Small molecule urea derivatives as STING antagonists

Abstract

The present invention relates to a compound of formula (I).The compound can be used to antagonize stimulator of interferon genes (STING) protein, thereby treating liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infantile onset (SAVI), Aicardi-Goutières syndrome (AGS), familial lupus pernio (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD). TIFF2024529089000116.tif28149

Description

Detailed Description of the Invention

[0001] The present invention relates to small molecule antagonists of the stimulator of interferon genes (STING) protein. Thus, the small molecule antagonists may be useful in the treatment of various inflammatory diseases, such as fatty liver disease, pulmonary fibrosis, pancreatitis, lupus, etc. The present invention extends to pharmaceutical compositions of the compounds themselves, methods of making the compounds, and methods of using these compounds to modulate STING protein.

[0002] STING (stimulator of interferon genes) is an innate signaling molecule that plays a pivotal role in mediating immune responses against cytosolic DNA.

[0003] The human immune system has evolved to recognize and respond to different types of threats and pathogens to maintain a healthy host. The innate arm of the immune system is primarily responsible for a rapid initial inflammatory response to danger signals associated with cell or tissue damage by bacteria, viruses, and other infectious threats. The innate immune system responds to these damage-associated molecular patterns (DAMPs) or microbial product pathogen-associated molecular patterns (PAMPs) through a series of sentinel proteins called pattern recognition receptors (PRRs) to provide the host with broad and sustained protection against a wide range of threats (P. Broz et al., Nat. Revs Immunol., 2013, 13 , 551).

[0004] PAMPs and DAMPs are often components or replicative intermediates of intracellular pathogens. PRRs include Toll-like receptors (TLRs; activated by endosomal nucleic acids), C-type lectin receptors, retinoic acid-inducible gene I (RIGI-like receptors; activated by cytosolic RNA), NOD-like receptors (NLRs), and double-stranded DNA sensors (Diebold et al., Science, 2004, 303 , 1529-1531; O. Takeuchi et al., Cell, 2010, 140 , 805;Pichlmair et al., 2006, 314, 997). PRRs respond to DAMPs and PAMPs by upregulating type 1 interferons and cytokines. Free cytosolic nucleic acids (DNA and RNA) are known PAMPs / DAMPs. The primary sensor of cytosolic DNA is cGAS (cyclic GMP-AMP synthase). Upon recognition of cytosolic dsDNA, cGAS triggers the production of one specific isomer of the cyclic dinucleotide (CDN) cGAMP, c[G(2',5')pA(3',5')p] (Gao et al., Cell, 2013, 153 , 1094).

[0005] CDNs are second messenger signaling molecules produced by a variety of bacteria and consist of two ribonucleotides connected via a phosphodiester bond to form a ring structure. The CDNs cyclo-di(GMP) (c-diGMP), cyclo-di(AMP) (c-diAMP) and hybrid cyclo-(AMP / GMP) (cGAMP) derivatives (A. Ablasser et al., Nature, 2013, 498 , 380) all bind tightly to the ER-transmembrane adaptor protein STING (D.L. Burdette et al., Nature, 2011, 478 , 515; H. Ishikawa, Nature, 2008, 455 , 674).

[0006] STING recognizes CDNs through its cytosolic carboxy-terminal domain, which forms homodimers and adopts a V-shaped binding pocket that binds CDNs (Zhang et al., Mol. Cell, 2013, 51 , 226; GN Barber et al., Nat. Immunol., 2011, 12 Ligand-induced activation of STING triggers a conformational change that facilitates its relocation to the Golgi and binding to TBK1, which in turn regulates the transcription factors IRF-3, STAT6, and NF-κB. KB to induce type I interferons and other cytokines and interferon-stimulated genes (C. Greenhill, Nat. Revs. Endocrinol., 2018, 14 , 192; Y. Li, HL Wilson, and E. Kiss-Toth, J. Inflamm., 2017, 14 Following its activation, STING is rapidly degraded in normal responses.

[0007] Excessive activation of STING is associated with a variety of monogenic autoinflammatory disorders called interferonopathies (Y.J. Crow and N. Manel, Nat. Revs Immunol., 2015, 15 Loss-of-function mutations in the human DNAse Trex1 are associated with elevated cGAMP levels and autoimmune diseases such as the rare but severe inflammatory disease Aicardi-Goutières syndrome (AGS), familial lupus pernio (FCL), systemic lupus erythematosus (SLE), and retinal vasculopathy (Y. Crow et al., Hum. Mol Gen., 2009, 429–440). 18 , R130).

[0008] Inhalation of silica particles can result in pulmonary inflammation and pulmonary fibrosis caused by lung cell death and release of dsDNA products. Benmerzoug et al. report that this increase in circulating dsDNA activates STING and causes lung inflammation through increased CXCL10 levels and IFN signaling (S. Benmerzoug et al., Nat. Comm, 2018, 9 , 5226).

[0009] In fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA), increased cytosolic dsDNA was detected, with the level of dsDNA correlating with the severity of rheumatoid synovitis (J. Wang et al., Int. Immunopharm., 2019, 76These findings indicate that increased dsDNA promotes inflammatory responses via the STING pathway in RA FLS and leads to increased STING expression, suggesting that cytosolic DNA accumulation is an important factor in RA-associated inflammation.

[0010] Patients with autosomal dominant gain-of-function mutations in STING have a pediatric autoinflammatory condition called SAVI (STING-associated vasculopathy of infancy), which clinically manifests with a skin rash, vasculopathy, lupus-like syndrome, and pulmonary fibrosis characterized by abnormal IFN production and systemic inflammation associated with high morbidity and mortality (N. Konig, et al., Ann. Rheum, Dis., 2017, 76 , 468). Mutations characterized in humans include V147L, N154S, V155M, and G166E, which are all located in the interface region between the transmembrane and ligand-binding domains and result in a ligand-independent constitutively activated protein. More recently, three other gain-of-function STING mutations C206Y, R281Q, and R284S have been identified in the cluster region that are proposed to promote STING aggregation and disfavor complex formation with the C-terminal tail region (H. Konno, et al., Cell Rep. 2018, 23, 1112 and I. Melki, et al., J Allergy Clin Immunol. 2017, 140(2), 543).

[0011] A recent report by Habtezion et al. showed that in mice with acute pancreatitis, STING responds to acinar cell death by detecting DNA from necrotic cells and promotes acute pancreatic inflammation (A. Habtezion et al., Gastroenterology, 2018, 154, 1822). STING knockout mice had less severe acute pancreatitis (less edema, less inflammation), whereas administration of a STING agonist resulted in more severe pancreatitis.

[0012] Luo et al. have also recently shown that levels of STING are increased in liver tissue from patients with nonalcoholic fatty liver disease and in mice with high-fat diet-induced fatty liver. Again, STING knockout mice developed less severe liver fibrosis and less acute inflammatory responses (X. Luo et al., Gastroenterology, 2018, 155, 1971).

[0013] Increased cGAMP levels in peripheral blood mononuclear cells of SLE patients are associated with higher disease scores (J. An et al., Arthritis Rheum., 2017, 69 , 800), suggested an association between disease severity and activation of the STING pathway in lupus.

[0014] Renal tubular cells from subjects with fibrosis have been shown to lack mitochondrial transcription factor A (TFAM). Mice lacking tubular TFAM suffered from severe mitochondrial loss and energy deficiency caused by abnormal packaging of mitochondrial DNA and its translocation to the cytosol, where the STING pathway was activated (KW Chung, Cell Metab., 2019, 30 , 1). The subsequent cytokine expression and inflammation led to renal fibrosis.

[0015] Bennion et al. demonstrated that N153S gain-of-function mutation knock-in mice showed enhanced susceptibility to viral infection and responded to infection with the murine gammaherpesvirus γHV68 with severe autoinflammation and pulmonary fibrosis (B. Bennion et al., J. Virol., 2019, 93 , e01806).

[0016] Another condition in which excessive immune system activation may be associated with STING pathway activation is the systemic inflammatory response syndrome (RK Boyapati et al., F1000 Res., 2017, 6 , 169), cardiovascular disease (KR King et al., Nat. Med, 2017, 23, 1481), stroke (AM Jeffries et al., Neurosci.Lett, 2017, 658 , 53) and age-related macular degeneration (N. Kerur et al., Nat. Med, 2018, 24 , 50).

[0017] Thus, there is compelling evidence that blocking, inhibiting or antagonizing the STING pathway may have therapeutic benefit in a number of conditions and disease states.

[0018] For example, T. Siu et al. (ACS Med Chem Letts, 2019, 10 Only a few small molecule antagonists of the STING protein have been reported by researchers such as S. Haag et al. (Nature, 2018, 92), but the compounds described therein reportedly have low cell-based potency. Other reports of STING antagonists include S. Haag et al. (Nature, 2018, 559 (7713), 269) and Z. Hong et al. (PNAS, 2021, 118 (24), e2105465118).

[0019] Therefore, there is an urgent need for improved small molecule blockers of the STING pathway, in particular small molecule direct antagonists of the STING protein.

[0020] The present invention arose from the inventors' research attempting to identify STING protein modulators.

[0021] According to a first aspect of the invention there is provided a compound of formula (I) or a pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof: [ka] [where, X 1 CR 1 or N, X 2 is CR 2 And X 3 CR3 or N, or X 2 is N and X 3 is CR 3 and X 6 is C=O or CR 7 R 8 and Z is CR 9 R 10 or NR 9 and X 7 are S, SO, SO2, O, and NR 11 or CR 11 R 12 and A is an optionally substituted C1-C 12 Alkylene, optionally substituted C-C 12 Alkenylene, optionally substituted C-C 12 alkynylene, optionally substituted C3-C6 cycloalkylene, or optionally substituted 3-6 membered heterocyclylene; n may be 0, 1 or 2; R 1 , R 4 and R 8 H, halogen, OR 13 , CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, monocyclic or bicyclic optionally substituted C6-C 12 are each independently selected from the group consisting of aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, and optionally substituted monocyclic or bicyclic 3-8 membered heterocycle; R 9 ~R 12 H, halogen, OR13 , CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 and X 2 CR 2 And X 3 CR 3 When R 2 and R 3 The other is H, halogen, OR 13 , CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, monocyclic or bicyclic optionally substituted C6-C 12 is selected from the group consisting of aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, and optionally substituted monocyclic or bicyclic 3-8 membered heterocycle; R 5 COOR 13 ,CONR 13 R 14, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, monocyclic or bicyclic optionally substituted C6-C 12 Aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle and L 1 -L 2 -R 16 is selected from the group consisting of R 7 H, halogen, OR 13 , CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, monocyclic or bicyclic optionally substituted C6-C 12 Aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle and L 1 -L 2 -R 16 is selected from the group consisting of Here, R 5 and R 7 At most one of them is -L 1 -L 2 -R 16 and R 13 and R 14is H, halogen, OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, monocyclic or bicyclic optionally substituted C6-C 12 each independently selected from the group consisting of aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy; L 1 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, O, S, S=O, SO2, or NR 19 and L 2 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, O, S, S=O, SO2, or NR 19 and R 15 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C 12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle; R 16is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, a monocyclic or bicyclic optionally substituted C6-C 12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle; R 17 ~R 19 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or CN. The compounds of formula (I) may be used as pharmaceuticals.

[0022] Thus, in a second aspect, there is provided a compound of formula (I), or a pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, for use as a medicament.

[0023] The inventors have found that compounds of formula (I) are useful in modulating the stimulator of interferon genes (STING) protein.

[0024] Thus, in a third aspect, there is provided a compound of formula (I), or a pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, for use in modulating the Stimulator of Interferon Genes (STING) protein.

[0025] Preferably, the compounds of formula (I) are for use in inhibiting or inactivating STING protein. The compounds of formula (I) may be for use in inhibiting or inactivating STING functional activity as evidenced by a reduction in one or more biological effects selected from the group consisting of cellular interferon-β production, cellular levels of interferon stimulated genes, production of cytokines, and phosphorylation of the transcription factors IRF-3 and NF-κB.

[0026] By inhibiting the STING protein, it is possible to treat, ameliorate or prevent liver fibrosis, fatty liver disease, pulmonary fibrosis, lupus, rheumatoid arthritis (RA), STING-associated vasculopathy of infancy (SAVI), pancreatitis, cardiovascular disease, non-alcoholic fatty liver disease and renal fibrosis.

[0027] By inhibiting the STING protein, it is possible to treat, ameliorate or prevent liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, rheumatoid arthritis (RA), STING-associated vasculopathy of infantile onset (SAVI), Aicardi-Goutières syndrome (AGS), familial lupus pernio (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD).

[0028] Thus, in a fourth aspect there is provided a compound of formula (I), or a pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, for use in the treatment, amelioration or prevention of a disease selected from liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infantile onset (SAVI), Aicardi-Goutières syndrome (AGS), familial lupus pernio (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD).

[0029] In a fifth aspect, there is provided a method of modulating a 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 pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof.

[0030] Preferably, the method includes the step of inhibiting the STING protein.

[0031] Preferably, the method is a method of inhibiting or inactivating a STING protein.

[0032] In a sixth aspect, there is provided a method of treating, ameliorating or preventing a disease selected from liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infantile onset (SAVI), Aicardi-Goutières syndrome (AGS), familial lupus pernio (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD), comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable complex, salt, solvate, tautomer or polymorph thereof.

[0033] It can be understood that the term "preventing" can mean "reducing the likelihood of."

[0034] In one preferred embodiment, the disease is fibrosis.Fibrosis may be selected from the group consisting of liver fibrosis, pulmonary fibrosis or renal fibrosis.In some embodiments, fibrosis patients may have STING expression and / or STING activity upregulated in tissue compared with that of healthy subjects.

[0035] In an alternative preferred embodiment, the disease is fatty liver disease. The fatty liver disease may be non-alcoholic (or simple) fatty liver or non-alcoholic steatohepatitis (NASH).

[0036] Unless the context indicates otherwise, the following definitions are used in connection with the compounds of the invention.

[0037] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises," mean including but not limited to and are not intended to exclude, for example, other additives, components, integers, or steps.

[0038] As used in this 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 a mixture of two or more such compositions.

[0039] "Optional" or "optionally" means that the subsequently described event, action, or circumstance may or may not occur, and that the description includes examples when the event, action, or circumstance occurs, as well as examples when the event, action, or circumstance does not occur.

[0040] The term "alkyl" as used herein, unless otherwise specified, refers to a saturated linear or branched hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 6 carbon atoms, i.e., C1-C6 alkyl. C1-C6 alkyl includes, for example, methyl, ethyl, n-propyl (1-propyl) and isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or can be selected from the group consisting of halogen, OR, aryl ... 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 Optionally substituted C1-C6 alkyl may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. Thus, optionally substituted C1-C6 alkyl may be substituted with optionally substituted C1-C6 haloalkyl, i.e., substituted with at least one halogen and OR 20 , optionally substituted C1-C6 alkoxy, CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 It will be understood that the C1-C6 alkyl may be optionally further substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. The optionally substituted C1-C6 alkyl may be polyfluoroalkyl, preferably C1-C3 polyfluoroalkyl.

[0041] R 20 and R 21is H, halogen, OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, monocyclic or bicyclic optionally substituted C6-C 12 R may be independently selected from the group consisting of aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy. 20 and R 21 may each be independently selected from the group consisting of H and halogen.

[0042] The term "alkylene", as used herein, unless otherwise specified, refers to a divalent saturated linear or branched hydrocarbon. In certain embodiments, the alkylene group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkylene group contains 1 to 6 carbon atoms, i.e., C1-C6 alkylene. C1-C6 alkylene includes, for example, methylene, ethylene, n-propylene and isopropylene, butylene, pentylene, hexylene, isobutylene, sec-butylene, tert-butylene, isopentylene, neopentylene, and isohexylene. The alkylene group may be as defined above for an alkyl group, except that a hydrogen atom has been removed from the alkyl group to make the group divalent. When an alkylene is described, for example, as eth-1,1-ylene, it can be understood that both points of attachment to the remainder of the structure are at the 1-position.

[0043] The term "halo" or "halogen" includes fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0044] The term "polyfluoroalkyl" may refer to a C1-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. This term may also include perfluoroalkyl groups, i.e., C1-C3 alkyl groups in which all hydrogen atoms are replaced by fluorine atoms. Thus, the term C1-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-1-(trifluoromethyl)ethyl.

[0045] "Alkoxy" is R 22 is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C2-C6 alkenyl group or an optionally substituted C2-C6 alkynyl group; 22 Exemplary C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy, and tert-butoxy. The alkoxy group can be unsubstituted or can include halogen, OR. 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0046] "Aryl" refers to an aromatic 6- to 12-membered hydrocarbon group. The term includes bicyclic groups in which one ring is aromatic and the other is not. C 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl, and indanyl. Aryl groups can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above.20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0047] "Arylene" refers to a divalent aromatic 6- to 10-membered hydrocarbon group. The arylene group may be as defined above for an aryl group, except that a hydrogen atom has been removed from the aryl group to make the group divalent.

[0048] The term "bicyclic" or "bicyclic" as used herein refers to a molecule featuring two fused rings, the fused rings being cycloalkyl, heterocyclyl, or heteroaryl. In one embodiment, the rings are fused across a bond between two atoms. A bicyclic moiety formed by fusion shares a bond between the rings. In another embodiment, a bicyclic moiety is formed by fusing two rings across a series of atoms in the rings to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or more atoms connecting two bridgeheads of a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" moiety. A spirocyclic group may be a C3-C6 cycloalkyl or a monocyclic or bicyclic 3-8 membered heterocycle bonded through a single carbon atom of the spirocyclic moiety to a single carbon atom of the carbocyclic or heterocyclic moiety. In one embodiment, a spirocyclic group is a cycloalkyl bonded to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is bonded to a heterocyclyl. In a further embodiment, the spirocyclic group is a heterocyclyl and is bonded to another heterocyclyl. In yet another embodiment, the spirocyclic group is a heterocyclyl and is bonded to a cycloalkyl. The spirocyclic group can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR. 20 , CN, oxo, C(O)R 20 , COOR 20, O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0049] "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3-6 membered ring system. Representative examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl groups can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR. 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20, OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0050] "Cycloalkylene" refers to a divalent non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3- to 6-membered ring system. A cycloalkylene group may be as defined above for a cycloalkyl group, except that a hydrogen atom has been removed from the cycloalkyl group to make the group divalent.

[0051] "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5-10 membered ring system in which at least one ring atom is a heteroatom. The term includes bicyclic groups in which one of the rings is aromatic and the other is not. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur and nitrogen. Examples of 5-10 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-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic 5-10 membered heteroaryl groups include those in which a phenyl, pyridine, pyrimidine, pyrazine, or pyridazine ring is fused to a 5- or 6-membered monocyclic heteroaryl ring. Heteroaryl groups can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0052] "Heterocycle" or "heterocyclyl" refers to a 3-8 membered monocyclic, bicyclic or bridged molecule 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. The heterocycle may be saturated or partially saturated. Exemplary 3-8 membered heterocycle groups include, but are not limited to, aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane and oxazine. The heterocyclic group can be unsubstituted or optionally substituted with C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR21 ), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0053] "Heterocyclylene" refers to a divalent 3- to 8-membered monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. A heterocyclylene group may be as defined above for a heterocyclyl group, except that a hydrogen atom has been removed from the heterocyclic group to make the group divalent.

[0054] "Alkenyl" refers to an olefinically unsaturated hydrocarbon group that may be unbranched or branched. In certain embodiments, an alkenyl group has 2 to 6 carbons, i.e., the alkenyl group is a C2-C6 alkenyl. C2-C6 alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. An alkenyl group may be unsubstituted or optionally substituted, such as C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR, or the like. 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20 and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0055] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group that may be unbranched or branched. In certain embodiments, an alkynyl group has 2 to 6 carbons, i.e., the alkynyl group is a C2-C6 alkynyl. C2-C6 alkynyl includes, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynyl groups may be unsubstituted or optionally substituted, such as C2-C6 alkenyl, optionally substituted C1-C6 alkoxy, halogen, OR, or aryl. 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 R may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle. 20 and R 21 may be as defined above. 20and R 21 may each be independently selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl.

[0056] The term "alkenylene", as used herein, unless otherwise specified, refers to a divalent olefinically unsaturated linear or branched hydrocarbon. An alkenylene group may be as defined above for an alkenyl group, except that a hydrogen atom is removed from an aryl group to make the group divalent. When an alkenylene is written as, for example, ethene-1,1-ylene, it can be understood that both points of attachment to the remainder of the structure are at the 1-position.

[0057] The term "alkynylene" as used herein, unless otherwise specified, refers to a divalent acetylenically unsaturated linear or branched hydrocarbon. An alkynylene group may be as defined above for an alkynyl group, except that a hydrogen atom is removed from an aryl group to make the group divalent. When an alkynylene is written as, for example, ethyne-1,1-ylene, it can be understood that both points of attachment to the remainder of the structure are at the 1-position.

[0058] "Alkylsulfonyl" refers to the group alkyl-SO2-, where alkyl is an optionally substituted C1-C6 alkyl, as defined above.

[0059] "Alkoxycarbonyl" refers to the group alkyl-OC(O)-, where alkyl is an optionally substituted C1-C6 alkyl. The alkoxycarbonyl group can be unsubstituted or optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R.20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 It may be substituted with one or more of aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-8 membered heterocycle.

[0060] "Aryloxy" refers to an optionally substituted C-C monocyclic or bicyclic aryloxy group as defined above. 12 Refers to the group Ar-O-, which is an aryl group.

[0061] "Heteroaryloxy" refers to the group heteroaryl-O-, where heteroaryl is a monocyclic or bicyclic optionally substituted 5 to 10 membered heteroaryl, as defined above.

[0062] "Heterocyclyloxy" refers to the group heterocycle-O-, where the heterocycle is an optionally substituted mono- or bicyclic 3- to 8-membered heterocycle, and is as defined above.

[0063] A complex of a compound of formula (I) can be understood to be a multicomponent complex in which 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 a solvate. Complexes of this type include clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound to each other through non-covalent interactions, but may also be complexes of neutral molecules with salts. Cocrystals may be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together - see Chem Commun, by O. Almarsson and MJ Zaworotko (2004), incorporated herein by reference. 17 , 1889-1896. For a general review of multicomponent complexes, see Haleblian (August 1975), J Pharm Sci, 1999, 14th ed., 1999, incorporated herein by reference. 64 (8), pp. 1269-1288.

[0064] The term "pharmaceutically acceptable salt" may be understood to refer to any salt of a compound described herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, adipic acid, aspartic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, and methanesulfonic acid. acetic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfuric acid or (2) base addition salts formed when an acidic proton present in the parent compound is coordinated with (a) a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, 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.

[0065] Pharmaceutically acceptable salts include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, as well as, when the compound contains a basic functional group, hydrohalides, e.g., hydrochlorides, hydrobromides, and hydroiodides, carbonates or bicarbonates, sulfates or bisulfates, borates, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamate, saccharates, stearates, sulfamate, nitrates, orotates, oxalates, palmitates, pamoates, and the like. , acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camsylate, citrate, cyclamate, benzoate, isethionate, esylate, formate, 3-(4-hydroxybenzoyl)benzoate, Picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulfate, naphthylate, 2-napsylate, nicotinate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2. The salts may include salts of non-toxic organic or inorganic acids such as 2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, xinafoate, and the like.

[0066] Hemisalts of acids and bases may also be made, such as hemisulfate salts. Those skilled in the art will recognize that such salts include salts where the counterion is optically active, for example, D-lactate, or racemic, for example, DL-tartrate.

[0067] For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0068] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting a compound of formula (I) with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) using a desired acid or base; or (iii) by converting one salt of a compound of formula (I) to another salt by reaction with an appropriate acid or base or by suitable ion exchange columns.

[0069] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to nearly non-ionized.

[0070] The term "solvate" can be understood to refer to a compound described herein or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.When the solvent is water, the solvate is a hydrate.Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent may be isotopically substituted, for example, DO, d6-acetone and d6-DMSO.

[0071] A currently accepted classification system for organic hydrates defines isolated site, channel, or metal ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by KR Morris (ed. HG Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are in lattice channels where they are next to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0072] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will become the norm.

[0073] The compounds of the present invention may exist in a continuum of solid states ranging from completely amorphous to completely crystalline, including polymorphs of said crystalline materials. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give a distinctive X-ray diffraction pattern, and while they exhibit the properties of a solid, they are more formally described as liquids. Upon heating, they undergo a change of state, typically second order ("glass transition"), from solid to liquid properties. The term "crystalline" refers to a solid phase in which the material has an ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with well-defined peaks. When such materials are heated sufficiently, they will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ("melting point").

[0074] The compounds of the invention may exist in a mesophase (mesophase or liquid crystal) when exposed to suitable conditions. The mesophase is intermediate between the true crystalline state and the true liquid state (either melt or solution). Liquid crystallinity resulting from a change in temperature is described as "thermotropic" and liquid crystallinity resulting from the addition of a second component such as water or another solvent is described as "lyotropic". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and may be characterized as having ionic (-COO - Na + , -COO - K + , or -SO3 - Na + etc.) or non-ionic (-N - N + For more information, see N. H. Hartshorne and A. Stuart, “Chemical Polymers,” which is incorporated herein by reference. Crystals and the Polarizing Microscope , 4th ed. (Edward Arnold, 1970).

[0075] The compounds of formula (I) may contain one or more asymmetric centers and therefore may exist as optical isomers, such as enantiomers and diastereomers, and all such isomers and mixtures thereof are included within the scope of the present invention.

[0076] It will be appreciated that the compounds described above may exist as enantiomeric and diastereomeric pairs, which are further embodiments of the present invention.

[0077] Conventional techniques for the preparation / isolation of the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC).

[0078] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol or, if the compound of formula (I) contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted into the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0079] The chiral compounds of the invention (and their chiral precursors) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% by volume, typically 2%-20% isopropanol, and 0-5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives the enriched mixture.

[0080] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, New York, 1994).

[0081] The term "STING" refers to stimulator of interferon genes, an adaptor protein functionally activated by cyclic dinucleotides that leads to the production of interferons and proinflammatory cytokines.

[0082] "Antagonists," or "inhibitors," as they relate to ligand and STING, will be understood to include molecules, combinations of molecules, or complexes that inhibit, suppress, downregulate, and / or desensitize STING activity. "Antagonists" encompass any reagent that inhibits the constitutive activity of STING. Constitutive activity is that which is evident in the absence of ligand / STING interaction. "Antagonists" also encompass any reagent that inhibits or prevents stimulated (or regulated) activity of STING.

[0083] Preferably, the compounds of formula (I) are inhibitors of the STING protein.

[0084] In some embodiments, X 1 is CR 1 R 1 R may be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 1 may be H, halogen, OH, CN, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 1 is H.

[0085] In an alternative embodiment, X 1 is N.

[0086] X 2 CR 2 And X 3 But, CR 3 or N, or X 2 is N and X 3 CR 3 Therefore, R 2 and R 3 It can be understood that at least one of X is present in the compound of formula (I). 2 CR 2 And X 3 CR 3 In an embodiment, R 2 and R3 Both are present in compounds of formula (I).

[0087] As specified above, R 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 Therefore, R 2 exists and R 3 In embodiments where R is absent, 2 A-A-NR 17 -C(O)-NR 18 -R 15 Conversely, R 2 does not exist, but R 3 In embodiments where R is present, 3 A-A-NR 17 -C(O)-NR 18 -R 15 Finally, R 2 and R 3 In embodiments where both are present, R 2 and R 3 Only one of them is -A-NR 17 -C(O)-NR 18 -R 15 It is.

[0088] In one embodiment, X 2 is N and X 3 is CR 3 In this embodiment, R 3 HA-A-NR 17 -C(O)-NR 18 -R 15 It is.

[0089] In an alternative embodiment, X 2 is CR 2 and X 3 is N. In this embodiment, R 2 A-A-NR 17 -C(O)-NR 18 -R 15 It is.

[0090] However, in a preferred embodiment, X 2 is CR 2 and X 3 is CR 3 In some embodiments, R 2 A-A-NR 17 -C(O)-NR 18 -R 15 In an alternative embodiment, R 3 A-A-NR 17 -C(O)-NR 18 -R 15 Thus, the compound may be of formula (Ia) or formula (Ib). [ka]

[0091] Preferably, R 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 and R 2 and R 3 The other is H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R 13 and R 14 are each independently selected from the group consisting of H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, and optionally substituted C2-C alkynyl. More preferably, R 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 and R 2 and R 3 The other is H, halogen, OH, CN, CONR13 R 14 , N.R. 13 R 14 , C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R 13 and R 14 are each independently selected from the group consisting of H, C1-C3 alkyl, C2-C3 alkenyl, and C2-C alkynyl. 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 and R 2 and R 3 The other is H, bromine or CONH. In a preferred embodiment, R 2 and R 3 One is -A-NR 17 -C(O)-NR 18 -R 15 and R 2 and R 3 The other is H.

[0092] Preferably, A is an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, or an optionally substituted C2-C6 alkynylene. Thus, A may be an optionally substituted methylene, an optionally substituted ethylene, an optionally substituted propylene, an optionally substituted butylene, an optionally substituted pentylene, an optionally substituted hexylene, an optionally substituted ethenylene, an optionally substituted propenylene, an optionally substituted butenylene, an optionally substituted pentenylene, an optionally substituted hexenylene, an optionally substituted ethynylene, an optionally substituted propynylene, an optionally substituted butynylene, an optionally substituted pentynylene, or an optionally substituted hexynylene. A may be optionally substituted methylene, optionally substituted eth-1,1-ylene, optionally substituted prop-1,1-ylene, optionally substituted but-1,1-ylene, optionally substituted penta-1,1-ylene, optionally substituted hex-1,1-ylene, optionally substituted ethene-1,1-ylene, optionally substituted propen-1,1-ylene, optionally substituted buten-1,1-ylene, optionally substituted penten-1,1-ylene, optionally substituted hexen-1,1-ylene, optionally substituted propyne-1,1-ylene, optionally substituted butyn-1,1-ylene, optionally substituted pentyn-1,1-ylene or optionally substituted hexyn-1,1-ylene. In some embodiments, A is optionally substituted methylene, optionally substituted etha-1,1-ylene, optionally substituted prop-1,1-ylene, optionally substituted but-1,1-ylene, or optionally substituted prop-2-en-1,1-ylene.

[0093] The alkylene, alkenylene or alkynylene may be unsubstituted or may be substituted with halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3-8 membered heterocycle. Preferably, alkylene, alkenylene, or alkynylene is unsubstituted or is selected from the group consisting of OR 20 , Oxo, COOR 20 ,CONR 20 R 21 , optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle. R 20 and R 21 are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C 12 It may be aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle. The alkyl, alkenyl, alkynyl, or alkoxy may be unsubstituted or may be substituted with halogen, OH, CN, or C. 1~6 Preferably, R 20 and R 21 are each independently H, methyl, OCH3, CH2CH2OH, CH2CH2OCH3, cyclopropyl, or pyridinyl.

[0094] When A is directly or indirectly substituted with optionally substituted aryl, the optionally substituted aryl may be optionally substituted phenyl. When A is directly or indirectly substituted with an optionally substituted heteroaryl, the optionally substituted heteroaryl may be optionally substituted 1H-pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,2,3-triazolyl, optionally substituted 1,2,4-triazolyl, optionally substituted tetrazolyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted 1,2,4-triazinyl or optionally substituted 1,2,5-triazinyl. When A is directly or indirectly substituted with optionally substituted cycloalkyl, the optionally substituted cycloalkyl may be optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. When A is directly or indirectly substituted with an optionally substituted heterocycle, the optionally substituted heterocycle may be optionally substituted pyrrolidinyl, optionally substituted pyrazolidinyl, optionally substituted imidazolinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyranyl, optionally substituted 1,3-dioxanyl, optionally substituted 1,4-dioxanyl, optionally substituted thianyl, optionally substituted 1,3-dithianyl, optionally substituted 1,4-dithianyl or optionally substituted morpholinyl.The aryl, heteroaryl, cycloalkyl or heterocycle may be unsubstituted or may be substituted with halogen, OH, CN or C. 1~6 Preferably, the aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with OH.

[0095] In some embodiments, A is -CH2-, [ka] may be also possible.

[0096] R 17 and R 18 may be independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 17 and R 18 may be independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. 17 and R 18 is H or methyl. Most preferably, R 17 and R 18 is H.

[0097] R 15 is an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, a monocyclic or bicyclic optionally substituted C6-C 12 It may be an aryl, a monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or an optionally substituted monocyclic or bicyclic 3-8 membered heterocycle.

[0098] R 15 In embodiments where R is aryl, it may be optionally substituted phenyl, optionally substituted 5,6,7,8-tetrahydronaphthalenyl, or optionally substituted 2,3-dihydro-1H-indenyl. 15In embodiments where R is an optionally substituted 5-10 membered heteroaryl, it is an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thiophenyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted isothiazolyl, an optionally substituted imidazolyl, an optionally substituted pyrazolyl, an optionally substituted pyridinyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted indolinyl, an optionally substituted 1H-indolyl, an optionally substituted 7-azaindolyl, an optionally substituted 1H-pyrrolo[3,2-b]pyridinyl, an optionally substituted benzofuranyl, an optionally substituted azaindolyl, an optionally substituted benzo ... R may be indolyl, optionally substituted benzisoxazolyl, optionally substituted azabenzimidazolyl, optionally substituted indazolyl, optionally substituted benzo[b]thiophenyl, optionally substituted benzimidazolyl, optionally substituted benzo[d]oxazolyl, optionally substituted benzo[d]thiazolyl, optionally substituted 1,4-benzodioxanyl, optionally substituted 1,2,3,4-tetrahydroquinolinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted 3,4-dihydro-2H-1,4-benzoxazyl or optionally substituted 7,8-dihydropyrido[4,3-d]pyrimidinyl. 15In embodiments where R is a 3-8 membered heterocycle, it may be optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyranyl, optionally substituted thianyl, optionally substituted morpholinyl, optionally substituted thiomorpholinyl, optionally substituted 1,2-oxazinyl, optionally substituted 1,3-oxazinyl, optionally substituted 1,4-oxazinyl, optionally substituted azepanyl, optionally substituted 1,2-diazepinyl, optionally substituted 1,3-diazepinyl, optionally substituted 1,4-diazepinyl, or optionally substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine. In preferred embodiments, R 15 is an optionally substituted 1H-indolyl. 15 may be optionally substituted 1H-indol-6-yl or optionally substituted 1H-indol-3-yl.

[0099] R 15 is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocycle, the heteroaryl, cycloalkyl or heterocycle may be unsubstituted or optionally substituted C1-C6 alkyl, halogen, OH, oxo, OP(O)(OR 20 )(OR 21 ), optionally substituted C1-C6 alkoxy, NR 20 R 21 ,CONR 20 R 21 , C.N., C(O)R. 20 , COOR 20 , NO2, azide, SO2R 20 , C(O)R 20 and N.R. 20 COR 21When the heteroaryl, cycloalkyl, or heterocycle is substituted with an optionally substituted alkyl, the alkyl may be unsubstituted or may be selected from the group consisting of halogen, OH, C1-C6 alkoxy, NR 20 R 21 , C(O)R 20 , CN, OXO, OP(O)(OR 20 )(OR 21 ), O.C.(O)R 20 , COOR 20 ,CONR 20 R 21 , C1-C6 alkenyl, C1-C6 alkynyl, =NOR 20 , N.R. 20 C(O)R 21 , SO2R 20 and SO2NR 20 R 21 The halogen may be F or Cl. Preferably, the halogen is F. R 20 and R 21 may be, independently, H or methyl. Thus, the heteroaryl, cycloalkyl or heterocycle may be optionally substituted with one or more substituents selected from the group consisting of F, oxo, CN, NH2, C(O)CH3, CONH2, CH3 and CH2COOH.

[0100] R 4 R may be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 4 may be H, halogen, OH, CN, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 4 is H.

[0101] R 5 -L 1 -L 2 -R 16 may be also possible.

[0102] Preferably, L 1 is absent, optionally substituted C1-C3 alkylene, optionally substituted C2-C3 alkenylene, or optionally substituted C2-C3 alkynylene. The alkylene, alkenylene, or alkynylene may be unsubstituted or substituted with halogen, OH, CN, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 and oxo. 20 and R 21 may be independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle. 20 and R 21 are independently H, methyl or cyclopropyl. 1 does not exist, CH2, CH2CH2, CO, [ka] Most preferably, L 1 is absent or CH2.

[0103] In some embodiments, L 2 does not exist.

[0104] Or, L. 2 is O, S, S=O, SO2 or NR 19R 19 may be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. 2 is O or S, most preferably O.

[0105] R 16 is an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, a monocyclic or bicyclic optionally substituted C6-C 12 It may be an aryl, a monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or an optionally substituted monocyclic or bicyclic 3-8 membered heterocycle. 16 is a monocyclic or bicyclic optionally substituted C6-C 12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle; 12The aryl may be an optionally substituted phenyl. The optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl includes optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted 1,2,3-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,2,5-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted 1H-indolyl, optionally substituted azaindolyl, optionally substituted benzoisoxazolyl, optionally substituted 4-azabenzimidazolyl, It may be optionally substituted 5-benzimidazolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, optionally substituted benzo[b]thiophenyl, optionally substituted benzo[d]isoxazolyl, optionally substituted benzo[d]isothiazolyl, optionally substituted imidazo[1,2-a]pyridinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted benzothiazole, optionally substituted 1,3-benzodioxolyl, optionally substituted benzofuranyl, optionally substituted 2,1,3-benzothiadiazolyl, optionally substituted 3,4-dihydro-2H,1,4-benzoxazinyl, or optionally substituted benzo-1,4-dioxanyl.The monocyclic or bicyclic 3- to 8-membered heterocycle may be optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyranyl, optionally substituted dioxanyl, optionally substituted thianyl, optionally substituted dithianyl or optionally substituted morpholinyl.

[0106] R 16 When is an aryl, heteroaryl, cycloalkyl, or heterocycle, the aryl, heteroaryl, cycloalkyl, or heterocycle may be unsubstituted or optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, OR 20 , CN, oxo, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 , OP(O)(OR 20 )(OR 21 ), optionally substituted C6 to C 12 The aryl, heteroaryl, cycloalkyl, or heterocycle may be substituted with one or more substituents selected from the group consisting of an optionally substituted 5-10 membered heteroaryl, an optionally substituted C3-C6 cycloalkyl, and an optionally substituted 3-8 membered heterocycle. The halogen may be F or Cl. When the aryl, heteroaryl, cycloalkyl, or heterocycle is directly or indirectly substituted with an optionally substituted alkyl, alkenyl, or alkynyl, the alkyl, alkenyl, or alkynyl may be unsubstituted or may be substituted with halogen, OH, C1-C6 alkoxy, NR20 R 21 ,CONR 20 R 21 , C(O)R 20 , CN, OXO, OP(O)(OR 20 )(OR 21 ), O.C.(O)R 20 , COOR 20 , C1-C6 alkenyl, C1-C6 alkynyl, =NOR 20 , N.R. 20 C(O)R 21 , SO2R 20 and SO2NR 20 R 21 Preferably, when an aryl, heteroaryl, cycloalkyl or heterocycle is directly or indirectly substituted with an optionally substituted alkyl, alkenyl or alkynyl, the alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more of halogen and OH. When an aryl, heteroaryl, cycloalkyl or heterocycle is substituted with an optionally substituted aryl or an optionally substituted heteroaryl, it may be substituted with an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl. R 20 and R 21 may be independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. 20 and R 21are independently H and optionally substituted methyl, more preferably H, CH3 or CF3. Thus, the cycloalkyl, aryl, heteroaryl or heterocycle may be unsubstituted or substituted with one or more of F, Cl, oxo, OH, CN, NH2, methyl, t-butyl, CF3, CH2OH, OCH3, OCHF2, OCF3, SCF3, COCH3, COOH, COOCH3, CONH2, SO2CH3, 1,2,4-triazolyl and phenyl. The aryl, heteroaryl, cycloalkyl or heterocycle is preferably unsubstituted or substituted with one or two substituents.

[0107] Therefore, R 16 is cyclopropyl, cyclopentyl, phenyl, [ka] More preferably, R 16 is phenyl or [ka] It is.

[0108] In an alternative embodiment, R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl. 5 R may be an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl, or an optionally substituted C2-C3 alkynyl. The alkyl, alkenyl, or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, CN, and oxo. 5 may be CH3 or CH2CN.

[0109] In one embodiment, X 6 CR 7 R 8 R7 and R 8 are independently H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 7 and R 8 are independently H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. 13 and R 14 is preferably H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl, most preferably H. The alkyl, alkenyl or alkynyl may be unsubstituted or may be substituted with halogen, OH, oxo, CN, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 and OP(O)(OR 20 )(OR 21 ) may be substituted with one or more of the following: R 20 and R 21 may be, independently, H or methyl. Preferably, R7 and R 8 are independently H, CN, CONH2, CH2NH2, CH2CH2OH, [ka] or [ka] Most preferably, R 7 and R 8 is H. Therefore, X 6 , CH2, [ka] Preferably, X 6 is CH2.

[0110] In an alternative embodiment, X 6 is CO.

[0111] In one embodiment, n is 0. 7 is CR 11 R 12 R 11 and R 12 may be independently H, halogen, OH, CN, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. 11 and R 12 is independently H or methyl. Most preferably, R 11 and R 12 is H.

[0112] In an alternative embodiment, n is 1.

[0113] In one embodiment, Z is CR 9 R 10 and X 7 is S, SO, SO2, O or NR 11 R9 and R 10 are, independently, OR 13 , H, halogen, CN, COOR 13 ,CONR 13 R 14 , N.R. 13 R 14 , N.R. 13 COR 14 , optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C2-C3 alkynyl. 13 and R 14 may be independently H, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl, or an optionally substituted C2-C3 alkynyl. The alkyl, alkenyl, or alkynyl may be unsubstituted or may be selected from the group consisting of halogen, OH, oxo, CN, C(O)R 20 , COOR 20 , O.C.(O)R 20 ,CONR 20 R 21 , N.R. 20 R 21 , N.R. 20 C(O)R 21 , =NOR 20 , S.R. 20 , SO2R 20 , OSO2R 20 , SO2NR 20 R 21 and OP(O)(OR 20 )(OR 21 ) may be substituted with one or more of the following: R 20 and R 21 may be, independently, H or methyl. Preferably, R 9 and R 10 are independently H, methyl, CH2CONH2 or CH2CN. More preferably, R 9 and R 10 is H. R 11 may be H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. 11 is H or methyl. More preferably, X 7is S, O, SO or NR 11 Most preferably, X 7 is S or O.

[0114] In an alternative embodiment, Z is NR 9 and X 7 is CR 11 R 12 R 9 R may be H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 9 may be H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. 9 is methyl. 11 and R 12 may be independently H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 11 and R 12 may be independently H, halogen, OH, CN, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. 11 and R 12 is H or methyl. 7 CR 11 R 12 and R 11 and R 12 In an embodiment where R 11 and R 12 The carbon to which is attached defines a chiral center. The chiral center may be an S or R chiral center. In some embodiments, the chiral center is an S chiral center.

[0115] In one embodiment, n is 1. Z is CR 9 R 10 X may be 7 is S, SO, SO2, O or NR 11 Alternatively, Z may be NR 9 X may be 7is CR 11 R 12 Thus, the compound may be of formula (II) or (III). [ka]

[0116] In an alternative embodiment, n is 0. 7 is CR 11 R 12 Thus, the compound may be of formula (IV): [ka]

[0117] In some embodiments, X 2 is CR 2 and X 3 is CR 3 In some embodiments, R 2 A-A-NR 17 -C(O)-NR 18 -R 15 In an alternative embodiment, R 3 A-A-NR 17 -C(O)-NR 18 -R 15 Thus, the compound of formula (II) or (III) may be a compound of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb). [ka]

[0118] In one embodiment of the compound of formula (II), (III), (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), R 5 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl. 5may be H, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl, or an optionally substituted C2-C3 alkynyl. The alkyl, alkenyl, or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, CN, and oxo. Preferably, R 5 is H or CH3.

[0119] In an alternative embodiment of the compound of formula (II), (III), (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), R 5 -L 1 -L 2 -R 16 Thus, the compound may be of formula (IIc), (IId), (IIIc), (IIId), (IVc) or (IVd). [ka]

[0120] In some embodiments, L 6 may not be present, and R 5 -L 5 -R 16 Thus, the compound may be of formula (IIci), (IIdi), (IIIci), (IIIdi), (IVci) or (IVdi). [ka]

[0121] In the compound of formula (II), (III), (IIa) to (IIdi), (IIIa) to (IIIdi) or (IVa) to (IVdi), X 6 is C=O or CR 7 R 8 In some embodiments, X 6 is C=O.

[0122] In the compounds of formula (II) or (IIa) to (IId), X7 may be S or O. Preferably, X 7 is S.

[0123] It will be understood that the compounds described herein, or a pharma- ceutically acceptable salt, solvate, tautomer or polymorph thereof, may be used in medicaments which may be used in monotherapy (i.e., use of the compound alone) to modulate STING protein and / or to treat, ameliorate or prevent disease.

[0124] Alternatively, the compounds or pharma- ceutically acceptable salts, solvates, tautomers or polymorphs thereof may be used as an adjunct to, or in combination with, known therapies to modulate STING protein and / or to treat, ameliorate or prevent disease.

[0125] The compound of formula (I) may be combined in a composition that has several different forms, depending in particular on the method that the composition is to be used.Thus, for example, the composition may be in the form of powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle solution, transdermal patch, liposomal suspension, or any other suitable form that can be administered to the human or animal that needs treatment.It will be understood that the vehicle of the pharmaceutical according to the present invention should be well tolerated by the subject that it is given to.

[0126] Medicaments containing the compounds described herein may be used in a number of ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhalation / intranasal, rectal / intravaginal, and ocular / aural administration.

[0127] Formulations suitable for the aforementioned modes of administration may be formulated for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

[0128] The compounds of the present 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 used, where the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing microparticles, liquids, or powders, lozenges (including liquid-filled lozenges), chewable tablets, multi- and nanoparticulates, gels, solid solutions, liposomes, films, ovules, sprays, liquid formulations, and buccal / mucoadhesive patches.

[0129] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as soft or hard capsule fillers and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid, for example, from a sachet.

[0130] The compounds of the present invention are disclosed in Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, or other fast-dissolving and fast-disintegrating formulations.

[0131] For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets will generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0132] Binders are commonly used to provide cohesiveness to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate.

[0133] Tablets may also optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and lubricants, such as silicon dioxide and talc. When present, the surfactants may constitute 0.2% to 5% by weight of the tablet, and the lubricants may constitute 0.2% to 1% by weight of the tablet.

[0134] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10% by weight of the tablet, preferably 0.5% to 3%. Other possible ingredients include antioxidants, colourants, flavourings, preservatives and taste-masking agents.

[0135] An exemplary tablet contains up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant. Tablet blends can be compressed directly or by roller to form tablets. Tablet blends or portions of blends can alternatively be wet granulated, dry granulated, or melt granulated, melt congealed, or extruded prior to tableting. The final formulation may include one or more layers, may be coated or uncoated, and may even be encapsulated. Tablet formulations are discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0136] Modified release formulations suitable for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al. (2001) Pharmaceutical Technology On-line, 25(2), 1-14. The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0137] The compounds of the present invention may be administered directly into the bloodstream, 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.

[0138] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of 3 to 9), although for some applications parenteral formulations may be more suitably formulated as sterile non-aqueous solutions or as a dry form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.

[0139] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0140] The solubility of the compound of formula (I) used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the compounds of the present invention may be formulated as solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

[0141] The compounds of the present invention may be administered topically to the skin or mucosa, i.e., 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, fibers, 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 may be incorporated - see, for example, J Pharm Sci by Finnin and Morgan (October 1999); 88 (10), 955-958.

[0142] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject™, Bioject™, etc.) injection.

[0143] The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, in admixture, e.g., in a dry blend with lactose, or as mixed component particles, e.g., mixed component particles mixed with a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to generate a fine mist), or nebulizer, 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 include a bioadhesive agent, e.g., chitosan or cyclodextrin.

[0144] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention, e.g., with ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or extending the release of the active agent, propellant(s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0145] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminuting method, such as spiral jet milling, fluid bed jet milling, and supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

[0146] Capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in inhalers or insufflators may be formulated to contain a powder mix of the compound of the invention and 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.

[0147] A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to generate a fine mist may contain 1 μg to 20 mg of the compound of the present invention per actuation, and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

[0148] 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.

[0149] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve which delivers a metered amount. Units according to the invention are typically arranged to administer a metered dose or "puff" containing 1 μg to 100 mg of the compound of formula (I). The total daily dose will typically be in the range of 1 μg to 200 mg which may be administered in a single dose or, more commonly, as divided doses throughout the day.

[0150] 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.

[0151] The compounds of the present invention may be directly administered to the eye or ear in the form of droplets of micronized suspension or solution, typically in isotonic pH-adjusted sterile saline.Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbent gel sponge, collagen) and non-biodegradable (e.g. silicone) implants, oblates, lenses, and microparticulate or vesicular systems such as niosomes or liposomes.Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated together with preservatives such as benzalkonium chloride.Such formulations may also be delivered by iontophoresis.

[0152] The compounds of the present invention may be administered directly to the site of interest by injection of a solution or suspension containing the active drug substance. The site of interest may be a tumor, and the compound may be administered via intratumoral injection. A typical injection solution consists of propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0153] The compounds of the present invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0154] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrins, examples of which can be found in International Patent Application Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0155] It will be understood that the amount of compound required will be determined by the biological activity and bioavailability of the compound, which in turn will depend on the mode of administration, the physiochemical properties of the compound, and whether the compound is used as a monotherapy or in a combination therapy. The frequency of administration will also be influenced by the half-life of the compound in the subject being treated. The optimal dosage to be administered can be determined by those skilled in the art and will vary depending on the specific compound being used, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Additional factors depending on the specific subject being treated, including the subject's age, weight, sex, diet, and time of administration, will result in the need to adjust the dosage.

[0156] In general, for administration to humans, the total daily dose of the compounds of the invention is typically in the range of 100 μg to 10 g, such as 1 mg to 1 g, e.g., 10 mg to 500 mg. For example, oral administration may require a total daily dose of 25 mg to 250 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside the typical ranges described herein. These dosages are based on an average human subject having a body weight of about 60 kg to 70 kg. A physician will be able to readily determine dosages for subjects whose body weight falls outside this range, such as infants and the elderly.

[0157] The compounds may be administered prior to, during or after the onset of the disease to be treated.

[0158] Known procedures, such as those conventionally used by the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.), can be used to generate specific formulations containing the compounds according to the invention and to formulate precise treatment regimes (such as daily doses and frequency of administration of the compounds).The inventors believe that they are the first to describe pharmaceutical compositions for treating diseases based on the use of the compounds of the invention.

[0159] Thus, in a seventh aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharma- ceutically acceptable salt, solvate, tautomer or polymorph thereof, and a pharma- ceutically acceptable vehicle.

[0160] The present invention also provides, in an eighth aspect, a process for producing a composition according to the seventh aspect, comprising the step of contacting a therapeutically effective amount of a compound of the first aspect, or a pharma- ceutically acceptable salt, solvate, tautomer or polymorph thereof, with a pharma- ceutically acceptable vehicle.

[0161] A "subject" may be a vertebrate, a mammal, or a domestic animal. Thus, the compounds, compositions and medicaments according to the invention may be used to treat any mammal, such as livestock (e.g., horses), pets, or in other veterinary applications. However, most preferably, the subject is a human.

[0162] A "therapeutically effective amount" of a compound is any amount that, when administered to a subject, is the amount of drug needed to treat a target disease or produce a desired effect, i.e., inhibit the STING protein.

[0163] For example, the therapeutically effective amount of the compound used may be about 0.01 mg to about 800 mg, preferably about 0.01 mg to about 500 mg. It is preferred that the amount of the compound is about 0.1 mg to about 250 mg, most preferably about 0.1 mg to about 20 mg.

[0164] A "pharmaceutically acceptable vehicle" as referred to herein is any known compound or combination of known compounds known to those of ordinary skill in the art to be useful in formulating a pharmaceutical composition.

[0165] In one embodiment, the pharma- ceutically acceptable vehicle may be solid and the composition may be in the form of a powder or tablet. The solid pharma- ceutically acceptable vehicle may contain one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet disintegrants. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is mixed with the finely divided active agent according to the present invention (i.e., the compound according to the first aspect). In tablets, the active compound may be mixed with a vehicle having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid vehicles include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.

[0166] However, the pharmaceutical vehicle may be liquid and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds according to the invention may be dissolved or suspended in a pharma- ceutically acceptable liquid vehicle, such as water, an organic solvent, a mixture of both, or a pharma- ceutically acceptable oil or fat. The liquid vehicle may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity regulators, stabilizers, or osmolality regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (water partially containing additives as described above, e.g. cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g. glycols) and derivatives thereof, and oils (e.g. fractionated coconut oil and peanut oil). For parenteral administration, the vehicle may 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 halogenated hydrocarbon or other pharma- ceutically acceptable propellant.

[0167] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The compounds may also be prepared as sterile solid compositions that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.

[0168] The compounds and compositions of the present invention may be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleic acid ester of sorbitol and its anhydrides, copolymerized with ethylene oxide), and the like. The compounds used according to the present invention can also be administered orally in either 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.

[0169] Those skilled in the art will know that active drug substances may be converted into prodrugs, which are metabolically unstable derivatives that are converted into active drug substances in the body. Also included within the scope of the present invention are prodrugs, which are compounds of formula (I) that contain a metabolically or hydrolytically unstable moiety that is converted into an active drug substance of formula (I) in vivo. The process by which prodrugs are converted into active drug substances is described in Beaumont et al., Curr. Drug Metab., 2003, 4 , 461-485 and Huttenen et al., Pharmacol. Revs., 2011, 63 Prodrug derivatives include, but are not limited to, ester or carbonate or carbamate hydrolysis, phosphate ester hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation as described in U.S. Pat. No. 7,500,633, and U.S. Pat. No. 7,500,633. Such prodrug derivatives may provide improved solubility, stability, or permeability compared to the parent drug substance, or may better enable the drug substance to be administered by an alternative route of administration, for example as an intravenous solution.

[0170] Also included within the scope of the present invention are soft drugs or antedrugs that are compounds of formula (I) that contain metabolically or hydrolytically unstable moieties that are converted in vivo to inactive derivatives. The process by which active drug substances are converted to inactive derivatives is described, for example, in Pearce et al., Drug Metab. Dispos., 2006, 34 , 1035-1040 and Comprehensive Medicinal Chemistry II, vol. 5, Elsevier, Oxford, 2007, pp. 1009-1041, in B. Testa, Prodrug and Soft Drug Design and Bodor, N. Chem. Tech. 1984, 14 These include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described in, for example, US Pat. No. 5,281,385.

[0171] The scope of the present invention includes all pharma- ceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0172] Examples of isotopes suitable for inclusion in the compounds of the present invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P, 35 Contains isotopes of sulfur such as S.

[0173] Certain isotopically labeled compounds of the present invention, e.g., those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and rapid means of detection. Deuterium, i.e. 2 Substitution with isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0174] 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 the appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0175] All of the features described in this specification (including any accompanying claims and abstract), and / or all of the steps of any method or process so disclosed, may be combined in any combination with any of the above aspects, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0176] General scheme General scheme 1 Compounds of formula (IVe) and (IVf) may be prepared from compounds of formula (VIa) and (VIb) using a urea bond forming reaction as shown below. [ka]

[0177] Typical reaction conditions for the activation of aromatic amines of compounds of formula (VIa) or (VIb) use 4-nitrophenyl chloroformate or triphosgene to generate an activated intermediate, which can be attacked by a suitable nucleophile, such as amine (Va), to give urea compounds of formula (IVe) or (IVf). Preferred organic bases include 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.

[0178] Alternatively, a compound of formula (IVe) or (IVf) can be prepared by reacting an isocyanate R 15 It can also be prepared using NCO(Vb) and a suitable organic base such as TEA or DIPEA. The reaction may be shaken or stirred at room temperature.

[0179] Compounds of formula (V) and (VI) are commercially available or may be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (VI) are described in general Schemes 2-4.

[0180] General scheme 2 Compounds of formula (X) may be synthesized from esters of formula (VII), where R is methyl, ethyl, benzyl or tert-butyl, by hydrolysis. [ka]

[0181] The ester of formula (VII) may be reduced using a suitable reducing agent such as borane-THF, NaBH4, DIBAL or LiAlH4 to give the corresponding alcohol (VIII). The hydroxyl function may then be chlorinated using, for example, thionyl chloride or oxalyl chloride to give the corresponding chloride (IX), which may then be aminated using any suitable primary or secondary amine, for example ammonia, to give the amine of formula (X).

[0182] General scheme 3 Compounds of formula (X) may be synthesized from esters of formula (VII), where R is methyl, ethyl, benzyl or tert-butyl, by hydrolysis. [ka]

[0183] The esters of formula (VII) may be hydrolyzed using suitable conditions, for example, using alkali NaOH, LiOH or KOH, to give acids (XI), which may then be converted to amides (XII) using standard amide coupling reactions. Typical conditions use activation of carboxylic acids (XI) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either HOBt, T3P, HATU, HBTU or EDCI with BOP. Preferred organic bases include 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. These amides (XII) may then be subjected to a dehydration reaction using a suitable dehydrating reagent, such as thionyl chloride or phosphorus pentoxide, to give the corresponding nitriles (XIII), which may then be reduced using a suitable reducing agent, such as LiAlH4, to give the corresponding amines (X). Alternatively, the amide (XII) may be directly reduced to an amine of formula (X) using a suitable reducing agent such as LiAlH 4 , typically in an ether or alcoholic solvent such as THF, to give the amine (X).

[0184] General Scheme 4 Compounds of formula (XVI) may be synthesized by one skilled in the art via alkylation / acylation / sulfonylation reactions on compounds of formula (XIV), where X is a leaving group such as optionally substituted alkylaryl (het), alkyl, aryl (het), cycloalkyl, alkylcycloalkyl halide, triflate or tosylate. [ka]

[0185] The compound of formula (XIV) may be reacted with the compound of formula (XV) in the presence of a suitable base such as NaH, NaHCO3 or TEA to give the compound of formula (XVI). Suitable reaction solvents include THF, DMA and DMF.

[0186] General scheme 5 Alternatively, compounds of formula (XIV) may be prepared from compounds of formula (XVII), where R is methyl, ethyl, benzyl or tert-butyl, in a two-step process as shown below. [ka]

[0187] First, a compound of formula (XVII) undergoes a nucleophilic substitution reaction with a compound of formula (XVIII) where R is methyl, ethyl, benzyl or tert-butyl to produce a compound of formula (XIX). The nucleophilic substitution reaction may be carried out 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.

[0188] The nitro group of the compound of formula (XIX) may then be reduced to an amino group using a suitable reducing agent such as Fe / AcOH, Zn / HCl, Zn / NH4Cl, Zn / HCOONH4, SnCl2 / HCl or Pd / C / H2 in a suitable solvent such as EtOH, MeOH or THF. The amino compound then typically undergoes in-situ cyclization leading to the production of a compound of formula (XIV).

[0189] The compound of formula (XIV) is R 5 is H and X 6 It will be understood that is a compound of formula (VII) where is C=O.

[0190] General Scheme 6 Compounds of formula (XXI) may be prepared from compounds of formula (XX), where R is methyl, ethyl, benzyl or tert-butyl. [ka]

[0191] The lactam carbonyl group of a compound of formula (XX) can be reduced to the corresponding methylene group of a compound of formula (XXI) using a borane-THF solution in a suitable solvent such as THF, typically at low temperature.

[0192] The compound of formula (XXI) is X 6 It will be appreciated that the compound of formula (XVI) is

[0193] General Scheme 7 Compounds of formula (XXIII) may be prepared from compounds of formula (XXII), where R is methyl, ethyl, benzyl or tert-butyl. [ka]

[0194] Compounds of formula (XXII) may undergo cyclization with 1,2-dibromoethane in a basic reaction medium to give fused morpholine derivative compounds of formula (XXIII).

[0195] The compound of formula (XXIII) is X 6 and Z is CH2, and X 7 is O and R 5 It will be understood that the compound is of formula (VII) wherein

[0196] General Scheme 8 Compounds of formula (XXIV) may be prepared from compounds of formula (XIV) in a one-step reaction as depicted in the following scheme, where R is methyl, ethyl, benzyl or tert-butyl. [ka]

[0197] Compounds of formula (XIV) may undergo Chan-Lam coupling reaction with a suitable boronic acid / boronic ester in the presence of a suitable catalyst and base to give compounds of formula (XXIV).

[0198] The compound of formula (XXIV) is X 6 It will be understood that is a compound of formula (VII) where is C=O.

[0199] General Scheme 9 Compounds of formula (XXVI) may be prepared from compounds of formula (XXV) in a one-step reaction as depicted in the following scheme, where R is methyl, ethyl, benzyl or tert-butyl. [ka]

[0200] The compound of formula (XXV) can be prepared by reacting a suitable halogenated aromatic compound (R 5 -X) to give compounds of formula (XXVI).

[0201] The compound of formula (XXVI) is X 6 CR 7 R 8 It will be appreciated that the compound is of formula (VII)

[0202] General scheme 10 Compounds of formula (XXXII) may be prepared from compounds of formula (VIII) in the sequence of reactions depicted in the following scheme, where R is H, alkyl, cyclo(het)alkyl, aryl(het). [ka]

[0203] Alcohol (VIII) may be converted to the corresponding aldehyde (XXVII) using suitable oxidation conditions, such as Swern, Dess-Martin periodinane, TPAP / NMO or PCC. Aldehyde (XXVII) may then be converted to sulfoximine (XXVIII) by treatment with tert-butylsulfonamide, which may then be reacted with a suitable nucleophile, such as a Grignard or other organometallic reagent derived from the required halide, to give addition product (XXIX). This reaction could potentially be adapted to prepare non-racemic materials using chiral non-racemic sulfonamide reagents suitable for preparing sulfoximines. In the example shown, addition product (XXIX) can undergo a hydrolysis reaction, for example using alkaline conditions, to give the corresponding acid (XXX). Acid (XXX) can then be used to generate amide (XXXI) using any standard amide coupling conditions. Typical conditions use activation of carboxylic acid (XI) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either HOBt, T3P, HATU, HBTU or EDCI with BOP. Preferred organic bases include 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. Finally, removal of the sulfoxyl group using acidic conditions, for example aqueous HCl, can give the target amine (XXXII).

[0204] General scheme 11 Compounds of formula (XXXIV) may be prepared from compounds of formula (XXVIII) in a two-step reaction as depicted in the following scheme, where R is alkyl, cyclo(het)alkyl, aryl(het). [ka]

[0205] Analogous to general Scheme 10, sulfoximine (XXVIII) can be reacted with a simple Grignard reagent to give the addition product (XXXIII), which after acidic elimination of the sulfoxyl group gives the alkylamine (XXXIV), which can be obtained using a similar sequence to give the alkylamine of formula (XXXIV).

[0206] General scheme 12 Compounds of formula (XXXV) may be prepared from compounds of formula (XXVII) in a one-step reaction as depicted in the following scheme, where R is methyl, ethyl, benzyl or tert-butyl. [ka]

[0207] Alternatively, aldehydes of formula (XXVII) as prepared in general scheme 10 may undergo direct conversion to amines of formula (XXXV) using ammonium acetate to generate the initial imine, which is then treated with a malonate ester suitable for addition to the imine to generate the amine (XXXV) after decarboxylation.

[0208] General synthetic procedure General purification and analysis methods All final compounds were purified by either Combi-flash or prep-HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following conditions.

[0209] Prep-HPLC Preparative HPLC was performed on a Waters autopurifier using a Gemini C18 column (250 × 21.2 mm, 10 μm) operated at ambient temperature with a flow rate of 16.0–25.0 mL / min.

[0210] Mobile phase 1: A=0.1% formic acid in water, B=acetonitrile; gradient profile: initial composition of mobile phase 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 the initial composition over 3 min.

[0211] Mobile phase 2: A = 10 mM ammonium acetate in water, B = acetonitrile; gradient profile: initial composition of mobile phase 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 the initial composition over 3 min.

[0212] LCMS method General 5 min method: Gemini C18 column (50 x 4.6 mm, 5 μm) operated 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: 90% A and 10% B to 70% A and 30 B in 1.5 min, then 10% A and 90% B in 3.0 min, held at this composition for 1.0 min, and finally returned to the initial composition over 2.0 min.

[0213] UPLC method UPLC was performed on a Waters UPLC using a Kinetex Evo C18 column (100×2.1 mm, 1.7 μm) at ambient temperature and a flow rate of 1.5 ml / min.

[0214] Mobile phase 1: A = 5 mM ammonium acetate in water, B = 5 mM ammonium acetate in 90:10 acetonitrile / water; gradient profile 95% A and 5% B to 65% A and 35% B in 2 min, then 10% A and 90% B in 3.0 min, held at this composition for 2.0 min, and finally returned to the initial composition over 6.0 min.

[0215] Mobile phase 2: A = 0.05% formic acid in water, B = acetonitrile; gradient profile from 95% A and 5% B over 1 min, then 90% A and 10% B over 1 min, then 2% A and 98% B over 4 min, then return to initial composition over 6 min.

[0216] General Procedure 1 (method a) [ka] To a stirred solution of aromatic amine of formula (VIa) (1.0 equiv.) in a suitable solvent such as THF, DMF, MeCN or DCM (8 mL / mmol) was added p-nitrophenyl chloroformate (1.2 equiv.) at 0-5° C. and the whole was stirred at room temperature for 1-3 h. The amine R 15 -NH-R 18 (Va) (1.1 eq.) and TEA or DIPEA (6 eq.) were added dropwise successively at 0-5°C and the whole was further stirred at room temperature for 1-5 h. The progress of the reaction was monitored by TLC / LCMS and after completion, the reaction mass was diluted with water and extracted with EtOAc. The combined organic layers were washed with a dilute solution of a suitable inorganic base such as NaHCO3 or 1N NaOH, followed by 1N HCl and finally with brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum to give a residue which was purified by column chromatography or combi-flash or prep-HPLC to give the compound of formula (IVe) (6-70% yield) as a solid. Following a similar procedure, all ureas of formula (IVe) can be synthesized.

[0217] General Procedure 1 (method b) [ka] To a stirred solution of aromatic amine of formula (VIb) (1.0 equiv.) in a suitable solvent such as THF, DMF, MeCN, or DCM (5.5 mL / mmol) is added R 15NCO(Vb) (1.08 equiv.) was added followed by TEA (1.08 equiv.) and the whole was stirred at the same temperature for 5-10 min. The reaction mixture was slowly brought to room temperature and stirred for 1-2 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give a crude solid, which was purified by column chromatography or combi-flash or prep-HPLC to give the compound of formula (IVf) (yield 10-70%) as a solid. Following a similar procedure, all ureas of formula (IVe) can be synthesized.

[0218] General Procedure 1 (method c) [ka] To a stirred solution of compound of formula (Va) (1.0 equiv.) in THF (10 mL / mmol) was added triphosgene (0.5 equiv.) at 0-5° C. The combined mixture was stirred at room temperature for 1 h. After the completion of the first step of the reaction was confirmed by TLC or UPLC-MS, compound of formula (VIa) (0.9 mmol) and TEA (2.5 equiv.) were added to the reaction mixture and stirring was continued at room temperature for 1-2 h. The progress of the reaction was monitored by TLC and / or UPLC-MS. After completion of the reaction, the solvent was evaporated in vacuum to give the crude material, which was purified by column chromatography or prep-HPLC to give compound of formula (IVe) (12-50% yield) as a solid.

[0219] General Procedure 2a [ka] To a stirred solution of compound of formula (VII) (1.0 equiv.) in dry THF (5 mL / mmol) at 0-5° C., borane-THF (9 equiv., 1M in THF) was added and the resulting solution was allowed to stir at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with methanol and concentrated in vacuo to give the crude compound, which was purified by column chromatography to give compound of formula (VIII) (70-75% yield) as an off-white solid.

[0220] General Procedure 2b [ka] A stirred solution of compound of formula (XX) (1.0 equiv.) in THF (5 mL / mmol) was cooled to 0-5° C. and borane-THF complex (1 M solution in THF) (10 mL / mmol, 10 equiv.) was added in portions. The resulting reaction mixture was allowed to warm to room temperature and then heated to reflux for 1-2 h. The progress of the reaction was monitored by UPLC-MS, which indicated the formation of compound of formula (XXI). After completion, the reaction mixture was diluted with methanol, which was refluxed for 5-10 min, and the solvent was evaporated to give the crude material, which was purified by Combi-flash or column chromatography to give compound of formula (XXI) as a colorless oil.

[0221] General Procedure 3 [ka] To a stirred solution of compound of formula (VIII) (1.0 equiv.) in DCM (7 mL / mmol) at room temperature, a few drops of DMF were added followed by the addition of SOCl2 (2.0 equiv.). The whole was stirred at room temperature for 1-2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give compound of formula (IX) as a thick crude oil, which was used in the next step without further purification.

[0222] General Procedure 4 [ka] To a stirred solution of compound of formula (IX) (1.0 equiv.) in a sealed tube containing THF (3 mL / mmol) was added ammonia in methanol (6 mL / mmol) at room temperature. The reaction mixture was stirred at 80° C. for 10-18 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and the residue was taken up in 10% MeOH in DCM and the remaining solid was filtered off. The filtrate was evaporated in vacuo to give the crude product which was triturated with hexane and diethyl ether to give compound of formula (X) as a crude solid which was used in the next step without further purification.

[0223] General Procedure 5 [ka] To a stirred solution of ester (VII) (1.0 equiv.) in a mixture of MeOH or THF (6.5 mL / mmol) and water (0.8 mL / mmol) at room temperature, LiOH, NaOH or KOH (2.0 equiv.) was added and the resulting reaction mixture was stirred at room temperature for 2-16 h. TLC indicated complete consumption of ester (VII). The solvent was evaporated in vacuum and the resulting residue was washed with ether. The residue was then acidified to pH 5-6 with 1N HCl, which resulted in the formation of a precipitate, which was filtered, washed with water and then dried by azeotropic distillation or under reduced pressure at 50-60° C. to afford the desired carboxylic acid of formula (XI) (70-85% yield) as a solid.

[0224] General Procedure 6 [ka] To a stirred solution of acid (XI) (1.0 equiv.) in DMF (3 mL / mmol) was added HATU (1.2 equiv.) and TEA (3.0 equiv.) at 0-5° C. The whole was stirred at room temperature for 10-15 min, followed by the addition of ammonium formate (10.0 equiv.). The resulting reaction mixture was stirred at room temperature for 16-20 h. The progress of the reaction was monitored by LCMS / TLC, and after completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the compound of formula (XII) as crude, which was used in the next step without further purification.

[0225] General Procedure 7 [ka] To a stirred solution of amide (XII) (1.0 equiv.) in THF (3 mL) / mmol, TEA (5.0 equiv.) and trifluoroacetic anhydride (5.0 equiv.) were added at 0-5° C. The whole was kept at room temperature for 1-2 h. The progress of the reaction was monitored by LCMS / TLC, and after completion of the reaction, the reaction mixture was quenched with ice water, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the compound of formula (XIII) as crude, which was used in the next step without further purification.

[0226] General Procedure 8 [ka] To a stirred solution of compound of formula (XIII) (1.0 equiv.) in MeOH (4 mL / mmol) was added (Boc)2O (2.0 equiv.), NiCl5.5H2O (0.5 equiv.) and NaBH4 (2.5 equiv.) at 5-10°C and the mixture was kept at 10-15°C to room temperature for 0.5-1 h. After completion of the reaction (monitored by TLC / LCMS), it was diluted with cold water, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the crude product, which was purified by trituration to give the intermediate Boc protected amine. This was dissolved in 20% TFA in DCM (8 mL / mmol) under inert atmosphere and stirred at room temperature for 0.5-1 h. Completion of the reaction was confirmed by LCMS, then the reaction mass was quenched with saturated NaHCO3 solution (pH about 8) and extracted with DCM, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to obtain the compound of formula (X) as crude, which was used in the next step without further purification.

[0227] General Procedure 9 [ka] Option A To a stirred solution of compound of formula (XIV) (1.0 equiv.) in DMF or THF (4 mL / mmol), K2CO3, Cs2CO3, Na2CO3, NaOH or NaH (1.1 equiv.) was added. When NaOH was used, TBAB (0.1 equiv.) was also added as a phase transfer catalyst, followed by the addition of compound of formula (XV) (1.05 equiv.) and the mixture was allowed to stir at room temperature for 0.5-1 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with a saturated solution of NH4Cl, diluted with ice-cold water and extracted with EtOAc or MTBE. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuum to give the crude product, which was purified by Combi-flash using a mixture of EtOAc in hexane as eluent to give compound of formula (XVI) (60-80% yield) as a colorless oil.

[0228] Option B Alternatively, to a stirred solution of compound of formula (XIV) (1.0 equiv.) in DCM or MeCN or THF (4 mL / mmol), TEA or DIPEA (2.0 equiv.) was added or without base, followed by the addition of compound of formula (XV) (1.5 equiv.) and the whole was allowed to stir at room temperature for 0.5-1 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 layer was evaporated in vacuum to give the crude product, which was purified by Combi-flash using a mixture of EtOAc in hexane as eluent to give compound of formula (XVI) (60-80% yield) as a colorless oil.

[0229] General Procedure 10 [ka] To a stirred solution of compound of formula (XVII) (1.0 equiv.) and suitable nucleophile (XVIII) (1.25 equiv.) in a suitable solvent (3 mL / mmol) such as 1,4-dioxane, MeCN, DMF or THF, a suitable base (1.5 equiv.) such as TEA, DBU, NaH or K2CO3 was added dropwise or in portions while cooling with an ice bath, and the combined mixture was allowed to stir at 0-25°C for 1-16 hours. The progress of the reaction was monitored by TLC or LCMS, and once the reaction was complete, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude compound of formula (XIX) obtained as a solid (60-95% yield) was pure enough to be used directly in the next step without further purification.

[0230] General Procedure 11 [ka] Option A (Fe / Zn-AcOH / HCl / NH 4 (reduction with Cl) To a stirred solution of compound of formula (XIX) (1.0 equiv.) in EtOH or MeOH (2 mL / mmol) was added an appropriate acid such as AcOH or aqueous HCl (3 mL / mmol) at room temperature followed by iron or zinc powder (4.0 equiv.). In some cases NH4Cl was also used as a source of hydrogen. The reaction mixture was stirred at 75-85°C for 1-5 h. The reaction was monitored by TLC or LCMS and after completion, the reaction mixture was poured into ice-cold water and filtered through a short bed of Celite. The filtrate was extracted with EtOAc and then washed with aqueous NaHCO3 and then with brine. The collected organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give compound of formula (XIV) (60-80% yield) as a crude solid, which was used in the next step without further purification.

[0231] Option B: (Reduction with Sodium Dithionate) To a stirred solution of compound of formula (XIX) (1.0 equiv.) in a mixture of either MeCN / H2O or THF / H2O (12 mL / mmol, 2:1) was added sodium hydrosulfite (8.0 equiv.), tetra-butylammonium hydrosulfate (0.5 equiv.) and K2CO3 (6.0 equiv.) at room temperature, and the mixture was then stirred for 1 h. The progress of the reaction was monitored by TLC and / or LCMS. After completion of the reaction, the solvent was evaporated in vacuum to give an oily liquid, which was dissolved in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The organics were filtered and evaporated in vacuum to give compound of formula (XIV) (80-90% yield) as a solid.

[0232] Option C: (Pd / C / H 2 (Rebate by To a stirred solution of compound of formula (XIX) (1.0 equiv.) in EtOAc, MeOH or EtOH (9.4 mL / mmol, 120 mL) was added 10% Pd-C (50% w / w in water) (77.8 mg / mmol) at room temperature under inert atmosphere. The reaction mixture was purged with H2 gas using balloon pressure and then allowed to stir further at room temperature for 3-5 h. The course of the reaction was monitored by TLC and / or LCMS. After completion of the reaction, the mixture was diluted with EtOAc, carefully filtered through a bed of celite and washed 4-5 times with EtOAc until the mother liquor showed no residual compound by TLC. The collected organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound of formula (XIV) (80-85% yield) as a semi-solid. The product was pure enough to be used in the next step without further purification.

[0233] General Procedure 12 [ka] To a stirred solution of compound of formula (XXII) (1.0 equiv.) in DMF or THF (1.6 mL / mmol) was added K2CO3, Cs2CO3, Na2CO3, NaOH or NaH (4.0 equiv.) at room temperature, followed by 1,2-dibromoethane (4.0 equiv.) and the reaction mass was kept at 80-85 °C for 10-16 h. The progress of the reaction was monitored by TLC and UPLC-MS, which indicated the formation of the desired product. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuum to obtain the crude material, which was purified by Combi-flash using a suitable solvent to obtain compound of formula (XXIII) (50-55% yield) as a solid.

[0234] General Procedure 13 [ka] A stirred solution of compound of formula (XIV) (1.0 equiv.) in EDC (1.1 mL / mmol) was added to a solution of R 5 A solution of -B(OH)2 / boronate (1.5 eq.), DBU (2.0 eq.) and Cu(OAc) (2.0 eq.) was added. The resulting reaction mixture was stirred at room temperature for 20-24 h. The progress of the reaction was monitored by LCMS and upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuum to give the crude material, which was purified by Combi-flash using a suitable solvent to give the compound of formula (XXIV) (34-40% yield) as a solid.

[0235] General Procedure 14 [ka] To a stirred solution of compound of formula (XXV) (1.0 equiv.) in toluene or dioxane or EDC (6 mL / mmol) at room temperature, 5 -X [wherein X is a suitable leaving group] (1.5 eq.), cesium carbonate (2.0 eq.) and BINAP (0.2 eq.) were added. The whole was degassed with nitrogen for 20 min, then palladium acetate (0.1 eq.) was added to the reaction mixture and stirring was continued at 100-110° C. for 20-24 h. The progress of the reaction was monitored by UPLC-MS and after completion, the reaction mixture was concentrated in vacuo to give the crude material which was purified by column chromatography using a suitable solvent to give the compound of formula (XXVI) (yield 30-35%) as a solid.

[0236] General Procedure 15 [ka] To a stirred solution of compound of formula (VIII) (1.0 equiv.) in DCM (6 mL / mmol), MnO2 (10.0 equiv.) was added and the reaction mixture was stirred at room temperature for 10-16 h. Completion of the reaction was confirmed by LCMS, then the reaction mixture was filtered through a bed of Celite and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography using a suitable solvent to give compound of formula (XXVII) (yield 50-60%).

[0237] General Procedure 16 [ka] To a stirred solution of compound of formula (XXVII) (1.0 equiv.) in THF (8 mL / mmol) was added 2-methylpropane-2-sulfinamide (1.5 equiv.) at room temperature. Then titanium isopropoxide (2.0 equiv.) was added dropwise to the solution at the same temperature and the reaction mixture was stirred for 15-20 h. Completion of the reaction was confirmed by LCMS, then the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the crude material, which was purified by silica gel column chromatography using a suitable solvent to obtain compound of formula (yield 55-60%).

[0238] General Procedure 17 [ka] To a stirred suspension of Zn (10. equiv.) in THF (10 mL / mmol) was added iodine (0.1 equiv.) at room temperature and the whole was heated to reflux for 30 min. Then, a mixture of compound of formula (XXVIII) (1.0 equiv.) and alkyl bromoacetate (4.0 equiv.) in THF (6 mL / mmol) was added to the reaction mixture. The resulting reaction mixture was refluxed for 2-3 h. The progress of the reaction was monitored by LCMS and after completion, the reaction was filtered through a bed of Celite. The filtrate was quenched with water and the organic portion was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude was purified by silica gel column chromatography using a suitable solvent to give the title compound (60-65% yield).

[0239] General Procedure 18 [ka] To a stirred solution of compound of formula (XXXI) (1.0 equiv.) in EtOH (11 mL / mmol) was added 1.25 M HCl in MeOH (2.3 mL / mmol) at 0-5° C. and the whole was stirred for 1-2 h. After completion of the reaction (monitored by LCMS), excess solvent was evaporated under reduced pressure and the reaction mass was quenched with saturated NaHCO3 solution and extracted with 10% MeOH-DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound of formula (XXXII) as crude, which was used in the next step without further purification.

[0240] General Procedure 19 [ka] A solution of compound of formula (XXVIII) (prepared according to the method described in General Procedure 16) (1.0 equiv.) in THF (6 mL / mmol) was charged at -78 °C by slow addition of R-Mg-Br (3.0 equiv.; 1M in diethyl ether). The mixture was stirred at the same temperature for 1-2 h. After completion of the reaction, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel column chromatography using a suitable solvent to obtain compound of formula (XXXIII) (yield 70-75%).

[0241] General Procedure 20 [ka] To a stirred solution of compound of formula (XXVII) (1.0 equiv.) in MeOH (10 mL / mmol) was added excess NHOAc (34 equiv.) and 3-alkyl-3-oxopropanoic acid (2.0 equiv.) at room temperature. The whole was allowed to stir at room temperature for 2-3 hours. Then another portion of NHOAc (34 equiv.) was added and the combined mixture was heated at 80-85° C. for 15-20 hours. The progress of the reaction was monitored by TLC / LCMS and after completion of the reaction, the solvent was evaporated to give the crude product which was purified by silica gel column chromatography using a suitable solvent to give compound of formula (XXXV) (yield 10-15%).

[0242] [Example] 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 (p / m) from tetramethylsilane (TMS) using conventional abbreviations for the designation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; 1 1H-NMR) and parts per million high magnetic field from trichloro-fluoro-methane ( 19For F NMR, the solvents are denoted as CDCl3, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol.

[0243] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI). Where relevant and unless otherwise stated, the m / z data given are isotopic. 19 F, 35 Cl, 79 Br and 127 It is about I.

[0244] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were carried out under a nitrogen atmosphere unless otherwise noted.

[0245] Flash column chromatography was performed using prepacked silica gel cartridges on a Combi-Flash platform. Prep-HPLC purification was performed according to the general purification and analytical methods described above. Thin layer chromatography (TLC) was performed on Merck silica gel 60 plates (5729). Unless otherwise stated, all final compounds were >95% pure as judged by LCMS or UPLC analytical methods described in the general purification and analytical methods above.

[0246] Example 1: 1-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)-3-(1H-indol-6-yl)urea [ka] Example 1 was prepared according to the methods described in General Procedures 1-4, 9-11 and the methods described below.

[0247] Preparation 1: (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine [ka]

[0248] Step 1: Methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate [ka] Methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) was taken up in MeCN (2.0 L) and TEA (7.61 g, 75.38 mmol) was added to the solution. The reaction mixture was cooled to 0-5 °C and ethyl thioglycolate (7.25 g, 62.7 mmol) was added dropwise. The reaction mixture was stirred at ice-cold temperature for 30 min. It was then diluted with EtOAc and washed with a saturated solution of NH4Cl and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to give the title compound (14.0 g, 46.82 mmol, 93% yield) as a yellow solid, which was pure enough to be used in the next step without further purification. LCMS m / z: 300.06 [M+H].

[0249] Step 2: Methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate [ka] To a stirred solution of methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (Preparation 1, 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. Upon completion (monitored by TLC), the reaction was cooled to room temperature and poured into 1N HCl (250 mL) and then stirred for 1 h. The resulting white precipitate was filtered off and washed with water. The resulting residue was redissolved in 5% MeOH in DCM (50 mL) and filtered through a bed of Celite. The filtrate was evaporated to dryness in vacuo to give the title compound (3.5 g, 15.6 mmol, 91% yield) as a pale yellow solid. LCMS m / z: 222.05 [MH].

[0250] Step 3: Methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate [ka] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 1, Step 2) (5.0 g, 22.2 mmol) in DMF (50 mL) at 0-5 °C, NaH (0.98 g, 24.4 mmol) was added in portions and the whole was stirred at the same temperature for another 5-10 min. Then, benzyl bromide (2.8 mL, 23.3 mmol) was added and the reaction mixture was stirred for 1 h. Completion of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with a saturated solution of NH4Cl and diluted with ice-cold water. The aqueous reaction mixture was extracted with MTBE and washed with brine. The separated organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (9.0 g) as a crude pale yellow solid, which was used in the next step without further purification. LCMS m / z: 314.16 [M+H].

[0251] Step 4: (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanol [ka] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 1, Step 3) (1.4 g, 4.47 mmol) in THF (15 mL) was added borane-THF complex (13.4 mL, 13.4 mmol; 1 M solution in THF) at 0-5 °C and the whole reaction mixture was refluxed for 2 h. UPLC indicated the formation of the desired compound and after completion of the reaction, the reaction mixture was cooled to room temperature and diluted with methanol (20 mL). The resulting mixture was further refluxed for 10 min and then the solvent was evaporated to give the crude material, which was purified by column chromatography to give the title compound (500 mg) as a white solid. LCMS m / z: 274 [M+H].

[0252] Step-5: 4-benzyl-6-(chloromethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine [ka] To a stirred solution of 4-benzyl-6-(hydroxymethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 1, Step 4) (900 mg, 3.32 mmol) in DCM (25 mL) was added a few drops of DMF at room temperature, followed by the addition of SOCl2 (790 mL, 6.63 mmol). The whole was stirred at room temperature for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the title compound (1.0 g, crude) as a brownish thick oil, which was used in the next step without further purification. LCMS m / z: 290 [M+H].

[0253] Step-6: (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine [ka] To a stirred solution of 4-benzyl-6-(chloromethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 1, Step 5) (900 mg, 3.11 mmol) in a sealed tube containing THF (10 mL) was added ammonia in methanol (20 mL) at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was evaporated and the residue was dissolved in 10% MeOH in DCM and the remaining solid was filtered off. The filtrate was evaporated in vacuum to give the crude product which was triturated with hexane and diethyl ether to give the title compound (450 mg, crude) as an off-white solid which was used in the next step without further purification. LCMS m / z: 271 [M+H].

[0254] Preparation 2: 1-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)-3-(1H-indol-6-yl)urea (Example 1) [ka] To a stirred solution of 6-NH2-indole (54 mg, 0.406 mmol) in THF (5 mL) was added triphosgene (54 mg, 0.406 mmol) at 0-5 °C and the temperature was maintained at room temperature for 1 h. TLC showed the reaction was complete, then (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine (Preparation 1, Step 6) (100 mg, 0.369 mmol) and TEA (0.176 mL, 1.217 mmol) were added at room temperature and the mixture was further stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS, after completion of the reaction it was diluted with EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the crude product, which was purified by prep-HPLC to give the title compound (7 mg, 4.4% yield) as a light brownish solid. Purity by HPLC: 97.99%; 1H NMR (400 MHz; DMSO-d6): δ 3.06 (t, J = 5.04 Hz, 2H), 3.63 (t, J = 4.8 Hz, 2H), 4.09 (d, J = 5.6 Hz, 2H), 4.53 (s, 2H), 6.30 (s, 1H), 6.35-6.40 (m, 1H),6.52 (d, J = 8 Hz, 1H), 7.67 (s, 1H), 6.77 (d, J = 8.64 Hz, 1H), 6.93 (d, J =7.88 Hz, 1H), 7.17 (t, J = 2.68 HZ, 1H), 7.21-7.23 (m, LCMS m / z:429.13 [M+H].

[0255] Example 2: 1-((4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea [ka] Example 2 was prepared according to the methods described in General Procedures 1-2, 5-11 and the methods described below.

[0256] Preparation 3: 7-(aminomethyl)-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ka]

[0257] Step 1: Methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate [ka] To a stirred solution of NaH (1.5 g, 376 mmol) in 1,4-dioxane (50 mL) was added methyl 2-hydroxyacetate (3.39 g, 376 mmol) at 5-10 °C and the reaction mixture was kept at the same temperature for 30 min followed by the addition of commercially available methyl 3-fluoro-4-nitrobenzoate (5.0 g, 251 mmol) in 1,4-dioxane (25 mL) solution. The whole was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice-cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried under vacuum to give the title compound (5.0 g, crude) as a pale yellow solid, which was used in the next step without further purification. LCMS m / z: 269.98 [M+H].

[0258] Step 2: Methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate [ka] To a stirred solution of methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate (Preparation 3, Step 1) (5.0 g, 18.57 mmol) in AcOH (25 mL) was added Fe powder (4.15 g, 74.304 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 2 h. The reaction was monitored by LCMS / TLC and after completion, the reaction mixture was quenched into ice-cold water (500 mL) and stirred for 30 min. The precipitated solid was filtered, washed with excess water and then dried under vacuum to give the title compound (3.8 g, crude) as a grey solid, which was used in the next step without further purification. LCMS m / z: 207.98 [M+H].

[0259] Step 3: Methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate [ka] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 3, Step 2) (2.0 g, 9.65 mmol) in DMF (20 mL) was added NaH (425 mg, 10.62 mmol) followed by benzyl bromide (1.27 mL, 10.62 mmol) at 0-10 °C. The whole was stirred at 10 °C to room temperature for 1 h. The reaction was monitored by LCMS / TLC and after completion, the reaction mixture was diluted with ice-cold water and the precipitated solid was filtered off, washed with excess water and dried in vacuum to give the title compound (2.6 g, crude) as a brown solid, which was used in the next step without further purification. LCMS m / z: 298.88 [M+H].

[0260] Step 4: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid [ka] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 3, Step 3) (2.6 g, 8.75 mmol) in THF (30 mL) and MeOH (15 mL) was added a solution of LiOH.H2O (1.83 g, 43.73 mmol) in water (15 mL) and the mixture was kept at room temperature for 24 h. After completion of the reaction, the solvent was evaporated to give a residue which was diluted with water, washed with diethyl ether and the aqueous portion was acidified with 6N HCl. The precipitated solid was filtered, washed and dried in vacuum to give the title compound (2.2 g, crude) as an off-white solid which was used in the next step without further purification. LCMS m / z: 284.02 [M+H].

[0261] Step 5: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide [ka] A stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (Preparation 3, Step 4) (500 mg, 1.765 mmol) in DMF (5 mL) was cooled to 0-5 °C followed by the addition of HATU (803 mg, 2.12 mmol) and TEA (0.764 mL, 5.23 mmol). The whole was stirred at room temperature for 10 min, followed by the addition of ammonium formate (1.1 g, 17.65 mmol) and the whole was kept at room temperature for 16 h. The progress of the reaction was monitored by LCMS / TLC and after completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the title compound (500 mg, crude) as a pale yellow oil which was used in the next step without further purification. LCMS m / z: 283 [M+H].

[0262] Step 6: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile [ka] A stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Preparation 3, Step 5) (0.5 g, 1.77 mmol) in THF (5 mL) was cooled to 0-5 °C, followed by the addition of TEA (1.28 mL, 8.85 mmol) and trifluoroacetic anhydride (0.744 mL, 5.313 mmol), and the whole was kept at room temperature for 1 h. The progress of the reaction was monitored by LCMS / TLC, and after completion of the reaction, the reaction mixture was quenched with ice water, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the title compound (500 mg, crude) as a pale yellow oil, which was used in the next step without further purification. LCMS m / z: 264.98 [M+H].

[0263] Step 7: tert-Butyl ((4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)carbamate [ka] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (Preparation 3, Step 6) (0.3 g, 1.14 mmol) in MeOH (5 mL) was added (Boc)2O (0.496 mL, 2.27 mmol), NiCl2.5H2O (135 mg, 0.57 mmol) and NaBH4 (108 mg, 2.84 mmol) at 5-10 °C and the mixture was kept at 10 °C to room temperature for 0.5 h. After completion of the reaction (monitored by TLC / LCMS), it was diluted with cold water, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the crude product, which was purified by trituration to give the title compound (300 mg, crude) as an off-white solid, which was used in the next step without further purification. LCMS m / z: 369 [M+H].

[0264] Step 8: 7-(aminomethyl)-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ka] A solution of tert-butyl ((4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)carbamate (Preparation 3, Step 7) (300 mg, 0.81 mmol) in 20% TFA in DCM (10 mL) under inert atmosphere was stirred at room temperature for 0.5 h. Completion of the reaction was confirmed by LCMS, then the reaction mass was quenched with saturated NaHCO3 solution (pH approx. 8), extracted with DCM, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the title compound (180 mg, crude) as an off-white solid, which was used in the next step without further purification. LCMS m / z: 269.8 [M+H].

[0265] Preparation 4: 1-((4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea (Example 2) [ka] To a stirred solution of 6-aminoindole (48 mg, 0.368 mmol) in THF (5 mL) at 0-5 °C was added triphosgene (50 mg, 0.167 mmol) and the mixture was kept at room temperature for 1 h. TLC showed the reaction was complete, then 7-(aminomethyl)-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one (90 mg, 0.335 mmol) (Preparation 3, Step 8) and TEA (0.16 mL, 1.105 mmol) were added. The resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by LCMS / TLC and after completion, the reaction mixture was diluted with EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the crude product, which was purified by prep-HPLC to give the title compound (20 mg, 14% yield) as an off-white solid. Purity by HPLC: 98.72%; 1H NMR (400 MHz; DMSO-d6): δ 4.21 (d, J = 8.84 Hz, 2H), 4.78 (s, 2H), 5.15 (s,2H), 6.29 (s, 1H), 6.48 (t, J = 5.92 Hz, 1H), 6.76-6.78 (m, 1H), 6.89-6.90 (m,1H), 6.96-7.00 (m, 2H), 7.17 (t, J = 2.64 Hz, 1H), 7.22-7.24 (m, 1H), 7.26-7.28 (m, 2H), 7.30 (bs, 1H), 7.32-7.35 (m, 2H), 7.72 (s, 1H), 8.39 (s,1H), 10.83 (s, 1H); LCMS m / z: 427.08 [M+H].

[0266] Example 3: 1-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea [ka] Example 3 was prepared according to the methods described in General Procedures 1-4, 10-11 and the methods described below.

[0267] Preparation 5: (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanamine [ka]

[0268] Step 1: (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanamine [ka] A stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Preparation 3, Step 5) (0.2 g, 0.71 mmol) in borane-THF (4.3 mL, 4.25 mmol) was refluxed at 60° C. for 1 h. After completion of the reaction, the reaction mixture was quenched with methanol, followed by evaporation of the solvent under vacuum. The reaction mixture was diluted with water, extracted with EtOAc, washed with water, followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the title compound (180 mg, crude) as a pale yellow oil, which was used in the next step without further purification. LCMS m / z: 255.14 [M+H].

[0269] Preparation 6: 1-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea (Example 3) [ka] To a stirred solution of 6-aminoindole (180 mg, 0.79 mmol) in THF (6 mL) was added triphosgene (117 mg, 0.39 mmol) at 0-5 °C and the mixture was kept at room temperature for 1 h. TLC showed the reaction was complete, then (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanamine (Preparation 5, Step 1) (125 mg, 0.95 mmol) and TEA (0.327 mL, 2.36 mmol) were added and the combined mixture was further stirred at room temperature for 1 h. The reaction progress was monitored by LCMS and after completion, the reaction mixture was diluted with EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give the crude product, which was purified by prep-HPLC to give the title compound (20 mg, 6% yield) as an off-white solid. Purity by HPLC: 98.72%;1 H NMR:(500 MHz; DMSO-d6): δ 4.16 (d, J = 5.3 Hz,2H), 4.26 (t, J = 4.15 Hz, 2H), 4.52 (S, 2H), 6.35 (s, 1H), 6.39 (t, J = 6.15Hz, 1H), 6.67-6.74 (m, 4H), 6.81-6.83 (dd, J1 = 1.6 Hz, J2 = 8.4 HZ, 1H), 7.23(t, J = 2.55 Hz, 1H), 7.30-7.41 (m, 7H), 7.81 (s, 1H), 8.38 (s, 1H), 10.90 (s,1H); LCMS m / z: 385.16 [M+H].

[0270] Example 4: 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide [ka] Example 4 was prepared according to the methods described in General Procedures 1-2, 6, 9, 15-18 and the methods described below.

[0271] Preparation 7: 3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-((tert-butylsulfinyl)amino)propanoic acid [ka]

[0272] Step 1: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbaldehyde [ka] To a stirred solution of (4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)methanol (Preparation 1, Step 4) (1.3 g, 4.79 mmol) in DCM (30.0 mL) was added MnO2 (4.16 g, 47.9 mmol) and the reaction mixture was stirred at room temperature for 16 h. Completion of the reaction was confirmed by LCMS, then the reaction mixture was filtered through a bed of Celite and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (5-10% EtOAc-Hexanes) to give the title compound (700 mg, 54.3% yield) as a yellow solid.

[0273] Step 2: N-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methylene)-2-methylpropane-2-sulfinamide [ka] To a stirred solution of 4-benzyl-2,3-dihydro-1,4-benzothiazine-6-carbaldehyde (Preparation 7, Step 1) (1.0 g, 3.71 mmol) in THF (30.0 mL) was added 2-methylpropane-2-sulfinamide (675 mg, 5.57 mmol) at room temperature. Titanium isopropoxide (2.25 mL, 7.42 mmol) was then added dropwise to the solution at the same temperature and the reaction mixture was stirred for 16 h. Completion of the reaction was confirmed by LCMS and then the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine solution (1 x 30 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (10-15% EtOAc-Hexanes) to give the title compound (800 mg, 57.9% yield) as a yellow solid. LCMS m / z: 372.2 [M+H].

[0274] Step 3: Ethyl 3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-((tert-butylsulfinyl)amino)propanoate [ka] To a stirred suspension of Zn (2.11 g, 32.3 mmol) in THF (30.0 mL) was added iodine (82 mg, 0.32 mmol) at room temperature and the whole was heated at reflux for 30 min. Then a mixture of N-[(4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)methylene]-2-methyl-propane-2-sulfinamide (Preparation 7, Step 2) (1.2 g, 3.23 mmol) and ethyl bromoacetate (1.43 mL, 12.9 mmol) in THF (20 mL) was added to the reaction mixture. The resulting reaction mixture was refluxed for 2 h. The progress of the reaction was monitored by LCMS and after completion, the reaction was filtered through a bed of Celite. The filtrate was quenched with water (50 mL) and the organic portion was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude was purified by silica gel column chromatography (40-60% EtOAc-Hexanes) to give the title compound (900 mg, 64.6% yield) as an off-white solid. LCMS m / z: 460.9 [M+H].

[0275] Step 4: 3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-((tert-butylsulfinyl)amino)propanoic acid [ka] To a stirred solution of ethyl 3-(4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)-3-(tert-butylsulfinylamino)propanoate (Preparation 7, Step 3) (1.0 g, 2.17 mmol) in THF:MeOH:H2O (20 mL, 2:1:1) was added LiOH (104 mg, 4.35 mmol) at room temperature and the reaction mixture was stirred at the same temperature for 2 h. The reaction progress was monitored by LCMS and after completion, the solvent was evaporated to give a residue which was diluted with water and acidified to pH 3-5 with 1N HCl solution. The product was extracted with 10% MeOH-DCM (3 x 50 mL) and the combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (3-5% MeOH-DCM) to give the title compound (700 mg, 74.4% yield) as an off-white solid. LCMS m / z: 433.2 [M+H].

[0276] Preparation 8: Step 1: 3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-((tert-butylsulfinyl)amino)-N,N-dimethylpropanamide [ka] To a stirred solution of 3-(4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)-3-(tert-butylsulfinylamino)propanoic acid (Preparation 7, Step 4) (700 mg, 1.62 mmol) in DMF (10 mL) was added HATU (1.23 g, 3.24 mmol), DIPEA (0.85 mL, 4.86 mmol) and dimethylamine (4.05 mL, 8.1 mmol, 2M in THF) at 0-5 °C and the resulting reaction mixture was stirred at the same temperature for 16 h. The progress of the reaction was monitored by LCMS and after completion, the reaction mixture was quenched with water and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with ice-cold water (5 x 30 mL), brine (1 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (3-5% MeOH-DCM) to give the title compound (450 mg, 60.4% yield) as an off-white solid. LCMS m / z: 460.4 [M+H].

[0277] Step 2: 3-amino-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide [ka] To a stirred solution of 3-(4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)-3-(tert-butylsulfinylamino)-N,N-dimethyl-propanamide (Preparation 8, Step 1) (400 mg, 0.87 mmol) in EtOH (10.0 mL) was added 1.25 M HCl in MeOH (2.09 mL, 2.61 mmol) at 0-5 °C and the whole was stirred for 1 h. After completion of the reaction (monitored by LCMS), excess solvent was evaporated under reduced pressure and the reaction mass was quenched with saturated NaHCO3 solution and extracted with 10% MeOH-DCM acetate (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (300 mg, crude). The crude was used in the next step without further purification. LCMS m / z: 356.38 [M+H].

[0278] Step 3: 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide (Example 4) [ka] To a stirred solution of 6-aminoindole (123 mg, 0.93 mmol) in THF (5 mL) was added p-nitrophenyl chloroformate (255 mg, 1.67 mmol) at 0-5 °C and the whole was stirred at room temperature for 3 h. Then to the reaction mixture was added TEA (0.58 mL, 4.23 mmol) and 3-amino-3-(4-benzyl-2,3-dihydro-1,4-benzothiazin-6-yl)-N,N-dimethyl-propanamide (Preparation 8, Step 2) (300 mg, 0.85 mmol) at the same temperature and the combined mixture was stirred for another 2 h. The progress of the reaction was monitored by LCMS and after completion, the reaction mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with brine solution (1 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (3-5% acetone-DCM) to give the title compound (150 mg, 34.6% yield) as an off-white solid. Purity by HPLC: 96.47%; 1 H NMR:(400 MHz; DMSO-d6): δ 2.55-2.60 (m, 2H),2.71 (s, 3H), 2.78 (s, 3H), 3.04 (t, J = 5.12 Hz, 2H), 3.61 (t, J = 4.8 Hz,2H), 4.53 (s, 2H), 4.93-4.95 (m, 1H), 6.27 (bs, 1H), 6.54-6.59 (m, 2H), 6.68(s, 1H), 6.73-6.75 (dd, J1 = 1.28 Hz, J2 = 8.32 Hz, 1H), 6.89 (d, J = 7.92 Hz,1H), 7.14 (t, J = 2.52 Hz, 1H), 7.19-7.22 (m, 1H), 7.29-7.33 (m, 5H), 7.70 (bs,1H), 8.45 (s, 1H), 10.81 (s, 1H); LCMS m / z: 514.52 [M+H].

[0279] Chiral separation of Example 4 The racemic compound 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide (Example 4) (50 mg) was subjected to chiral separation to give two enantiomers. Enantiomer 1: Example 5 8 mg, HPLC purity 96.2%; 1 H NMR: (400 MHz; DMSO-d6): δ 2.55-2.59 (m, 2H), 2.71 (s, 3H), 2.80 (s, 3H), 3.04 (s, 2H), 3.61(m, 2H), 4.54 (s, 2H), 4.93 (t, J = 5.04 Hz, 1H), 6.27 (bs, 1H), 6.54-6.59 (m,2H), 6.68 (s, 1H), 6.74 (d, J = 5.12 Hz, 1H), 6.89 (d, J = 8.08 Hz, 1H), 7.14(bs, 1H), 7.20-7.22 (m, 1H), 7.29-7.33 (m, 5H), 7.70 (bs, 1H), 8.45 (s, 1H),10.80 (s, 1H); LCMS m / z: 514.51 [M+H]. Enantiomer 2: Example 6 7 mg, HPLC purity 94.36%; 1 H NMR: (400 MHz; DMSO-d6):δ 2.55-2.59 (m, 2H), 2.71 (s, 3H), 2.76 (s, 3H), 3.05(d, J = 4.96 Hz, 2H), 3.61 (d, J = 4.36 Hz, 2H), 4.53 (s, 2H), 4.94 (t, J =7.68 Hz, 1H), 6.27 (bs, 1H), 6.54-6.59 (m, 2H), 6.68 (s, 1H), 6.74 (d, J = 4.52Hz, 1H), 6.89 (d, J = 7.96 Hz, 1H), 7.14 (bs, 1H), 7.21-7.22 (m, 1H), 7.29-7.33(m, 5H), 7.70 (bs, 1H), 8.44 (s, 1H), 10.80 (s, 1H); LCMS m / z: 514.51 [M+H].

[0280] Chiral separation methods: Column Chiralpak IA (250 x 20 mm) 5u; Dissolved MeOH Wavelength 240nm Mobile phase Hexane / EtOH / DCM:70 / 15 / 15 Drive time 20 minutes; Flow rate 25g / min

[0281] Examples 7 and 8: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea [ka] Examples 7 and 8 were prepared according to the methods described in General Procedures 1-2, 9, 15-16, 19 and the methods described below.

[0282] Preparation 9: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)but-3-en-1-yl)-3-(1H-indol-6-yl)urea [ka]

[0283] Step 1: N-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide [ka] A solution of N-((4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methylene)-2-methylpropane-2-sulfinamide (prepared according to the method described for the synthesis of Preparation 7, Step 2) (300 mg, 0.84 mmol) in THF (5 mL) was treated with slow addition of allyl-Mg-Br (2.53 mL, 2.53 mmol, 1 M in diethyl ether) at -78 °C. The mixture was stirred at the same temperature for 1 h. After completion of the reaction, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (30-50% EtOAc-Hexanes) to give the title compound (250 mg, 74.4% yield) as an off-white solid. LCMS m / z: 399.2 [M+H].

[0284] Step 2: 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)but-3-en-1-amine [ka] To a stirred solution of N-[1-(4-benzyl-2,3-dihydro-1,4-benzoxazin-6-yl)but-3-enyl]-2-methyl-propane-2-sulfinamide (Preparation 9, Step 1) (250 mg, 0.70 mmol) in EtOH (5.0 mL) was added 1.25 M HCl in MeOH (1.68 mL, 2.11 mmol) at 0-5 °C and the whole was stirred for 3 h. After completion of the reaction, excess solvent was concentrated under reduced pressure and the reaction mixture was quenched with NaHCO3 solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were then washed with brine solution (1 x 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (3-5% MeOH-DCM) to give the title compound (150 mg, 72.6% yield) as an off-white solid.

[0285] Step 3: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)but-3-en-1-yl)-3-(1H-indol-6-yl)urea [ka] To a stirred solution of 6-aminoindole (74.1 mg, 0.56 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (154 mg, 0.77 mmol) at 0-5 °C and the whole was stirred at room temperature for 3 h. Then to the reaction mixture was added TEA (0.35 mL, 2.55 mmol) and 1-(4-benzyl-2,3-dihydro-1,4-benzoxazin-6-yl)but-3-en-1-amine (Preparation 9, Step 2) (150 mg, 0.51 mmol) at the same temperature and the combined mixture was stirred for another 2 h. The reaction was monitored by LCMS. The reaction mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with brine solution (1 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel column chromatography (3-5% acetone-DCM) to give the title compound (100 mg, 43.3% yield) as an off-white solid. LCMS m / z: 453.49 [M+H].

[0286] Preparation 10: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea [ka] To a stirred solution of 1-[1-(4-benzyl-2,3-dihydro-1,4-benzoxazin-6-yl)but-3-enyl]-3-(1H-indol-6-yl)urea (Preparation 9, Step 3) (100 mg, 0.22 mmol) in acetone:H2O (3 mL, 9:1) was added N-methylmorpholine N-oxide (51.8 mg, 0.44 mmol) and OsO4 (5.63 mg, 0.02 mmol) at 0-5 °C and the whole was stirred at the same temperature for 2 h. The progress of the reaction was monitored by LCMS and after completion of the reaction, excess solvent was evaporated in vacuum to give a residue which was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with brine solution (1 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (50 mg, crude) as a brown solid. LCMS m / z: 487.52 [M+H].

[0287] 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea (Preparation 10) Chiral separation of Racemic compound 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea (Preparation 10) (50 mg) was subjected to normal phase chiral HPLC separation to give the two enantiomers as light brown solids.

[0288] Enantiomer 1: Example 7. 4 mg, HPLC purity 98.28%; 11H NMR: (400 MHz; DMSO-d6): δ 1.62 (bs, 1H), 1.70 (bs, 1H), 3.22 - 3.29 (m, 4H), 4.14 (s, 2H), 4.43 - 4.47 (m, 4H), 4.69 (d, J = 6.08 Hz, 1H), 6.22 (s, 1H), 6.36 (d, J = 7.72 Hz, 1H), 6.49 (d, J = 8.56 Hz, 1H), 6.63 (d, J = 8.04 Hz, 1H), 6.71 (d, J = 8.52 Hz, 1H), 6.78 (s, 1H), 7.14 (s, 1H), 7.22 - 7.23 (m, 1H), 7.30 - 7.33 (m, 5H), 7.69 (s, 1H), 8.15 (s, 1H), 10.80 (s, 1H); LCMS m / z: 487.4 [M + H]. Enantiomer 2: Example 8. 5 mg, HPLC purity 98.26%; 1 H 1H NMR: (400 MHz; DMSO-d6): δ 1.47 (bs, 1H), 1.70 - 1.73 (bs, 1H), 3.19 - 3.23 (m, 3H), 3.50 (bs, 1H), 4.15 (s, 2H), 4.43 - 4.45 (m, 3H), 4.61 (d, J = 4.64 Hz, 1H), 4.77 (bs, 1H), 6.28 (s, 1H), 6.40 (d, J = 8.36 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.36 Hz, 1H), 6.72 - 6.74 (m, 2H), 7.15 (s, 1H), 7.22 (d, J = 6.32 Hz, 1H), 7.27 - 7.34 (m, 5H), 7.70 (s, 1H), 8.30 (s, 1H), 10.81 (s, 1H); LCMS m / z: 487.4 [M + H].

[0289] Chiral separation methods: Column Chiralpak IA(250×20mm)5u; Dissolved in MeOH Wavelength 240nm Mobile phase Hexane / EtOH / DCM:70 / 15 / 15 Drive time 20 minutes; Flow rate 25g / min

[0290] Preparation 11: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)but-3-en-1-yl)-3-(1H-indol-6-yl)urea (Example 9) [ka] To a stirred solution of 6-aminoindole (32.8 mg, 0.25 mmol) in dry THF (3.0 ml) was added TEA (0.09 ml, 0.68 mmol) and 4-nitrophenyl chloroformate (68.2 mg, 0.34 mmol) at 0-5° C. The resulting reaction mixture was stirred at 0-5° C. for 30 min, then 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)but-3-en-1-amine (prepared according to the method described for the synthesis of Preparation 9, Step 2) (70.0 mg, 0.23 mmol) was added at 0-5° C. The whole was stirred for 16 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC and LCMS, and after completion of the reaction, the solvent was evaporated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), followed by brine (1×20 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by Combi-flash to give the title compound (13 mg, 12.3% yield) as a brown solid. Purity by HPLC: 94.01%; 1 H NMR:(400 MHz; DMSO-d6): δ 2.31-2.40 (m, 2H),2.97 (d, J = 2.68 Hz, 2H), 3.63 (s, 2H), 4.55 (bs, 3H), 4.91-4.97 (m, 2H),5.52-5.57 (m, 1H), 6.28-6.32 (m, 2H), 6.51 (d, J = 8.32 Hz, 1H), 6.63 (s, 1H),6.71 (d, J = 8.04 Hz, 1H), 6.91 (d, J = 7.72 Hz, 1H), 7.15 (s, 1H), 7.21 (bs,1H), 7.29-7.34 (m, 5H), 7.68 (s, 1H), 8.22 (s, 1H), 10.80 (s, 1H); LCMS m / z:469.27 [M+H].

[0291] Example 10: 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoic acid [ka] Example 10 was prepared according to the methods described in General Procedures 1-2, 5, 9, 15, 20 and the methods described below.

[0292] Preparation 12; Step 1: Methyl 3-amino-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoate [ka] 4-Benzyl-2,3-dihydro-1,4-benzothiazine-6-carbaldehyde (Preparation 7, Step 1) (600 mg, 2.23 mmol) was dissolved in MeOH (25 mL). Then, NHOAc (515.79 mg, 77.08 mmol) and 3-methoxy-3-oxopropanoic acid (0.47 ml, 4.46 mmol) were added to the reaction mixture at room temperature. The whole was allowed to stir at room temperature for 2 hours. Then, another portion of NHOAc (515.79 mg, 77.08 mmol) was added and the combined mixture was heated at 80° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS, and after completion of the reaction, the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (5% MeOH-DCM) to give the title compound (100 mg, 13.1% yield) as a yellow solid. LCMS m / z: 343.66 [M+H].

[0293] Step 2: Methyl 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoate [ka] To a reaction mixture of methyl 3-amino-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoate (Preparation 12, Step 1) (100 mg, 0.29 mmol) and TEA 0.13 ml, 0.87 mmol) was added a solution of triphosgene (87 mg, 0.29 mmol) in DCM (2 mL) at 0-5 °C under nitrogen atmosphere. The resulting mixture was stirred at 0-5 °C for 30 min, then a solution of 6-aminoindole (48 mg, 0.292 mmol) in DCM (5 mL) was added dropwise at 0-5 °C and the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS, and after completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2×20 mL), brine (2×20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (60-70% EtOAc-Hexanes) to give the title compound (40 mg, 28% yield) as a yellow solid. LCMS m / z: 501.3 [M+H].

[0294] Step 3: 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoic acid (Example 10) [ka] To a stirred solution of methyl 3-(3-(1H-indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoate (Preparation 12, Step 2) (40 mg, 0.08 mmol) in a mixture of MeOH-THF-H2O (10 mL, 3:1:1) was added LiOH (4.8 mg, 0.2 mmol) and the resulting solution was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mass was acidified to pH 5 using 3N HCl and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product, which was purified by RP HPLC to give the title compound (6 mg, 15% yield) as an off-white solid. Purity by HPLC: 97.72%; 1 H NMR:(400 MHz; DMSO-d6): δ 2.55-2.57 (m, 2H),3.03 (t, J = 5.12 Hz, 2H), 3.59 (t, J = 4.84 Hz, 2H), 4.53 (s, 2H), 4.88-4.93(m, 1H), 6.28 (s, 1H), 6.54-6.58 (m, 2H), 6.74 (t, J = 8.76 Hz, 2H), 6.63 (s,1H), 6.91 (d, J = 7.88 Hz, 1H), 7.15 (t, J = 2.6 Hz, 1H), 7.22-7.34 (m, 5H), 7.69 (s, 1H), 8.35 (s, 1H), 10.81 (s, 1H); LCMS m / z: 487 [M+H].

[0295] Example 11: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea [ka] Example 11 was prepared according to the methods described in General Procedures 1-2, 5, 9 and the methods described below.

[0296] Preparation 13: Methyl 2-amino-2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)acetate [ka]

[0297] Step 1: Methyl 2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-((diphenylmethylene)amino)acetate [ka] To a stirred solution of 4-benzyl-6-bromo-3,4-dihydro-2H-benzo[b][1,4]thiazine (prepared from commercially available 6-bromo-2H-benzo[b][1,4]thiazine-3(4H)-one by reduction of the cyclic amide followed by benzylation as described in general procedures 2 and 9) (360 mg, 1.12 mmol) in toluene (8 mL) was added methyl 2-((diphenylmethylene)amino)acetate (313 mg, 1.23 mmol), K3PO4 (716 mg, 3.34 mmol) and bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.01 mmol). The resulting reaction mixture was degassed with N2 gas for 10 minutes. After this time, the entire reaction mixture was capped and stirred at 100 °C for 20 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine solution (1×50 mL), dried over anhydrous Na2SO4, and evaporated in vacuum to give the title compound (200 mg, crude) as a reddish gummy oil. LCMS m / z: 493.2 [M+H].

[0298] Step 2: Methyl 2-amino-2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)acetate [ka] A solution of methyl 2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-((diphenylmethylene)amino)acetate (Preparation 13, Step-1) (840 mg, 1.70 mmol) in 4M HCl in dioxane (4.2 mL, 17.0 mmol) was stirred at room temperature for 4 h. After completion of the reaction, the solvent was evaporated and the crude residue was neutralized with NaHCO3 solution and extracted with 10% MeOH / DCM (4 x 100 mL). The combined organic layers were washed with brine solution (1 x 50 mL), dried over anhydrous Na2SO4 and evaporated in vacuum to give the title compound (400 mg, 72% yield) as a gummy solid. LCMS m / z: 329.2 [M+H].

[0299] Preparation 14; Step 1: Methyl 2-(3-(1H-indol-6-yl)ureido)-2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)acetate [ka] To a stirred solution of 6-aminoindole (80.51 mg, 0.60 mmol) in dry THF (6.0 mL) was added TEA (0.255 mL, 1.82 mmol) and 4-nitrophenyl chloroformate (184 mg, 0.91 mmol) at 0-5 °C. The whole reaction was stirred at the same temperature for 30 min. TLC confirmed that the starting material was consumed. Then methyl 2-amino-2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)acetate (Preparation 13, Step 2) (200 mg, 0.60 mmol) was added to the reaction mixture at 0-5 °C and stirring was continued overnight. TLC showed one polar spot and then product formation was confirmed by LCMS. Once the reaction was complete, the reaction mixture was evaporated to give a residue which was diluted with water (20 mL) and extracted with EtOAC (2 x 20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by Combi-flash (1-2% acetone-DCM) to give the title compound (53 mg, 18% yield) as a brown solid. LCMS m / z: 487.2 [M+H].

[0300] Step 2: 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea (Example 11) [ka] To a stirred solution of methyl 2-(3-(1H-indol-6-yl)ureido)-2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)acetate (Preparation 14, Step 1) (70 mg, 0.14 mmol) in THF (2 mL) was added DIBAl-H (0.29 mL, 0.29 mmol, 1 M in toluene) dropwise at 0-5 °C. The reaction mixture was stirred at the same temperature for 2 h. Then the reaction mixture was quenched by dropwise addition of a saturated solution of Rochelle's salt at 0-5 °C and the resulting solution was stirred at the same temperature for 1 h. The reaction mass was filtered through a Celite bed. The Celite bed was washed with EtOAc. The filtrate was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase prep-HPLC to give the title compound (14 mg, 21% yield) as an off-white solid. Purity by HPLC: 99.34%; 1 H NMR:(400 MHz; DMSO-d6): δ 3.04-3.06 (m, 2H),3.40-3.44 (m, 1H), 3.48-3.52 (m, 1H), 3.59-3.61 (m, 2H), 4.51-4.53 (m, 3H),4.83 (t, J = 5.2 Hz, 1H), 6.28 (s, 1H), 6.42 (d, J = 7.88 Hz, 1H), 6.53 (d, J =7.96 Hz, 1H), 6.68 (s, 1H), 6.71-6.74 (dd, J1 = 1.6 Hz, J2 = 8.48 Hz, 1H), 7.91(d, J = 7.88 Hz, LCMS m / z: 459.2 [M+H].

[0301] 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea (Example 11) Chiral separation of Racemic 1-(1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea (Preparation 14, Step 2) (14 mg) was subjected to normal phase chiral HPLC separation to give the two enantiomers.

[0302] Enantiomer 1: Example 12. 4.22 mg, HPLC purity 92.71%; 1 H NMR: (400 MHz; DMSO-d6): δ 3.04 (t, J = 5.56 Hz, 2H), 3.41-3.42 (m, 1H), 3.48-3.51 (m, 1H),3.59-3.61 (m, 2H), 4.53 (s, 3H), 4.87 (bs, 1H), 6.28 (d, J = 2.56 Hz, 1H), 6.54(t, J = 8.92 Hz, 2H), 6.69 (s, 1H), 6.74 (d, J = 8.16 Hz, 1H), 6.90 (d, J =7.84 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.20-7.21 (m, 1H), 7.27-7.34 (m, 5H),7.68 (s, 1H), 8.49 (s, 1H), 10.80 (s, 1H); LCMS m / z: 459.15 [M+H]. Enantiomer 2: Example 13. 5.12 mg, HPLC purity 91.26%; 1 H NMR: (400 MHz; DMSO-d6):δ 3.04 (t, J = 4.68 Hz, 2H), 3.41-3.42 (m, 1H),3.48-3.50 (m, 1H), 3.59-3.60 (m, 2H), 4.53 (s, 3H), 4.87 (bs, 1H), 6.28 (bs,1H), 6.53 (d, J = 7.76 Hz, 2H), 6.68 (s, 1H), 6.73 (d, J = 8.56 Hz, 1H), 6.91(d, J = 7.84 Hz, 1H), 7.14 (bs, 1H), 7.20-7.21 (m, 1H), 7.29-7.34 (m, 5H), 7.68(s, 1H), 8.47 (s, 1H), 10.80 (s, 1H); LCMS m / z: 487.4 [M+H].

[0303] Chiral separation methods: Column Chiralpak IA (250 x 21 mm) 5u; Dissolved MeOH Wavelength 240nm Mobile phase Hexane / EtOH / DCM: 50 / 25 / 25 Drive time 15 minutes; Flow rate 21mL / min

[0304] Example 14: 1-(1H-indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)urea [ka] Example 14 was prepared according to the methods described in General Procedures 1-4, 9, 14 and the methods described below.

[0305] Preparation 15: (4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine [ka]

[0306] Step 1: Methyl 3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate [ka] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 1, Step 2) (2.5 g, 11 mmol) in dry THF at 0-5° C., borane-THF (22.4 mL, 22.42 mmol, 1M in THF) was added and the resulting solution was allowed to stir at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with methanol and concentrated under vacuum to give the crude compound, which was purified by Combi-flash chromatography to give the title compound (1.8 g, 77% yield) as an off-white solid. LCMS m / z: 210.0 [M+H].

[0307] Step 2: Methyl 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate [ka] To a degassed solution of methyl 3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 15, Step 1) (850 mg, 4.06 mmol) in toluene was added iodobenzene (0.907 mL, 8.12 mmol), K3PO4 (2.58 g, 12.2 mmol), X-Phos (194 mg, 0.40 mmol) and Pd2(dba)3 (372.5 mg, 0.40 mmol). The resulting reaction mixture was heated at 100 °C under nitrogen atmosphere for 16 h. The progress of the reaction was monitored by LCMS and after completion, the reaction mass was filtered through a bed of celite and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Combi-flash chromatography to give the title compound (500 mg, 47% yield) as a gummy solid. LCMS m / z: 286.24 [M+H].

[0308] Step 3: 4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid [ka] To a stirred solution of methyl 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 15, Step 2) (1.0 g, 3.50 mmol) in a mixture of THF:MeOH:H2O (50 mL 2:2:1) was added lithium hydroxide monohydrate (737 mg, 17.54 mmol) and the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was removed under vacuum and the reaction mass was quenched with 1N aqueous HCl at 0-5 °C. The neutralized reaction mixture was extracted with 10% MeOH-DCM, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give the title compound (800 mg, 84% yield) as a white solid. LCMS m / z: 270.0 [M+H].

[0309] Step 4: 4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide [ka] To a stirred solution of 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 15, Step 3) (400 mg, 1.47 mmol) in DCM (7 mL) was added oxalyl chloride (0.25 ml, 2.95 mmol) at 0-5 °C and the reaction mixture was stirred at the same temperature for 2 h. NH3 0.5 M in dioxane (8.84 mL) was added dropwise to the reaction mixture at 0-5 °C. The entire reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated and the crude reaction mass was taken up in EtOAc (25 mL). The organic portion was washed with water (2 x 15 mL), brine (2 x 15 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give the title compound (350 mg, 88% yield) as an off-white solid. LCMS m / z: 271.22 [M+H].

[0310] Step 5: (4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine [ka] To a stirred solution of 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (Preparation 15, Step 4) (200 mg, 0.74 mmol) in THF (5 mL) was added borane-THF (1 M solution in THF, 4.2 mL) at 0-5 °C and the reaction mixture was heated to reflux for 3 h. The reaction was monitored by LCMS and upon completion, the reaction mixture was cooled in an ice bath, quenched with methanol and concentrated to dryness under vacuum. The crude product was purified by Combi-flash column chromatography to give the title compound (100 mg, 52.7% yield) as an off-white solid. GCMS m / z: 256.1.

[0311] Preparation 15: 1-(1H-indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)urea (Example 14) [ka] To a stirred solution of (4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methanamine (Preparation 15, Step 5) (55 mg, 0.21 mmol) in DCM (1 mL) was added a solution of TEA (0.09 mL, 0.64 mmol) and triphosgene (0.63 mg, 0.21 mmol) in DCM (1 mL) at 0-5 °C under nitrogen atmosphere. The whole was stirred at the same temperature for 1 h, then 6-aminoindole (22.68 mg, 0.17 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature for 1 h. After completion (monitored by LCMS), the solvent was removed under vacuum and the crude product was purified by Combi-flash chromatography to give the title compound (14 mg, 15% yield) as an off-white solid. HPLC purity 99.44%; 1 H NMR:(400 MHz; DMSO-d6): δ 3.08 (t, J = 5.12 Hz,2H), 3.87-3.87 (m, 2H), 4.07 (d, J = 5.8 Hz, 2H), 6.28 (s, 1H), 6.33 (t, J =5.88 Hz, 1H), 6.72-6.77 (m, 3H), 7.01 (t, J = 7.32 Hz, 1H), 7.07 (d, J = 7.96Hz, 1H), 7.12 (d, J = 7.72 Hz, 2H), 7.16 (t, J = 2.52 Hz, 1H), 7.27-7.34 (m, 3H), 7.67 (s, 1H), 8.26 (s, 1H), 10.81 (s, 1H); LCMS m / z: 425.09 [M+H].

[0312] Examples 15-37 The examples in the following table were prepared following the methods used above to prepare examples 1-14 as described in general procedures 1-20 using the appropriate amines. Purification was as described in the previous methods.

[0313] [Table 1] TIFF2024529089000110.tif214149 TIFF2024529089000111.tif209149 TIFF2024529089000112.tif186149

[0314] Biological assays Reporter gene expression assay in THP-1 cells THP1-Dual™ cells (Invivogen) were derived from the human THP-1 monocytic cell line by stable integration of two inducible reporter constructs. As a result, THP1-Dual™ cells allow the simultaneous study of the IRF pathway by assessing the activity of secreted luciferase (Lucia) and the NF-κB pathway by monitoring the activity of secreted SEAP. 5×10 4 THP1-Dual™ cells were seeded in 384-well plates in growth medium and pre-incubated with novel compounds for 10 minutes, followed by stimulation with 5 μM 2',3'-cGAMP. After 20 hours of stimulation, supernatants were removed and IRF pathway reporter proteins were readily measured in cell culture supernatants using QUANTI-Luc™ (Invivogen) (luciferase detection reagent) on a Spectramax i3X luminometer.

[0315] The following table shows the IC of exemplary compounds: 50 Enter the value range. IC 50 Ranges are designated "A" for values ​​up to 1 μM, "B" for values ​​greater than 1 μM up to 10 μM, and "C" for values ​​greater than 10 μM.

[0316] Activity Data [Table 2]

Claims

1. Formula (I): 【Chemical 1】 [wherein, X １ is CR1, X ２ is CR ２ and X ３ is CR3, and X ６ is C=O or CR ７ R ８ wherein Z is CR ９ R10, and X ７ is S, SO, or O, and A is optionally substituted C １ -C6 alkylene, optionally substituted C ２ -C6 alkenylene or optionally substituted C ２ -C6 alkynylene, and n is 1, R １ 、 R ４ and R ８ are each independently selected from the group consisting of H, halogen, OR １３ , CN, CONR １３ R １４ , NR １３ R １４ , NR １３ COR １４ , optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, monocyclic or bicyclic optionally substituted C ６ -C １２ aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl and optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic rings, respectively R ９ and R10 are each independently selected from the group consisting of H, halogen, OR １３ , CN, CONR １３ R １４ , NR １３ R １４ , NR １３ COR １４ , optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkenyl or optionally substituted C ２ -C ６ alkynyl, respectively R ２ and R ３ One of them is -A-NR １７ -C(O)-NR １８ -R １５ wherein R ２ and R ３ The other is H, halogen, OR １３ , CN, COOR １３ , CONR １３ R １４ , NR １３ R １４ , NR １３ COR １４ , optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, monocyclic or bicyclic optionally substituted C ６ -C １２ aryl, monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl and optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring, and is selected from the group consisting of R ５ is H, CONR １３ R １４ , optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ alkylsulfonyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, optionally substituted monocyclic or bicyclic C ６ -C １２ aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle and L １ -L ２ -R １６ and is selected from the group consisting of, R ７ is selected from the group consisting of H, halogen, CONR １３ R １４ , optionally substituted C １ -C ６ alkyl, optionally substituted monocyclic or bicyclic C ３ -C ６ cycloalkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted monocyclic or bicyclic C ６ -C １２ aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring and L １ -L ２ -R １６ and is selected from the group consisting of Here, R ５ and R ７ Of these, at most one is -L １ -L ２ -R １６ is, R １３ and R １４ are each independently selected from the group consisting of H, halogen, OH, CN, COOH, CONH ２ , NH ２ , NHCOH, optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ alkylsulfonyl, optionally substituted monocyclic or bicyclic C ３ to C ６ cycloalkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C １ to C ６ alkoxy, optionally substituted C １ to C ６ alkoxycarbonyl group, optionally substituted monocyclic or bicyclic C ６ to C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy, respectively independently selected from the group consisting of L １ is absent or optionally substituted C １ -C ６ alkylene, optionally substituted C ２ -C ６ alkenylene, optionally substituted C ２ -C ６ alkynylene, O, S, S=O, SO ２ or NR １９ and L ２ is absent or optionally substituted C １ -C ６ alkylene, optionally substituted C ２ -C ６ alkenylene, optionally substituted C ２ -C ６ alkynylene, O, S, S=O, SO ２ or NR １９ and R １５ is a monocyclic or bicyclic C ３ to C ６ cycloalkyl, a monocyclic or bicyclic optionally substituted C ６ to C １２ aryl, a 5- to 10-membered heteroaryl which is monocyclic or bicyclic and optionally substituted or a 3- to 8-membered heterocyclic ring which is monocyclic or bicyclic and optionally substituted, R １６ is optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted monocyclic or bicyclic C ３ to C ６ cycloalkyl, monocyclic or bicyclic optionally substituted C ６ to C １２ aryl, monocyclic or bicyclic optionally substituted 5- to 10-membered heteroaryl or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring, R １７ ~R １９ is independently H, optionally substituted C １ ~C ６ alkyl or optionally substituted C ２ ~C ６ alkenyl.] a compound (provided that the compound is not [Chemical 2] ) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof.

2. R １ is H, halogen, OH, CN, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl or C ２ ~C ６ alkynyl, and the compound according to claim 1.

3. R ２ and R ３ one of which is -A-NR １７ -C(O)-NR １８ -R １５ wherein R ２ and R ３ the other of which is H, halogen, OH, CN, COOR １３ CONR １３ R １４ NR １３ R １４ NR １３ COR １４ or optionally substituted C １ -C ６ alkyl, and R １３ and R １４ are each independently selected from the group consisting of H, optionally substituted C １ -C ３ alkyl, optionally substituted C ２ -C ３ alkenyl and optionally substituted C ２ -C3 alkynyl, the compound according to claim 1 or 2.

4. R ２ and R ３ one of which is -A-NR １７ -C(O)-NR １８ -R １５ wherein R ２ and R ３ the other of which is H, halogen, OH, CN, CONR １３ R １４ , NR １３ R １４ or C １ -C ３ alkyl, and R １３ and R １４ are each independently selected from the group consisting of H, C １ -C ３ alkyl, C ２ -C ３ alkenyl and C ２ -C3 alkynyl, the compound according to claim 3.

5. A is optionally substituted C １ ~C ６ alkylene, optionally substituted C ２ ~C ６ alkenylene or optionally substituted C ２ ~C ６ is alkynylene, and the alkylene, alkenylene or alkynylene is unsubstituted or halogen, OR ２０ , CN, oxo, C(O)R ２０ , COOR ２０ , OC(O)R ２０ , CONR ２０ R ２１ , NR ２０ R ２１ , NR ２０ C(O)R ２１ , =NOR ２０ , SR ２０ , SO ２ R ２０ , OSO ２ R ２０ , SO ２ , NR ２０ R ２１ , OP(O)(OR ２０ )(OR ２１ ), optionally substituted C ６ ~C １２ aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３ ~C ６ The compound according to claim 1 or 2, which is substituted with one or more of cycloalkyl or optionally substituted 3- to 8-membered heterocyclic ring.

6. A is, -CH ２ -, 【Chemical Formula 3】 The compound according to claim 5, wherein is

7. R ４ wherein R is H, halogen, OH, CN or optionally substituted C １ -C ６ -C alkyl, the compound according to claim 1 or 2.

8. R ５ is - L １ -L ２ -R １６ The compound according to claim 1 or 2, wherein

9. L １ is absent or optionally substituted C １ ~C ３ alkylene, optionally substituted C ２ ~C ３ alkenylene or optionally substituted C ２ ~C ３ alkynylene, and L2 is absent or is O, S, S=O, SO2 or NR19, and / or R16 is optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted monocyclic or bicyclic C6-C12 aryl, optionally substituted monocyclic or bicyclic 5-10 membered heteroaryl or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, the compound according to claim 8.

10. R ５ is optionally substituted C １ -C ６ alkyl, the compound according to claim 1 or 2.

11. X ６ is CR ７ R ８ wherein R ７ and R ８ are independently H, halogen, OH, CONR １３ R １４ , optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkenyl or optionally substituted C ２ -C ６ alkynyl, and the compound according to claim 1 or 2.

12. X ６ The compound according to claim 1 or 2, wherein X is CO.

13. Z is CR ９ R １０ and X ７ is S, SO, SO ２ , O or NR １１ and R ９ and R １０ are independently H, halogen, OR １３ , CN, COOR １３ , CONR １３ R １４ , NR １３ R １４ , NR １３ COR １４ , optionally substituted C １ ~C ３ alkyl, optionally substituted C ２ ~C ３ alkenyl or optionally substituted C ２ ~C ３ alkynyl, R １３ and R １４ are, independently, H, optionally substituted C １ -C ３ alkyl, optionally substituted C ２ -C ３ alkenyl or optionally substituted C ２ -C ３ alkynyl, and R １１ is H, C １ to C ３ alkyl, C ２ to C ３ alkenyl or C ２ to C ３ alkynyl, or, Z is NR9, X7 is CR11R12, R9 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, and R11 and R12 are independently H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, the compound according to claim 1 or 2.

14. 1-((4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)-3-(1H-indol-6-yl)urea; 1-((4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea; 1-((4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3-(1H-indol-6-yl)urea; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide; (S)-3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide; (R)-3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N,N-dimethylpropanamide; (R)-1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea; (R)-1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)but-3-en-1-yl)-3-(1H-indol-6-yl)urea; (R)-3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanoic acid; (R)-1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea; (R)-1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea; (S)-1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-hydroxyethyl)-3-(1H-indol-6-yl)urea; (R)-1-(1H-Indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)urea; (R)-1-((4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-3-(1H-indol-6-yl)urea; (R)-1-((4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl)-3-(1H-indol-6-yl)urea; (R)-1-((4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl)-3-(1H-indol-6-yl)urea; 1-((4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl)-3-(1H-indol-6-yl)urea; 1-(1H-Indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)urea; 1-(1H-Indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)methyl)urea; 1-(1H-Indol-6-yl)-3-((4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)urea; 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-morpholinopropyl)-3-(1H-indol-6-yl)urea; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)propanamide; 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-hydroxypropyl)-3-(1H-indol-6-yl)urea; 1-(1-(4-Benzyl-1-oxide-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3,4-dihydroxybutyl)-3-(1H-indol-6-yl)urea; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-methylpropanamide; 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-oxo-3-(pyrrolidin-1-yl)propyl)-3-(1H-indol-6-yl)urea; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-methoxy-N-methylpropanamide; 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(3-hydroxypyrrolidin-1-yl)-3-oxopropyl)-3-(1H-indol-6-yl)urea; 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-morpholino-3-oxopropyl)-3-(1H-indol-6-yl)urea; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-(2-hydroxyethyl)-N-methylpropanamide; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-cyclopropyl-N-methylpropanamide; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-(2-methoxyethyl)-N-methylpropanamide; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-(pyridin-3-yl)propanamide; 3-(3-(1H-Indol-6-yl)ureido)-3-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-(2-hydroxyethyl)propanamide; 1-(1-(4-(2-Chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)but-3-en-1-yl)-3-(1H-indol-6-yl)urea; or 1-(1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)but-3-en-1-yl)-3-(1H-indol-3-yl)urea The compound according to claim 1, which is as defined above.

15. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, tautomer or polymorph thereof, and a pharmaceutically acceptable vehicle.

16. A pharmaceutical composition for use in the treatment, remission or prevention of a disease selected from liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, neonatal onset STING-associated vasculopathy (SAVI), Ehlers-Danlos syndrome (EDS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD), wherein the pharmaceutical composition has the formula (1): 【Chemical Formula 4】 [wherein, X1 is CR1, X2 is CR2, X3 is CR3, X6 is C=O or CR7R8, Z is CR9R10, X7 is S, SO or O, A is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene or optionally substituted C2-C6 alkynylene, n is 1, R1, R4 and R8 are each independently selected from the group consisting of H, halogen, OR13, CN, CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl and optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, R9 and R10 are each independently selected from the group consisting of H, halogen, OR13, CN, CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, One of R2 and R3 is -A-NR17-C(O)-NR18-R15, and the other of R2 and R3 is H, halogen, OR13, CN, COOR13, CONR13R14, NR13R14, NR13COR14, optionally substituted C1-C6 alkyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl and optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, selected from the group consisting of: R5 is selected from the group consisting of H, CONR13R14, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle and L1-L2-R16; R7 is selected from the group consisting of H, halogen, CONR13R14, optionally substituted C1-C6 alkyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocycle and L1-L2-R16; wherein at most one of R5 and R7 is -L1-L2-R16; R13 and R14 are each independently selected from the group consisting of H, halogen, OH, CN, COOH, CONH2, NH2, NHCOH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl group, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl, optionally substituted monocyclic or bicyclic 3-8 membered heterocyclic ring, optionally substituted aryloxy, optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy; L1 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, O, S, S=O, SO2 or NR19; L2 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, O, S, S=O, SO2 or NR19; R15 is optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl or optionally substituted monocyclic or bicyclic 3-8 membered heterocyclic ring; R16 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, monocyclic or bicyclic optionally substituted C6-C12 aryl, monocyclic or bicyclic optionally substituted 5-10 membered heteroaryl or optionally substituted monocyclic or bicyclic 3-8 membered heterocycle, R17 to R19 are independently H, optionally substituted C1-C6 alkyl or optionally substituted C2-C6 alkenyl.] A compound or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, or The pharmaceutical composition comprises a compound of formula (1) or a pharmaceutically acceptable complex, salt, solvate, tautomer or polymorph thereof, and a pharmaceutically acceptable vehicle, a pharmaceutical composition. [

17. ] The disease is fibrosis, and the fibrosis is selected from the group consisting of liver fibrosis, pulmonary fibrosis or renal fibrosis, or The disease is fatty liver disease, and the fatty liver disease is non-alcoholic (or simple) fatty liver or non-alcoholic steatohepatitis (NASH), the pharmaceutical composition for use according to claim 16.

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