CN118159535A

CN118159535A - Small molecule STING antagonists

Info

Publication number: CN118159535A
Application number: CN202280061293.7A
Authority: CN
Inventors: M·班纳吉; S·巴苏; R·K·什里瓦斯塔瓦; D·C·普里德; S·K·米蒂雅; R·高希; D·B·亚达夫; A·苏里亚
Original assignee: Curadev Pharma Pvt Ltd
Current assignee: Curadev Pharma Pvt Ltd
Priority date: 2021-08-11
Filing date: 2022-08-11
Publication date: 2024-06-07

Abstract

The present invention relates to compounds of formula (I). The compounds are useful for antagonizing interferon gene stimulatory factor (Stimulator of Interferon Genes; STING) proteins and may thus treat liver fibrosis, fatty liver disease, nonalcoholic steatohepatitis (non-alcoholic steatohepatitis; NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (rheumatoid arthritis; RA), type I diabetes, post-infancy associated vascular disease (STING-associated vasculopathy with onset IN INFANCY; SAVI), akadine-gules syndrome (Aicart-Goutieres syndrome; AGS), familial chilblain-like lupus (familial chilblain lupus; FCL), systemic lupus erythematosus (systemic lupus erythematosus; SLE), retinal vascular disease, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke, and age-related macular degeneration (age-related macular degeneration; AMD).

Description

Small molecule STING antagonists

The present invention relates to small molecule antagonists of the interferon gene stimulating factor (STING) protein. Thus, the small molecule antagonists are useful in the treatment of various inflammatory diseases, such as fatty liver disease, pulmonary fibrosis, pancreatitis, lupus, and the like. The invention extends to pharmaceutical compositions of the compounds themselves, methods of making the compounds, and methods of using these compounds to modulate STING proteins.

STING (interferon gene stimulators) is an innate signaling molecule that plays a key role in mediating immune responses to cytosolic DNA.

The human immune system has evolved to recognize and respond to different types of threats and pathogens to maintain a healthy host. The innate arms of the immune system are primarily responsible for the rapid initial inflammatory response to the danger signals associated with cellular or tissue damage from bacterial, viral and other infection threats. The innate immune system reacts to molecular patterns (DAMP) associated with these lesions or molecular patterns (PAMPs) associated with microbial product pathogens through a series of sentinel proteins known as Pattern Recognition Receptors (PRRs) to provide extensive and durable protection to the host from a wide range of threats (p. briz (Broz) et al, natural review immunology, 2013,13,551).

PAMPs and DAMP are typically components of intracellular pathogens or replicative intermediates. PRR includes bell-like receptors (TLR; activated by endosomal nucleic acid), C-lectin receptors, retinoic acid-inducible gene I (RIGI-like receptors; activated by cytosolic RNA), NOD-like receptors (NLR) and double stranded DNA sensors (dibold et al, journal of science, 2004,303,1529-1531; o.bamboon et al, journal of cells, 2010,140,805, pi Jile micel (PICHLMAIR) et al, 2006,314,997). PRR responds to DAMP and PAMP by up-regulating type 1 interferon and cytokines. Free cytosolic nucleic acid (DNA and RNA) is known as PAMP/DAMP. The primary sensor of cytosolic DNA is cGAS (cyclic GMP-AMP synthase). Once cytosolic dsDNA is recognized, cGAS triggers the formation of one specific isoform c [ G (2 ', 5') pA (3 ', 5') p ] of the Cyclic Dinucleotide (CDN) cGAMP (Gao et al, journal of cells, 2013,153,1094). CDNs are second messenger signaling molecules produced by a variety of bacteria and are composed of two ribonucleotides linked via a phosphodiester linkage to form a cyclic structure. CDN cyclo-bis (GMP) (c-diGMP), cyclo-bis (AMP) (c-diAMP) and hybrid cyclo- (AMP/GMP) (cGAMP) derivatives (A. Abrasol (Ablasser) et al, J. Nature, 2013,498,380) are tightly bound to ER-transmembrane adaptor protein STING (D.L. Burdette) et al, J. Nature, 2011,478,515; H. Shichun (Ishikawa), J. Nature, 2008,455,674).

STING recognizes CDNs through its cytosolic carboxy-terminal domain, which forms homodimers and employs V-shaped binding pockets to bind CDNs (Zhang et al, journal of molecular cells, 2013,51,226; g.n. baber et al, natural immunology, 2011,12,929). Ligand-induced STING activation triggers its relocation to the golgi apparatus and conformational change to promote binding to TBK1.TBK1 in turn signals through transcription factors IRF-3, STAT6 and NF _K B to induce type I interferon and other cytokines and interferon-stimulating genes (C. Green Hill (GREENHILL), "Nature reviewed in Endocrinology, 2018,14,192; Y. Li, H.L. Wilson, and E.kesh-Toth (Kiss-Toth)," J. Inflammation study, 2017,14,11). After activation, STING rapidly degrades in normal reactions.

Excessive activation of STING is associated with a series of monogenic autoinflammatory disorders called interferon disease (y.j. Clausia (Crow) and n. Ma Naer (Manel), journal of natural review immunology, 2015,15,429-440). The loss-of-function mutations in human DNAse Trex1 are associated with high levels of cGAMP and autoimmune diseases, such as the rare but severe inflammatory diseases of icardi-gutters syndrome (Aicardi-Goutieres syndrome, AGS), familial chilblain-like lupus (FCL), systemic Lupus Erythematosus (SLE), and retinal vascular disorders (y.

Inhalation of silica particles can cause lung inflammation and lung fibrosis, triggered by lung cell death and release of dsDNA products. This increased activation of STING by circulating dsDNA and increased levels of signaling through CXCL10 and IFN have been reported by Ma Erzu g (Benmerzoug) et al to produce pulmonary inflammation (s. This Ma Erzu g et al, natural communication 2018,9,5226).

Cytosolic dsDNA increases were detected in Fibroblasts Like Synoviocytes (FLS) taken from Rheumatoid Arthritis (RA) patients and dsDNA content correlated with the severity of rheumatoid synovitis (j. King et al, international journal of immunopharmacology, 2019,76,105791). These findings indicate that increased dsDNA promotes inflammatory responses via STING pathways in RA FLS and causes increased expression of STING, suggesting that cytosolic DNA accumulation is an important factor in RA-associated inflammation.

Patients with chromosomal dominant gain-of-function mutations in STING suffer from pediatric autoimmune inflammatory conditions called SAVI (STING-related vasculopathy in infancy), which are manifested clinically as rashes, vasculopathies, lupus-like syndromes and pulmonary fibrosis, characterized by abnormal IFN production and systemic inflammation, associated with high morbidity and mortality (n. Ke Nixi (Konig) et al, yearbook.rheumatics 2017,76,468). Characteristic mutations in humans include V147L, N154S, V M and G166E, which are both located in the interface region between the transmembrane domain and the ligand binding domain and cause ligand independent constitutive activated proteins. Recently, three other functionally acquired STING mutations, C206Y, R281Q and R284S, have been identified in the clustered regions that promote STING aggregation and are detrimental to the complexing of the C-terminal tail region (h.kano (Konno) et al, cell report, 2018,23,1112 and i.mel (Melki) et al, journal of allergy and clinical immunology, 2017,140 (2), 543).

Recent reports of halberyl (Habtezion) et al have shown that STING responds to acinar cell death by detecting DNA from necrotic cells and promotes acute pancreatitis in mice with acute pancreatitis (a. Halberyl et al, journal of gastroenteropathy, 2018,154,1822). STING knockout mice suffer from less severe acute pancreatitis (less edema, less inflammation), while administration of STING agonists causes more severe pancreatitis.

Row (Luo) et al have also recently shown an increased content of STING in liver tissue from mice with high-fat diet-induced liver steatosis in patients with non-alcoholic fatty liver disease. Again, STING knockout mice develop less severe liver fibrosis and less acute inflammatory response (x. Ro et al, journal of gastroenterology, 2018,155,1971). Elevated cGAMP levels in peripheral blood mononuclear cells of SLE patients correlated with higher disease scores (j. An et al, journal of rheumatology, 2017,69,800), indicating that the severity of lupus disease correlates with activation of STING pathway.

The tubular cells of individuals with fibrosis have been shown to be deficient in mitochondrial Transcription Factor A (TFAM). Mice lacking tubular TFAM develop severe mitochondrial losses and energy shortages caused by abnormal packaging of mitochondrial DNA and its translocation to the cytosol where the STING pathway is activated (k.w. clock (Chung), journal of cell metabolism, 2019,30,1). Subsequent expression of cytokines and inflammation cause renal fibrosis.

Benian (Bennion) et al have demonstrated that obtaining a functionally mutated N153S knock-in mouse shows an increased susceptibility to viral infection and a response to infection with murine gamma herpes virus gamma HV68 with severe autoinflammation and pulmonary fibrosis (B. Benian et al J.Virol.2019, 93, e 01806).

Other conditions in which excessive immune system activation may be associated with STING pathway activation include systemic inflammatory response syndrome (r.k. bosa panti (Boyapati) et al, F1000 journal of research, 2017,6,169), cardiovascular disease (k.r. gold (King) et al, journal of natural medicine, 2017,23,1481), stroke (a.m. Jeffries et al, journal of neuroscience, 2017,658,53) and age-related macular degeneration (n. kluya (Kerur) et al, journal of natural medicine, 2018,24,50).

Thus, a great deal of convincing evidence suggests that blocking, inhibiting or antagonizing STING pathways may have therapeutic benefit in many disorders and disease states. Few reports have been made regarding small molecule antagonists of STING proteins, such as t.west wu (Siu) et al (ACS pharmaceutical chemistry express, 2019,10 (1), 92), but the compounds described therein are reported to have low cell-based potency. Other reports of STING antagonists include s. Ha Ge (Haag) et al (journal of nature, 2018,559 (7713), 269) and z.flood (Hong) et al (journal of national academy of sciences, 2021,118 (24), e 2105465118).

Thus, there is an urgent need for improved small molecule blockers of STING pathways, and in particular small molecule direct antagonists of STING proteins. The present invention arose from the work of the inventors in attempting to identify modulators of STING proteins.

According to a first aspect of the present invention there is provided a compound of formula (I):

Wherein X ² is CR ² and X ³ is CR ³ or N; or X ² is N and X ³ is CR ³;

x ⁶ is c=o or CR ⁷R⁸;

Z is CR ⁹R¹⁰ or NR ⁹;

X ⁷ is S, SO ₂、O、NR¹¹ or CR ¹¹R¹²;

Wherein when Z is CR ⁹R¹⁰ then X ⁷ is S, SO ₂, O or NR ¹¹ and when Z is NR ⁹ then X ⁷ is CR ¹¹R¹²;

R ¹、R⁴、R⁷ and R ⁸ are each independently selected from the group consisting of: H. halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, and optionally substituted mono-or bicyclic 3-to 8-membered heterocycle;

R ⁹ to R ¹² are each independently selected from the group consisting of: H. halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl;

One of R ² and R ³ is:

And when X ² is CR ² and X ³ is CR ³, the other of R ² and R ³ is selected from the group consisting of: H. halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, and optionally substituted mono-or bicyclic 3-to 8-membered heterocycle;

A is CR ¹⁹ or N;

x is CR ²⁰ or N;

Y is CR ²¹ or N;

t is CR ²² or N;

Q is H or optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, COOR ¹³、COR¹³ or CONR ¹³R¹⁴;

P is selected from the group consisting of: H. halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl and optionally substituted mono-or bicyclic 3-to 8-membered heterocycle;

R ⁵ is selected from the group consisting of: COOR ¹³、CONR¹³R¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, optionally substituted mono-or bicyclic 3-to 8-membered heterocycle and L ¹-L²-R¹⁵;

R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. halogen, OH, CN, COOH, CONH ₂、NH₂, NHCOH, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, optionally substituted C ₁-C₆ alkoxycarbonyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, optionally substituted mono-or bicyclic 3-to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy;

L ¹ is absent or is optionally substituted C ₁-C₆ alkylene, optionally substituted C ₂-C₆ alkenylene, optionally substituted C ₂-C₆ alkynylene, O, S, S = O, SO ₂ or NR ¹⁸;

L ² is absent or is optionally substituted C ₁-C₆ alkylene, optionally substituted C ₂-C₆ alkenylene, optionally substituted C ₂-C₆ alkynylene, O, S, S = O, SO ₂ or NR ¹⁸;

R ¹⁵ is optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl or optionally substituted mono-or bicyclic 3-to 8-membered heterocycle; and

R ¹⁶ to R ¹⁸ are independently H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl or CN;

R ¹⁹ to R ²² are independently H, halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5 to 10 membered heteroaryl, and optionally substituted mono-or bicyclic 3 to 8 membered heterocycle;

Or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof;

wherein the compound is not

The compounds of formula (I) are useful as pharmaceutical agents.

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.

The inventors have found that compounds of formula (I) are useful for modulating interferon gene stimulating factor (STING) proteins.

Thus, in a third aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, for use in modulating an interferon gene stimulating factor (STING) protein.

Preferably, the compounds of formula (I) are used to inhibit or deactivate STING proteins. As demonstrated by a reduction in one or more biological effects selected from the group consisting of: production of cellular interferon beta, cellular content of interferon-stimulated genes, production of cytokines, and phosphorylation of transcription factors IRF-3 and NF- κB.

By inhibiting STING protein, can be used for treating, improving or preventing liver fibrosis, fatty liver disease, pulmonary fibrosis, lupus, rheumatoid Arthritis (RA), STING-related vasculopathy (SAVI) in infancy, pancreatitis, cardiovascular disease, nonalcoholic fatty liver disease and renal fibrosis.

By inhibiting STING proteins, it can be used for treating, improving or preventing liver fibrosis, fatty liver disease, nonalcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, rheumatoid Arthritis (RA), STING-related vasculopathy (SAVI) in infancy, icaldi-gules syndrome (AGS), familial lupus erythematosus (FCL), systemic Lupus Erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke, and age-related macular degeneration (AMD).

Accordingly, in a fourth aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, for use in the treatment, amelioration or prophylaxis of a disease selected from: liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid Arthritis (RA), type I diabetes, STING-related vasculopathy (SAVI) in infancy, icadi-gules syndrome (AGS), familial lupus erythematosus (FCL), systemic Lupus Erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke, and age-related macular degeneration (AMD).

In a fifth aspect, there is provided a method of modulating STING protein in a subject, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

Preferably, the method comprises inhibiting STING protein.

Preferably, the method is a method of inhibiting or not activating STING proteins.

In a sixth aspect, there is provided a method of treating, ameliorating or preventing a disease selected from the group consisting of: liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid Arthritis (RA), type I diabetes, STING-related vasculopathy (SAVI) in infancy, icadi-gules syndrome (AGS), familial lupus erythematosus (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 a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

It is understood that the term "preventing" may mean "reducing … … the likelihood". In a preferred embodiment, the disease is fibrosis. The fibrosis may be selected from the group consisting of: liver fibrosis, lung fibrosis or kidney fibrosis. In some embodiments, the fibrotic patient may have up-regulated STING expression and/or STING activity in the tissue as compared to a healthy individual.

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

The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise.

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

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

"Optional" or "optionally" means that the subsequently described event, operation or circumstance may or may not occur, and that the description includes instances where the event, operation or circumstance occurs and instances where it does not.

The term "alkyl" as used herein refers to saturated straight or branched chain hydrocarbons unless specified otherwise. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group comprises one to six carbon atoms, i.e., a C ₁-C₆ alkyl group. C ₁-C₆ alkyl includes, for example, methyl, ethyl, n-propyl (1-propyl), 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 C ₁-C₆ alkoxy, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. Thus, it will be appreciated that an optionally substituted C ₁-C₆ alkyl group may be an optionally substituted C ₁-C₆ haloalkyl, i.e. a C ₁-C₆ alkyl group substituted with at least one halogen, and optionally in turn substituted with one or more of the following: OH, optionally substituted C ₁-C₆ alkoxy, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. The optionally substituted C ₁-C₆ alkyl group may be a polyfluoroalkyl group, preferably a C ₁-C₃ polyfluoroalkyl group.

R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen, OH, CN, COOH, CONH ₂、NH₂, NHCOH, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, optionally substituted C ₁-C₆ alkoxycarbonyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, optionally substituted mono-or bicyclic 3-to 8-membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy and optionally substituted heterocyclyloxy. R ²³ and R ²⁴ may each be independently selected from the group consisting of: h and halogen.

The term "alkylene" as used herein refers to a divalent saturated straight or branched chain hydrocarbon, unless specified otherwise. In certain embodiments, the alkylene is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkylene group comprises one to six carbon atoms, i.e., a C ₁-C₆ alkylene group. C ₁-C₆ alkylene includes, for example, methylene, ethylene, n-and i-propylenes, butylenes, pentylenes, hexylenes, i-butylenes, sec-butylenes, t-butylenes, i-pentylenes, neopentylenes and i-hexylenes. The alkylene group may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, halogen, OH, optionally substituted C ₁-C₆ alkoxy, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. Thus, it will be appreciated that the optionally substituted C ₁-C₆ alkylene may be an optionally substituted C ₁-C₆ haloalkylene, i.e. a C ₁-C₆ alkylene substituted with at least one halogen, and optionally in turn substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, OH, optionally substituted C ₁-C₆ alkoxy, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. It will be appreciated that the optionally substituted C ₁-C₆ alkylene may be an optionally substituted polyfluoroalkyl group, preferably a C ₁-C₃ polyfluoroalkyl group. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

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

The term "polyfluoroalkyl" may denote a C ₁-C₃ alkyl group in which two or more hydrogen atoms are replaced by fluorine atoms. The term may include perfluoroalkyl groups, i.e., C ₁-C₃ alkyl groups in which all hydrogen atoms are replaced with fluorine atoms. Thus, the first and second substrates are bonded together, the term C ₁-C₃ polyfluoroalkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, 2-trifluoroethyl pentafluoroethyl, 3-trifluoropropyl 2, 3-pentafluoropropyl and 2, 2-trifluoro-1- (trifluoromethyl) ethyl.

"Alkoxy" refers to the group R ²² -O-, wherein R ²² is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. Exemplary C ₁-C₆ alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy (1-propoxy), n-butoxy, and t-butoxy. Alkoxy groups may be unsubstituted or substituted with one or more of the following: halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"Aryl" refers to an aromatic 6 to 12 membered hydrocarbon group. The term includes bicyclic groups in which one of the rings is aromatic and the other is not. Examples of C ₆-C₁₂ aryl include, but are not limited to, phenyl, α -naphthyl, β -naphthyl, biphenyl, tetrahydronaphthyl, and indanyl. Aryl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

The term "bicyclic" or "bicyclic" as used herein refers to a molecule characterized by two fused rings, which rings are cycloalkyl, heterocyclyl or heteroaryl. In one embodiment, the ring is fused across a bond between two atoms. The bicyclic moieties thus formed share bonds between the rings. In another embodiment, the bicyclic moiety is formed by two rings fused across a series of atoms of the rings to form a bridgehead. Similarly, a "bridge" is an undivided branch of one or more atoms in a polycyclic compound connecting two bridgeheads. In another embodiment, the bicyclic molecule is a "spiro" or "spiro" moiety. The spiro group may be a C ₃-C₆ cycloalkyl or a monocyclic or bicyclic 3 to 8 membered heterocycle bound to a single carbon atom of the carbocyclic or heterocyclic moiety through a single carbon atom of the spiro moiety. In one embodiment, the spiro group is cycloalkyl and is bound to another cycloalkyl. In another embodiment, the spiro group is cycloalkyl and is bound to a heterocyclyl. In another embodiment, the spiro group is a heterocyclyl group and is bound to another heterocyclyl group. In yet another embodiment, the spiro group is heterocyclyl and is bound to cycloalkyl. The spiro group may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic, or polycyclic hydrocarbon 3-to 6-membered ring system. Representative examples of C ₃-C₆ cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"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 of the rings is aromatic and the other is not. The or each heteroatom may be independently selected from the group consisting of: oxygen, sulfur and nitrogen. Examples of 5-to 10-membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, 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 those in which the phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5-or 6-membered monocyclic heteroaryl ring. Heteroaryl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"Heterocycle" or "heterocyclyl" refers to a 3 to 8 membered monocyclic, bicyclic, or bridged molecule wherein 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 heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, oxypropylene, thiocyclopropane, dihydropyrrole, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3, 6-tetrahydropyridin-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane (thiine), piperazine, azepane, diazepane, and oxazine. The heterocyclic group may be unsubstituted or substituted with one or more of the following: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"Alkenyl" refers to an ethylenically unsaturated hydrocarbon group that may be unbranched or branched. In certain embodiments, the alkenyl group has 2 to 6 carbons, i.e., it is a C ₂-C₆ alkenyl group. C ₂-C₆ alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl, and hexenyl. Alkenyl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

"Alkynyl" refers to an acetylenically unsaturated hydrocarbon radical that may be unbranched or branched. In certain embodiments, the alkynyl has 2 to 6 carbons, i.e., it is a C ₂-C₆ alkynyl. C ₂-C₆ alkynyl includes, for example, propargyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynyl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. R ²³ and R ²⁴ may be as defined above. R ²³ and R ²⁴ may each be independently selected from the group consisting of: H. halogen and optionally substituted C ₁-C₆ alkyl.

The term "alkenylene" as used herein refers to a divalent ethylenically unsaturated straight or branched chain hydrocarbon, unless specified otherwise. Alkenylene groups may be as defined above for alkenyl groups, but from which a hydrogen atom is removed to make the group divalent.

The term "alkynylene" as used herein refers to a divalent acetylenically unsaturated straight or branched chain hydrocarbon, unless otherwise specified. Alkynylene may be as defined above with respect to alkynyl groups, but from which a hydrogen atom is removed to make the group divalent.

"Alkylsulfonyl" refers to the group alkyl-SO ₂ -, wherein alkyl is optionally substituted C ₁-C₆ alkyl, and is as defined above.

"Alkoxycarbonyl" refers to the group alkyl-O-C (O) -, wherein alkyl is optionally substituted C ₁-C₆ alkyl. Alkoxycarbonyl groups may be unsubstituted or substituted with one or more of the following: optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, OH, CN, oxo 、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle.

"Aryloxy" refers to the group Ar-O-, wherein Ar is an optionally substituted monocyclic or bicyclic C ₆-C₁₂ aryl, as defined above.

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

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

The complex which liberates the compound of formula (I) is a multicomponent complex in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. The complex may not be a salt or solvate. Complexes of this type include the crystal cage compounds (drug-host packages and complexes) and the co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components that are bound together by non-covalent interactions, but may also be a complex of neutral molecules and salts. The co-crystals may be prepared by melt crystallization, by recrystallization from a solvent, or by physical grinding of the components together, see chemical communications of o. almasen (Almarsson) and m.j. Zatoppec (Zaworotko) (2304), 17,1889-1896, which are incorporated herein by reference. For a general review of multicomponent complexes, see Haributilan (Haleblian) (month 8 in 1975), journal of pharmacy, 64 (8), 1269-1288, which is incorporated herein by reference.

It is understood that the term "pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains the biological properties of the compound and is non-toxic or otherwise undesirable for pharmaceutical use. These salts may be derived from a variety of organic and inorganic counterions well known in the art. These salts include (but are not limited to): (1) Acid addition salts with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminobenzenesulfonic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthalene acid, salicylic acid, stearic acid, cyclohexylaminobenzenesulfonic acid, quinic acid, mucic acid, and the like; or (2) a base addition salt formed when acidic protons present in the parent compound are (a) replaced with a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonium hydroxide, or (b) complexed with an organic base, e.g., an aliphatic, alicyclic, or aromatic organic amine, e.g., ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, guanylic acid, choline, N' -diphenylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, ginseng (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, and the like.

Pharmaceutically acceptable salts may include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains basic functionalities, salts of non-toxic organic or inorganic acids, such as hydrohalides, for example, hydrochloride, hydrobromide and hydroiodide, carbonate or bicarbonate, sulfate or bisulfate, borate, phosphate, hydrogen phosphate, dihydrogen phosphate, jiao Fuan acid salt, glucarate, stearate, sulfamate, nitrate, orotate, oxalate, palmitate, pamoate, acetate, trifluoroacetate, trichloroacetate, propionate, caproate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, tannate, tartrate (tartrate), tosylate, sorbate, ascorbate, malate, maleate, fumarate, tartrate (tartarate), camphorsulfonate, citrate, cyclosulfonate, benzoate, isethionate, ethanesulfonate, formate, 3- (4-hydroxybenzoyl) benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), methylsulfate, naphtalate, 2-naphtalate, nicotinate, ethanesulfonate, 1, 2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-naphthalenesulfonate, 2-naphtalenesulfonate, 2-methylbenzenesulfonate, 2-octanesulfonate, 2-methylbenzenesulfonate, 2-octanesulfonate), glucoheptonate, 3-phenylpropionate, trimethyl acetate, t-butyl acetate, dodecyl sulfate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, maritime benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quininate, mucinate, xin Nuo acid salts, and the like.

Semi-salts of acids and bases, for example, hemisulfate salts, may also be formed.

Those skilled in the art will appreciate that the foregoing salts include those in which the counter ion is optically active (e.g., D-lactate), or racemic (e.g., DL-tartrate).

For a review of suitable salts, see the "handbook of pharmaceutically acceptable salts" of stell (Stahl) and vitamin Mutter (wermth): properties, selection and use "(Willi chemical Press, wei Yinhai m, germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of three methods:

(i) By reacting the compound of formula (I) with the desired acid or base;

(ii) Removing acid or base labile protecting groups from suitable precursors of the compounds of formula (I) by using the desired acid or base; or (b)

(Iii) Converting one salt of the compound of formula (I) into another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can range from fully ionized to almost non-ionized. It is understood that the term "solvate" refers to a compound provided herein or a salt thereof, which in turn includes a stoichiometric or non-stoichiometric amount of a 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 invention include those in which the crystallization solvent may be isotopically substituted, such as D ₂O、d₆ -acetone and D ₆ -DMSO.

The currently accepted classification system for organic hydrates is one that defines isolation sites, channels, or metal-ion coordination hydrates, see the polymorphism in pharmaceutical solids of k.r. Morris (h.g. briton (Brittain) code, makinder, 1995), which is incorporated herein by reference. Spacer site hydrates are those in which water molecules are isolated from each other by intervening organic molecules. In channel hydrates, the water molecules are located in the lattice channel where they are adjacent to other water molecules. In metal-ion coordination hydrates, the water molecules are bonded to metal ions.

When solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water linkage is weak, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions. In these cases, the non-stoichiometry will become normal.

The compounds of the present invention may exist as solid state continuum ranging from fully amorphous to fully crystalline, including polymorphs of the crystalline material. The term "amorphous form" refers to a state in which the material lacks long-range order at the molecular level, and depending on temperature, may exhibit physical properties of a solid or a liquid. Typically these materials do not produce a unique X-ray diffraction pattern and, while exhibiting solid properties, are more formally described as liquid. Upon heating, a change in the solid to liquid nature occurs, characterized by a change in state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with specified peaks. These materials will also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in the mesogenic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate between the true crystalline state and the true liquid state (melt or solution). The mesogenic phenomenon due to temperature variations is described as "thermally induced" and the mesogenic phenomenon resulting from the addition of a second component (e.g. water or another solvent) is described as 'dissolved'. Compounds that are likely to form a lyotropic mesophase are described as 'amphiphilic' and are composed of molecules having polar head groups that are ionic (e.g., -COO ^-Na⁺、-COO^-K⁺ or-SO ₃ ^-Na⁺) or nonionic (e.g., -N ^-N⁺(CH₃)₃). For more information, see crystal and polarizing microscopes, 4 th edition (Edwardsied Arnold Press, 1970) of N.H. Hazhu (Harshorne) and A. Stuart, which are incorporated herein by reference.

The compounds of formula (I) may comprise 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.

It will be appreciated that the above-described compounds may exist in enantiomeric forms and as diastereomeric pairs. These isomers also represent other embodiments of the present invention. Conventional techniques for preparing/separating the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Or the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, in the case of compounds of formula (I) containing an acidic or basic moiety, with a base or acid, for example 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 converted to the corresponding pure enantiomers by means well known to the skilled artisan.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing from 0% to 50% by volume of isopropanol, typically from 2% to 20% by volume, and from 0% to 5% by volume of alkylamine, typically 0.1% diethylamine. The concentration of the elution liquid provides an enriched mixture.

The mixture of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, e.g., stereochemistry of "organic compounds" of e.l. illier (Eliel) and s.h. vinylon (Wilen) (wili, new york, 1994).

The term "STING" refers to an interferon gene stimulator, a functionally cyclic dinucleotide activated adaptor protein, which causes the production of interferon and inflammatory cytokines.

It will be appreciated that the 'antagonists' or 'inhibitors' associated with the ligand and STING comprise molecules, combinations of molecules or complexes that inhibit, counteract, down-regulate, and/or desensitize STING activity. An 'antagonist' comprises any agent that inhibits the constitutive activity of STING. Constitutive activity is activity that is exhibited in the absence of ligand/STING interactions. An 'antagonist' also comprises any agent that inhibits or prevents the stimulatory (or regulatory) activity of STING.

Preferably, the compounds of formula (I) are inhibitors of STING proteins.

R ¹ can be H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. R ¹ can be H, halogen, OH, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. Preferably, R ¹ is H.

It can be appreciated that since X ² is CR ² and X ³ is CR ³ or N; or X ² is N and X ³ is CR ³, at least one of R ² and R ³ is present in the compound of formula (I). In embodiments where X ² is CR ² and X ³ is CR ³, both R ² and R ³ are present in the compound of formula (I).

As specified above, one of R ² and R ³ is:

Thus, in embodiments where R ² is present and R ³ is absent, R ² will be Conversely, in embodiments where R ² is absent but R ³ is present, R ³ will beFinally, in embodiments where both R ² and R ³ are present, only one of R ² and R ³ is

In one embodiment, X ² is N and X ³ is CR ³. In this embodiment, R ³ is

In an alternative embodiment, X ² is CR ² and X ³ is N. In this embodiment, R ² is

However, in a preferred embodiment, X ² is CR ² and X ³ is CR ³. In some embodiments, R ² isIn an alternative embodiment, R ³ isThus, the compound may be a compound of formula (Ia) or formula (Ib):

Preferably, one of R ² and R ³ is And the other of R ² and R ³ is H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl. More preferably, one of R ² and R ³ isAnd the other of R ² and R ³ is H, halogen, OH, CN, CONR ¹³R¹⁴、NR¹³R¹⁴、C₁-C₃ alkyl, C ₂-C₃ alkenyl, or C ₂-C₃ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. c ₁-C₃ alkyl, C ₂-C₃ alkenyl and C ₂ -C alkynyl. Preferably, one of R ² and R ³ isAnd the other of R ² and R ³ is H, bromo or CONH ₂. In a preferred embodiment, one of R ² and R ³ isAnd the other of R ² and R ³ is H.

R ¹⁶ and R ¹⁷ may independently be H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl. R ¹⁶ and R ¹⁷ may independently be H, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. Preferably, R ¹⁶ and R ¹⁷ are H or methyl. Most preferably, R ¹⁶ and R ¹⁷ are H.

P may be H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl. Preferably, P is H, halogen, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. In a preferred embodiment, P is H or methyl.

Q may be H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl. Preferably, Q is H, halogen, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. In a preferred embodiment, Q is H.

A. at least one of X, Y and T may be N. Thus, in one embodiment, A is N, X is CR ²⁰, Y is CR ²¹ and T is CR ²². In another embodiment, A is CR ¹⁹, X is N, Y is CR ²¹ and T is CR ²². In another embodiment, a is CR ¹⁹, X is CR ²⁰, Y is N and T is CR ²². In yet another embodiment, a is CR ¹⁹, X is CR ²⁰, Y is CR ²¹ and T is N.

Alternatively a may be CR ¹⁹, X may be CR ²⁰, Y may be CR ²¹ and T may be CR ²².

R ¹⁹ to R ²² may independently be H, halogen, CN, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, or optionally substituted mono-or bicyclic 3-to 8-membered heterocycle. Preferably, R ¹⁹ to R ²² are independently H, halogen, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl, C ₂-C₃ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, or optionally substituted mono-or bicyclic 5 to 10 membered heteroaryl.

When one or more of R ¹⁹ to R ²² is halogen, the or each halogen may be fluorine, chlorine, bromine or iodine. Preferably, halogen is fluorine, chlorine or bromine.

When one or more of R ¹⁹ to R ²² is optionally substituted aryl, the or each optionally substituted aryl may be optionally substituted phenyl. The or each aryl group may be unsubstituted or substituted with one or more of: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen 、OH、CN、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴ OR OP (O) (OR ²³)(OR²⁴).

Preferably, the or each aryl group may be unsubstituted or substituted with one or more of: optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted C ₁-C₃ alkoxy, halogen, OH, CN, COOR ²³、CONR²³R²⁴、SO₂R²³ or OSO ₂R²³. Preferably, R ²³ and R ²⁴ are independently H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl. More preferably, R ²³ and R ²⁴ are independently H or methyl. The or each alkyl, alkenyl, alkynyl or alkoxy group may be unsubstituted or substituted with: halogen, OH, CN, C ₁-C₃ alkoxy or C ₃-C₆ cycloalkyl. Thus, in a most preferred embodiment, the or each aryl group may be unsubstituted or substituted with one or more of the following: fluorine, chlorine, methyl, ethyl, isopropyl 、CHF₂、CF₃、CH₂OH、CH₂CH₂OH、CH₂CH₂OCH₃、CH₂CH(OH)CH₃、CH₂CH₂CN、OCH₃、OCF₃、 cyclopropylmethyl, OH, CN, CONH ₂ or SO ₂CH₃.

When one or more of R ¹⁹ to R ²² is optionally substituted heteroaryl, the or each optionally substituted heteroaryl may be optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,2, 4-triazolyl, optionally substituted 1,2, 3-triazolyl, optionally substituted tetrazolyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, Optionally substituted 1,2, 5-oxadiazolyl, optionally substituted 1,2, 3-oxadiazolyl, optionally substituted 1,2, 5-thiadiazolyl, optionally substituted 1,3, 4-thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted 1,2, 4-triazinyl, optionally substituted 1,3, 5-triazinyl, optionally substituted indolinyl, optionally substituted 1H-indolyl, optionally substituted 2H-isoindolyl, optionally substituted indolizinyl, Optionally substituted 1H-indazolyl, optionally substituted benzimidazolyl, optionally substituted 4-azaindolyl, optionally substituted 5-azaindolyl, optionally substituted 6-azaindolyl, optionally substituted 7-azaindolyl, optionally substituted benzofuranyl, optionally substituted benzo [ b ] thienyl or optionally substituted 1, 3-benzodioxolyl. The or each heteroaryl group may be unsubstituted or substituted with one or more of: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen, oxo 、OH、CN、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴ OR OP (O) (OR ²³)(OR²⁴). Preferably, the or each heteroaryl group may be unsubstituted or substituted with one or more of: optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted C ₁-C₃ alkoxy, halogen, oxo, OH, CN, COOR ²³、CONR²³R²⁴、SO₂R²³ or OSO ₂R²³. Preferably, R ²³ and R ²⁴ are independently H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl. More preferably, R ²³ and R ²⁴ are independently H or methyl. The or each alkyl, alkenyl, alkynyl or alkoxy group may be unsubstituted or substituted with: halogen, OH, CN, C ₁-C₃ alkoxy or C ₃-C₆ cycloalkyl. Thus, in a most preferred embodiment, the or each aryl group may be unsubstituted or substituted with one or more of the following: fluorine, chlorine, methyl, ethyl, isopropyl 、CHF₂、CF₃、CH₂OH、CH₂CH₂OH、CH₂CH₂OCH₃、CH₂CH(OH)CH₃、CH₂CH₂CN、OCH₃、OCF₃、 cyclopropylmethyl, oxo, OH, CN, CONH ₂ or SO ₂CH₃.

Preferably, R ¹⁹ is H, halogen, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. More preferably, R ¹⁹ is H or fluoro. Most preferably, R ¹⁹ is H.

Preferably, R ²⁰ is H, halogen, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. More preferably, R ²⁰ is H or fluoro. Most preferably, R ¹⁹ is H.

Preferably, R ²¹ is H, halogen, CN, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, or optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl. In some embodiments, R ²¹ is H, fluorine, chlorine, bromine, CN,

Preferably, R ²² is H, halogen, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. More preferably, R ²² is H or fluoro. Most preferably, R ²² is H.

R ⁴ can be H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. R ⁴ can be H, halogen, OH, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. Preferably, R ⁴ is H.

R ⁵ may be-L ¹-L²-R¹⁵.

Preferably, L ¹ is optionally substituted C ₁-C₃ alkylene, optionally substituted C ₂-C₃ alkenylene or optionally substituted C ₂-C₃ alkynylene. The alkylene, alkenylene, or alkynylene group may be unsubstituted or substituted with one or more of the following: halogen 、OH、CN、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴ and oxo. R ²³ and R ²⁴ may independently be H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl or optionally substituted mono-or bicyclic 3-to 8-membered heterocycle. Preferably, R ²³ and R ²⁴ are independently H, methyl or cyclopropyl. Preferably, L ¹ is CH ₂、CH₂CH₂, CO, More preferably, L ¹ is CH ₂ or CO.

Or L ¹ may not be present.

In some embodiments, L ² is absent.

Or L ² can be O, S, S = O, SO ₂ or NR ¹⁹.R¹⁹ can be H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl. Preferably, L ² is O or S, and most preferably O.

R ¹⁵ can be optionally substituted monocyclic or bicyclic C ₃-C₆ cycloalkyl, optionally substituted monocyclic or bicyclic C ₆-C₁₂ aryl, optionally substituted monocyclic or bicyclic 5-to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-to 8-membered heterocycle. Preferably, R ¹⁵ is an optionally substituted monocyclic or bicyclic C ₆-C₁₂ aryl, an optionally substituted monocyclic or bicyclic 5 to 10 membered heteroaryl, or an optionally substituted monocyclic or bicyclic 3 to 8 membered heterocycle. More preferably, R ¹⁵ is optionally substituted phenyl or optionally substituted 5 to 10 membered heteroaryl. Optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The optionally substituted monocyclic or bicyclic 5-to 10-membered heteroaryl group 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 5-benzimidazolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, optionally substituted benzo [ b ] thienyl, 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 mono-or bicyclic 3-to 8-membered heterocycle may be optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyranyl, optionally substituted dioxanyl, optionally substituted thialkyl, optionally substituted dithianyl or optionally substituted morpholinyl.

When R ¹⁵ is aryl, cycloalkyl, heteroaryl, or heterocycle, the aryl, cycloalkyl, heteroaryl, or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of: optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted C ₁-C₆ alkoxy, halogen 、OH、CN、C(O)R²³、COOR²³、OC(O)R²³、CONR²³R²⁴、NR²³R²⁴、NR²³C(O)R²⁴、＝NOR²³、SR²³、SO₂R²³、OSO₂R²³、SO₂NR²³R²⁴、OP(O)(OR²³)(OR²⁴)、 optionally substituted C ₆-C₁₂ aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C ₃-C₆ cycloalkyl and optionally substituted 3 to 8 membered heterocycle. More preferably, when R ¹⁵ is aryl, cycloalkyl, heteroaryl, or heterocycle, the aryl, cycloalkyl, heteroaryl, or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of: optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted C ₁-C₃ alkoxy, fluoro, chloro, OH, CN, COOR ²³ and CONR ²³R²⁴. Preferably, R ²³ and R ²⁴ are independently H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl. More preferably, R ²³ and R ²⁴ are independently H or methyl. Thus, when R ¹⁵ is aryl, cycloalkyl, heteroaryl, or heterocycle, the aryl, cycloalkyl, heteroaryl, or heterocycle may be unsubstituted or substituted with one or more substituents selected from the group consisting of: methyl, OCH ₃, fluorine, chlorine, OH, CH and CONH ₂.

Thus, R ¹⁵ can be phenyl,

In an alternative embodiment, R ⁵ is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. R ⁵ can be optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, or optionally substituted C ₂-C₃ alkynyl. The alkyl, alkenyl, or alkynyl group may be unsubstituted or substituted with one or more of the following: halogen, OH, CN and oxo. R ⁵ can be CH ₃ or CH ₂ CN. Preferably, R ⁵ is CH ₃.

In some embodiments, X ⁶ is CO.

In alternative embodiments, X ⁶ is CR ⁷R⁸.R⁷ and R ⁸ can independently be H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. R ⁷ and R ⁸ may independently be H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl. R ¹³ and R ¹⁴ are preferably H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl, and most preferably H. The alkyl, alkenyl, or alkynyl group may be unsubstituted or substituted with one or more of the following: halogen, OH, oxo 、CN、C(O)R²⁰、COOR²⁰、OC(O)R²⁰、CONR²⁰R²¹、NR²⁰R²¹、NR²⁰C(O)R²¹、＝NOR²⁰、SR²⁰、SO₂R²⁰、OSO₂R²⁰、SO₂NR²⁰R²¹ and OP (O) (OR ²⁰)(OR²¹).R²⁰ and R ²¹ may independently be H OR methyl preferably R ⁷ and R ⁸ are independently H, CN, CONH ₂、CH₂NH₂、CH₂CH₂ OH,Most preferably, R ⁷ and R ⁸ are H.

In one embodiment, Z is CR ⁹R¹⁰ and X ⁷ is S, SO ₂, O, or NR ¹¹. More preferably, X ⁷ is S, O, SO or NR ¹¹. Most preferably, X ⁷ is S or O. R ⁹ and R ¹⁰ may independently be H, halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl. R ¹³ and R ¹⁴ may independently be H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl. The alkyl, alkenyl, or alkynyl group may be unsubstituted or substituted with one or more of the following: halogen, OH, oxo 、CN、C(O)R²⁰、COOR²⁰、OC(O)R²⁰、CONR²⁰R²¹、NR²⁰R²¹、NR²⁰C(O)R²¹、＝NOR²⁰、SR²⁰、SO₂R²⁰、OSO₂R²⁰、SO₂NR²⁰R²¹ and OP (O) (OR ²⁰)(OR²¹).R²⁰ and R ²¹ may independently be H OR methyl preferably R ⁹ and R ¹⁰ are independently H, methyl, CH ₂CONH₂ OR CH ₂ CN. More preferably, R ⁹ and R ¹⁰ are H. R ¹¹ can be H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl. R ¹¹ can be H, C ₁-C₃ alkyl, C ₂-C₃ alkenyl, or C ₂-C₃ alkynyl. Preferably, R ¹¹ is H or methyl.

In an alternative embodiment, Z is NR ⁹ and X ⁷ is CR ¹¹R¹².R⁹ may be H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, or optionally substituted C ₂-C₃ alkynyl. Preferably, R ⁹ is methyl. R ¹¹ and R ¹² may independently be H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl. R ¹¹ and R ¹² may independently be H, halogen, OH, CN, C ₁-C₃ alkyl, C ₂-C₃ alkenyl or C ₂-C₃ alkynyl. Preferably, R ¹¹ and R ¹² are H or methyl. In embodiments, wherein X ⁷ is CR ¹¹R¹² and R ¹¹ and R ¹² are different, the carbon to which R ¹¹ and R ¹² are bound defines a chiral center. The chiral center may be an S or R chiral center. In some embodiments, the chiral center is an S chiral center.

It will be appreciated that the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomeric forms or polymorphic forms thereof, may be used in medicaments for use in monotherapy (i.e. the compounds are used alone) to modulate STING proteins and/or to treat, ameliorate or prevent diseases.

Or a compound or a pharmaceutically acceptable salt, solvate, tautomer or polymorphic form thereof, may be used as an adjunct to, or in combination with, known therapies for modulating STING proteins and/or treating, ameliorating or preventing a disease.

The compounds of formula (I) may be combined in compositions having many different forms, in particular depending on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, lozenge, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposomal suspension, or any other suitable form that can be administered to a human or animal in need of treatment. It will be appreciated that the vehicle of the medicament according to the invention should be well tolerated by the individual to whom it is administered.

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

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

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which administration the compound enters the blood stream directly from the oral cavity. Formulations suitable for oral administration include solid formulations such as lozenges, capsules containing granules, liquids or powders, buccal tablets (including liquid filled), chewable tablets, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations may be used as fillers in soft or hard capsules and typically comprise a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying and/or suspending agents. Liquid formulations can also be prepared by, for example, reconstitution of solids from a pouch.

The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in the therapeutic patents expert opinion of the beam (Liang) and Chen (2001), 11 (6), 981-986.

For a lozenge dosage form, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form, depending on the dosage. In addition to the drug, lozenges generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low-carbon alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise from 1 to 25% by weight, preferably from 5 to 20% by weight of the dosage form.

Binders are generally used to impart cohesive qualities to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrate, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

The lozenge may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise from 0.2% to 5% by weight of the lozenge and the glidant may comprise from 0.2% to 1% by weight of the lozenge.

Lozenges also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant generally comprises from 0.25% to 10% by weight, preferably from 0.5% to 3% by weight of the lozenge. Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste masking agents.

Exemplary lozenges contain up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant, and about 0.25% to about 10% by weight lubricant. The lozenge blend may be compressed directly or by rollers to form a lozenge. The lozenge blend or portions of the blend may alternatively be wet, dry or melt granulated, melt coagulated or extruded prior to the preparation of the lozenge. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. H. Li Boman (Lieberman) and l. raman (Lachman): lozenge "formulation of lozenge is discussed in volume 1 (majordre, new york, 1980).

Modified release formulations suitable for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release techniques, such as high energy dispersions and osmotic and coated particles, are found in Vilma (Verma) et al (2001), "on-line pharmaceutical techniques", 25 (2), 1-14. Controlled release using chewing gum is described in WO 00/35298.

The compounds of the invention may also be administered directly into the blood stream, into the muscle or into internal organs. Modes suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably to a pH of 3 to 9), but for some applications they may be more suitable for formulation into sterile nonaqueous solutions or into dry forms to be used in combination with a suitable vehicle (e.g. sterile, pyrogen-free water).

Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily performed using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (I) for use in preparing parenteral solutions may be increased by using appropriate formulation techniques (e.g. incorporating solubility enhancers). Formulations for parenteral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present invention may be formulated as solid, semi-solid, or thixotropic liquids for administration as an implantable depot providing modified release of the active compound. Examples of such formulations include drug coated stents and poly (dl-lactic-co-glycolic) acid (PGLA) microspheres.

The compounds of the invention may also be administered topically, i.e. transdermally or transdermally, to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohols, water, mineral oils, liquid paraffin, white paraffin, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated, see, for example, fennin (Finnin) and Morgan (Morgan, journal of pharmacy, U.S. Pat. No. 88 (10), 955-958 (10, 1999).

Other means of topical application include delivery by electroporation, iontophoresis, sonophoresis, microneedle or needleless (e.g., powderject ^TM、Bioject^TM, etc.) injection.

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in mixtures, e.g., dry blends with lactose, or as mixed component particles, e.g., with phospholipids, for example phosphatidylcholine mixing) or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably a nebulizer that generates a fine mist using electrohydrodynamic) or nebulizer, with or without the use of a suitable propellant, such as 1, 2-tetrafluoroethane or 1,2, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

Pressurized containers, pumps, sprays, nebulizers, or atomizers contain solutions or suspensions of the compounds of the invention comprising, for example, ethanol, aqueous ethanol, or alternative agents suitable for dispersing, solubilizing, or prolonging the release of the active substance, a propellant as a solvent, and optionally a surfactant (e.g., sorbitol trioleate, oleic acid, or oligolactic acid).

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

Capsules (e.g., made of gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base (e.g., lactose or starch) and a performance modifying agent (e.g., L-alanine, mannitol, or magnesium stearate). The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

Solution formulations suitable for use in atomizers using electrohydrodynamic to produce fine mist can contain from 1 μg to 20mg of a compound of the invention per actuation and actuation volumes can vary from 1 μl to 100 μl. Typical formulations may comprise a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or sodium saccharin, may be added to the formulations of the present invention intended for inhalation/intranasal administration.

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

The compounds of the invention may be administered rectally or vaginally, for example, in the form of suppositories, pessaries, microbiocides, pessaries or enemas. Cocoa butter is a conventional suppository base, but various alternatives may optionally be used.

The compounds of the invention may also be applied directly to the eye or ear, typically in the form of droplets of micronized suspension or solution 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, wafers, lenses, and microparticle or vesicle systems, such as vesicles or liposomes. Polymers (e.g., crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid), cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose), or heteropolysaccharide polymers (e.g., gellan gum) may be incorporated along with a preservative (e.g., algicidal amine). These formulations may also be delivered by iontophoresis.

The compounds of the invention may also be administered directly to the site of interest by injection of a solution or suspension containing the active pharmaceutical substance. The site of interest may be a tumor and the compound may be administered by injection through the tumor. Typical injection solutions comprise propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

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

Drug-cyclodextrin complexes, for example, are found to be generally suitable for use in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which are described in International patent application Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

It will be appreciated that the amount of the compound required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, physicochemical properties of the compound and whether it is used as monotherapy or in 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 dosage to be administered can be determined by one of skill in the art and will vary with the particular compound used, the strength of the pharmaceutical composition, the mode of administration, and the progression of the disease. Additional factors depending on the particular individual being treated will result in the need to adjust dosages, including individual age, weight, sex, diet, and time of administration.

Generally, for human administration, the total daily dose of the compounds of the invention is typically in the range of 100 μg to 10g, such as 1mg to 1g, such as 10mg to 500 mg. For example, oral administration may require a total daily dose of 25mg to 250 mg. The total daily dose may be administered in a single dose or in divided doses and may be outside the typical ranges given herein at the discretion of the physician. These doses are based on a common human individual weighing about 60kg to 70 kg. The physician will be able to readily determine the dosage for individuals with body weights outside this range, such as infants and elderly.

The compounds may be administered before, during or after onset of the disease to be treated.

Known procedures, such as those commonly used by the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.), can be used to form specific formulations comprising compounds according to the invention and precise treatment regimens (e.g., daily dosages and frequency of administration of the compounds). The inventors believe that they are the first to describe a pharmaceutical composition for the treatment of diseases based on the use of the compounds of the present invention.

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

In an eighth aspect, the present invention also provides a method for making a composition according to the seventh aspect, the method comprising contacting with 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.

The "individual" may be a vertebrate, mammal, or livestock. Thus, the compounds, compositions and medicaments according to the invention may be used for the treatment of any mammal, such as livestock (e.g. horses), pets, or in other veterinary applications. Most preferably, however, the subject is a human.

A "therapeutically effective amount" of a compound is any amount that, when administered to an individual, is the amount of drug required to treat the disease of interest or to produce the desired effect (i.e., inhibit STING protein).

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

A "pharmaceutically acceptable vehicle" as referred to herein is any known compound or combination of known compounds known to those skilled in the art to be suitable for formulating pharmaceutical compositions.

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

However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The compounds according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle, such as water, an organic solvent, a mixture of both 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, thickening agents, colors, viscosity regulators, stabilizers or osmotically adjusted agents. Examples of liquid vehicles suitable for oral and parenteral administration include water (partially containing additives as described above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., ethylene glycol), and their derivatives, and oils (e.g., fractionated coconut oil and arachis 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 use in sterile liquid form compositions for parenteral administration. The liquid vehicle used to pressurize the composition may be a halocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions or suspensions may be utilized by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and in particular subcutaneous injection. The compounds may be prepared as sterile solid compositions which may be dissolved or suspended at the time of administration using sterile water, saline or other suitable sterile injectable medium.

The compounds and compositions of the invention may be administered in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., saline or dextrose sufficient to render the solution isotonic), bile salts, gum arabic, gelatin, sorbitol monooleate, polysorbate 80 (oleic acid esters of sorbitol and its anhydrides copolymerized with ethylene oxide), and the like. The compounds used according to the invention may also be administered orally in the form of liquid or solid compositions. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, lozenges and powders, and liquid forms such as solutions, syrups, elixirs and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

Those skilled in the art will appreciate that an active pharmaceutical ingredient may be converted to a prodrug, which is a metabolically labile derivative that is converted in vivo to the active pharmaceutical substance. Prodrugs of the compounds of formula (I) which contain metabolically or hydrolytically unstable moieties which are converted in vivo to the active agent of formula (I) are also included within the scope of the invention. Methods of converting the prodrugs to the active drug substance include, but are not limited to, hydrolysis of esters or carbonates or carbamates, hydrolysis of phosphate esters, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described in Boaumont et al, current drug metabolism, 2003,4,461-485 and Heteng (Huttentn) et al, pharmacological review, 2011,63,750-771. These prodrug derivatives may provide improved solubility, stability, or permeability compared to the parent drug substance, or may better allow administration of the drug substance by alternative routes of administration, for example as intravenous solutions.

Also included within the scope of the invention are soft or safe agents that are compounds of formula (I), which contain metabolically or hydrolytically unstable moieties that are converted in vivo to inactive derivatives. Methods of converting active drug substances into inactive derivatives include, but are not limited to, ester hydrolysis, S-oxidation, N-oxidation, dealkylation and metabolic oxidation as described, for example, in Peers (Pearce) et al, drug metabolism and treatment, 2006,34,1035-1040 and B, testa (Testa), prodrug and soft drug design, in Integrated pharmaceutical chemistry II, vol.5, estrene, oxford, 2007, pages 1009 to 1041 and Bodol (Bodor), nature chemical technology 1984,14,28-38.

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 which is predominant in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen (e.g., ² H and ³ H), isotopes of carbon (e.g., ¹¹C、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., ¹⁵O、¹⁷ O and ¹⁸ O), isotopes of phosphorus (e.g., ³² P), and isotopes of sulfur (e.g., ³⁵ S).

Certain isotopically-labeled compounds of the present invention (e.g., those into which they are incorporated) are useful in pharmaceutical and/or tissue distribution studies. The radioactive isotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly suitable for this purpose because they are easy to incorporate and easy to detect. Substitution with isotopes (e.g., deuterium, ² 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. Substitution with positron emitting isotopes (such as ¹¹C、¹⁸F、¹⁵ O and ¹³ N) may be useful in Positron Emission Tomography (PET) studies to examine occupancy of a substrate receptor.

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 previously employed unlabeled reagent.

General scheme

General scheme 1

As shown below, compounds of formulas (IVe) and (IVf) can be prepared from compounds of formulas (VIa) and (VIb) using a urea bond formation reaction.

Typical reaction conditions for activating aromatic amines of formula (VIa) or (VIb) employ 4-nitrophenyl chloroformate or triphosgene to produce an activated intermediate, which may be challenged with a suitable nucleophile, such as an amine (Va), to produce a urea compound of formula (IVe) or (IVf). Preferred organic bases include DIPEA or TEA in a suitable organic solvent (e.g., DCM, DMF, DMA or MeCN). The reaction may be shaken or stirred at room temperature.

Alternatively, the compounds of formula (IVe) or (IVf) can also be prepared from isocyanates (Vb) in a suitable solvent, for example THF, DMF or MeCN, and preferably an organic base, for example TEA or DIPEA. The reaction may be shaken or stirred at room temperature.

The compounds of the formulae (V) and (VI) are commercially available or can be synthesized by a person skilled in the art. In particular, methods for synthesizing compounds of formula (VI) are described in general schemes 2-4.

General scheme 2

As shown below, compounds of formulas (VIa) and (VIb) can be synthesized from compounds of formula (VII) using the Curtius (Curtius) reaction.

Typical reaction conditions include treatment of the compound of formula (VII) with the reagents diphenylphosphoryl azide (DPPA) and a base (e.g., TEA) to yield the corresponding acyl azide, which may be refluxed in t-butanol again to provide the BOC protected amine as an intermediate. The corresponding intermediate may be deprotected in an acidic environment to give the free amine of formula (VIa) or may be first substituted with a suitable agent (e.g., R ¹⁶ -X) using the methods described in general procedure (iv) followed by deprotection in an acidic environment to give the N-substituted amine of formula (VIb).

The compounds of formula (VII) are commercially available or can be synthesized by one skilled in the art. In particular, the methods for synthesizing compounds of formula (VII) are described in general schemes 3-4.

General scheme 3

The compounds of formula (VII) may be synthesized from esters of formula (VIII) wherein R is methyl, ethyl, benzyl or tert-butyl by hydrolysis.

The compound of formula (VIII) may be reacted with a suitable alkali metal or base to subject it to hydrolysis and provide the compound of formula (VII). The suitable alkali metal or base may be LiOH, KOH, naOH or K ₂CO₃ and the reaction may be carried out in aqueous solution.

General scheme 4

The compounds of formula (IX) may 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, alkylcycloalkyl halide, triflate or tosylate.

The compound of formula (VIII) may be reacted with a compound of formula (X) in the presence of a suitable base (e.g., naH, K ₂CO₃、NaHCO₃、Cs₂CO₃, or TEA) to provide a compound of formula (IX). Suitable reaction solvents include THF, CAN, DMA and DMF. In some cases we have also used 18-crown-6.

General scheme 5

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

First, the compound of formula (XIV) is subjected to nucleophilic substitution reaction with a compound of formula (XIII) wherein R is methyl, ethyl, benzyl or tert-butyl to produce the compound of formula (XII). The nucleophilic substitution reaction may be performed in the presence of a mild base (e.g., DBU, naH, TEA, DIPEA, K ₂CO₃、Cs₂CO₃ or KHCO ₃). The solvent used may be 1, 4-dioxane, acetone, meCN, THF or DMF.

The nitro group of the compound of formula (XII) may then be reduced to an amine group using a suitable reducing agent (e.g. Fe/AcOH, zn/HCl, zn/NH ₄Cl、Zn/HCOONH₄、SnCl₂/HCl or Pd/C/H ₂) in a suitable solvent (e.g. EtOH, meOH or THF). Subsequent amine-based compounds typically undergo in situ cyclization, resulting in the formation of the compound of formula (XI).

The compound of formula (XI) will be a compound of formula (VIII) wherein R ⁵ is H and X ⁶ is c=o.

General scheme 6

The compounds of formula (XV) can be prepared from compounds of formula (XIX) wherein R is methyl, ethyl, benzyl or tert-butyl in a four-step process as shown below.

First, the compound of formula (XIX) can be brominated using Br ₂ or a bromine source (e.g., NBS) to produce the compound of formula (XVIII). This compound may then be aminated by bromine substitution using R ⁹NH₂ to provide the compound of formula (XVII). The nitro group on the compound of formula (XVII) can then be reduced using a suitable reducing agent, such as those described in general scheme 5, to provide the compound of formula (XVI). The compound of formula (XVI) may then be reacted with a suitable carbonyl source to provide the compound of formula (XV). The carbonyl source may, for example, be 1, 1-carbonyl-diimidazole, phosgene or triphosgene.

Compounds of formula (XV) will be described as compounds of formula (VIII) wherein R ⁵ is H, X ⁶ is C=O, Z is NR ⁹,X⁷ is CR ¹¹R¹² and n is 1.

General scheme 7

The compounds of formula (XX) can be prepared from compounds of formula (XXV) wherein R is methyl, ethyl, benzyl or tert-butyl in a five-step process as shown below.

First, the compound of formula (XXV) can be protected with a suitable acetyl group using a reagent (e.g., TFAA, BOC-anhydride or acetic anhydride) to yield the compound of formula (XXIV). This compound may be alkylated using a suitable alkyl halide (R ⁹ -X) in the presence of a suitable base (e.g. NaH, K ₂CO₃、KHCO₃、Cs₂CO₃ or ^t BuCOOK/Na) to give a compound of formula (XXIII). The nitration reaction may then be carried out on the compound of formula (XXIII) as a nitration mixture, such as a mixture of nitric acid and sulfuric acid, to produce the 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 dithiosulfinate and TBASH as described in general procedure 6b to give the corresponding amine derivative. This amine is in turn reacted with an alkyl chloroformate RO (CO) Cl in the presence of a suitable organic or inorganic base, such as pyridine or K ₂CO₃, to provide the compound of formula (XXI). This compound may then be subjected to a cyclization process by using a suitable base and solvent combination (e.g., K ₂CO₃ and methanol) to produce the compound of formula (XX).

Compounds of formula (XX) are described as compounds of formula (VIII) wherein R ⁵ is H, X ⁶ is C=O, Z is NR ⁹,X⁷ is CH (S) R ¹¹ and n is 1.

General scheme 8

The 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.

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 amine group and provide the compound of formula (XXVIII). This compound may then be used to form the corresponding carbamate in the presence of a suitable organic or inorganic base, such as pyridine or K ₂CO₃, using a suitable chloroformate to provide a compound of formula (XXVII). The compound of formula (XXVII) may be converted to a cyclized compound of formula (XXVI) in a series of reactions, for example with a suitable amine R ⁹-NH₂ in the presence of an organic base such as TEA or DIPEA to form a schiff base, followed by reduction of the resulting imine with a mild reducing agent such as Na (AcO) ₃BH、NaCNBH₃ or NaBH ₄ in methanol. The resulting amine is typically subjected to secondary cyclization in situ to provide the compound of formula (XXVI).

Compounds of formula (XXVI) are described as compounds of formula (VIII) wherein R ⁵ is H, X ⁶ is C=O, Z is NR ⁹,X⁷ is CHR ¹¹ and n is 1.

General scheme 9

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

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 a borane-THF solution in a suitable solvent, such as THF, typically at low temperature.

The compound of formula (XXX) will be a compound of formula (VIII) wherein X ⁶ is CH ₂.

General scheme 10

Compounds of formula (XXXII) may be prepared from compounds of formula (XXXIII) in which R is methyl, ethyl, benzyl or tert-butyl.

The compound of formula (XXXIII) may undergo cyclization with 1, 2-dibromoethane in a basic reaction medium to produce a fused morpholine derivative compound of formula (XXXIII).

Compounds of formula (XXXII) will be described as compounds of formula (VIII) in which X ⁶ and Z are CH ₂ and X ⁷ is O.

General scheme 11

The compounds of formula (XXXIV) may be prepared from compounds of formula (XXXIX) in a series of reactions described in the schemes below, wherein X is halogen.

The compound of formula (XXXIX) may be subjected to acylation with a suitable acylating agent in an acetone or alcohol solvent to produce a compound of formula (XXXVIII), which may be cyclized in situ after introduction of amine R ¹¹NH₂ to produce a compound of formula (XXXVII). The compound of formula (XXXVII) may be reacted with a compound of formula (X), wherein X is a suitable leaving group, such as halide, tosylate or triflate, in the presence of a suitable base, such as NaH, naHCO ₃ or TEA, to provide a compound of formula (XXXVI). Suitable reaction solvents include THF, DMA and DMF. The lactam carbonyl group of the compound of formula (XXXV) can be reduced to the corresponding methylene group of the compound of formula (XXXV) using a borane-THF solution in a suitable solvent, such as THF, typically at low temperature. The nitro group of the compound of formula (XXXV) may be reduced to its corresponding amine group of the compound of formula (XXXIV) using NiCl ₂.6H₂ O and sodium borohydride in a polar solvent, such as methanol.

General scheme 12

Compounds of formulas (XL), (XLI) and (XLII) may be prepared from compounds of formula (XLV) in a series of reactions described in the schemes below.

The compound of formula (XLV) can be reduced to the corresponding alcohol with a reducing agent (e.g., DIBAL-H) and then subsequently converted to a leaving group, e.g., silyl ether (OTMS), with TMSOTf to produce the compound of formula (XLIV). The leaving group may be displaced by a suitable nucleophile to produce a compound of formula (XLIII). The suitable nucleophile may be CN or allyl. The allyl-containing compound of formula (XLIII) may then undergo hydroxylation with OsO ₄ to produce the compound of formula (XL). The compound of formula (XL) may be oxidized to the corresponding aldehyde using NaIO ₄ and then subsequently reduced to the corresponding primary alcohol (XLI) using a suitable reducing reagent, such as NaBH ₄. The nitro group of the compound of formula (XLIII) may also be reduced to the corresponding amine (XLII) using a suitable reducing reagent, such as Fe/AcOH or Zn/AcOH or Fe/NH ₄ Cl.

General scheme 13

The compounds of formula (XLVI) may be prepared from compounds of formula (XI) wherein R is methyl, ethyl, benzyl or t-butyl in a one-step reaction as described in the schemes below.

The compound of formula (XI) may be subjected to Chen Lin (Chan-Lam) coupling reaction with a suitable boric acid/borate in the presence of a suitable catalyst and a base to give the compound of formula (XLVI).

The compound of formula (XLVI) will be a compound of formula (VIII) wherein X ⁶ is c=o.

General scheme 14

The compounds of formula (XLVIII) may be prepared from compounds of formula (XLIX) wherein R is methyl, ethyl, benzyl or t-butyl in a one-step reaction as described in the schemes below.

The compound of formula (XLIX) may be subjected to a Buchwald (Buchwald) coupling reaction with a suitable aromatic halide (R ⁵ -X) to produce the compound of formula (XLVIII).

The compound of formula (XLVIII) will be described as a compound of formula (VIII) wherein X ⁶ is CR ⁷R⁸.

General scheme 15

The compounds of formula (L) may be prepared from compounds of formula (LI) wherein R is methyl, ethyl, benzyl or tert-butyl in a one-step reaction as described in the schemes below.

The compound of formula (LI) may be treated with a suitable base (e.g., liHMDS) to produce an anion at the most acidic methylene position, which anion may then be alkylated with a suitable electrophile (e.g., XCH ₂ CN) to produce the compound of formula (L).

Compounds of formula (L) are described as compounds of formula (VIII) wherein X ⁶ is C=O, Z is CHR ⁹ and n is 1.

General scheme 16

The compounds of formula (LII) may be prepared from compounds of formula (LVI) wherein R is methyl, ethyl, benzyl or t-butyl in a series of reactions as described in the schemes below.

First, compounds of formula (LVI) may be alkylated with a suitable alkylating agent in a suitable solvent (e.g., ACN, THF, or DMF) in the presence of a suitable base to produce compounds of formula (LV), which may be subjected to ester hydrolysis to produce compounds of formula (LIV). The acid functional group can then be converted to the corresponding amide with a suitable amine under typical amide coupling reaction conditions to provide the compound of formula (LIII). Finally, the nitro group of the compound of formula (LIII) may be reduced to the corresponding amine in the compound of formula (LII) using a suitable reducing reagent.

Library general scheme 1

Compounds of formula (LVII) may be prepared in parallel from compounds of formula (LVIII) by a metal-catalyzed carbon-carbon bond formation reaction as described in the schemes below using library or array techniques.

Compounds of formula (LVII) can be synthesized by Suzuki-Miyaura cross-coupling using the desired boronic acid or boronic ester in the presence of a suitable metal catalyst and an inorganic base in a suitable solvent under an inert atmosphere at elevated temperature.

General Synthesis procedure

General purification and analysis methods

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

Preparative HPLC

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

Mobile phase 1: a=0.1% formic acid in water, b=acetonitrile; gradient profile: the mobile phase had an initial composition of 80% a and 20% b, then after 3min it became 60% a and 40% b, then after 20min it became 30% a and 70% b, then after 21min it became 5%A and 95% b, at this composition it was held for 1min to clean the column, then returned to the initial composition for 3min.

Mobile phase 2: a=10 mM aqueous ammonium acetate solution, b=acetonitrile; gradient profile: the mobile phase had an initial composition of 90% a and 10% b, then after 2min it became 70% a and 30% b, then after 20min it became 20% a and 80% b, then after 21min it became 5%A and 95% b, at this composition it was held for 1min to clean the column, then returned to the initial composition for 3min.

LCMS method

The general 5min method is as follows: gemini C18 column (50X 4.6mm,5 μm) operated at ambient temperature and flow rate of 1.2 mL/min. Mobile phase: a=10 mM aqueous ammonium acetate solution, b=acetonitrile; gradient profile: 90% a and 10% B to 70% a and 30B in 1.5min, and then to 10% a and 90% B in 3.0min, held at this composition for 1.0min, and finally returned to the initial composition for 2.0min.

UPLC method

UPLC was performed on a Waters UPLC using Kinetex EVo C column (100X2.1 mm,1.7 μm) at ambient temperature and flow rate of 1.5 ml/min.

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

Mobile phase 2: a=0.05% formic acid in water, b=acetonitrile; the gradient profile was from 95% a and 5% b, then 90% a and 10% b, for 1min, then 2%A and 98% b, for 4min, and then returned to the initial composition, for 6min.

General procedure 1 (method a)

To a stirred solution of an aromatic amine of formula (VIa) (1.0 eq.) in a suitable solvent (e.g. THF, DMF, meCN or DCM (8 mL/mmol)) at 0 to 5 ℃ was added p-nitrophenyl chloroformate (1.2 eq.) and the whole stirred at room temperature for 1 to 3h. Amine (Va) (1.1 eq.) and TEA or DIPEA (6 eq.) were then added dropwise in sequence at 0 to 5 ℃ and the whole stirred at room temperature for a further 1 to 5h. The progress of the reaction was monitored by TLC/LCMS and after completion the reaction mass was diluted with water and extracted with EtOAc. The combined organic layers were washed with a dilute solution of a suitable inorganic base such as NaHCO ₃ or 1N naoh, then 1N HCl and finally brine. The organic layer was dried over anhydrous Na ₂SO₄ and evaporated in vacuo to give a residue which was purified by column chromatography or combined flash chromatography or preparative HPLC to provide the compound of formula (IVe) as a solid (yield 6 to 70%). A similar procedure can be followed to synthesize all ureas of formula (IVe).

General procedure 1 (method b)

To a stirred solution of aromatic amine of formula (VIa) (1.0 eq.) in a suitable solvent (e.g. THF, DMF, meCN or DCM) (5.5 mL/mmol) was added (Vb) (1.08 eq.) at 0 to 5 ℃ followed by TEA (1.08 eq.) and the whole stirred at the same temperature for 5 to 10min. The reaction mixture was allowed to slowly warm to room temperature and stirred for 1 to 2h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄, filtered and evaporated under reduced pressure to afford a crude solid which was purified by column chromatography or combination flash chromatography or preparative HPLC to afford the compound of formula (IVe) as a solid (yield 10 to 70%). A similar procedure can be followed to synthesize all ureas of formula (IVe).

General procedure 1 (method c)

Triphosgene (0.5 eq.) was added to a stirred solution of compound of formula (Va) (1 eq.) in THF (10 mL/mmol) at 0 to 5 ℃. The combined mixture was stirred at room temperature for 1h. Completion of the first stage of the reaction was confirmed by TLC or UPLC-MS, and then an aromatic amine compound of formula (VIa) (1.8 eq.) and TEA (2.5 eq.) were added to the reaction mixture and stirring was continued at room temperature for 1 to 2h. The progress of the reaction was monitored by TLC or UPLC-MS. After completion of the reaction, the solvent is evaporated in vacuo to afford the crude material, which is purified by column chromatography or preparative HPLC to give the compound of formula (IVe) as a solid (12 to 50% yield).

General procedure 2

To a stirred solution of the compound of formula (VII) (1.0 eq.) in a suitable solvent (e.g. MeCN, THF or DCM) (3.5 mL/mmol) at 0 to 5 ℃ under an inert atmosphere was added TEA (1.5 eq.) followed by DPPA (2.0 eq.) and the whole stirred at the same temperature for 5 to 10min. The reaction mixture was then allowed to warm to room temperature and stirred for 4 to 6h. The formation of the corresponding acyl azide was confirmed by TLC and UPLC-MS by quenching an aliquot of the reaction mixture with methanol. The solvent was evaporated in vacuo and tert-butanol (3.5 mL/mmol) was added to the resulting residue. The mixture was then refluxed overnight. Completion of the reaction was monitored by TLC and LC-MS, which showed formation of BOC protected amine compound of formula (VIa) and complete consumption of the starting material of formula (VII). After completion of the reaction, the solvent was evaporated in vacuo to obtain crude oil, which was adsorbed on silica gel and purified by combined flash to provide the BOC-protected intermediate amine compound of formula (VIa) (40 to 80% yield).

The resulting 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 to 5℃and the whole was stirred for 5 to 10min. The reaction mixture was then allowed to slowly warm to room temperature overnight. Completion of the reaction was confirmed by UPLC-MS and the solvent was evaporated in vacuo after completion. The resulting crude product was washed with NaHCO ₃ solution and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give the compound of formula (VIa) as a dark yellow solid (yield 50 to 90%).

General procedure 3

To a stirred solution of the ester (VIII) (1.0 eq.) in MeOH or a mixture of THF (6.5 mL/mmol) and water (0.8 mL/mmol) was added LiOH, naOH or KOH (2.0 eq.) at room temperature and the resulting reaction mixture was stirred at room temperature for 2 to 16h. TLC showed complete consumption of the ester (VIII). The solvent was evaporated in vacuo and the resulting residue was washed with ether. The residue is then acidified with 1N HCl to a pH of 5 to 6, which causes the formation of a precipitate, which is filtered and washed with water and then dried by azeotropic distillation or under reduced pressure at 50 to 60 ℃ to provide the desired carboxylic acid of formula (VII) (70 to 85% yield) as a solid.

General procedure 4

Option a

To a stirred solution of the compound of formula (VIII) (1.0 eq.) in DMF or THF or ACN (4 mL/mmol) was added K ₂CO₃、Cs₂CO₃、K₂CO₃、Na₂CO₃, naOH or NaH (1.1 eq.). In the case of using NaOH, TBAB (0.1 equivalent) was also added as a phase transfer catalyst, and in the case of using K ₂CO₃, 18-crown-6 (0.4 equivalent) was also added as a phase transfer catalyst, followed by the addition of the compound of formula (X) (1.05 equivalent) and allowing the mixture to stir at room temperature for 0.5 to 1h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with a saturated solution of NH ₄ Cl, diluted with ice-cold water and extracted with EtOAc or MTBE. The organic layer was washed with brine, dried over anhydrous Na ₂SO₄ and evaporated in vacuo to afford the crude product which was purified by combined flash chromatography using a mixture of EtOAc in hexanes as a solvent-out to give the compound of formula (IX) as a colourless oil (60 to 80% yield).

Option B

Or to a stirred solution of the compound of formula (VIII) (1, 0 eq.) in DCM or MeCN or THF (4 mL/mmol) was added TEA or DIPEA (2.0 eq.) or no base followed by the compound of formula (X) (1.5 eq.) and the whole was allowed to stir at room temperature for 0.5 to 1h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na ₂SO₄. The organic layer was evaporated in vacuo to give the crude product, which was purified by combined flash chromatography using a mixture of EtOAc in hexanes as a solvent-out to afford the compound of formula (IX) as a colorless oil (60 to 80% yield).

General procedure 5

To a stirred solution of the compound of formula (XIV) (1.0 eq.) and the appropriate nucleophile (XIII) (1.25 eq.) in a suitable solvent (e.g. 1, 4-dioxane, meCN, DMF or THF) (3 mL/mmol) is added dropwise or in portions a suitable base (e.g. TEA, DBU, naH or K ₂CO₃) (1.5 eq.) and the ice bath cooled and the combined mixture is allowed to stir at 0 to 25℃for 1 to 16h. The progress of the reaction was monitored by TLC or LCMS and once the reaction was complete, the mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and evaporated to dryness in vacuo. The crude compound of formula (XII) obtained as a solid (60 to 95% yield) is sufficiently pure to be used directly in the next step without any further purification.

General procedure 6

Option a (reduction by Fe/Zn-AcOH/HCl/NH ₄ Cl)

To a stirred solution of the compound of formula (XII) (1.0 eq.) in EtOH or MeOH (2 mL/mmol) at room temperature was added the appropriate acid (e.g. AcOH or aqueous HCl) (3 mL/mmol) followed by iron or zinc powder (4.0 eq.). In some cases, NH ₄ Cl is also used as a hydrogen source. The reaction mixture was stirred at 75 to 85 ℃ for 1 to 5h. The reaction was monitored by TLC or LCMS and after completion the reaction mixture was poured into ice cold water and filtered through a bed of short kieselguhr. The filtrate was extracted with EtOAc and then washed with aqueous NaHCO ₃ and then brine. The collected organic layer was dried over anhydrous Na ₂SO₄ and concentrated in vacuo to afford the compound of formula (XI) as a crude solid (60 to 80% yield), which was used in the next step without any further purification.

Option B: (reduction by sodium disulfonate)

To a stirred solution of the compound of formula (XII) (1.0 eq.) in MeCN/H ₂ O or THF/H ₂ O (12 mL/mmol, 2:1) at room temperature was added sodium bisulphite (8.0 eq.), tetrabutylammonium bisulfide (0.5 eq.) and K ₂CO₃ (6.0 eq.) and the mixture was then stirred for 1H. 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 Na ₂SO₄. The organics were filtered and evaporated in vacuo to give the compound of formula (XI) as a solid (80 to 90% yield).

Option C: (reduction by Pd/C/H ₂)

To a stirred solution of the compound of formula (XII) (1.0 eq.) in EtOAc, meOH or EtOH (9.4 mL/mmol,120 mL) under an inert atmosphere at room temperature was added 10% Pd-C (50% w/w in water) (77.8 mg/mmol). The reaction mixture was purged with H ₂ gas using balloon pressure and then allowed to stir at room temperature for another 3 to 5 hours. The reaction progress was monitored by TLC and/or LCMS. After the reaction was complete, the mixture was diluted with EtOAc, carefully filtered through a bed of celite and washed 4 to 5 times with EtOAc until the mother liquor showed no compound residue by TLC. The collected organic layer was then dried over anhydrous Na ₂SO₄, filtered and concentrated under reduced pressure to give the compound of formula (XI) as a semi-solid (80 to 85% yield). The product was pure enough to be used in the next step without any further purification.

Option D: (reduction by NiCl ₂.6H₂O/NaBH₄)

To a stirred solution of the compound of formula (XXXV) (1.0 eq.) in MeOH (9 mL/mmol) at 5 to 10 ℃ was added Boc ₂ O (1.5 eq.) followed by NiCl ₂.6H₂ O (0.5 eq.) and NaBH ₄ (2.5 eq.). The combined mixture was then allowed to warm to room temperature over 3 to 5 hours. The progress of the reaction was monitored by TLC and UPLC-MS, which showed the formation of intermediate products. After completion, the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄, filtered and evaporated under reduced pressure to afford the crude product which was purified by combined flash chromatography to afford the Boc-protected amine compound (90 to 96% yield). The material was dissolved in DCM (9 mL/mmol) and TFA (4 mL/mmol) and the whole was stirred at room temperature for 4 to 6h. UPLC-MS showed formation of the desired product. The solvent was evaporated in vacuo to give the crude product, which was neutralized with aqueous sodium carbonate and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na ₂SO₄, filtered and evaporated under reduced pressure to afford the compound of formula (XXXIV) as a semi-solid (80 to 85% yield).

General procedure 7

To a stirred solution of the compound of formula (XIX) (1.0 eq.) in a suitable solvent (e.g. carbon tetrachloride or trifluoromethylbenzene) (100 mL) was added NBS (1.2 eq.) and AIBN or benzoyl peroxide (0.1 eq.). The reaction mixture was heated at 70 to 100 ℃ for 12 to 16h. After complete consumption of the starting material, the reaction mixture was quenched with a saturated solution of Na ₂S₂O₃ and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na ₂SO₄. The crude product obtained after concentrating the organic layer in vacuo is purified by column chromatography to provide the compound of formula (XVIII) in 30 to 40% yield.

General procedure 8

To a stirred solution of the compound of formula (XVIII) (1.0 eq.) in a suitable solvent (e.g. THF) (5 mL/mmol) at room temperature is added a suitable amine (e.g. MeNH ₂) (3 mL/mmol,2M solution in THF) and the combined mixture is stirred at the same temperature or elevated temperature (60 to 90 ℃) for 10 to 16h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated brine solution, dried over anhydrous Na ₂SO₄ and concentrated in vacuo to afford the compound of formula (XVII) as a gummy solid (60 to 70% yield).

General procedure 9

To a stirred solution of the compound of formula (XVI) (1.0 eq) in a suitable solvent (e.g. DCM or THF) (5 mL/mmol) at 0 to 5 ℃ is added a suitable carbonyl source equipped with a suitable leaving group (e.g. 1, 1-carbonyl-diimidazole, phosgene or triphosgene) (1.1 eq) followed by the addition of a suitable base (e.g. TEA or DIPEA) (3.0 eq) and stirring the reaction mixture at room temperature under an inert atmosphere for 2 to 4h. The reaction mixture was quenched by addition of saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to provide a crude residue that was purified by silica gel column chromatography and eluted with 1% MeOH in DCM to provide the compound of formula (XV) as a solid (20 to 30% yield).

General procedure 10

TFAA (2.0 eq.) is added dropwise to a stirred solution of the compound of formula (XXV) (1.0 eq.) in toluene (1.8 mL/mmol) at 10 to 15℃over 20 to 30min and the resulting reaction mixture is stirred at 25 to 30℃for 1 to 5h. The progress of the reaction 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 saturated aqueous NaHCO ₃, brine, and then dried over anhydrous Na ₂SO₄. The filtered organics were evaporated under reduced pressure to provide the compound of formula (XXIV) as a solid (85 to 90% yield). The product was pure enough to be used in the next step without any further purification.

General procedure 11

A mixture of a compound of formula (XXIV) (1.0 eq) and an alkyl or aryl halide (R ⁹ -X) (2.0 eq) in DMF (1.1 mL/mmol) was added dropwise to a stirred solution of NaH (1.2 eq, 60% suspension in oil) in DMF (1.65 mL/mmol) at 10 to 15 ℃ using a dropping funnel over 20 to 30min and the resulting reaction mixture was then stirred at 20 to 25 ℃ for 2h. Completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into an ice-water mixture and extracted with EtOAc. The combined organics were washed with a saturated solution of 1n hcl, nahco ₃ and then brine. The organic layer was dried over anhydrous Na ₂SO₄ and evaporated under reduced pressure to afford the compound of formula (XXIII) as a solid (90 to 95% yield). The product was pure enough to be used in the next step without any further purification.

General procedure 12

The compound of formula (XXIII) (1.0 equivalent) was added in portions to a nitration mixture of previously prepared concentrated sulfuric acid (2.17 mL/mmol) and fuming nitric acid (0.73 mL/mmol) while maintaining the internal temperature between 0 and 5 ℃ for a period of 30 min. The resulting mixture was stirred at 20 to 25 ℃ for 1 to 2h. Completion of the reaction was confirmed by UPLC-MS, and after consumption of starting material, the reaction mixture was poured into an ice-water mixture and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO ₃, then a saturated brine solution, dried over anhydrous Na ₂SO₄ and evaporated under reduced pressure to give the compound of formula (XXII) as a thick oil (yield 85 to 95%). The product was pure enough to be used in the next step without any further purification.

General procedure 13

Option a

To a stirred solution of the compound of formula (XXII) (1.0 eq) in 1, 4-dioxane (3.34 mL/mmol, degassed with nitrogen) under an inert atmosphere was added 10% Pd-C (0.167 g/mmol,50% w/w in water) and the resulting reaction mixture was stirred at room temperature under H ₂ balloon pressure overnight. The progress of the reaction was monitored by TLC and UPLC-MS, which showed complete conversion of the nitro group to its corresponding amine group. The balloon was removed and solid K ₂CO₃ (1.66 eq.) was added to the reaction vessel at room temperature followed by dropwise addition of ethyl chloroformate (1.34 eq). The resulting reaction mixture was stirred overnight. UPLC-MS indicates completion of the reaction; 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, then brine, dried over anhydrous Na ₂SO₄ 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 (80 to 85% yield).

Option B

To a stirred solution of the compound of formula (XXII) (1.0 eq.) in THF (6.68 mL/mmol) at 10 to 15℃was added a solution of K ₂CO₃ (6.0 eq.) in water (3 mL/mmol), followed by the addition of sodium dithiosulfinate (8.0 eq.), TBASH (0.5 eq.) and water (0.4 mL/mmol) in portions. The resulting reaction mixture was stirred at room temperature (20 to 25 ℃) for a further 2 to 3 hours. The reaction was monitored by UPLC-MS and after completion the reaction mixture was left to stand to allow separation of the organic and aqueous layers. The aqueous layer was then extracted with THF. The combined organic layers were dried over anhydrous Na ₂SO₄ and then pyridine (0.8 mL/mmol) was added. The mixture was then evaporated under reduced pressure at-40 ℃ to afford 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 to 15 ℃ followed by dropwise addition of ethyl chloroformate (5.0 eq). The resulting reaction mixture was stirred at room temperature for a further 2 to 3 hours. UPLC-MS showed completion of the reaction. The reaction mixture was diluted with water and allowed to stand to allow separation of layers. The aqueous layer was washed with DCM and the combined organics were washed with 0.5n hcl, saturated solution of nahco ₃ and finally brine. The organic layer obtained was dried over anhydrous Na ₂SO₄ and evaporated in vacuo to give the crude product as a pale yellow thick oil. The oil was purified by trituration with hexane to give the compound of formula (XXI) as a solid (85 to 90% yield).

General procedure 14

To a stirred solution of the compound of formula (XXI) (1.0 eq.) in methanol (3.8 mL/mmol) at room temperature was added K ₂CO₃ (2.0 eq.) and the resulting reaction mixture was heated to 60 to 65℃over 2 to 3h. The progress of the reaction was monitored by UPLC-MS and after completion the reaction mass was cooled to 5 to 10℃and acidified with 2N HCl to pH 3 to 4. The solvent was evaporated under reduced pressure at 40 to 45 ℃ to give the crude product, which was dissolved in EtOAc, washed successively with saturated brine solution, 2n hcl, nahco ₃ solution and finally brine again, dried over anhydrous Na ₂SO₄ and evaporated under reduced pressure to give the crude compound as a brown solid. This compound was purified by trituration with n-hexane to give the compound of formula (XX) as a solid (80 to 85% yield).

General procedure 15

Pyridine (2.2 eq.) and alkyl (aryl) chloroformate (1.2 eq.) are added to a stirred solution of compound of formula (XXVIII) (1.0 eq.) in DCE (1.8 mL/mmol) at0 to 5 ℃ and the mixture stirred at room temperature for 1 to 2h. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was quenched with 1N HCl solution and extracted with DCM, followed by brine wash. The organic layer was dried over anhydrous Na ₂SO₄ and concentrated in vacuo to afford the compound of formula (XXVII) as a solid (70 to 75% yield), which was used in the next step without any further purification.

General procedure 16

To a stirred solution of amine R ⁹-NH₂. HCl (1.0 eq.) in MeOH (5 mL/mmol) under an inert atmosphere was added TEA (1.2 eq.) and the whole stirred for 30min. Then, the compound of formula (XXVII) (1.0 equivalent) was added and stirring was continued for 20 to 24 hours. During this time, the solution becomes a suspension. NaBH ₄ (1.5 eq) was added and the reaction mixture was stirred for a further 20 to 24h. 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, followed by brine wash. The organic layer was dried over anhydrous Na ₂SO₄ and concentrated in vacuo to afford the compound of formula (XXVI) as a solid.

General procedure 17

A stirred solution of the compound of formula (XXXI) (1.0 eq., 0.96 mmol) in THF (5 mL/mmol) was cooled to 0 to 5℃and the borane-THF complex (1M solution in THF) (10 mL/mmol,10 eq.) was added in portions. After the addition was completed, the mixture was allowed to warm to room temperature and then heated to reflux for 1 to 2 hours. The progress of the reaction was monitored by UPLC-MS, which showed the formation of the compound of formula (XXX). Upon completion the reaction mixture is diluted with methanol and refluxed for 5 to 10min, and the solvent is evaporated to give the crude material which is purified by combined flash chromatography or column chromatography to provide the compound of formula (XXX) as a colourless oil.

General procedure 18

To a stirred solution of the compound of formula (XXXIII) (1.0 eq.) in DMF or THF (1.6 mL/mmol) at room temperature was added K ₂CO₃、Cs₂CO₃、Na₂CO₃, naOH or NaH (4.0 eq.) and then 1, 2-dibromoethane (4.0 eq.) and the reaction mass was maintained at 80 to 85℃for 10 to 16h. 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 Na ₂SO₄ and evaporated in vacuo to afford the crude material which was purified by combined flash chromatography to afford the compound of formula (XXXII) (50 to 55% yield) as a solid.

General procedure 19

To a stirred solution of the compound of formula (XXXIX) (1.0 eq.) in acetone (3.2 mL/mmol) at room temperature was added the appropriate haloacetyl halide (1.3 eq.) and the combined mixture was stirred at room temperature for 1 to 2h. The progress of the reaction was monitored by TLC and UPLC-MS and after 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 provide the compound of formula (XXXVIII) as a brown solid (85 to 90% yield).

General procedure 20

DIBAL-H (1.5 eq.) was added to a stirred solution of the compound of formula (XLV) (1.0 eq) in DCM (10 mL/mmol) at-78℃under nitrogen. The whole was stirred at the same temperature for 1 to 2h and then pyridine (3.5 eq) and TMSOTf (3.0 eq) were added to the reaction mixture. The reaction temperature was then allowed to slowly rise to 0 to 5 ℃. The progress of the reaction was monitored by TLC and after completion of the reaction Et ₂ O (285 mL/mmol) was added and the mixture was filtered. The collected organic layer was then concentrated in vacuo to provide the compound of formula (XLIV) as a crude solid.

General procedure 21

To a stirred solution of the compound of formula (XLIV) (1.0 eq.) in DCM (10 mL/mmol) under nitrogen at-78 ℃ was added allyl-TMS (4.0 eq.) and BF ₃.Et₂ O (4.0 eq.). The temperature was then slowly raised to 0 to 5 ℃. 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 Na ₂SO₄, filtered and evaporated to dryness. The crude product was purified by column chromatography to provide the title compound of formula (XLIII) as a pure solid (70 to 75% yield).

General procedure 22

To a stirred solution of the compound of formula (XLIII) (1.0 eq) in ^tBuOH/H₂ O solution (12 mL/mmol, 1:1) were added OsO ₄ (0.09 eq) and NMO (1.4 eq). The resulting reaction mixture was stirred at room temperature for 10 to 12h. The progress of the reaction was checked by LCMS and after completion of the reaction, it was diluted again with EtOAc. The organic layer was separated and washed with 10% HCl, water and finally brine. It is then dried and concentrated in vacuo to provide the compound of formula (XL) as a crude solid.

General procedure 23

To a stirred solution of the compound of formula (XL) (1.0 eq) in ^tBuOH/H₂ O (12 mL/mmol, 1:1) at room temperature was added NaIO ₄ (4.0 eq). The resulting reaction mixture was stirred at room temperature for 10 to 12h. The progress of the reaction was checked by LCMS and after completion of the reaction, it was diluted with water and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to afford the corresponding crude aldehyde, which was dissolved in methanol (12 mL/mmol) and NaBH ₄ (2.0 eq.) was added at 0 to 5 ℃. The reaction mixture was stirred at room temperature for a further 1 to 2h. After completion of the reaction, it was quenched with NH ₄ Cl solution and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to provide the compound of formula (XLI) as a crude solid.

General procedure 24

To a stirred solution of the compound of formula (XI) (1.0 eq.) in EDC (1.1 mL/mmol) at room temperature was added a solution of R ⁵-B(OH)₂/borate (1.5 eq.) in EDC or toluene (1.1 mL/mmol), DBU (2.0 eq.) and Cu (OAc) (2.0 eq.). The resulting reaction mixture was stirred at room temperature for 20 to 24 hours. The reaction progress was monitored by LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂SO₄ and evaporated in vacuo to afford crude material which was purified by combination flash chromatography to afford the compound of formula (XLVI) as a solid (34 to 40% yield).

General procedure 25

To a stirred solution of the compound of formula (XLIX) (1.0 eq.) in toluene or dioxane or EDC (6 mL/mmol) at room temperature was added R ⁵ -X (where X is the appropriate leaving group) (1.5 eq.), cesium carbonate (2.0 eq.) and BINAP (0.2 eq.). The whole was degassed with nitrogen for 20min, then Pd (OAc) ₂ (0.1 eq) was added to the reaction mixture and stirring was continued at 100 to 110 ℃ for 20 to 24h. The reaction progress was monitored by UPLC-MS and after completion the reaction mixture was concentrated in vacuo to yield crude material which was purified by column chromatography to provide the compound of formula (XLVIII) as a solid (30 to 35% yield).

General procedure 26

To a stirred solution of the compound of formula (LI) (1.0 eq.) in anhydrous Et ₂ O or THF (6 mL/mmol) at-78deg.C under an inert atmosphere was added LiHMDS (1.5 eq.) and stirred for 5 to 10min. R ⁹ -X, for example bromoacetonitrile (1.2 eq.) is then added to the reaction mixture and stirring is continued for 30min at the same temperature. Thereafter, the reaction mixture was allowed to slowly warm to room temperature and stirred for 1 to 2 hours. The progress of the reaction was monitored by UPLC-MS and after completion of the reaction, it was quenched with a saturated solution of NH ₄ Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄, filtered and concentrated under reduced pressure to provide the crude product which was purified by combined flash chromatography to provide the compound of formula (L) as a solid (45 to 50% yield).

General procedure 27

To a stirred solution of the compound of formula (LIV) (1.0 eq.) in DMF (5.5 mL/mmol) at 0 to 5℃are added an amide coupling reagent such as EDC-HCl (1.5 eq.) and DIPEA (3.0 eq.) and the reaction mixture is stirred at this temperature for 5 to 10min. R-NH2 (5.0 eq) was then added and the reaction mixture stirred at room temperature for 10 to 16h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure to yield a residue, which was extracted with EtOAc and the combined organic layers were dried over anhydrous Na ₂SO₄, filtered and evaporated under reduced pressure to afford the crude product. This crude material was purified by column chromatography to give the compound of formula (LIII) as a solid (70 to 75% yield).

Library general procedure 28

To a degassed solution of a compound of formula (LVIII) (1.0 eq, 100mg,0.2 mmol) in a mixture of 1, 4-dioxane and water (50 mL/mmol, 9:1) was added the appropriate boric acid or borate (1.2 eq), sodium carbonate (2.0 eq) and Pd (dppf) Cl ₂ (0.1 eq). The whole was heated to 80 to 110 ℃ under an atmosphere of N ₂ for 3 to 16h. Completion of the reaction was confirmed by LCMS and TLC. The reaction mass was then filtered through a bed of celite and the filtrate concentrated under reduced pressure to give the crude product which was purified by combination flash chromatography or preparative HPLC to provide the compound of formula (LVII) as an off-white to white solid (25 to 15% yield).

Examples

Nuclear Magnetic Resonance (NMR) spectra were consistent with the proposed structure in all cases. The characteristic chemical shift (δ) is given in parts per million from the low field of tetramethylsilane (for ¹ H-NMR) and from the high field of trichloro-fluoro-methane (for ¹⁹ F NMR), the main peaks are specified using conventional abbreviations: e.g., s, unimodal; d, double peaks; t, triplet; q, quartet; m, multiple peaks; br, broad peak. The following abbreviations have been used for common solvents: CDCl ₃, deuterated chloroform; d ₆ -DMSO, deuterated dimethyl sulfoxide; and CD ₃ OD, deuterated methanol.

Mass spectra, MS (m/z), were recorded using electrospray ionization (ESI). In related cases and unless otherwise indicated, the m/z data provided by the present invention apply to the isotopes ¹⁹F、³⁵Cl、⁷⁹ Br and ¹²⁷ I. All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. Unless otherwise indicated, all reactions were carried out under a nitrogen atmosphere.

Flash column chromatography was performed using a preloaded silica gel cassette in a combination flash chromatography platform. Preparative HPLC purification was performed according to the general purification and analysis methods described above. Thin Layer Chromatography (TLC) was performed on Merck silica gel 60 disc (5729). Unless otherwise indicated, all final compounds were >95% pure as judged by LCMS or UPLC analysis methods described in the general purification and analysis methods above.

Example 1:1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea

Example 1 was prepared according to the methods described in general procedures 1-6, and the methods described below.

Preparation 1: 3-oxo-3, 4-dihydro-2H-1, 4-benzothiazine-6-carboxylic acid methyl ester

Step 1:4- ((2-ethoxy-2-oxoethyl) thio) -3-nitrobenzoic acid methyl ester

Methyl 4-fluoro-3-nitrobenzoate (10.0 g,50.2 mmol) was dissolved in MeCN (2.0L) and TEA (7.61 g,75.38 mmol) was added to the solution. The reaction mixture was cooled to 0 to 5 ℃ and ethyl thioglycolate (7.25 g,62.7 mmol) was added dropwise. The reaction mixture was stirred for 30min under ice-cold temperature. The reaction mixture was then diluted with EtOAc and washed with saturated solution of NH ₄ Cl and brine. The organic layer was dried over anhydrous Na ₂SO₄ and evaporated to dryness in vacuo to give the title compound as a yellow solid (14.0 g,46.82mmol,93% yield) which was sufficiently pure to be used in the next step without any further purification. LCMS m/z 300.06[ m+h ].

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

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℃for 3h. Once complete (monitored by TLC), the reaction was cooled to room temperature and poured onto 1N HCl (250 mL) and then stirred for 1h. The resulting white precipitate was filtered off and washed with water. The residue obtained was redissolved in 5% MeOH in DCM (50 mL) and filtered through a bed of celite. The filtrate was evaporated to dryness in vacuo to afford the title compound (3.5 g,15.6mmol,91% yield) as a pale yellow solid. LCMS m/z 222.05[ M-H ].

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

To a stirred solution of methyl 3-oxo-3, 4-dihydro-2H-benzo [ b-1,4] thiazine-6-carboxylate (preparation 1, step 2) (5.0 g,22.2 mmol) in DMF (50 mL) at 0 to 5 ℃ was added NaH (0.98 g,24.4 mmol) in portions and the whole was stirred at the same temperature for an additional 5 to 10min. Bromotoluene (2.8 mL,23.3 mmol) was then added and the reaction mixture was stirred for 1h. Completion of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with a saturated solution of NH ₄ Cl 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 Na ₂SO₄ and concentrated under reduced pressure to afford the title compound (9.0 g) as a pale yellow solid which was used in the next step without any further purification. LCMS m/z 314.16[ m+h ].

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

To a stirred solution of methyl 4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 2) (9.0 g,28.8 mmol) in a mixture of solvent THF/MeOH/H ₂ O (160 ml, 2:1:1) was added lioh.h ₂ O (4.8 g,115.2 mmol) at room temperature and the combined mixture was stirred at the same temperature for 2H. The progress of the reaction was monitored by TLC and LC-MS, which showed complete consumption of 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 with 1N HCl to pH 5 to 6 to obtain a precipitate, which was filtered, collected and dried by azeotropic distillation with MeCN to provide the title compound (5.0 g) as a crude white solid. LCMS m/z 300.13[ m+h ].

Preparation 4: (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamic acid tert-butyl ester

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) under an inert atmosphere was added TEA (3 mL,21.6 mmol), followed by DPPA (6.3 mL,28.8 mmol) and then stirring was continued for 5min at the same temperature. The reaction mixture was allowed to slowly warm to room temperature and stirred for 4h. Formation of the corresponding acyl azide was confirmed by TLC and UPLC-MS by quenching an aliquot of the reaction mixture into methanol. The solvent was evaporated, tert-butanol (50 mL) was added to the reaction mixture and the whole was refluxed overnight. Completion of the reaction was monitored by TLC and LC-MS, which showed formation of the desired product and complete consumption of starting material. The solvent was evaporated in vacuo to give crude oil, which was adsorbed onto silica gel and purified by combined flash chromatography to afford the title compound as an off-white solid (4.2 g,80% yield). LCMS m/z 317.15[ M+H ].

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

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 to 5℃and the combined mixture was stirred for 5min. The reaction mixture was then stirred at room temperature overnight. UPLC shows consumption of starting material. The solvent was evaporated in vacuo. The resulting crude product residue was then washed with NaHCO ₃ solution and extracted with EtOAc. It was then evaporated in vacuo to give the title compound as a dark yellow solid (750 mg,90.5% yield). LCMS m/z 271.23[ M+H ].

Preparation 6:1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea (example 1)

To a stirred solution of 6-amino-4-benzyl-2H-benzo [ b ] [1,4] thiazin-3 (4H) -one (preparation 5) (100 mg,0.37 mmol) in THF (2.5 mL) was added p-nitrophenyl chloroformate (89.22 mg,0.44 mmol) at 0 to 5 ℃ and the combined mixture was stirred for 5min and then allowed to slowly warm to room temperature over 1H, at which point the formation of the carbamate was confirmed by TLC. Then, 6-amino-5-fluoro-indole hydrochloride (69.03 mg,0.37 mmol) was added to THF (2.5 mL) at 0 to 5 ℃, followed by TEA (0.16 mL,1.11 mmol) and the reaction mixture was stirred at room temperature for an additional 1h. Urea formation was detected by UPLC-MS and TLC, and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with 10% sodium bicarbonate solution, then 1N HCl and finally brine, dried over anhydrous Na ₂SO₄, filtered and evaporated under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound as a brick-red solid (22 mg,14% yield). Purity by UPLC ：95.24％;1H NMR(500MHz;DMSO-d₆):δ3.64(s,2H),5.18(s,2H),6.94(t,J＝8.85Hz,1H),7.20(t,J＝9.6Hz,1H),7.19-7.25(m,4H),7.30-7.35(m,5H),7.52(s,1H),8.50(s,1H),8.67(s,1H),10.87(s,1H);LCMS m/z:447.16[M+H].

Example 2:1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea

Example 2 was prepared according to the general procedure 1, 4, 6 and the methods described below.

Preparation 7:4- (2-chloro-6-fluorobenzyl) -7-nitro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one

To a stirred solution of commercially available 7-nitro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (1.0 g,5.15 mmol) in DMF (10.0 mL) was added Cs ₂CO₃ (3.35 g,10.30 mmol) and 2-chloro-6-fluoro-bromotoluene (1.06 mL,7.73 mmol) at room temperature and stirred at the same temperature for 3H. The progress of the reaction was monitored by LCMS and after completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate. The product was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine solution (1 x 30 ml), dried over anhydrous Na ₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by combination flash chromatography (10 to 15% EtOAc-hexanes) to afford the title compound (1.0 g,57.6% yield) as an orange solid. LCMS m/z 337.1[ M+H ].

Preparation 8: 7-amino-4- (2-chloro-6-fluorobenzyl) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one

To a stirred solution of 4- (2-chloro-6-fluorobenzyl) -7-nitro-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (preparation 7) (300.0 mg,0.89 mmol) in acetone/water (4:1 mL) was added ammonium chloride (476.59 mg,8.91 mmol) and zinc powder (291.26 mg,4.45 mmol) at room temperature. The whole was allowed to stir at room temperature for 10min, at which time TLC indicated consumption of starting material and new poles had formed. The reaction was filtered through a celite bed and washed with EtOAc. The solvent was then evaporated to give the crude material which was purified by combined flash chromatography using 5% MeOH in DCM as solvent to afford the title compound as a yellow solid (180 mg,65.8% yield). LCMS m/z 307.01[ M+H ].

Preparation 9:1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea (example 2)

To a stirred solution of 7-amino-4- (2-chloro-6-fluorobenzyl) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one (preparation 8) (200 mg,0.65 mmol) in THF (5 mL) at 0to 5℃was added p-nitrophenyl chloroformate (197mg, 0.98 mmol) and the mixture stirred at room temperature for 3H. Triethylamine (0.45 mL,3.26 mmol) and 3-aminoindole hydrochloride (86.1 mg,0.65 mmol) were then added to the reaction mixture at room temperature and the resulting mixture was stirred at 70℃for an additional 2h. After completion (monitored by LCMS), the reaction mixture was quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (2×20 ml), dried over anhydrous Na ₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to afford the title compound as a brown solid (20 mg,6.6% yield). Purity by HPLC ：97.77％;1H NMR(400MHz;DMSO-d₆):δ4.65(s,2H),5.27(s,2H),6.92-7.01(m,3H),7.08(t,J＝7.12Hz,1H),7.12-7.22(m,1H),7.27(d,J＝2.0Hz,1H),7.31-7.38(m,3H),7.45(d,J＝2.32Hz,1H),7.48(d,J＝7.84Hz,1H),8.43(s,1H),8.54(s,1H),10.71(s,1H);LCMS m/z:465.23[M+H].

Examples 3 to 37

The examples in the following table were prepared according to the above method for making examples 1 and 2 as described in general procedures 1-6 using the appropriate amine. Purification was performed as described in the previous method.

Example 38:1- (5- (1H-pyrazol-5-yl) -1H-indol-3-yl) -3- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea

Example 38 was prepared according to general procedures 1-6, library general procedure 28, and methods described below.

Preparation 12: 5-bromo-1H-indol-3-amine hydrochloride

Step 1: (5-bromo-1H-indol-3-yl) carbamic acid tert-butyl ester

To a stirred solution of commercially available 5-bromo-1H-indole-3-carboxylic acid (5.0 g,20.83 mmol) in THF (50 mL) was added triethylamine (5.37 mL,25 mmol) and DPPA (3.48 mL,25 mmol) at room temperature and the mixture was stirred at the same temperature overnight. After completion of the reaction (monitored by LCMS), the solvent was evaporated under pressure and the resulting reaction mixture was dissolved in t-butanol (50 mL) and refluxed for 5h. The reaction mixture was then concentrated in vacuo and dissolved in EtOAc (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (3 x 100 ml), water (3 x 100 ml), brine (3 x 100 ml), dried over Na ₂SO₄ and concentrated to give the crude product, which was purified on silica gel column chromatography to afford the title compound as an off-white solid (3.5 g,79.6% yield). LCMS m/z 311.0[ M+H ].

Step 2: 5-bromo-1H-indol-3-amine hydrochloride

To a solution of tert-butyl (5-bromo-1H-indol-3-yl) carbamate (preparation 12, step 1) (3.0 g,9.64 mmol) in 1, 4-dioxane (45 mL) was added dropwise 4M HCl in 1, 4-dioxane (25 mL) at 0 to 5 ℃. After the addition was completed, the reaction mixture was stirred at room temperature for 5h. The reaction progress was monitored by LCMS and after completion, the reaction mixture was concentrated under vacuum to give a green solid which was triturated with ether-pentane to afford the title compound as a pale green solid (3.0 g, as HCl salt). LCMS m/z 211.0[ m+h ].

Preparation 13:1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-bromo-1H-indol-3-yl) urea

A stirred solution of 4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid (preparation 3) (5.0 g,16.7 mmol) was dissolved in DCM (50 mL) under an atmosphere of N ₂. Triethylamine (3.49 mL,25.06 mmol) was then added at 0 to 5℃followed by diphenyl azide phosphate (7.18 mL,33.41 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated to obtain a residue, which was dissolved in acetonitrile (50 mL) and 5-bromoindol-3-amine (preparation 12, step 2) (4.41 g,33.41 mmol) was added under an atmosphere of N ₂. The resulting reaction mixture was refluxed for 6h. The reaction progress was monitored by LCMS and after completion the reaction mixture was concentrated under vacuum to give a crude product which was purified by silica gel column chromatography to afford the title compound as an off-white solid (3.0 g,41.9% yield). LCMS m/z 505.2[ m+h ].

Preparation 14:1- (5- (1H-pyrazol-5-yl) -1H-indol-3-yl) -3- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea (example 38)

To a degassed solution of 1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-bromo-1H-indol-3-yl) urea (preparation 13) (100 mg,0.2 mmol) in a mixture of 1, 4-dioxane and water (10 mL, 9:1) was added (1H-pyrazol-5-yl) boronic acid (26.6 mg,0.24 mmol), sodium carbonate (41.9 mg,0.4 mmol) and Pd (dppf) Cl ₂ (14.5 mg,0.02 mmol) and the whole was heated to 90℃under an atmosphere of N ₂ for 3H. Completion of the reaction was confirmed by LCMS and TLC. The reaction mass was then filtered through a bed of celite and the filtrate concentrated under reduced pressure to give the crude product which was purified by preparative HPLC to provide the title compound as an off-white solid (18 mg,18.4% yield). Purity by HPLC ：99.53％;¹H NMR(400MHz;DMSO-d₆):δ3.63(s,2H),5.18(s,2H),6.60(s,2H),7.23-7.33(m,8H),7.45-7.56(m,2H),7.73-7.74(m,1H),7.97(bs,1H),8.56-8.60(m,2H),10.71(s,1H),12.71(s,1H);LCMS m/z:495.26[M+H].

Examples 39 to 68 and 112

The examples in the table below were prepared according to the above method for making example 38 as described in general procedures 1-6 and library general procedure 28 using the appropriate amine. Purification was performed as described in the previous method.

Example 69:1- (4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea

Example 69 was prepared according to general procedures 1-6, 17 and the methods described below.

Preparation 15: 2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester

Step 1:4- ((1-ethoxy-1-oxopropan-2-yl) thio) -3-nitrobenzoic acid methyl ester

To a stirred solution of commercially available methyl 4-fluoro-3-nitrobenzoate (8.0 g,33.72 mmol) in acetonitrile (80 mL) were added TEA (14.5 mL,101 mmol) and ethyl 2-mercaptopropionate (6.84 mL,43.83 mmol) and the whole was maintained at room temperature for 1h. UPLC showed formation of the desired compound, evaporation of the solvent to afford the crude product, which was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂SO₄ and evaporated to afford the title compound (13.0 g) as a pale yellow solid, which was used in the next step without any further purification. LCMS m/z 312[ M+H ].

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

To a stirred solution of methyl 4- ((1-ethoxy-1-oxopropan-2-yl) thio) -3-nitrobenzoate (preparation 15, step 1) (13.0 g,41.53 mmol) in AcOH (100 mL) was added iron powder (10.79 g,166.10 mmol) and the whole stirred at 80℃for 1.5h. UPLC showed formation of the desired compound, quench the reaction mass by pouring ice-cold water (600 mL) and stir the whole for 30min. The precipitated solid was filtered and washed with cold water, dried in a vacuum oven at 60 ℃ overnight to afford the title compound (9.8 g) as a pale brown solid, which was used in the next step without any further purification. LCMS m/z 238[ M+H ].

Preparation 16:4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine hydrochloride

Step 1:4- (3, 5-Difluorobenzyl) -2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester

To a stirred solution of methyl 2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 15, step 2) (2.0 g,8.4 mmol) in DMF (20 mL) was added NaH (371 mg,9.3 mmol) at 0 to 5 ℃ followed by 1- (bromomethyl) -3, 5-difluorobenzene (1.13 mL,8.7 mmol). The resulting reaction mixture was warmed to room temperature and stirred for 2h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with MTBE. The organic layer was then washed with brine solution and concentrated in vacuo to give the crude product, which was purified by combined flash chromatography (elution in 15% EtOAc/hexanes) to afford the title compound as a white solid (3.0 g,98% yield). LCMS m/z 364.1[ M+H ].

Step 2:4- (3, 5-Difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester

A solution of BH ₃. THF (30 mL,27 mmol) was added to 4- (3, 5-difluorobenzyl) -2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester (preparation 16, step 1) (3.0 g,8.26 mmol) at 0 to 5℃and then slowly warmed to room temperature and stirred for 4H. Consumption of starting material was confirmed by TLC and LC-MS, which showed formation of the desired product. After completion of the reaction, the reaction mixture was quenched with methanol and concentrated in vacuo to give a crude residue, which was diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂SO₄ and then concentrated in vacuo to give a yellow liquid which was purified by combined flash chromatography (elution in 12% EtOAc/hexanes) to afford the title compound (2.67 g,93% yield) as a pale yellow solid. LCMS m/z 439.2[ M+H ].

Step 3:4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid

To a stirred solution of methyl 4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 16, step 2) (2.67 g,7.65 mmol) in a mixture of solvent THF/MeOH/H ₂ O (48 ml, 1:1:1) was added lioh.h ₂ O (1.28 g,30.6 mmol). The reaction mixture was then stirred at room temperature for 16h. Consumption of starting material was confirmed by TLC and LC-MS. The solvent was evaporated under reduced pressure to give a residue, which was diluted with water and washed with MTBE. The resulting aqueous solution was then neutralized with 2M HCl solution and the desired product was extracted with EtOAc. The organic layer was then concentrated in vacuo to afford the title compound (2.2 g, crude) as a white solid. LCMS m/z 334.1[ M+H ].

Step 4: (4- (3, 5-Difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamic acid tert-butyl ester

To a stirred solution of 4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid (preparation 16, step 3) (2.2 g,6.57 mmol) in DCM (30 mL) was added TEA (1.37 mL,9.85 mmol) followed by DPPA (2.1 mL,9.85 mmol) at 0 to 5 ℃. The resulting reaction mixture was stirred at room temperature for 2h. Consumption of starting material was confirmed by LC-MS. After completion of the reaction, the reaction mixture was concentrated in vacuo to give a residue, which was diluted with t-BuOH and stirred at 90 ℃ for an additional 5h. LC-MS showed formation of the desired product. The solvent was evaporated under vacuum to give a crude product which was purified by combined flash chromatography (elution in 10% etoac/hexanes) to afford the title compound (2.0 g,75% yield) as a pale yellow solid. LCMS m/z 407.2[ m+h ].

Step 5:4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine hydrochloride

To a stirred solution of tert-butyl (4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamate (preparation 16, step 4) (600 mg,1.47 mmol) in 1, 4-dioxane (5 mL) was added 1N HCl solution (15 mL) at 0 to 5 ℃. The reaction mixture was then stirred at room temperature for 3h. Consumption of starting material was confirmed by LCMS. After completion of the reaction, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by trituration with hexane to afford the title compound as a pale yellow solid (600 mg, crude). LCMS m/z 307.1[ M+H ].

Preparation 17:1- (4- (3, 5-Difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea (example 69)

To a stirred solution of 4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine (preparation 16, step 5) (600 mg,1.47 mmol) in toluene (10 mL) was added TEA (0.4 mL,2.94 mmol) at room temperature followed by 5-fluoro-1H-indole-3-carbonyl azide (344 mg,1.68mmol, synthesized from 5-fluoro-1H-indole-3-carboxylic acid, respectively, using DPPA as described in preparation 12, step 1). The reaction mixture was stirred at 100 ℃ for 2h. Completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated in vacuo to give a crude material which was purified by combined flash chromatography followed by preparative HPLC to afford the title compound as a pale brown solid (115 mg,16% yield). Purity by UPLC ：97.61％;¹H NMR(500MHz;DMSO-d₆):δ1.30(d,J＝6.4Hz,3H),3.33-3.34(m,2H),3.70-3.72(m,1H),4.56-4.59(m,2H),6.72(s,1H),6.82-6.87(dd,J1＝8.25Hz,J2＝19.25Hz,2H),6.93(t,J＝9.15Hz,1H),7.00(d,J＝7.05Hz,2H),7.12(t,J＝9.45Hz,1H),7.17(d,J＝9.75Hz,1H),7.13-7.34(m,1H),7.49(s,1H),8.28(d,J＝12.55Hz,2H),10.82(s,1H);LCMS m/z:483.15[M+H].

Example 70:1- (4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea

Example 70 was prepared according to general procedures 1-6, 17 and the methods described below.

Preparation 18: (6-amino-2-methyl-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) (phenyl) methanone hydrochloride

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

A solution of methyl 2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 15, step 2) (1.0 g,4.21 mmol) in borane. THF complex (1M solution in THF) (12.6 mL,12.64 mmol) was stirred at room temperature for 3H. The progress of the reaction was monitored by UPLC-MS, which showed the formation of the desired product and, after completion, the reaction mixture was diluted with MeOH (10 mL) and refluxed for 10min. The solvent was then evaporated in vacuo to give a residue, which was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na ₂SO₄ and evaporated in vacuo to afford the title compound (824 mg, crude) as a pale yellow solid, which was used in the next step without any further purification. LCMS m/z 224[ M+H ].

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

To a stirred solution of methyl 2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 18, step 1) (0.284 g,3.69 mmol) in DCM (10 mL) was added TEA (1.33 mL,9.23 mmol) and benzoyl chloride (0.55 mL,3.93 mmol) at room temperature. The resulting solution was stirred at room temperature for 1h, at which time UPLC-MS showed the formation of the desired product. The solvent was evaporated in vacuo to give a crude material which was purified by combined flash chromatography (20 g column) to afford the title compound as a white solid (1.2 g,99% yield). LCMS m/z 328[ M+H ].

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

To a stirred solution of methyl 4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 18, step 2) (1.2 g,3.67 mmol) in a mixture of solvent MeOH (5 mL), THF (5 mL) and H ₂ O (10 mL) was added lioh.h ₂ O (770 mg,18.33 mmol) and the whole was maintained at room temperature for 1.5H. UPLC-MS showed completion of the reaction. The solvent and aqueous residue were then evaporated in vacuo, washed with diethyl ether and acidified with 1N HCl. The acidified aqueous part was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na ₂SO₄ and evaporated under reduced pressure to afford the title compound (1.18 g, crude) as a pale brown solid, which was used in the next step without any further purification. LCMS m/z 314[ M+H ].

Step 4: (4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamic acid tert-butyl ester

To a stirred solution of 4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid (preparation 18, step 3) (1.15 g,3.67 mmol) in DCM (20 mL) was added TEA (0.79 mL,5.50 mmol) at 0 to 5 ℃, followed by DPPA (1.59 mL,7.34 mmol) and the resulting reaction mixture was stirred at room temperature for 3H. UPLC-MS showed formation of the desired product. Then, the solvent was evaporated in vacuo to afford the corresponding acyl azide intermediate (2.0 g) as a pale brown oil, which was dissolved in t-BuOH (15 mL) and refluxed for 16h. The progress of the reaction was monitored by UPLC-MS, which showed the formation of the desired compound. The solvent was then evaporated in vacuo and the crude product was purified by combined flash chromatography (40 g column) using 25% EtOAc in hexanes to provide the title compound as an off-white solid (900 mg,40% yield). LCMS m/z 383[ M+H ].

Step 5: (6-amino-2-methyl-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) (phenyl) methanone hydrochloride

Tert-butyl (4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamate (preparation 18, step 4) (900 mg,2.34 mmol) in 4M HCl in dioxane (15 mL) was allowed to slowly warm to room temperature over 1H at 0 to 5 ℃. The reaction was monitored by UPLC-MS and after completion of the reaction, the solvent was evaporated under reduced pressure to give the crude product, which was washed with hexane, dried and evaporated in vacuo to afford the title compound (770 mg, crude) as a pale yellow solid. The crude material was used in the next step without any further purification. LCMS m/z 285[ M+H ].

Preparation 19:1- (4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea (example 70)

To a stirred solution of (6-amino-2-methyl-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) (phenyl) methanone hydrochloride (preparation 18, step 5) (500 mg,1.56 mmol) in DCM (20 mL) was added 3-NCO-indole (369.54 mg,2.34 mmol) followed by TEA (0.254 mL,1.56 mmol) at 0 to 5 ℃. The resulting reaction mixture was stirred at room temperature for 2.5h, and UPLC-MS showed completion of the reaction. The solvent was then evaporated in vacuo to yield a crude material which was purified by combined flash chromatography (40 g column) using 55% EtOAc in hexanes to afford the title compound as a pale brown solid (300 mg,44% yield). Purity by UPLC ：98.63％;¹H NMR(400MHz;DMSO-d₆):δ1.35(d,J＝6.4Hz,3H),3.17(d,J＝6Hz,1H),3.70-3.78(m,1H),4.06-4.13(m,1H),6.86(s,1H),6.97(t,J＝7.2Hz,1H),7.07(t,J＝7.2Hz,1H),7.12(d,J＝8.8Hz,1H),7.24-7.26(dd,J1＝2.0Hz,J2＝8.8Hz,1H),7.30-7.37(m,5H),7.38-7.42(m,3H),8.26(s,1H),8.31(s,1H),10.67(s 1H);LCMS m/z:441.11[M-H].

Examples 71 to 101 and 109 to 111

The examples in the following table were prepared according to the above method for making examples 69 and 70 as described in general procedures 1 to 6 and 17 using the appropriate amine. Purification was performed as described in the previous method.

Example 102:1- (4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea

Example 102 was prepared according to general procedures 1-6, 17, 25 and the methods described below.

Preparation 20:4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine

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

BH ₃. THF (30 mL,27 mmol) was added with stirring to methyl 3-oxo-3, 4-dihydro-2H-benzo [ b-1,4] thiazine-6-carboxylate (preparation 1, step 2) (2.0 g,9.0 mmol) at 0 to 5℃under an inert atmosphere. After the addition was completed, the mixture was warmed to room temperature and stirred for 3h. Completion of the reaction was confirmed by TLC and UPLC-MS. The reaction mixture was quenched by addition to methanol in portions in an erlenmeyer flask and stirring until all boiling had ceased. The reaction mixture was then concentrated in vacuo to yield a crude material, which was mixed with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na ₂SO₄, 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 ].

Step 2:4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester

A stirred solution of 3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid methyl ester (preparation 20, step 1) (400 mg,1.9 mmol), 6-chloro-3-fluoro-2-methylpyridine (400 mg,2.76 mmol), potassium phosphate (1.5 g,7 mmol), and Xphos (183mg, 0.38 mmol) in toluene (10 mL) was degassed with N ₂ at room temperature. Then, pd ₂(dba)₃ (94 mg,0.1 mmol) was added to the solution and the whole was stirred at 110℃for 16h. Completion of the reaction was confirmed by LC-MS. The reaction mixture was then concentrated in vacuo to give crude material which was purified by column chromatography to afford the title compound as a pale yellow solid (550 mg,91% yield). UPLC-MS m/z 319.1[ M+H ].

Step 3:4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid

To a stirred solution of methyl 4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylate (preparation 20, step 2) (550 mg,1.73 mmol) in THF (4 mL) and MeOH (4 mL) was added lioh.h ₂ O (300 mg,7.14 mmol). The reaction mixture was stirred at room temperature for 16h. Consumption of starting material was confirmed by TLC and LC-MS and after completion the solvent was evaporated under reduced pressure to yield the crude product, which was diluted with water and washed with MTBE. The aqueous solution was then neutralized with 2M HCl solution and the product extracted with EtOAc. The organic layer was dried over anhydrous Na ₂SO₄ and concentrated in vacuo to give the title compound as a white solid (400 mg, crude). UPLC-MS m/z 305.1[ M+H ].

Step 4: (4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamic acid tert-butyl ester

To a stirred solution of 4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-6-carboxylic acid (preparation 20, step 3) (400 mg,1.3 mmol) in DCM (6 mL) was added TEA (274 μl,1.97 mmol) and DPPA (335 μl,1.56 mmol) at 0 to 5 ℃. The resulting reaction mixture may be allowed to slowly warm to room temperature over 2 hours. Consumption of starting material was confirmed by LC-MS. After completion of the reaction, the reaction mixture was concentrated in vacuo and the resulting residue was diluted with t-BuOH. The resulting reaction mixture was stirred at 90℃for a further 1h. The reaction progress was monitored by LC-MS and after completion, the solvent was concentrated in vacuo to give crude material which was purified by combined flash chromatography to afford the title compound as a pale yellow solid (270 mg,55% yield). UPLC-MS m/z 376.2[ M+H ].

Step 5:4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine hydrochloride

To a stirred solution of tert-butyl (4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) carbamate (preparation 20, step 4) (270 mg,0.72 mmol) in dioxane (2 mL) was added a solution of 4NHCl (6 mL,24 mmol) at 0 to 5 ℃. The reaction mixture was then stirred at room temperature for 3h. Consumption of starting material was confirmed by LC-MS. After completion of the reaction, the reaction mixture was concentrated in vacuo to afford a crude product which was purified by trituration with hexane to give the title compound as a pale yellow solid (210 mg, crude). UPLC-MS m/z 276.1[ M+H ].

Preparation 21:1- (4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea (example 102)

To a stirred solution of 4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-amine hydrochloride (preparation 20, step 5) (190 mg,0.61 mmol) in toluene (4 mL) was added TEA (127. Mu.L, 0.9 mmol) and freshly prepared 1H-indole-3-carbonyl azide (75 mg,0.4 mmol). The resulting reaction mixture was stirred at 100℃for 2h. Completion of the reaction was confirmed by LC-MS. Thereafter, the reaction mixture was concentrated in vacuo to give a crude material which was purified by combined flash chromatography followed by preparative HPLC to afford the title compound as a pale yellow solid (15 mg,9% yield). Purity by UPLC ：99.22％;1H NMR(400MHz;DMSO-d₆):δ2.37(s,3H),3.09(d,J＝5.4Hz,2H),4.10(t,J＝5.2Hz,2H),6.85-6.88(dd,J1＝2.8Hz,J2＝9.04Hz,1H),6.99(t,J＝7.64Hz,1H),7.05-7.12(m,3H),7.31(d,J＝8.0Hz,1H),7.42-7.49(m,4H),8.36(s,1H),8.55(s,1H),10.69(s,1H);UPLC-MS m/z:434.32[M+H].

Examples 102 to 106

The examples in the following table were prepared according to the above method for making example 102 as described in general procedures 1 to 6, 17 and 25 using the appropriate amine. Purification was performed as described in the previous method.

Example 107: (S) -1- (1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazolin-7-yl) -3- (1H-indol-3-yl) urea

Example 107 was prepared according to the methods described in general procedures 1-4, 10-14 and the methods described below.

Preparation 22: (S) -methyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylic acid ester

(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 WO 2018/234808.

Preparation 23: (S) -1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylic acid methyl ester

To a stirred solution of (S) -methyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylate (preparation 22) (1.0 g,4.26 mmol) in DMF (12 mL) was added NaH (187 mg,4.69 mmol) followed by bromotoluene (0.53 mL,4.48 mmol) at 0 to 5 ℃. The combined mixture was stirred at room temperature for 30min. TLC showed complete consumption of the starting cyclic urea. The reaction mixture was then quenched with ice-water to produce a precipitate, which was filtered, washed with hexane and dried under high vacuum to afford the title compound as a white solid (1.1 g,80% yield). LCMS m/z 325[ M+H ].

Preparation 24: (S) -1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylic acid

To a stirred solution of methyl (S) -1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylate (preparation 23) (0.5 g,1.54 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of lioh.h ₂ O (258 mg,6.16 mmol) in water (2.5 mL) and the combined mixture was stirred at room temperature for 2h. TLC showed completion of the reaction. The solvent was evaporated and the residue diluted with water, washed with MTBE and the aqueous layer acidified to pH 4 to 5 with 1N HCl. The aqueous layer was extracted with EtOAc, washed with brine, dried over anhydrous MgSO ₄, filtered and concentrated in vacuo to afford the title compound (450 mg, crude) as a white solid. LCMS m/z 311[ M+H ].

Preparation 25: (S) -7-amino-1-benzyl-3, 4-dimethyl-3, 4-dihydro-quinazolin-2 (1H) -one

A stirred solution of (S) -1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazoline-7-carboxylic acid (preparation 24) (0.3 g,0.97 mmol) in DCM (5 mL) was cooled to 0 to 5℃and TEA (0.209 mL,1.45 mmol) was added in one portion followed by DPPA (0.419 mL,1.93 mmol) and then the whole stirred at room temperature for 3h. UPLC-MS showed formation of the desired product. The solvent was evaporated to afford the corresponding acyl azide as an intermediate, which was dissolved in t-butanol (10 mL) and refluxed at 100 ℃ for 24h. UPLC-MS showed formation of the corresponding Boc protected amine intermediate. The solvent was evaporated in vacuo to give a crude product which was purified by combination flash chromatography and the Boc group was removed during purification to afford the title compound as a white solid (100 mg, crude) which was used in the next step without any further purification. LCMS m/z 282[ M+H ].

Preparation 26: (S) -1- (1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazolin-7-yl) -3- (1H-indol-3-yl) urea (example 107)

To a stirred solution of (S) -7-amino-1-benzyl-3, 4-dimethyl-3, 4-dihydroquinazolin-2 (1H) -one (preparation 25) (100 mg,0.36 mmol) in THF (5 mL) was added 3-isocyanato-1H-indole (56 mg,0.36 mmol) followed by TEA (0.102 mL,0.71 mmol) and the whole was maintained at room temperature for 1H at 0 to 5 ℃. UPLC showed completion of the reaction. The reaction mixture was diluted with EtOAc and with 10% sodium bicarbonate solution, followed by 1N HCl and finally brine, dried over anhydrous Na ₂SO₄ and evaporated in vacuo to afford the crude product which was purified by combined flash chromatography followed by preparative HPLC to afford the title compound as a pale brown solid (10 mg,6.4% yield). Purity by UPLC ：95.09％;1H NMR(400MHz;DMSO-d₆):δ1.19(d,J＝6.25Hz,3H),2.90(s,3H),4.44(d,J＝6.35Hz,1H),4.89-4.92(m,1H),5.04-5.07(m,1H),6.85(s,1H),6.91(d,J＝7.5Hz,1H),6.95(d,J＝8.15Hz,1H),7.00(d,J＝7.65Hz,1H),7.08(d,J＝8.01Hz,1H),7.13-7.17(m,3H),7.24-7.26(m,3H),7.38-7.42(m,2H),8.46(s,1H),8.58(s,1H),10.63(s,1H);UPLC-MS m/z:440.15[M+H].

Biological analysis

Reporter gene expression analysis in THP-1 cells

THP1-Dual ^TM cells (Invivogen) were derived from the human THP-1 monocytic cell line by stable integration of the two inducible reporter constructs. Thus, THP1-Dual ^TM cells allow simultaneous investigation of the IRF pathway and NF- κB pathway by assessing the activity of secreted luciferase (Lucia) and by monitoring the activity of secreted SEAP. 5X 10 ⁴ THP1-Dual ^TM cells were inoculated into 384-well plates of growth medium and pre-incubated with the novel compounds for 10 minutes, followed by stimulation with 5 μm2',3' -cGAMP. After 20h of stimulation, the supernatant was removed and IRF pathway reporter protein was readily measured in cell culture supernatant using QUANTI-Luc ^TM (invitrogen) (luciferase detection test agent on spectromax i3X photometer).

In the table below, ranges of IC ₅₀ values for the exemplary compounds are given. The IC ₅₀ range is indicated as "A" for values less than or equal to 1 μM, as "B" for values greater than 1 μM and less than or equal to 10 μM, and as "C" for values greater than 10 μM.

Activity data

Claims

1. A compound of the formula (I),

Wherein X ² is CR ² and X ³ is CR ³ or N; or X ² is N and X ³ is CR ³;

x ⁶ is c=o or CR ⁷R⁸;

Z is CR ⁹R¹⁰ or NR ⁹;

X ⁷ is S, SO ₂、O、NR¹¹ or CR ¹¹R¹²;

One of R ² and R ³ is;

A is CR ¹⁹ or N;

x is CR ²⁰ or N;

Y is CR ²¹ or N;

t is CR ²² or N;

R ⁵ is selected from the group consisting of: COOR ¹³、CONR¹³R¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₁-C₆ alkylsulfonyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted C ₂-C₆ alkenyl, optionally substituted C ₂-C₆ alkynyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, optionally substituted mono-or bicyclic 3-to 8-membered heterocycle and-L ¹-L²-R¹⁵;

wherein the compound is not

2. The compound of claim 1, wherein R ¹ is H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl.

3. The compound of claim 1 or claim 2, wherein X ² is CR ² and X ³ is CR ³.

4. The compound of claim 3, wherein one of R ² and R ³ isAnd the other of R ² and R ³ is H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl.

5. The compound of claim 4, wherein one of R ² and R ³ isAnd the other of R ² and R ³ is H, halogen, OH, CN, CONR ¹³R¹⁴、NR¹³R¹⁴、C₁-C₃ alkyl, C ₂-C₃ alkenyl, or C ₂-C₃ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. c ₁-C₃ alkyl, C ₂-C₃ alkenyl and C ₂ -C alkynyl.

6. The compound of any preceding claim, wherein R ¹⁶ and R ¹⁷ are independently H, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl.

7. The compound of any preceding claim, wherein P is H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl.

8. The compound of any preceding claim, wherein Q is H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl, and R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H. optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl and optionally substituted C ₂ -C alkynyl.

9. A compound according to any preceding claim, wherein:

A is N, X is CR ²⁰, Y is CR ²¹ and T is CR ²²;

A is CR ¹⁹, X is N, Y is CR ²¹ and T is CR ²²;

A is CR ¹⁹, X is CR ²⁰, Y is N and T is CR ²²; or (b)

A is CR ¹⁹, X is CR ²⁰, Y is CR ²¹ and T is N.

10. A compound according to any one of claims 1 to 8, wherein a is CR ¹⁹, X is CR ²⁰, Y is CR ²¹ and T is CR ²².

11. The compound of any preceding claim, wherein R ¹⁹ to R ²² are independently H, halogen, CN, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl, optionally substituted C ₂-C₃ alkynyl, optionally substituted mono-or bicyclic C ₃-C₆ cycloalkyl, optionally substituted mono-or bicyclic C ₆-C₁₂ aryl, optionally substituted mono-or bicyclic 5-to 10-membered heteroaryl, or optionally substituted mono-or bicyclic 3-to 8-membered heterocycle.

12. The compound of any preceding claim, wherein R ⁴ is H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl.

13. A compound according to any preceding claim, wherein R ⁵ is-L ¹-L²-R¹⁵.

14. The compound of claim 13, wherein L ¹ is optionally substituted C ₁-C₃ alkylene, optionally substituted C ₂-C₃ alkenylene, optionally substituted C ₂-C₃ alkynylene, or absent.

15. The compound of claim 13 or claim 14, wherein L ² is absent or O, S, S = O, SO ₂ or NR ¹⁹.

16. The compound of any one of claims 13-15, wherein R ¹⁵ is optionally substituted monocyclic or bicyclic C ₃-C₆ cycloalkyl, optionally substituted monocyclic or bicyclic C ₆-C₁₂ aryl, optionally substituted monocyclic or bicyclic 5-to 10-membered heteroaryl, or optionally substituted monocyclic or bicyclic 3-to 8-membered heterocycle.

17. The compound of any one of claims 1 to 12, wherein R ⁵ is optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl.

18. A compound according to any preceding claim, wherein X ⁶ is CO.

19. The compound of any one of claims 1-17, wherein X ⁶ is CR ⁷R⁸ and R ⁷ and R ⁸ are independently H, halogen, OH, CN, COOR ¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl, or optionally substituted C ₂-C₆ alkynyl.

20. A compound according to any preceding claim, wherein:

Z is CR ⁹R¹⁰;

X ⁷ is S, O, SO or NR ¹¹;

R ⁹ and R ¹⁰ are independently H, halogen 、OR¹³、CN、COOR¹³、CONR¹³R¹⁴、NR¹³R¹⁴、NR¹³COR¹⁴、 optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl; and

R ¹¹ is H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl.

21. A compound according to any one of claims 1 to 19, wherein:

Z is NR ⁹;

X ⁷ is CR ¹¹R¹²;

R ⁹ is H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl;

R ¹¹ is H, optionally substituted C ₁-C₃ alkyl, optionally substituted C ₂-C₃ alkenyl or optionally substituted C ₂-C₃ alkynyl; and

R ¹² is H, halogen, OH, CN, optionally substituted C ₁-C₆ alkyl, optionally substituted C ₂-C₆ alkenyl or optionally substituted C ₂-C₆ alkynyl.

22. The compound of claim 1, wherein the compound is:

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-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- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-bromo-1H-pyrrolo [2,3-b ] pyridin-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-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- (2-methyl-1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-chloro-1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-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-pyrrolo [2,3-b ] pyridin-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-pyrrolo [3,2-c ] pyridin-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-pyrrolo [2,3-c ] pyridin-3-yl) urea;

1- (1H-indol-3-yl) -3- (4-methyl-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-pyrrolo [3,2-b ] pyridin-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (1H-indol-3-yl) -3- (3-oxo-4- (pyridin-2-ylmethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (1H-indol-3-yl) -3- (3-oxo-4- (pyridin-4-ylmethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

3- ((6- (3- (1H-indol-3-yl) ureido) -3-oxo-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) methyl) benzamide;

2- ((6- (3- (1H-indol-3-yl) ureido) -3-oxo-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) methyl) benzamide;

4- ((6- (3- (1H-indol-3-yl) ureido) -3-oxo-2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) methyl) benzamide;

1- (1H-indol-3-yl) -3- (3-oxo-4- (pyridin-3-ylmethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (4- (2-chloro-6-fluoro-3-methoxybenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-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-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (5-chloro-1H-indol-3-yl) -3- (4- (2-chloro-6-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (4-benzyl-2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -2-methyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluoro-3-hydroxybenzyl) -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- (5-cyano-1H-indol-3-yl) urea;

1- (5- (1H-pyrazol-5-yl) -1H-indol-3-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- (5- (oxazol-5-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3, 5-difluorophenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (2-methyl-oxazol-5-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (isothiazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3- (hydroxymethyl) phenyl) -1H-indol-3-yl) urea;

1- (5- (1H-pyrazol-4-yl) -1H-indol-3-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- (5- (3-cyanophenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1-ethyl-1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

3- (3- (3- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) ureido) -1H-indol-5-yl) benzamide;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (pyridin-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (2-cyanoethyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3-methoxyphenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3- (methylsulfonyl) phenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (pyridin-3-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (pyrimidin-5-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (5-chloropyridin-3-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3- (trifluoromethoxy) phenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1-isopropyl-1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (cyclopropylmethyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (5- (hydroxymethyl) pyridin-3-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (2-oxoindol-6-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (6-hydroxypyridin-3-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (thiazol-5-yl) -1H-indol-3-yl) urea;

1- (5- (benzo [ d ] [1,3] dioxol-5-yl) -1H-indol-3-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- (5- (isoxazol-4-yl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (3- (trifluoromethyl) phenyl) -1H-indol-3-yl) urea;

1- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5- (1- (2-hydroxypropyl) -1H-pyrazol-4-yl) -1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4-benzoyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (1H-indol-3-yl) -3- (4-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (4-benzoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2, 6-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-fluoro-6-methylbenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (2-chloro-6-fluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (1H-indol-3-yl) -3- (4- ((3-methylisoxazol-5-yl) methyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) urea;

1- (4- (2-cyanobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) -3- (1H-indol-3-yl) urea;

1- (1H-indol-3-yl) -3- (4- (pyridin-2-ylmethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (3, 5-difluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

2- ((7- (3- (1H-indol-3-yl) ureido) -2, 3-dihydro-4H-benzo [ b ] [1,4] thiazin-4-yl) methyl) benzamide;

1- (1H-indol-3-yl) -3- (4- ((5-methylisoxazol-3-yl) methyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) urea;

1- (4-benzyl-2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (6-fluoro-1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) urea;

1- (4- (3-chloro-5-fluorobenzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea;

1- (4- (5-fluoro-6-methylpyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

1- (1H-indol-3-yl) -3- (4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (1H-indol-3-yl) -3- (4-phenyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-7-yl) urea;

1- (1H-indol-3-yl) -3- (4- (pyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (4- (6-fluoropyridin-2-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (1H-indol-3-yl) urea;

(S) -1- (1-benzyl-3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazolin-7-yl) -3- (1H-indol-3-yl) urea;

(S) -1- (1- (2-chloro-6-fluoro-3-hydroxybenzyl) -3, 4-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinazolin-7-yl) -3- (1H-indol-3-yl) urea;

1- (4-benzyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-cyano-1H-indol-3-yl) urea;

1- (5-fluoro-1H-indol-3-yl) -3- (4- ((3-methylisoxazol-5-yl) methyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) urea;

1- (4- (3-chloro-5-fluorobenzyl) -2-methyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-fluoro-1H-indol-3-yl) urea; or (b)

1- (4-Benzyl-3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-6-yl) -3- (5-bromo-1H-indol-3-yl) urea.

23. A pharmaceutical composition comprising a compound according to any preceding claim, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

24. A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 23, for use as a medicament.

25. A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 23, for use in modulating an interferon gene stimulating factor (STING) protein.

26. A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 23, for use in the treatment, amelioration or prophylaxis of a disease selected from: liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid Arthritis (RA), type I diabetes, STING-related vasculopathy (SAVI) in infancy, icaldi-gules syndrome (aicadi-Goutieres syndrome, AGS), familial lupus chilblain (FCL), systemic Lupus Erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke, and age-related macular degeneration (AMD).