GB2563642A - Small molecule modulators of human STING - Google Patents

Small molecule modulators of human STING Download PDF

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Publication number
GB2563642A
GB2563642A GB1709959.9A GB201709959A GB2563642A GB 2563642 A GB2563642 A GB 2563642A GB 201709959 A GB201709959 A GB 201709959A GB 2563642 A GB2563642 A GB 2563642A
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Prior art keywords
carboxamide
optionally substituted
oxo
dihydro
thiazine
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GB1709959.9A
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GB201709959D0 (en
Inventor
Banerjee Monali
Middya Sandip
Basu Sourav
Ghosh Rajib
Cameron Pryde David
Yadav Dharmendra
Shrivastava Ritesh
Surya Arjun
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Curadev Pharma Ltd
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Curadev Pharma Ltd
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Priority to GB1709959.9A priority Critical patent/GB2563642A/en
Publication of GB201709959D0 publication Critical patent/GB201709959D0/en
Priority to EP18737372.5A priority patent/EP3642198B1/en
Priority to MX2019015468A priority patent/MX2019015468A/en
Priority to CA3067257A priority patent/CA3067257A1/en
Priority to TW107121352A priority patent/TWI799426B/en
Priority to JP2020520838A priority patent/JP2020524717A/en
Priority to UAA202000289A priority patent/UA125730C2/en
Priority to SG11201912397RA priority patent/SG11201912397RA/en
Priority to KR1020207001712A priority patent/KR102628892B1/en
Priority to US16/625,032 priority patent/US20200138827A1/en
Priority to PCT/GB2018/051727 priority patent/WO2018234805A1/en
Priority to JP2020520840A priority patent/JP7296954B2/en
Priority to CN201880054141.8A priority patent/CN111132972A/en
Priority to PE2019002587A priority patent/PE20200696A1/en
Priority to BR112019027127-9A priority patent/BR112019027127A2/en
Priority to US16/625,047 priority patent/US11571423B2/en
Priority to EP18737370.9A priority patent/EP3642184A1/en
Priority to PCT/GB2018/051730 priority patent/WO2018234808A1/en
Priority to AU2018288018A priority patent/AU2018288018C1/en
Publication of GB2563642A publication Critical patent/GB2563642A/en
Priority to ARP190101730A priority patent/AR114975A1/en
Priority to PH12019502870A priority patent/PH12019502870A1/en
Priority to IL271522A priority patent/IL271522B2/en
Priority to ZA2019/08496A priority patent/ZA201908496B/en
Priority to CL2019003793A priority patent/CL2019003793A1/en
Priority to CONC2020/0000562A priority patent/CO2020000562A2/en
Priority to ECSENADI20204580A priority patent/ECSP20004580A/en
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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Abstract

(I) A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, for use in therapy is provided, wherein X is CR9R10, O, S, S=O or SO2; X1 is CR1 or N; X2 is CR2 or N; X3 is CR3 or N; the or each Z is independently CR11R12 or NR11; n is 1 or 2; Q is C=O, S=O, SO2, C=S or CR4R5; L is optionally substituted C1-C6alkyl, C1-C3polyfluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, C=O, S=O, SO2, -CH2C(O)-, -CH2CONH- or -CONH-; Y is an optionally substituted C1-C6alkyl, C1-C3polyfluoroalkyl, an optionally substituted C2-C6alkenyl, an optionally substituted C2-C6alkynyl, an optionally substituted C3-C6cycloalkyl, an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R6 is mono or bicyclic optionally substituted C5-C10aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R8 is mono or bicyclic optionally substituted C5-C10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C3-C6cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R1, R2, R3, R4, R5, R7, R9, R10, R11 and R12 are each independently substituents as herein defined, with the proviso that the compound of formula (I) is not a compound as herein defined. The compounds of formula (I) are for use in modulating the stimulator of interferon genes (STING) protein, preferably for the treatment of disease such as cancer and microbial infections. Per se compounds of formula (I) as herein defined are also provided.

Description

Small Molecule Modulators of Human STING
The present invention relates to small molecules for use in modulating the Stimulator of Interferon Genes (STING) protein. Accordingly, the small molecules maybe for use in the treatment of diseases, such as cancer and microbial infections, and so on. The invention extends to the compounds per se pharmaceutical compositions, methods of making the compounds and methods of modulating the STING protein.
The human immune system may generally be divided into two arms, referred to as the ‘innate immune system’ and the ‘adaptive immune system’. The innate arm is mainly responsible for an initial inflammatory response via a number of soluble factors such as cytokines, chemokines and complement factors. These factors act upon a number of different cell types including mast cells, macrophages, dendritic cells and natural killer cells. The adaptive arm involves a delayed and longer lasting response to challenge via antibody production together with CD8+ and CD4+ T-cell responses that are critical for immunological memory.
Research has been conducted for many years on how the immune system can recognise and eliminate malignant tumors (Parish et. al., Immunol and Cell Biol, 2003, 81,106-113). One of the pioneers in this area is William Coley, who in the late 1800’s noted that a cancer patient had a complete remission of their cancer after acute infection with the bacteria Streptococcus pyogenes. Subsequent studies with Coley’s toxin and with bacille Calmette-Guerin (BCG) for cancer immunotherapy provided some clinical success but by no means offered a panacea for tumor treatment (Coley, Am J Med Sci., 1893,10s, 487-511). Through the 1900’s, opinions fluctuated on the benefits of immunotherapy, with theories of acquired immunological tolerance (Burnet,, Lancet, 1967,1,1171-1174 and Matzinger, Ann. Rev. Immunol., 1994,12, 991-1045 and Smyth et. al., Nat Immunol., 2.001, 2, 293-299) and tumor-associated antigens (Rosenberg et. al., Immunity, 1999,10, 281-287) gaining support with the emergence of the innate immune system as an important mediator of immunity (Lanier, Nat Med. 2001, z, 1178-1180 and Mayardomo et al., Nat Med. 1995,1,1297-1302 and Medzhitov et al., Trends Microbiol., 2000, 8, 452-456 and Akira et. al., Nat. Immunol., 2001, 2, 675-680). The detection of pathogen-associated molecular patterns (PAMPs) such as nucleic acids is now recognized as a central strategy by which the innate immune system senses microbes and tumor-associated antigens to then initiate protective responses (Barbalat et. al., Annu. Rev. Imunol., 2011, 29.185-214).
Tumor immunosurveillance does occur with, for example, thriving tumors having been immunoselected to evade immune elimination and indeed, the crucial role that the innate immune system plays in tumor clearance puts Coley’s original findings in a new light. It is now clear that fragments of cyclic nucleotides, oligonucleotides and double stranded motifs can all activate the innate immune system through toll-like receptors (Horscroft, J.Antimicrob. Ther., 2.012., 6z(4), 789-801 and Diebold et al., Science, 2004,303.1529-1531), RIG-I like receptors (Pichlmair et. al., Science, 2006,314, 997-1001) and stimulator of IFN genes (STING) adaptor proteins (Burdette et. al., Nat. Immunol., 2013,14(1), 19-26).
This developing knowledge has stimulated considerable research into possible therapeutic applications of immunomodulation via some of these target classes. The TFR family has received much attention over the past decade, but establishing a useful window between sufficient stimulation of a TFR for efficacy without overstimulation and unwanted side effects has proved very challenging, most notably for systemic applications of TFR agonists (Kaczanowska et. al., J. Leukoc. Biol., 2013, 93, 847-863). STING has emerged more recently as a critical signalling molecule in the innate response to cytosolic nucleic acid molecules (Burdette and Vance, Nat. Immunol, 2013, 14,19-26). STING plays a role in the transcriptional induction of type I interferons and coregulated genes in response to nucleic acids in the cytosol. Studies in STING-deficient mice have confirmed the role of STING in innate responses to cytosolic nucleic-acid ligands, particularly double stranded DNA and bacterial nucleic acids based on a cyclic dinucleotide structure (Ishikawa et. al., Nature, 2009, 461, 788-792). STING has a critical role in the innate response to many bacterial, viral and eukaryotic pathogens (Watson et. al., Cell, 2012,150, 803-815; de Almeida et. al., PLoS One, 2011, 6, 623135; Holm et. al, Nat. Immunol, 2012,13, 737-743; Stein et. al., J. Virol., 2012, 86.4527-4537; Sharma et. al., Immunity, 2011,35,194-207). STING is broadly expressed throughout the body, for example in the spleen, heart, thymus, placenta, lung and peripheral leukocytes, indicating a role in the immune system (Sun et. al., PNAS, 2009,106, 8653-8658). It is expressed in several transformed cell lines including HEK293 human embryonic kidney cells, A549 adenocarcinomic human alveolar basal epithelial cells, THP-i monocytic cells and U937 leukemic monocytic lymphoma cells. STING also has a central role in certain autoimmune disorders initiated by inappropriate recognition of self DNA (Gall et. al., Immunity, 2.012., 26.120-131) and has been proposed to sense membrane-fusing events associated with viral entry, in a manner independent of the sensing of nucleic acids (Holm et. al., Nat. Immunol., 2012,13, 737-743)·
Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of cyclic dinucleotides (CDNs). 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), cyclo-di(AMP) and hybrid cyclo-(AMP/GMP) derivatives all bind to STING with subsequent activation of the interferon pathway (Gao et. al., Cell, 2013,153,1094-1107; Zhang et. al., Mol. Cell, 2013,51, 226-235). The canonical s’-3’ phosphodiester linkage is recognised along with various other linkage isomers (notably the 5’-2’ linkage, e.g. c[G(2’,5’)pA(3’,5’)p]) which all bind to STING with various affinities (Shi et. al., PNAS, 2015,112,1947-8952). These observations have been corroborated by structural studies (Gao et. al.,
Cell, 2013,154, 748-762) of various linkage isomers of CDNs bound to the human and mouse STING proteins. STING is comprised of an N-terminal transmembrane domain, a central globular domain and a C-terminal tail. The protein forms a symmetrical dimer in both the apo and the ligand bound states, with the cyclic dinucleotides binding at a dimer interface binding pocket. Binding of CDNs to STING activates a cascade of events whereby the protein recruits and activates IkB kinase (IKK) and TANK-binding kinase (TBKi), which following their phosphorylation activate nuclear transcription factors (NFkB) and interferon regulatory factor 3 (IRF3), respectively. These activated proteins translocate to the nucleus to induce transcription of the genes that encode type I interferon and cytokines for promoting intercellular immune system defense. Human and mouse STING exhibit high sequence identities and overall structural similarity. However, sequence variations are known between human and mouse proteins, and between proteins within the human population. Several naturally occurring variant alleles have been identified.
Derivatives of the CDN class are currently being developed as antitumor agents upon intratumoral injection (Corrales et.al., Cell Rep., 2015,19,1018-1030). The xanthene- based small molecule 5,6-dimethyl-xanthenone acetic acid (DMXAA) was initially identified as a small molecule exhibiting immune modulatory activities through induction of cytokines and disrupting tumor vascularization in mouse xenograft models (Baguley and Ching, Int. J. Radiat. Oncol. Biol. Phys., 2002, 54,1503-1511). This promising efficacy led to its investigation in a Phase II clinical trial against non-small cell lung carcinoma but subsequently failed its endpoints. The mechanism of DMXAA’s activity against murine tumors was eventually ascribed to its activity as a murine STING activator. Its failure in human clinical trials was due to the fact that DMXAA was only capable of activating mouse STING and not human STING (Lara et. al., J.
Clin. Oncol., 2011, 29, 2965-2971; Conlon et. al., J. Immunol., 2013,190, 5216-5225). This lack of human activity has hampered all further attempts to develop this agent as a tumor therapy. Recently, a related small molecule io-carboxymethyl-9-acridanone (CMA) (Caviar et. al., EMBOJ., 2013,32,1440-1450) has been found to bind to mouse STING, but also not to human STING. Both DMXAA and CMA have been shown to bind two molecules of each ligand to the STING dimer at a region close to the dimer interface.
Accordingly, there remains a need in the art for improved therapies for treating diseases, such as cancer, which can be refractory to traditional therapeutic approaches. Immunologic strategies show promise for the treatment of cancer, and there is a need to develop improved compositions and methods in this field. In particular, there is a need for compounds that modulate the human STING protein, as well as methods for treating diseases that can benefit from such modulation.
The present invention has arisen from the inventors work in attempting to identify STING protein modulators.
Hence, in a first aspect of the invention, there is provided a compound of formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR9R10, O, S, S=0 or S02;
X1 is CR1 orN; X2is CR2orN; X3is CR3orN; the or each Z is independently CRUR12 or NR11; n is l or 2; Q is C=O, S=O, S02, C=S or CR4R5; L is optionally substituted C1-C6 alkyl, C1-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C=O, S=O, S02, -CH2C(0)-, -CH2C0NH-, or -CONH-; Y is an optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR’R2, NR’R2, NHCOR1, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, 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 Ci-C6 alkoxycarbonyl group, mono or bicyclic optionally substituted C5-Ci0 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; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted (Co-Ce) cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring; R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NFUR2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R9 and R10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R11 and R12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is - CH2-; Y is -CH2-; R7 is H; and R6 is unsubstituted phenyl
or then R8 is not unsubstituted furanyl; and when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; 1 R7 is H; and R6 is then R8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, for use in therapy.
Preferably, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is an optionally substituted phenyl then R8 is not an
optionally substituted 5 membered heteroaryl. Optionally, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is an optionally substituted phenyl then R8 is not an optionally substituted 5 or 6 membered heteroaryl.
Preferably, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is unsubstituted phenyl, then R8 is not unsubstituted phenyl.
Preferably, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is an optionally substituted phenyl then R8 is not an unsubstituted phenyl.
The inventors have also found that compounds of formula (I) are useful in modulating the Stimulator of Interferon Genes (STING) protein.
Hence, in a second 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 activating, or agonising, the STING protein.
By modulating the STING protein, it is possible to treat, ameliorate or prevent cancer, bacterial infection, viral infection, parasitic infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
Accordingly, 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 treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, immune-mediated
disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
Preferably, the disease is cancer.
In a fourth aspect, there is provided a method of modulating the Stimulator of Interferon Genes (STING) protein in a subject, the method comprising administering, to a subject in need of such treatment, a 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 activating the STING protein.
In a fifth aspect, there is provided a method of treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
Preferably, the disease is cancer.
It maybe appreciated that the term “preventing” can mean “reducing the likelihood of’.
The neurodegenerative disease may be Alzheimer’s disease or dementia. The parasitic infection maybe malaria. The mood disorder maybe depression. The sleep disorder maybe insomnia.
In one preferred embodiment, the disease is cancer. The cancer maybe selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukaemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, pancreatic carcinoma or renal carcinoma.
In an alternative preferred embodiment, the disease is a viral infection. The viral infection may be a hepatitis C virus (HCV) infection.
The inventors believe that a number of the compounds which fall within the scope of formula (I) are novel and inventive per se.
Hence, in a sixth aspect, there is provided a compound of formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR9R°, O, S, S=0 or S02; XUs CR1 orN; X2 is CR2 or N; X3is CR3orN; the or each Z is independently CRUR12 or NR11; n is l or 2; Q is C=0, S=0, S02, C=S or CR4R5; L is optionally substituted C1-C6 alkyl, C1-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C=0, S=0, S02, -CH2C(0)-, -CH2C0NH-, or -C0NH-; Y is an optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR’R2, NR’R2, NHCOR1, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, 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 Ci-C6 alkoxycarbonyl group, mono or bicyclic optionally substituted C5-Ci0 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; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted (C3-C6) cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring; R6 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R9 and R10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R11 and R12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is - ) CH2-; Y is -CH2-; R7 is H; and R6 is then R8 is not unsubstituted furanyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
then R8 is not unsubstituted phenyl, unsubstituted thiophenyl, unsubstituted pyridinyl, unsubstituted furanyl, unsubstituted tetrahydrofuranyl,
when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2CH2-; R7 is H; and R6 is
then R8 is not unsubstituted phenyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is
I R7 is H; and R6 is then R8 is not unsubstituted phenyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is unsubstituted phenyl then R8 is not unsubstituted furanyl, unsubstituted phenyl
when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O or CH2; L is -CH2-; Y is -I CH2-; R7 is H; and R6 is then R8 is not unsubstituted furanyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
hen R8 is not unsubstituted furanyl;
when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=0; L is -CH2-; Y is -CH2-;
I R7 is H; and R6 is then R8 is not unsubstituted furanyl, when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
then R8 is not unsubstituted furanyl or
; and when X is S; X1, X2 andX3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is
R7 is H; and R6 is
then R8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
Preferably, when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is an optionally substituted phenyl then R8 is not an optionally substituted 5 or 6 membered heteroaryl or tetrahydrofuranyl.
Preferably, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; R7 ) is H; and R6 is then R8 is not an unsubstituted phenyl or unsubstituted cyclohexane.
Preferably, when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is -CH2-; Y is an optionally substituted Ci-C2 alkyl; R7 is H; and R6 is an optionally substituted phenyl then R8 is not an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted phenyl or tetrahydrofuranyl.
The following definitions are used in connection with the compounds of the present 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, 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 compositions. “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.
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 methyl, ethyl, n-propyl (l-propyl) and isopropyl (2-propyl, l-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, ferf-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more of halogen, OH, Ci-C5 alkoxy, NFTR2, CONR’R2, CN, COOH, C5-Ci0 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl and 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, C1-C6 alkoxy, NR’R2, CONR’R2, CN, COOH, C5-Ci0 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl and 3 to 8 membered heterocycle.
The term “halo” includes fluoro (-F), chloro (-C1), bromo (-Br) and iodo (-1).
The term “polyfluoroalkyl” may denote a Ci-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. The term may include perfluoroalkyl groups, i.e. a Ci-C3 alkyl group in which all the hydrogen atoms are replaced by fluorine atoms. Accordingly, the term Ci-C3 polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-i- (trifluoromethyl)ethyl. “Alkoxy” refers to the group R13-O- where R13 is an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C6 cycloalkyl group. Exemplary C1-C6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy (l-propoxy), n-butoxy and ferf-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, alkoxy, NR’R2, CONR1 R2, CN, COOH, aryl, heteroaryl, cycloalkyl and heterocycle. “Thioalkyl” refers to the group R1!-S- where R13 is an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C6 cycloalkyl group. A thioalkyl group can be unsubstituted or substituted with one or more of halogen, OH, alkoxy, NR3R2, CONR’R2, CN, COOH, aryl, heteroaryl, cycloalkyl and heterocycle. “Aryl” refers to an aromatic 5 to 10 membered hydrocarbon group. Examples of a C5-C10 aryl group include, but are not limited to, phenyl, a-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl and indanyl. An aryl group can be unsubstituted or substituted with one or more of substituted C1-C6 alkyl, halogen, OH, substituted C1-C6 alkoxy, NR’R2, CONR’R2, CN, COOH, N02, azido, Ci-C3 polyfluoroalkyl, aryloxy, heteroaryloxy, 5 to 10 membered heteroaryl, 3 to 8 membered heterocycle, S02R1 and NHCOR1.
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 the rings to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or 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 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 bound to a cycloalkyl. A spirocyclic group can be unsubstituted or substituted with one or more of substituted C1-C6 alkyl, halogen, OH, substituted C1-C6 alkoxy, NFbR2, CONR’R2, CN, COOH, N02, azido, Ci-Cj polyfluoroalkyl and NHCOR1. “Alkoxycarbonyl” refers to the group alkyl-O-C(O)-, where alkyl is a C1-C6 alkyl. An alkoxycarbonyl group can be unsubstituted or substituted with one or more of halogen, OH, NR’R2, CN, C1-C6 alkoxy, COOH, C5-Ci0 aryl, 5 to 10 membered heteroaryl or C3-C6 cycloalkyl. “Aryloxy” refers to the group Ar-O- where Ar is a mono or bicyclic optionally substituted C5-Ci0 aryl group, as defined above. “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, halogen, CN, hydroxyl, COOH, CONR’R2, NR’R2, NHCOR1, Ci-Ce alkoxy, azido, Ci-Cj polyfluoroalkyl, aryloxy, heteroaryloxy, 5 to 10 membered heteroaryl, S02RS mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, C3-C6 cycloalkyl. “Heteroaryl” refers to a monocyclic or bicyclic aromatic 5 to 10 membered ring system 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. Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-i,2,4-triazole, iH-tetrazole, i-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5 to 10 membered heteroaryl groups include those where a 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 C1-C6 alkyl, halogen, OH, CN, NFCR2, azido, COOH, C1-C6 alkoxycarbonyl, C1-C3 polyfluoroalkyl, CONR’R2, N02, NHCOR1 and S02R1. “Heteroaryl” refers to a monocyclic or bicyclic aromatic 5 to 10 membered ring system 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. Examples of 5 to 10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-i,2,4-triazole, lH-tetrazole, l-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5 to 10 membered heteroaryl groups include those where a 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 C1-C6 alkyl, halogen, OH, CN, NR’R2, azido, COOH, C1-C6 alkoxycarbonyl, Ci-C3 polyfluoroalkyl, CONR’R2, N02, NHCOR1 and S02R1. “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 membered heterocyclyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-i-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, oxazine. A heterocyclyl group can be unsubstituted or substituted with one or more of optionally substituted C1-C6 alkyl, halogen, Ci-Ce alkoxy, OH, NRqR2, COOH, Ci-Ce alkoxycarbonyl, C0NRqR2, N02, NHCOR1, mono or bicyclic optionally substituted C5-Ci0 aryl and S02R1. “Alkenyl” refers to olefinically unsaturated hydrocarbon groups which can be 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 C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, NRlR2, CONR’R2, SO2R1, NHCOR1, CN, COOH, C5-C10 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl, aryloxy, heteroaryloxy, and 3 to 8 membered heterocycle. “Alkynyl” refers to 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, propynyl, butynyl, pentynyl and hexynyl. An alkynyl group can be unsubstituted or substituted with one or more of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, NR‘R2, CONR'R2, SO2R1, NHCOR1, CN, COOH, C5-C10 aryl, 5 to 10 membered heteroaryl, C3-C6 cycloalkyl, aryloxy, heteroaryloxy, and 3 to 8 membered heterocycle. “Alkylsulfonyl” refers to the group alkyl-S02- where alkyl is an optionally substituted C1-C6 alkyl, and is as defined as above. “Heteroaryloxy” refers to the group heteroaryl-O- 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-O- where heterocycle is an 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 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 prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17,1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.
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, but are not limited to: (l) 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, 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-i-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the 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 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-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 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, 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, 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-i-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluceptate, gluconate, glucoronate, hexafluorophosphate, hibenzate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, xinofoate and the like.
Hemisalts of acids and bases may also be formed, for example, hemisulphate salts.
The skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example D-lactate, or racemic, for example DL-tartrate.
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) maybe prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (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.
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.
The term “solvate” maybe 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. D20, d6-acetone and d6-DMS0. 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), 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.
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 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 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’). 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’).
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 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 Na+, -COO K+, or -SO3 Na+) or non-ionic (such as -N N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope bv N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970), incorporated herein by reference.
In one embodiment, n is 1. Accordingly, the compound may have formula (Ia):
In an alternative embodiment, n is 2. Accordingly, the compound may have formula (Ib):
X may be CR9R10 and the or each Z may be CRnR12. Alternatively, X may be CR9R10 and the or each Z may be NR11. X may be S and the or each Z may be CRnR12. X may be O and the or each Z may be CRUR12. X may be S02 and the or each Z may be CRUR12. X may be S=O and the or each Z may be CRUR12.
Hence compounds of the invention may also be represented by the below structures (Ia-I) - (Ia-VI):
It will be appreciated that analogous structures of (Ib) are also within the scope of the present invention and are also incorporated herein. L maybe CH2, C=O or S02. Accordingly, compounds of the invention may also be represented by the below structures (I-I) to (I-ΠΙ);
Q maybe C=O, S02, S=O, CR4R5 or C=S. Accordingly, using (Ia-I) as an exemplar, compounds of the invention may also be represented by the below structures (Ia-I-I) to (Ia-I-V);
It will be appreciated that analogous structures of (Ia-Π) to (Ia-VI) and (Ib) are also within the scope of the present invention and are also incorporated herein.
In one embodiment X1 is CR1, X2 is CR2 and X3 is CR3. R1, R2 and R3 may each independently be selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl. Preferably, R1, R2 and R3 are each independently selected from the group consisting of H, halogen, and C1-C3 alkyl. More preferably, R1, R2 and R3 are each independently selected from the group consisting of H, halogen, and methyl. Most preferably, R1, R2 and R3 are each H.
In an alternative embodiment, one or two of X1, X2 and X3 is N. Accordingly, X1 may be N, X2 may be CR2 and X3 may be CR3, X1 may be CR1, X2 may be N and X3 may be CR3 or X1 may be CR1, X2 may be CR2 and X3 may be N.
Hence the compounds of the invention may also be represented by the below structures (Ia-I-I-I) to (Ia-1-Ι-ΠΙ);
Preferably X2 is CR2. Accordingly, X1 may be CR1 or N and X3 may be CR3 or N. X1 may be N, X2 may be CR2 and X3 may be CR3, or X1 may be CR1, X2 may be CR2 and X3 may
be N, or X1 may be N, X2 may be CR2 and X3 may be N. Preferably, R2 is H, halogen or Ci-C3 alkyl. More preferably, R2 is H, halogen or methyl. Most preferably, R2 is each H.
Preferably, R1 and/or R3, in embodiments where they are present, are independently H, halogen or C1-C3 alkyl. More preferably, R1 and/or R3, in embodiments where they are present, are independently H, halogen or methyl. Most preferably, R1 and/or R3, in embodiments where they are present, are H.
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 mixtures thereof are included within the scope of the present invention.
In a preferred embodiment, X is CR9R10. Accordingly, the compound may be a compound of formula (I)-ent 1 or (I)-ent 2:
In an alternative embodiment, Q is CR4R5. Accordingly, the compound may be a compound of formula (I)-ent 3 or (I)-ent 4:
Similarly, in embodiments where Z is CR”R12 the compound may possess a chiral centre at this location. Accordingly, the compound may be a compound of formula (I)-ent 5 or (I)-ent 6:
In yet another embodiment, where X is CR9R10, Z is CRUR12 and n is l, the compound could possess two chiral centres, and could be compound of formula (iA-I)-ent 1, formula (iA-I)-ent 2, formula (iA-I)-ent 3 or formula (iA-I)-ent 4:
In an embodiment, where Q is CR4R5, X is CR9R10, n is 2 and each Z is CRnR12, the compound could possess four chiral centres, and could be any one of 16 possible enantiomers.
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 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) maybe obtained in 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 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
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).
In a preferred embodiment, X is O, S or CR9R10. More preferably, X is S or CR9R10.
Preferably, at least one of R9 and R10 is an optionally substituted C1-C6 alkyl, halogen, H, a C3-C6 cycloalkyl or C1-C3 polyfluoroalkyl. More preferably, at least one of R9 and R10 is a C1-C6 alkyl, H or a C3-C6 cycloalkyl, even more preferably a Ci-C3 alkyl, H or a C3-C6 cycloalkyl, and most preferably at least one of R9 and R10 is H, methyl, ethyl, isopropyl or cyclopropyl. In one embodiment, both R9 and R10 are an optionally substituted C1-C6 alkyl or H. In one embodiment, both R9 and R10 are a C1-C6 alkyl, more preferably a Ci-C3 alkyl, even more preferably methyl, ethyl or isopropyl, and most both R9 and R10 are methyl. In a most preferred embodiment, both R9 and R10 are H.
Preferably, n is 1.
In some embodiments, Z is NR11. R11 maybe an optionally substituted C1-C6 alkyl, H, a C3-C6 cycloalkyl or Ci-C3 polyfluoroalkyl. More preferably, R9 is a C1-C6 alkyl or a C3-C6 cycloalkyl, even more preferably a Ci-C3 alkyl or a C3-C6 cycloalkyl, and most preferably R9 is methyl, ethyl or cyclopropyl.
In a preferred embodiment, Z is CRUR12.
Preferably, at least one of R11 and R12 is H. In one embodiment, both R11 and R12 is H.
Preferably, at least one of R11 and R12 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, a C3-C6 cycloalkyl or Ci-C3 polyfluoroalkyl. More preferably, at least one of R11 and R12 is a C1-C6 alkyl, a C2-C6 alkenyl, or a C3-C6 cycloalkyl, even more preferably a Ci-C3 alkyl, a C2-C3 alkenyl or a C3-C6 cycloalkyl, and most preferably at least one of R11 and R12 is methyl, ethyl, isopropyl or cyclopropyl.
In one embodiment, one of R11 and R12 is H and the other is an optionally substituted C1-C6 alkyl or an optionally substituted C2-C6 alkenyl. More preferably, one or R11 and R12 is H and the other is a Ci-C3 alkyl or a C2-C3 alkenyl. Even more preferably, one or R11 and R12 is H and the other is methyl, ethyl, propyl or CH=CHCH2-. Most preferably, one or R11 and R12 is H and the other is methyl.
In a preferred embodiment, Q is C=O, S02 or CR4R5. Preferably, Q is C=O or CR4R5. Preferably, R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring. Accordingly, R4 and R5 may both be H. Alternatively, R4 and R5 may both be Me or R4 may be Me and R5 may be H.
Most preferably, Q is C=O. L maybe C=O or S02. However, in a preferred embodiment, L is optionally substituted C1-C6 alkyl, -CH2C(0)- or -CH2C0NH-. Preferably, L is optionally substituted Ci-C3 alkyl, more preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, C(Me)H, CF2 or C(H)F and most preferably -CH2-.
Preferably, R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocyclyl. More preferably, R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl. Most preferably, R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl. R6 may comprise between 1 and 5 substituents. The or each substituent maybe independently selected from the list consisting of halogen, C1-C6 alkyl, CN, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, azido, CONR’R2 and -OH. Preferably, the or each substituent is selected from the list consisting of halogen, C1-C6 alkyl, CN, OMe, OEt, OCF3, CF3, azido, C0NH2 and -OH.
Preferably, R6 is an optionally substituted C5-Ci0 aryl, wherein the C5-Ci0 aryl is a phenyl or a naphthyl. Most preferably, the C5-Ci0 aryl is phenyl. Preferably, C5-Ci0 aryl is substituted with methyl, ethyl, propyl, azido or halogen. More preferably, the C5-Ci0 aryl is substituted with at least one halogen. Accordingly, the C5-Ci0 aryl may be substituted by 1 or 2 halogens. Preferably, the or each halogen is fluorine or chlorine.
In some embodiments, when X1 is CH, X2 is CH and X3 is CH then R6 may not be an unsubstituted phenyl.
Alternatively, R6 may comprise an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted thiazole or an optionally substituted isoxazole. R7 is preferably H or an optionally substituted C1-C6 alkyl, more preferably H or a C1-C3 alkyl, and most preferably R7 is H. Preferably, Y is an optionally substituted C1-C6 alkyl, more preferably a Ci-C3 alkyl, even more preferably -CH2-, -CH2CH2- or -CH2CH2CH2-, and most preferably -CH2-.
Preferably, Y is an optionally substituted C1-C6 alkyl, more preferably a Ci-C3 alkyl, even more preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(F)- and -CF2- and most preferably -CH2-.
Preferably, R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocyclyl.
In some embodiments, R8 may be an optionally substituted an optionally substituted C3-C6 cycloalkyl or C3-C6 heterocyclyl. R8 may comprise a C6 cycloalkyl or a 6 membered heterocycle. The Cc, cycloalkyl or 6 membered heterocycle may be substituted with an optionally substituted C1-C6 alkyl or a mono or bicyclic optionally substituted C5-Ci0 aryl· Preferably, the C6 cycloalkyl or 6 membered heterocycle is substituted with a phenyl or a Ci-C3 alkyl substituted with a phenyl, more preferably the C& cycloalkyl or 6 membered heterocycle is substituted with a phenyl or -CH2-phenyl.
Preferably, R8 is optionally substituted cyclohexane, optionally substituted piperidine or optionally substituted piperazine. More, preferably, R8 is substituted piperidine.
Accordingly, R8 maybe:
wherein p is o or l.
However, in a preferred embodiment, R8 is a mono or bicyclic optionally substituted C5-Cio aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl. R8 may be an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole. The mono or bicyclic C5-Ci0 aryl or the mono or bicyclic 5 to 10 membered heteroaryl maybe substituted with between 1 and 5 substituents. The or each substituent may independently be selected from the list consisting of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, C1-C3 polyfluoroalkyl, CONR’R2, CN and azido. Preferably, the or each substituent is independently selected from the list consisting of C1-C6 alkyl, halogen, OH, OMe, OEt, OCF3, CF3, C0NH2, CN and azido. More preferably, the mono or bicyclic C5-CiO aryl or the mono or bicyclic 5 to 10 membered heteroaryl may be substituted with at least one C1-C6 alkyl or halogen, even more preferably at least one Ci-C3 alkyl or halogen, and most preferably at least one methyl or fluorine.
In a preferred embodiment, R8 is an optionally substituted benzofuranyl. Preferably, R8 is an unsubstituted benzofuranyl.
In an alternative preferred embodiment, R8 is an optionally substituted furanyl. The furanyl maybe an unsubstituted furanyl. Alternatively, the furanyl maybe substituted. Preferably, the furanyl is substituted with at least one of Ci-C3 alkyl or halogen, more preferably at least one of methyl or fluorine and most preferably with one methyl group.
In an alternative preferred embodiment, R8 is an optionally substituted phenyl. The phenyl may be unsubstituted. Alternatively, the phenyl may be substituted. Preferably,
the phenyl is substituted with at least one of Ci-C3 alkyl or halogen, more preferably at least one of methyl or fluorine and most preferably with l, 2 or 3 fluorines.
In a preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; n is 1; Z is CRUR12; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X1 is CR1; X2 is CR2; X3 is N; n is 1; Z is CRUR12; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; n is 1; Z is CR1 ‘R12; Q is CR4R5; L is C=O; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X1 is CR1; X2 is CR2; X3 is CR3; n is 1; Z is CRUR12; Q is CR4R5; L is S02; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X is CR9R10; X1 is CR1; X2 is CR2; X3 is CR3; n is 1; Z is NR11; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X is CR9R10; X1 is N; X2 is CR2; X3 is CR3; n is 1; Z is NR11; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
In a further preferred embodiment, X is CR9R10; X1 is CR1; X2 is CR2; X3 is N; n is 1; Z is NR11; Q is CO; L is -CH2-; Y is -CH2-; and R7 is H.
In a further preferred embodiment X is S, O or CR9R10. Preferably, X2 is CR2. Preferably, n is 1. Preferably, Q is C=O or CR4R< Preferably, L is optionally substituted Ci-C3 alkyl or Ci-C3 polyfluoroalkyl. L is most preferably Ci-C2 alkyl. Preferably, Y is an optionally substituted C1-C6 alkyl, more preferably a Ci-C3 alkyl, and most preferably a Ci-C2 alkyl. Preferably, R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, and optionally substituted mono or bicyclic C3-C6 cycloalkyl. Preferably, R4 and R5 are each independently selected from the group consisting of H and C1-C6 alkyl. Preferably, R6 is a mono or bicyclic substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C3-C6 cycloalkyl. Preferably, R7 is H. Preferably, R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C3-C6 cycloalkyl. Preferably, R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, azido, NR’R2, Ci-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy or optionally substituted C2-C6 alkenyl. Preferably, R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, azido, NR’R2, Ci-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy or optionally substituted C2-C6 alkenyl.
In a more preferred embodiment X is S or CR9R10. Preferably, X1 is CH or N.
Preferably, X2 is CH. Preferably, X3 is CH or N. Preferably, Z is CRUR12. Preferably, n is 1. Preferably, Q is C=O. Preferably, L is a C1-C2 alkyl. More preferably, L is -CH2-. Preferably, Y is a Ci-C2 alkyl. More preferably, Y is -CH2-. Preferably, R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl, more preferably an optionally substituted phenyl ring. Preferably, R6 is substituted with at least one halogen. Most preferably, R6 is substituted with one or two halogens. The or each halogen is preferably independently chlorine or fluorine. Preferably, R7 is H. Preferably, R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl. Most preferably, R8 is a substituted phenyl ring.
Preferably, R8 is substituted with at least one halogen. Preferably, R8 is substituted with 1, 2 or 3 halogens, more preferably 2 or 3 halogens. Preferably, the or each halogen is fluorine. Preferably, R9 and R10 are each independently selected from the group consisting of C1-C6 alkyl, H, halogen, CN and azido. More preferably, R9 and R10 are each independently selected from the group consisting of Ci-C3 alkyl and H. More preferably, R9 and R10 are each independently selected from the group consisting of CH3 and H. Preferably, R11 and R12 are each independently selected from the group consisting of C1-C6 alkyl, H, halogen, CN and azido. More preferably, R11 and R12 are each independently selected from the group consisting of Ci-C3 alkyl and H. More preferably, R11 and R12 are each independently selected from the group consisting of CH3 and H.
It will be appreciated that an ‘agonist’, an ‘effector’ or an activator, as it relates to a ligand and STING, comprises a molecule, combination of molecules, or a complex, that stimulates STING. Conversely, an ‘antagonist’, as it relates to a ligand and STING, comprises a molecule, combination of molecules, or a complex, that inhibits, counteracts, downregulates, and/or desensitizes STING. ‘Antagonist’ encompasses any reagent that inhibits a constitutive activity of STING. A constitutive activity is one that is manifest in the absence of a ligand/STING interaction. ‘Antagonist’ also encompasses any reagent that inhibits or prevents a stimulated (or regulated) activity of STING.
Preferably, the compound of formula (I) is an activator of the STING protein.
It will be appreciated that the compounds described herein or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof maybe used in a medicament which maybe used in a monotherapy (i.e. use of the compound alone), for modulating the STING protein and/or treating, ameliorating or preventing a disease.
Alternatively, the compounds or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof may be used as an adjunct to, or in combination with, known therapies for modulating the STING protein and/or treating, ameliorating or preventing a disease.
Accordingly, in one aspect, a second therapeutic agent maybe administered with a compound of Formula (I). The compound of Formula (I) maybe administered before, after, and/or together with the second therapeutic agent. The second therapeutic agent may comprise an antiviral agent, an anti-inflammation agent, conventional chemotherapy, an anti-cancer vaccine and/or hormonal therapy. Alternatively, or additionally, the second therapeutic agent may comprise a By costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO/TDO inhibitor (such as Epacadostat and GDC-0919), a PD-i inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, and MDX-1106), a PD-Li inhibitor (such as Durvalumab, Avelumab and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB/CD137 ligand, a CD27 ligand, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund’s complete or incomplete adjuvant, a TLR agonist (such as Poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine and a CpG dinucleotide) and/or detoxified endotoxins.
Methods for co-administration with an additional therapeutic agent are well known in the art (Hardman et. al. (eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed., 2001, McGraw-Hill New York, NY; Poole and Peterson (eds.), Pharmacotherapeutics for Advanced Practice: A Practical Approach, 2001, Lippincott,
Williams and Wilkins, Philadelphia, PA; Chabner and Longo (eds.), Cancer
Chemotherapy and Biotherapy, 2001, Lippincott, Williams and Wilkins, Philadelphia, PA).
In one aspect, the disease is cancer and a chemotherapeutic agent may be administered with a compound of Formula (I). The chemotherapeutic agent maybe selected from a group further consisting of a cancer vaccine, a targeted drug, a targeted antibody, an antibody fragment, an antimetabolite, an antineoplastic, an antifolate, a toxin, an alkylating agent, a DNA strand breaking agent, a DNA minor groove binding agent, a pyrimidine analogue, a ribonucleotide reductase inhibitor, a tubulin interactive agent, an anti-hormonal agent, an immunomodulator, an anti-adrenal agent, a cytokine, radiation therapy, a cell therapy, cell depletion therapy such as B-cell depletion therapy and a hormone therapy. Alternatively or additionally, the chemotherapeutic agent may comprise abiraterone, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, bleomycin, cachectin, cemadotin, chlorambucil, cyclophosphamide, docetaxol, doxetaxel, carboplatin, cysplatin, cytarabine, dactinomycin, daunorubicin, decitabine, doxorubicin, etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea, streptozocin, mitomycin, methotrexate, taxanes, tamoxifen, vinblastine, vincristine and/ or vindesine.
The compound of Formula (I) maybe combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension or any other suitable form that may be administered to a person or animal in need of treatment. It will be appreciated that the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given.
Medicaments comprising the compounds described herein may be used in a number of ways. Suitable modes of administration include oral, intra-tumoral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration.
Formulations suitable for the aforementioned modes of administration maybe formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, n (6), 981-986, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkylsubstituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation.
Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends maybe compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in “Pharmaceutical Dosage Forms: Tablets”, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in “Pharmaceutical Technology On-line”, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral solutions maybe increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers maybe incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This maybe achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from lpg to 20mg of the compound of the invention per actuation and the actuation volume may vary from lpl to toopl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff’ containing from lpg to loomg of the compound of formula (I). The overall daily dose will typically be in the range lpg to 2oomg which may be administered in a single dose or, more usually, as divided doses throughout the day.
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
The compounds of the invention may also be administered directly to a site of interest by injection of a solution or suspension containing the active drug substance. The site of interest may be a tumour and the compound may by administer via intratumoral injection. Typical injection solutions are comprised of propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which maybe used instead of propylene glycol include glycerol and polyethylene glycol.
The compounds of the invention may be combined with soluble macro molecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin maybe used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
It will be appreciated that the amount of the compound that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is being used as a monotherapy, or in a combined therapy. The frequency of administration will also be influenced by the half-life of the compound within the subject being treated. Optimal dosages to be administered maybe determined by those skilled in the art, and will vary with the particular compound in use, the strength of the pharmaceutical composition, the mode of administration, and the advancement of the disease. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
Generally, for administration to a human, the total daily dose of the compounds of the invention is typically in the range toopg to tog, such as lmg to lg, for example lomg to 500mg. For example, oral administration may require a total daily dose of from 25mg to 25omg. The total daily dose may be administered in single or divided doses and may, at the physician’s discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 6okg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
However, it is appreciated by those skilled in the art that for agents that modulate the immune system, both the dose and the frequency of administration may be different to those of more traditional therapies. In particular, for agents that stimulate the immune system, for example through modulation of STING, they maybe administered in small doses, and quite infrequently, for example twice weekly, weekly or monthly. Smaller doses may also be effective when administered topically to a small area of skin.
The compound may be administered before, during or after onset of the disease to be treated.
Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to form specific formulations comprising the compounds according to the invention and precise therapeutic regimes (such as daily doses of the compounds and the frequency of administration). The inventors believe that they are the first to describe a pharmaceutical composition for treating a disease, based on the use of the compounds of the invention.
Hence, in a seventh aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.
The invention also provides, in an eighth aspect, a process for making the composition according to the seventh aspect, the process comprising contacting a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle. A “subject” maybe a vertebrate, mammal, or domestic animal. Hence, compounds, compositions and medicaments according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or maybe used in other veterinary applications. Most preferably, however, the subject is a human being. A “therapeutically effective amount” of compound is any amount which, when administered to a subject, is the amount of drug that is needed to treat the target disease, or produce the desired effect, i.e. modulate the STING protein.
For example, the therapeutically effective amount of compound used may be from about o.oi mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. It is preferred that the amount of compound is an amount from about 0.1 mg to about 250 mg, and most preferably from about 0.1 mg to about 20 mg. A “pharmaceutically acceptable vehicle” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions.
In one embodiment, the pharmaceutically acceptable vehicle maybe a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet-disintegrating agents. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is in admixture with the finely divided active agents (i.e. the compound according to the first, second and third aspects) according to the invention. In tablets, the active compound maybe mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutical vehicle maybe a gel and the composition may be in the form of a cream or the like.
However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compound according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection. The compound maybe prepared as a sterile solid composition that maybe dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
The compound and compositions of the invention may be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The compounds used according to the invention can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
Also included within the scope of the invention are soft drugs or antedrugs which are compounds of formula (I) which contain metabolically or hydrolytically labile moieties which in vivo are converted into inactive derivatives. The processes by which the active drug substance is converted into an inactive derivative include, but are not limited to, ester hydrolysis, S-oxidation, A-oxidation, dealkylation and metabolic oxidation as described for example in Pearce et al., Drug Metab. Dispos., 2006, 24,1035-1040 and B. Testa, Prodrug and Soft Drug Design, in Comprehensive Medicinal Chemistry II, Volume 5, Elsevier, Oxford, 2007, pp. 1009-1041 and Bodor, N. Chem. Tech. 1984,14, 28-38.
The scope of the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as Ή and 3H, carbon, such as UC, 13C and 14C, chlorine, such as 36C1, fluorine, such as l8F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as >0,17O and l8O, phosphorus, such as 32P, and sulphur, such as 33S.
Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence maybe preferred in some circumstances. Substitution with positron emitting isotopes, such as nC, l8F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
In accordance with a further aspect of the invention, there is provided a compound of the formula (II) or (III):
wherein, X, X1, X2, X3,n, Z, Q, L, Y, R6, R7 and R8 are as defined in the first aspect; and R is H or a C1-C6 alkyl, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
It will be appreciated that compounds of formula (II) and (III) may be used to synthesise compounds of formula (I).
Preferably, X is CR9R10, O or S.
When X is CR9R10, R9 and R10 are preferably independently C1-C6 alkyl, hydroxyl, halogen or CN. More preferably, R9 and R1Q are independently hydrogen, methyl, hydroxyl, halogen or CN. In one embodiment, at least one of R9 and R10 is methyl. Preferably, one of R9 and R10 is methyl and the other is hydrogen or methyl. In a preferred embodiment, at least one of R9 and R10 is hydrogen, and preferably both R9 and R10 are hydrogen.
Preferably, X2 is CH.
Preferably, Q is C=O, S02 or CR4R5. More preferably, Q is C=O.
Preferably, L is C1-C6 alkyl, more preferably C1-C3 alkyl, and most preferably -CH2-.
Preferably, R6 is optionally substituted C5-Ci0 aryl. More preferably, R6 is substituted phenyl. Even more preferably, R6 is phenyl substituted with at least one halogen. Most preferably, R6 is phenyl substituted with one or two halogens. Preferably, the or each halogen is chlorine or fluorine.
Preferably, R is H or methyl, ethyl, benzyl or tert-butyl. More preferably, R is H or methyl.
The compound of formula (II) maybe selected from:
Preferably, Y is C1-C6 alkyl, more preferably C1-C3 alkyl, and most preferably -CH2-.
Preferably, R7 is H.
Preferably, R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocyclyl. Preferably, R8 is a mono or bicyclic C5-Ci0 aryl or a mono or bicyclic 5 to 10 membered heteroaryl substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, CONR’R2, CN and azido. More preferably, R8 maybe an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole.
The compound of formula (III) maybe selected from:
All features described herein (including any accompanying claims and abstract), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.
General Schemes
General Scheme 1
Compounds of formula (I) may be prepared from compounds of formula (II) and (III) using an amide bond forming reaction, as shown below.
Typical conditions employ activation of the carboxylic acid of the compound of formula (II) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either EDCI with HOBt, T3P, HATU, HBTU or BOP. Preferred organic bases comprise either DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature.
Compounds of formula (II) and (III) are commercially available or may be synthesized by those skilled in the art. In particular, methods of synthesising compounds of formula (II) are described in General Schemes 2 to 4 (below).
General Scheme 2
Compounds of formula (II) may be synthesized from esters of formula (IV), where R is methyl, ethyl, benzyl or tert-butyl, by a hydrolysis reaction.
The compound of Formula (TV) may be reacted with a suitable alkali or base to cause it to undergo hydrolysis and provide a compound of formula (II). The suitable alkali or base maybe LiOH, KOH, NaOH or K2CO3, and the reaction maybe conducted in an aqueous solution.
General Scheme 3
Alternatively, compounds of formula (II) can be obtained from a halide of formula (V) as shown in the general scheme below.
First the compound of formula (V) undergoes a cyanation reaction to give a compound of formula (VI). This could be conducted in the using CuCN or ZnCN2 in a polar solvent at elevated temperatures with a suitable catalyst. The polar solvent could be NMP, DMF, DMA or MeCN oand catalyst could be tetrakistriphenylphosphine palladium(o).
The compound of formula (VI) may then undergo hydrolysis to give the compound of formula (II). In particular, the compound of formula (II) maybe hydrolysed using an aquesous solution of an alkali, such as NaOH, LiOH and KOH, or an acid, such as HC1, at an elevated temperature.
General Scheme 4
In a further alternative process, the compound of formula (V) may undergo a direct carbonylation reaction to produce a compound of formula (II), as shown below.
The reaction could be conducted using CO gas in the presence of a suitable catalyst in an appropriate polar solvent. The catalyst maybe aPd, Rh, Ir or Fe catalyst, and the solvent may be NMP, DMF, DMA or MeCN with the reaction carried out in the presence of a suitable nucleophile such as water or alcohols (to prepare the corresponding esters).
General Scheme 5
Compounds of formulae (TV), (V) and (VI) may be synthesized by those skilled in the art via an alkylation/acylation/sulfonylation reaction with a compound of formula (VII), where G is a leaving group such as an optionally substituted alkylaryl(het), alkyl, aryl(het), cycloalkyl, alkylcycloalkyl halide, tritiate or tosylate.
General Scheme 6
Alternatively, a compound of formula (IX) maybe prepared in a five-step process, as shown below, from a compound of formula (XIV), where R is methyl, ethyl, benzyl or tert-butyl.
First, the compound of formula (XIV) undergoes a nucleophilic substitution reaction with a compound of formula (XI), where R is methyl, ethyl, benzyl or tert-butyl, to produce a compound of formula (XIII). The nucleation substitution reaction may be conducted in the presence of a mild base, such as DBU, NaH, TEA, DIPEA, K2CO3, Cs2CO3 or KHCO3. The solvent used may be 1,4-dioxane, acetone, MeCN, THF or DMF.
The nitro group on the compound of formula (XIII) may then be reduced to an amino group by using a reducing agent, such as Fe/AcOH, Zn/HCl, Zn/NH4C1, Zn/HCOONH4, SnCl2/HCl or Pd/C/H2,in a suitable solvent, such as EtOH, MeOH or THF. The ensuing amino compounds undergoes in-situ cyclization resulting in the formation of a compound of formula (XII).
The compound of formula (XII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XI). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (X). Finally, this compound maybe reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (IX).
It will be appreciated that the compound of formula (IX) is a compound of formula (I) where Q is C=O.
General Scheme 7
Alternatively, a compound of formula (XV) may be prepared in a five-step process, as shown below, from a compound of formula (XII), where R is methyl, ethyl, benzyl or tert-butyl.
Firstly, the carbonyl group of the compound of formula (XII) may be reduced to the corresponding methylene group to give a compound of formula (XVIII). This can be achieved by using a suitable reducing agent, such as borane-THF or borane-DMSO, in a solvent such as THF or DMSO.
The compound of formula (XVIII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XVII). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XVI). Finally, this compound maybe reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XV).
It will be appreciated that the compound of formula (IX) is a compound of formula (I) where Q is CH2.
General Scheme 8 A compound of formula (XIX) may be prepared in a six-step process, as shown below, from a compound of formula (XXV), where R is methyl, ethyl, benzyl or tert-butyl.
First the compound of formula (XXV) may react with an active olefin-containing compound via a Heck alkenylation reaction to give a compound of formula (XXIV). This reaction will be conducted in a sealed tube at an elevated temperature using a suitable transition metal catalyst and a suitable base in a suitable solvent. The transition metal catalyst might be a palladium catalyst, such as tetrakistriphenylphosphine palladium(o) or Ataphose, the base may be TEA or DIPEA and the solvent may be NMP, DMF, DMA or MeCN.
The compound of formula (XXIV) may then be reduced using a hydrogenation reaction with hydrogen gas and a suitable catalyst in a suitable solvent to provide a compound of formula (XXIII). The catalyst maybe palladised charcoal and the solvent may EtOH or MeOH.
The compound of formula (XXIII) may then undergo a cyclization reaction to provide a compound of formula (XXII). The reaction maybe conducted in an acidic medium at an elevated temperature in a suitable solvent, such as toluene, DMF, DMA or MeCN.
The compound of formula (XXII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XXI). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XX). Finally, this
compound maybe reacted with a compound of formula (III), as described in General Scheme l, to give a compound of formula (XIX).
It will be appreciated that when m is o the compound of formula (XIX) is a compound of formula (I) where X is CH2 and Z is CH2, and when m is l the compound of formula (XIX) is a compound of formula (I) where X is CH2, one Z is CH2 and the other may be any one of the groups defined in claim l.
General Scheme Q A compound of formula (XXVI) may be prepared in a five-step process, as shown below, from a compound of formula (XXVI), where R is methyl, ethyl, benzyl or tertbutyl.
First, the compound of formula (XXXI) may undergo an amide formation to provide a compound of formula (XXX). The conditions used may be similar to those described under General Scheme 5.
The compound of formula (XXX) may then be cyclized to give a compound of formula (XXIX). For instance, a Friedel-Crafts cyclisation reaction could be used. This reaction would use a suitable Lewis acid reagent at elevated temperatures and in a suitable solvent. The Lewis acid reagent could be A1C13 or FeCl3, and the solvent could be MeCN, toluene, EDC or MeOAc. Alternatively, Bronsted acids, such as TfOH, may be used to cause the compound of formula (XXX) to cyclise.
The compound of formula (XXIX) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XXVIII). This compound may undergo a hydrolysis reaction,
as described in General Scheme 2, to give a compound of formula (XXVII). Finally, this compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XXVI).
It will be appreciated that the compound of formula (XXVI) is a compound of formula (I) where X is R9R10, Q is C=O, n is 1 and Z is CH2.
General Scheme 10 A compound of formula (XXXII) maybe prepared in a four- or five-step process, as shown below, from a compound of formula (XXXV),, where R is methyl, ethyl, benzyl or tert-butyl.
The compound of formula (XXXV) is reacted with a suitable base and a suitable electrophile to cause an alkylation reaction and provide the compound of formula (XXXIII). The base may be a mild base, such as TEA, DIPEA, K2CO3, Cs2CO3 or KHCO3, or a stronger base, such as NaH or LiHMDS. The electrophile may be R9-G and/or R10-G where G is a suitable leaving group. The process may comprise sequential alkylation reactions, analogous to steps (xi) and (xii) shown above, or a double alkylation, analogous to step (xii).
The compound of formula (XXXIII may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, a hydrolysis reaction, as described in General Scheme 2, and then the resulting compound maybe reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XXXII).
It will be appreciated that the compound of formula (XXXII) is a compound of formula (I) where Q is C=O, n is l and Z is CRUR12.
General Scheme 11 A compound of formula (XXXVI) may be prepared in a seven-step process, as shown below, from a compound of formula (XLIII),, where R is methyl, ethyl, benzyl or tertbutyl.
First, the compound of formula (XLIII) can be brominated, using either Br2 or a bromine source, such as NBS, to give a compound of formula (XLII). This compound can then be aminated, using NR9H2, to provide a compound of formula (XLI). The nitro group on the compound of formula (XLI) can then be reduced, as described in General Scheme 6, to provide a compound of formula (XL). The compound of formula (XL) may then be reacted with a suitable carbonyl source to provide a compound of formula (XXXIX). The carbonyl source maybe 1,1-carbonyl-diimidazole, phosgene or triphosgene.
The compound of formula (XXXIX) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XXVIII). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XXXVII). Finally,
this compound may be reacted with a compound of formula (III), as described in General Scheme l, to give a compound of formula (XXXVI).
It will be appreciated that the compound of formula (XXXVI) is a compound of formula (I) where X is CR9R10, Q is C=O, n is l and Z is NR9.
General Scheme 12
Compounds of formula (XLIV) and (XLV) can be synthesized by S-oxidation of compounds of formula (XLVI) with suitable oxidizing agent, such as mCPBA, hydrogen peroxide or oxygen, in a solvent such as DCM, CHC13, CC14 or EDC.
It will be appreciated that the compound of formula (XLV) is a compound of formula (I) where X is SO and the compound of formula (XLV) is a compound of formula (I) where X is S02.
General Synthetic Procedures
General Procedure 1
To a stirred solution of a carboxylic acid (II) (1.277 mmol) in a suitable solvent, such as DCM, DMF, DMA or MeCN, (10 mL) was added amine (III) (1.2 eq.) and a coupling reagent, such as T3P, HATU, EDC1, HOBT, BOP or HBTU, (1.5 eq.), followed by addition of an organic base, such as DIPEA or TEA, (2.0 eq.) drop wise to the solution and the mixture allowed to stir at RT for 2-3 h. When UPLC or TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3 solution followed by dilute aqueous HC1 and finally with brine, and then dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude material which was
purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (I) (70-80% yield) as a pale yellow solid. A similar procedure can be followed to synthesize all amides of formula (I).
Compounds of formula (I) were also prepared in parallel using library or array techniques according to one of the following methods.
Library General Procedure 1
Method 1
To a stirred solution of carboxylic acid (0.084 mmol, 1 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.) and T3P (0.251 mmol, 3.0 eq.) at RT and stirred for 5 min. The corresponding amine (1.5 eq.) was added and the whole stirred for 16 h at RT. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.
Method 2
To a stirred solution of carboxylic acid (0.084 mmol, 1.0 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.) and the corresponding amine (1.5 eq.) followed by HATU (0.125 mmol, 1.5 eq.) and stirred for 16 h at RT. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.
Method 3
To a stirred solution of carboxylic acid (0.084 mmol, 1.0 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.), HOBT (0.1 mmol, 1.2 eq.) and EDC.HC1 (0.167 mmol, 2.0 eq.) followed by corresponding amine (1.5 eq.) and stirred for 16 h at room temperature. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.
General Purification and Analytical Methods
All final compounds were purified by either Combi-flash or prep-HPLC purification, and analysed for purity and product identity by UPLC or LCMS according to one of the below conditions.
Prep-HPLC
Preparative HPLC was carried out on a Waters auto purification instrument using either a YMC Triart C18 column (250 x 20 mm, 5 pm) or a Phenyl Hexyl column (250 x 21.2 mm, 5 pm) operating at between ambient temperature and 50 °C with a flow rate of 16.0 - 50.0 mL/min.
Mobile phase 1: A = 20mM Ammonium Bicarbonate in water, B = Acetonitrile;
Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B after 3 min., then to 30% A and 70% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min.
Mobile phase 2: A = lomM Ammonium Acetate in water, B = Acetonitrile; Gradient Profile: Mobile phase initial composition of 90% A and 10% B, then to 70% A and 30% B after 2 min., then to 20% A and 80% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min. LCMS method
General 5 min method: Zorbax Extend C18 column (50 x 4.6 mm, 5pm) operating at ambient temperature and a flow rate of 1.2 mL/min. Mobile phase: A = 10 mM Ammonium Acetate in water, B = Acetonitrile; Gradient profile: from 90 % A and 10 % B to 70 % A and 30 B in 1.5 min, and then to 10 % A and 90 % B in 3.0 min, held at this composition for 1.0 min, and finally back to initial composition for 2.0 min. UPLC method UPLC was carried out on a Waters auto purification instrument using a Zorbax Extend C18 column (50 x 4.6 mm, 5pm) at ambient temperature and a flow rate of i.5ml/min. Mobile phase 1: A = 5 mM Ammonium Acetate in water, B = 5 mM Ammonium Acetate in 90:10 Acetonitrile/water; Gradient profile from 95% A and 5% B to 65% A and 35% B in 2 min., then to 10% A and 90% B in 3.0 min., held at this composition for 4.0 min. and finally back to the initial composition for 5.0 min.
Mobile phase 2: A = 0.05 % formic acid in water, B = Acetonitrile; Gradient profile from 98 % A and 2 % B over 1 min., then 90 % A and 10 % B for 1 min., then 2 % A and 98 % B for 2 min. and then back to the initial composition for 3 min.
General procedure 2
To a stirred solution of ester (IV) (1.49 mmol) in a mixture of MeOH or THF (10 mL) and water (5 mL) was added LiOH, NaOH or KOH (2.0 eq.) at RT and the resulting reaction mixture was stirred at RT for 2-16 h. TLC showed complete consumption of the ester (TV), upon which the solvent was evaporated under reduced pressure and the resulting residue was washed with ether. The residue was then acidified with lN HC1 to pH 2-4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under reduced pressure at 5O-6o°C to afford the desired carboxylic acid of formula (II) (70-85% yield) as an off white solid.
General procedure 2
Option 1
To a stirred solution of a compound of formula (VIII) (2.77 mmol, 1.0 eq.) in DMF or THF (4 mL/mmol) was added K2CO3, Cs2CO3, Na2CO3, NaOH or NaH (2.0 eq.) - in the case where NaOH was used, TBAB (0.1 eq.) was also added as a phase transfer catalyst - followed by addition of a compound of formula (VII) (1.5 eq.) and the mixture allowed to stir at RT for 0.5-1 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na2SO4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford compounds of formula (TV) (80-90% yield) as colorless oils.
Option 2
Alternatively, to a stirred solution of a compound of formula (VIII) (2.77 mmol) in DCM or MeCN or THF (4 mL/mmol) was added TEA or DIPEA (2.0 eq.) followed by addition of a compound of formula (VII) (1.5 eq.) and the whole allowed to stir at RT
for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4.
The organic layers were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (IV) (80-90% yield) as a colourless oil.
Compounds of formula (I) were prepared using a modification of General Procedure 3 in parallel using library or array techniques starting from the corresponding amide version of the compound of formula (VIII) according to one of the following methods.
Library General Procedure 2
Method 1
To a stirred suspension of lactam (0.104 mmol, 1.0 eq.) in EDC (1.5 mL/mmol) was added NaOH (2.0 eq., dissolved in 1.5 mL water) and TBAB (5 mg). The resulting reaction mixture was stirred for 1 h at RT, then corresponding aryl halide (1.5 eq.) was added to it. The reaction mixture was further stirred for 3-4 h at RT. The progress of the reactions was monitored by LCMS and after completion of reaction, the reaction mixture was diluted with DCM and washed with water. The organic layers were dried over anhydrous Na2SO4 and evaporated to dryness to obtain the crude product, which was purified by prep-HPLC.
Method 2
To a stirred solution of the lactam (0.104 mmol, 1.0 eq.) in DMF (3 mL/mmol) was added Cs2CO3 (1.5 eq.) at RT. After 10-15 min stirring, the corresponding aryl halides (1.5 eq.) were added and the whole stirred at 60 °C for 12 h. Progress of the reactions was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.
General procedure 4
To a stirred solution of a compound of formula (XIV) (50.2 mmol, 1.0 eq.) and an appropriate nucleophile (XI) (1.25 eq.) in a suitable solvent, such as 1,4-dioxane, MeCN, DMF or THF, (3 mL/mmol) was added drop wise/portion wise a suitable base, such as TEA, DBU, NaH, K2CO3, (1.5 eq.) with ice bath cooling and allowed to stir at o-25 °C for 1-16 h. The progress of the reaction was monitored by TLC or LCMS and on completion of the reaction, quenched with NH4C1 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The crude compound of formula (XIII) (60-95% yield) obtained as a yellow solid were pure enough to be used directly in the next step without further purification.
General procedure 5
To a stirred solution of a compound of formula (XIII) (46.7 mmol, 1.0 eq.) in a suitable acid, such as AcOH or aq. HCI, (3 mL/mmol) was added iron powder or zinc powder (4.0 eq.) at RT. The reaction mixture was stirred at 75-85 °C for 2-5 h. The reaction was monitored by TLC or LCMS and on completion of the reaction, cooled to room temperature and poured into lN HCI and then stirred for 1-2 h. The white precipitate was filtered off and washed with excess water. The residue obtained was re-dissolved in 5% MeOH in DCM and filtered through a bed of celite. The filtrate was evaporated under reduced pressure to obtain a compound of formula (XII) (80-95% yield) as a white solid which were pure enough to proceed in to the next step.
General procedure 6
To a stirred solution of ester (XII) (2.24 mmol, 1.0 eq.) in a suitable solvent, such as THF or DMSO, was added borane-THF or borane-DMSO (5 eq.; lM solution) at 0-5 °C. The reaction mixture was allowed to stir at room temperature for 12-16 h. The progress of the reaction was monitored by TLC or LCMS and upon completion the reaction was
quenched by drop wise addition of an appropriate amount of MeOH with ice cooling. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to providethe crude product (XVIII) (85-96% yield) which was used without further purification.
General procedure 7
To a stirred solution of a compound of formula (XXV) (8.65 mmol, 1.0 eq.) in a suitable dry solvent, such as DMF, NMP or DMA, (1.5 mL/mmol) was added an olefin derivative (3.8 eq.) and a base, such as TEA or DIPEA, in a sealed tube reaction container at RT and the resulting reaction mixture degassed by bubbling N2 gas through the solution for 5-10 min. A metal catalyst, such as bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II), (0.03 eq.) was added and the solution was further degassed for 5-10 min. The tube was then sealed and heated at 130-140 °C for 10-16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was filtered through a small pad of celite and then thoroughly washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography by using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XXIV) (20-50% yield).
General procedure 8
To a stirred solution of a compound of formula (XXIV) (2.32 mmol, 1.0 eq.) in a suitable solvent, for example MeOH or EtOAc, (5 mL/mmol) was added an appropriate amount of Pd-C (10% w/w) under a N2 gas atmosphere at 0-25 °C. The resulting reaction mixture was stirred at RT under H2 gas balloon pressure for 2-4 h. On completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed under a N2 gas atmosphere. The filtrate was concentrated under reduced pressure to obtain the crude product which was purified by column chromatography on silica gel using mixtures of EtOAc in hexanes as eluent to afford the reduced alkane derivative (XXIII) (80-85% yield).
General procedure 9
To a stirred solution of a compound of formula (XXIII) (1.9 mmol, 1.0 eq.) in a suitable solvent, such as toluene, DMF, DMA or MeCN, (5 mL/mmol) was added formic acid (1.5 mL/mmol) and the resulting reaction mixture was heated to reflux (100-115 °C) for 1-12 h. After completion of the reaction the mixture was concentrated under reduced pressure to obtain a residue which was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to yield the cyclized compound of formula (XXII) in 60-70% yield.
General procedure 10
To a stirred solution of a compound of formula (XXX) (0.86 mmol, 1.0 eq.) in a suitable solvent such as EDC or MeCN under an inert atmosphere was added anhydrous A1C13 or FeCl3 (4.0 eq.) portionwise and the whole heated at reflux temperature for 1-2 h. After completion of the reaction (TLC/LCMS), the reaction
mixture was diluted with EDC and washed with dilute HCI followed by brine solution. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to obtain the crude product which was purified by column chromatography on silica gel using mixtures of EtOAc in hexanes as eluent to afford the desired compound of formula (XXIX) (50-55% yield) as a brown solid.
General procedure 11
To a stirred solution of a compound of formula (XXXV) (26.16 mmol, 1.0 eq.) in DMF or THF (150 mL) at -65 to -78 °C was added dropwise a suitable base such as LiHMDS, LDA or NaH (1.0 eq.) and the mixture allowed to stir for 15-30 min. A suitable alky/aryl (het) halide (R9-L-G) (1.0 eq.) was added at the same temperature. The whole was allowed to stir at 0 to -10 °C for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with an aqueous solution of NH4C1, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using EtOAc in hexanes as eluent to afford a compound of formula (XXXIV) (25-30% yield) as a light orange to faint pink solid.
General procedure 12
To a stirred solution of (XXXIV) (26.16 mmol, 1.0 eq.) in DMF or THF (150 mL) at -65 to -78 °C was added dropwise a suitable base, such as LiHMDS, LDA or NaH, (1.0 eq.) and the whole allowed to stir for 15-30 min., then a suitable alky/aryl(het) halide (R10-L-G) (1.0 eq.) was added at the same temperature. The whole was allowed to stir at 0 to -10 °C for 0.5 to 1 h. After completion of the reaction, the mixture was quenched with an aqueous solution of NH4C1, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The dried organics were
evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using 35-50% EtOAc in hexanes as eluent to afford a compound of formula (XXXIII) (65-70% yield) as a light orange to faint pink solid.
General procedure 13
To a stirred solution of a compound of formula (XLIII) (1.0 eq.) in a suitable solvent such as carbon tetrachloride or trifluoro toluene (100 mL) was added NBS (1.2 eq.) and AIBN or benzoyl peroxide (0.1 eq.). The reaction mixture was heated at 70-100 °C for 12-16 h. After complete consumption of starting material, the reaction mixture was quenched with a saturated solution of Na2S2O3 and extracted with EtOAc. The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. The crude product obtained after concentration of the organic layer under reduced pressure was purified by column chromatography to afford a compound of formula (XLII) in 30-40% yield.
General procedure 14
To a stirred solution of a compound of formula (XLII) (9.124 mmol, 1.0 eq.) in a suitable solvent such as THF was added an appropriate amine, such as MeNH2, (25 mL, 2M solution in THF) at RT for 10-16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with a saturated brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a compound of formula (XLI) (60-70% yield) as a red gummy solid.
General procedure 15
To a stirred solution of a compound of formula (XL) (3.61 mmol, 1.0 eq.) in a suitable solvent, such as DCM or THF, (5 mL/mmol) was added a suitable carbonyl source equipped with suitable leaving groups, such 1,1-carbonyl-diimidazole, phosgene or triphosgene, (1.1 eq.) followed by a suitable base, such as TEA or DIPEA, (3.0 eq.) at o-5 °C and the reaction mixture was stirred at room temperature under an inert atmosphere for 2-4 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a crude residue which was purified by silica gel column chromatography and eluted with 1% MeOH in DCM to afford a compound of formula (XXXIX) (20-30% yield) as an off white solid.
General procedure 16
To a stirred solution of a compound of formula (XLVI) (1.0 eq.) in suitable solvents, such as DCM, CHC13, CC14 or EDC, (2 mL) was added mCPBA (1.0-3.0 eq.) at RT. The reaction mixture was further stirred at the same temperature for 2-16 h. The progress of the reaction was monitored by TLC and after completion of the reaction the mixture was diluted with more solvent and washed with a saturated solution of aqueous NaHCO3 followed by brine. The organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by prep-HPLC to afford sulfoxide (XLV) and sulfone (XLIV) as off white solids.
Examples
Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for Ή-NMR) and upfield from trichloro-fluoro-methane (for 19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDC13, deuterochloroform; d6-DMSO, deuterodimethylsulphoxide; and CD3OD, deuteromethanol.
Mass spectra, MS (m/z), were recorded using electrospray ionisation (ESI). Where relevant and unless otherwise stated the m/z data provided are for isotopes 19F, ssci, 79Br and 127I.
All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were performed under an atmosphere of nitrogen unless otherwise noted.
Flash column chromatography was carried out using pre-packed silica gel cartridges in a Combi-Flash platform. Prep-HPLC purification was carried out according to the General purification and analytical methods described above. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). All final compounds were >95% pure as judged by the LCMS or UPLC analysis methods described in the General purification and analytical methods above unless otherwise stated.
Example 1: 4-(2-chlorobenzyl)-IV-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2JJ-benzorb-i,4.1thiazine-6-carboxamide
Example 1 was prepared according to the methods described in General Procedures 1-3, and the methods described below.
Preparation l: Methyl 3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxylate
Step l: Methyl 4-ff2-ethoxy-2-oxoethyl')thio')-3-nitrobenzoate
Methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) was taken up in MeCN (2.0 L) and TEA (7.61 g, 75.376 mmol) was added to it. The reaction mixture was cooled to 0 °C and ethyl thioglycolate (7.25 g, 62.7 mmol) was added drop wise. The reaction mixture was stirred for 30 min. at ice cold temperature. It was then diluted with EtOAc and washed with saturated solution of NH4C1 and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (14.0 g, 46.822 mmol, 93% yield) as a yellow solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 300.06 [M+H].
Step 2: Methyl 3-oxo-3,4-dihydro-2fl-benzorb-i,4lthiazine-6-carboxylate
To a stirred solution of methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (step 1) (5.0 g, 16.7 mmol) in acetic acid (50 mL) was added iron powder (3.73 g, 66.8 mmol). The resulting reaction mixture was stirred at 80 °C for 3 h. On completion (monitored by TLC), it was cooled to room temperature and poured onto lN HCI (250 mL) and then stirred for lh. The white precipitate was filtered off and washed with water. The residue obtained was re-dissolved in 5% MeOH in DCM (50 mL) and filtered through a bed of celite. The filtrate was evaporated to dryness to afford the methyl 3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (3.5 g, 15.6 mmol, 91% yield) as a golden white solid. LCMS m/z: 222.05 [M-H].
Preparation 4: Methyl 4-(2-chlorobenzyl)-3-oxo-3.4-dihydro-2H-benzorb-i.4lthiazine-6 carboxylate
To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation l) (0.3 g, 1.343 mmol) in EDC (5 mL) was added NaOH solution (0.107 g, 2.686 mmol in 5 mL H20) portion wise followed by TBAB (0.05 g, 0.15 mmol) at RT. The whole was stirred for 30 min at RT and then 2-chloro-benzyl bromide (0.209 mL, 1.61 mmol) was added drop wise. The reaction mixture was then stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and after completion; the reaction mixture was diluted with DCM, washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (0.32 g, 0.922 mmol, 69% yield) which was used directly in Preparation 5. LCMS m/z: 348.19 [M+H].
Preparation 5: 4-(2-ChlorobenzyD-3-oxo-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxvlic acid
To a stirred solution of methyl 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxylate (Preparation 4) (0.32 g, 0.922 mmol) in a mixture of MeOH, water and THF (1:1:2; 12 mL) was added Li0H.H20 (0.077 g, 1-84 mmol) at RT. The reaction was allowed to stir at RT for 2 h. Elpon completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to ~pH 5. The acidified aqueous solution was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to give 4-(2-chlorobenzyl)-3-0x0-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylic acid (0.22 g. 0.66 mmol, 72%
yield) as a colorless solid which was used in the next step without any further purification. LCMS m/z: 332.12 [M-H].
Preparation 6: 4-(2-chlorobenzvl)-jY-(ftiran-2-vlmethvl)-2-oxo-2.4-dihvdro-2H-benzorb-i.4lthiazine-6-carboxamide
To a stirred solution of 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxylic acid (Preparation 5) (0.1 g, 0.3 mmol) in DMF (5 mL) was added HATU (0.136 g, 0.36 mmol) followed by TEA (0.104 mL, 1.03 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min. then i-(furan-2-yl)-methanamine (0.026 mL, 0.27 mmol) was added and stirring continued at RT for 2 h. After this time, the reaction mixture was diluted with EtOAc and washed with chilled water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The crude material obtained was purified by prep-HPLC to afford 4-(2-chlorobenzyl)-2V-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (0.04 g, 0.097 mmol, 32% yield) as a white solid. LCMS m/z: 413.18 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 3-76 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.24 (s, 2H), 6.20 (d, J = 2.7 Hz, lH), 6.37-6.38 (dd, Λ = 1.85 Hz, J2 = 2.9 Hz, lH), 7.07 (d, J = 7.55 Hz, lH), 7-26-7.31 (m, 2H), 7-49-7-52 (m, 2H), 7-55-7-57 (m, 3H), 9-00 (t, J = 5.65 Hz, lH).
Examples 2-49
Examples 2-49 were prepared according to the above methods used to make Example 1 as described in General Procedures 1-3 using the appropriate amines and acids. Purification was as stated in the aforementioned methods.
Examples 106-118
Examples 106-112 were prepared according to the above methods used to make Example 1 as described in General Procedures 1-3 using the appropriate amines and acids. Purification was as stated in the aforementioned methods.
Examples 113-118 were prepared using Library general procedure 1 or 2 as indicated in the table below.
Examples 119-128
Certain analogous (Examples 119-128) derivative compounds of formula (I) may also be obtained from commercial suppliers, which are also incorporated herein.
Example 12Q: 4-Benzyl-N-(furan-2-ylmethyl)-2.2-dimethyl-3-oxo-3.4-dihydro-2H-benzorb-i,4.1thiazine-6-carboxamide
Preparation 7: Methyl benzyl-2-oxo-2.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxvlate
To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 1) (1.0 g, 4.478 mmol) in EDC (20 mL) was added NaOH solution (0.358 g, 5.377 mmol in 20 mL H20) portionwise followed by TBAB (0.105 g, 0.325 mmol) at RT. The whole was stirred for 30 min at RT and then benzyl bromide (0.643 mL, 5.377 mmol) was added dropwise. The reaction mixture was further stirred at RT for 2.5 h. Progress of the reaction was monitored by TLC and after completion; the reaction mixture was diluted with DCM, washed with water and brine solution. The
combined organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give crude material which was purified by column chromatography eluting with 20% EtOAc in hexanes to afford methyl benzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (0.75 g, 2.396 mmol, 54% yield) as a white solid. LCMS m/z: 314.09 [M+H].
Preparation 8: Methyl 4-benzvl-2.2-dimethvl-2-oxo-2.4-dihvdro-2H-i.4-benzothiazine-6-carboxylate
To a stirred solution of methyl benzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 7) (0.15 g, 0.48 mmol) in THE (2 mL) at -78 °C was added LiHMDS (0.52 mL, lM solution in THE) drop wise. The mixture was stirred at -78 °C for 15 min. then Mel (0.032 mL, 0.527 mmol) added and the whole allowed to stir for another 30 min. at the same temperature then the reaction mixture was slowly brought to RT and further stirred for 3 h. The reaction mixture was quenched with aqueous NH4C1 solution and extracted with DCM. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a crude product which was purified by column chromatography using 10% EtOAc in hexanes as eluent to afford methyl 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxylate (0.13 g, 0.381 mmol, 80% yield) as a viscous oil. LCMS m/z: 342.29 [M+H].
Preparation 9: 4-Benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxvlic acid
To a stirred solution of methyl 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxylate (Preparation 8) (0.13 g, 0.381 mmol) in a mixture of MeOH, water and THE (1:1:2; 1.7 mL) was added Li0H.H20 (0.032 g, 0.761 mmol) at
RT. The reaction was allowed to stir at RT for 3 h. On completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to ~pH 5 with dilute HC1 and the resulting aqueous solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to give 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylic acid (0.075 g· 0.229 mmol, 60% yield) as a colorless solid which was used in the next step without any further purification. LCMS m/z: 326.13 [M-H].
Preparation 10: 4-Benzyl-N-ffuran-2-ylmethyl')-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
To a stirred solution of 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxylic acid (Preparation 9) (0.07 g, 0.21 mmol) in DMF (2 mL) was added HATU (0.098 g, 0.257 mmol) followed by TEA (0.066 mL, 0.47 mmol) at RT. The resulting reaction mixture was stirred at RT for 15 min. then i-(furan-2-yl)-methanamine (0.021 mL, 0.237 mmol) was added and the whole further stirred at RT for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with chilled water and brine. The organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The crude material obtained was purified by prep-HPLC to afford 4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (0.015 g, 0.036 mmol, 18% yield) as a white solid. LCMS m/z: 407.25 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 1.43 (s, 6H), 4.42 (d, J= 5-55 Hz, 2H), 5.28 (s, 2H), 6.23 (bs, lH), 6.39 (s, lH), 7.17 (d, J = 7-75 Hz, 2H), 7-23-7-25 (m, lH), 7-31-7-34 (m, 2H), 7.51 (d, J = 8.05 Hz, lH), 7.56 (d, J = 8.35 Hz, 2H), 7.64 (s, lH), 9.02 (t, J = 5.5 Hz, lH).
Examples 130-144
Preparation 2: Methyl 2-bromo-3-oxo-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxvlate
To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxylate (Preparation 1) (1.0 g, 4.48 mmol) in CC14 was added NBS (0.797 g, 4-48 mmol) and benzoyl peroxide (0.035 g· 0-144 mmol) at ice cold temperature. The reaction was allowed to warm to RT and then refluxed at 70 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the solid obtained was filtered off. It was washed with water and dried under reduced pressure to obtain pure methyl 2-bromo-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate (0.8 g, 2.649 mmol, 60% yield) as a white solid. LCMS m/z: 238.05 [M-H] in MeCN.
Preparation 3: Methyl 2-fdimethvlamino')-2-oxo-2.4-dihvdro-2H-i.4-benzorb-i.4lthiazine-6-carboxylate
To a stirred solution of methyl 2-bromo-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate (Preparation 2) (0.25 g, 0.82 mmol) in THF (2.5 mL) was added dimethyl amine.HCl (0.202 g, 2.4 mmol) followed by TEA (0.7 mL, 4.92 mmol) at RT. The resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water and brine. The combined organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the methyl 2-(dimethylamino)-3-oxo-3,4-dihydro-2H-i,4-benzo[b-i,4]thiazine-6-carboxylate (0.2 g, 0.75 mmol, 90% yield) as a crude sticky residue which was used as such without any further purification. LCMS m/z: 267.10 [M+H],
Examples 130-144 were prepared according to the above method used to make Example 129 and Preparation 3 as described in General Procedure 11 using the appropriate reagents. Purification was as stated in the aforementioned methods.
Example 145: i-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-:LH-pyridor2,3-b-i,4lthiazine-7-carboxamide
Preparation 11: Methyl 6-ff2-ethoxy-2-oxoethyl')thio')-5-nitro nicotinate
To a stirred solution of methyl-6-chloro-5-nitronicotinate (0.8 g, 3.703 mmol) in acetonitrile (10 mL) was added TEA (1.03 mL, 7.407 mmol) followed by ethyl thioglycolate (0.50 mL, 5.629 mmol) dropwise at RT. The reaction mixture was stirred for 15 min. and then diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give methyl 6-((2-ethoxy-2-oxoethyl)thio)-5-nitronicotinate (1.1 g, 3.66
mmol, 99% yield) as a yellowish solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 301.07 [M+H].
Preparation 12: Methyl 2-oxo-2.3-dihydro-iH-pyridor2.3-biri.4.1thiazine-7-carboxylate
To a stirred solution of methyl 6-((2-ethoxy-2-oxoethyl)thio)-5-nitronicotinate (Preparation 11) (1.0 g, 3.66 mmol) in AcOH (10 mL) was added iron powder (0.819 g, 14.66 mmol) at RT. The resulting reaction mixture was stirred at 90 °C for 2.5 h, after which time the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give methyl 2-oxo-2,3-dihydro-iH-pyrido[2,3-b][i,4]thiazine-7-carboxylate (1.0 g, 4.46 mmol, 99% yield) as a brown solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 225.03 [M+H].
Preparation 13: i-f2-Chloro-6-fluorobenzyl')-N-ffuran-2-ylmethyl')-2-oxo-2.2-dihydro-iH-pyridor2,3-b-i,4lthiazine-7-carboxamide
i-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-iH-pyrido[2,3-b- i,4]thiazine-7-carboxamide (Example 145) was made from methyl 2-oxo-2,3-dihydro-iH-pyrido[2,3-b][i,4]thiazine-7-carboxylate (Preparation 10) using the methods described in Preparation 4, Preparation 5 and Preparation 6, using 2-chloro-6-fluoro-benzyl chloride and i-(furan-2-yl)-methanamine. LCMS m/z: 432.05 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 3.77 (s, 2H), 4.48 (d, J = 5.5 Hz, 2H), 5.34 (s, 2H), 6.29 (d, J = 2.35 Hz, lH), 6.42 (s, lH), 7.14 (t, J = 9.25 Hz, lH), 7-25-7-33 (m, 2H), 7.61 (s, lH), 8.03 (s, lH), 8.54 (s, lH), 9.14 (t, J = 5.5 Hz, lH).
Examples 146-159
Example 146-159 were prepared according to the methods described for the synthesis of Example 145 as described in General Procedures 4 and 5 and 1-3 starting from an appropriate pyridine and using the appropriate benzyl halides and amines.
Certain analogous compounds (Example 150-159) of formula (I) were prepared according to the above methods used to make Example 1 as described in General procedures 1-3 using the appropriate amines and acids. These analogues may also be obtained from commercial suppliers, and are incorporated herein.
Example 160: 4.-Benzvl-8-cvano-N-(furan-2-vlmeLhvl)-2-oxo-2.4.-dihvdro-2/i-benzol b-i.4. lLhiazine-6-earboxamide
Preparation 14: Methyl 3-bromo-4-ff2-ethoxy-2-oxoethyl')thio')-5-nitrobenzoate
To a stirred solution of commercially available methyl 3-bromo-4-fluoro-5-nitrobenzoate (0.25 g, 0.89 mmol) in MeCN (10 mL) was added ethyl thioglycolate
(o.n8 mL, 0.98 mmol) followed by TEA (0.188 mL, 1.85 mmol) at 0-5 °C and further stirred at the same temperature for 10 min. The reaction performance was monitored by TLC and after completion the reaction mixture was diluted with EtOAc and washed with water followed by brine. The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to dryness to afford methyl 3-bromo- 4-((2-ethoxy-2-oxoethyl)thio)-5-nitrobenzoate (0.30 g, 0.79 mmol, 89% yield) which was used in the next step as such. LCMS m/z: 378.09 [M+H].
Preparation 15: Methyl 8-bromo-3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxvlate
Methyl 8-bromo-3-oxo-3,4-dihydro-2H-i,4-benzothiazine-6-carboxylate was made from methyl 3-bromo-4-((2-ethoxy-2-oxoethyl)thio)-5-nitrobenzoate (Preparation 14) using the method described for Preparation 1. LCMS m/z: 300.01 [M-H].
Preparation 16: 8-bromo-4-f2-fluorobenzyl')-N-ffuran-2-ylmethyl')-3-oxo-3.4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
8-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide was made from methyl 8-bromo-3-oxo-3,4-dihydro-2H- i,4-benzothiazine-6-carboxylate (Preparation 15) using the methods described in Preparation 4, Preparation 5 and Preparation 6, using 2-fluorobenzyl chloride and 1-(furan-2-yl)-methanamine. LCMS m/z: 474.88 [M+H]. Ή NMR (500 MHz; DMSO-de): δ 3.82 (s, 2H), 4.42 (d, J = 5.55 Hz, 2H), 5.27 (s, 2H), 6.24 (d, J = 3.05 Hz, lH), 6.39-6.40 (m, lH), 7.11-7.12 (m, 2H), 7-21-7-25 (m, lH), 7-30-7-33 (m, lH), 7.58-7.61 (m, 2H), 7.89 (d, J = 1.20 Hz, lH), 9.11 (t, J = 5.5 Hz, lH).
Preparation 17: 4-Benzyl-8-cyano-N-ffuran-2-ylmethyl')-3-oxo-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
A stirred solution of 4-benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Preparation 16) (0.095 g, 0.20 mmol) in NMP (20 mL) was degassed thoroughly with Ar. To the mixture was added CuCN (0.093 g> 1.03 mmol) under an Ar atmosphere and the resulting reaction mixture was heated at 145-150 °C for 16 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mass was cooled to RT, diluted with EtOAc and washed with an aqueous FeCl3 solution followed by water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product obtained was purified by column chromatography using 30% EtOAc in hexanes as eluent to afford 4-Benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2ft-benzo[b-i,4]thiazine-6-carboxamide (0.02 g, 0.049 mmol, 25% yield) as an off white solid. LCMS m/z: 402.28 [M-H]; Ή NMR (500 MHz; DMSO-d6): δ 3-91 (s, 2H), 4-43 (d, J = 5-35 Hz, 2H), 5.30 (s, 2H), 6.26 (d, J = 2.6 Hz, lH), 6.40 (s, lH), 7.20-7.26 (m, 3H), 7-31-7-34 (m, 2H), 7-59 (s, lH), 7.85 (s, lH), 8.04 (s, lH), 9.16 (t, J = 5.25 Hz, lH).
Examples 161 and 165
Examples 161 and 165 were prepared in an entirely analogous manner to Example 160 using the methods described in Preparations 15 and 16, as described in General Procedures 4, 5 and 1-3 starting with an appropriate nitroarene and using the appropriate benzyl amine and i-(furan-2-yl)-methanamine.
Example 166: 4-(2-Fluorobenzyl)-N-(ftiran-2-ylmethyD-8-methyl-3-oxo- 2,4-dihvdro-2/i-benzo| b-1,4 lLhiazine-6-earboxaniide
Preparation 18
To a stirred solution of 8-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 162) (0.08 g, 0.201 mmol) in a mixture of 1,4-dioxane and water (10:1; 9 mL) was added trimethylboroxine (0.07 mL, 0.504 mmol) and K2CO3 (0.056 g, 0.402 mmol) at RT in a sealed tube. The
resulting reaction mixture was degassed with Ar for 15 min. then Pd(PPh3)4 (0.047 g, 0.040 mmol, 20 mol%) was added at RT. Finally, the reaction mixture was heated at 110 °C for 16 h. The progress of reaction was monitored by TLC/LCMS and after completion; the reaction mixture was cooled down to RT, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by prep-HPLC to give 4-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-8-methyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (0.02 g, 0.048 mmol, 25% yield) as an off white solid. LCMS m/z: 411.01 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 2.36 (s, 3H), 3.70 (s, 2H), 4.42 (d, J = 5.20 Hz, 2H), 5.28 (s, 2H), 6.21 (s, lH), 6.39 (s, lH), 7.09-7-12 (m, 2H), 7.22 (t, J = 9.7 Hz, lH), 7-30-7-33 (m, lH), 7.49-7.61 (m, 3H), 8.97 (bs, lH).
Example 167
Example 167 was prepared in an entirely analogous manner to Example 169 (below) starting from Example 162.
Example 168: 4.-benzyl-8-bromo-JV-(furan-2-ylmethyl)-3-oxo-3,4.-dihydro-2/i-i,4.-benzo|b-i,4. lLhiazine-6-earboxamide
Preparation iq: Methyl 2-bromo-4-fluoro-.i:;-nitrobenzoate
Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.31 mmol) was dissolved in H2SO4 (10 mL) and cooled to 0-5 °C, then potassium nitrite (0.43 g, 4.31 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mass was poured into crushed ice and stirred for 30 min. The solid obtained was filtered, washed with cold water and dried under reduced pressure to obtain methyl 2-bromo-4-fluorobenzoate (0.86 g, 3.09 mmol, 72% yield) as a yellow solid which was pure enough to be used in the next step. LCMS m/z: 276.07 [M-H].
Preparation 20: Methyl 7-bromo-3-oxo-3.4-dihydro-2H-benzorbiri.4lthiazine-6-carboxvlate
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate was made from methyl 2-bromo-4-fluoro-5-nitrobenzoate (Preparation 19) using the method described in Preparation 1. LCMS m/z: 300.03 [M-H].
Preparation 21: 4-benzyl-8-bromo-iV-ffuran-2-ylmethyl')-3-oxo-3,4-dihydro-2H-i,4-benzo[b-i,4lthiazine-6-carboxamide
4-benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2if-i,4-benzo[b- i,4]thiazine-6-carboxamide was made from Methyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate (Preparation 20) using the methods described in Preparations 4 to 6, according to the General Procedures 1-3 using 2-fluorobenzyl chloride and i-(furan-2-yl)-methanamine. LCMS m/z: 474.85 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 3.74 (s, 2H), 4.37 (d, J = 5.7 Hz, 2H), 5.24 (s, 2H), 6.15 (d, J =2.65 Hz, lH), 6.38 (s, lH), 7-09-7-15 (m, 3H), 7.24 (t, J = 9-8 Hz, lH), 7-32-7-36 (m, lH), 7.55 (s, lH), 7.78 (s, lH), 8.91 (bs, lH).
Example 169
Preparation 22: 7-cyclopropyl-4-f2-fluorobenzyl')-N-ffuran-2-ylmethyl')-3-oxo-3,4-dihydro-2H-benzorb-i.4lthiazine-6-carboxamide
To a stirred solution of 4-benzyl-8-bromo-2V-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-i,4-benzo[b-i,4]thiazine-6-carboxamide (Example 168/Preparation 21) (0.14 g, 0.294 mmol) in a mixture of 1,4-dioxane and water (10:1; 11 mL) was added cyclopropylboronic acid (0.076 g, 0.88 mmol) and sodium ferf-butoxide (0.056 g, 0.58 mmol) at RT in a sealed tube. The resulting reaction mixture was degassed with Ar for 15 min. then tricyclohexylphosphine (0.016 g, 0.058 mmol) and PdCl2(PPh3)2 (0.020 g, 0.029 mmol, 10 mol%) was added at RT. Finally, the reaction mixture was heated at 110 °C for 16 h. The progress of reaction was monitored by TLC/LCMS and after completion; the reaction mixture was cooled down to RT, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude material which was purified by prep-HPLC to give 7-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (0.01 g, 0.022 mmol, 8% yield) as an off white solid. LCMS m/z: 437.36 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 0.64 (d, J = 4.1 Hz, 2H), 0.83 (d, J = 7.85 Hz, 2H), 2.11 (bs, lH), 3.68 (s, 2H), 4.38 (d, J = 5.3 Hz, 2H), 5.22 (s, 2H), 6.07 (s, lH), 6.37 (s, lH), 6.98 (d, J = 15.15 Hz, 2H), 7-08-7.15 (m, 2H), 7.25 (t, J = 9-55 Hz, lH), 7-33-7-34 (m, lH), 7.53 (s, lH), 8.80 (bs, lH).
Example 170: 4-benzyl-N-(furan-2-ylmethyl)-7-methyl-3-oxo-3,4-dihydro-2H-benzorb-i,4.1thiazine-6-carboxamide
Example 170 was prepared in an entirely analogous manner to Example 166 from Example 168.
Example 171: 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzorb-i.4loxazine-6-carboxamide
Example 171 was prepared in an entirely analogous manner to Example 1, as described in General procedures 1-6, starting with an appropriate alcohol in place of the thiol.
Preparation 22: Methyl 4-ffi-ethoxy-i-oxopropan-2-yl')oxy')-2-nitrobenzoate
Methyl-4-fluoro-3-nitrobenzoate (0.5 g, 2.5 mmol) and 2-hydroxy methyl propionate (0.356 g, 0.301 mmol) were dissolved in 1,4-dioxane (5 mL) at RT. In to the resulting reaction mixture, NaH (0.0726 g, 3.01 mmol; 60% suspension in oil) was added portionwise with ice bath cooling and allowed to stir at room temperature for 16 h. On completion of the reaction it was quenched with aqueous NH4C1 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford methyl 4-((i-ethoxy-i-oxopropan-2-yl)oxy)-3-nitrobenzoate (0.6 g, 2.02 mmol, 81% yield) as a colourless oil which was used directly in the next step without further purification. LCMS m/z: 298.16 [M+H].
Preparation 24: Methyl 2-methyl-3-oxo-3.4-dihydro-2H-i.4-benzoxazine-6-carboxylate
Methyl 2-methyl-3-oxo-3,4-dihydro-2H-i,4-benzoxazine-6-carboxylate was prepared from Preparation 23 using the method described in Preparation 1. LCMS m/z: 222.06 [M+H],
Example 172
Preparation 25: 2-Methyl-4-(3.s-difluorobenzyl')-3-oxo-A-(2.4.6-trifluorobenzyl)-3.4-dihvdro-2H-i.4-benzoxazine-6-carboxamide
Example 172 was made from Preparation 24 using the methods described in Preparations 4 to 6, using 3,5-difluorobenzyl chloride and 1-(2,4,6-trifluorophenyl)methanamine. LCMS m/z: 477.28 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 1.53 (d, J = 6.65 Hz, 3H), 4.41 (s, 2H), 5.02-5.10 (m, 2H), 5.29 (d, J = 16.8 Hz, lH), 6.99 (d, J = 6.5 Hz, 2H), 7-H-7-17 (m, 4H), 7-41 (s, lH), 7.53 (d, J = 8.25 Hz, lH), 8.73 (bs, lH).
Examples 173-175
Examples 173-175 were prepared in an analogous manner to Example 172, following the methods described in Preparations 23 to 25, starting with an appropriate nitroarene and alcohol.
Examples 176-181
Examples 176-181 were prepared in an entirely analogous manner to Examples 173-175 as described in General Procedures 1-5, starting with an appropriate alcohol in place of the thiol.
Example 182
Preparation 26: 4-f2-chloro-6-fluorobenzyl')-N-ffuran-2-ylmethyl')-3-oxo-3,4-dihydro-2H-benzo- Tb-i.4 thiazine-6-carboxamide l-oxide
To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 129) (0.03 g 0.0696 mmol) in dry DCM (2 mL) was added mCPBA (0.012 g, 0.0696 mmol) at 0-5 °C. The resulting reaction mixture was stirred at room temperature for 1 h. It was then quenched with saturated Na2S203 solution and extracted with EtOAc. The combined organics were washed with NaHCO3 solution followed by water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product obtained was purified by prep-HPLC to obtain 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo- [b-1,4 thiazine-6-carboxamide l-oxide (0.008 g, 0.017 mmol, 26% yield) as an off white solid. LCMS m/z: 447.09 [M+H]. Ή NMR (500 MHz; DMSO-de): δ 4.28 (s, 2H), 4.48 (t, J = 4.75 Hz, 2H), 5.36 (d, J = 15.9 Hz, iH), 5-45 (d, J = 15-9 Hz, lH), 6.29 (d, J = 2.8 Hz, lH), 6.41-6.42 (m, lH), 7.15 (t, J = 9.05 Hz, lH), 7-30-7-35 (m, 2H), 7.60 (d, J = 0.8 Hz, lH), 7.73 (d, J = 7.9 Hz, lH), 7.92 (d, J = 8.1 Hz, 2H), 9.18 (t, J = 5.5 Hz, lH).
Example 182: 4-benzvl-N-(furan-2-vlmethvl)-2.4-dihvdro-2H-henzolb-i.4.1thiazine-6-carboxamide
Preparation 27: Methyl 4-benzyl-3.4-dihydro-2H-benzorbiri.4lthiazine-6-carboxylate
To a stirred suspension of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxylate (Preparation 7) (0.25 g, 0.798 mmol) in THF (2.5 mL) was added borane-THF solution (5.6 mL, 0.9 mol/L solution in THF) at 0-5 °C. The resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was quenched by dropwise addition of MeOH (15 mL) at 0-5 °C. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product obtained of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate (0.25 g, 0.835 mmol) was used in next step without any further purification. LCMS m/z: 300.19 [M+H],
Preparation 28: 4-benzyl-N-ffuran-2-ylmethyl')-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 183) was prepared from methyl 4-benzyl-3,4-dihydro-2H-i,4-benzothiazine- 6- carboxylate (Preparation 27) using an identical procedure to that described for Preparations 5 and 6. LCMS m/z: 365.22 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 3.13 (t, J = 5.0 Hz, 2H), 3-63-3-65 (m, 2H), 4.38 (d, J = 5.65 Hz, 2H), 4.62 (s, 2H), 6.18 (d, J = 2.85 Hz, lH), 6.37 (s, lH), 7-04-7-09 (m, 2H), 7.17 (s, lH), 7-24-7-30 (m, 3H), 7- 34-7-37 (m, 2H), 7.55 (s, lH), 8.76 (t, J = 5.6 Hz, lH).
Examples 184-186
Examples 184-186 were prepared in an analogous manner to Example 183 as described in General Procedure 6 starting from the appropriate lactam.
Example 187: 4-(4-chlorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo rb-i,4lthiazine-6-carboxamide ~
0
Compound (Example 187) was purchased from a commercial supplier. LCMS m/z: 399.24 [M+H],
Example 188
Preparation 2Q: 4-benzyl-N-(furan-2-ylmethyl')-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxamide l-oxide
4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1-oxide (Example 188) was prepared from 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 183) using an identical procedure to that described in Preparation 26 and described in General Procedure 16. LCMS m/z: 381.29 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 2.93-2.99 (m, lH), 3.16-3.19 (m, lH), 3.66-3.68 (m, lH), 3.95 (t, J = 13 Hz, lH), 4.41 (d, J = 5.60 Hz, 2H), 4.78-4.88 (q, J = 17.2 Hz, 2H), 6.20 (d, J = 2.7 Hz, lH), 6.38 (s, lH), 7.13 (d, J = 8.3 Hz, lH), 7.29 (t, J = 6.95 Hz, 4H), 7-34-7-37 (m, 2H), 7-57-7-61 (m, 2H), 9-00 (t, J = 5.6 Hz, lH).
Example i8q
Preparation 30: 4-benzyl-N-(furan-2-ylmethyl')-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxamide 1.1-dioxide
To a stirred solution of 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide (Example 183) (0.1 g 0.274 mmol) in dry DCM (2 mL) was added mCPBA (0.142 g, 0.822 mmol) in 3 equal portions at an interval of 6 h between portions at 0-5 °C under an inert atmosphere. The resulting reaction mixture was then stirred at room temperature for 20 h. It was quenched with saturated Na2S203 solution and extracted with EtOAc. The combined organics were washed with NaHCO3 solution followed by water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product obtained was purified by prep-HPLC to obtain 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1,1-dioxide (0.03 g, 0.075 mmol, 28% yield) as an off white solid. LCMS m/z: 397.21 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 3.65-3.67 (m, 2H), 3.97-3.99 (m, 2H), 4.41 (d, J = 5.60 Hz, 2H), 4.78 (s, 2H), 6.21 (d, J = 2.9 Hz, lH), 6.38 (s, lH), 7.21-7.24 (m, 2H), 7.27-7.30 (m, 3H), 7-35-7-38 (m, 2H), 7.57 (s, lH), 7.71 (d, J = 8.15 Hz, lH), 9.04 (t, J =5-6 Hz, iH).
Example iqo: 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
Preparation 31: Methyl-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxylate
Methyl-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate was prepared from methyl 3-oxo-3,4-dihydro-2H-benzo[b-i,4]- thiazine-6-carboxylate (Preparation 1, step 2) using an identical procedure to that described for Preparation 27. LCMS m/z: 210.08 [M+H],
Preparation 32: Methyl 4-f2-fluorobenzoyD-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxvlate
To a stirred solution of methyl 3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 31) (0.2 g, 0.956 mmol) in dry DCM (5 mL) was added TEA (0.33 mL, 2.39 mmol) at RT, then 2-fluorobenzoyl chloride (0.227,1.435 mmol) was added dropwise with ice cooling and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction it was diluted with DCM and washed successively with lN HCI, saturated NaHCO3 solution and then brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude product of methyl 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (0.25 g, 0.755 mmol, 79% yield) obtained was used in the next step with no further purification. LCMS m/z: 332.15 [M+H],
Preparation 33: 4-f2-fluorobenzoyP-3.4.-dihydro-2H-benzorbHT.4lthiazine-6-carboxvlic acid
To a stirred solution of methyl 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxylate (Preparation 32) (0.25 g, 0.755 mmol) in a mixture of MeOH, water and THF (1:1:2; 20 mL) was added Li0H.H20 (0.064 g, 1-51 mmol) at RT. The reaction was allowed to stir at room temperature for 16 h. Upon completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to -pH 5 with dilute HCI. The acidified aqueous solution was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to give 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylic acid (0.2 g. 0.631 mmol, 84% yield) as an off white solid which was used in the next step without any further purification. LCMS m/z: 316.12 [M+H].
Preparation 34: 4-(2-fluorobenzoyl')-N-(fnran-2-ylmethyl')-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxamide
4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 190) was prepared from 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-i,4]-thiazine-6-carboxylic acid (Preparation 33) following the method described for Example 1. LCMS m/z: 397.23 [M+H]; Ή NMR (500 MHz; DMSO-de): δ 3.32 (bs, 2H), 3-37 (s, 2H), 4-34 (bs, 2H), 6.12 (bs, lH), 6.39 (s, lH), 7.05-7.23 (m, 3H), 7.32 (d, J = 8.25 Hz, 2H), 7-33-7-45 (m, 2H), 7-52-7-53 (m, lH), 7.57 (s, lH), 8.70 (bs, iH).
Example 191
Preparation 35: 4-(2-fluorobenzoyl')-N-(furan-2-ylmethyl')-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxamide 1.1-dioxide
4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1,1-dioxide (Example 191) was prepared from 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 190) following the method described for Preparation 30/Example 189. LCMS m/z: 429.23 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 3.92 (s, 2H), 4-38 (bs, 4H), 6.18 (s, iH), 6.41 (s, iH), 7.22-7.29 (m, 2H), 7-54-7-59 (m, 3H), 7-69 (bs, iH), 7.84 (d, J = 8.05 Hz, iH), 7.98 (d, J = 7.8 Hz, iH), 9.11 (bs, iH).
Examples 192-195
Examples 192-195 were prepared in an analogous manner to that described for Example 190 starting from Preparation 31 using the appropriate acyl halides and amines.
Example iq6: 4-(phenylsulfonyD-N-i2.4.6-trifluorobenzyl)-3.4.-dihydro-2H-benzorb-i.4.1thiazine-6-carboxamide
Preparation 36: Methyl 4-fphenylsulfonyl)-3.4-dihydro-2H-benzorb-i.4lthiazine-6-carboxvlate
To a stirred solution of methyl 3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 31) (0.15 g, 0.72 mmol) in dry pyridine (6 mL) was added DMAP (0.01 g, 0.082 mmol) at RT, then benzenesulfonyl chloride (0.142 mL, 1.1 mmol) was added dropwise with ice cooling, then the reaction mixture was stirred at 60 °C for 4 h. After this time, the reaction mixture was acidified with 3N HCI and the resulting solution was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and then brine and then dried over anhydrous Na2SO4 and evaporated to dryness. The crude product of methyl 4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (0.2 g, 0.57 mmol, 80% yield) obtained was used in the next step with no further purification. LCMS m/z: 350.16 [M+H].
Preparation 37: 4-fphenylsulfonyl')-N-f2,4,6-trifluorobenzyl')-3,4-dihydro-2H-benzorb-i,4lthiazine-6-carboxamide
4-(phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 196) was prepared using the method described in Preparation 36 and Example 1 using the General Procedures 1-3. LCMS m/z: 479.27 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 2.90 (t, J = 5-4 Hz, 2H), 3-93 (t, J = 5-35 Hz, 2H), 4-46 (d, J = 4.85 Hz, 2H), 7-20-7.23 (m, 3H), 7-51-7-64 (m, 5H), 7.70 (t, J = 6.9 Hz, lH), 8.04 (d, J = 1.25 Hz, lH), 8.92-8.94 (m, lH).
Example 197: 4-((3,.5-difluorophenyl)sulfonyl)-N-(2,4,6-trifluorobenzyl)- 3,4-dihvdro-2H-benzo| b-1,4 lthiazine-6-earboxamide
Example 197 was prepared in an analogous manner to Example 196 using 3,5-dlifluorobenzene sulfonyl chloride and 2,4,6-trifluorobenzyl amine.
Examples 108-200
Examples 198-200 were prepared in an entirely analogous manner to Example 192-195, starting with the appropriate lactam and using the appropriate acyl halide, alkyl halide and amine as described in General Procedures 1-3 and 6.
Example 201: 4-benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2U-benzorb-i,4lthiazine-6-carboxamide
Preparation 38: Methyl 4-benzyl-3-thioxo-3.4-dihydro-2H-benzorbiri.4lthiazine-6-carboxvlate
To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 7) (0.24 g, 0.799 mmol) in xylene (8 mL) was added Lawesson's reagent (0.258 g, 0.639 mmol) at RT. The resulting reaction mixture was heated at 115-120 °C for 24 h. TLC and LCMS showed product formation along with some starting material. The reaction mixture was diluted with water, extracted with EtOAc; the combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography using 5-10% EtOAc in hexanes to afford methyl 4-benzyl-3-thioxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxylate (0.12 g, 0.364 mmol, 46% yield) as a yellow solid. LCMS m/z: 330.2 [M+H].
Preparation 39: 4-benzvl-N-ffiiran-2-vlmethvO-3-thioxo-3,4-dihvdro-2H-benzorb-i,4lthiazine-6-carboxamide
4-benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide (Example 201) was prepared from methyl 4-benzyl-3-thioxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxylate (Preparation 38) using identical methods described in Preparations 5 and 6. LCMS m/z: 393.0 [M-H]; Ή NMR (400 MHz;
CDC13): δ 0.86-0.88 (m, ιΗ), 4.03 (s, 2H), 4.55 (d, J = 4.84 Hz, 2H), 5.91 (s, 2H), 6.25 (s, lH), 6.14 (s, lH), 6.24 (s, lH), 6.33 (s, lH), 7.19-7.20 (m, lH), 7-25-7-33 (m, 3H), 7-36-7-39 (m, 2H), 7.68 (bs, lH).
Example 202: i-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2.4..6-Lrifluorobenzvl)-i.2.2.4.-LeLrahvdroauinoline-7-earboxamide
Preparation 40: Methyl i-f2-chloro-6-fluorobenzyl')-2-oxo-i.2.2.4-tetrahydroauinoline-7-carboxvlate
Methyl i-(2-chloro-6-fluorobenzyl)-2-oxo-i,2,3,4-tetrahydroquinoline-7-carboxylate was prepared from commercially available methyl 2-oxo-i,2,3,4-tetrahydroquinoline-7-carboxylate and 2-chloro-6-fluoro-benzyl chloride using identical method described in Preparation 4. LCMS m/z: 348.14 [M+H].
Preparation 41: Methyl i-f2-chloro-6-fluorobenzyl')-2-methyl-2-oxo-i.2.2.4-tetrahydroquinoline-7-carboxylate
To a stirred solution of methyl i-(2-chloro-6-fluorobenzyl)-2-oxo-i,2,3,4 tetrahydroquinoline-7-carboxylate (Preparation 40) (0.6 g, 0.28 mmol) in dry THE (20 mL) was added LiHMDS (1.6 mL, 2.07 mmol) at -78 °C and allowed to stir for 15 min. at -78 C followed by addition of Mel (0.16 mL, 2.07 mmol) and maintained at -78% for 30 min. After completion of reaction (monitored by TLC/LCMS), the reaction mixture was quenched with water, extracted with EtOAc, dried and evaporated to obtain the
crude which was purified by Combi-flash (4.0 g column) and eluted with 32% EtOAc in hexanes to afford methyl i-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-i,2,3,4-tetrahydroquinoline-7-carboxylate (0.11 g, 0.348 mmol, 17% yield) as a colourless oil. LCMS m/z: 362.21 [M+H],
Preparation 42: i-f2-chloro-6-fluorobenzyl')-3-methyl-2-oxo-N-f2.4..6-trifluorobenzyl')- i.2.2.4-tetrahvdroqiiinoline-7-carboxamide
i-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4-tetrahydroquinoline-7-carboxamide (Example 202) was prepared from methyl 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-i,2,3,4-tetrahydroquinoline-7-carboxylate (Preparation 41) using identical methods described in Preparations 5 and 6. LCMS m/z: 491.27 [M+H]; Ή NMR (500 MHz; DMSO-d6): δ 1.14 (d, J = 6.4 Hz, 3H), 2.56-2.68 (m, 2H), 2.93-2.96 (m, lH), 4.39-4.48 (m, 2H), 5.16 (d, J = 15.85 Hz, lH), 5.45 (d, J = 15.9 Hz, lH), 7.10-7.14 (m, lH), 7.21 (t, J = 8.7 Hz, 2H), 7-27-7-32 (m, 3H), 7-41-7-43 (dd, Λ = 7.7 Hz, J2 = 0.95 Hz, lH), 7.50 (s, lH), 8.78 (t, J = 5.1 Hz, lH).
Examples 203-206
Examples 203-206 were prepared in an identical manner to that described for Example 202 starting from an appropriate nitroarene and using the appropriate benzyl halides and amines as described for General procedures 7-10.
Example 207: 5-(3,5-difluorobenzyl)-6-oxo-N-(2,4.,6-trifluorobenzyl)-S.6.7.8-LeLrahvdro-i.s-nanhLhvridine-u-earboxamide
Preparation 43: (E)-methyl 5-amino-6-f3-ethoxy-3-oxoprop-i-en-i-yPnicotinate
A sealed tube was charged with commercially available 5-amino-6-bromo-nicotinic acid methyl ester (2.0 g, 8.658 mmol), DMF (1.0 mL), ethyl acrylate (2.16 mL, 20.304 mmol) and then TEA (2.19 mL, 15.7 mmol) and the whole degassed with N2 gas for 15 min. ATAPHOS (0.307 g, 0.4336 mmol, 50 mol%) was then added at RT. The resulting reaction mixture was heated at 140 °C for 12 h. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography to afford (E)-methyl 5-amino-6-(3-ethoxy-3-oxoprop-i-en-i-yl)nicotinate (0.95 g, 3.8 mmol, 44% yield). LCMS m/z: 251.2 [M+H].
Preparation 44: Methyl 5-amino-6-(A-ethoxv-2-oxopropvPnicotinate
To a stirred solution of (E)-methyl 5-amino-6-(3-ethoxy-3-oxoprop-i-en-i-yl)nicotinate (Preparation 43) (0.5 g, 2.0 mmol) in MeOH (15 mL) was added Pd/C (0.55 g, 10% w/w) under a N2 gas atmosphere at RT. The resulting reaction mixture was stirred under H2 gas balloon pressure at 0-5 °C for 2 h. The reaction was monitored by TLC and after completion the whole was filtered through a celite bed and washed with MeOH. The filtrate was concentrated under reduced pressure to give methyl 5-amino-
6-(3-ethoxy-3-oxopropyl)nicotinate (0.45 g, 1.785 mmol, 89% yield) as a crude solid which was used as such in the next step without further purification. LCMS m/z: 252.9 [M+H],
Preparation 4S: Methyl 6-oxo-s.6.7.8-tetrahydro-i.s-naphthyridine-2-carboxylate
To a stirred solution of methyl 5-amino-6-(3-ethoxy-3-oxopropyl)nicotinate (Preparation 44) (0.4 g, 1.587 mmol) in toluene (5 mL) was added formic acid (3.0 mL) at RT. The resulting mixture was heated to reflux for lh. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a yellow residue, which was diluted with water and extracted with EtOAc. The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product which was purified by column chromatography to afford methyl 6-oxo-5,6,7,8-tetrahydro-i,5-naphthyridine-3-carboxylate (0.25 g, 1.213 mmol, 76% yield) as an off white solid. LCMS m/z: 207.1 [M+H].
Preparation 46: s-f2.s-difluorobenzyl')-6-oxo-N-f2.4.6-trifluorobenzyl')-s.6.7.8-tetrahydro-i,5-naphthyridine-3-carboxamide
F 5-(3,5-difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-i,5- naphthyridine-3-carboxamide (Example 207) was prepared from methyl 6-OXO-5,6,7,8-tetrahydro-i,5-naphthyridine-3-carboxylate (Preparation 45) using identical methods described in Preparations 5 and 6. LCMS m/z: 462.1 [M+H]; Ή NMR (400 MHz; DMSO-de): δ 2.87 (t, J = 7.76 Hz, 2H), 3.18 (t, J = 7.12 Hz, 2H), 4.43 (d, J = 4.24 Hz, 2H), 5.15 (s, 2H), 6.68 (d, J = 6.24 Hz, 2H), 7.09-7.18 (m, 3H), 7.51 (s, lH), 8.56 (s, lH), 9.02 (bs, lH).
Examples 208-214
Examples 208-214 were made in an analogous manner to Example 207 starting from the appropriate pyridine and using the appropriate benzyl halides and amines as described for General procedures 7-10.
Example 215: i-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4.,6- trifluorobenzyh-i.2.3.4.-tetrahydroauinazoline-7-carboxamide
c
Preparation 47: Methyl 4-(bromomethyl)-3-nitrobenzoate
To a stirred solution of methyl 4-methyl-3-nitrobenzoate (4.0 g, 20.51 mmol) in trifluoro toluene (85 mL) was added NBS (5.477 g, 30.769 mmol) and benzoyl peroxide (0.746 g, 3.077 mmol) at RT. The resulting reaction mixture was heated at 100 °C for i6h. After completion, the reaction mixture was quenched with a saturated solution of Na2S203 (too mL) and extracted with EtOAc. The combined organics were washed with brine and concentrated under reduced pressure to give the crude product which was purified by column chromatography using 2% EtOAc in hexanes to afford methyl 4-(bromomethyl)-3-nitrobenzoate (2.5 g, 9.124 mmol, 44% yield) as a brown gummy solid. Ή NMR (400 MHz; CDC13): δ 3-97 (s, 3W, 4-83 (s, 2H), 7.66 (d, J = 7.32. Hz, iH), 8.24 (d, J = 6.64 Hz, iH), 8.65 (s, iH).
Preparation 48: Methyl 4-ffmethylamino')methyl')-3-nitrobenzoate
MeNH2 (25 mL, lM solution in THF) was added to methyl 4-(bromomethyl)-3-nitrobenzoate (Preparation 47) (2.5 g, 9.124 mmol) at RT and the resulting reaction mixture was stirred at RT for i6h. Progress of reaction was monitored by TLC and after completion, the reaction mixture was diluted with water (80 mL) and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford methyl 4- ((methylamino)methyl)-3-nitrobenzoate (1.4 g, 6.25 mmol, 68% yield) as a red gummy solid. LCMS m/z: 225 [M+H].
Preparation 49: Methyl 3-amino-4-ffmethylamino')methyl)benzoate
To a stirred solution of methyl 4-((methylamino)methyl)-3-nitrobenzoate (Preparation 48) (1.4 g, 6.25 mmol) in EtOAc (25 mL) was added Pd/C (0.5 g, 10% w/w) under N2 gas atmosphere. The resulting reaction mixture was stirred at RT for 3h under H2 gas balloon pressure. The reaction was monitored by TLC and after completion the reaction mixture was filtered through a celite bed and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford methyl 3-amino-4-((methylamino)methyl)benzoate (1.2 g, 6.185 mmol, 99% yield) as a brownish gum. LCMS m/z: 195 [M+H].
Preparation 50: Methyl 3-methyl-2-oxo-i.2,3,4-tetrahydroquinazoline-7-carboxylate
To a stirred solution of methyl 3-amino-4-((methylamino)methyl)benzoate (preparation 49) (0.7 g, 3.608 mmol) in DCM (15 mL) was added triphosgene (1.07 g, 3.608 mmol) followed by TEA (1.257 mL, 9.021 mmol) at 0-5 °C and the reaction mixture was stirred at RT under an inert atmosphere for 3h. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was quenched with saturated NaHCO3 solution (30 mL) and extracted with DCM. The combined organics were
washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel using 1% MeOH in DCM as eluent to afford methyl 3-methyl-2-oxo-i,2,3,4-tetrahydroquinazoline-7-carboxylate (0.19 g, 0.8636 mmol, 24% yield) as an off white solid. LCMS m/z: 221 [M+H].
Preparation si: i-f.2.s-difluorobenzyl')-2-methyl-2-oxo-N-f2.4.6-trifluorobenzyl)- i,2,3,4-tetrahydroquinazoline-7-carboxamide
1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinazoline-7-carboxamide (Example 215) was prepared from methyl 3-methyl-2-oxo-i,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 50) using identical methods described in Preparations 5 and 6. LCMS m/z: 476.3 [M+H]; Ή NMR (400 MHz; DMSO-de): δ 2.95 (s, 3H), 4.38 (s, 2H), 4.52 (s, 2H), 5.11 (s, 2H), 6.93 (d, J = 6.64 Hz, 2H), 7.11-7.16 (m, 4H), 7.23 (d, J = 7.52 Hz, lH), 7.42 (d, J = 7.08 Hz, lH), 8.81 (bs, lH).
Examples 216-221
Examples 216-221 were made in an analogous manner to Example 215 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described for General Procedures 13-15.
Biological Assays
Stable cell line generation a) Stable STING expressing cells - Stable HEK293T STING-expressing cell lines were generated using plasmids purchased from Invivogen, CA, USA, that contain STING cDNA cloned into the pUNO-i vector under hEFi-HTLV promoter and containing the Blasticidin selection cassette. The plasmids hSTING(R232), hSTING(H232), hSTING(HAQ) were directly procured from Invivogen while hSTING (AQ) and hSTING (Q) were derived from hSTING(HAQ) and hSTING (R232) plasmids respectively by using a PCR based site directed mutagenesis method. These vectors were individually transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Blasticidin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected with each of the above
mentioned human STING variants. Only those clones were selected in which ligand independent activation of STING was minimal. b) Stable Luciferase reporter gene expressing cells - Stable HEK293T Luciferase reporter gene expressing cell lines were generated using pCDNA4 plasmids under an IRF-inducible promoter. This promoter is comprised of five tandem interferon-stimulated response elements (ISRE) fused to an ISG54 minimal promoter. This vector was transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Zeocin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected the Luciferase reporter construct. Only those clones were selected in which ligand independent induction of luciferase was minimal. .
Luciferase Assay 5 x 105 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 384-well plates in growth medium and stimulated with known STING agonist or novel compounds. After 2ohr of stimulation supernatant were removed and secretary reporter gene activity were measured using the Quanti-Luc detection system (Invivogen) on a Spectramax 13X luminometer.
In the tables below, EC50 value ranges for exemplary compounds are given. The EC50 ranges are indicated as “A” for values less than or equal to 1 μΜ, “B” for values greater than 1 pM and less than or equal to 10 pM, and “C” for values greater than 10 pM.
All compounds were first tested in a primary screen to obtain a ‘fold-induction’ over baseline levels of protein activity. Only those compounds that had a fold induction >1 have been included in the table and all are considered ‘active’.
Results
Conclusion
The inventors have synthesised a large number of compounds which fall within the general formula (I). They have shown that these compounds activate the STING protein, and so could be used to treat a number of diseases, including cancer.

Claims (46)

  1. Claims l. A compound of formula (I):
    or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR9R°, O, S, S=0 or S02; XUs CR1 orN; X2is CR2orN; X3is CR3orN; the or each Z is independently CRUR12 or NR11; n is l or 2; Q is C=0, S=0, S02, C=S or CR4Rs; L is optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, optionally substituted C3-C&amp; cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C=0, S=0, S02, -CH2C(0)-, -CH2C0NH-, or -C0NH-; Y is an optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONFER2, NR’R2, NHCOR1, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, 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 Ci-C6 alkoxycarbonyl group, mono or bicyclic optionally substituted C5-Ci0 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; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted (Co-Ce) cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring;
    R6 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R9 and R10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryl oxy; or R11 and R12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O, L is - CH2-; Y is -CH2-; R7 is H; and R6 is unsubstituted phenyl
    or then R8 is not unsubstituted furanyl; and when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O, L is -CH2-; Y is -CH2-; 1 R7 is H; and R6 ii then R8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, for use in therapy.
  2. 2. A compound according to claim l, wherein X1 is CR1, X2 is CR2 and X3 is CR3.
  3. 3. A compound according to claim 1, wherein one or two of X1, X2 and X3 is N.
  4. 4. A compound according to any preceding claim, wherein R1, R2 and R3 are each H.
  5. 5. A compound according to any preceding claim, wherein X is O, S or CR9R10.
  6. 6. A compound according to claim 5, wherein X is S or CR9R10.
  7. 7. A compound according to any preceding claim, wherein at least one of R9 and R10 is an optionally substituted C1-C6 alkyl, halogen, H, a C3-C6 cycloalkyl or C1-C3 polyfluoroalkyl.
  8. 8. A compound according to claim 7, wherein both R9 and R10 are H.
  9. 9. A compound according to any preceding claim, wherein n is 1.
  10. 10. A compound according to any preceding claim, wherein Z is NR11 and R11 is an optionally substituted C1-C6 alkyl, H, a C3-C6 cycloalkyl or Ci-C3 polyfluoroalkyl.
  11. 11. A compound according to any one of claims l to 9, wherein Z is CRUR12.
  12. 12. A compound according to claim 11, wherein at least one of R11 and R12 is H.
  13. 13. A compound according to claim 12, wherein both R11 and R12 is H.
  14. 14. A compound according to claim 12, wherein one of R11 and R12 is H and the other is an optionally substituted C1-C6 alkyl or an optionally substituted C2-C6 alkenyl.
  15. 15. A compound according to any preceding claim, wherein Q is C=O, S02 or CR^Rs.
  16. 16. A compound according to claim 15, wherein Q is C=O.
  17. 17. A compound according to any preceding claim, wherein L is C=O or S02, an optionally substituted C1-C6 alkyl, -CH2C(0)- or -CH2C0NH-.
  18. 18. A compound according to claim 17, wherein L is -CH2-, -CH2CH2-, - CH2CH2CH2-, C(Me)H, CF2 or C(H)F.
  19. 19. A compound according to any preceding claim, wherein R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocyclyl.
  20. 20. A compound according to claim 19, wherein R6 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted thiazole or an optionally substituted isoxazole.
  21. 21. A compound according to either claim 19 or claim 20, wherein R6 is a mono or bicyclic C5-Ci0 aryl or a mono or bicyclic 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of halogen, C1-C6 alkyl, CN, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, azido, CONR’R2 and -OH.
  22. 22. A compound according to any one of claims 19 to 21, wherein the aryl is phenyl or naphthyl.
  23. 23- A compound according to claim 22, wherein phenyl or the naphthyl is substituted by 1 or 2 halogens.
  24. 24. A compound according to any preceding claim, wherein when X1 is CH, X2 is CH and X3 is CH then R6 does not comprise an unsubstituted phenyl.
  25. 25. A compound according to any preceding claim, wherein R7 is preferably H or an optionally substituted C1-C6 alkyl.
  26. 26. A compound according to any one of claims 1 to 24, wherein Y is an optionally substituted C1-C6 alkyl.
  27. 27. A compound according to claim 26, wherein Y is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH(F)- and -CF2-.
  28. 28. A compound according to any preceding claim, wherein R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted C3-C6 heterocyclyl.
  29. 29. A compound according to claim 28, wherein R8 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole.
  30. 30. A compound according to either claim 28 or claim 29, wherein R8 is a mono or bicyclic C5-Ci0 aryl or a mono or bicyclic 5 to 10 membered heteroaryl substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of C1-C6 alkyl, halogen, OH, C1-C6 alkoxy, Ci-C3 polyfluoroalkyl, CONR’R2, CN and azido.
  31. 31. A compound according to claim 1, wherein: Xis S, Oor CR9R10; X2 is CR2; n is l; Q is C=0 or CR4R5; L is optionally substituted C1-C3 alkyl or Ci-C3 polyfluoroalkyl; Y is an optionally substituted C1-C6 alkyl; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, and optionally substituted mono or bicyclic C3-C6 cycloalkyl; R4 and R3 are each independently selected from the group consisting of H and C1-C6 alkyl; R6 is a mono or bicyclic substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C3-C6 cycloalkyl; R7is H; R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C3-C6 cycloalkyl; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, azido, NR’R2, Ci-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy or optionally substituted C2-C6 alkenyl; and R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, azido, NR’R2, Ci-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy or optionally substituted C2-C6 alkenyl.
  32. 32. A compound according to claim 31, wherein: L is a C1-C2 alkyl; and Y is a C1-C2 alkyl.
  33. 33. A compound according to claim 33, wherein: X is S or CR9R1Q; XUs CH orN; X2 is CH; X3is CH orN; nis 1; Q is C=O; L is a C1-C2 alkyl; Y is a C1-C2 alkyl; R6 is a mono or bicyclic optionally substituted C5-Ci0 aryl; R7is H; R8 is a mono or bicyclic optionally substituted C5-Ci0 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; R9 and R10 are each independently selected from the group consisting of C1-C6 alkyl, H, halogen, CN and azido; and R11 and R12 are each independently selected from the group consisting of C1-C6 alkyl, H, halogen, CN and azido.
  34. 34. A compound according to claim 33, wherein: L is -CH2-; Yis -CH2-; R6 is a phenyl ring substituted with at least one chlorine and/or fluorine; R8 is a phenyl ring substituted with at least one fluorine; R9 and R10 are each independently selected from the group consisting of C1-C3 alkyl and H; and R11 and R12 are each independently selected from the group consisting of Ci-C3 alkyl and H.
  35. 35. A compound according to claim 1, wherein the compound is: 4-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-phenylethyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-(indolin-i-yl)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-(pyridin-4-ylamino)ethyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-(phenylamino)ethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(benzo[d]thiazol-2-ylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(benzo[d]oxazol-2-ylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-phenethyl-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(2-((2-aminopyrimidin-5-yl)amino)-2-oxoethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; 4-benzyl-N-((i-methyl-iH-pyrrol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2,3-dichlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2,3-dimethylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2,6-dimethylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(naphthalen-i-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(cyclohexylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; N-(furan-2-ylmethyl)-4-(2-hydroxy-2-phenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; (S)-N-(i-cyclohexylethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; (R)-N-(i-cyclohexylethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(cyclopropylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; N,4-bis(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N-((6,6-dimethylbicyclo[3.i.i]heptan-3-yl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; N-(i-((3r,5r,7r)-adamantan-i-yl)ethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-((3r,5r,7r)-adamantan-i-ylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2,3-dimethylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(naphthalen-i-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(i-phenylethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,6-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-N-methyl-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine- 6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(cyclopentylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b]- ,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-((6-methylpyridin-3-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(3-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 3- oxo-4-(pyridin-4-ylmethyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4- (2-chloro-6-fluorobenzyl)-N-(3-cyano-2-phenylpropyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; N-benzhydryl-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][i,4]thiazine-6- carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2-cyclohexyl-2-phenylethyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-((i-benzylpiperidin-3-yl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-3-oxo-N-((i-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-([i,i'-biphenyl]-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-([i,i'-biphenyl]-3-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-((i-benzylpiperidin-4-yl)methyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b][i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-3-oxo-N-((i-phenylpiperidin-3-yl)methyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-3-oxo-N-((4-oxo-3,4-dihydrophthalazin-i-yl)methyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-((6-aminopyridin-3-yl)methyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-(2-(dimethylamino)-i-phenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(pyrimidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(2,3-dichlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N,4-dibenzyl-N-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(i-(4-(methylsulfonyl)phenyl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(oxazol-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-3-oxo-N-(thiazol-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-3-oxo-N-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-benzyl-N-((5-methyloxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-((5-methylthiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-((4-methylthiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-((3-methyl-i,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-((i-methyl-iH-pyrazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-(i-(furan-2-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N-(benzofuran-2-ylmethyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N-(benzofuran-3-ylmethyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-3-oxo-N-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(4-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-3-oxo-N-(i-phenylcyclopentyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-((2-methylthiazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-(2-(2-fluorophenyl)propan-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-(i,2-diphenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(4-isopropylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(2-cyclohexylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(2,3-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(3-methyl-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((3-methyl-i,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro- 2H-benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((5-methylisoxazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-(3-carbamoylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chlorophenethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(3-chlorophenethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethyl)phenethyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-(2-cyanobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-((5-chlorothiophen-2-yl)methyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((2-methylthiazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((i-methylpiperidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-(2-chloro-5-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(3-chloro-5-(trifluoromethyl)benzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(phenylsulfonyl)ethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(imidazo[2,i-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide 4-((4,5-dimethyl-4H-i,2,4-triazol-3-yl)methyl)-N-(furan-2-ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(p>Tidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(p>Tidin-3-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(cyclohexyl(phenyl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-benzyl-N-(2-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N,4-dibenzyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; 4-(4-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-(4-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-benzyl-N-((i-methyl-iH-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(2-chlorobenzyl)-N-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N,4-bis(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; N-(2-chlorobenzyl)-4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(4-chlorobenzyl)-3-oxo-N-(i-phenylethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-((i-(4-methylbenzyl)piperidin-4-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-phenethyl-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide;
    4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 2-methyl-2V-2,4,6-trifluorobenzyl-4-[(i-methyl-iH-pyrazol-4-yl)methyl]-3-oxo-3,4- dihydro-2H-i,4-benzothiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 2-(dimethylamino)-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2-fluorobenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 2-ethoxy-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro- 2H-benzo[b-i,4]thiazine-6-carboxamide; 2-(4-(2-fluorobenzyl)-6-((furan-2-ylmethyl)carbamoyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazin-2-yl)acetic acid; 4-(2-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(2-chlorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b- 1.4] thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 2-allyl-4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-2-propyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; i-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-iH-pyrido[2,3-b- 1.4] thiazine-7-carboxamide; i-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH- pyrido[2,3-b-i,4]thiazine-7-carboxamide; i-(2-chloro-6-fluorobenzyl)-N-(cyclohexylmethyl)-2-oxo-2,3-dihydro-iH-pyrido[2,3-b- 1.4] thiazine-7-carboxamide; i-benzyl-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-iH-pyrido[2,3-b-i,4]thiazine-7- carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b- 1.4] thiazine-6-carboxamide; i-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-iH-pyrido[3,4-b- 1.4] thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2- b-i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H- pyrido[3,2-b-i,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H- pyrido[3,2-b-i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro- 2H-pyrido[3,2-b-i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H- pyrido[3,2-b-i,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-3,4-dihydro- 2H-pyrido[3,2-b-i,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-i,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-i,4]thiazine-6-carboxamide; N-benzyl-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b- i,4]thiazine-6-carboxamide;
    4-Benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 8-cyano-4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 8-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 4-(4-fluorobenzyl)-8-(2-hydroxyethyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro- 2H-benzo[b][i,4]thiazine-6-carboxamide; 4-(4-fluorobenzyl)-8-(i-hydroxyethyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro- 2H-benzo[b][i,4]thiazine-6-carboxamide; 8-(aminomethyl)-4-(4-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][i,4]thiazine-6-carboxamide hydrochloride; 4-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-8-methyl-3-oxo-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; 8-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-i,4-benzo[b- 1.4] thiazine-6-carboxamide; 7-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H- benzo[b-i,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-7-methyl-3-oxo-3,4-dihydro-2H-benzo[b-i,4]thiazine- 6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b- 1.4] oxazine-6-carboxamide;
    2-Methyl-4-(3,5-difluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-i,4- benzoxazine-6-carboxamide; (R) -4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-i,4]oxazine-6-carboxamide; (S) -4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-i,4]oxazine-6-carboxamide; (S)-N-(benzofuran-2-ylmethyl)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro- 2H-benzo[b-i,4]oxazine-6-carboxamide; i-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH-pyrido[2,3-b- 1.4] oxazine-7-carboxamide; (S)-i-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH- pyrido[2,3-b-i,4]oxazine-7-carboxamide; (R) -i-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH-pyrido[2,3-b-i,4]oxazine-7-carboxamide; i-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH- pyrido[2,3-b-i,4]oxazine-7-carboxamide; i-(3j5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-iH- pyrido[2,3-b-i,4]oxazine-7-carboxamide; (S) -N-(benzofuran-2-ylmethyl)-i-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-iH-pyrido[2,3-b][i,4]oxazine-7-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo- [b-1,4 thiazine-6-carboxamide l-oxide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; N-(furan-2-ylmethyl)-4-(2-hydroxy-2-phenylethyl)-3,4-dihydro-2H-benzo[b- i,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-2H-benzo[b][i,4]thiazine- 6-carboxamide; 4-(4-chlorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1-oxide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1,1-dioxide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide 1,1-dioxide; 4-benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][i,4]thiazine-6- carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(cyclohexylmethyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H- benzo[b][i,4]thiazine-6-carboxamide; 4-(phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-i,4]thiazine-6- carboxamide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-i,4]oxazine-6- carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b- i,4]oxazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b- i,4]oxazine-6-carboxamide; 4- benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-i,4]thiazine-6-carboxamide; i-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinoline-7-carboxamide; i-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-i,2,3,4-tetrahydroquinoline-7- carboxamide; i-(2-chloro-6-fluorobenzyl)-N-(4-fluorobenzyl)-2-oxo-i,2,3,4-tetrahydroquinoline-7- carboxamide; i-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-4,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinoline-7-carboxamide; 5- (3,5-difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-i,5- naphthyridine-3-carboxamide; N-(2,4-difluorobenzyl)-5-(3,5-difluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-i,5- naphthyridine-3-carboxamide; N-(benzofuran-2-ylmethyl)-5-(3,5-difluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-i,5- naphthyridine-3-carboxamide; N-(2,4-difluorobenzyl)-8-(3,5-difluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-i,8- naphthyridine-2-carboxamide; N-(2,4-difluorobenzyl)-5-(4-fluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-i,5-naphthyridine- 3-carboxamide; N-(benzofuran-2-ylmethyl)-8-(3,5-difluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-i,8- naphthyridine-2-carboxamide; N-(2,4-difluorobenzyl)-8-(4-fluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-i,8-naphthyridine- 2- carboxamide; (3,5-difluorobenzyl)-7-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-i,8- naphthyridine-2-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-i,2,3,4- tetrahydroquinazoline-7-carboxamide; 3- cyclopropyl-i-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(2,4-difluorobenzyl)-i-(3,5-difluorobenzyl)-3-methyl-2-oxo-i,2,3,4- tetrahydroquinazoline-7-carboxamide; i-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinazoline-7-carboxamide; i-(4-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i,2,3,4- tetrahydroquinazoline-7-carboxamide; or 1-(3,5-difluorobenzyl)-3-ethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-i, 2,3,4- tetrahydroquinazoline-7-carboxamide
  36. 36. A pharmaceutical composition comprising a compound of Formula (I), as defined by any one of claims 1 to 35, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.
  37. 37. A process for making the composition of claim 36, the process comprising contacting a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.
  38. 38. A compound according to any one of claims 1 to 37 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 31, for use in modulating the Stimulator of Interferon Genes (STING) protein. 39· A compound or pharmaceutical composition for use according to claim 38, wherein the compound or composition is for use in activating, or agonising, the STING protein.
  39. 40. A compound according to any one of claims 1 to 35 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 31, for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, parasitic infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.
  40. 41. A compound or pharmaceutical composition for use according to claim 40, wherein the disease is cancer.
  41. 42. A compound or pharmaceutical composition for use according to claim 41, wherein the cancer is selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukaemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, pancreatic carcinoma or renal carcinoma.
  42. 43. A compound or pharmaceutical composition for use according to any one of claims 40 to 42, wherein the compound is for use with a second therapeutic agent, optionally wherein the second therapeutic agent comprises an antiviral agent, an antiinflammation agent, conventional chemotherapy, an anti-cancer vaccine and/or hormonal therapy.
  43. 44. A compound or pharmaceutical composition for use according to claim 43, wherein the second therapeutic agent comprises a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTFA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO/TDO inhibitor (such as Epacadostat and GDC-0919), a PD-i inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, and MDX-1106), a PD-Fi inhibitor (such as Durvalumab, Avelumab and Atezolizumab), an OX-40 ligand, a FAG3 inhibitor, a CD40 ligand, a 41BB/CD137 ligand, a CD27 ligand, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund’s complete or incomplete adjuvant, a TFR agonist (such as Poly I:C, MPF, EPS, bacterial flagellin, imiquimod, resiquimod, loxoribine and a CpG dinucleotide) and/or detoxified endotoxins.
  44. 45. A compound of formula (I):
    or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR9R10, O, S, S=0 or S02; XUs CR1 orN; X2is CR2orN; X3is CR3orN; the or each Z is independently CRUR12 or NR11; n is 1 or 2; Q is C=0, S=0, S02, C=S or CR4R5; L is optionally substituted C1-C6 alkyl, C1-C3 polyfluoroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C=0, S=0, S02, -CH2C(0)-, -CH2C0NH-, or -C0NH-; Y is an optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl; R1, R2 and R3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR’R2, NR’R2, NHCOR1, optionally substituted C1-C6 alkyl, Ci-C3 polyfluoroalkyl, 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 Ci-C6 alkoxycarbonyl group, mono or bicyclic optionally substituted C5-Ci0 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; R4 and R5 are each independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted (C3-Ce) cycloalkyl or R4 and R5 together with the atom to which they are attached form a spirocyclic ring;
    R6 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R7 is H, optionally substituted C1-C6 alkyl, optionally substituted sulfonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; R8 is mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C3-C6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R9 and R10 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R9 and R10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; and R11 and R12 are each independently selected from the group consisting of optionally substituted C1-C6 alkyl, H, halogen, CN, hydroxyl, C02H, CONR’R2, azido, sulfonyl, NR’R2, NHCOR1, Ci-C3 polyfluoroalkyl, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, mono or bicyclic optionally substituted C5-Ci0 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryl oxy; or R11 and R12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X1, X2 and X3 are CH; n is 1; Z is CH2; Q is C=O; L is - CH2-; Y is -CH2-; R7 is H; and R6 isthen R8 is not unsubstituted furanyl;
    when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=0; L is -CH2-; Y is -CH2-; R7 is H; and R6 ii
    then R8 is not unsubstituted phenyl, unsubstituted thiophenyl, unsubstituted pyridinyl, unsubstituted furanyl, unsubstituted tetrahydrofuranyl,
    when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2CH2-; R7 is H; and R6 is
    then R8 is not unsubstituted phenyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y i;
    R7 is H; and R6 is
    then R8 is not unsubstituted phenyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is unsubstituted phenyl then R8 is not unsubstituted furanyl, unsubstituted phenyl,
    when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O or CH2; L is -CH2-; Y is - CH2-; R7 is H; and R6 is
    then R8 is not unsubstituted furanyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
    then R8 is not unsubstituted furanyl; when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
    then R8 is not unsubstituted furanyl,
    when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=0; L is -CH2-; Y is -CH2-; R7 is H; and R6 is
    then R8 is not unsubstituted furanyl or
    ; and when X is S; X1, X2 and X3 are CH; n is l; Z is CH2; Q is C=O; L is -CH2-; Y is
    R7 is H; and R6 is
    then R8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
  45. 46. A compound of the formula (II) or (III):
    Formula (III) Formula (II) wherein, X, X1, X2, X3,n, Z, Q, L, Y, R6, R7 and R8 are as defined in any one of claims 1 to 35; and R is H or a C1-C6 alkyl, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
  46. 47. A compound according to claim 46, wherein the compound is selected from:
    International Classification:
GB1709959.9A 2017-06-22 2017-06-22 Small molecule modulators of human STING Withdrawn GB2563642A (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
GB1709959.9A GB2563642A (en) 2017-06-22 2017-06-22 Small molecule modulators of human STING
AU2018288018A AU2018288018C1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human STING
CN201880054141.8A CN111132972A (en) 2017-06-22 2018-06-21 Small molecule modulators of human STING
BR112019027127-9A BR112019027127A2 (en) 2017-06-22 2018-06-21 small molecule human sting modulators
CA3067257A CA3067257A1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
TW107121352A TWI799426B (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
JP2020520838A JP2020524717A (en) 2017-06-22 2018-06-21 Small molecule regulator of human STING
UAA202000289A UA125730C2 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
SG11201912397RA SG11201912397RA (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
KR1020207001712A KR102628892B1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human STING
US16/625,032 US20200138827A1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
PCT/GB2018/051727 WO2018234805A1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
JP2020520840A JP7296954B2 (en) 2017-06-22 2018-06-21 Small Molecule Regulators of Human STING
EP18737372.5A EP3642198B1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
PE2019002587A PE20200696A1 (en) 2017-06-22 2018-06-21 HUMAN STING SMALL MOLECULES MODULATORS
MX2019015468A MX2019015468A (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting.
US16/625,047 US11571423B2 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
EP18737370.9A EP3642184A1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
PCT/GB2018/051730 WO2018234808A1 (en) 2017-06-22 2018-06-21 Small molecule modulators of human sting
ARP190101730A AR114975A1 (en) 2017-06-22 2019-06-21 HUMAN STING SMALL MOLECULE MODULATORS, CONJUGATES AND THERAPEUTIC APPLICATIONS
PH12019502870A PH12019502870A1 (en) 2017-06-22 2019-12-18 Small molecule modulators of human sting
IL271522A IL271522B2 (en) 2017-06-22 2019-12-18 Small molecule modulators of human sting
ZA2019/08496A ZA201908496B (en) 2017-06-22 2019-12-19 Small molecule modulators of human sting
CL2019003793A CL2019003793A1 (en) 2017-06-22 2019-12-20 Small molecule modulators of human sting.
CONC2020/0000562A CO2020000562A2 (en) 2017-06-22 2020-01-20 Human sting small molecule modulators
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