Small molecule stimulator of interferon genes (STING) antagonists

Abstract

The present invention relates to compounds of formula (I). The compounds can be used to antagonize the stimulator of interferon genes (STING) protein and thereby treat liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infancy (SAVI), Aicardi-Gutierrez syndrome (AGS), 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).

Description

Technical Field

[0001] The present invention relates to small molecule antagonists of the Stimulator of Interferon Gene (STING) protein. Therefore, small molecule antagonists can be used to treat various inflammatory diseases, such as fatty liver disease, pulmonary fibrosis pancreatitis, lupus, etc. The present invention relates to pharmaceutical compositions of the compounds themselves, methods for preparing the compounds, and methods for regulating the STING protein. Background Art

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

[0003] The human immune system has evolved to recognize and respond to different types of threats and pathogens to maintain a healthy subject. The innate arm of the immune system is primarily responsible for rapid initial inflammatory responses to danger signals associated with cell or tissue damage from bacteria, viruses, and other infectious threats. The innate immune system responds to these damage-associated molecular patterns (DAMPs) or microbial-product pathogen-associated molecular patterns (PAMPs) via an array of sentinel proteins called pattern recognition receptors (PRRs), thereby providing 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 usually components or replication 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 formation of a specific isomer of the cyclic dinucleotide (CDN) cGAMP, c[G(2',5')pA(3',5')p] (Gao et al., Cell, 2013, 153 ,1094).

[0005] CDN is a second messenger that transmits signals to molecules produced by different bacteria and consists of two ribonucleotides connected by a phosphodiester bond to produce a ring structure. CDN 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) both strongly bind to the ER transmembrane adaptor protein STING (DL Burdette et al., Nature, 2011, 478 ,515; H.Ishikawa, Nature, 2008, 455 ,674).

[0006] STING recognizes CDN via its cytosolic carboxy-terminal domain, which forms a homodimer and employs a V-shaped binding pocket to bind CDN (Zhang et al., Mol. Cell, 2013, 51 , 226; GN Barber et al., Nat. Immunol., 2011, 12 ,929). Ligand-induced activation of STING triggers its relocation relative to the Golgi apparatus and conformational changes, thereby promoting its binding to TBK1. TBK1 in turn activates TBK1 through transcription factors IRF-3, STAT6, and NF K B transduces signals to induce type I interferon and other cytokines and interferon-stimulated genes (C. Greenhill, Nature Reviews: Endocrinol., 2018, 14 , 192; Y. Li, HL Wilson and E. Kiss-Toth, J. Inflamm., 2017, 14,11). After its activation, STING is rapidly degraded in normal responses.

[0007] Overactivation of STING is associated with a series of monogenic autoinflammatory disorders called interferonopathies (YJ Crow and N. Manel, Nature Reviews Immunology, 2015, 15 , 429-440). Loss-of-function mutations in the human DNA enzyme Trex1 are associated with elevated levels of cGAMP and autoimmune diseases, such as the rare but severe inflammatory disease Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE), and retinal vasculopathy (Y. Crow et al., Hum. Mol. Gen., 2009, 18 ,R130).

[0008] Inhalation of silica particles can lead to lung inflammation and pulmonary fibrosis, which is triggered by lung cell death and release of dsDNA products. Benmerzoug et al. have reported that this increase in circulating dsDNA activates STING, and increased levels of CXCL10 and IFN signaling lead to lung inflammation (S. Benmerzoug et al., Nature Communications (Nat. Comm.), 2018, 9 ,5226).

[0009] Increased cytosolic dsDNA was detected in fibroblast-like synoviocytes (FLS) obtained from patients with rheumatoid arthritis (RA), and the level of dsDNA correlated with the severity of rheumatoid synovitis (J. Wang et al., Int. Immunopharm., 2019, 76 , 105791). These findings suggest that increased dsDNA triggers an inflammatory response in RA FLS via the STING pathway and leads to increased expression of STING, indicating that cytosolic DNA accumulation is an important consideration in RA-associated inflammation.

[0010] Patients with autosomal dominant gain-of-function mutations in STING suffer from a pediatric autoinflammatory condition called SAVI (STING-associated vasculopathy of infancy), clinically characterized by rash, vasculopathy, lupus-like syndrome, and pulmonary fibrosis, characterized by aberrant IFN production and systemic inflammation, which clinical expression is associated with high morbidity and mortality (N. Konig, et al., Ann. Rheum., Dis., 2017, 76 , 468). Characterized mutations in humans include V147L, N154S, V155M, and G166E, all of which are located at the interface region between the transmembrane domain and the ligand binding domain and produce a ligand-independent constitutively activated protein. Recently, three other gain-of-function STING mutations, C206Y, R281Q, and R284S, have been identified in cluster regions that are proposed to promote STING aggregation and are not conducive to complexing 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] Recent reports by Hazleton et al. have shown that in mice with acute pancreatitis, STING responds to acinar cell death and causes acute pancreatic inflammation by detecting DNA from necrotic cells (A. Hazleton et al., Gastroenterology, 2018, 154, 1822). STING knockout mice suffer less severe acute pancreatitis (less edema, less inflammation), while administration of STING agonists results in more severe pancreatitis.

[0012] Luo et al. also recently showed that STING levels were increased in liver tissue of patients with non-alcoholic fatty liver disease and mice with high-fat diet-induced hepatic steatosis. Again, STING knockout mice suffered less severe liver fibrosis and less acute inflammatory response (X. Luo et al., Gastroenterology, 2018, 155, 1971).

[0013] Elevated 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), indicating a link between lupus disease severity and STING pathway activation.

[0014] It has been shown that tubular cells of individuals with fibrosis lack mitochondrial transcription factor A (TFAM). Mice lacking tubular TFAM develop severe mitochondrial loss and energy deficiency caused by abnormal packaging of mitochondrial DNA and its translocation to the cytosol, where the STING pathway is activated (KW Chung, Cell Metab., 2019, 30 ,1). The ensuing cytokine expression and inflammation cause renal fibrosis.

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

[0016] Other conditions where excessive immune system activation may be associated with STING pathway activation include 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., Nature Medicine, 2018, 24 ,50).

[0017] Thus, there is compelling evidence that blocking, inhibiting or antagonizing the STING pathway may have therapeutic benefit for a wide range of conditions and disease states. Thus, there is an urgent need for improved small molecule blockers of the STING pathway, and in particular, there is a need for small molecule direct antagonists of the STING protein. Summary of the invention

[0018] The present invention arose from the work of the inventors attempting to identify modulators of the STING protein.

[0019] In a first aspect of the present invention, there is provided a compound of formula (I):

[0020]

[0021] Where X 2 CR 2 or N;

[0022] X 3 CR 3 or N;

[0023] X 6 C=O、C=S or CR 7 R 8 ;

[0024] The Z or each Z is independently CR 9 R 10 or NR 9 ;

[0025] X 7 for S, SO, SO2, O, NR 11 or CR 11 R 12 ;

[0026] n is 0, 1 or 2;

[0027] R 1 , R 4 , R 8 , R 9 , R 10 , R 11 and R 12 Each independently selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0028] R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and when X 2 CR2 And X 3 CR 3 When R 2 and R 3 The other of is selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0029] R 5 and R 7 Each independently selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyloxy, and L 5 -L 6 -R 16 ; where R 5 and R 7 At most one of them is -L 5 -L 6 -R 16 ;

[0030] R 13 and R 14 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, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0031] L 1 Does not exist or is NR 17 O, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0032] L 2 Not present or C=O, C=S, C=NR 19 or SO2;

[0033] L 3 Does not exist or is NR 18 O, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0034] L 4 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0035] L 5is 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 ;

[0036] L 6 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 ;

[0037] 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, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle;

[0038] R 16 is H, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle; and

[0039] R 17 To R 19 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or CN;

[0040] Among them, when X 2 When N, X 3 CR 3 ;and

[0041] When L 1 does not exist and L 2 When C=O, L 3 Not for NR 18 ;

[0042] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

[0043] The compounds of formula (I) are useful as medicines.

[0044] Thus, in a second aspect there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof for use as a medicament.

[0045] The present inventors have found that the compounds of formula (I) are useful for modulating the stimulator of interferon genes (STING) protein.

[0046] Therefore, in a third aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof for use in regulating the stimulator of interferon genes (STING) protein.

[0047] Preferably, the compounds of formula (I) are used to inhibit or inactivate the STING protein. The compounds of formula (I) can be used to inhibit or inactivate the functional activity of STING, as demonstrated by a reduction in one or more biological effects selected from the group consisting of: cellular interferon beta production, cellular levels of interferon-stimulated genes, cytokine production, and phosphorylation of transcription factors IRF-3 and NF-κB.

[0048] By inhibiting STING protein, 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 can be treated, alleviated or prevented.

[0049] By inhibiting STING protein, liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, rheumatoid arthritis (RA), STING-associated vasculopathy of infancy (SAVI), Aicardi-Gutierrez syndrome (AGS), 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) can be treated, alleviated or prevented.

[0050] Therefore, in a fourth aspect, a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof is provided for use in treating, alleviating or preventing a disease selected from the following: liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infancy (SAVI), Aicardi-Gutierrez syndrome (AGS), 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).

[0051] In a fifth aspect, a method of regulating the STING protein in an individual is provided, the method comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof. Preferably, the method comprises inhibiting the STING protein.

[0052] Preferably, the method is a method of inhibiting or inactivating STING protein.

[0053] In the sixth aspect, a method for treating, alleviating or preventing a disease selected from the following is provided: liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infancy (SAVI), Aicardi-Gutierrez syndrome (AGS), 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); the method comprises administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

[0054] It will be appreciated that the term "prevent" may mean "reduce the likelihood of."

[0055] In a preferred embodiment, the disease is fibrosis. Fibrosis may be selected from the group consisting of liver fibrosis, lung fibrosis or kidney fibrosis. In some embodiments, compared to healthy individuals, tissues of patients with fibrosis may have upregulated STING expression and / or STING activity.

[0056] 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). DETAILED DESCRIPTION

[0057] Unless the context indicates otherwise, the following definitions apply in conjunction with the compounds of the present invention.

[0058] Throughout the embodiments 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.

[0059] As used in the embodiments and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a mixture of two or more such compositions.

[0060] “Optionally” or “optionally” means that the subsequently described event, operation or circumstance may or may not occur, and means that the embodiments include instances where the event, operation or circumstance occurs and instances where it does not occur.

[0061] Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to six carbon atoms, i.e., a C1-C6 alkyl group. The C1-C6 alkyl group 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. The alkyl group may be unsubstituted or substituted with one or more of the following: halogen, OH, optionally substituted C1-C6 alkoxy, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 8-membered heterocycle. Thus, it is understood that the optionally substituted C1-C6 alkyl may be an optionally substituted C1-C6 haloalkyl, i.e., a C1-C6 alkyl substituted with at least one halogen and optionally further substituted with one or more of the following: OH, optionally substituted C1-C6 alkoxy, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 The optionally substituted C1-C6 alkyl group may be a polyfluoroalkyl group, preferably a C1-C3 polyfluoroalkyl group.

[0062] R 20 and R 21 The alkyl radicals may be 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, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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. 20 and R 21 may be independently selected from the group consisting of H and halogen.

[0063] Unless otherwise specified, the term "alkylene" as used herein refers to a divalent saturated straight or branched hydrocarbon. In certain embodiments, an alkylene group is a primary, secondary or tertiary hydrocarbon. In certain embodiments, an alkylene group includes one to six carbon atoms, i.e., a C1-C6 alkylene group. C1-C6 alkylene groups include, for example, methylene, ethylene, n-propylene and isopropylene, butylene, pentylene, hexylene, isobutylene, sec-butylene, tert-butylene, isopentylene, neopentylene and isohexylene. Alkylene groups may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, halogen, OH, optionally substituted C1-C6 alkoxy, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 8-membered heterocycle. Thus, it is understood that the optionally substituted C1-C6 alkylene may be an optionally substituted C1-C6 haloalkylene, i.e., a C1-C6 alkylene substituted with at least one halogen and optionally further substituted with one or more of the following: optionally substituted C1-C6 alkyl, OH, optionally substituted C1-C6 alkoxy, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR21 ), optionally substituted C6-C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 8-membered heterocycle. It should be understood that the optionally substituted C1-C6 alkylene may be an optionally substituted polyfluoroalkylene, preferably a C1-C3 polyfluoroalkylene. R 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0064] The term "halo" or "halogen" includes fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0065] The term "polyfluoroalkyl" may refer to a C1-C3 alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. The term may include perfluoroalkyl groups, i.e., C1-C3 alkyl groups in which all hydrogen atoms are replaced by fluorine atoms. Thus, the term C1-C3 polyfluoroalkyl groups include, but are 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.

[0066] "Alkoxy" refers to the group R 22 -O-, where R 22 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl. Exemplary C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy, and tert-butoxy. Alkoxy groups may be unsubstituted or substituted with one or more of the following: halogen, OH, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0067] "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 aromatic. 12 Examples of aryl groups include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, tetrahydronaphthyl, and dihydroindenyl. Aryl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0068] "Arylene" refers to a divalent aromatic 6- to 10-membered hydrocarbon radical. Arylene can be as defined above for aryl, but with hydrogen atoms removed therefrom to render the radical divalent.

[0069] As used herein, the term "bicyclic" or "bicyclic" refers to a molecule characterized by two fused rings, which are cycloalkyl, heterocyclic or heteroaryl. In one embodiment, the ring is fused across the bond between two atoms. The bicyclic moiety formed by it shares a bond between the rings. In another embodiment, the bicyclic moiety is formed by the fusion of a series of atoms across the ring to form a bridgehead. Similarly, a "bridge" is a non-branched chain of one or more atoms connecting two bridgeheads in a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spiro" moiety. The spiro group can be a C3-C6 cycloalkyl or a monocyclic or bicyclic 3-8 heterocycle that is bonded to a single carbon atom of a carbocyclic or heterocyclic moiety via a single carbon atom of the spiro moiety. In one embodiment, the spiro group is a cycloalkyl and is bonded to another cycloalkyl. In another embodiment, the spiro group is a cycloalkyl and is bonded to a heterocyclic group. In another embodiment, the spiro group is a heterocyclic group and is bonded to another heterocyclic group. In another embodiment, the spirocyclic group is a heterocyclic group and is bonded to a cycloalkyl group. The spirocyclic group may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0070] "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3- to 6-membered ring system. Representative examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0071] "Cycloalkylene" refers to a divalent non-aromatic saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3-6 membered ring system. Cycloalkylene may be as defined above for cycloalkyl, but with hydrogen atoms removed therefrom to render the group divalent.

[0072] "Heteroaryl" refers to a monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. The term includes bicyclic groups in which one ring is aromatic and the other is not aromatic. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, and nitrogen. Examples of 5- to 10-membered heteroaryls 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- to 10-membered heteroaryl groups include heteroaryl groups in which a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5- or 6-membered monocyclic heteroaryl ring. The heteroaryl group may be unsubstituted or substituted with one or more of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0073] "Heteroarylene" refers to a divalent monocyclic or bicyclic aromatic 5- to 10-membered ring system in which at least one ring atom is a heteroatom. Heteroarylene may be as defined above for heteroaryl, but with hydrogen atoms removed therefrom to render the group divalent.

[0074] "Heterocycle" or "heterocyclyl" refers to a 3- to 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- to 8-membered heterocyclyls include, but are not limited to, aziridine, oxirane, ethylene oxide, ethylene sulfide, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, cyclopentane sulfide, thioin, piperazine, azepane, diazepane, and oxazine. The heterocyclic group may be unsubstituted or substituted with one or more of the following: optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0075] "Heterocyclylene" refers to a divalent 3- to 8-membered monocyclic, bicyclic or bridged molecule in which at least one ring atom is a heteroatom. Heterocyclylene may be as defined above for a heterocyclic group, but with hydrogen atoms removed therefrom to render the group divalent.

[0076] "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., it is a C2-C6 alkenyl group. C2-C6 alkenyl groups include, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. An alkenyl group may be unsubstituted or substituted with one or more of the following: optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0077] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group that can be unbranched or branched. In certain embodiments, the alkynyl group has 2 to 6 carbons, i.e., it is a C2-C6 alkynyl group. C2-C6 alkynyl groups include, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. The alkynyl group may be unsubstituted or substituted with one or more of the following: optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkoxy, halogen, OH, 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 、SO2R 20、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 R is an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted C3-C6 cycloalkyl group, and an optionally substituted 3- to 8-membered heterocyclic ring. 20 and R 21 May be as defined above. 20 and R 21 may each independently be selected from the group consisting of H, halogen and optionally substituted C1-C6 alkyl.

[0078] Unless otherwise specified, the term "alkenylene" as used herein refers to a divalent ethylenically unsaturated straight or branched chain hydrocarbon.Alkenylene may be as defined above for alkenyl, but with hydrogen atoms removed therefrom to render the group divalent.

[0079] Unless otherwise specified, the term "alkynylene" as used herein refers to a divalent acetylenically unsaturated straight or branched chain hydrocarbon. Alkynylene may be as defined above for alkynyl, but with hydrogen atoms removed therefrom to render the group divalent.

[0080] "Alkylsulfonyl" refers to the group alkyl-SO2- wherein alkyl is optionally substituted C1-C6 alkyl and is as defined above.

[0081] "Alkoxycarbonyl" refers to the group alkyl-OC(O)-, where alkyl is an optionally substituted C1-C6 alkyl. Alkoxycarbonyl can be unsubstituted or substituted with one or more of the following: optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12The following examples include aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 8-membered heterocyclic ring.

[0082] "Aryloxy" refers to the group Ar-O-, wherein Ar is an optionally substituted monocyclic or bicyclic C6-C 12 Aryl.

[0083] "Heteroaryloxy" refers to the group heteroaryl-O-, where heteroaryl is an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl and is as defined above.

[0084] "Heterocyclyloxy" refers to the group heterocycle-O-, wherein heterocycle is an optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle and is as defined above.

[0085] The complex of the compound of formula (I) can be understood as a multi-component complex, in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The complex may be a substance other than a salt or a solvate. This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components bound together via non-covalent interactions, but may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together, see O. Almarsson and MJ Zaworotko, Chem Commun, incorporated herein by reference, 17 , 1889-1896 (2004). For a general review of multicomponent complexes, see Haleblian, J Pharm Sci, incorporated herein by reference. 64 (8), 1269-1288 (August 1975).

[0086] The term "pharmaceutically acceptable salt" is understood to refer to any salt of the compounds provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from various organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with, for example, the following organic or inorganic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, adipic acid, aspartic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, caproic 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, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic 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, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate or (2) base addition salts formed when an acidic proton present in the parent compound is: (a) replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or an alkali or alkaline earth metal hydroxide such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium, or ammonia, or (b) by a reaction with, for example, a fatty acid. The invention can be coordinated with an organic base such as aliphatic, alicyclic or aromatic organic amine (e.g., ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzhydrylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and the like).

[0087] Pharmaceutically acceptable salts may include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides, hydrobromides and hydroiodides), carbonates or bicarbonates, sulfates or bisulfates, borates, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glucarates, stearates, sulfamates, nitrates, orotates, oxalates, palmitates, Pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate, toluenesulfonate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, camphorsulfonate, citrate, cyclohexanesulfonate, benzoate, isethionate, ethanesulfonate, formate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate , 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, pivalate, tert-butylacetate, lauryl sulfate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminesulfonate, quinate, muconate, hydroxynaphthoate and the like.

[0088] Hemi-salts of acids and bases, such as hemisulphates, can also be formed. Those skilled in the art will appreciate that the aforementioned salts include those in which the counter ion is optically active, such as D-lactate, or those in which the counter ion is racemic, such as DL-tartrate.

[0089] For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002). Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods:

[0090] (i) by reacting a compound of formula (I) with a desired acid or base;

[0091] (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) by using the required acid or base; or

[0092] (iii) converting one salt of a compound of formula (I) into another salt by reaction with an appropriate acid or base or with the aid of a suitable ion exchange column.

[0093] All three reactions are usually carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

[0094] The term "solvate" is understood to refer to a compound or salt thereof provided herein, which further includes a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces. In the case where the solvent is water, the solvate is a hydrate. Pharmaceutically acceptable solvates according to the present invention include solvates wherein the crystallization solvent may be isotopically substituted, such as D2O, d6-acetone and d6-DMSO.

[0095] The currently recognized classification system for organic hydrates is the classification system defining isolated site, channel or metal ion coordinated hydrates, see KR Morris, Polymorphism in Pharmaceutical Solids (HG Brittain, ed., Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are hydrates in which water molecules are separated from each other by intervening organic molecules and are not in direct contact. In channel hydrates, water molecules are in lattice channels next to other water molecules. In metal ion coordinated hydrates, water molecules are bound to metal ions.

[0096] 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 (such as in channel solvates and hygroscopic compounds), the water / solvent content will depend on humidity and drying conditions. In these cases, non-stoichiometry will be the norm.

[0097] The compounds of the present invention may exist in a continuum of solid states ranging from completely amorphous to completely crystalline, including polymorphs of the crystalline material. The term 'amorphous' refers to a state in which a material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or a liquid, depending on the temperature. Such materials generally do not produce a unique X-ray diffraction pattern, and although they exhibit solid properties, they are more formally described as liquids. Upon heating, a change in solid properties to liquid properties occurs, characterized by a change in state, typically secondary ('glass transition'). The term 'crystalline' refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase transition, typically primary ('melting point').

[0098] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that occurs as a result of temperature changes is described as 'thermotropic', while mesomorphism that occurs as a result of the addition of a second component (e.g. water or another solvent) is described as 'lyotropic'. Compounds that are able to form lyotropic mesophases are described as 'amphiphilic' and consist of a molecule with an ionic polar head group (e.g. -COO - Na + 、-COO - K + or -SO3 - Na + ) or a nonionic polar head group (e.g. -N - N + (CH3)3). For more information, see NH Hartshorne and A. Stuart, incorporated herein by reference. Crystals and the Polarizing Microscope , 4th edition (Edward Arnold, 1970).

[0099] The compounds of formula (I) may contain one or more stereogenic centers and may therefore exist in the form of optical isomers such as enantiomers and diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention.

[0100] It should be understood that the above compounds can exist in the form of enantiomers as well as in the form of diastereoisomeric pairs. These isomers also represent other embodiments of the present invention.

[0101] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0102] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomer by methods well known to those skilled in the art.

[0103] The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (usually HPLC) on an asymmetric resin with a mobile phase consisting of a hydrocarbon (usually heptane or hexane) and containing 0% to 50% by volume (usually 2% to 20%) isopropanol and 0% to 5% by volume alkylamine (usually 0.1% diethylamine). Concentrating the eluent yields an enriched mixture.

[0104] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art; see, for example, EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994).

[0105] 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 It can be H, halogen, OH, CN, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 1 For H.

[0106] X 2 Can be CR 2 .

[0107] X 3 Can be CR 3 .

[0108] In one embodiment, X 2 N and X 3 CR 3 In this embodiment, R 3 For -L 1 -L 2-L 3 -L 4 -R 15 .

[0109] In an alternative embodiment, X 2 CR 2 And X 3 is N. In this embodiment, R 2 For -L 1 -L 2 -L 3 -L 4 -R 15 .

[0110] However, in a preferred embodiment, X 2 CR 2 And X 3 CR 3 In some embodiments, R 2 For -L 1 -L 2 -L 3 -L 4 -R 15 In an alternative embodiment, R 3 For -L 1 -L 2 -L 3 -L 4 -R 15 Therefore, the compound may be a compound of formula (Ia) or formula (Ib):

[0111]

[0112] Preferably, R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other is H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl, and R 13 and R 14Each is independently selected from the group consisting of H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, and optionally substituted C2-C3 alkynyl. More preferably, R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other is H, halogen, OH, CN, CONR 13 R 14 NR 13 R 14 , C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl, and R 13 and R 14 Each is independently selected from the group consisting of: H, C1-C3 alkyl, C2-C3 alkenyl and C2-C3 alkynyl. Preferably, R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other of is H, bromine or CONH2. In a preferred embodiment, R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other one is H.

[0113] Preferably, L 1 To L 4 At least one of exists.

[0114] In some embodiments, L 1 Does not exist or is NR 17 .L 2 Can be C=O, C=S, C=NR 19 Or SO2. 3 May not exist or be NR 18 Therefore, in some embodiments, -L 1 -L 2 -L 3 -Can be The asterisk indicates the 4 The bond point, or at L 4 In the absence of embodiments, it is indicated with R 15 The key point of .

[0115] R 17 and R 18 R may independently be H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 17 and R 18 R may independently be H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 17 and R 18 It is H or methyl.

[0116] R 19 It can be H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or CN. 19 It can be H, methyl or CN. Preferably, R 19 is H or CN.

[0117] In an alternative embodiment, L 1 L is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene or optionally substituted C2-C6 alkynylene. 1 Not present or C1-C3 alkylene. 1 It may not exist or be CH2. 2 It doesn't exist. 3 Therefore, in some embodiments, -L 1 -L 2 -L 3 - may be -O-* or -CH2O-*, where the asterisk indicates the same 4 The bond point or L 4 In the absence of embodiments, it is indicated with R 15 The key point of .

[0118] In another alternative embodiment, L 1 It may be an optionally substituted C3-C6 cycloalkylene group, an optionally substituted C6-C 12 arylene, an optionally substituted 5- to 10-membered heteroarylene, or an optionally substituted 3- to 8-membered heterocyclylene. 1 L may be an optionally substituted C3-C6 cycloalkylene group, an optionally substituted C6 arylene group, an optionally substituted 5-membered or 6-membered heteroarylene group, or an optionally substituted 3-membered to 6-membered heterocyclylene group. 1It may be a C5-C6 cycloalkylene group, a C6 arylene group, a 5-membered or 6-membered heteroarylene group, or a 5-membered to 6-membered heterocyclylene group. The cycloalkylene group may be a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, or a cyclohexylene group. 1 It can be a 5-membered heteroarylene group. The heteroarylene group can be a pyrrolylene group, a pyrazolylene group, an imidazolylene group, a 1,2,4-triazolylene group, a 1,2,3-triazolylene group, a furanylene group, a thienylene group, an oxazolylene group, an isoxazolylene group, a thiazolylene group or an isothiazolylene group. 1 It can be a 6-membered heterocyclic group. The heterocyclic group can be a pyrrolidinylene, pyrazolidinylene, imidazolidinylene, tetrahydrofuranylene, 3-dioxolylene, tetrahydrothienylene, piperidinylene, piperazinylene, tetrahydropyranylene, cyclopentylene sulfide, morpholinylene or morpholinylene thio. 2 It doesn't exist. 3 Therefore, in some embodiments, -L 1 -L 2 -L 3 -Can be The asterisk indicates the 4 The bond point, or at L 4 In the absence of embodiments, it is indicated with R 15 The key point of .

[0119] In some embodiments, L 4 is absent, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene or optionally substituted C2-C6 alkynylene. Preferably, L 4 is absent or is C1-C3 alkenylene. More preferably, L 4 Absent or CH2, CH2CH2 or CH2CH2CH2.

[0120] In an alternative embodiment, L 4 is an optionally substituted C3-C6 cycloalkylene group, an optionally substituted C6-C 12 arylene, an optionally substituted 5- to 10-membered heteroarylene, or an optionally substituted 3- to 8-membered heterocyclylene. 4 is an optionally substituted C3-C6 cycloalkylene group, an optionally substituted C6 arylene group, an optionally substituted 5- to 6-membered heteroarylene group, or an optionally substituted 3- to 6-membered heterocyclylene group. More preferably, L 4 is a C5-C6 cycloalkylene group, a C6 arylene group, a 5-membered to 6-membered heteroarylene group or a 5-membered to 6-membered heterocyclylene group. The cycloalkylene group may be a cyclopropylene group, a cyclobutylene group, a cyclopentylene group or a cyclohexylene group. 4L may be a 5-membered heteroaryl group. The heteroaryl group may be a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,4-triazolyl group, a 1,2,3-triazolyl group, a furanyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group or an isothiazolyl group. The heterocyclyl group may be a pyrrolidinyl group, a pyrazolyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 3-dioxolyl group, a tetrahydrothienyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a cyclopentylene sulfide group, a morpholinyl group or a morpholinyl sulfide group. Therefore, in some embodiments, L 4 Can The asterisk indicates 15 The key point of .

[0121] Therefore, in some embodiments, -L 1 -L 2 -L 3 -L 4 - may be -OCH2CH2-*, -CH2OCH2-*, The asterisk indicates the 15 Preferably, R 17 and R 18 are independently H or CH3.

[0122] In one embodiment, R 15 is an optionally substituted monocyclic or bicyclic C6-C 12 Aryl. Optionally substituted C6-C 12 The aryl group may be an optionally substituted phenyl, 5,6,7,8-tetrahydronaphthyl or 2,3-dihydro-1H-indenyl. The aryl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, halogen, OH, oxo, OP(O)(OR 20 )(OR 21 ), optionally substituted C1-C6 alkoxy, NR 20 R 21 ,CONR 20 R 21 、CN、C(O)R 20 、COOR 20 , NO2, azido, SO2R 20 、C(O)R 20 and NR 20 COR 21 When the aryl group is substituted with an optionally substituted alkyl group, the alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6 alkoxy, NR 20 R 21 、C(O)R20 、CN、Oxo、OP(O)(OR 20 )(OR 21 ), OC(O)R 20 、COOR 20 , C1-C6 alkenyl, C1-C6 alkynyl, =NOR 20 NR 20 C(O)R 21 、SO2R 20 and SO2NR 20 R 21 The halogen may be F. R 20 and R 21 and CH2COOH.

[0123] In an alternative embodiment, R 15is an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 3- to 8-membered heterocyclic ring. The optionally substituted 5- to 10-membered heteroaryl can be optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted indolyl, optionally substituted indolyl, optionally substituted 1H-indolyl, optionally substituted 7-azaindolyl, optionally substituted 1H-pyrrolo[3,2-b]pyridinyl, optionally substituted benzofuranyl, optionally substituted optionally substituted 1,2,3,4-tetrahydroquinolyl, optionally substituted quinazolinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted 1,2,3,4-tetrahydroisoquinolyl, optionally substituted 3,4-dihydro-2H-1,4-benzoxazolyl, or optionally substituted 7,8-dihydropyrido[4,3-d]pyrimidinyl. The optionally substituted 3- to 8-membered heterocycle can 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-diazepanyl, optionally substituted 1,3-diazepanyl, optionally substituted 1,4-diazepanyl, or optionally substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine. The heteroaryl, cycloalkyl or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, halogen, OH, oxo, OP(O)(OR 20 )(OR 21 ), optionally substituted C1-C6 alkoxy, NR 20 R 21 ,CONR20 R 21 、CN、C(O)R 20 、COOR 20 , NO2, azido, SO2R 20 、C(O)R 20 and NR 20 COR 21 When the heteroaryl, cycloalkyl or heterocycle is substituted with an optionally substituted alkyl, the alkyl may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6 alkoxy, NR 20 R 21 、C(O)R 20 、CN、Oxo、OP(O)(OR 20 )(OR 21 ), OC(O)R 20 、COOR 20 ,CONR 20 R 21 , C1-C6 alkenyl, C1-C6 alkynyl, =NOR 20 NR 20 C(O)R 21 、SO2R 20 and SO2NR 20 R 21 The halogen may be F or Cl. Preferably, the halogen is F. 20 and R 21 and cycloalkyl. Thus, the heteroaryl, cycloalkyl or heterocycle may be substituted with one or more substituents selected from the group consisting of F, oxo, CN, NH2, C(O)CH3, CONH2, CH3 and CH2COOH. For example, the optionally substituted 5- to 10-membered heteroaryl may be optionally substituted with methyl and optionally one or more other substituents. Thus, the optionally substituted 5- to 10-membered heteroaryl may be optionally substituted 1-methylindolyl, optionally substituted 2-methyl-1H-indolyl, optionally substituted 5-methyl-1H-indolyl, optionally substituted N-methylimidazolyl, optionally substituted N-methylpyrazolyl or optionally substituted N-methylbenzimidazolyl.

[0124] Therefore, R 15 It can be phenyl,

[0125]

[0126] In some embodiments, R 15 is 1H-indolyl or NR 20 R21 Preferably, R 15 It is 1H-indolyl or phenyl substituted with NH2.

[0127] 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 It can be H, halogen, OH, CN, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 4 For H.

[0128] R 5 Can be -L 5 -L 6 -R 16 .

[0129] Preferably, L 5 is an optionally substituted C1-C3 alkylene, an optionally substituted C2-C3 alkenylene or an optionally substituted C2-C3 alkynylene. The alkylene, alkenylene or alkynylene may be unsubstituted or substituted with one or more of the following: halogen, OH, CN, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 And oxo. 20 and R 21 R may independently be 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. Preferably, R 20 and R 21 are independently H, methyl or cyclopropyl. Preferably, L 5 CH2, CH2CH2, CO,

[0130] Or, L 5 But it doesn't exist.

[0131] In some embodiments, L 6 Does not exist.

[0132] Or, L 6 Can be O, S, S=O, SO2 or NR 19 . R 19 L may be H, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl or an optionally substituted C2-C3 alkynyl. 6 is O or S, and most preferably is O.

[0133] R 16 It may be an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted monocyclic or bicyclic C6-C 12 Preferably, R 16 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocyclic ring. 12The aryl group may be an optionally substituted phenyl group. The optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl may be optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted 1,2,3-oxadiazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,2,5-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted 1H-indolyl, optionally substituted azaindolyl, optionally substituted benzisoxazolyl, optionally substituted 4-azabenzimidazolyl, optionally substituted 1H-indol ... 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 can 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.

[0134] When R 16 When aryl, the aryl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)R 20 、COOR 20 、OC(O)R 20 ,CONR 20 R 21 NR 20 R 21 NR20 C(O)R 21 , =NOR 20 , SR 20 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 8-membered heterocycle. Halogen may be F or Cl. When R 16 When it is a cycloalkyl, heteroaryl or heterocycle, the cycloalkyl, heteroaryl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, halogen, OH, CN, oxo, C(O)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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 OP(O)(OR 20 )(OR 21 ), optionally substituted C6-C 12 wherein the cycloalkyl, aryl, heteroaryl or heterocycle is substituted directly or indirectly with an optionally substituted alkyl, alkenyl, alkynyl or alkoxyl, the alkyl, alkenyl, alkynyl or alkoxyl may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, OH, C1-C6 alkoxyl, NR 20 R 21 ,CONR 20 R 21 、C(O)R 20 、CN、Oxo、OP(O)(OR 20 )(OR21 ), OC(O)R 20 、COOR 20 , C1-C6 alkenyl, C1-C6 alkynyl, =NOR 20 NR 20 C(O)R 21 、SO2R 20 and SO2NR 20 R 21 . Preferably, when the cycloalkyl, aryl, heteroaryl or heterocycle is substituted directly or indirectly with an optionally substituted alkyl, alkenyl, alkynyl or alkoxy, the alkyl, alkenyl, alkynyl or alkoxy is unsubstituted or substituted with one or more of halogen and OH. When the cycloalkyl, aryl, heteroaryl 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-membered or 6-membered heteroaryl. R 20 and R 21 R may independently be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. 20 and R 21 substituted with methyl, and more preferably H, CH or CF. Thus, cycloalkyl, aryl, heteroaryl or heterocycle may be unsubstituted or substituted with one or more of the following: F, Cl, oxo, OH, CN, NH, methyl, tert-butyl, CF, CHOH, OCH, OCHF, OCF, SCF, COCH, COOH, COOCH, CONH, SOCH, 1,2,4-triazolyl and phenyl. For example, an optionally substituted 5- to 10-membered heteroaryl may be optionally substituted with methyl and one or more other substituents optionally present. Thus, an optionally substituted 5- to 10-membered heteroaryl may be an optionally substituted 1-methylindolyl, an optionally substituted N-methylimidazolyl, an optionally substituted N-methylpyrazolyl or an optionally substituted N-methylphenylimidazolyl. The aryl, heteroaryl or heterocycle is preferably unsubstituted or substituted with 1 or 2 substituents.

[0135] Therefore, R 16 Can be cyclopropyl, cyclopentyl, phenyl,

[0136]

[0137] In an alternative embodiment, R 5 R is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 5R may be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, CN and oxo. 5 It can be H, CH3 or CH2CN.

[0138] X 6 Can be CO or CR 7 R 8 . R 7 and R 8 can be independently H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 13 COR 14 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 7 and R 8 can be independently H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 13 COR 14 , optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. 13 and R 14 Preferably, it is H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl, and most preferably H. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted by one or more of the following: halogen, OH, oxo, CN, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 and OP(O)(OR 20 )(OR21 ). 20 and R 21 R may be independently H or methyl. 7 and R8 are independently H, CN, CONH2, CH2NH2, CH2CH2OH,

[0139] In one embodiment, X 6 For CO.

[0140] In an alternative embodiment, X 6 For CH2,

[0141] In one embodiment, n is 0. 7 Can be CR 11 R 12 . R 11 and R 12 R may independently be H, halogen, OH, CN, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. 11 and R 12 are independently H or methyl. Most preferably, R 11 and R 12 For H.

[0142] In an alternative embodiment, n is 1.

[0143] In one embodiment, Z is CR 9 R 10 And X 7 S, SO, SO2, O or NR 11 . R 9 and R 10 R may independently be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 9 and R 10 can be independently H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 13 COR 14 , optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. 13 and R 14may be independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of the following: halogen, OH, oxo, CN, 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 、SO2R 20 、OSO2R 20 、SO2NR 20 R 21 and OP(O)(OR 20 )(OR 21 ). 20 and R 21 R may be independently H or methyl. 9 and R 10 are independently H, methyl, CH2CONH2 or CH2CN. More preferably, R 9 and R 10 For H. R 11 R may be H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 11 It can be H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 11 is H or methyl. More preferably, X 7 S, O, SO or NR 11 Most preferably, X 7 It is S or O.

[0144] In an alternative embodiment, Z is NR 9 And X 7 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 It can be H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. 9 R is methyl. 11 and R 12R may independently be H, halogen, OH, CN, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 11 and R 12 R may independently be 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 With R 12 In various embodiments, R 11 and R 12 The bonded carbon defines a chiral center. The chiral center can be an S or R chiral center. In some embodiments, the chiral center is an S chiral center.

[0145] In some embodiments, X 2 CR 2 , X 3 CR 3 , and n is 1. Z can be CR 9 R 10 , and X 7 Can be S, SO, SO2, O or NR 11 Alternatively, Z may be NR 9 , and X 7 Can be CR 11 R 12 Therefore, the compound may be a compound of formula (II) or (III):

[0146]

[0147] In an alternative embodiment, X 2 CR 2 , X 3 CR 3 , and n is 0. X 7 Can be CR 11 R 12 Therefore, the compound may be a compound of formula (IV):

[0148]

[0149] In some embodiments, R 2 For -L 1 -L 2 -L 3 -L 4 -R 15 In an alternative embodiment, R 3 For -L 1-L 2 -L 3 -L 4 -R 15 Thus, the compound of formula (II), (III) or (IV) may be a compound of formula (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb):

[0150]

[0151] In one embodiment of the compound of Formula (II), (III), (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), R 5 R is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 5 R may be H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, CN and oxo. Preferably, R 5 It is H or CH3.

[0152] In an alternative embodiment of the compound of Formula (II), (III), (IIa), (IIb), (IIIa), (IIIb), (IVa) or (IVb), R 5 For -L 5 -L 6 -R 16 Thus, the compound may be a compound of formula (IIc), (IId), (IIIc), (IIId), (IVc) or (IVd):

[0153]

[0154]

[0155] In some embodiments, L 6 may not exist, and R 5 Can be -L 5 -R 16 Therefore, the compound may be a compound of formula (IIci), (IIdi), (IIIci), (IIIdi), (IVci) or (IVdi):

[0156]

[0157] In the compounds of formula (II), (III), (IIa) to (IIdi), (IIIa) to (IIIdi), (IV) or (IVa) to (IVdi), X6 Can be C=O or CR 7 R 8 In some embodiments, X 6 It is C=O.

[0158] In the compounds of formula (II) or (IIa) to (IId), X 7 It can be S or O. Preferably, X 7 For S.

[0159] The term 'STING' refers to stimulator of interferon genes, an adaptor protein that is functionally activated via cyclic dinucleotides that induce the production of interferons and inflammatory cytokines.

[0160] It is understood that an 'antagonist' or 'inhibitor' as it relates to ligand and STING includes a molecule, combination of molecules, or complex that inhibits, counteracts, downregulates, and / or desensitizes STING activity. An 'antagonist' encompasses any agent that inhibits the constitutive activity of STING. Constitutive activity is activity that is manifested in the absence of a ligand / STING interaction. An 'antagonist' also encompasses any agent that inhibits or prevents the stimulated (or regulated) activity of STING.

[0161] Preferably, the compound of formula (I) is an inhibitor of STING protein.

[0162] It will be appreciated that the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomeric forms or polymorphic forms thereof, can be used in medicaments that can be used in monotherapy (i.e., using only the compound) for modulating STING protein and / or treating, alleviating or preventing disease.

[0163] Alternatively, the compound or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof can be used as an adjuvant to a known therapy or in combination with a known therapy for regulating the STING protein and / or treating, alleviating or preventing a disease.

[0164] Formula (I) compound can be combined in the form of composition, and the composition has a variety of different forms, especially depending on the mode of using the composition. Therefore, for example, the composition can be in the form of powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, microgel solution, transdermal patch, liposome suspension or any other suitable form that can be applied to the human or animal in need of treatment. It should be understood that the medium of the medicine according to the present invention should be a medium that is fully tolerated by the individual receiving it.

[0165] Drugs comprising the compounds described herein can be used in a variety of ways. Suitable modes of administration include oral, intratumoral, parenteral, topical, inhaled / intranasal, rectal / intravaginal, and ocular / aural administration. Formulations suitable for the aforementioned modes of administration can be formulated into immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0166] The compounds of the present invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the bloodstream directly from the oral cavity. Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled lozenges), chewable tablets, multi-particulates and nanoparticles, gels, solid solutions, liposomes, films, oval suppositories, sprays, liquid formulations, and buccal / mucosal adhesive patches.

[0167] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid (e.g., a solid from a sachet).

[0168] The compounds of the invention may also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6),981-986,(2001).

[0169] For tablet dosage forms, depending on the dosage, the drug may account for 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 generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked providone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with a low carbon number alkyl group, starch, pregelatinized starch, and sodium alginate. In general, the disintegrant will account for 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0170] Binders are generally used to impart a cohesive quality to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

[0171] Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet, while glidants may comprise 0.2% to 1% by weight of the tablet.

[0172] Tablets generally also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally account for 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

[0173] Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder by weight, about 0% to about 85% diluent by weight, about 2% to about 10% disintegrant by weight, and about 0.25% to about 10% lubricant by weight. Tablet blends can be compressed directly or by rollers to form tablets. Tablet blends or portions of blends can alternatively be wet granulated, dry granulated, or melt granulated, melt agglomerated, or extruded before tableting. The final formulation can include one or more layers and can be coated or uncoated; it can even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets" by H. Lieberman and L. Lachman, Vol. 1, (Marcel Dekker, New York, 1980).

[0174] Modified release formulations suitable for achieving the purposes of the present invention are described in U.S. Pat. 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., Pharmaceutical Technology On-line, 25(2), 1-14, (2001). The use of chewable tablets to achieve controlled release is described in WO 00 / 35298.

[0175] The compounds of the invention can also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable modes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0176] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffers (preferably buffered to a pH of 3 to 9), but for some applications they may be more suitably formulated as sterile non-aqueous solutions or in a dry form to be used in conjunction with a suitable vehicle (e.g., sterile pyrogen-free water).

[0177] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0178] The solubility of the compound of formula (I) for preparing parenteral solutions can be increased by using appropriate formulation techniques such as incorporating solubility enhancers. Formulations for parenteral administration can be formulated into immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Therefore, the compounds of the present invention can be formulated into solid, semisolid, or thixotropic liquids to be administered in the form of implantable reservoirs, thereby providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-coglycolic acid copolymers) (poly (dl-lactic-coglycolic) acid; PGLA) microspheres.

[0179] The compounds of the present invention can also be topically applied to the skin or mucous membrane, i.e., through the dermis or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, powder sheets, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated, see, for example, J Pharm Sci by Finnin and Morgan, 88 (10),955-958(October 1999).

[0180] Other means of local administration include electroporation, iontophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject TM 、Bioject TM etc.) for delivery by injection.

[0181] The compounds of the invention may also be administered intranasally or by inhalation, usually in the form of dry powders (alone, in a mixture, for example, in a dry blend with lactose; or in the form of mixed component particles, for example, mixed with phospholipids (e.g., phosphatidylcholine)) from a dry powder inhaler; or in the form of an aerosol spray from a pressurized container, pump, sprayer, nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist) or aerosolizer with or without a suitable propellant (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). For intranasal use, the powder may contain a bioadhesive, for example, polyglucosamine or cyclodextrin.

[0182] The pressurized container, pump, spray, nebulizer or aerosol contains a solution or suspension of the compound of the invention, comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, dissolving or prolonging the release of the active substance, a propellant as a solvent and optionally a surfactant (for example, sorbitan trioleate, oleic acid or oligolactic acid).

[0183] Prior to use in dry powder or suspension formulations, the drug is micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, and supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0184] Capsules (e.g. made of gelatin or hydroxypropylmethylcellulose), blister shells and filter cartridges for use in inhalers or insufflators may be formulated as a powder mix containing a compound of the invention, a suitable powder base (e.g. lactose or starch) and a performance modifier (e.g. L-leucine, mannitol or magnesium stearate). Lactose may be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0185] Solution formulations suitable for atomizers that use electrohydrodynamics to generate fine mist may contain 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume may vary from 1 μL to 100 μL. Typical formulations may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0186] Suitable flavoring agents (eg, menthol and levomenthol) or sweetening agents (eg, saccharin or saccharin sodium) may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0187] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered dose. The unit according to the invention is usually 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 usually be in the range of 1 μg to 200 mg, which can be administered in a single dose or more usually in divided doses throughout the day.

[0188] 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 where appropriate.

[0189] The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of micronized suspensions or solution drops in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, powder tablets, crystals, and granular or cystic systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) may be combined with preservatives (e.g., benzalkonium chloride). Such formulations may also be delivered by iontophoresis.

[0190] The compounds of the present invention can also 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 by intratumoral injection. Typical injection solutions include propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0191] The compounds of the 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 when used in any of the aforementioned modes of administration.

[0192] For example, it is found that drug-cyclodextrin complexes are generally suitable for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as vehicles, diluents or solubilizers. Alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin are most commonly used for these purposes, examples of which can be found in international patent applications Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0193] It should be understood that the amount of the compound required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the compound, and whether it is used in the form of monotherapy or combination therapy. The frequency of administration will also be affected by the half-life of the compound in the individual being treated. The most preferred dose to be administered can be determined by a person skilled in the art and will vary with the specific compound used, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Additional factors depending on the specific individual being treated will cause the need to adjust the dose, including individual age, weight, sex, diet, and time of administration.

[0194] In general, for administration to humans, the total daily dose of the compounds of the present invention is generally in the range of 100 μg to 10g, such as 1 mg to 1g, such as 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 a single dose or divided doses, and may exceed the typical range given herein at the discretion of the physician. These doses are based on an average human individual weighing about 60 kg to 70 kg. The physician will be able to easily determine the dose for individuals whose weight exceeds this range (e.g., infants and the elderly).

[0195] The compounds may be administered before, during or after the onset of the disorder to be treated.

[0196] Known procedures such as those routinely employed by the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.) can be used to formulate specific formulations and exact treatment regimens (e.g., daily dosages and frequency of administration of the compounds) comprising the compounds of the invention. 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.

[0197] Therefore, in a seventh aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof and a pharmaceutically acceptable vehicle.

[0198] In an eighth aspect, the present invention also provides a method for preparing a composition according to the seventh aspect, the method comprising contacting a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof and a pharmaceutically acceptable vehicle.

[0199] "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 a domestic animal (e.g., a horse), a pet or may be used in other veterinary applications. However, most preferably, the subject is a human.

[0200] A "therapeutically effective amount" of a compound is any amount which, when administered to a subject, is required to treat the disease of interest or produce the desired effect (ie, inhibition of the STING protein).

[0201] For example, the therapeutically effective amount of the compound used may be from about 0.01 mg to about 800 mg, and preferably from about 0.01 mg to about 500 mg. The amount of the compound is preferably from about 0.1 mg to about 250 mg and most preferably from about 0.1 mg to about 20 mg.

[0202] As referred to herein, "pharmaceutically acceptable vehicle" is any known compound or combination of known compounds known to those of ordinary skill in the art that is suitable for formulating pharmaceutical compositions.

[0203] In one embodiment, the pharmaceutically acceptable medium may be solid, and the composition may be in the form of a powder or tablet. Solid pharmaceutically acceptable medium may include one or more substances, which may also serve as flavoring agents, lubricants, solubilizers, suspending agents, dyes, fillers, sliding agents, compression aids, inert adhesives, sweeteners, preservatives, dyes, coatings or tablet disintegrants. The medium may also be an encapsulation material. In powder, the medium is a fine powder solid blended with a fine powder 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 medium having necessary compression properties in a suitable ratio and compacted in a desired shape and size. Powders and tablets preferably contain up to 99% active compounds. Suitable solid media include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidone, low melting point wax and ion exchange resins. In another embodiment, the pharmaceutical medium may be a gel and the composition may be in the form of an ointment or the like.

[0204] However, the pharmaceutical vehicle can be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid vehicle, such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid vehicle may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers or osmotic regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives such as above, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohol (including monohydric alcohols and polyols, such as glycols) and derivatives thereof and oils (such as 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 suitable for compositions in sterile liquid form for parenteral administration. The liquid vehicle for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0205] Liquid pharmaceutical compositions as sterile solutions or suspensions can be utilized, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The compound can be prepared as a sterile solid composition that can be dissolved or suspended when administered using sterile water, physiological saline or other suitable sterile injectable media.

[0206] The compounds and compositions of the present invention can be administered in the form of sterile solutions or suspensions containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate of sorbitol and anhydride copolymerized with ethylene oxide) and the like. The compounds used according to the present invention can also be administered orally in the form of liquid compositions or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders and liquid forms such as solutions, pastes, elixirs and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

[0207] Those skilled in the art will appreciate that an active drug ingredient may be converted into a prodrug, which is a metabolically unstable derivative that is converted in vivo to an active drug substance. Also included within the scope of the present invention are prodrugs that are compounds of formula (I) containing a metabolically or hydrolytically unstable moiety that is converted in vivo to an active drug of formula (I). Methods by which a prodrug may be converted to an active drug substance include, but are not limited to, ester or carbonate or carbamate hydrolysis, phosphate hydrolysis, S-oxidation, N-oxidation, dealkylation, and metabolic oxidation, as described in Beaumont et al., Curr. Drug Metab., 2003,4 , 461-485 and Huttenen et al., Pharmacol. Revs., 2011, 63 Such prodrug derivatives may provide improved solubility, stability, or permeability compared to the parent drug substance, or may better allow the drug substance to be administered by alternative routes of administration, such as in the form of an intravenous solution.

[0208] Also included within the scope of the present invention are soft drugs or prodrugs, which are compounds of formula (I) containing metabolically or hydrolytically unstable moieties that are converted in vivo to inactive derivatives. Methods by which active drug substances are converted to inactive derivatives include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation, as described, for example, in Pearce et al., Drug Metab. Dispos., 2006, 34 , pp. 1035-1040 and B. Testa, Prodrug and Soft Drug Design, Comprehensive Medicinal Chemistry II, Vol. 5, Elsevier, Oxford, 2007, pp. 1009-1041 and Bodor, N. Chem. Tech. 1984, 14 , described in 28-38.

[0209] The scope of the present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention wherein 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 predominantly found in nature.

[0210] Examples of suitable isotopes for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C and 14 C; isotopes of chlorine, e.g. 36 Cl; isotopes of fluorine, e.g. 18 F; isotopes of iodine, e.g. 123 I and 125 I; isotopes of nitrogen, e.g. 13 N and 15 N; isotopes of oxygen, e.g. 15 O. 17O and 18 O; isotopes of phosphorus, e.g. 32 P; and isotopes of sulfur, e.g. 35 S.

[0211] Certain isotopically-labeled compounds of the invention (e.g., those into which a radioactive isotope is incorporated) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon 14 (i.e. 14 C) is particularly suitable for this purpose due to its ease of incorporation and ready means of detection. 2 Isotopic substitution with positron emitting isotopes (e.g., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. 11 C. 18 F. 15 O and 13 N) substitutions may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0212] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0213] In another aspect of the present invention, there is provided a compound of formula (V):

[0214]

[0215] Where X 1 CR 1 or N;

[0216] X 2 CR 2 or N;

[0217] X 3 CR 3 or N;

[0218] X 4 CR 4 or N;

[0219] X 5 NR 5 or CR 5 R 6 ;

[0220] X 6 NR 7 , C=O, C=S or CR7 R 8 ;

[0221] The Z or each Z is independently CR 9 R 10 or NR 9 ;

[0222] X 7 for S, SO, SO2, O, NR 11 or CR 11 R 12 ;

[0223] n is 0, 1 or 2;

[0224] R 1 , R 4 , R 6 , R 8 , R 9 , R 10 , R 11 and R 12 Each independently selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0225] R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and when X 2 CR 2 And X 3 CR 3 When R 2 and R 3The other of is selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0226] R 5 and R 7 Each independently selected from the group consisting of: H, halogen, OH, CN, COOR 13 ,CONR 13 R 14 NR 13 R 14 NR 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, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyloxy, and L 5 -R 16 ; where R 5 and R 7 At most one of them is -L 5 -R 16 ;

[0227] R 13 and R 14each 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, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 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;

[0228] L 1 Does not exist or is NR 17 O, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0229] L 2 Not present or C=O, C=S, C=NR 19 or SO2;

[0230] L 3 Does not exist or is NR 18 O, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0231] L 4 is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C3-C6 cycloalkylene, optionally substituted C6-C 12 arylene, optionally substituted 5- to 10-membered heteroarylene, or optionally substituted 3- to 8-membered heterocyclylene;

[0232] L 5is absent or is optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, S═O, SO2 or NR 19 ;

[0233] 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, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle;

[0234] R 16 is H, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle; and

[0235] R 17 To R 19 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl;

[0236] Among them, when X 2 When N, X 3 CR 3 ;and

[0237] When L 1 does not exist and L 2 When C=O, L 3 Not for NR 18 ;

[0238] or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

[0239] X 1 Can be CR 1 .X 4 Can be CR 4 .

[0240] In one embodiment, X 5 NR 5 or CR 5 R 6 And R 5 For -L 5 -R 16.X 5 Can be NR 5 And R 5 Can be -L 5 -R 16 .

[0241] In an alternative embodiment, X 5 NR 5 or CR 5 R 6 , and R 5 and R 6 R is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl. 5 and R 6 X may be independently H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl. Alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more of halogen, OH, CN and oxo. Preferably, X 5 NR 5 . R 5 Can be H or CH3.

[0242] In some embodiments, X 1 CR 1 , X 2 CR 2 , X 3 CR 3 , X 4 CR 4 , X 5 NR 5 , and n is 1. Z can be CR 9 R 10 , and X 7 Can be S, SO, SO2, O or NR 11 Alternatively, Z may be NR 9 , and X 7 Can be CR 11 R 12 .

[0243] All features described herein (including any accompanying claims and abstract) and / or all steps of any method or process so disclosed may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0244] General process

[0245] General process 1

[0246] Compounds of formula (IVe) and (IVf) can be prepared according to compounds of formula (VIa) and (VIb) using a urea bond forming reaction as shown below.

[0247]

[0248] Typical reaction conditions for activating aromatic amines of compounds of formula (VIa) or (VIb) employ 4-nitrophenyl chloroformate or triphosgene to produce an activated intermediate which can be attacked by a suitable nucleophile such as amine (Va) to give a urea compound 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 reactants may be shaken or stirred at room temperature.

[0249] Alternatively, compounds of formula (IVe) or (IVf) can also be prepared in a suitable solvent such as THF, DMF or MeCN and preferably an organic base such as TEA or DIPEA using an isocyanate R 15 Preparation of NCO(Vb). The reactants may be shaken or stirred at room temperature.

[0250] Compounds of formula (V) and (VI) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (VI) are described in general schemes 2 to 4.

[0251] General process 2

[0252] Compounds of formula (VIa) and (VIb) can be synthesized from compounds of formula (VII) using the Curtius reaction as shown below.

[0253]

[0254] Typical reaction conditions include treatment of the compound of formula (VII) with the reagent diphenylphosphoryl azide (DPPA) and a base such as TEA to produce the corresponding acyl azide, which is further refluxed in tert-butanol to give a BOC-protected amine as an intermediate. The protecting group of the corresponding intermediate can be removed in an acidic environment to give the free amine of formula (VIa), or the corresponding intermediate can be first subjected to reaction with, for example, R using the methods described in general procedure (iv). 17 Substitution of -X with a suitable reagent followed by deprotection in an acidic environment affords the N-substituted amine of formula (VIb).

[0255] Compounds of formula (VII) are commercially available or can be synthesized by one skilled in the art. In particular, methods for synthesizing compounds of formula (VII) are described in General Schemes 3 to 4.

[0256] General process 3

[0257] The compound of formula (VII) can be synthesized from an ester of formula (VIII) wherein R is methyl, ethyl, benzyl or tert-butyl by hydrolysis reaction.

[0258]

[0259] The compound of formula (VIII) can be reacted with a suitable alkali metal or base so that it undergoes hydrolysis and provides a compound of formula (VII). The suitable alkali metal or base can be LiOH, KOH, NaOH or K2CO3, and the reaction can be carried out in aqueous solution.

[0260] General process 4

[0261] Compounds of formula (IX) can be synthesized by one skilled in the art via alkylation / acylation / sulfonylation reactions with compounds of formula (VIII), wherein X is a leaving group such as optionally substituted alkylaryl(het), alkyl, aryl(het), cycloalkyl, halogenated alkylcycloalkyl, triflate or tosylate.

[0262]

[0263] The compound of formula (VIII) can be reacted with a compound of formula (X) in the presence of a suitable base such as NaH, NaHCO3 or TEA to give a compound of formula (IX). Suitable reaction solvents include THF, DMA and DMF.

[0264] General process 5

[0265] Alternatively, compounds of formula (XI) can be prepared from compounds of formula (XIV) wherein R is methyl, ethyl, benzyl or tert-butyl in a two-step process as shown below.

[0266]

[0267] First, a compound of formula (XIV) is subjected to a nucleophilic substitution reaction with a compound of formula (XIII) to produce a compound of formula (XII), wherein R is a methyl group, an ethyl group, a benzyl group or a tert-butyl group. The nucleophilic substitution reaction can be carried out in the presence of a weak base such as DBU, NaH, TEA, DIPEA, K2CO3, Cs2CO3 or KHCO3. The solvent used can be 1,4-dioxane, acetone, MeCN, THF or DMF.

[0268] The nitro group of the compound of formula (XII) can 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 resulting amino compound typically undergoes an in situ cyclization to form a compound of formula (XI).

[0269] It will be appreciated that compounds of formula (XI) are those wherein R 5 H and X 6 The compound of formula (VIII) is C=O.

[0270] General process 6

[0271] Compounds of formula (XV) can be prepared from compounds of formula (XIX) wherein R is methyl, ethyl, benzyl or tert-butyl according to a four-step process as shown below.

[0272]

[0273] First, the compound of formula (XIX) can be brominated using Br2 or a bromine source such as NBS to obtain a compound of formula (XVIII). 9 The compound is aminated with NH2 to obtain a compound of formula (XVII). The nitro group on the compound of formula (XVII) can then be reduced using a suitable reducing agent (e.g., those described in General Scheme 5) to obtain a compound of formula (XVI). The compound of formula (XVI) can then be reacted with a suitable carbonyl source to obtain a compound of formula (XV). The carbonyl source can be 1,1-carbonyl-diimidazole, phosgene or triphosgene.

[0274] It will be appreciated that compounds of formula (XV) are those wherein R 5 H, X 6 C=O, Z is NR 9 , X 7 CR 11 R 12 and n is 1 in the formula (VIII).

[0275] General process 7

[0276] Compounds of formula (XX) can be prepared from compounds of formula (XXV) wherein R is methyl, ethyl, benzyl or tert-butyl according to a five step process as shown below.

[0277]

[0278] First, the compound of formula (XXV) can be protected by a suitable acetyl group using a reagent such as TFAA, BOC-anhydride or acetic anhydride to obtain a compound of formula (XXIV). t BuCOOK / Na in the presence of a suitable base using a suitable alkyl halide (R 9 -X) to alkylate the compound to obtain a compound of formula (XXIII). A subsequent nitration reaction of the compound of formula (XXIII) can be performed with a nitration mixture such as a mixture of nitric acid and sulfuric acid to obtain a compound of formula (XXII). The nitro group on the compound of formula (XXII) can then be reduced by Pd-catalyzed hydrogenation or by using sodium disulfide and TBASH as described in General Procedure 6b to obtain the corresponding amino derivative. The amine is further reacted with an alkyl chloroformate RO(CO)Cl in the presence of a suitable organic or inorganic base such as pyridine or K2CO3 to obtain a compound of formula (XXI). The compound can then be subjected to a cyclization process using a suitable base and solvent combination such as K2CO3 and methanol to obtain a compound of formula (XX).

[0279] It should be understood that the compound of formula (XX) is one in which R 5 H, X 6 C=O, Z is NR 9 , X 7 CH(S)R 11 and n is 1 in the formula (VIII).

[0280] General process 8

[0281] Compounds of formula (XXVI) can be prepared from compounds of formula (XXIX) wherein R is methyl, ethyl, benzyl or tert-butyl in a three step process as shown below.

[0282]

[0283] First, the compound of formula (XXIX) can be reduced using any of the methods described in general scheme 5 (e.g., Fe / Zn-AcOH / HCl) to convert the nitro group to an amino group and to obtain a compound of formula (XXVIII). The compound can then be used to form the corresponding carbamate using a suitable chloroformate in the presence of a suitable organic or inorganic base such as pyridine or K2CO3 to obtain a compound of formula (XXVII). The compound of formula (XXVII) can be reacted with a suitable amine R in the presence of an organic base such as TEA or DIPEA. 9-NH2 is converted into a cyclized compound of formula (XXVI) in a series of reactions (e.g., Schiff base formation), followed by reduction of the resulting imine with a mild reducing agent (e.g., Na(AcO)3BH, NaCNBH3, or NaBH4) in methanol. The resulting amine typically undergoes spontaneous cyclization in situ to give the compound of formula (XXVI).

[0284] It will be appreciated that compounds of formula (XXVI) are those wherein R 5 H, X 6 C=O, Z is NR 9 , X 7 For CHR 11 and n is 1 in the formula (VIII).

[0285] General process 9

[0286] Compounds of formula (XXX) can be prepared from compounds of formula (XXXI) wherein R is methyl, ethyl, benzyl or tert-butyl.

[0287]

[0288] The lactam carbonyl group of the compound of formula (XXXI) can be reduced to the corresponding methylene group of the compound of formula (XXX) using borane-THF solution in a suitable solvent such as THF, typically at low temperature.

[0289] It should be understood that compounds of formula (XXX) are those wherein X 6 The compound of formula (VIII) is CH2.

[0290] General process 10

[0291] Compounds of formula (XXXII) can be prepared from compounds of formula (XXXIII) wherein R is methyl, ethyl, benzyl or tert-butyl.

[0292]

[0293] Compounds of formula (XXXIII) can undergo cyclization using 1,2-dibromoethane in a basic reaction medium to give fused morpholine derivatives of compounds of formula (XXXII).

[0294] It should be understood that the compound of formula (XXXII) is one in which X 6 and Z is CH2 and X 7 The compound of formula (VIII) is O.

[0295] General process 11

[0296] Compounds of formula (XXXIV) can be prepared from compounds of formula (XXXIX) wherein X is halogen in a series of reactions described in the following schemes.

[0297]

[0298] The compound of formula (XXXIX) can be subjected to acylation with a suitable acylating agent in acetone or an alcohol solvent to produce a compound of formula (XXXVIII), which can be used to introduce an amine R 11 NH2 is then cyclized in situ to obtain a compound of formula (XXXVII). The compound of formula (XXXVII) can be reacted with a compound of formula (X) such as a halide, tosylate or triflate (wherein X is a suitable leaving group) in the presence of a suitable base such as NaH, NaHCO3 or TEA to obtain a compound of formula (XXXVI). Suitable reaction solvents include THF, DMA and DMF. Borane-THF solutions in suitable solvents such as THF can be used at low temperatures to reduce the lactam carbonyl of the compound of formula (XXXVI) to the corresponding methylene of the compound of formula (XXXV). NiCl2.6H2O and sodium borohydride can be used in polar solvents such as methanol to reduce the nitro group of the compound of formula (XXXV) to its corresponding amino group in the compound of formula (XXXIV).

[0299] General process 12

[0300] Compounds of formula (XL), (XLI) and (XLII) can be prepared from compounds of formula (XLV) in a series of reactions described in the following schemes.

[0301]

[0302] The compound of formula (XLV) can be reduced to the corresponding alcohol with a reducing agent such as DIBAL, and then converted into a leaving group, such as silyl ether (OTMS) with TMSOTf to obtain a compound of formula (XLIV). The leaving group can be replaced with a suitable nucleophilic agent to produce a compound of formula (XLIII). A suitable nucleophilic agent can be CN or an allyl group. Then, the compound of formula (XLIII) containing an allyl group can be subjected to hydroxylation with OsO4 to obtain a compound of formula (XL). The compound of formula (XL) can be oxidized to the corresponding aldehyde with NaIO4, and then reduced to the corresponding primary alcohol (XLI) with a suitable reducing agent such as NaBH4. The nitro reduction of the compound of formula (XLIII) can also be obtained with a suitable reducing agent such as Fe / AcOH or Zn / AcOH or Fe / NH4Cl to obtain the corresponding amine (XLII).

[0303] General process 13

[0304] Compounds of formula (XLVI) can be prepared from compounds of formula (XI) wherein R is methyl, ethyl, benzyl or tert-butyl in a one-step reaction as described in the following scheme.

[0305]

[0306] Compounds of formula (XI) can be subjected to Chan-Lam coupling reaction using a suitable boronic acid / boronic ester in the presence of a suitable catalyst and a base to give compounds of formula (XLVI).

[0307] It will be appreciated that compounds of formula (XLVI) are those wherein X 6 The compound of formula (VIII) is C=O.

[0308] General process 14

[0309] Compounds of formula (XLVIII) can be prepared from compounds of formula (XLIX) wherein R is methyl, ethyl, benzyl or tert-butyl in a one-step reaction as described in the following scheme.

[0310]

[0311] Suitable aromatic halides (R 5 -X) subjecting the compound of formula (XLIX) to a Buchwald coupling reaction to obtain a compound of formula (XLVIII).

[0312] It will be appreciated that compounds of formula (XLVIII) are those wherein X 6 CR 7 R 8 A compound of formula (VIII).

[0313] General process 15

[0314] Compounds of formula (L) can be prepared from compounds of formula (LI) in a one-step reaction as described in the following scheme, wherein R is methyl, ethyl, benzyl or tert-butyl.

[0315]

[0316] Compounds of formula (LI) may be treated with a suitable base such as LiHMDS to generate an anion at the most acidic methylene position, which may then be alkylated with a suitable electrophile such as XCH2CN to generate compounds of formula (L).

[0317] It will be appreciated that compounds of formula (L) are those wherein X 6 C=O, Z is CHR 9 and n is 1 in the formula (VIII).

[0318] General process 16

[0319] Compounds of formula (LII) can be prepared from compounds of formula (LVI) in a series of reactions described in the following schemes, wherein R is methyl, ethyl, benzyl or tert-butyl.

[0320]

[0321] First, a compound of formula (LVI) can be alkylated with a suitable alkylating agent in the presence of a suitable base in a suitable solvent such as ACN, THF or DMF to obtain a compound of formula (LV), which can undergo ester hydrolysis to produce a compound of formula (LIV). Next, the acid functional group can be converted to the corresponding amide with a suitable amine under typical amide coupling reaction conditions to obtain a compound of formula (LIII). Finally, the nitro group of the compound of formula (LIII) can be reduced to the corresponding amine in the compound of formula (LII) with a suitable reducing agent.

[0322] Library general process 1

[0323] Compounds of formula (LVII) can be prepared in parallel from compounds of formula (LX) in a series of reactions described in the following schemes using library or array technology.

[0324]

[0325] Compounds of formula (LX) can be alkylated with a suitable compound of formula (X) in which X is a leaving group in the presence of a suitable base such as NaH, CsCO, NaHCO or TEA as described in general scheme 4 (but usually carried out on a scale of 0.1-0.2 mmol) to give compounds of formula (LIX). Suitable reaction solvents include THF, DMA and DMF. The SEM protecting group of the alkylated compound of formula (LIX) can then be removed by treatment with a fluorine source such as TBAF or HF or with a suitable acid such as TFA to give a final product of formula (LVII). The progress of the reaction is monitored by LCMS and upon completion, the reaction mixture is purified by preparative HPLC. Alternatively, the order of the reactions can be reversed, wherein the SEM group can first be removed from the compound of formula (LX) to give an indole derivative of formula (LVIII), followed by an alkylation reaction to give product (LVII).

[0326] Library general process 2

[0327] Compounds of formula (LX) can be prepared in parallel from compounds of formula (LXII) in a series of reactions described in the following schemes using library or array technology.

[0328]

[0329] The compound of formula (LXII) can be reduced using a suitable reducing agent such as Fe / AcOH, Zn / AcOH, Zn / HCl, Zn / NH4Cl, Zn / HCOONH4, SnCl2 / HCl or by hydrogenation in the presence of a suitable catalyst such as Pd / C, PtO2 or any Rh or Ru based catalyst system in a suitable solvent such as EtOH, MeOH or THF to give the amine of formula (LXI). The compound of formula (LXI) can then be reacted with any suitable amine (Va) as described in general scheme 1 to give the urea compound of formula (LX). Preferred organic bases for this reaction include DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN, wherein amine activation is typically performed using 4-nitrophenyl chloroformate or triphosgene on a 0.1-0.2 mmol scale. The reactants can be shaken or stirred at room temperature. The progress of the reaction is monitored by LCMS and upon completion, the reaction mixture is purified by preparative HPLC.

[0330] General synthesis procedure

[0331] General Purification and Analysis Methods

[0332] All final compounds were purified by Combi-flash or preparative HPLC purification and analyzed for purity and product identity by UPLC or LCMS according to one of the following conditions.

[0333] Preparative HPLC

[0334] Preparative HPLC was performed on a Waters automated purification instrument using a Gemini C18 column (250 x 21.2 mm, 10 μm) operating at a flow rate of 16.0-25.0 mL / min at ambient temperature.

[0335] Mobile phase 1: A = 0.1% formic acid / water, B = acetonitrile; Gradient profile: the initial composition of the mobile phase is 80% A and 20% B, then after 3 min it becomes 60% A and 40% B, then after 20 min it becomes 30% A and 70% B, then after 21 min it becomes 5% A and 95% B, maintains at this composition for 1 min for column washing, then returns to the initial composition and maintains for 3 min.

[0336] Mobile phase 2: A = 10 mM ammonium acetate in water, B = acetonitrile; Gradient profile: initial composition of mobile phase was 90% A and 10% B, then changed to 70% A and 30% B after 2 min, then changed to 20% A and 80% B after 20 min, then changed to 5% A and 95% B after 21 min, kept at this composition for 1 min for column washing, then returned to the initial composition and kept for 3 min.

[0337] LCMS method

[0338] General 5 min method: Gemini C18 column (50×4.6 mm, 5 μm) was run at ambient temperature and a flow rate of 1.2 mL / min. Mobile phase: A=10 mM ammonium acetate in water, B=acetonitrile; Gradient profile: from 90% A and 10% B to 70% A and 30 B in 1.5 min, and then to 10% A and 90% B in 3.0 min, kept at this composition for 1.0 min, and finally returned to the initial composition for 2.0 min.

[0339] UPLC Method

[0340] UPLC was performed on a Waters UPLC using a Kinetex EVo C18 column (100 x 2.1 mm, 1.7 μm) at ambient temperature and a flow rate of 1.5 ml / min.

[0341] Mobile phase 1: A = 5 mM ammonium acetate in water, B = 5 mM ammonium acetate in 90:10 acetonitrile / water; gradient profile: from 95% A and 5% B to 65% A and 35% B in 2 min, then to 10% A and 90% B in 3.0 min, hold at this composition for 2.0 min, and finally return to the initial composition for 6.0 min.

[0342] Mobile phase 2: A = 0.05% formic acid / water, B = acetonitrile; gradient profile: 95% A and 5% B for 1 min, then 90% A and 10% B for 1 min, then 2% A and 98% B for 4 min, and then back to the initial composition for 6 min.

[0343] General Procedure 1 (Method a)

[0344]

[0345] To a stirred solution of an aromatic amine of formula (VIa) (1.0 eq.) in a suitable solvent (8 mL / mmol) such as THF, DMF, MeCN or DCM is added p-nitrophenyl chloroformate (1.2 eq.) at 0-5°C and the whole reaction is stirred at RT for 1-3 h. Then, amine R is added dropwise at 0-5°C.15 -NH-R 18 (Va) (1.1 eq.) and TEA or DIPEA (6 eq.), and the whole reactant is further stirred at RT for 1-5 h. The progress of the reaction is monitored by TLC / LCMS, and upon completion, the reaction is diluted with water and extracted with EtOAc. The combined organic layers are washed with a dilute solution of a suitable inorganic base (e.g., NaHCO3) or 1N NaOH, followed by 1N HCl, and finally with brine. The organic layer is dried over anhydrous Na2SO4 and evaporated in vacuo to give a residue, which is purified by column chromatography or combi-flash or preparative HPLC to give a compound of formula (IVe) as a solid (yield 6-70%). A similar procedure can be followed to synthesize all ureas of formula (IVe).

[0346] General Procedure 1 (Method b)

[0347]

[0348] To a stirred solution of an aromatic amine of formula (VIa) (1.0 eq.) in a suitable solvent such as THF, DMF, MeCN or DCM (5.5 mL / mmol) was added R 15 NCO (Vb) (1.08 eq.), followed by TEA (1.08 eq.), and all reactants were stirred at the same temperature for 5-10 h. The reaction mixture was slowly allowed to reach RT and stirred for 1-2 h. The reaction progress 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 preparative HPLC to give a solid compound of formula (IVe) (yield 10-70%). A similar procedure can be followed to synthesize ureas of all formulas (IVe).

[0349] General Procedure 1 (Method c)

[0350]

[0351] Triphosgene (0.5 eq) was added to a stirred solution of compound (Va) (68 mg, 0.519 mmol) in THF (10 mL / mmol) at 0-5 °C. The combined mixture was stirred for 1 h at RT. The first stage of the reaction was confirmed to be complete by TLC or UPLC-MS, after which aromatic amine compound (VIa) (0.9 mmol) and TEA (2.5 eq) were added to the reaction mixture and stirred for 1-2 h at RT. The progress of the reaction was monitored by TLC and / or UPLC-MS. After the reaction was completed, the solvent was evaporated in vacuo to obtain a crude material, which was purified by column chromatography or preparative HPLC to obtain a solid compound (yield 12-50%) of formula (IVe).

[0352] General Program 2

[0353]

[0354] To a stirred solution of the compound of formula (VII) (1.0 equiv) in a suitable solvent (3.5 mL / mmol) such as MeCN, THF or DCM is added TEA (1.5 equiv) at 0-5 ° C under an inert atmosphere, followed by DPPA (2.0 equiv) and all reactants are stirred at the same temperature for 5-10 min. The reaction mixture is then allowed to reach RT and stirred for 4-6 h. The formation of the corresponding acyl azide is confirmed by TLC and UPLC-MS by quenching an aliquot of the reaction mixture with methanol. The solvent is evaporated in vacuo, and tert-butyl alcohol (3.5 mL / mmol) is added to the resulting residue. The mixture is then refluxed overnight. The completion of the reaction is monitored by TLC and LC-MS, which show the formation of a BOC-protected amine compound of formula (VIa) and complete consumption of the starting material compound of formula (VII). After completion of the reaction, the solvent was evaporated in vacuo to obtain a crude oil which was adsorbed on silica gel and purified by Combi flash to afford the intermediate, BOC protected amine compound of formula (VIa) as an off-white solid (yield 40-80%).

[0355] The obtained compound was dissolved in 1,4-dioxane (5.5 mL / mmol), and a solution of 4M HCl in 1,4-dioxane (5.5 mL / mmol) was added at 0-5 °C, and all the reactants were stirred for 5-10 min. The reaction mixture was then slowly warmed to room temperature overnight. The reaction was confirmed to be complete by UPLC-MS, and the solvent was evaporated in vacuo after completion. Then, the obtained crude material was washed with NaHCO3 solution and extracted with EtOAc. The organic matter was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a compound of formula (VIa) as a dark yellow solid (yield 50-90%).

[0356] General Program 3

[0357]

[0358] To a stirred solution of ester (VIII) (1.0 eq.) in a mixture of MeOH or THF (6.5 mL / mmol) and water (0.8 mL / mmol) is added LiOH, NaOH or KOH (2.0 eq.) at RT, and the resulting reaction mixture is stirred for 2-16 h at RT. TLC shows that ester (VIII) is completely consumed. The solvent is evaporated in vacuo, and the resulting residue is washed with ether. The residue is then acidified to pH 5-6 with 1N HCl, so that a precipitate is formed, which is filtered and washed with water, then dried by azeotropic distillation or dried under reduced pressure at 50-60° C. to give the desired formic acid of formula (VII) as a solid (yield 70-85%).

[0359] General Program 4

[0360]

[0361] Option A

[0362] K2CO3, Cs2CO3, Na2CO3, NaOH or NaH (1.1 equivalents) are added to a stirred solution of the compound of formula (VIII) (1.0 equivalents) in DMF or THF (4mL / mmol). In the case of using NaOH, TBAB (0.1 equivalents) is also added as a phase transfer catalyst, followed by addition of the compound of formula (X) (1.05 equivalents), and the mixture is stirred at RT for 0.5-1h. The reaction is monitored by TLC. After the reaction is completed, the reaction mixture is quenched with a saturated solution of NH4Cl, diluted with ice-cold water and extracted with EtOAc or MTBE. The organic layer is washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to obtain a crude product, which is purified by Combi-flash using a mixture of EtOAc / hexanes as an eluent to obtain a compound of formula (IX) (yield 60-80%) as a colorless oil.

[0363] Option B

[0364] Alternatively, TEA or DIPEA (2.0 equivalents) or no alkali is added to a stirred solution of compound (VIII) (1.0 equivalents) in DCM or MeCN or THF (4 mL / mmol), followed by addition of compound (X) (1.5 equivalents), and all reactants are stirred at RT for 0.5 to 1 h. The reaction progress is monitored by TLC. After the reaction is complete, the mixture is diluted with water, extracted with EtOAc, and the combined organic layers are washed with brine and dried over anhydrous Na2SO4. The organic layer is evaporated in vacuo to obtain a crude product, which is purified by Combi-flash using a mixture of EtOAc / hexanes as an eluent to give a compound (IX) (yield 60-80%) as a colorless oil.

[0365] General Program 5

[0366]

[0367] Under ice-bath cooling, to a stirred solution of a compound of formula (XIV) (1.0 equivalent) and a suitable nucleophile (XIII) (1.25 equivalents) in a suitable solvent (3 mL / mmol) such as 1,4-dioxane, MeCN, DMF or THF, a suitable base (1.5 equivalents) such as TEA, DBU, NaH or KCO is added dropwise or in batches, and the combined mixture is stirred at 0-25 ° C for 1-16 h. The progress of the reaction is monitored by TLC or LCMS, and when the reaction is complete, the mixture is quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness in vacuo. The resulting crude compound of formula (XII) (yield 60-95%) as a solid is sufficiently pure to be used directly in the next step without any further purification.

[0368] General Program 6

[0369]

[0370] Option A (reduction by Fe / Zn-AcOH / HCl / NH4Cl)

[0371] To a stirred solution of the compound of formula (XII) (1.0 equivalent) in EtOH or MeOH (2mL / mmol) at RT, a suitable acid (3mL / mmol) such as AcOH or HCl aqueous solution is added, followed by addition of iron powder or zinc powder (4.0 equivalents). In some cases, NH4Cl is also used as a hydrogen source. The reaction mixture is stirred at 75-85°C for 1-5h. The reaction is monitored by TLC or LCMS, and after completion, the reaction mixture is poured into ice-cold water and filtered through a short diatomaceous earth bed. The filtrate is extracted with EtOAc, and then washed with NaHCO3 aqueous solution and then with brine. The collected organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to give a compound of formula (XI) (yield 60-80%) as a crude solid, which is used in the next step without any further purification.

[0372] Option B: (reduced by sodium disulfide)

[0373] To a stirred solution of the compound of formula (XII) (1.0 eq.) in a mixture of MeCN / H2O or THF / H2O (12 mL / mmol, 2:1) was added sodium bisulfite (8.0 eq.), tetrabutylammonium hydrogen sulfate (0.5 eq.) and K2CO3 (6.0 eq.) at RT, 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 vacuo 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. Filtration and evaporation of the organics in vacuo gave the compound of formula (XI) as a solid (yield 80-90%).

[0374] Option C: (reduction by Pd / C / H2)

[0375] To a stirred solution of the compound of formula (XII) (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 an inert atmosphere. The reaction mixture was purged with H2 gas using balloon pressure and then further stirred for 3-5 h at room temperature. 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 diatomaceous earth bed, and washed 4-5 times with EtOAc until the mother liquor showed no remaining compound by TLC. The collected organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the compound of formula (XI) as a semisolid (yield 80-85%). The product was pure enough to be used in the next step without any further purification.

[0376] Option D: (reduced by NiCl2.6H2O / NaBH4)

[0377]

[0378] To a stirred solution of the compound of formula (XXXV) (1.0 eq., 0.53 mmol) in MeOH (9 mL / mmol) was added Boc2O (1.5 eq.) followed by NiCl2.6H2O (0.5 eq.) and NaBH4 (2.5 eq.) at 5-10°C. The combined mixture was then allowed to warm to RT over 3-5 h. The progress of the reaction was monitored by TLC and UPLC-MS, which showed the formation of an intermediate product. Upon completion, the reaction mixture was diluted with cooling 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 the crude product, which was purified by Combi-flash to give the Boc-protected amine compound (yield 90-96%, 0.51 mmol). The material was dissolved in DCM (9 mL / mmol) and TFA (4 mL / mmol) and the entire reaction was stirred at RT for 4-6 h. UPLC-MS showed the formation of the desired product. The solvent was evaporated in vacuo to give the crude product, which was neutralized with aqueous sodium carbonate solution and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the compound of formula (XXXIV) as a semi-solid (yield 80-85%).

[0379] General Program 7

[0380]

[0381] To a stirred solution of the compound of formula (XIX) (1.0 eq.) in a suitable solvent (100 mL) such as carbon tetrachloride or trifluoromethylbenzene is added NBS (1.2 eq.) and AIBN or benzoyl peroxide (0.1 eq.). The reaction mixture is heated at 70-100° C. for 12-16 h. After complete consumption of the starting material, the reaction mixture is quenched with a saturated solution of Na2S2O3 and extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous Na2SO4. The crude product obtained after vacuum concentration of the organic layer is purified by column chromatography to give the compound of formula (XVIII) in 30-40% yield.

[0382] General Program 8

[0383]

[0384] To a stirred solution of the compound of formula (XVIII) (1.0 equiv.) in a suitable solvent such as THF (5 mL / mmol) is added a suitable amine such as MeNH2 (3 mL / mmol, 2M solution in THF) at RT, and the combined mixture is stirred at the same temperature or at an elevated temperature (60-90°C) for 10-16 h. After completion of the reaction, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with saturated brine solution, dried over anhydrous Na2SO4 and concentrated in vacuo to give the compound of formula (XVII) as a gummy solid (yield 60-70%).

[0385] General Program 9

[0386]

[0387] To a stirred solution of the compound of formula (XVI) (1.0 eq.) in a suitable solvent (5 mL / mmol) such as DCM or THF, a suitable carbonyl source (e.g., 1,1-carbonyl-diimidazole, phosgene or triphosgene) (1.1 eq.) with a suitable leaving group is added at 0-5° C., followed by a suitable base (3.0 eq.) such as TEA or DIPEA, and the reaction mixture is stirred at room temperature under an inert atmosphere for 2-4 h. The reaction mixture is quenched by addition of saturated aqueous NaHCO and extracted with DCM. The combined organic layers are dried over anhydrous NaSO, filtered and concentrated in vacuo to give a crude residue which is purified by silica gel column chromatography and eluted with 1% MeOH / DCM to give the compound of formula (XV) as a solid (yield 20-30%).

[0388] General Program 10

[0389]

[0390] TFAA (2.0 equivalents) was added dropwise to a stirred solution of the compound of formula (XXV) (1.0 equivalents) in toluene (1.8 mL / mmol) at 10-15 ° C over 20-30 min, and the resulting reaction mixture was stirred at 25-30 ° C for 1-5 h. The reaction progress was monitored by UPLC-MS. After completion, the reaction mixture was poured into crushed ice and extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaHCO3, brine and then dried over anhydrous Na2SO4. The organic matter was filtered and evaporated under reduced pressure to obtain a solid compound of formula (XXIV) (yield 85-90%). The product was pure enough to be used in the next step without any further purification.

[0391] General Program 11

[0392]

[0393] To a stirred solution of NaH (1.2 eq., 60% suspension in oil) in DMF (1.65 mL / mmol) was added the compound of formula (XXIV) (1.0 eq.) and an alkyl or aryl halide (R) dropwise over 20-30 min at 10-15 °C using a dropping funnel. 9 -X) (2.0 equiv.) in DMF (1.1 mL / mmol), and then stirred the resulting reaction mixture at 20-25 ° C for 2 h. The reaction was confirmed to be complete by UPLC-MS. The reaction mixture was poured into an ice-water mixture and extracted with EtOAc. The combined organics were washed with 1N HCl, NaHCO3 saturated solution and then with brine. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a solid compound of formula (XXIII) (yield 90-95%). The product was pure enough to be used in the next step without any further purification.

[0394] General Program 12

[0395]

[0396] Formula (XXIII) compound (1.0 equivalent) is added in batches to the nitrated mixture of pre-prepared concentrated sulfuric acid (2.17mL / mmol) and fuming nitric acid (0.73mL / mmol), while the internal temperature is maintained between 0-5°C in a time period of 30min. The obtained mixture is stirred at 20-25°C for 1-2h. The reaction is confirmed to be complete by UPLC-MS, and after consuming the starting material, the reaction mixture is poured into an ice-water mixture and extracted with EtOAc. The organic matter combined is washed with NaHCO3 saturated solution, then washed with saturated brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain formula (XXII) compound (yield 85-95%) in a thick oil. The product is pure enough to be used in the next step without any further purification.

[0397] General Program 13

[0398]

[0399] Option A

[0400] To a stirred solution of the compound of formula (XXII) (1.0 eq.) in 1,4-dioxane (3.34 mL / mmol, degassed with nitrogen) was added 10% Pd-C (0.167 g / mmol, 50% w / w in water) under an inert atmosphere, and the resulting reaction mixture was stirred overnight at RT under a balloon pressure of H2 gas. The progress of the reaction was monitored by TLC and UPLC-MS, which showed that the nitro group was completely converted to its corresponding amino group. The balloon was removed, and solid K2CO3 (1.66 eq.) was added to the reaction vessel at RT, followed by dropwise addition of ethyl chloroformate (1.34 eq.). The resulting reaction mixture was further stirred overnight. UPLC-MS showed that the reaction was complete; the reaction mixture was filtered through a bed of celite, and the bed was washed with DCM. The filtrate was evaporated in vacuo to give the crude product, which was dissolved in EtOAc, washed with water followed by brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product as a thick oil, which was purified by trituration with n-hexane and dried to give the compound of formula (XXI) as a solid (yield 80-85%).

[0401] Option B

[0402] To a stirred solution of the compound of formula (XXII) (1.0 eq.) in THF (6.68 mL / mmol) was added a solution of KCO (6.0 eq.) in water (3 mL / mmol) at 10-15°C, followed by sodium dithiosulfinate (8.0 eq.), TBASH (0.5 eq.) and water (0.4 mL / mmol) in portions. The resulting reaction mixture was stirred at RT (20-25°C) for an additional 2-3 h. The reaction was monitored by UPLC-MS, and upon completion, the reaction mixture was left to settle, allowing separation of the organic and aqueous layers. The aqueous layer was then extracted with THF. The combined organic layers were dried over anhydrous Na2SO4 and then pyridine (0.8 mL / mmol was added. The mixture was then evaporated under reduced pressure at about 40°C to give the crude product, which was dissolved in DCM (6.7 mL / mmol) and another portion of pyridine (0.8 mL / mmol) was added at 10-15°C followed by dropwise addition of ethyl chloroformate (5.0 eq). The resulting reaction mixture was further stirred at RT for 2-3 h. UPLC-MS showed the reaction was complete. The reaction mixture was diluted with water and allowed to settle to allow separation of the layers. The aqueous layer was washed with DCM and the combined organics were washed with 0.5 N HCl, a saturated solution of NaHCO3 and finally brine. The obtained organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product as a slightly yellow thick oil. The oil was purified by trituration with hexanes to give the compound of formula (XXI) as a solid (yield 85-90%).

[0403] General Program 14

[0404]

[0405] K2CO3 (2.0 equiv) was added to a stirred solution of the compound of formula (XXI) (1.0 equiv) in methanol (3.8 mL / mmol) at RT, and the resulting reaction mixture was heated to 60-65 ° C for 2-3 h. The reaction progress was monitored by UPLC-MS, and after completion, the reaction mass was cooled to 5-10 ° C and acidified to pH about 3-4 with 2N HCl. The solvent was evaporated under reduced pressure at 40-45 ° C to obtain a crude product, which was dissolved in EtOAc, washed with saturated brine solution, 2N HCl, NaHCO3 solution, and finally washed with brine again, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude compound as a light brown solid. The compound was purified by wet grinding with n-hexane to obtain a solid compound of formula (XX) (yield 80-85%).

[0406] General Program 15

[0407]

[0408] To a stirred solution of the compound of formula (XXVIII) (1.0 eq.) in DCE (1.8 mL / mmol) was added pyridine (2.2 eq.) and alkyl(aryl)chloroformate (1.2 eq.) at 0-5°C, and the mixture was stirred for 1-2 h at RT. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was quenched with 1N HCl solution and extracted with DCM, followed by washing with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford the compound of formula (XXVII) as a solid (yield 70-75%), which was used in the next step without any further purification.

[0409] General Program 16

[0410]

[0411] At RT under inert atmosphere to amine R 9-NH2.HCl (1.0 equivalent) was added to a stirred solution in MeOH (5 mL / mmol) with TEA (1.2 equivalents), and all reactants were stirred for 30 min. Then, compound (XXVII) (1.0 equivalent) was added, and stirring was continued for 20-24 h. During this period, the solution became a suspension. NaBH4 (1.5 equivalents) was added, and the reaction mixture was further stirred for 20-24 h. The completion of the reaction was monitored by TLC and LC-MS, and after completion, the reaction mixture was diluted with water and extracted with EtOAc, and then washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a solid compound of formula (XXVI).

[0412] General Program 17

[0413]

[0414] The stirred solution of compound of formula (XXXI) (1.0 equivalent, 0.96mmol) in THF (5mL / mmol) was cooled to 0-5°C, and borane-THF complex (1M solution in THF) (10mL / mmol, 10 equivalents) was added portionwise. After completion of the addition, the mixture was warmed to RT, and then heated to reflux for 1-2h. The reaction progress was monitored by UPLC-MS, which showed the formation of compound of formula (XXX). After completion, the reaction mixture was diluted with methanol and refluxed for 5-10min, the solvent was evaporated to obtain a crude material, which was purified by Combi-flash or column chromatography to obtain a compound of formula (XXX) as a colorless oil.

[0415] General Program 18

[0416]

[0417] To a stirred solution of the compound of formula (XXXIII) (1.0 eq.) in DMF or THF (1.6 mL / mmol) was added KCO, CsCO, NaCO, NaOH or NaH (4.0 eq.) and then 1,2-dibromoethane (4.0 eq.) at RT and the reaction mass was maintained at 80-85°C for 10-16 h. The progress of the reaction was monitored by TLC and UPLC-MS which showed 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 NaSO and evaporated in vacuo to give the crude material which was purified by Combi-flash to give the compound of formula (XXXII) as a solid (yield 50-55%).

[0418] General Program 19

[0419]

[0420] To a stirred solution of the compound of formula (XXXIX) (1.0 eq.) in acetone (3.2 mL / mmol) was added the appropriate haloacetyl halide (1.3 eq.) at RT and the combined mixture was stirred at RT for 1-2 h. The progress of the reaction was monitored by TLC and UPLC-MS, and upon completion, the reaction mixture was quenched with ice-cold water to give a solid precipitate, which was filtered, washed with water and then dried in a vacuum oven to give the compound of formula (XXXVIII) as a light brown solid (yield 85-90%).

[0421] General Program 20

[0422]

[0423] To a stirred solution of the compound of formula (XLV) (1.0 eq.) in DCM (10 mL / mmol) was added DIBAL-H (1.5 eq.) at -78 °C under nitrogen atmosphere. The entire reaction was stirred at the same temperature for 1-2 h, and then pyridine (3.5 eq.) and TMSOTf (3.0 eq.) were added to the reaction mixture. The temperature of the reactants was then slowly raised to 0-5 °C. The progress of the reaction was monitored by TLC, and after the reaction was complete, Et2O (285 mL / mmol) was added and the mixture was filtered. The collected organic layer was then concentrated in vacuo to give the compound of formula (XLIV) as a crude solid.

[0424] General Program 21

[0425]

[0426] To a stirred solution of the compound of formula (XLIV) (1.0 eq.) in DCM (10 mL / mmol) was added allyl-TMS (4.0 eq.) and BF3.Et2O (4.0 eq.) at -78°C under nitrogen. The temperature was then slowly raised to 0-5°C. The progress of the reaction was checked by UPLC-MS, and after completion of the reaction, it was quenched with water and extracted with EtOAc. The combined organic layers were collected, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give the title compound of formula (XLIII) as a pure solid (yield 70-75%).

[0427] General Program 22

[0428]

[0429] To the compound of formula (XLIII) (1.0 equivalent) t OsO4 (0.09 eq.) and NMO (1.4 eq.) were added to a stirred solution in BuOH / H2O solution (12 mL / mmol, 1:1). The resulting reaction mixture was stirred at RT for 10-12 h. The progress of the reaction was checked by LCMS, and after completion of the reaction, it was further diluted with EtOAc. The organic layer was separated and washed with 10% HCl, water, and finally with brine. It was then dried and concentrated in vacuo to give the compound of formula (XL) as a crude solid.

[0430] General Procedure 23

[0431]

[0432] At RT, the compound of formula (XL) (1.0 equivalent) was added to t NaIO4(4.0 equivalents) was added in the stirred solution in BuOH / HO solution (12mL / mmol, 1:1). The obtained reaction mixture was stirred for 10-12h at RT. The reaction process was checked by LCMS, and after the reaction was completed, it was diluted with water and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to obtain the crude corresponding aldehyde, which was dissolved in methanol (12mL / mmol) and NaBH4(2.0 equivalents) was added at 0-5°C. The reaction mixture was further stirred for 1-2h at RT. After the reaction was completed, it was quenched with NH4Cl solution and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to obtain the formula (XLI) compound as a crude solid.

[0433] General Program 24

[0434]

[0435] To a stirred solution of the compound of formula (XI) (1.0 equiv.) in EDC (1.1 mL / mmol) was added a mixture containing R at RT. 5 -B(OH)2 / borate (1.5 eq) in EDC or toluene (1.1 mL / mmol), DBU (2.0 eq) and Cu(OAc) solution (2.0 eq). The resulting reaction mixture was stirred at RT 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 vacuo to give a crude material which was purified by Combi-flash to give the compound of formula (XLVI) as a solid (yield 34-40%).

[0436] General Program 25

[0437]

[0438] To a stirred solution of the compound of formula (XLIX) (1.0 eq.) in toluene or dioxane or EDC (6 mL / mmol) was added R 5 -X (wherein X is a suitable leaving group) (1.5 eq.), cesium carbonate (2.0 eq.) and BINAP (0.2 eq.). The whole reactants were 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 upon completion, the reaction mixture was concentrated in vacuo to give a crude material, which was purified by column chromatography to give the compound of formula (XLVIII) as a solid (yield 30-35%).

[0439] General Procedure 26

[0440]

[0441] To a stirred solution of the compound of formula (LI) (1.0 eq) in anhydrous Et2O or THF (6 mL / mmol) was added LiHMDS (1.5 eq) at -78°C under inert atmosphere and stirred for 5-10 min. 9 -X (e.g. bromoacetonitrile) (1.2 equivalents) is added to the reaction mixture, and stirring is continued for 30 min at the same temperature. Thereafter, the reaction mixture is slowly brought to room temperature and stirred for 1-2 h. The reaction progress is monitored by UPLC-MS, and after the reaction is completed, it is quenched with NH4Cl saturated solution and extracted with EtOAc. The combined organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product, which is purified by combi-flash to obtain a solid formula (L) compound (yield 45-50%).

[0442] General Program 27

[0443]

[0444] To a stirred solution of the compound of formula (LIV) (1.0 eq.) in DMF (5.5 mL / mmol) is added an amide coupling agent such as EDC-HCl (1.5 eq.) and DIPEA (3.0 eq.) at 0-5°C and the reaction mixture is stirred at this temperature for 5-10 min. R-NH2 (5.0 eq.) is then added and the reaction mixture is stirred at RT for 10-16 h. After completion of the reaction (monitored by TLC), the solvent is evaporated under reduced pressure to give a residue, which is extracted with EtOAc and the combined organic layers are dried over anhydrous Na2SO4, filtered under reduced pressure and evaporated to give a crude product. This crude material is purified by column chromatography to give the compound of formula (LIII) as a solid (yield 70-75%).

[0445] Library General Program 28

[0446]

[0447] To a stirred solution of the compound of formula (LX) (1.0 eq.) in an appropriate amount of DMF was added cesium carbonate (2.0 eq.) at room temperature under nitrogen atmosphere, followed by the addition of XL 5 -L 6 -R 16 (X) (1.5 equivalents). The reaction mixture was then stirred at RT for 15-20 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mass was diluted with diethyl ether and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give a solid compound of formula (LIX), which was used in the next step without any further purification.

[0448] Library General Program 29

[0449]

[0450] To a stirred solution of the compound of formula (LIX) (1.0 equivalent) in a suitable amount of THF is added ethylenediamine (6.0 equivalent) at 0-5 ° C. Thereafter, TBAF (12.0 equivalent) is added dropwise at the same temperature. The resulting reaction mixture is stirred at 70-75 ° C for 48-72 h. The reaction progress is monitored by LC-MS. After the reaction is complete, the reaction mass is diluted with water and extracted with EtOAc. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product, which is purified by column chromatography or preparative HPLC to obtain a solid compound of formula (LVII).

[0451] Examples

[0452] Nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given relative to tetramethylsilane ( 1 H-NMR) parts per million at low field and relative to trichlorofluoromethane ( 19 F NMR) parts per million upfield are given: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations are used for common solvents: CDCl3, deuterated chloroform; d6-DMSO, deuterated dimethyl sulfoxide; and CD3OD, deuterated methanol.

[0453] Mass spectra, MS (m / z), were recorded using electrospray ionization (ESI). Where appropriate and unless otherwise stated, m / z data provided are for isotopes 19 F. 35 Cl, 79 Br and 127 I's.

[0454] All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. Unless otherwise noted, all reactions were carried out under a nitrogen atmosphere.

[0455] Flash column chromatography was performed in a Combi-Flash platform using pre-packed silica gel cartridges. Preparative HPLC purifications were 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 determined by LCMS or UPLC analytical methods described above in the general purification and analytical methods.

[0456] Example 1: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indole Indole-6-yl ) Urea

[0457]

[0458] Example 1 was prepared according to the methods described in General Procedures 1 to 6 and the methods described below.

[0459] Preparation 1: 3-Oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid methyl ester

[0460]

[0461] Step 1: Methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate

[0462]

[0463] Methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) was dissolved 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 hydrothioacetate (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 NH4Cl saturated solution and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated 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 any further purification. LCMS m / z: 300.06 [M+H].

[0464] Step 2: 3-oxo-3,4-dihydro-2 H -Benzo[b-1,4]thiazine-6-carboxylic acid methyl ester

[0465]

[0466] To a stirred solution of methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (step 1) (5.0 g, 16.7 mmol) in acetic acid (50 mL) was added iron powder (3.73 g, 66.8 mmol). The resulting reaction mixture was stirred at 80 °C for 3 h. Upon completion (monitored by TLC), the reactants were cooled to room temperature and poured onto 1 N HCl (250 mL) and then stirred for 1 h. The resulting white precipitate was filtered off and washed with water. The obtained residue was redissolved in 5% MeOH / DCM (50 mL) and filtered through a celite bed. 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].

[0467] Preparation 2: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester

[0468]

[0469] To a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid methyl ester (Preparation 1, Step 2) (5.0 g, 22.2 mmol) in DMF (50 mL) was added NaH (0.98 g, 24.4 mmol) in portions at 0-5 ° C., and the entire reactant was stirred for another 5-10 min at the same temperature. Then, bromotoluene (2.8 mL, 23.3 mmol) was added, and the reaction mixture was stirred for 1 h. The 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 light yellow solid, which was used in the next step without any further purification. LCMS m / z: 314.16 [M+H].

[0470] Preparation 3: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0471]

[0472] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 2) (9.0 g, 28.8 mmol) in a mixture of solvents THF / MeOH / HO (160 mL, 2:1:1) was added LiOH.HO (4.8 g, 115.2 mmol) at RT, and the combined mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC and LC-MS, which showed complete consumption of the starting material. The solvent was evaporated in vacuo, and the resulting residue was diluted with water and washed with EtOAc. The aqueous layer was collected and acidified to pH 5-6 with 1N HCl to obtain a precipitate, which was filtered, collected, and dried by azeotropic distillation with MeCN to give the title compound (5.0 g) as a crude white solid. LCMS m / z: 300.13 [M+H].

[0473] Preparation 4: tert-Butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate ester

[0474]

[0475] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 3) (4.5 g, 14.4 mmol) in DCM (50 mL) was added TEA (3 mL, 21.6 mmol) followed by DPPA (6.3 mL, 28.8 mmol) at 0-5°C under inert atmosphere, and stirring was then continued for 5 min at the same temperature. The reaction mixture was allowed to slowly reach room temperature and stirred for 4 h. The formation of the corresponding acyl azide was confirmed by TLC and UPLC-MS by quenching an aliquot of the reaction mixture in methanol. The solvent was evaporated, tert-butyl alcohol (50 mL) was added to the reaction mixture, and the entire reactant was refluxed overnight. The completion of the reaction was monitored by TLC and LC-MS, which showed the formation of the desired product and complete consumption of the starting material. The solvent was evaporated in vacuo to give a crude oil which was adsorbed onto silica gel and purified by combi flash to give the title compound as an off-white solid (4.2 g, 80% yield). LCMS m / z: 317.15 [M+H].

[0476] Preparation 5: 6-amino-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one

[0477]

[0478] To a stirred solution of tert-butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (Preparation 4) (1.0 g, 2.7 mmol) in 1,4-dioxane (15 mL) was added HCl (15 mL, 4M HCl in 1,4-dioxane) at 0-5°C, and the combined mixture was stirred for 5 min. The reaction mixture was then stirred at room temperature overnight. UPLC showed that the starting material was consumed. The solvent was evaporated in vacuo. The resulting crude residue was then washed with NaHCO3 solution and extracted with EtOAc. It was then evaporated in vacuo to give the title compound (750 mg, 90.5% yield) as a dark yellow solid. LCMS m / z: 271.23 [M+H].

[0479] Preparation 6: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indole Indole-6-yl)urea (Example 1)

[0480]

[0481] To a stirred solution of 6-amino-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 5) (0.650 g, 2.39 mmol) in THF (15 mL) was added p-nitrophenyl chloroformate (0.580 g, 2.87 mmol) at 0-5°C and the combined mixture was stirred for 5 min and then allowed to slowly warm to room temperature over 1 h, at which time carbamate formation was confirmed by TLC. 6-aminoindole (0.349 g, 2.64 mmol) was added at 0-5°C, followed by TEA (1 mL, 7 mmol), and the reaction mixture was stirred for another 1 h at room temperature. Urea formation was detected by UPLC-MS and TLC, and upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with 1N NaOH solution, followed by brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound as a white solid (270 mg, 27% yield). UPLC purity: 99.32%; 1 H NMR (400MHz; DMSO-d6): δ3.64(s,2H),5.18(s,2H),6.32(s,1H),6.80(d,J=8.32Hz, 1H),7.18-7.40(m,10H),7.75(s,1H),8.57(s,1H),8.67(s,1H),10.92(s,1H); LCMS m / z: 429.35[M+H].

[0482] Example 69: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indole Indole-6-yl ) Urea

[0483]

[0484] Example 69 was prepared according to General Procedures 1 to 6 and the methods described below.

[0485] Preparation 44: 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0486]

[0487] Step 1: Methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate

[0488]

[0489] To a stirred solution of NaH (1.5 g, 37.6 mmol, 60% suspension in mineral oil) in 1,4-dioxane (50 mL) was added commercially available methyl 2-hydroxyacetate (3.39 g, 37.6 mmol) at 5-10 °C, and the combined mixture was stirred for 30 min. 1,4-dioxane (25 mL) containing methyl 3-fluoro-4-nitrobenzoate (5.0 g, 25.11 mmol) was added, and the whole reaction was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and UPLC-MS, and upon completion, the reaction mixture was diluted with ice-cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried in a vacuum oven at 60 °C for 2.5 h to give the title compound (5.0 g) as a pale yellow crude solid. UPLC-MS m / z: 269.98 [M+H].

[0490] Step 2: 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0491]

[0492] To a stirred solution of methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate (Preparation 44, Step 1) (5.0 g, 18.57 mmol) in AcOH (25 mL) was added iron powder (4.15 g, 74.304 mmol) at RT. The resulting reaction mixture was stirred at 90 °C for 2 h. TLC and UPLC-MS showed the formation of the desired compound, and after completion of the reaction, the reaction mixture was quenched by pouring into ice-cold water (500 mL) and stirring for 30 min. The precipitated solid was filtered and washed with water several times. The washed solid material was then dried in a vacuum oven at 60 °C for 6 h to give the title compound as a grey solid (3.8 g). UPLC-MS m / z: 207.98 [M+H].

[0493] Preparation 45: 7-amino-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0494]

[0495] Step 1: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0496]

[0497] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 44, Step 2) (2.0 g, 9.65 mmol) in DMF (20 mL) was added NaH (425 mg, 10.62 mmol) followed by bromotoluene (1.27 mL, 10.62 mmol) at 0-10°C. The whole reaction was allowed to warm to RT slowly over 1 h. TLC and UPLC-MS showed the formation of the desired product, and after completion of the reaction, the mixture was diluted with cooling water to give a solid precipitate, which was filtered and dried in a vacuum oven to give the title compound as a grey solid (2.6 g, 90% yield). UPLC-MS m / z: 298.88 [M+H].

[0498] Step 2: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid

[0499]

[0500] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 45, Step 1) (2.6 g, 8.75 mmol) in a mixture of THF (30 mL) and MeOH (15 mL) was added a solution of LiOH.HO (1.83 g, 43.73 mmol) in water (15 mL) at RT. The mixture was stirred for 124 h at RT. The progress of the reaction was monitored by UPLC-MS, and upon completion, the solvent was evaporated in vacuo to give a residue, which was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6N HCl to give a precipitate, which was filtered and dried in a rotary evaporator with acetonitrile as a co-solvent to give the title compound as an off-white crude solid (2.2 g, 89% yield). UPLC-MS m / z: 284.02 [M+H].

[0501] Step 3: tert-Butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate ester

[0502]

[0503] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (Preparation 45, Step 2) (200 mg, 0.7 mmol) in DCM (5 mL) was added DMF (0.05 mL) and oxalyl chloride (0.092 mL, 1.06 mmol) at 0-5 °C. The combined mixture was stirred at RT for 1 h. TLC showed the formation of the corresponding acid chloride. The solvent was evaporated in vacuo to give an orange crude material, which was treated with a saturated solution of NaN3 (91.78 mg, 1.41 mmol) in water (5 mL) and further stirred at RT for 1 h. TLC showed that the reaction was complete. The reaction mixture was diluted with water and extracted with MTBE. The organic layer was washed with aqueous sodium bicarbonate and brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the corresponding crude acyl azide (250 g) intermediate, which was dissolved in t-BuOH (10 mL) and stirred at 90°C for 1 h. After complete consumption of the azide intermediate (monitored by UPLC-MS), the solvent was evaporated in vacuo to give the crude product, which was purified by Combi-flash (20 g column) using 20% ​​EtOAc / hexane as eluent to give the title compound (120 g, 42% yield) as a white solid. UPLC-MS m / z: 355.13 [M+H].

[0504] Step 4: 7-amino-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0505]

[0506] A solution of tert-butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate (Preparation 45, Step 3) (120 mg, 0.34 mmol) in 4M HCl in dioxane (3.5 mL) was stirred at RT under inert atmosphere for 2 h. UPLC-MS showed the formation of the desired product. The solvent was evaporated to give the title compound (120 mg) as a crude yellow sticky material, which was used in the next step without any further purification. UPLC-MS m / z: 254.98 [M+H].

[0507] Preparation 46: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indole Indole-6-yl)urea (Example 69)

[0508]

[0509] To a stirred solution of 6-aminoindole (68 mg, 0.519 mmol) in THF (5 mL) was added triphosgene (70 mg, 0.235 mmol) at 0-5 °C. The combined mixture was stirred at RT for 1 h. The first stage of the reaction was confirmed to be complete by TLC, after which 7-amino-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Preparation 45, Step 4) (120 mg, 0.472 mmol) and TEA (0.225 mL, 1.557 mmol) were added to the reaction mixture and stirring was continued for 1 h at RT. The progress of the reaction was monitored by TLC, and upon completion, the solvent was evaporated in vacuo to give a crude material, which was purified by preparative HPLC to give the title compound as a light brown solid (23 mg, 12% yield). UPLC purity: 96.28%; 1 H NMR (400MHz; DMSO-d6): δ4.76(s,2H),5.13(s,2H),6.30(t,J=1.04Hz,1H),6.90-6.94(m,2H),6.97-6.99(m,1 UPLC-MS m / z: 413.11[M+H].

[0510] Examples 2 to 4, 6, 9, 12, 16 to 19, 22 to 33, 51 to 53, 59 to 60, 87 to 96, 99, 116, 124 to 142, 144 to 162, 164 to 166 and 193-195

[0511] The examples in the table below were prepared according to the methods used above for the preparation of Examples 1 and 69 using the appropriate amines as described in General Procedures 1 to 6. Purification was as stated in the preceding methods.

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542] Examples 97 to 98, 100 to 115, 117 to 123, 143 and 163

[0543] Examples 97-98, 100-115, 117-123, 143 and 163 were prepared using library general procedures 28 and 29 using appropriate aryl halides. Purification was as described in the previous methods.

[0544]

[0545]

[0546]

[0547]

[0548] Example 38: (S)-1-(1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-3- (4-Fluorophenyl ) Urea

[0549]

[0550] Example 38 was prepared according to the methods described in General Procedures 1 to 4, 10 to 14 and the methods described below.

[0551] Preparation 7: (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

[0552]

[0553] (S)-Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate was prepared in five steps according to the method described in patent WO2018 / 234808.

[0554] Preparation 8: (S)-1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester

[0555]

[0556] To a stirred solution of (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 7) (1.0 g, 4.26 mmol) in DMF (12 mL) was added NaH (187 mg, 4.69 mmol) at 0-5 ° C., followed by bromotoluene (0.53 mL, 4.48 mmol). The combined mixture was stirred at RT for 30 min. TLC showed that the starting cyclic urea was completely consumed. The reaction mixture was then quenched with ice water to give a precipitate, which was filtered, washed with hexane and dried under high vacuum to give the title compound as a white solid (1.1 g, 80% yield). LCMS m / z: 325 [M+H].

[0557] Preparation 9: (S)-1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

[0558]

[0559] To a stirred solution of (S)-1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester (Preparation 8) (0.5 g, 1.54 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of LiOH.HO (258 mg, 6.16 mmol) in water (2.5 mL), and the combined mixture was stirred at room temperature for 2 h. TLC showed that the reaction was complete. The solvent was evaporated, and the residue was diluted with water, washed with MTBE, and the aqueous layer was acidified to pH 4-5 with 1N HCl. The aqueous portion was extracted with EtOAc, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (450 mg, crude material). LCMS m / z: 311 [M+H].

[0560] Preparation 10: (S)-1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonyl azide thing

[0561]

[0562] To a stirred solution of (S)-1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 9) (200 mg, 0.65 mmol) in anhydrous solvents DMF (50 μL) and DCM (10 mL) was added oxalyl chloride (164 mg, 1.29 mmol) at 0-5°C. The whole reaction was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS, and after completion, the reaction mass was poured into a NaN3 aqueous solution (209 mg, 3.22 mmol in 10 mL of water) with stirring. After completion of the acyl azide formation (confirmed by LCMS), the product was extracted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (210 mg, crude material) as a white solid. LCMS m / z: 336.35 [M+H].

[0563] Preparation 11: (S)-1-(1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3- (4-Fluorophenyl)urea (Example 38)

[0564]

[0565] To a stirred solution of (S)-1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonyl azide (Preparation 10) (192 mg, 0.57 mmol) in DMF (6 mL) was added 4-fluoroaniline (254 mg, 2.29 mmol) at RT. The whole reaction was stirred at 83 ° C overnight. The progress of the reaction was monitored by TLS / LCMS, and after completion, the reaction mixture was diluted with EtOAc and washed with cold water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (196 mg, 82% yield) as an off-white solid. UPLC purity: 99.05%; 1 H NMR (400MHz; DMSO-d6): δ1.27(d,J=6.35Hz,3H),2.98(s,3H),4.52(q,J=6.4Hz,1H),4.96-5.10(m,2H),6.87(s, 1H),7.04-7.12(m,4H),7.21-7.23(m,3H),7.31-7.34(m,2H),7.39-7.42(m,2H),8.55(s,1H),8.61(s,1H); LCMS m / z: 419.12[M+H].

[0566] Example 39: 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)- Urea

[0567]

[0568] Example 39 was prepared according to the methods described in General Procedures 1b to 4, 15, 16 and the methods described below.

[0569] Preparation 12: 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester

[0570]

[0571] Step 1: Methyl 3-amino-4-formylbenzoate

[0572]

[0573] To a stirred solution of commercially available methyl 4-formyl-3-nitrobenzoate (2.0 g, 9.56 mmol) in EtOH (20 mL) was added iron powder (2.14 g, 38.24 mmol), followed by 0.12 N HCl. The reaction mixture was refluxed for 30 min. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was quenched with a saturated NaHCO solution and extracted with DCM, followed by washing with brine. The organic layer was dried over anhydrous NaSO, filtered and concentrated in vacuo to give the title compound (2.0 g, crude) as a yellow solid, which was used in the next step without any further purification. LCMS m / z: 180.01 [M+H].

[0574] Step 2: Methyl 3-((ethoxycarbonyl)amino)-4-formylbenzoate

[0575]

[0576] To a stirred solution of methyl 3-amino-4-formylbenzoate (Preparation 12, Step 1) (2.0 g, 11.16 mmol) in DCE (20 mL) was added pyridine (1.98 mL, 24.56) and ethyl chloroformate (1.27 mL, 13.39 mmol) at 0-5°C. The whole reaction was stirred at 0-5°C for 1 h. The reaction was confirmed to be complete by TLC and LC-MS. The reaction mixture was quenched by 1N HCl solution and extracted with DCM, followed by washing with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.0 g, crude) as a yellow solid, which was used in the next step without any further purification. LCMSm / z: 252.03 [M+H].

[0577] Step 3: 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester

[0578]

[0579] To a stirred solution of methylamine hydrochloride (0.27 g, 3.98 mmol) in MeOH (20 mL) was added TEA (0.67 mL, 4.78 mmol) at RT under an inert atmosphere, and the resulting clear solution was then stirred for 30 min. 3-((ethoxycarbonyl)amino)-4-formylbenzoic acid methyl ester (Preparation 12, Step 2) (1.0 g, 3.987 mmol) was added in batches, and the combined mixture was stirred at room temperature for 24 h. During this period, the reaction mixture became a suspension. NaBH4 (227 mg, 5.97 mmol) was added, and the mixture was further stirred for 24 h. The reaction progress was monitored by TLC and LC-MS, and after completion, the reaction mixture was diluted with water and extracted with EtOAc, followed by washing with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (750 mg, crude material) as a yellow solid, which was used in the next step without any further purification. LCMS m / z: 221.04 [M+H].

[0580] Preparation 13: 1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester

[0581]

[0582] To a stirred solution of methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 12, Step 3) (300 mg, 1.36 mmol) in DMF (3 mL) was added NaH (65 mg, 1.63 mmol) and bromotoluene (183 μL, 1.50 mmol) at 10 °C under nitrogen atmosphere. The whole reaction was stirred at room temperature for 1 h. TLC showed complete consumption of the cyclic urea intermediate, and the reaction mixture was then quenched with ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the title compound (390 mg, crude) as a light brown solid, which was used in the next step without any further purification. LCMS m / z: 311.28 [M+H].

[0583] Preparation 14: 1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

[0584]

[0585] To a stirred solution of 1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid methyl ester (Preparation 13) (390 mg, 1.26 mmol) in THF (10 mL) and MeOH (5 mL) was added a solution of LiOH (264 mg, 6.28 mmol) in water (1.5 mL), and the combined mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The solvent was evaporated in vacuo to give a residue, which was diluted with water, washed with MTBE, and the aqueous layer was acidified with 6N HCl to give a precipitate. The precipitate was filtered off and dried in vacuo to give the title compound (330 mg, crude material) as an off-white solid, which was used in the next step without any further purification. LCMS m / z: 297.46 [M+H].

[0586] Preparation 15: tert-Butyl (1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamate

[0587]

[0588] To a stirred solution of 1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 14) (0.33 g, 1.11 mmol) in DCM (10 mL) was added TEA (0.241 mL, 1.67 mmol) followed by DPPA (0.483 mL, 2.23 mmol) at 0-5°C. The whole reaction was stirred at room temperature for 3 h. The progress of the reaction was monitored by UPLC-MS, and upon completion, the solvent was evaporated to give the desired carbamate (350 mg) as a light brown solid, which was then dissolved in tert-butanol (10 mL) and refluxed for 24 h. UPLC-MS showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was purified by Combi-flash to give the title compound (225 mg, 55% yield) as an off-white solid. LCMS m / z: 368.6 [M+H].

[0589] Preparation 16: 7-amino-1-benzyl-3-methyl-3,4-dihydroquinazolin-2(1H)-one

[0590]

[0591] To a stirred solution of (1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamic acid tert-butyl ester (Preparation 15) (225 mg, 0.61 mmol) in THF (5 mL) was added dropwise 4M HCl in dioxane (5 mL) under inert atmosphere at 0-5°C. The whole reaction was stirred at room temperature for 24 h. TLC showed the formation of the desired compound. The solvent was evaporated in vacuo, and the resulting residue was dissolved in water, and neutralized with NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and then evaporated in vacuo to give the title compound (190 mg, crude) as a light brown oil, which was used in the next step without any further purification. LCMS m / z: 268.4 [M+H].

[0592] Preparation 17: 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)- Urea (Example 39)

[0593]

[0594] To a stirred solution of 7-amino-1-benzyl-3-methyl-3,4-dihydroquinazolin-2(1H)-one (Preparation 16) (85 mg, 0.317 mmol) in DCM (10 mL) was added 4-fluorophenyl isocyanate (44 μL, 0.308 mmol) and TEA (55 μL, 0.308 mmol) at 0-5°C. The whole reaction was stirred at RT for 1 h. TLC showed complete consumption of the starting material. The solvent was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (14 mg, 11% yield) as a light yellow solid. UPLC purity: 96.6%; 1 H NMR (500MHz; DMSO-d6): δ2.96(s,3H),4.41(s,2H),5.03(bs,2H),6.86(d,J=1.2H,1H),7.05(d,J=8.2Hz,1H), 7.11(t,J=8.8Hz,3H),7.21-7.25(m,3H),7.31-7.34(m,2H),7.39-7.42(m,2H),8.68(s,1H),8.73(s,1H); LCMS m / z: 405.36[M+H].

[0595] Example 40

[0596] Example 40 was prepared according to the method used above for the preparation of Example 39 using the appropriate amine or isocyanate as described in General Procedures 1b to 4, 15, 16. Purification was as stated in the previous methods.

[0597]

[0598]

[0599] Example 41: 4-(2-Chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazine-3-yl (4H)-Keto

[0600]

[0601] Example 41 was prepared according to the methods described in General Procedures 4 to 6 and the methods described below.

[0602] Preparation 18: 6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0603]

[0604] The title compound 6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one was prepared in two steps following the same procedure as described in Preparation 1, Steps 1 to 2.

[0605] Preparation 19: 4-(2-Chloro-6-fluorobenzyl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0606]

[0607] To a stirred solution of 6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 18) (1.0 g, 5.102 mmol) in anhydrous DMF (10 mL) was added K2CO3 (1.408 g, 10.204 mmol) followed by 2-chloro-6-fluorobenzyl bromide (1.053 mL, 7.653 mmol) at room temperature. The whole reaction was then stirred at 90-120°C for 12 h. The progress of the reaction was monitored by TLC and LC-MS, and upon 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 concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound as an off-white solid (0.6 g, 34.81% yield). LCMS m / z: 338 [M+H].

[0608] Preparation 20: 4-(2-Chloro-6-fluorobenzyl)-6-hydroxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0609]

[0610] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 19) (400 mg, 1.187 mmol) in anhydrous DCM (5 mL) was added BBr3 (0.5 mL, 1 M solution in DCM) dropwise at 0-5°C. The whole reaction was then stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was evaporated to dryness, then diluted with EtOAc, washed with NaHCO3 solution, followed by water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 52% yield) as an off-white solid. LCMS m / z: 324 [M+H].

[0611] Preparation 21: 4-(2-chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazine-3-yl (4H)-Keto (Example 41)

[0612]

[0613] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-6-hydroxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 20) (110 mg, 0.341 mmol) in anhydrous acetone (3 mL) was added KCO (94 mg, 0.681 mmol) followed by KI (2.002 mg, 0.014 mmol) at room temperature. After 5 min, 1-(2-bromoethyl)-4-fluorobenzene (103.7 mg, 0.511 mmol) was added and the combined mixture was stirred at reflux for 16 h. The progress of the reaction was monitored by TLC and LC-MS, which confirmed the formation of the desired product. The reaction mixture was evaporated to dryness, then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC to give the title compound as an off-white solid (25 mg, 16.46% yield). HPLC purity: 96.99%; 1 H NMR (400MHz; DMSO-d6): δ2.97(s,2H),3.48(s,2H),4.11(d,J=6.36Hz,2H),5.35(s,2H),6.57 (d,J=8.76Hz,1H),6.79(s,1H),7.10-7.15(m,3H),7.22-7.25(m,2H),7.28-7.32(m,3H); LCMS m / z: 446.2[M+H].

[0614] Example 42: 4-(2-chloro-6-fluorobenzyl)-6-(((4-fluorobenzyl)oxy)methyl)-2H-benzo[b][1,4] Thiazide-3(4H)-one

[0615]

[0616] Example 42 was prepared according to the methods described in General Procedures 3 to 6 and the methods described below.

[0617] Preparation 22: 4-(2-Chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0618]

[0619] The title compound 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid was prepared in four steps using the same procedure as described in Preparations 1 to 3.

[0620] Preparation 23: 4-(2-chloro-6-fluorobenzyl)-6-(hydroxymethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0621]

[0622] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (250 mg, 0.712 mmol) in anhydrous THF (10 mL) was added TEA (0.985 mL, 0.712 mmol) at 0-5°C, and the resulting reaction mixture was treated with isobutyl chloroformate (96.866 mg, 0.712 mmol). The whole reaction was then stirred at 0-5°C for another 2 h. The reaction mixture was filtered and washed with THF. The filtrate was then stirred at 0-5°C while NaBH4 (53.889 mg, 1.425 mmol) was first added in portions and then water (3 mL) was added. The resulting suspension was allowed to warm to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC and LC-MS, which confirmed the formation of the desired product. The reaction mixture was neutralized with 1N HCl and diluted with water. The aqueous mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude compound, which was purified by column chromatography to give the title compound as an off-white solid (200 mg, 83.13% yield). LCMS m / z: 338 [M+H].

[0623] Preparation 24: 4-(2-chloro-6-fluorobenzyl)-6-(((4-fluorobenzyl)oxy)methyl)-2H-benzo[b][1,4] Thiazide-3(4H)-one (Example 42)

[0624]

[0625] To a stirred suspension of 60% NaH (28.48 mg, 0.712 mmol) in THF (5 mL) was added a solution of 4-(2-chloro-6-fluorobenzyl)-6-(hydroxymethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 23) (200 mg, 0.593 mmol) in THF (1.5 mL) at 0-5°C. The mixture was stirred at room temperature for 10 min, after which a solution of 4-fluorobenzyl bromide (224.3 mg, 1.18 mmol) in THF (1 mL) was added to the reaction mixture, and stirring was continued at room temperature for 2 h. TLC and LCMS showed the formation of the desired product, and the reaction mixture was then quenched with water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound (50 mg, 19% yield) as a white solid. HPLC purity: 98.89%; 1 H NMR (400MHz; DMSO-d6): δ3.55(s,2H),4.40(s,4H),5.37(s,2H),6.95(d,J=7.92Hz,1H),7.05-7.10(m,1H),7.16-7.27(m,5H),7.33-7.35(m,3H); LCMS m / z: 446.0[M+H].

[0626] Example 43: 4-(2-Chloro-6-fluorobenzyl)-6-(5-phenyl-1H-imidazol-2-yl)-2H-benzo[b][1,4]thiazol Oxazine-3(4H)-one

[0627]

[0628] Example 43 was prepared according to the methods described in General Procedures 3 to 6 and the methods described below.

[0629] Preparation 25: 4-(2-Chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid 2-Oxo-2-phenylethyl ester

[0630]

[0631] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (300 mg, 0.822 mmol) in DMF (5 mL) was added DIPEA (429.93 mg, 2.466 mmol) followed by 2-bromo-1-phenylethanol (327.189 mg, 1.644 mmol) and the whole was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LC-MS and upon completion, the reaction mixture was diluted with cold water and extracted with MTBE. The combined organics were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by trituration with pentane and diethyl ether to give the title compound as an off-white solid (250 mg, 64.73% yield). LCMS m / z: 470 [M+H].

[0632] Preparation 26: 4-(2-chloro-6-fluorobenzyl)-6-(5-phenyl-1H-imidazol-2-yl)-2H-benzo[b][1,4]thiol Oxazine-3(4H)-one (Example 43)

[0633]

[0634] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid 2-oxo-2-phenylethyl ester (Preparation 25) (70 mg, 0.149 mmol) in AcOH (3 mL) was added NH4OAc (287.3 mg, 3.73 mmol) at room temperature. After the addition was complete, the reaction mixture was heated at 120°C for 48 h. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was concentrated in vacuo until dryness. The residue was diluted with water, neutralized with NaHCO3 solution, then extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound (10 mg, 14.89% yield) as a light yellow solid. HPLC purity: 95.41%; 1 H NMR (400MHz; DMSO-d6, at 100℃): δ3.55(s,2H),5.45(s,2H),7.07(t,J=8.96Hz,1H),7.19-7.30(m,3H),7.36-7 .39(m,2H),7.45(d,J=8.0Hz,1H),7.53-7.71(m,2H),7.86(d,J=7.56Hz,2H),7.95(s,1H),12.33(s,1H); LCMS m / z: 450.2[M+H].

[0635] Example 44: 4-(2-chloro-6-fluorobenzyl)-6-(5-phenyl-1H-1,2,4-triazol-3-yl)-2H-benzo[b] [1,4]Thiazin-3(4H)-one

[0636]

[0637] Example 44 was prepared according to the methods described in General Procedures 3 to 6 and the methods described below.

[0638] Preparation 27: 2-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6- tert-Butyl (carbonyl)hydrazinecarboxylate

[0639]

[0640] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (400 mg, 1.14 mmol) was slowly added SOCl2 (10 mL) at 0-5°C, and the combined reaction mixture was then refluxed for 2 h. The mixture was evaporated under reduced pressure to give a crude residue, which was diluted with THF. TEA was added dropwise at 0-5°C, followed by tert-butyl hydrazinecarboxylate (300.85 mg, 2.279 mmol). The combined mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was diluted with EtOAc, washed with water, NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (400 mg, 75.33% yield, crude material) as an off-white solid. LCMS m / z: 466 [M+H].

[0641] Preparation 28: 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide Hydrochloride

[0642]

[0643] To tert-butyl 2-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl)hydrazinecarboxylate (Preparation 27) (400 mg, 0.86 mmol) was slowly added 4M HCl (10 mL, 4M solution in dioxane) with stirring at 0-5°C, and then the mixture was slowly warmed to room temperature over 4 h. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was concentrated in vacuo until dryness, then diethyl ether was added to give a precipitate, which was filtered off and dried under inert atmosphere to give the title compound as an off-white solid (280 mg, 89.22% yield). LCMS m / z: 366 [M+H].

[0644] Preparation 29: 4-(2-chloro-6-fluorobenzyl)-6-(5-phenyl-1H-1,2,4-triazol-3-yl)-2H-benzo[b] [1,4]Thiazin-3(4H)-one (Example 44)

[0645]

[0646] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide hydrochloride (Preparation 28) (100 mg, 0.215 mmol) and ethyl benzimidate hydrochloride (44.237 mg, 0.237 mmol) in MeCN (6 mL) was added TEA (15.639 mg, 0.155 mmol) dropwise at RT. The whole reaction was stirred at 100 °C for 6 h. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was quenched with cold water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound (15 mg, 15.47% yield) as a white solid. HPLC purity: 99.77%; 1 H NMR (400MHz; DMSO-d6, at 100℃): δ3.58(s,2H),5.47(s,2H),7.06(t,J=8.24Hz,1H),7.21-7.29(m,2H) ,7.48-7.55(m,4H),7.68(d,J=8.12Hz,1H),7.96(s,1H),8.07(d,J=7.32Hz,2H),14.21(s,1H); LCMS m / z: 451[M+H].

[0647] Example 45: 6-(5-Benzyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl)-2H-benzo[b] [1,4]Thiazin-3(4H)-one

[0648]

[0649] Example 45 was prepared according to the methods described in General Procedures 4 to 6 and the methods described below.

[0650] Preparation 30: 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile

[0651]

[0652] The title compound 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile was prepared in three steps using the same procedure as described in Preparations 18 and 19.

[0653] Preparation 31: 6-(5-Benzyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl)-2H-benzo[b] [1,4]Thiazin-3(4H)-one (Example 45)

[0654]

[0655] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile (Preparation 30) (50 mg, 0.151 mmol) in n-BuOH (2 mL) was added K2CO3 (41.566 mg, 0.301 mmol) followed by 2-phenylacetohydrazide (22.617 mg, 0.151 mmol). The whole reaction was stirred at 150 °C for 15 h. The progress of the reaction was monitored by TLC and LC-MS, and upon completion, the reaction mixture was quenched with cold water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound as an off-white solid (20 mg, 29% yield). HPLC purity: 90.01%; 1 H NMR (400MHz; DMSO-d6): δ3.58(s,2H),4.08(s,2H),5.40(s,2H),7.05-7.07(m,1H),7.21-7.28( LCMS m / z: 465.2[M+H].

[0656] Example 46: 4-(2-Chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazin-3-yl (4H)-Keto

[0657]

[0658] Example 46 was prepared according to the methods described in General Procedures 3 to 6 and the methods described below.

[0659] Preparation 32: 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid 2-Oxo-2-phenylethyl ester

[0660]

[0661] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (100 mg, 0.285 mmol) in EtOH (2 mL) was added TEA (0.079 mL, 0.57 mmol) followed by 2-bromo-1-phenylethanol (68 mg, 0.342 mmol) under an inert atmosphere at RT. The resulting reaction mixture was stirred at 60 ° C for 2 h. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and then with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the title compound (85 mg, 63% yield) as a pale yellowish white solid. LCMS m / z: 470 [M+H].

[0662] Preparation 33: 4-(2-chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazine-3-yl (4H)-Keto (Example 46)

[0663]

[0664] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid 2-oxo-2-phenylethyl ester (Preparation 32) (100 mg, 0.213 mmol) in xylene (2 mL) was added BF3.Et2O (0.02 mL) followed by AcNH2 (62.9 mg, 1.066 mmol) at RT. The resulting reaction mixture was heated at 150 °C for 15 h. The progress of the reaction was monitored by LCMS, and upon completion, the reaction mixture was cooled to RT and quenched with water. The resulting reaction mass was extracted with EtOAc, washed with water, then with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the title compound (70 mg, 73% yield) as an off-white solid. HPLC purity: 97.23%; 1 H NMR (400MHz; CDCl3): δ.3.50(s,2H),5.56(s,2H),6.85-6.91(m,1H),7.08-7.10(m,2H),7.32-7.36(m,1H),7.39-7 .45(m,3H),7.67(dd,J'=1.24Hz,J"=7.96Hz,1H),7.80(d,J=7.44Hz,2H),7.90(d,J=1.12Hz,1H),7.94(s,1H); LCMS m / z: 451.2[M+H].

[0665] Example 47: N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indole Indole-6-yl ) Acetamide

[0666]

[0667] Example 47 was prepared according to the methods described in General Procedures 2 to 4, 6 and the methods described below.

[0668] Preparation 34: N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indole)- Indole-6-yl)acetamide (Example 47)

[0669]

[0670] To a stirred solution of 2-(1H-indol-6-yl)acetic acid (30 mg, 0.174 mmol) in THF (1.5 mL) was added HOBT.HO (23 mg, 0.174 mmol), DIPEA (146 μl, 0.86 mmol) and EDCI.HCl (49 mg, 0.26 mmol) at 0-5°C and the combined mixture was stirred for 15 min. Then, 6-amino-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 5) (55 mg, 0.204 mmol) was added to the reaction mixture and the whole was stirred at RT overnight. Product formation was confirmed by TLC and UPLC. The reaction mixture was evaporated in vacuo to a small volume and then extracted with EtOAc, washed with 1N HCl solution to remove excess amine, and further washed with KCO saturated solution followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the crude product, which was purified by preparative HPLC to yield a gummy material. The material was triturated with hexanes and diethyl ether to give the title compound as a white solid (13 mg, 18% yield). HPLC purity: 99.1%; 1 H NMR (500MHz; DMSO-d6): δ.3.64(s,4H),5.14(s,2H),6.39(s,1H),6.93(d,J=6.85Hz,1H), 7.22-7.32(m,9H),7.46(d,J=7.05Hz,1H),7.56(s,1H),10.22(s,1H),11.04(s,1H); LCMS m / z: 428.4[M+H].

[0671] Examples 48 and 55

[0672] Examples 48 and 55 were prepared according to the method used above for the preparation of Example 47 using appropriate acids as described in General Procedures 2 to 4, 6. Purification was as described in the preceding methods.

[0673]

[0674] Example 49: 4-Benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl Amide

[0675]

[0676] Example 49 was prepared according to General Procedure 17 and the methods described below.

[0677] Preparation 35: 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl chloride

[0678]

[0679] Commercially available 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g) was added in batches to stirring chlorosulfonic acid (3 mL) at 0-5 °C. The cooling bath was removed and the combined mixture was stirred at RT for 2 h. During this period, the reaction mixture turned dark blue. The progress of the reaction was monitored by UPLC and TLC. After the reaction was completed, it was poured into cold water and further stirred for 30 min to obtain a precipitate, which was filtered out and washed with water and then with hexane to obtain the title compound as a white solid (600 mg, 38% yield). LCMS m / z: 262 [MH].

[0680] Preparation 36: N-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide

[0681]

[0682] To a stirred solution of furan-2-ylmethylamine (80 mg, 0.823 mmol) in DCM (6 mL) was added TEA (0.287 mL) at 0-5 ° C. Thereafter, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl chloride (Preparation 35) (216.64 mg, 0.823 mmol) was added to the reaction mixture, and the entire reaction was stirred at RT for 30 min. The progress of the reaction was monitored by TLC and LCMS, and upon completion, the reaction mixture was poured into ice-cold water and extracted with DCM. The organic extract was then washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under high vacuum to give the title compound (220 mg, 84% yield) as a white solid. LCMS m / z: 325 [M+H].

[0683] Preparation 37: N-(Furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide

[0684]

[0685] To a stirred solution of N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide (Preparation 36) (300 mg, 0.925 mmol) in THF (4 mL) was added dropwise borane-THF solution (318 mg, 3.7 mL, 3.703 mmol, 1 M solution in THF) under an inert atmosphere at 0-5 ° C. The resulting reaction mixture was stirred at RT for 12 h. After the reaction was completed (monitored by TLC or LCMS), the reaction mixture was quenched by dropwise addition of MeOH (5 mL) at 0-5 ° C. The solvent was evaporated under reduced pressure to obtain a residue, which was distributed between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to give the title compound (120 mg, 42% yield) as a yellow sticky solid, which was used in the next step without any further purification.

[0686] Preparation 38: 4-Benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl Amide (Example 49)

[0687]

[0688] To a stirred solution of N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide (Preparation 37) (60 mg, 0.193 mmol) in anhydrous DCM (3 mL) was added TEA (58 mg, 0.581 mmol) at 0-5°C. The resulting reaction mixture was stirred for 5 min. Benzoyl chloride (41 mg, 0.290 mmol) was then added and stirring was continued for another 5 h. The progress of the reaction was monitored by TLC and LCMS, and upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound as a white solid (20 mg, 25% yield). HPLC purity: 98.32%; 1 H NMR (500MHz; DMSO-d6): δ3.04(dd,J'=3.0Hz,J"=4.85Hz,2H),3.50(dd,J'=3.8Hz,J"=6.5Hz,2H),4.93(s,2H),6.18(d,J=3.1Hz,1H LCMS m / z: 415.07[M+H].

[0689] Example 50: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indole-6-yl)- Urea

[0690]

[0691] Example 50 was prepared according to General Procedures 1 to 6, 17 and the methods described below.

[0692] Preparation 39: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0693]

[0694] Step 1: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester

[0695]

[0696] A solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 2) (1.0 g, 3.19 mmol) in borane-THF complex (10.6 mL, 9.5 mmol; 0.9 M solution in THF) was stirred at 0-5°C for 2 h. UPLC-MS showed the formation of the desired product. After the reaction was complete, the excess borane was quenched with methanol at the same temperature. The solvent was evaporated in vacuo, and the residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material, which was purified by column chromatography using 10% EtOAc / hexanes as eluent to give the title compound as a white solid (900 mg, 94% yield). LCMS m / z: 300.23 [M+H].

[0697] Step 2: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0698]

[0699] To a stirred solution of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 39, Step 1) (120 mg, 0.4 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of LiOH (84 mg, 2.0 mmol) in water (2.5 mL), and the mixture was maintained at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuo to give a crude material, which was diluted with water and acidified with 6N HCl. The product was extracted with EtOAc, and the combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the title compound as a light brown solid (100 mg, crude), which was used in the next step without any further purification. LCMS m / z: 286.22 [M+H].

[0700] Step 3: tert-Butyl (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate

[0701]

[0702] A stirred solution of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 39, Step 2) (100 mg, 0.35 mmol) in DCM (10 mL) was cooled to 0-5 ° C, and TEA (0.075 mL, 0.53 mmol) was added at RT, followed by DPPA (0.152 mL, 0.7 mmol). The combined mixture was stirred for 3 h at RT. UPLC-MS showed that the starting material was consumed. The solvent was evaporated in vacuo to give an intermediate product (130 mg) as a light brown solid. The solid was dissolved in tert-butyl alcohol (10 mL) and refluxed for 24 h. The reaction progress was monitored by UPLC-MS, and after the reaction was complete, the solvent was evaporated in vacuo to give a residue, which was purified by Combi-flash (12 g column) using 55% EtOAc / hexane as eluent to give the title compound (100 mg, 80% yield) as an off-white viscous oil. LCMS m / z: 357.3 [M+H].

[0703] Step 4: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0704]

[0705] A stirred solution of tert-butyl (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (Preparation 39, Step 3) (100 mg, 0.28 mmol) in THF (2.5 mL) was cooled to 0-5 °C, and dioxane (2.5 mL) containing 4M HCl was added dropwise under an inert atmosphere. The entire reactant was allowed to slowly warm to RT over 24 h. The progress of the reaction was monitored by UPLC-MS. After the reaction was complete, the solvent was evaporated, and the obtained crude material was dissolved in water and washed with ether. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give the title compound (80 mg, crude material) as a slightly brown oil, which was used as is in the next step. LCMS m / z: 257.22 [M+H].

[0706] Preparation 40: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indole-6-yl)- Urea (Example 50)

[0707]

[0708] To a stirred solution of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine (Preparation 39, Step 4) (80 mg, 0.312 mmol) in THF (10 mL) was added p-nitrophenyl chloroformate (63 mg, 0.374 mmol) at 0-5°C, and the mixture was slowly warmed to RT over 1 h. TLC showed that the first part of the reaction was complete. 6-Amino-indole (45 mg, 0.34 mmol) and TEA (0.067 mL, 0.468 mmol) were added, and the combined mixture was maintained at RT for another 1 h. TLC and UPLC-MS showed complete consumption of the intermediate. The solvent was evaporated in vacuo to give the crude material, which was purified by preparative HPLC to give the title compound as a light brown solid (8 mg, 6% yield). UPLC purity: 97.3%; 1 H NMR (400MHz; DMSO-d6): δ.3.04-3.07(m,2H),3.65-3.67(m,2H),4.55(s,2H),6.30-6.31(m,1H),6.75(t,J=2.16Hz,1H),6.77-6.78(m,2H),6.86 (d,J=8.64Hz,1H),7.19-7.20(m,1H),7.26-7.30(m,3H),7.35-7.38(m,3 H),7.74(t,J=0.86Hz,1H),8.33(s,1H),8.42(s,1H),10.87(s,1H); LCMS m / z: 415.28[M+H].

[0709] Example 62: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indole-6- Urea

[0710]

[0711] Example 62 was prepared according to General Procedures 1 to 6, 18 and the methods described below.

[0712] Preparation 42: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine

[0713]

[0714] Step 1: 3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0715]

[0716] To a stirred solution of commercially available methyl 4-amino-3-hydroxybenzoate (0.5 g, 2.99 mmol) in DMF (5 mL) was added K2CO3 (2.75 g, 11.96 mmol) and 1,2-dibromoethane (1.035 mL, 11.96 mmol) at RT. The whole reaction was stirred at 80 °C for 16 h. TLC and UPLC-MS showed the formation of the desired product, and after the reaction was complete, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the crude material, which was purified by Combi-flash (20 g column) using 20% ​​EtOAc / hexanes as eluent to give the title compound as a light yellow solid (0.3 g, 52% yield). UPLC-MS m / z: 193.98 [M+H].

[0717] Step 2: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0718]

[0719] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 42, Step 1) (300 mg, 1.55 mmol) in DMF (3 mL) was added NaH (68 mg, 1.71 mmol) portionwise at 0-5°C. After the addition was complete, bromotoluene (0.204 mL, 1.71 mmol) was added, and all the reaction was slowly warmed to RT over 1.5 h. TLC and UPLC-MS showed the formation of the desired product, and after complete consumption of the starting material, 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 in vacuo to give the title compound (420 g, 95% yield) as a light yellow solid. UPLC-MS m / z: 284.3 [M+H].

[0720] Step 3: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine

[0721]

[0722] The title compound was prepared according to the method described for the preparation of Example 50 (Preparation 40, Steps 2 to 4) starting with 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester (Preparation 42, Step 2) instead of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 40, Step 1). UPLC-MS m / z: 241.4 [M+H].

[0723] Preparation 43: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indole-6-yl)- Urea (Example 62)

[0724]

[0725] To a stirred solution of 6-aminoindole (60 mg, 0.416 mmol) in THF (5 mL) was added triphosgene (61 mg, 0.208 mmol) at 0-5 °C. The resulting reaction mixture was allowed to warm to RT over 1 h. 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (Preparation 42, Step 3) (100 mg, 0.416 mmol) and TEA (0.198 mL, 1.217 mmol) were then added to the reaction mixture and further stirred at RT for 1 h. TLC showed complete consumption of the amine and new polar material was observed. The solvent was evaporated in vacuo to give the crude material, which was purified by preparative HPLC to give the title compound (35 mg, 21% yield) as a light brown solid. UPLC purity: 98.94%; 1H NMR (400MHz; DMSO-d6): δ3.27-3.34(m,2H),4.20-4.22(m,2H),4.40(s,2H),6.31-6.32(m,1H), 6.62(d,J=8.76Hz,1H),6.71(dd,J'=8.68Hz,J"=2.44Hz,1H),6.80(dd,J'=8.44Hz,J"=1.84Hz, 1H),6.97(d,J=2.4Hz,1H),7.19-7.20(m,1H),7.22-7.27(m,1H),7.31-7.33(m,3H),7.34-7.35 (m,1H),7.37-7.39(m,1H),7.77-7.78(m,1H),8.24(s,1H),8.42(s,1H),10.89(s,1H); UPLC-MS m / z: 399.1[M+H].

[0726] Example 176: 4-Benzyl-N-(1H-indol-6-ylsulfonylamino)-2,3-dihydro-1,4-benzoxazin-6-amine

[0727]

[0728] Example 176 was prepared according to General Procedures 1 to 6, 17 and the methods described below.

[0729] Preparation 77: N-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxooxazolidine-3-yl Sulfonamide

[0730]

[0731] Chlorosulfonyl isocyanate (82 mg, 0.58 mmol) was dissolved in DCM (2 mL) and allowed to cool to 0-5 °C. Bromoethanol (46.52 mg, 0.58 mmol) was then added dropwise thereto and the mixture was stirred at 0-5 °C for 30 min. To this reaction vessel was added a mixture of 4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-6-amine (Preparation 39, Step 4) (140 mg, 0.58 mmol) and Et3N (0.13 ml, 0.96 mmol) in DCM (1 mL) at 0-5 °C. The entire reaction mixture was stirred at 0-5 °C for 30 min, then warmed to RT and stirred at RT for 10 min. The progress of the reaction was checked by LCMS, and after completion of the reaction, the solvent was evaporated in vacuo to give the title compound (150 mg, crude) as a crude solid, which was used in the next step without any further purification.

[0732] Preparation 78: 4-Benzyl-N-(1H-indol-6-ylaminosulfonyl)-2,3-dihydro-1,4-benzoxazin-6-amine (Example 176)

[0733]

[0734] To a solution of N-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxooxazolidine-3-sulfonamide (Preparation 77) (150.0 mg, 0.38 mmol) in acetonitrile (5 mL) was added 6-amino-indole (61.0 mg, 0.46 mmol) and Et3N (0.16 ml, 0.96 mmol) at RT, and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was checked by LCMS, and after the completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was purified by reverse phase preparative HPLC to give the title compound as a black sticky solid (15 mg, yield 8.96%). UPLC purity: 98.94%; 1 H NMR (400MHz; DMSO-d6): δ3.27(m,2H),4.12(s,2H),4.30(s,2H),6.34(s,1H),6.36(s,1H),6.45(s,1H),6.56 UPLC-MS m / z: 435.07[M+H].

[0735] Examples 56 to 57, 63 to 68, 167 to 174 and 177 to 180

[0736] The examples in the table below were prepared according to the methods used above for the preparation of Examples 50, 62 and 176 using the appropriate amines as described in General Procedures 1 to 6, 17 and 18. Purification was as stated in the preceding methods.

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743] Example 72: 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl) Urea

[0744]

[0745] Example 72 was prepared according to General Procedures 1 to 6, 17, 25 and the methods described below.

[0746] Preparation 47: 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0747]

[0748] Step 1: 3,4-Dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester

[0749]

[0750] BH3-THF (30 mL, 27 mmol) was added to 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid methyl ester (Preparation 1, Step 2) (2.0 g, 9.0 mmol) at 0-5 ° C under stirring in an inert atmosphere. After the addition was completed, the mixture was allowed to reach RT and stirred for 3 h. The reaction was confirmed to be complete by TLC and UPLC-MS. The reaction mixture was quenched by adding to methanol in a conical flask portion by portion and stirring until bubbling completely stopped. Then, the reaction mixture was concentrated in vacuo to give a crude material, which was mixed with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.8 g) as a pale yellow crude solid. UPLC-MS m / z: 209.9 [M+H].

[0751] Step 2: 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester

[0752]

[0753] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 47, Step 1) (500 mg, 2.39 mmol) in toluene (15 mL) was added phenyl iodide (0.4 mL, 3.6 mmol), cesium carbonate (1.56 g, 4.78 mmol) and BINAP (298 mg, 0.48 mmol) at RT. The whole reaction was degassed with nitrogen for 20 min, then palladium acetate (54 mg, 0.24 mmol) was added to the reaction mixture and stirring was continued at 110 °C for 24 h. The progress of the reaction was monitored by UPLC-MS, which showed about 40% formation of the desired product. The reaction mixture was concentrated in vacuo to give the crude material, which was purified by column chromatography to give the title compound (240 mg, 35% yield) as a light yellow solid along with recovered unreacted starting material. UPLC-MS m / z: 285.98 [M+H].

[0754] Step 3: 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine hydrochloride

[0755]

[0756] The title compound was prepared according to the method described for the preparation of Example 50 (Preparation 40, Steps 2 to 4) starting with 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 50, Step 2) instead of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 40, Step 1). UPLC-MS m / z: 242.96 [M+H].

[0757] Preparation 48: 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl) Urea (Example 72)

[0758]

[0759] To a stirred solution of 6-amino-indole (147 mg, 1.11 mmol) in THF (6 mL) was added triphosgene (157 mg, 0.53 mmol) at 0-5 ° C. The reaction mixture was stirred at RT for 1.5 h. 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine (Preparation 47, Step 3) (50 mg, 0.18 mmol) was then added at 0-5 ° C, followed by TEA (0.77 mL, 5.5 mmol). The entire reactant was stirred for another 2 h at RT. The progress of the reaction was monitored by UPLC-MS, and upon completion, the reaction mixture was concentrated in vacuo to give a residue, which was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a crude product, which was purified by preparative HPLC to give the title compound (12 mg, 17% yield) as a yellow solid. UPLC purity: 96.74%; 1 H NMR (400MHz; DMSO-d6): δ3.10(t,J=3.16Hz,2H),3.85-3.88(m,2H),6.30(s,1H),6.74-6.77(m,1H),6.87(s,1H),6.96-7.00(m, 2H),7.09(t,J=7.36Hz,1H),7.19-7.20(m,3H),7.35-7.39(m,3H),7.71(s,1H),8.43(s,1H),8.50(s,1H),10.86(s,1H); UPLC-MS m / z: 401.12[M+H].

[0760] Example 75: 1-(1H-indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxadiazine Oxazine-7-yl)urea

[0761]

[0762] Example 75 was prepared according to General Procedures 1 to 6, 24 and the methods described below.

[0763] Preparation 53: 7-amino-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0764]

[0765] Step 1: 3-Oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester

[0766]

[0767] To a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester (Preparation 44, Step 2) (800 mg, 3.86 mmol) in EDC (4 mL) was added phenylboronic acid (706 mg, 5.79 mmol) in EDC (4 mL), DBU (1.176 mL, 7.72 mmol) and Cu(OAc) solution (1.40 g, 7.72 mmol) at RT. The resulting reaction mixture was stirred at RT for 24 h. UPLC-MS showed about 50% conversion. 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 vacuo to give a crude material, which was purified by Combi-flash (20 g column) using 35% EtOAc / hexanes as eluent to give the title compound (420 mg, 38% yield) as an off-white solid.

[0768] Step 2: 3-Oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl azide

[0769]

[0770] To a stirred solution of methyl 3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 53, Step 1) (420 mg, 1.48 mmol) in THF (8 mL) and MeOH (4 mL) was added a solution of LiOH.HO (249 mg, 5.93 mmol) in water (4 mL) and the reaction was maintained at RT for 2 h. TLC showed the reaction was complete. The solvent was evaporated in vacuo to give the crude material, which was dissolved in water, washed with MTBE, and the aqueous layer was acidified with 6N HCl. The neutralized aqueous material was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO and evaporated in vacuo to give the corresponding intermediate acid (400 mg), which was then dissolved in DCM (45 mL) and HATU (845 mg, 2.22 mmol) and TEA (0.641 mL, 4.45 mmol) were added at RT. The whole reaction was stirred at RT for 24 h. UPLC-MS confirmed the formation of the intermediate HATU adduct. Sodium bicarbonate solution (10%) was added and the layers were separated. The organic layer was evaporated to give a crude material, to which a saturated solution of sodium azide was added, and the whole reaction was stirred at RT for 30 min. UPLC-MS showed that the reaction was complete, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give the title compound (250 mg, crude material) as a light yellow solid. UPLC-MS m / z: 194.98 [M+H].

[0771] Step 3: 7-amino-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0772]

[0773] A stirred solution of 3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl azide (Preparation 53, Step 2) (0.25 g, 0.85 mmol) in tert-butanol (5 mL) was heated to 90 °C for 1 h. UPLC-MS showed the formation of the desired intermediate. The solvent was evaporated to give the crude material, which was purified by Combi-flash to give the corresponding Boc-NH2 intermediate (130 mg). The Boc-NH2 intermediate (130 mg, 0.38 mmol) was dissolved in DCM (10 mL) containing 20% ​​TFA at RT under inert atmosphere and further stirred at RT for 1 h. UPLC showed the formation of the desired compound. The reaction mixture was quenched with saturated sodium bicarbonate solution (pH about 8) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give the title compound (90 mg, crude) as an off-white solid. UPLC-MS m / z: 241.3 [M+H].

[0774] Preparation 54: 1-(1H-indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxane Oxazine-7-yl)urea (Example 75)

[0775]

[0776] A stirred solution of 6-amino-indole (54 mg, 0.411 mmol) in THF (5 mL) was cooled to 0-5 °C before adding triphosgene (55 mg, 0.187 mmol) and maintaining at RT for 1 h, followed by the addition of 7-amino-4-phenyl-2H-benzo[b][1,4]oxazine-3(4H)-one 1 (Preparation 53, Step 3) (90 mg, 0.374 mmol) and TEA (0.178 mL, 1.23 mmol) at RT. The resulting reaction mixture was stirred at RT for 1 h. TLC showed that the reaction was complete, then the reaction mixture was diluted with EtOAc and washed with water, followed by 1N HCl and finally with brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude material, which was purified by preparative HPLC to give the title compound (38 mg, 25.5% yield) as an off-white solid. UPLC purity: 99.18%; 1 H NMR (400MHz; DMSO-d6): δ4.80 (s, 2H), 6.22 (d, 1H, J = 8.64), 6.33 (s, 1H), 6.85 (t, 2H, J = 9.04Hz )7.21(s,1H),7.60-7.33(m,7H),7.79(s,1H),8.62(s,1H),8.76(s,1H),10.91(s,1H); UPLC-MS m / z: 398.99[M+H].

[0777] Examples 175, 181 to 185

[0778] The examples in the table below were prepared according to the methods used above for the preparation of Examples 72 and 75 using the appropriate amines as described in General Procedures 1 to 6, 17, 18 and 24 to 25. Purification was as stated in the preceding methods.

[0779]

[0780]

[0781] Example 73: 1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(1H-indol-6-yl)urea

[0782]

[0783] Example 73 was prepared according to General Procedures 4 to 5, 6d, 8, 17 and the methods described below.

[0784] Preparation 49: 4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-amine

[0785]

[0786] Step 1: 2-Chloro-N-(2-fluoro-5-nitrophenyl)acetamide

[0787]

[0788] To a stirred solution of commercially available 2-fluoro-5-nitroaniline (1.5 g, 9.61 mmol) in acetone (30 mL) was added chloroacetyl chloride (0.994 mL, 12.49 mmol) at RT, and the reaction mixture was then stirred at RT for 1 h. TLC and UPLC-MS showed that the reaction was complete. Thereafter, ice-cold water was added to the reaction mixture to give a solid precipitate, which was filtered, washed with water and then dried in an oven to give the title compound as a light brown solid (2.0 g, crude material). UPLC-MS m / z: 231.3 [MH].

[0789] Step 2: 4-Methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one

[0790]

[0791] To a stirred solution of 2-chloro-N-(2-fluoro-5-nitrophenyl)acetamide (Preparation 49, Step 1) (2.0 g, 1.07 mmol) in ethanol (5 mL) was added a solution of methylamine in THF (25.79 mL, 2M solution) at RT, and the whole was stirred at 90 °C for 16 h. TLC and UPLC-MS showed the reaction was complete. Thereafter the solvent was evaporated in vacuo to give the crude product, which was purified by Combi-flash (20 g column) using EtOAC as eluent to give the title compound (1.3 g, 73% yield) as a yellow solid. UPLC-MS m / z: 206 [MH].

[0792] Step 3: 1-Benzyl-4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one

[0793]

[0794] To a stirred solution of 4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one (Preparation 49, Step 2) (1.0 g, 4.83 mmol) in DMF (15 mL) was added NaH (212 mg, 5.31 mmol) followed by bromotoluene (0.64 mL, 5.31 mmol) at 0-10°C and the reaction mixture was slowly warmed to RT over 8 h. TLC and UPLC-MS showed the formation of the desired product as well as the dibenzylated compound. The reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the crude product, which was purified by Combi-flash (20 g column). The title compound (400 mg, 28% yield) was eluted with 50% EtOAc / hexanes as a light brown solid, and the undesired benzhydrylated compounds (C-benzylated product and N-benzylated product) were eluted with 35% EtOAc / hexanes as a light brown solid. UPLC-MS m / z: 298.88 [M+H].

[0795] Step 4: 4-Benzyl-1-methyl-6-nitro-1,2,3,4-tetrahydroquinoxaline

[0796]

[0797] Borane-THF complex (2.02 mL, 2.024 mmol, 1 M solution in THF) was added portionwise to 1-benzyl-4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one (Preparation 49, Step 3) (200 mg, 0.67 mmol) at 5-10°C with stirring. After the addition was complete, the combined mixture was stirred at RT for 1 h. UPLC-MS showed the formation of the desired compound. The reaction mixture was diluted with MeOH (5 mL) and further stirred at RT for 10 min to quench any excess borane. The solvent was evaporated in vacuo to give a residue, which 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 the crude product, which was purified by Combi-flash (12 g column) using 30% EtOAc / hexane as eluent to give the title compound (150 mg, 79% yield) as an orange solid. UPLC-MS m / z: 284.3 [M+H].

[0798] Step 5: 4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-amine

[0799]

[0800] To a stirred solution of 4-benzyl-1-methyl-6-nitro-1,2,3,4-tetrahydroquinoxaline (Preparation 49, Step 4) (150 mg, 0.53 mmol) in MeOH (5 mL) was added Boc2O (0.173 mL, 0.79 mmol) followed by NiCl2.6H2O (63 mg, 0.26 mmol) and NaBH4 (50 mg, 1.32 mmol) at 5-10°C. The combined mixture was then allowed to warm to RT over 5 h. The progress of the reaction was monitored by TLC and UPLC-MS, which showed the formation of an intermediate product. Upon completion, the reaction mixture was diluted with cold 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 the crude product, which was purified by Combi-flash (12 g column) using 35% EtOAc / hexane as eluent to give the Boc-protected amine compound (180 mg, 96% yield). The material was dissolved in DCM (5 mL) and TFA (2 mL), and the whole reaction was stirred at RT for 4 h. UPLC-MS showed the formation of the desired product. The solvent was evaporated in vacuo to give the crude product, which was neutralized with aqueous sodium carbonate solution and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the title compound (110 mg, crude) as a brown semi-solid, which was used in the next step without any further purification. UPLC-MS m / z: 254.23 [M+H].

[0801] Preparation 50: 1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(1H-indol-6-yl)urea (Example 73)

[0802]

[0803] To a stirred solution of 6-amino-indole (63 mg, 0.477 mmol) in THF (5 mL) was added triphosgene (64 mg, 0.217 mmol) at RT. The mixture was stirred for 1 h, then 4-benzyl-1-methyl-1,2,3,4-tetrahydroquinoxaline-6-amine (Preparation 49, Step 5) (110 mg, 0.434 mmol) and TEA (0.206 mL, 1.432 mmol) were added to the reaction mixture, and the whole was stirred at RT for 1 h. TLC showed complete consumption of the amine, and a new polar spot was observed. The solvent was evaporated in vacuo to give a residue, which 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 product, which was purified by preparative HPLC to give the title compound (40 mg, 22% yield) as a light green solid. UPLC purity: 97.7%; 1H NMR (400MHz; DMSO-d6): δ2.75 (s, 3H), 3.16 (t, J = 4.96 Hz, 2H), 3.49 (t, J = 4. 52Hz,2H),4.45(s,2H),6.30(s,1H),6.42(d,J=8.48Hz,1H),6.53(d,J=2.24 Hz,1H),6.65-6.67(m,1H),6.73-6.76(m,1H),7.17(d,J=2.48Hz,1H),7.19 -7.37(m,6H),7.75(s,1H),8.05(s,1H),8.30(s,1H),10.84(s,1H); UPLC-MS m / z: 410.21[MH].

[0804] Example 74: 1-(1-Benzylindolin-6-yl)-3-(1H-indol-6-yl)urea

[0805]

[0806] Example 74 was prepared according to General Procedures 1 to 6 and the methods described below.

[0807] Preparation 51: 1-Benzylindoline-6-amine hydrochloride

[0808]

[0809] Step 1: Methyl 1-benzylindoline-6-carboxylate

[0810]

[0811] NaH (12.4 mg, 0.31 mmol) was added to a stirred solution of commercially available indoline-6-carboxylic acid methyl ester (50 mg, 0.28 mmol) in DMF (1 mL) at 0-5 ° C under an inert atmosphere. After 15 min, bromotoluene (0.035 ml, 0.3 mmol) was added to the reaction mixture and stirred for 2 h at RT. The reaction was confirmed to be complete by UPLC-MS. The reaction mixture was diluted with water (20 mL) and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (72 mg) as a crude yellow solid, which was used in the next step without any further purification. UPLC-MSm / z: 268 [M+H].

[0812] Step 2: 1-Benzylindoline-6-amine hydrochloride

[0813]

[0814] The title compound was prepared according to the method described for the preparation of Example 50 (Preparation 39, Steps 2 to 4) starting with 1-benzylindoline-6-carboxylic acid methyl ester (Preparation 54, Step 1) instead of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 40, Step 1). UPLC-MS m / z: 225 [M+H].

[0815] Preparation 52: 1-(1-Benzylindolin-6-yl)-3-(1H-indol-6-yl)urea (Example 74)

[0816]

[0817] To a stirred solution of 1-benzylindoline-6-amine hydrochloride (Preparation 51, Step 2) (30 mg, 0.12 mmol) in THF (3 mL) was added TEA (0.016 mL, 0.12 mmol) at RT. After the addition was complete, the mixture was stirred at room temperature for 30 min. Triphosgene (13.66 mg, 0.05 mmol) was added and stirring was continued for 1 h at RT. 6-NH2-indole (22.8 mg, 0.17 mmol) and TEA (0.032 ml, 0.24 mmol) were then added, and the entire reaction was stirred at RT overnight. The progress of the reaction was monitored by UPLC-MS, and after completion, the mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (3 mg, 7% yield) as a white solid. UPLC purity: 96.11%; 1 H NMR (400MHz; DMSO-d6): δ2.84(t,J=8.16Hz,2H),3.26-3.28(m,2H),4.25(s,2H),6.31(s,1H),6.62-6.65(m,1H),6.80-6.82(m, 2H),6.91-6.93(m,1H),7.20(t,J=2.64Hz,1H),7.26-7.39(m,6H),7.78(s,1H),8.48(s,1H)8.57(s,1H),10.88(s,1H); UPLC-MS m / z: 383.11[M+H].

[0818] Example 76: 2-(6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]thiazin-2-yl)acetamide

[0819]

[0820] Example 76 was prepared according to General Procedures 1 to 6, 26 and the methods described below.

[0821] Preparation 55: 4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate acid

[0822]

[0823] Step 1: 4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate Methyl ester

[0824]

[0825] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (Preparation 2) (1.0 g, 3.2 mmol) in anhydrous THF (20 mL) was added LiHMDS (3.6 mL, 4.8 mmol) and stirred for 5 min at -78 °C under inert atmosphere, then bromoacetonitrile (270 μL, 3.85 mmol) was added to the reaction mixture and stirring was continued for 30 min at the same temperature. Thereafter, the reaction mixture was allowed to reach room temperature and stirred for 1 h. The completion of the reaction was monitored by TLC and UPLC-MS, after which the reaction mass was quenched with saturated ammonium chloride solution and extracted with EtOAc, followed by washing with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude viscous oil, which was purified by combi-flash on a 20 g column by eluting with 30% EtOAc / hexanes as eluent to give the title compound as a light yellow solid (550 mg, 48% yield). UPLC-MS m / z: 353 [M+H].

[0826] Step 2: 4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate acid

[0827]

[0828] To a stirred solution of methyl 4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 55, Step 1) (0.6 g, 1.7 mmol) in a mixture of THF:MeOH:HO (12 mL, 2:1:1) was added LiOH.HO (0.29 g, 6.8 mmol) at RT and stirred at the same temperature for 2 h. When TLC and UPLC-MS showed complete consumption of the starting material and formation of the desired hydrolyzate, the solvent was evaporated under reduced pressure. The resulting residue was diluted with water and extracted with MTBE. The aqueous layer was collected and acidified to pH 5-6 with 1N HCl, then extracted with EtOAc, and the organic layer was separated, washed with brine, dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the title compound (550 mg, crude) as a light yellow solid, which was used in the next step without any further purification. UPLC-MS m / z: 337 [MH].

[0829] Preparation 56: 1-(4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine- 6-yl)-3-(1H-indol-6-yl)urea (Example 77)

[0830]

[0831] To a stirred solution of 4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 55, Step 2) (0.10 g, 0.30 mmol) in DCM (5 mL) was added TEA (0.065 mL, 0.45 mmol) at 0-5 °C under inert atmosphere, followed by DPPA (0.095 mL, 0.45 mmol) and stirring was continued at the same temperature for 5 min. The reaction mixture was then allowed to slowly reach RT and stirred overnight. The formation of the intermediate acyl azide was confirmed by TLC and UPLC-MS. The reaction mixture was then concentrated and toluene (5 mL) was added, followed by 6-amino-indole (60 mg, 0.45 mmol), and the entire reaction was refluxed for 3 h. The reaction was confirmed to be complete by TLC and UPLC-MS, after which the solvent was removed on a rotary evaporator to give a crude material, which was purified by preparative HPLC to give the title compound as a black solid (40 mg, 28% yield). UPLC purity: 97.92%; 1 H NMR (400MHz; DMSO-d6): δ1.66-1.75(m,2H),3.47-3.57(m,3H),3.95-3.98(dd,1H,J1=1.88Hz ,J2=10.68Hz),4.17-4.20(dd,1H,J1=1.28Hz,J2=10.68Hz),4.42-4.51(m,3H),6.29(s,1H), 6.60-6.65(m,3H),6.74-6.77(dd,1H,J1=1.68Hz,J2=8.48Hz),7.18(t,1H,J=2.52Hz),7.24- 7.26(m,1H),7.30-7.36(m,5H),7.73(s,1H),8.19(s,1H),8.38(s,1H),10.84(s,1H); UPLC-MS m / z: 468.15[M+H].

[0832] Preparation 57: 2-(6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo [b][1,4]thiazin-2-yl)acetamide (Example 76)

[0833]

[0834] To a stirred solution of 1-(4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea (Example 77) (100 mg, 0.21 mmol) in DMSO (1 mL) was added potassium carbonate (150 mg, 1.05 mmol) followed by hydrogen peroxide solution (1.5 mL) at RT, and the combined mixture was stirred for 1 h. The completion of the reaction was monitored by TLC and UPLC-MS. After completion of the reaction, the mixture was quenched with a saturated solution of sodium bisulfite and extracted with EtOAc, followed by washing with brine. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound (8 mg, 8% yield) as a light yellow solid. UPLC purity: 95.05%; 1 H NMR (400MHz; DMSO-d6): δ2.36-2.42(m,1H),2.73-2.78(m,1H),3.91-3.95(s,1H),4.51-4.23(m,1H),6.31(s,1H),6.62-6.84(m,1H),6.98(s, 2H),7.18-7.24(m,5H),7.27-7.37(m,3H),7.39-7.43(m,1H),7.44-7.4 5(m,2H),7.76(s,1H),8.88(s,1H),9.03(s,1H),10.89(s,1H); UPLC-MS m / z: 484.15[MH]

[0835] Example 78: 1-(3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H- Indol-6-yl)urea

[0836]

[0837] Example 78 was prepared according to General Procedures 1, 4, 6, 20-21 and the methods described below.

[0838] Preparation 58: 3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

[0839]

[0840] Step 1: 4-Benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxathiocarbamate Oxazine

[0841]

[0842] To a stirred solution of 4-benzyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (synthesized from commercially available 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one according to the method described in Preparation 2) (200 mg, 0.7 mmol) in DCM (7 mL) was added DIBAL-H (1 mL, 1.06 mmol) under nitrogen atmosphere at -78 °C. The combined mixture was stirred at the same temperature for 2 h, and then pyridine (0.33 mL, 2.46 mmol) and TMSOTf (0.38 mL, 2.11 mmol) were added to the reaction mixture. The temperature of the reactants was then slowly raised to 0-5 °C. The progress of the reaction was monitored by TLC, and after completion of the reaction, EtO (200 mL) was added and the mixture was filtered. The separated organic layer was then concentrated in vacuo to give the title compound (240 mg, crude) as a yellow solid, which was used in the next step without any further purification.

[0843] Step 2: 3-Allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0844]

[0845] To a stirred solution of 4-benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 1) (240 mg, 0.67 mmol) in DCM (7 mL) was added allyl-TMS (0.42 mL, 2.68 mmol) and BF3.Et2O (0.55 mL, 2.68 mmol) at -78°C under nitrogen. The temperature was then slowly raised to 0-5°C. The progress of the reaction was checked by UPLC-MS, and upon completion, the reactant was quenched with water (50 mL) and extracted with EtOAc. The separated organic layer was collected, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give the title compound (160 mg, 73% yield) as a yellow solid. UPLC-MS m / z: 311 [M+H].

[0846] Step 3: 3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

[0847]

[0848] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (110 mg, 0.35 mmol) in EtOH (4 mL) was added Fe powder (197.9 mg, 3.54 mmol) and NH4Cl (4 mL) at RT. It was then heated to 90°C for 1 h. The progress of the reaction was monitored by UPLC-MS. After completion of the reaction, it was diluted with water and extracted with EtOAc. The separated organic layer was collected and filtered through a silica gel bed. The filtrate was collected, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (150 mg, crude material). The obtained crude material was used in the next step. UPLC-MS m / z: 281 [M+H].

[0849] Preparation 59: 1-(3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H- Indol-6-yl)urea (Example 78)

[0850]

[0851] To a stirred solution of 6-amino-indole (84.88 mg, 0.64 mmol) in THF (4 mL) was added triphosgene (55.58 mg, 0.19 mmol) under nitrogen at 0-5 ° C. Stirring was continued at RT for 1 h, then 3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (Preparation 58, Step 3) (150 mg, 0.54 mmol) and TEA (0.18 mL, 1.34 mmol) were added, and the combined mixture was further stirred at RT for 2 h. Completion of the reaction was confirmed by UPLC-MS, and after completion the solvent was evaporated, and the resulting residue was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give a crude material, which was purified by Combi-flash followed by preparative HPLC to give the title compound as a yellow solid (27.2 mg, 76% yield). UPLC purity: 98.59%; 1 H NMR (400MHz; DMSO-d6): δ2.31-2.38(m,1H),2.36-2.39(m,1H),3.50(s,1H),3.96(d,1H,J=9.6Hz),4.15(d,1H,J=10.5Hz),4.52(s,2H),5.09(m,2H ),5.86(m,1H),6.31(s,1H),6.65(d,3H),6.76(d,1H,J=8.36Hz),7.19-7 .37(m,7H),7.75(s,1H),8.23(s,1H),8.41(s,1H),10.87(s,1H); UPLC-MS m / z: 439[M+H].

[0852] Example 79: 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-yl)- 1H-Indol-6-yl)urea

[0853]

[0854] Example 79 was prepared according to General Procedures 1, 4, 6, 20 to 22 and the methods described below.

[0855] Preparation 60: 3-(4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2- Diol

[0856]

[0857] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (250 mg, 0.81 mmol) in t-BuOH / H2O solution (10 mL, 1:1) was added OsO4 (20.48 mg, 0.08 mmol) and NMO (188.7 mg, 1.61 mmol). The resulting reaction mixture was stirred at RT for 12 h. The progress of the reaction was checked by LCMS and after completion of the reaction, it was further diluted with EtOAc. The organic layer was washed with 10% HCl, water and finally with brine. The organics were then dried over Na2SO4 and concentrated in vacuo to give the title compound (240 mg, crude) as a brown solid. UPLC-MS m / z: 445 [M+H].

[0858] Example 79: 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-yl)- 1H-Indol-6-yl)urea

[0859]

[0860] To a stirred solution of 6-amino-indole (133.7 mg, 1.01 mmol) in THF (4 mL) was added triphosgene (120 mg, 0.4 mmol) under nitrogen at 0-5° C. Stirring was continued at RT for 1 h, then 3-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2-diol (prepared from 3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2-diol (Preparation 60) according to the method described in Preparation 58, Step 3) (212 mg, 0.67 mmol) and TEA (340.6 mg, 3.37 mmol) were added and the combined mixture was further stirred at RT for 2 h. The completion of the reaction was confirmed by UPLC-MS, after which the solvent was evaporated and the resulting residue was purified by preparative HPLC to give the title compound as a grey solid (60 mg, yield 19%). UPLC purity: 96.96%; 1 H NMR (400MHz; DMSO-d6): δ1.35-1.46(m,1H),1.73-1.80(m,1H),3.20-3.30( m,1H),3.57-3.59(m,2H),4.0-4.01(m,1H),4.17-4.24(m,1H),4.42-4.50(m 1H),4.54-4.67(m,2H),6.30(bs,1H),6.59-6.65(m,3H),6.73-6.77(m,1H),7.18(bs,1H),6.23-6.26( UPLC-MS m / z: 473[M+H].

[0861] Example 80: 1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- (1H-Indol-6-yl)urea

[0862]

[0863] Example 80 was prepared according to General Procedures 1, 4, 6, 20 to 23 and the methods described below.

[0864] Preparation 61: 2-(4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol

[0865]

[0866] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (250 mg, 0.81 mmol) in t-BuOH / H2O solution (10 mL, 1:1) was added OsO4 (20.48 mg, 0.08 mmol) and NMO (188.7 mg, 1.61 mmol). The resulting reaction mixture was stirred at RT for 12 h. The progress of the reaction was checked by LCMS, and upon completion, the reactant was diluted with EtOAc and washed with 10% HCl, water, and finally with brine. The organics were dried and concentrated in vacuo to give the crude corresponding diol intermediate. The crude product was dissolved in t-BuOH / H2O solution (10 mL, 1:1) and NaIO4 (689.19 mg, 3.22 mmol) was added at RT. The resulting reaction mixture was stirred at RT for 12 h. The reaction progress was checked by LCMS, and after the reaction was completed, it was diluted with water and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to give a crude corresponding aldehyde (200 mg, 0.64 mmol), which was dissolved in methanol (8 mL) and NaBH4 (48.67 mg, 1.28 mmol) was added at 0-5 ° C. The reaction mixture was then further stirred for 2 h at RT. After the reaction was completed, NH4Cl solution (20 mL) was quenched. The aqueous reaction mixture was extracted with EtOAc. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (200 mg, crude material), which was used in the next step without any further purification. UPLC-MS m / z: 315 [M+H].

[0867] Example 80: 1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- (1H-Indol-6-yl)urea

[0868]

[0869] To a stirred solution of 6-aminoindole (81.72 mg, 0.62 mmol) in THF (4 mL) was added triphosgene (66.81 mg, 0.23 mmol) under nitrogen at 0-5° C. Stirring was continued for 1 h at RT, then 2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol (prepared from 2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol (Preparation 61) according to the method described in Preparation 58 Step 3) (160 mg, 0.56 mmol) and TEA (0.17 ml, 1.24 mmol) were added and the whole reaction was further stirred at RT for 12 h. The completion of the reaction was confirmed by UPLC-MS, and upon completion, the solvent was evaporated and the resulting residue was purified by preparative HPLC to give the title compound as a grey solid (40 mg, yield 16%). UPLC purity: 99.5%; 1 H NMR (400MHz; DMSO-d6): δ1.66-1.75(m,2H),3.47-3.57(m,3H),3.95-3.98(dd,1H,J1=1.88Hz ,J2=10.68Hz),4.17-4.20(dd,1H,J1=1.28Hz,J2=10.68Hz),4.42-4.51(m,3H),6.29(s,1H), 6.60-6.65(m,3H),6.74-6.77(dd,1H,J1=1.68Hz,J2=8.48Hz),7.18(t,1H,J=2.52Hz),7.24- 7.26(m,1H),7.30-7.36(m,5H),7.73(s,1H),8.19(s,1H),8.38(s,1H),10.84(s,1H); UPLC-MS m / z: 443[M+H].

[0870] Example 81: 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indole Indole-6-yl ) Urea

[0871]

[0872] Example 81 was prepared according to General Procedures 1, 4, 6, 20 and the methods described below.

[0873] Preparation 62: 6-Amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0874]

[0875] Step 1: 4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0876]

[0877] To a stirred solution of 4-benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 1) (355 mg, 0.99 mmol) in DCM (10 mL) was added TMSCN (0.49 mL, 3.96 mmol) and BF3.Et2O (0.81 mL, 3.96 mmol) at -78 °C under nitrogen. The temperature was then slowly raised to 0-5 °C. The progress of the reaction was checked by UPLC and the formation of the desired product was confirmed after 2 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic layers were collected, dried over Na2SO4 and evaporated in vacuo to give the crude product, which was purified by Combi-flash chromatography to give the title compound (190 mg, 65% yield) as a yellow solid. UPLC-MS m / z: 296 [M+H].

[0878] Step 2: 6-Amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0879]

[0880] To a stirred solution of 4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile (Preparation 62, Step 1) (0.180 g, 0.61 mmol) in ethanol (4 mL) was added Fe powder (0.33 mg, 6.1 mmol) and NH4Cl saturated solution (4 mL) in ice-cold water. The mixture was kept at ice-cold temperature for 5 min, after which the mixture was refluxed for 1 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was filtered through a celite pad and washed with ethanol. The ethanol mixture was evaporated under reduced pressure, diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the title compound (160 mg, crude) as a brown oily crude material, which was used in the next step without any further purification. UPLC-MS m / z: 264.15 [M+H].

[0881] Example 81: 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indole Indole-6-yl)urea

[0882]

[0883] To a stirred solution of 6-aminoindole (0.120 g, 0.9 mmol) in THF (3 mL) was added triphosgene (0.108 g, 0.39 mmol) at 0-5° C. and the mixture was stirred for five minutes before stirring at RT for 1 h. The first stage of the reaction was confirmed to be complete by TLC, and then 6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile (Preparation 62, Step 2) (0.160 g, 0.60 mmol) and TEA (0.500 mL, 0.6 mmol) were added to the reaction mixture at 0-5° C. The resulting reaction mixture was stirred at RT for 1 h. UPLC and TLC showed the mass of the desired product. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with 1N NaOH solution followed by brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to obtain a crude product which was purified by column chromatography using 2.5% MeOH / DCM as eluent to afford the title compound as a black solid (180 mg, 72% yield). UPLC purity: 93.27%; 1 H NMR (400MHz; DMSO-d6): δ3.34(d,2H,J=11.2Hz),4.56(m,2H),4.89(s,1H),6.31(s,1H),6.76- 6.86(m,3H),7.21-7.75(m,8H),7.75(s,1H),8.27(s,1H),8.38(s,1H),10.89(s,1H); UPLC-MS m / z: 424.19[M+H].

[0884] Preparation 63: 1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- (1H-Indol-6-yl)urea (Example 82)

[0885]

[0886] To a stirred solution of 1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea (Example 81) (80 mg, 0.189 mmol) in methanol (2 mL) was added NiCl2.6H2O (45 mg, 0.014 mmol) and NaBH4 (4.2 mg, 0.11 mmol) at 0-5°C. The reaction mixture was stirred at RT for 30 min and after completion of the reaction (monitored by LCMS and TLC), the reaction mixture was quenched with NH4Cl solution. Methanol was evaporated under reduced pressure and the resulting residue was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to give the title compound (10 mg, 12% yield) as a yellow solid. UPLC purity: 96.85%; 1 HNMR (400MHz; DMSO-d6): δ2.56-2.61(m,1H),2.68-2.72(m,1H),3.10-3.25(m, 2H),3.86(d,1H,J=9.8Hz),4.41(d,1H,J=10.56Hz)4.54(s,2H),6.29(s,1H),6. 58-6.64(m,3H),6.77(d,1H,J=8.28Hz),7.17(s,1H),7.24(d,1H,J=6.56Hz),7 .30-7.34(m,5H),7.74(s,1H),8.48(s,1H),8.65(s,1H),10.83(s,1H); UPLC-MS m / z:428.32[M+H].

[0887] Preparation 64: 6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxadiazine Oxazine-3-carboxamide (Example 83)

[0888]

[0889] To a stirred solution of 1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea (Example 81) (100.0 mg, 0.24 mmol) in MeOH (8 mL) was added K2CO3 (163.18 mg, 1.18 mmol) at 0-5°C and the whole reaction was stirred for 5 min. Then H2O2 (0.6 mL, 30% aqueous solution) was added at 0-5°C and stirring was continued for 2 h. The reaction was monitored by LCMS, which showed the formation of the desired product. The solvent was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (12 mg, 12% yield) as a yellow solid. UPLC purity: 96.11%; 1 H NMR (400MHz; DMSO-d6): δ4.00 (s, 2H), 4.32 (d, 1H, J = 16.5Hz), 4.50 (d, 1H, J = 9Hz), 4.72 (d, 1H, J = 16.44Hz), 6. 30(s,1H),6.59-6.80(m,4H),7.18-7.34(m,9H),7.97(s,1H),8.31(s,1H),8.44(s,1H),10.85(s,1H); UPLC-MS m / z: 442.31[M+H].

[0890] Examples 186 to 188

[0891] The examples in the table below were prepared according to the methods used above for the preparation of Examples 78 to 83 using the appropriate amines as described in General Procedures 1 to 6. Purification was as stated in the preceding methods.

[0892]

[0893]

[0894] Example 84: 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl 2-Phenylacetamide

[0895]

[0896] Example 84 was prepared according to General Procedures 1, 3 to 4, 6, 27 and the methods described below.

[0897] Preparation 65: 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide

[0898]

[0899] Step 1: Methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate

[0900]

[0901] To a stirred solution of commercially available 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2 g, 11.1 mmol) in ACN (40.0 mL) was added methyl 2-bromo-2-phenylacetate (5.23 mL, 33.3 mmol) and the reaction mixture was stirred in a sealed tube at 100 °C for 16 h. Excess solvent was concentrated under reduced pressure, and the reaction mixture was quenched with Na2CO3 solution, and the organics were extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (1×30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (5-10% EtOAc-hexanes) to give the title compound (1.8 g, 49% yield) as a yellow sticky solid. LCMS m / z: 329.1 [M+H].

[0902] Step 2: 2-(6-Nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetic acid

[0903]

[0904] To a stirred solution of methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 65, Step 1) (0.200 g, 0.609 mmol) in THF:MeOH:water (10 mL, 2:1:1, v / v / v) was added LiOH.HO (0.102 g, 2.437 mmol) at 0-5°C, and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (confirmed by LCMS), water was added, and the reaction mixture was acidified with 1N HCl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO and evaporated under reduced pressure to give the title compound (172 mg, 90% yield) as a yellow solid. LCMS m / z: 315.2 [M+H].

[0905] Step 3: 2-(6-Nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide

[0906]

[0907] To a stirred solution of 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetic acid (Preparation 65, Step 2) (0.172 g, 0.55 mmol) in DMF (3 mL) was added EDC-HCl (0.157 g, 0.82 mmol) and DIPEA (0.21 mL, 1.64 mmol) at 0-5° C. and the reaction mixture was stirred for 10 min keeping the temperature at 0-5° C., then NH4Cl (0.150 g, 2.74 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure, extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography using 40% EtOAc / hexane as eluent to give the title compound (120 mg, 70% yield) as an off-white solid. LCMS m / z: 314.1 [M+H].

[0908] Step 4: 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide

[0909]

[0910] To a stirred solution of 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide (Preparation 65, Step 3) (0.200 g, 0.638 mmol) in MeOH (6 mL) was added Pd-C (0.05 g, 10% w / w) and the reaction mixture was stirred under hydrogen balloon pressure for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with MeOH. The filtrate was evaporated under reduced pressure to give the crude material, which was purified by column chromatography using 40% EtOAc / hexanes as eluent to give the title compound as a gummy solid (100 mg, crude). LCMS m / z: 284.2 [M+H].

[0911] Preparation 66: 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl)ureido 2-Phenylacetamide (Example 84)

[0912]

[0913] To a stirred solution of 1H-indol-6-amine (51.3 mg, 0.39 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (107 mg, 0.53 mmol) at 0-5 °C, and the whole reaction was stirred at room temperature for 3 h. TEA (0.2 mL, 1.41 mmol) and 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide (Preparation 65, Step 4) (100 mg, 0.35 mmol) were then added to the reaction mixture at the same temperature, and the combined mixture was stirred for another 2 h. The reaction was monitored by LCMS. After completion, the solvent was evaporated to obtain the crude product. The crude material was purified by reverse phase preparative HPLC to give the title compound (14 mg, 9% yield) as an off-white solid. UPLC purity: 99.36%; 1 H NMR (400MHz; DMSO-d6): δ2.81-2.85(m,1H),3.33-3.38(m,1H),3.88(t,1H,J=7.56Hz),4.12(m,1H),5.35(s,1H),6.30(s,1H),6.60(d,1H) ,J=8.44Hz),6.80-6.71(m,2H),6.83(s,1H),7.17(s,1H),7.32-7.41(m,7H),7.76(s,2H),8.16(s,1H),8.42(s,1H),,10.85(s,1H); LCMS m / z: 442.2[M+H].

[0914] Example 85: 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- (1H-Indol-6-yl)urea

[0915]

[0916] Example 85 was prepared according to General Procedures 1, 3 to 4, 6 and the methods described below.

[0917] Preparation 67: Methyl 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate

[0918]

[0919] To a stirred and degassed solution of methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 65, Step 1) (0.530 g, 1.614 mmol) in MeOH (20 ml) was added Pd-C (0.055 g, 10% w / w). The reaction mixture was then stirred at RT for 4 h in the presence of hydrogen. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed three times with MeOH. The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography using 30% EtOAc / hexane as eluent to give the title compound (0.4 g, 90% yield) as a yellow gummy solid. LCMS m / z: 299.25 [M+H].

[0920] Preparation 68: 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-yl 2-Benzyl)-2-phenylacetic acid methyl ester (Example 86)

[0921]

[0922] To a stirred solution of 1H-indol-6-amine (0.05 g, 0.37 mmol) in THF (2.5 mL) was added Et3N (0.14 mL, 1.01 mmol) and p-nitrophenyl chloroformate (0.10 g, 0.50 mmol) at 0-5°C and the resulting reaction mixture was stirred at 0-5°C for 1 h. Methyl 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 67) (0.10 g, 0.34 mmol) in THF (1.5 mL) was added to the reaction mixture at 0-5°C and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC, 5% acetone / DCM), the solvent was evaporated under reduced pressure and extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a crude product, which was purified by column chromatography using 2% acetone / DCM as eluent followed by trituration with pentane to afford the title compound as an off-white solid (0.05 g, 35% yield). UPLC purity: 97.85%; 1H NMR (400MHz; DMSO-d6): δ2.83(d,1H,J=12.44Hz),3.41-3.48(m,1H),3.75( s,3H),3.92(t,1H,J=9.24Hz),4.13(t,1H,J=94Hz),5.71(s,1H),6.31(s,1 H),6.63(d,1H,J=8.68Hz),6.73-6.81(m,2H),6.97(s,1H),7.19(s,1H),7. 33-7.45(m,6H),7.79(s,1H),8.25(s,1H),8.42(s,1H),10.87(s,1H); LCMS m / z: 457.36[M+H].

[0923] Preparation 69: 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3- (1H-Indol-6-yl)urea (Example 85)

[0924]

[0925] To a stirred solution of methyl 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Example 86) (100 mg, 0.22 mmol) in THF (3 mL) was added DIBAL-H (0.66 mL, 0.66 mmol, 1 M in toluene) dropwise at 0-5 °C. The mixture was then stirred at the same temperature for 2 h. The reaction mixture was quenched by adding a saturated solution of Rochelle salt dropwise at RT, and the resulting solution was stirred at RT for 1 h. The reaction mass was filtered through a bed of celite. The celite bed was washed with EtOAc, the organics were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude material was purified by reverse phase preparative HPLC to give the title compound as a yellow solid (16 mg, 17% yield). UPLC purity: 98.85%; 1H NMR (400MHz; DMSO-d6): δ3.31 (s, 1H), 3.51 (s, 1H), 3.91 (t, 2H, J = 5.35Hz), 4.05 (d, 1H, J = 6.24Hz), 4.12 (d, 1H, J = 5.12Hz), 4.84 (t, 1H, J = 6.74Hz), 4. 99(t,1H,J=6.74Hz)6.31(s,1H),6.55(m,2H),6.78(s,2H),6.90(s,1H),7. 19-7.38(m,6H),7.77(s,1H),8.14(s,1H),8.32(s,1H),10.85(s,1H); LCMS m / z: 429.2[M+H].

[0926] Examples 189 to 190

[0927] The examples in the table below were prepared according to the methods used above for the preparation of Examples 84 to 86 using the appropriate amines as described in General Procedures 1, 3 to 4, 6, 27. Purification was as stated in the preceding methods.

[0928]

[0929]

[0930] Example 191: 6-(4-(1H-indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3-yl (4H)-Keto

[0931]

[0932] Example 191 was prepared according to General Procedures 4, 25 and the methods described below.

[0933] Preparation 70: 4-Benzyl-6-bromo-2H-benzo[b][1,4]thiazin-3(4H)-one

[0934]

[0935] K2CO3 (627 mg, 4.54 mmol) was added to a solution of commercially available 6-bromo-2H-benzo [b] [1,4] thiazine-3 (4H) -one (500 mg, 3.026 mmol) in DMF (3 mL) at RT. After the mixture was stirred for 2-3 min, bromotoluene (0.395 mL, 3.33 mmol) was added to the mixture, and all reactants were heated at 80 ° C for 12 h. The reaction progress was monitored by LCMS, and after completion, the reaction mass was quenched with ice water. The product was extracted with EtOAc. The combined organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (450 mg, 44.5% yield) as a white solid.

[0936] Preparation 71: 6-(Piperazin-1-yl)-1H-indole

[0937]

[0938] Step 1: tert-Butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate

[0939]

[0940] LiHMDS (1.12 mL, 1.12 mmol) was added to a degassed mixture of commercially available 6-bromo-1H-indole (100 mg, 0.51 mmol), tert-butyl piperazine-1-carboxylate (114 mg, 0.61 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and X-Phos (7.3 mg, 0.015 mmol) in THF (2 mL) in a sealed tube at RT. The tube was purged with argon again and then sealed. The mixture was stirred for 1-2 min at RT and then heated at 65 ° C for 24 h. The progress of the reaction was monitored by LCMS, and after completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography to give the title compound (100 mg, 65% yield) as a white solid.

[0941] Step 2: 6-(Piperazin-1-yl)-1H-indole

[0942]

[0943] 1,4-Dioxane (3 mL) containing 4M HCl was added to a solution of tert-butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate (Preparation 71, Step 1) (600 mg, 1.99 mmol) in dioxane at 0-5 °C. Thereafter the reaction was stirred at RT for 3 h. The reaction mass was quenched with saturated aqueous NaHCO3 and the product was extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (210 mg, 52.4% yield) as a brown solid. LCMS m / z: 202 [M+H].

[0944] Preparation 72: 6-(4-(1H-indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3-yl (4H)-Keto (Example 191)

[0945]

[0946] A mixture of 6-(piperazin-1-yl)-1H-indole (Preparation 71, Step 2) (60 mg, 0.29 mmol), 4-benzyl-6-bromo-3,4-dihydro-2H-1,4-benzothiazin-3-one (Preparation 70) (149 mg, 0.45 mmol), BrettPhos-Pd-G3 (27 mg, 0.03 mmol) and Cs2CO3 (291 mg, 0.894 mmol) in dioxane (4 mL) was heated at 100° C. for 24 h. The progress of the reaction was monitored by LCMS, and after completion, the solvent was evaporated under reduced pressure to give the crude compound, which was purified by preparative HPLC to give the title compound (15 mg, 11% yield) as an off-white sticky solid. HPLC purity 93.36%; H NMR (400MHz; DMSO-d6): δ2.85(s,4H),2.88(s,4H),3.77(s,2H),5.30(s,2H),6.51(d,1H,J= 2.96Hz), 6.77 (s, 1H), 6.85 (d, 1H, J = 8.8Hz), 7.21-7.43 (m, 9H), 7.61 (d, 1H, J = 8.32Hz); LCMS m / z: 455.33[M+H].

[0947] Example 192: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-cyano- 3-(1H-Indol-6-yl)guanidine

[0948]

[0949] Example 192 was prepared according to General Procedures 2 to 4 and the methods described below.

[0950] Preparation 73: 6-isothiocyanato-1H-indole

[0951]

[0952] To a stirred solution of 6-aminoindole (200 mg, 1.52 mmol) in DMF (10 mL) was added dropwise DMF (2 mL) containing sulfanyl-CDI (297 mg, 1.67 mmol) at 0-5 ° C. The reactant was stirred for 2 h at RT. After the reaction was completed (checked by LCMS), it was quenched with ice-cold water (20 mL) and extracted with EtOAc. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the title compound (40 mg, yield 20%) as a dark brown solid. The crude material was used in the next step without any further purification.

[0953] Preparation 74: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indole Indole-6-yl)thiourea

[0954]

[0955] To a stirred solution of 6-isothiocyanato-1H-indole (Preparation 73) (40 mg, 0.23 mmol) in DCM (2.0 mL) was added 6-amino-4-benzyl-1,4-benzothiazin-3-one (Preparation 5) (62.1 mg, 0.23 mmol) at RT, and the reaction mixture was stirred at the same temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mass was evaporated to dryness to give the title compound (80 mg, 78% yield) as a brown solid. The crude material was used in the next step without any further purification. LCMSm / z: 445.41 [M+H].

[0956] Preparation 75: Methyl-N'-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N- (1H-Indol-6-yl)carbamimidothioate

[0957]

[0958] To a solution of 1-(4-benzyl-3-oxo-1,4-benzothiazin-6-yl)-3-(1H-indol-6-yl)thiourea (Preparation 74) (80 mg, 0.18 mmol) in acetone (2 mL) was added KCO (62.3 mg, 0.45 mmol) and MeI (0.03 mL, 0.45 mmol) at RT. The reaction mixture was stirred for 4 h at RT. The progress of the reaction was monitored by LCMS, and after completion, the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give the title compound (50 mg, 61% yield) as a brown solid. The crude material was used in the next step without any further purification. LCMS m / z: 459.17 [M+H].

[0959] Preparation 76: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-cyano- 3-(1H-Indol-6-yl)guanidine (Example 192)

[0960]

[0961] A stirred solution of 3-(4-benzyl-3-oxo-1,4-benzothiazin-6-yl)-1-(1H-indol-6-yl)-2-methyl-isothiourea (Preparation 75) (50 mg, 0.11 mmol) in 2-propanol (1 mL) was treated with sodium hydrocyanamide (8.74 mg, 0.14 mmol) and heated in a microwave at 80 ° C for 1 h. After the reaction was completed (monitored by LCMS), the solvent was evaporated to obtain a crude product, which was purified by preparative HPLC to give the title compound (6 mg, 12.2% yield) as an off-white sticky solid. HPLC purity 99.26%; 1H NMR (400MHz; DMSO-d6): δ3.63(s,2H),5.12(s,2H),6.39(s,1H),6.85(d,1H,J=7.92Hz), 7.00(d,1H,J=7.96Hz),7.19-7.47(m,10H),9.15(s,1H),9.38(s,1H),11.08(s,1H); LCMS m / z: 453.29[M+H].

[0962] Biological analysis

[0963] Reporter gene expression analysis in THP-1 cells

[0964] THP1-Dual TM The cells (Invivogen) are derived from the human THP-1 monocytic cell line by stably integrating two inducible reporter constructs. TM The cells allow the study of the IRF pathway by assessing the activity of secreted luciferase (Lucia) while the study of the NF-κB pathway by monitoring the activity of secreted SEAP. 4 THP1-Dual TM Cells were seeded in growth medium in 384-well plates and pre-incubated with novel compounds for 10 minutes before stimulation with 5 μM 2',3'-cGAMP. After 20 hours of stimulation, the supernatant was removed and a luciferase detection reagent, QUANTI-Luc, was used. TM IRF pathway reporter proteins are easily measured in cell culture supernatants on a Spectramax i3X photometer (Invivogen).

[0965] In the following table, the IC values ​​of exemplary compounds are given. 50 Value range. IC 50 Values ​​less than or equal to 1 μM in the range are denoted as “A”, values ​​greater than 1 μM and less than or equal to 10 μM are denoted as “B”, and values ​​greater than 10 μM are denoted as “C”.

[0966] Activity data

[0967]

[0968]

[0969]

Claims

1. A compound of formula (I), Where X 2 CR 2 ; X 3 CR 3 ; X 6 C=O or CR 7 R 8 ; Z is CR 9 R 10 ; X 7 is S or O; n is 1; R 1 and R 4 All are H, R 7 and R 8 Each independently selected from the group consisting of: H, CN, CONR 13 R 14 , optionally substituted C1-C6 alkyl and optionally substituted C2-C6 alkenyl, wherein when R 7 and / or R 8 When it is an optionally substituted C1-C6 alkyl or an optionally substituted C2-C6 alkenyl, the alkyl or alkenyl is unsubstituted or substituted with OH and NR 20 R 21 One or more substitutions in; R 9 and R 10 Each is independently selected from the group consisting of: H and optionally substituted C1-C6 alkyl, wherein when R 9 and / or R 10 When it is an optionally substituted C1-C6 alkyl group, the alkyl group is unsubstituted or substituted with CN, COOR 20 and CONR 20 R 21 One or more substitutions in; R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other of is selected from the group consisting of: H, halogen and CONR 13 R 14 ; R 5 For L 5 -L 6 -R 16 ; R 13 and R 14 Each is independently selected from the group consisting of: H and C1-C6 alkyl; L 1 NR 17 ; L 2 C=O; L 3 NR 18 ; L 4 is absent, C1-C6 alkylene, cyclohexylene or 5-membered heteroarylene; L 5 and L 6 None or L 5 is an optionally substituted C1-C6 alkylene group and L 6 does not exist or is 0, when L 5 When it is an optionally substituted C1-C6 alkylene group, the alkylene group is unsubstituted or substituted with an oxo group, OH, COOR 20a and CONR 20a R 21a One or more substitutions in; R 15 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl or an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein when R 15 When it is an optionally substituted aryl group, the aryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, NR 20 R 21 ,CONR 20 R 21 and CN, and when R 15 When it is an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, the heteroaryl, cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, oxo, NR 20 R 21 ,CONR 20 R 21 , and CN; R 16 is an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, wherein when R 16 When it is an optionally substituted aryl group, the aryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: C1-C6 alkyl optionally substituted with halogen and / or OH, C1-C6 alkoxy optionally substituted with halogen and / or OH, halogen, OH, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 aryl and 5- to 10-membered heteroaryl, and when R 16 When it is an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocycle, the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl optionally substituted with halogen and / or OH, C1-C6 alkoxy optionally substituted with halogen and / or OH, halogen, OH, oxo, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 Aryl and 5- to 10-membered heteroaryl; R 17 and R 18 are independently H or C1-C6 alkyl; R 20 and R 21 are each independently selected from the group consisting of: H and C1-C6 alkyl optionally substituted with halogen; and R 20a and R 21a Each is independently selected from the group consisting of: H, C1-C3 alkyl and C3-C6 cycloalkyl; or a pharmaceutically acceptable salt thereof; and wherein the compound is not 2. The compound according to claim 1, wherein L 4 is absent or is C1-C6 alkylene.

3. The compound according to claim 1 or claim 2, wherein -L 1 -L 2 -L 3 -L 4 -for The asterisk indicates 15 The key point of .

4. The compound according to claim 1 or claim 2, wherein R 15 Phenyl, 5. The compound according to claim 1 or 2, wherein L 5 is absent or optionally substituted C1-C3 alkylene.

6. The compound according to claim 5, wherein L 5 CH2, CH2CH2, CO, Or does not exist.

7. The compound according to claim 1 or 2, wherein R 16 Cyclopropyl, cyclopentyl, phenyl, 8. The compound according to claim 1 or claim 2, wherein R 7 and R 8 are independently H, CN, CONH2, CH2NH2, CH2CH2OH, 9. The compound according to claim 1 or 2, wherein R 13 and R 14 It is H or C1-C3 alkyl.

10. The compound according to claim 1, wherein the compound is: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-phenylurea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-fluorophenyl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(pyridin-3-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(pyridin-4-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-5-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-cyanobenzyl)urea; 1-(4-Fluorophenyl)-3-(3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Fluorophenyl)-3-(3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-7-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxazin-6-yl)urea; 1-(4-(Benzo[d]isoxazol-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(3-aminophenyl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-fluorophenyl)-3-(4-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1-methyl-1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indazol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)urea; 1-(1H-benzo[d]imidazol-6-yl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)-1-methylurea; 1-(4-Benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-phenylurea; 4-(3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)ureido)benzamide; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(4-fluorophenyl)urea; 1-(4-(3-aminobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 3-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1-(1H-indol-6-yl)-1-methylurea; 1-(1H-indol-6-yl)-3-(4-((2-methylpyridin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(5-methyl-1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(2-methyl-1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,3-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((2,3-dihydrobenzo[b][1,4]dioxazin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 3-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-(3-chloro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-(2-chlorophenoxy)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-([1,1'-biphenyl]-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-chloro-5-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(4-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(3-chloro-4-(trifluoromethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-fluoro-3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(difluoromethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chlorophenethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-chloro-4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,5-dimethoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(Benzo[d]thiazol-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 6-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)nicotinic acid; 1-(4-(Benzo[c][1,2,5]thiadiazol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-cyano-2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(4-chloro-2-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluoro-3-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluoro-3-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluoro-4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluoro-4-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(1H-1,2,4-triazol-1-yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(Benzo[c][1,2,5]oxadiazol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(furan-2-ylmethyl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)urea; 1-((1H-pyrrol-3-yl)methyl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)urea; 1-(4-((5-(tert-butyl)-1,2,4-oxadiazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(2,3-dihydro-1H-inden-2-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(4-phenylcyclohexyl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea; 1-(4-(4-Hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; Methyl 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(indolin-6-yl)urea; 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid; 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-((1,4-dioxan-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(Hydroxymethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 3-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-(3-(Hydroxymethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(2-Hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyrimidin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-((1H-pyrazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((1H-imidazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((1,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(isoxazol-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide; 1-(4-Benzyl-6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 2-amino-N-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea; 1-(4-(Cyclopropylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-(cyclopentylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-fluorophenyl)urea; 1-(4-(2-fluoro-4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[3,2-b]pyridin-6-yl)urea; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)-1-methylurea; 6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; 1-(4-Benzyl-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 2-(6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)acetamide; 1-(3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxamide; 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxamide; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide; 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetic acid methyl ester; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-methyl-2-phenylacetamide; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-cyclopropyl-2-phenylacetamide; or 1-(4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, for the manufacture of a medicament for regulating the stimulator of interferon genes (STING) protein, Where X 2 CR 2 ; X 3 CR 3 ; X 6 C=O or CR 7 R 8 ; Z is CR 9 R 10 ; X 7 is S or O; n is 1; R 1 and R 4 All are H, R 7 and R 8 Each independently selected from the group consisting of: H, CN, CONR 13 R 14 , optionally substituted C1-C6 alkyl and optionally substituted C2-C6 alkenyl, When R 7 and / or R 8 When it is an optionally substituted C1-C6 alkyl or an optionally substituted C2-C6 alkenyl, the alkyl or alkenyl is unsubstituted or substituted with OH and NR 20 R 21 One or more substitutions in; R 9 and R 10 Each is independently selected from the group consisting of: H and optionally substituted C1-C6 alkyl, wherein when R 9 and / or R 10 When it is an optionally substituted C1-C6 alkyl group, the alkyl group is unsubstituted or substituted with CN, COOR 20 and CONR 20 R 21 One or more substitutions in; R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other of is selected from the group consisting of: H, halogen and CONR 13 R 14 ; R 5 For L 5 -L 6 -R 16 ; R 13 and R 14 Each is independently selected from the group consisting of: H and C1-C6 alkyl; L 1 NR 17 ; L 2 C=O; L 3 NR 18 ; L 4 is absent, C1-C6 alkylene, cyclohexylene or 5-membered heteroarylene; L 5 and L 6 None or L 5 is an optionally substituted C1-C6 alkylene group and L 6 does not exist or is 0, when L 5 When it is an optionally substituted C1-C6 alkylene group, the alkylene group is unsubstituted or substituted with an oxo group, OH, COOR 20a and CONR 20a R 21a One or more substitutions in; R 15 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl or an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein when R 15 When it is an optionally substituted aryl group, the aryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, NR 20 R 21 ,CONR 20 R 21 and CN, and when R 15 When it is an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, the heteroaryl, cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, oxo, NR 20 R 21 ,CONR 20 R 21 , and CN; R 16 is an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, wherein when R 16 When it is an optionally substituted aryl group, the aryl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl optionally substituted by halogen and / or OH, C1-C6 alkoxy optionally substituted by halogen and / or OH, halogen, OH, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 aryl and 5- to 10-membered aryl, and when R 16 When it is heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycle, the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl optionally substituted with halogen and / or OH, C1-C6 alkoxy optionally substituted with halogen and / or OH, halogen, OH, oxo, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 Aryl and 5- to 10-membered heteroaryl; R 17 and R 18 are independently H or C1-C6 alkyl; R 20 and R 21 are each independently selected from the group consisting of: H and C1-C6 alkyl optionally substituted with halogen; and R 20a and R 21a Each is independently selected from the group consisting of: H, C1-C3 alkyl and C3-C6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

13. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, for the manufacture of a medicament for treating, alleviating or preventing a disease selected from the group consisting of liver fibrosis, fatty liver disease, nonalcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy of infancy (SAVI), Aicardi-Gutierrez syndrome (AGS), 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), Where X 2 CR 2 ; X 3 CR 3 ; X 6 C=O or CR 7 R 8 ; Z is CR 9 R 10 ; X 7 is S or O; n is 1; R 1 and R 4 All are H, R 7 and R 8 Each independently selected from the group consisting of: H, CN, CONR 13 R 14 , optionally substituted C1-C6 alkyl and optionally substituted C2-C6 alkenyl, When R 7 and / or R 8 When it is an optionally substituted C1-C6 alkyl or an optionally substituted C2-C6 alkenyl, the alkyl or alkenyl is unsubstituted or substituted with OH and NR 20 R 21 One or more substitutions in; R 9 and R 10 Each is independently selected from the group consisting of: H and optionally substituted C1-C6 alkyl, wherein when R 9 and / or R 10 When it is an optionally substituted C1-C6 alkyl group, the alkyl group is unsubstituted or substituted with CN, COOR 20 and CONR 20 R 21 One or more substitutions in; R 2 and R 3 One of them is -L 1 -L 2 -L 3 -L 4 -R 15 , and R 2 and R 3 The other of is selected from the group consisting of: H, halogen and CONR 13 R 14 ; R 5 For L 5 -L 6 -R 16 ; R 13 and R 14 Each is independently selected from the group consisting of: H and C1-C6 alkyl; L 1 NR 17 ; L 2 C=O; L 3 NR 18 ; L 4 is absent, C1-C6 alkylene, cyclohexylene or 5-membered heteroarylene; L 5 and L 6 None or L 5 is an optionally substituted C1-C6 alkylene group and L 6 does not exist or is 0, when L 5 When it is an optionally substituted C1-C6 alkylene group, the alkylene group is unsubstituted or substituted with an oxo group, OH, COOR 20a and CONR 20a R 21a One or more substitutions in; R 15 is an optionally substituted monocyclic or bicyclic C6-C 12 aryl or an optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein when R 15 When it is an optionally substituted aryl group, the aryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, NR 20 R 21 ,CONR 20 R 21 and CN, and when R 15 When it is an optionally substituted heteroaryl, an optionally substituted cycloalkyl or an optionally substituted heterocyclyl, the heteroaryl, cycloalkyl or heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halogen, OH, oxo, NR 20 R 21 ,CONR 20 R 21 , and CN; R 16 is an optionally substituted monocyclic or bicyclic C3-C6 cycloalkyl, an optionally substituted monocyclic or bicyclic C6-C 12 aryl, optionally substituted monocyclic or bicyclic 5- to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3- to 8-membered heterocycle, wherein when R 16 When it is an optionally substituted aryl group, the aryl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl optionally substituted by halogen and / or OH, C1-C6 alkoxy optionally substituted by halogen and / or OH, halogen, OH, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 aryl and 5- to 10-membered aryl, and when R 16 When it is heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycle, the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C6 alkyl optionally substituted with halogen and / or OH, C1-C6 alkoxy optionally substituted with halogen and / or OH, halogen, OH, oxo, CN, COOR 20 NR 20 R 21 ,CONR 20 R 21 , SR 20 、SO2R 20 、C6-C 12 Aryl and 5- to 10-membered heteroaryl; R 17 and R 18 are independently H or C1-C6 alkyl; R 20 and R 21 are each independently selected from the group consisting of: H and C1-C6 alkyl optionally substituted with halogen; and R 20a and R 21a Each is independently selected from the group consisting of: H, C1-C3 alkyl and C3-C6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

14. The use according to claim 13, wherein the disease is fibrosis, and the fibrosis is selected from the group consisting of liver fibrosis, lung fibrosis or kidney fibrosis.

15. The use according to claim 13, wherein the disease is fatty liver disease, and the fatty liver disease is non-alcoholic fatty liver disease or non-alcoholic steatohepatitis (NASH).

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