;
1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-6-yl)-3-(1H -indol-
6-yl)urea;
1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-
10 6-yl)urea;
1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H -benzo[b] [1,4 ]thiazin-7-yl)-3-(1H -indol-
6-yl)urea;
1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-6-
yl)urea;
15 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-fluorophenyl)urea;
1-(4-(2-fluoro-4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-
3-(1H-indol-6-yl)urea;
4-benzyl-N-( 1H-indol-6-ylsulfamoyl )-2,3 -dihydro-1,4-benzoxazin -6-amine
1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[3,2-b]pyridin-6-
20 yl)urea;
1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)-1-methylurea;
6-(3-( 1H-indol-6-yl )ureido )-4-benzyl-3,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazine-7-
carboxamide;
1-(4-benzyl-7-bromo-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-6-yl)-3-(1H -indol-6-yl)urea;
25 1-(1H-Indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H -benzo[b ][1,4 ]thiazin-6-yl)urea;
1-(1H-Indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)urea;
N-1H-indol-6-yl-N'-(4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-?-yl)sulfuric diamide
1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea;
1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)urea;
30 1-( 1H-indol-6-yl )-3-(3-oxo-4-phenyl-3,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazin -6-yl )urea;
1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea;
1-(1H -indol-6-yl)-3-( 4-( oxazol-2-yl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -7-yl)urea;
1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(1H-indol-6-yl)urea;
1-(1-Benzylindolin-6-yl)-3-(1H -indol-6-yl)urea;
35 2-(6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3-0X0-3,4-dihydro-2H-benzo[b][1,4]thiazin-
2-yl)acetamide;
AMENDED SHEET (ARTICLE 19)
18
1-(3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea;
1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-6-yl)-3-(1Hindol-
6-yl)urea;
1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -6-yl)-3-(1H-
5 indol-6-yl)urea;
1-( 4-Benzyl-3-cyano-3 ,4 -dihydro-2H-benzo [b] [ 1,4 ]oxazin -6-yl )-3-( 1H-indol-6-yl )urea;
1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-
6-yl)urea;
6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-
10 carboxamide;
1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-?-yl)-3-(1H-indol-6-yl)urea;
1-(3-(aminomethyl)-4-benzyl-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin-7-yl)-3-(1H -indol-
6-yl)urea;
7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-
15 carboxamide;
2-( 6-(3-(1H-Indol-6-yl)ureido )-2,3-dihydro-4H -benzo[b] [1,4 ]oxazin-4-yl)-2-
phenylacetamide;
1-(4-(2-Hydroxy-l-phenylethyl)-3,4-dihydro-2H -benzo[b] [1,4 ]oxazin -6-yl)-3-(1Hindol-
6-yl)urea;
20 Methyl 2-( 6-(3-( 1H-indol-6-yl )ureido )-2,3 -dihydro-4H-benzo [b] [ 1,4 ]oxazin -4-yl )-2-
phenylacetate;
2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-methyl-2-
phenylacetamide;
2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-
25 cyclopropyl-2-phenylacetamide;
6-(4-(1H-Indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one;
1-( 4-Benzyl-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-2-cyano-3-( 1H-indol-6-
yl)guanidine; or
1-( 4-Benzyl-2-( cyanomethyl )-3-oxo-3,4 -dihydro-2H-benzo [b] [ 1,4 ]thiazin -6-yl )-3 -( 1H-
30 indol-6-yl)urea.
35
35. A pharmaceutical composition comprising a compound according to any
preceding claim, or a pharmaceutically acceptable salt, solvate, tautomeric form or
polymorphic form thereof, and a pharmaceutically acceptable vehicle.
AMENDED SHEET (ARTICLE 19)
Dated this 06th day of September 2022
Archana Shanker
Of Anand and Anand, Advocates
Agents for the Applicants
19
36. A compound, as defined in any one of claims 1 to 34, or a pharmaceutically
acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, of a
pharmaceutical composition, as defined by claim 35, for use as a medicament.
5 37· A compound, as defined in any one of claims 1 to 34, or a pharmaceutically
acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, of a
pharmaceutical composition, as defined by claim 35, for use in modulating the
STimulator of INterferon Genes (STING) protein.
10 38. A compound, as defined in any one of claims 1 to 34, or a pharmaceutically
acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, of a
pharmaceutical composition, as defined by claim 35, for use in treating, ameliorating or
preventing a disease selected from liver fibrosis, fatty liver disease, non-alcoholic
steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA),
15 type I diabetes, STING-associated vasculopathy with onset in infancy (SAVI), AicardiGoutieres
syndrome (AGS), familial chilblain lupus (FCL), systemic lupus
erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory
response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and agerelated
macular degeneration (AMD ).
20
39. The compound or composition for use according to claim 38, wherein the
disease is fibrosis, and the fibrosis is selected from the group consisting of liver fibrosis,
pulmonary fibrosis or renal fibrosis.
25 40. The compound or composition for use according to claim 38, wherein the
disease is fatty liver disease, and the fatty liver disease is non-alcoholic (or simple) fatty
liver or non-alcoholic steatohepatitis (NASH).