HK1256199B - Nrf2 regulators - Google Patents

Description

Nrf2 modulators

Technical Field

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 modulators.

Background

Nrf2(NF-E2 related factor 2) is a member of the cap and collar (CNC) family of transcription factors containing a characteristic basic-leucine zipper motif. Under basal conditions, Nrf2 levels were tightly controlled by the cytoplasmic actin binding repressor KEAP1 (Kelch-like ECH-associated protein 1), KEAP1 bound Nrf2 and targeted Nrf2 for ubiquitination and proteasome degradation via the Cul 3-based E3-ubiquitin ligase complex. Under conditions of oxidative stress, DJ1(PARK7) is activated and stabilizes Nrf2 protein by preventing Nrf2 from interacting with KEAP 1. Likewise, modification of the reactive cysteine on KEAP1 may result in a conformational change in KEAP1 that alters Nrf2 binding and promotes Nrf2 stabilization. Thus, the level of Nrf2 in the cytosol was low under normal conditions, but the system was designed to respond rapidly to environmental stress by increasing Nrf2 activity.

Inappropriately low Nrf2 activity in the face of sustained oxidative stress appears to be a potential pathological mechanism for Chronic Obstructive Pulmonary Disease (COPD). This may be the result of a change in the balance between an inappropriate absence of Nrf2 regulator from a positive regulator (e.g., DJ1) and an excess of negative regulators (e.g., Keap1 and Bach 1). Thus, restoration of Nrf2 activity in the lungs of COPD patients should restore the imbalance and mitigate deleterious processes such as apoptosis and inflammation of structural cells, including alveolar epithelial cells and endothelial cells. The result of these effects is an enhanced cytoprotective effect, maintenance of lung structure and structural repair in COPD lungs, slowing down disease progression. Thus, Nrf2 modulators can treat COPD (Boutten, a., et al 2011.Trends mol. med.17: 363-.

One example of inappropriately low Nrf2 activity is found in lung macrophages from COPD patients. These cells have impaired bacterial phagocytosis compared to similar cells from control patients, and this effect is reversed by the addition of Nrf2 activator in vitro. Thus, in addition to the effects mentioned above, restoration of appropriate Nrf2 activity may also save COPD exacerbations by reducing lung infections. This was demonstrated by the Nrf2 activator Sulforaphane (Sulforaphane), which increases the presence of COPD macrophages and alveolar macrophages from mice exposed to cigarette smokeCollagen structure Macrophage receptor of(MARCO), thereby increasing bacterial phagocytosis (Pseudomonas aeruginosa, atypical Haemophilus influenzae) and bacterial clearance in vitro and in vivo in these cells (Harvey, C.J., et al 2011.Sci. Transl. Med.3:78ra 32).

The therapeutic potential to target Nrf2 in the lung is not limited to COPD. More specifically, targeting the Nrf2 pathway can treat other human lung and respiratory diseases that present oxidative stress components, such as chronic and acute asthma, lung disease secondary to environmental exposure (including but not limited to ozone, diesel exhaust, and occupational exposure), fibrosis, acute lung infection (e.g., viral (Noah, t.l. et al 2014.PLoS ONE 9(6): e98671), bacterial or fungal), chronic lung infection, alpha 1 antitrypsin disease, and cystic fibrosis (CF, Chen, j. et al 2 008.PLoS One.2008；3(10):e3367)。

Therapies targeting the Nrf2 pathway also have a variety of potential uses outside the lung and respiratory system. Many diseases for which Nrf2 activators may be useful are autoimmune diseases (psoriasis, IBD, MS), suggesting that Nrf2 activators may be useful in autoimmune diseases in general.

Clinically, drugs targeting the Nrf2 pathway (bardoxolone methyl) have shown efficacy in diabetic patients with diabetic nephropathy/Chronic Kidney Disease (CKD) (Aleksunes, l.m., et al 2010.j. pharmacol. exp. ther.335:2-12), but phase III trials with this drug have been terminated in patients with the most severe stage of CKD. Furthermore, there is evidence to speculate that such treatment would be effective in sepsis-induced acute Kidney injury, other Acute Kidney Injury (AKI) (Shelton, l.m., et al 2013.Kidney International, Jun 19. doi: 10.1038/ki.2013.248), and renal disease or renal dysfunction observed during renal transplantation.

Bardoxolone methyl is currently being studied in patients with pulmonary hypertension in the cardiac region, and therefore drugs that target Nrf2 by other mechanisms may also be used in the disease. Also, it can be used in a variety of cardiovascular diseases, including but not limited to atherosclerosis, hypertension and heart failure (Oxidative Medicine and Cellular Longevity Volume 2013(2013), articule ID 104308, page 10).

Drugs that activate the Nrf2 pathway may also be useful in the treatment of severe neurodegenerative diseases including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS) (Brain res.2012mar 29; 1446:109-18.2011.12.064.Epub 2012Jan 12.) and Multiple Sclerosis (MS). Several in vivo models have demonstrated that Nrf2 KO mice are more susceptible to neurotoxic injury than their corresponding wild-type. Treatment of rats with the Nrf2 activator tert-butylhydroquinone (tBHQ) reduced cortical injury in rats in a cerebral ischemia-reperfusion model, and cortical glutathione levels increased following tBHQ administration in Nrf2 wild-type but not KO mice (Shih, a.y., et al 2005.j. neurosci.25: 10321-. Tecfidera^TM(dimethyl fumarate) (activation thereofOther targets, including Nrf2) have been approved in the united states for the treatment of relapsing-remitting Multiple Sclerosis (MS). Activation of Nrf2 also helps in the treatment of friedreich ataxia cases, where increased sensitivity to oxidative stress and impaired Nrf2 activation have been reported (Paupe v, et al, 2009, PLoS One; 4(1): e 4253).

There is preclinical evidence for specific protection of the Nrf2 pathway in models of inflammatory bowel disease (IBD, crohn's disease and ulcerative colitis) and/or colon Cancer (Khor, t.o., et al, 2008.Cancer prev.res. (philia) 1: 187-191).

Age-related macular degeneration (AMD) is a common cause of blindness in people over the age of 50. Smoking is a major risk factor for the development of non-neovascular (dry) AMD, and may also be a major risk factor for neovascular (wet) AMD. The findings in vitro and in preclinical species support the notion that the Nrf2 pathway is involved in the regulation of antioxidant responses in retinal epithelial cells and inflammation in preclinical models of ocular injury (Schimel, et al, 2011 am.j.pathol.178: 2032-. Fuchs Endothelial Dystrophy (FECD) is a progressive blinding disease characterized by apoptosis of Corneal Endothelial cells. This is an elderly disease and increased oxidative stress is associated with low levels of Nrf2 expression and/or function (Bitar, m.s., et al 2012 Invest ophthalmol. vis.sci., August 24,2012vol.53no. 95806-5813). In addition, Nrf2 activators may be useful in uveitis or other inflammatory eye diseases.

Nonalcoholic fatty liver disease (NASH) is a disease of fat deposition, inflammation and injury in the liver, which occurs in patients who drink little or no alcohol. In preclinical models, the development of NASH was greatly accelerated in KO mice lacking Nrf2 when challenged with methionine-and choline-deficient diets (chowdry s., et al 2010.Free rad.biol. & med.48: 357-) -371). Administration of the Nrf2 activators oltipraz and NK-252 significantly attenuated the progression of histological abnormalities, in particular liver fibrosis, in rats fed a choline-deficient L-amino acid-defined diet (Shimozono r. et al 2012, Molecular pharmacology.84: 62-70). Other liver diseases amenable to Nrf2 regulation are toxin-induced liver disease (e.g., acetaminophen-induced liver disease), viral hepatitis and liver cirrhosis (Oxidative Medicine and Cellular Longevity Volume 2013(2013), articule ID 763257, page 9).

Recent studies have also begun to elucidate the role of ROS in skin diseases such as psoriasis. Studies carried out in psoriasis patients show an increase in serum malondialdehyde and nitric oxide end-products and a decrease in erythrocyte-superoxide dismutase activity, catalase activity and total antioxidant status, which in each case correlate with a severity index of the disease (Dipali P.K., et al Indian J Clin biochem.2010 October; 25(4): 388-. Similarly, Nrf2 modulators may be useful in treating the local effects of dermatitis/radiation: (M. et al 2010 Genes&Devl.24: 1045-; 124(2):730-41).

Also data indicate that Nrf2 activators may be beneficial in preeclampsia, a disease that occurs in 2-5% of pregnant people and involves hypertension and proteinuria (Annals of anatomiy-Anatomischer Anzeiger Volume 196, Issue 5, 9 months 2014, p 268-277).

Preclinical data have shown that compounds with Nrf2 activating activity are better at reversing high altitude-induced lesions than compounds without Nrf2 activity, using animal and cell models of acute mountain sickness (Lisk c. et al, 2013, Free Radic Biol med. oct 2013; 63: 264-.

Disclosure of Invention

In one aspect of the invention, there are provided aryl analogs, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing them.

In a second aspect, the present invention provides the use of compounds of formulae (I) and (II) as Nrf2 modulators.

In another aspect, the invention provides the use of compounds of formulae (I) and (II) in the treatment and prevention of disorders associated with an imbalance in Nrf 2.

In one aspect, the present invention provides a pharmaceutical composition comprising a compound according to formulae (I) and (II) of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present invention relates to a pharmaceutical composition for use in the treatment of Nrf 2-modulated diseases or disorders, wherein the composition comprises a compound according to formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating respiratory and non-respiratory diseases including COPD, asthma, fibrosis, chronic and acute asthma, pulmonary disease secondary to environmental exposure, acute lung infection, chronic lung infection, α 1 antitrypsin disease, cystic fibrosis, autoimmune disease, diabetic nephropathy, chronic nephropathy, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), renal disease or renal insufficiency during kidney transplantation, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Friedreich's Ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry) AMD and neovascular (wet) AMD, ocular trauma, rheumatoid arthritis (PD), rheumatoid arthritis (ra), rheumatoid arthritis (ra), rheumatoid arthritis (ra), rheumatoid arthritis (ra), rheumatoid arthritis (rheumatoid arthritis, fulvestrant corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g. acetaminophen-induced liver disease), viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia, and altitude sickness comprising administering to a human in need thereof a compound of formula (I) or formula (II).

In another aspect, the invention provides the use of compounds of formulae (I) and (II) in the treatment of respiratory and non-respiratory diseases, including COPD, asthma, fibrosis, chronic and acute asthma, pulmonary disease secondary to environmental exposure, acute pulmonary infection, chronic pulmonary infection, alpha 1 antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic nephropathy, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), renal disease or renal insufficiency during renal transplantation, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Reed-Reichi ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry) AMD and neovascular (wet) AMD, Ocular trauma, fukes corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced liver disease), viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia, and altitude sickness.

In another aspect, the invention relates to the use of compounds of formulae (I) and (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of respiratory and non-respiratory diseases including COPD, asthma, fibrosis, chronic and acute asthma, pulmonary disease secondary to environmental exposure, acute lung infection, chronic lung infection, α 1 antitrypsin disease, cystic fibrosis, autoimmune disease, diabetic nephropathy, chronic nephropathy, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), renal disease or renal insufficiency during kidney transplantation, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Friedreich's Ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, colon cancer, Non-neovascular (dry) AMD and neovascular (wet) AMD, ocular trauma, fukes corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g. acetaminophen-induced liver disease), viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia, and altitude sickness.

In another aspect, the present invention relates to compounds of formulae (I) and (II), or pharmaceutically acceptable salts thereof, for use in medical therapy.

In another aspect, the invention relates to compounds of formulae (I) and (II), or pharmaceutically acceptable salts thereof, for use in the treatment of respiratory and non-respiratory diseases including COPD, asthma, fibrosis, chronic and acute asthma, pulmonary disease secondary to environmental exposure, acute pulmonary infection, chronic pulmonary infection, α 1 antitrypsin disease, cystic fibrosis, autoimmune disease, diabetic nephropathy, chronic nephropathy, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), renal disease or renal insufficiency during kidney transplantation, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Friedreich's Ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry) AMD and neovascular (wet) AMD, Ocular trauma, fukes corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced liver disease), viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia, and altitude sickness.

In another aspect, the invention relates to the use of a compound of formula (I) or formula (II) in the treatment of COPD.

In another aspect, the invention relates to the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.

In another aspect, the invention relates to compounds of formulae (I) and (II), or pharmaceutically acceptable salts thereof, for use in the treatment of COPD.

In another aspect, the invention relates to a method of treating COPD which comprises administering to a human in need thereof a compound of formula (I) or formula (II).

In another aspect, the present invention relates to the use of a compound of formula (I) or formula (II) for the treatment of heart failure.

In another aspect, the invention relates to a method of treating heart failure, comprising administering to a human in need thereof a compound of formula (I) or formula (II).

In another aspect, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of heart failure.

In another aspect, the present invention relates to a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure.

The compounds of formulae (I) and (II) and pharmaceutically acceptable salts thereof are useful in combination with one or more other drugs useful in the prevention or treatment of, for example, allergic diseases, inflammatory diseases, autoimmune diseases; antigen immunotherapy, antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), iNO inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., β -2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate (sodium chloromoglycate), 5-lipase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K δ inhibitors, ITK inhibitors, LP (lysophosphatidic acid) inhibitors or FLAP (5-lipase activating protein) inhibitors (e.g., 3- (3- (tert-butylsulfanyl) -1- (4- (6-ethoxypyridin-3-yl) benzyl) -5- ((5-methylpyridin-2-yl) methoxy) -1H-indol-2-yl) -2, 2-dimethylpropionic acid sodium), bronchodilators (e.g., muscarinic antagonists, β -2 agonists), methotrexate, and the like; monoclonal antibody therapies such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and the like; cytokine receptor therapies such as etanercept and similar drugs; antigen non-specific immunotherapy (e.g., interferons or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4, or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists, and similar drugs).

The compounds may also be used in combination with drugs that aid in transplantation, including cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, daclizumab, basiliximab, or OKT 3.

They can also be used in combination with drugs for diabetes: metformin (biguanides), meglitinide, sulfonylureas, DPP-4 inhibitors, thiazolidinediones, α -glucosidase inhibitors, starch-insoluble mimetics, incretin mimetics and insulin.

The compounds are useful in combination with antihypertensive drugs, such as diuretics, ACE inhibitors, ARBS, calcium channel blockers and beta blockers.

In one embodiment, the present invention relates to the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance. More specifically, the invention provides the use of compounds described herein for the treatment of respiratory and non-respiratory diseases, in particular, the diseases and disorders described herein. Accordingly, the present invention provides the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of humans suffering from respiratory and non-respiratory diseases in need thereof, in particular, the diseases and disorders described herein. In particular, the present invention provides the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of COPD.

In one embodiment, the invention relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of respiratory and non-respiratory diseases, such as the diseases and disorders described herein. The invention further provides the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of respiratory and non-respiratory diseases, for example the diseases and disorders described herein. In particular, the invention further provides the use of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.

Other aspects and advantages of the present invention are further described in the following detailed description of the preferred embodiments.

Detailed Description

The present invention provides compounds of formulae (I) and (II):

wherein:

b is benzotriazolyl, phenyl, triazolopyridyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, -O-C_1-3Alkyl, CN, - (CH)₂)₂–O–(CH₂)₂-OR₄And halogen;

d is-C (O) OH, -C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃5- (trifluoromethyl) -4H-1,2, 4-triazol-2-yl or tetrazolyl;

R₁Independently of one another is hydrogen, C_1-3Alkyl radical F, C_3-6Spirocycloalkyl, propylene oxide, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

R₄is hydrogen or C_1-3An alkyl group;

a is tetrahydrobenzoxazepinonenyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl or tetrahydro-pyridoxazepinonenyl, all of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, halogen, CN, -OC_1-3Alkyl, -CH₂-O-CH₃、C_3-6Spirocycloalkyl and OH;

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

Wherein:

b is benzotriazolyl, phenyl, triazolopyridyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, -O-C_1-3Alkyl, CN, - (CH)₂)₂–O–(CH₂)₂-OR₄And halogen;

d is-C (O) OH, -C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃5- (trifluoromethyl)Yl) -4H-1,2, 4-triazol-2-yl or tetrazolyl;

R₁independently of one another is hydrogen, C_1-3Alkyl radical F, C_3-6Spirocycloalkyl, propylene oxide, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

R₂is ═ O or hydrogen;

R₄is hydrogen or-C_1-3An alkyl group;

the linking group being-CH₂、-O-C(O)-、-CH₂-C(O)-、–C(O)-、-CH(CH₃) -C (O) -or-N (CH) ₃)-C(O)-；

A is cyclohexyl, cyclopentyl, phenyl or decahydronaphthyl; all of these groups may be unsubstituted or independently substituted with a substituent selected from: c_1-3Alkyl, CN and halogen;

or A is C_4-5Alkyl, which may be substituted by-OC_1-3Alkyl substituted;

n is 1 or 2;

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

"alkyl" refers to a monovalent saturated hydrocarbon chain having the number of carbon member atoms specified. E.g. C_1-4Alkyl refers to alkyl groups having 1 to 4 carbon member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl) and butyl (n-butyl, isobutyl, sec-butyl and tert-butyl).

“C_3-6Spirocycloalkyl "refers to spirocyclopropyl, spirobutyl, spirocyclopentane and spirohexane.

As used herein, the terms 'halogen' and 'halo' include fluoro, chloro, bromo and iodo, and fluoro, chloro, bromo and iodo, respectively.

When referring to a group, "substituted" means that one or more hydrogen atoms attached to a member atom in the group is replaced with a substituent selected from the defined group of substituents. It is to be understood that the term "substituted" includes the implicit proviso that the substitution complies with the valency allowed by the atom being substituted and the substituent, and that the substitution results in a stable compound (i.e., the compound does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, or elimination, and the compound is sufficiently robust to be isolated from the reaction mixture). When it is stated that a group may contain one or more substituents, one or more (if desired) member atoms within the group may be substituted. Furthermore, a single member atom within the group may be substituted with more than one substituent, provided that such substitution complies with the permitted valency of the atom. Suitable substituents are as defined herein for each substituted or optionally substituted group.

The term "independently" means that when more than one substituent is selected from a plurality of possible substituents, those substituents may be the same or different. In other words, each substituent is individually selected from the entire set of possible substituents.

The invention also includes various isomers of the compounds of formula (I) and (II) and mixtures thereof. "isomers" refer to compounds having the same composition and molecular weight but different physical and/or chemical properties. The structural difference may be in the ability to construct (geometric isomers) or rotate the plane of polarized light (stereoisomers). The compounds of formula (I) or (II) contain one or more asymmetric centers (also known as chiral centers) and may therefore exist as individual enantiomers, diastereomers or other stereoisomeric forms, or as mixtures thereof. All such isomeric forms are included within the scope of the present invention, including mixtures thereof.

Chiral centers may also be present in substituents such as alkyl groups. When the stereochemistry of a chiral center present in formula (I) and (II) or in any of the chemical structures described herein is not specifically indicated, the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, the compounds of formulae (I) and (II) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures or as the corresponding isomerically pure individual stereoisomers.

The individual stereoisomers of the compounds of formulae (I) and (II) containing one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such a resolution can be performed by: (1) forming a diastereomeric salt, complex or other derivative; (2) selectively reacting with a stereoisomer-specific reagent, such as an enzymatic oxidation reaction or a reduction reaction; or (3) by gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support such as a silica gel bound to a chiral ligand or in the presence of a chiral solvent. It will be appreciated by those skilled in the art that when the desired stereoisomer is converted to another chemical entity by one of the above separation procedures, a further step of liberating the desired form is required. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting one enantiomer into the other by asymmetric transformation.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The skilled person will appreciate that pharmaceutically acceptable salts of the compounds of formulae (I) and (II) may be prepared. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound or by separately treating the purified compound in its free acid or free base form with the appropriate base or acid, respectively.

In some embodiments, the compounds of formula (I) and (II) may contain acidic functional groups and are therefore capable of forming pharmaceutically acceptable base addition salts by treatment with an appropriate base. Examples of such bases include a) hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum and zinc; and b) primary, secondary and tertiary amines, including aliphatic, aromatic, aliphatic diamines and hydroxyalkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine and cyclohexylamine.

In some embodiments, the compounds of formula (I) and (II) may contain basic functional groups and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include pharmaceutically acceptable inorganic and organic acids. Representative pharmaceutically acceptable acids include hydrochloric, hydrobromic, nitric, sulfuric, sulfonic, phosphoric, acetic, glycolic, phenylacetic, propionic, butyric, valeric, maleic, acrylic, fumaric, succinic, malic, malonic, tartaric, citric, salicylic, benzoic, tannic, formic, stearic, lactic, ascorbic, methanesulfonic, p-toluenesulfonic, oleic, lauric and the like.

The term "compound of formula (I) or (II)" or "said compound of formula (I) or (II)" as used herein refers to one or more compounds of formula (I) or (II). The compounds of formulae (I) and (II) may be present in solid or liquid form. In the solid state, it may be present in crystalline or amorphous form or in the form of a mixture thereof. It is understood by those skilled in the art that pharmaceutically acceptable solvates may be formed from crystalline compounds, wherein solvent molecules are incorporated in the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may include water as the solvent, which is incorporated in the crystal lattice. When water is the solvent incorporated in the crystal lattice, such solvates are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The present invention includes all such solvates.

The skilled person will also appreciate that some compounds of the invention, including various solvates thereof, that exist in crystalline form may exist in polymorphic form (i.e. the ability to occur in different crystalline structures). These different crystalline forms are often referred to as "polymorphs". The present invention includes all such polymorphs. Polymorphs have the same chemical composition, but differ in the packing, geometric arrangement and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically have different melting points, IR spectra and X-ray powder diffraction patterns, which can be used for identification. The skilled person understands that different polymorphs can be produced, e.g. by changing or adjusting the reaction conditions or reagents used in the preparation of the compounds. For example, changes in temperature, pressure or solvent can result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The present invention also includes isotopically-labeled compounds, which are identical to those recited in formulas (I) and (II) and their attendant formulas, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, for example²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I。

compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. in which a radioactive isotope is incorporated, e.g.³H，¹⁴Those compounds of C are used in drug and/or substrate tissue distribution assays. Tritiated i.e.³H and carbon-14 i.e¹⁴The C isotope is particularly preferred because of its ease of preparation and ease of detection.¹¹C and¹⁸the F isotope is particularly useful in PET (positron emission tomography),¹²⁵the I isotope is particularly useful in SPECT (single photon emission computed tomography), all of which are used in brain imaging. In addition, with heavier isotopes such as deuterium ²Some therapeutic advantages are obtained by H substitution due to higher metabolic stability such as half-life in vivoIncreased or reduced dosage requirements and are therefore preferred in some circumstances. Isotopically labeled compounds of formulae (I) and (II) of the present invention and ancillary compounds thereof can generally be prepared by carrying out the procedures described in the schemes and/or in the examples below, wherein a non-isotopically labeled reagent is replaced by a readily available isotopically labeled reagent.

Representative embodiments

In one embodiment of the compounds of formula (I):

b is benzotriazolyl, phenyl, triazolopyridyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, -O-C_1-3Alkyl, CN, - (CH)₂)₂–O–(CH₂)₂-OR₄And halogen;

d is-C (O) OH, -C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃5- (trifluoromethyl) -4H-1,2, 4-triazol-2-yl or tetrazolyl;

R₁independently of one another is hydrogen, C_1-3Alkyl radical F, C_3-6Spirocycloalkyl, propylene oxide, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

R₄is hydrogen or C_1-3An alkyl group;

a is tetrahydrobenzoxazepinonenyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl or tetrahydro-pyridoxazepinonenyl, all of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C _1-3Alkyl, halogen, CN, -OC_1-3Alkyl, -CH₂-O-CH₃、C_3-6Spirocycloalkyl and OH; and

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (I):

b is benzotriazolyl or- (CH)₂)₂Triazolyl, each of which may beUnsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C_1-3Alkyl and halogen;

d is-C (O) OH;

R₁independently is hydrogen or methyl, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

a is tetrahydrobenzoazepinotrienyl, tetrahydrobenzoazepinotrienyl or tetrahydro-pyridoazepinotrienyl, all of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C_1-3Alkyl, halogen or CN or-O C_1-3An alkyl group; and

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (I):

b is a benzotriazolyl or phenyl group, each of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C_1-3Alkyl, halogen and CN;

d is-C (O) OH;

R₁independently is hydrogen or C_1-3An alkyl group;

a is tetrahydrobenzoxazepinonenyl, tetrahydrobenzazepinyl, tetrahydroimidazodiazepinyl or tetrahydro-pyridoxazepinonenyl, all of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C _1-3Alkyl, halogen, CN, -OC_1-3Alkyl, -CH₂-O-CH₃、C_3-6Spirocycloalkyl and OH; and

n is 1;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (I):

b is a benzotriazolyl group which may be unsubstituted or substituted by 1,2 or 3 groups independently selected from-C_1-3Alkyl is substituted by a substituent;

d is-C (O) OH;

R₁independently is hydrogen or C_1-3An alkyl group;

a is tetrahydrobenzoxazepinonenyl which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, -OC_1-3Alkyl, CN and halogen; and

n is 1;

or a pharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula (II):

b is benzotriazolyl, phenyl, triazolopyridyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1,2 or 3 substituents independently selected from: -C_1-3Alkyl, -O-C_1-3Alkyl, CN, - (CH)₂)₂–O–(CH₂)₂-OR₄And halogen;

d is-C (O) OH, -C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃5- (trifluoromethyl) -4H-1,2, 4-triazol-2-yl or tetrazolyl;

R₁independently of one another is hydrogen, C_1-3Alkyl radical F, C_3-6Spirocycloalkyl, propylene oxide, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

R₂is ═ O or hydrogen;

R₄is hydrogen or C _1-3An alkyl group;

the linking group being-CH₂-、-O-C(O)-、-CH₂-C(O)-、–C(O)-、-CH(CH₃) -C (O) -or-N (CH)₃)-C(O)-；

A is cyclohexyl, cyclopentyl, phenyl or decahydronaphthyl; all of these groups may be unsubstituted or independently substituted with a substituent selected from: c_1-3Alkyl, CN and halogen;

or A is C_4-5Alkyl, which may be substituted by-OC_1-3Alkyl substituted;

n is 1 or 2; and

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (II):

b is benzotriazolyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C_1-3Alkyl and halogen;

d is-C (O) OH;

R₁independently is hydrogen or methyl, or two R₁The groups together with the carbon to which they are attached form a cyclopropyl group;

R₂is ═ O or hydrogen;

the linking group being-CH₂-、-O-C(O)-、-CH(CH₃) -C (O) -or-N (CH)₃)-C(O)-；

A is cyclohexyl or cyclopentyl, each of which may be unsubstituted or independently substituted with a substituent selected from: c_1-3Alkyl, CN and halogen;

n is 1; and

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (II):

b is benzotriazolyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C _1-3Alkyl and-O-C_1-3An alkyl group;

d is-C (O) OH;

R₁independently is hydrogen;

R₂is hydrogen;

the linking group being-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydronaphthyl; all of these groups may be unsubstituted or independently substituted with a substituent selected from: c_1-3Alkyl, CN and halogen;

or A is C_4-5Alkyl, which may be substituted by-OC_1-3Alkyl substituted;

n is 1; and

x is CH₂；

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compounds of formula (II):

b is benzotriazolyl or- (CH)₂)₂Triazolyl, each of which may be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: -C_1-3Alkyl and-O-C_1-3An alkyl group;

d is-C (O) OH;

R₁independently is hydrogen;

R₂is ═ O;

the linking group being-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydronaphthyl; all of these groups may be unsubstituted or independently substituted with a substituent selected from: c_1-3Alkyl, CN and halogen;

or A is C_4-5Alkyl, which may be substituted by-OC_1-3Alkyl substituted;

n is 1; and

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

It is to be understood that the invention encompasses all combinations of the specific groups described hereinabove.

Specific examples of the compounds of the present invention include the following:

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (3,3-3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {1- [ (4-ethylcyclohexyl) methyl ] -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid;

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid;

3- [1- (decahydronaphthalen-2-ylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- { 2-oxo-1- [ (4-propylcyclohexyl) methyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- [1- (2-cyclohexylacetyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-methylpentanoyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- {1- [2- (2-chlorophenyl) acetyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [2- (2-cyanophenyl) acetyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

dimethylbutyryl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- {1- [ butyl (methyl) carbamoyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1-ethyl-4-methyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- [1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,5H,9 bH-benzo [ g ] indol-8-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- [3- (cyclohexylmethyl) -2-oxo-2H, 3aH,8H,8 aH-indeno [1,2-d ] [1,3] oxazol-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- [3- (7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,2, 7-trimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (7-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,2, 8-trimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (8-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -2, 2-dimethylpropanoic acid; formic acid;

3- [3- (7-cyano-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid; formic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2R) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- [3- (8-cyano-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid; formic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

(3S) -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [ (3R) -3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2R) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- {3- [ (2R) -2-ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2S) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- (3- {2H,3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2S) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid; formic acid;

3- (4-cyano-2-methylphenyl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- { 3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl } propanoic acid; formic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid; trifluoroacetic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -5- (2-ethyl-2H-1, 2,3, 4-tetrazol-5-yl) -2, 2-dimethylpentanoic acid; formic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid;

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (R) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (R) -3- (2, 2-dimethyl-2, 3-dihydropyrido [4,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [4,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid; or

5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid;

or a pharmaceutically acceptable salt thereof.

Preparation of compounds

It will be appreciated by those skilled in the art that if a substituent described herein is incompatible with the synthetic methods described herein, the substituent may be protected with an appropriate protecting group that is stable to the reaction conditions. The protecting group may be removed at an appropriate point in the reaction sequence to give the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting various substituents using the suitable protecting groups are well known to those skilled in the art; examples of suitable protecting groups may be found in t.greene and p.wuts, Protecting Groups in Chemical Synthesis(3rd ed.)，John Wiley&Sons, NY (1999). In some examples, substituents that are reactive under the reaction conditions used may be specifically selected. In these cases, the reaction conditions convert the selected substituent to another substituent that is used as an intermediate compound or a desired substituent in the target compound.

The synthesis of compounds of general formulae (I) and (II) and pharmaceutically acceptable derivatives and salts thereof can be accomplished as shown in schemes 1-21 below. In the following description, unless otherwise indicated, the radicals are as defined above for the compounds of formulae (I) and (II). Abbreviations are as defined in the examples section. The starting materials are either commercially available or prepared from commercially available starting materials using methods known to those skilled in the art.

Scheme 1

Conditions are as follows: a) NBS, TFA, H₂SO₄；b)i)MeNH₂(or) EtNH₂ THF；ii)Zn,HOAc；iii)NaNO₂,H₂SO₄

Scheme 1 shows a general scheme for the preparation of 5-bromo-4-methyl-1H-benzo [ d ] [1,2,3] triazole. Starting with commercially available 1-fluoro-3-methyl-2-nitrobenzene, bromination with NBS afforded intermediate 2. Replacement of the fluorine with the appropriate amine followed by zinc metal reduction of the nitro group to form aniline, diazotization and cyclization gives the desired triazole 3.

Scheme 2

Conditions are as follows: a) k₂CO₃,MeI,DMF；b)Br₂Acetic acid; c) NaH, MeI, DMF; d) zinc, acetic acid; e) NaNO₂,H₂SO₄

Scheme 2 shows the preparation of 5-bromo-7-methoxy-1-methyl-1H-benzo [ d][1,2,3]General scheme for triazoles. Starting from commercially available 2-amino-3-nitrophenols, using K₂CO₃And MeI methylates the phenol (step a) to provide intermediate 2, which can be brominated with NBS (step c). Methylation of the aniline (step d) followed by reduction of the nitro group (step d), and diazotization and cyclization (step e) provides the desired triazole 5.

Scheme 3

Conditions are as follows: a) NaIO₄/H₂SO₄,I₂,Ac₂O/AcOH；b)CuI,Cs₂CO₃,MeOH；

Scheme 3 shows a general scheme for the preparation of 5-bromo-7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazole. This two-step process starts with the iodination at the C7 position of 5-bromo-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazole. Copper mediated iodide displacement with methanol provided the desired species.

Scheme 4

Conditions are as follows: a) h₂O₂,TFA；b)(ii)KNO₃,H₂SO₄；(ii)CH₃NH₂；c)Ni,EtOH,40psi；d)NaNO₂,H₂SO₄

Scheme 4 shows a general scheme for the preparation of 6-chloro-3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridine. Starting from commercially available 2-chloro-5-fluoropyridine, oxidation gave intermediate 2. Which is subsequently converted to nitro intermediate 3. Displacement of fluoride with the appropriate amine followed by nickel metal reduction of the nitro group to aniline gives intermediate 4. The diazotization and cyclization is carried out to provide the desired triazole 5.

Scheme 5

Conditions are as follows: a) h₂NCH₂C(R₈)(R₉)OH,NaBH₄,NaOH,MeOH；b)Cs₂CO₃CuI, IPA; or KO_tBu, DMSO; c) boc anhydride, Et₃N, THF; d) HCl, dioxane

Scheme 5 alternatively shows the preparation of 2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f ] compounds for use in the present invention][1,4]Oxazepine and 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]General scheme for oxazepine. In scheme 5, R₇is-C_1-3Alkyl, halogen, CN, -OC_1-3Alkyl, -CH₂-O-CH₃Or OH; and R is₈And R₉Is hydrogen, C_1-3Alkyl, or C_3-6Spirocycloalkyl. Substituted 2-bromobenzaldehydes or substituted 2-fluorobenzaldehydes described as starting materials are commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and reagents used are possible.

Reductive amination of the starting aldehyde with the appropriate amino alcohol followed by displacement of the bromide or fluoride affords the desired intermediate 3. It was then protected as Boc carbamate to facilitate purification. Those skilled in the art will appreciate that alternative protecting groups may be used. Deprotection yields the desired amine 5.

Scheme 6

Conditions are as follows: a) h₂NCH₂CH(R₈)OH,NaBH₄,NaOH,MeOH；b)PPh₃DEAD, THF; c) boc anhydride, Et₃N, THF; d) HCl, dioxane

Scheme 6 shows the preparation of (R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f ] useful in the present invention ][1,4]Oxazepine and 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]General scheme for oxazepine. In scheme 6, R₇And R₈As previously defined. Substituted 2-hydroxybenzaldehydes described as starting materials are commercially available. Inverse directionThe conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Reductive amination of the aldehyde with the appropriate amino alcohol followed by a Mitsunobo reaction affords the desired intermediate 3. It was then protected as Boc carbamate to facilitate purification. Those skilled in the art will appreciate that alternative protecting groups may be used. Deprotection yields the desired amine 5.

Scheme 7

Conditions are as follows: a) k₂CO₃,THF；b)NaOMe,DMF；c)LAH,THF

Scheme 7 shows the preparation of substituted-tetrahydrobenzo [ f ] s for use in the present invention][1,4]General scheme for oxazepine. In scheme 7, R₈As previously defined. 2-hydroxybenzamides described as starting materials are commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Reaction of 2-hydroxybenzamide with the appropriate bromoacetate affords intermediate 3. Cyclization under basic conditions followed by reduction of the resulting imide with LAH affords the desired amine 5.

Scheme 8

Conditions are as follows: a) h₂NCH₂C(R₈)(R₉)OH,NaBH₄,NaOH,MeOH；b)Cs₂CO₃CuI, IPA; or KO_tBu, DMSO; c) boc anhydride, Et₃N, THF; d) HCl, dioxane

Scheme 8 shows the preparation of tetrahydropyrido [1,4 ] used in the present invention]General scheme for oxazepine hydrochlorides. In scheme 8, R₈And R₉As previously defined. Fluorinated nicotinaldehyde, chlorinated nicotinaldehyde or brominated nicotinaldehyde described as starting materials are commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Reductive amination of the starting aldehyde with the appropriate amino alcohol followed by displacement of the bromide or fluoride affords the desired intermediate 3. It was then protected as Boc carbamate to facilitate purification. Those skilled in the art will appreciate that alternative protecting groups may be used. Deprotection yields the desired amine 5 as the hydrochloride salt.

Scheme 9

Conditions are as follows: a) h₂NCH₂CH(R₈)OH,NaBH₄,NaOH,MeOH；b)PPh₃DEAD, THF; c) boc anhydride, Et₃N, THF; d) HCl, dioxane

Scheme 9 shows the preparation of (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [2,3-f ] used in the present invention][1,4]Oxazacycloheptatriene hydrochloride and 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [2,3-f][1,4]General scheme for oxazepine hydrochlorides. In scheme 9, R ₈As previously defined. 3-hydroxypyridine-2-carbaldehyde described as the starting material is commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Reductive amination of a commercially available aldehyde with an appropriate amino alcohol followed by a Mitsunobo reaction affords the desired intermediate 3. It was then protected as Boc carbamate to facilitate purification. Those skilled in the art will appreciate that alternative protecting groups may be used. Deprotection yields the desired amine 5.

Scheme 10

Conditions are as follows: a) NH (NH)₄OH; b) (R) - (2) -ethyloxirane, EtOH; c) KO (Ko)_tBu,DMF

Scheme 10 shows a general scheme for the preparation of (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine used in the present invention. 2-bromo-3- (bromomethyl) pyridine described as the starting material is commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Commercial 2-bromo-3- (bromomethyl) pyridine was treated with ammonium hydroxide to produce primary amine 2. Alkylation of the epoxide opening followed by displacement of the bromide affords intermediate 4.

Scheme 11

Conditions are as follows: a) amine, K₂CO₃THF, water; b) cs₂CO₃,CuI,IPA

Scheme 11 shows the preparation of 2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f ] used in the present invention][1,4]Oxazacycloheptatriene hydrochloride and 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]General scheme for oxazepine hydrochlorides. In scheme 11, R₇、R₈And R₉As previously defined. Substituted 1-bromo-2- (bromomethyl) benzenes described as starting materials are commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Alkylation with the appropriate amino alcohol followed by displacement of the bromide affords the desired intermediate 3.

Scheme 12

Conditions are as follows: a) POCl₃(ii) a b) NaOH, DCM; c) borane dimethyl sulfide, THF; d) (i) KO_tBu, DMSO; (ii) boc anhydride, Et₃N, THF; d) HCl, dioxane

Scheme 12 represents a general scheme for the preparation of 2,2, 8-trimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ] [1,4] oxazepine hydrochloride for use in the present invention. In this scheme, 4-hydroxy-6-methylnicotinic acid, described as the starting material, is commercially available. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible.

Using POCl₃Conversion of the commercially available acid 1 to the acid chloride followed by amide formation affords intermediate 3. Reduction of the amide with borane dimethyl sulfide yields amine 4. Cyclization with potassium tert-butoxide as base followed by protection of the amine as the tert-butyl carbamate group affords compound 5. Deprotection under acidic conditions affords the desired amine 6.

Scheme 13

Conditions are as follows: a) NaBH₄,MeOH,THF；b)PMBCl,NaH；c)n-BuLi,DMF；d)t-BuLi,4,THF；e)(i)Cl₃CCN,DBU,MeCN；(ii)Tf₂NH,Me₂C＝C(OR²)OTMS,MeCN；f)DDQ；g)(i)8,SOCl₂,DCM；(ii)9,K₂CO₃,NaI,MeCN(iii)NaOH,MeOH/H₂O

Scheme 13 represents a general scheme for the preparation of intermediates 4, 8 and compounds of formula (I). In scheme 13, R₆Is C_1-3Alkyl, halogen or-OC_1-3Alkyl radical, R₇、R₈And R₉As previously defined. Y is independently CH or N.

Starting from commercially available indanone 1, with NaBH₄Reduction produces the desired alcohol intermediate 2. The intermediate 2 hydroxyl group can be protected as a PMB ether by treatment with NaH and PMBCl to give intermediate 3. It will be understood by those skilled in the art that the protecting group may vary and is not limited to PMB. In addition, intermediate 3 was converted to the desired aldehyde by treatment with butyllithium and DMF to give the desired intermediate 4. The coupling of 4 and 5 is accomplished by treating 5 with t-butyllithium and intermediate 4 to form alcohol 6. First by using Cl₃CCN and DBU processing, followed by Tf₂Alcohol 6 is converted to 7 by treatment with the desired commercially available silyl ketene acetal in the presence of NH. Intermediate 7 was deprotected with DDQ to form intermediate 8. First using SOCl ₂Then with amines 9 and K₂CO₃Intermediate 8 was treated with NaI and then hydrolyzed with NaOH to form final product 10.

Scheme 14

Conditions are as follows: a) bis (pinacolato) diboron, Pd (dppf) Cl₂,KOAc,DMF；b)NaBH₄,MeOH；c)CH₂＝CHCO₂C_1-2Alkyl, Pd (OAc)₂,P(o-Tol)₃,DMF；d)2,Rh(cod)Cl₂,TEA；e)(i)5,SOCl₂,DCM；(ii)6,K₂CO₃,NaI,MeCN(iii)NaOH,MeOH/H₂O

Scheme 14 represents a general scheme for the preparation of intermediates 2 and 5 and compounds of formula (I). In scheme 14, R₆、R₇、R₈、R₉And Y is as previously defined. Z is CH or N.

Commercially available indanone 1 is first reduced to hydroxyindane and then converted to the boronic ester, or directly converted to the boronic ester by treatment with bis (pinacolato) diboron in the presence of a palladium catalyst to give 2. Intermediate 3 is converted to 4 under Heck reaction conditions. (for intermediate 3, in the case of Z ═ N,the chloride was used for Heck coupling in the presence of tetrakis (triphenylphosphine) palladium instead of bromide. ) Rhodium-catalyzed michael addition of 2 to 4 affords ester 5. If desired, with NaBH₄Reduction can convert intermediate 5 to hydroxyindane, then by reaction with SOCl₂And processed to convert into chloride. By using 6 and K₂CO₃The chloride is treated with NaI and then hydrolyzed with NaOH to complete the conversion to the final product 7.

Scheme 15

Conditions are as follows: a) LiHMDS, BrCH₂CO₂Bn, THF; b) bis (pinacolato) diboron, PdCl₂(dppf)-CH₂Cl₂KOAc,1, 4-dioxane; c) p-TolSO₂CH₂NC, KOBu-t, THF; d) LAH, THF; e) ethyl acrylate Pd (OAc) ₂,P(o-tol)₃,DIEA,DMF；f)[RhCl(cod)]₂TEA,1, 4-dioxane, H₂O；g)(i)Pd/C,H₂,MeOH；(ii)6,T3P,TEA,DCM；h)(i)TFA,Et₃SiH,MeCN；(ii)NaOH,MeOH/H₂O

Scheme 15 represents a general scheme for the preparation of intermediates 3, 6 and compounds of formula (II). In scheme 15, R₆As previously defined. R₁₀Is C_1-3Alkyl and CN. Commercially available indanone 1 is reacted with LiHMDS and benzyl bromoacetate in the presence of a suitable solvent to yield the desired intermediate 2. Intermediate 2 is further treated with bis (pinacolato) diboron, PdCl in a suitable solvent₂(dppf)-CH₂Cl₂And KOAc conversion to produce the desired intermediate 3. Commercially available Ketone 4 with p-TolSO₂CH₂NC, KOBu-t are reacted in a suitable solvent to give the desired intermediate 5, which can be further converted to amine 6 by LAH reduction. The triazole 7 described as the starting material can be synthesized from readily available materials. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible. Triazole 7 is treated with ethyl acrylate in the presence of palladium (II) acetate and diisopropylethylamine in the presence of a suitable solvent to give the desired Heck cross-coupled product 8. Under appropriate conditions, 3 and 8 with [ RhCl (cod) ]]₂Coupling to intermediate 9, whichCan be further converted to 10 by Pd/hydro carbon followed by amide formation with amine 6 using T3P. Intermediate 10 was first treated with TFA and Et ₃SiH cyclization followed by hydrolysis with NaOH to yield the desired product 11.

Scheme 16

Conditions are as follows: a) LiHMDS, BrCH₂CO₂Me,THF；b)HONH₂.HCl,NaOAc,MeOH；c)(i)Zn,HOAc；(ii)BH₃.Me₂S,THF；d)(i)Boc₂O, TEA, DCM; (ii) bis (pinacolato) diboron, PdCl₂(dppf)-CH₂Cl₂KOAc,1, 4-dioxane; e) ethyl acrylate Pd (OAc)₂,P(o-tol)₃,DIEA,DMF；f)[RhCl(cod)]₂TEA,1, 4-dioxane, H₂O；g)NaOH,MeOH/H₂O

Scheme 16 represents a general scheme for the preparation of intermediates 5 and 8. In scheme 16, R₆As previously defined.

Commercially available indanone 1 is reacted with LiHMDS and methyl bromoacetate in the presence of a suitable solvent to produce intermediate 2. Further conversion of intermediate 2 with hydroxylamine hydrochloride and sodium acetate in methanol gives the desired intermediate 3. Intermediate 3 was first treated with a solution of Zn in HOAc and then with BH₃·Me₂Treatment of the S in THF afforded amine 4. First in DCM with Boc₂O and TEA, followed by bis (pinacolato) diboron, PdCl in a suitable solvent₂(dppf)-CH₂Cl₂And KOAc conversion 4 to produce the desired intermediate 5. The triazole 6 described as the starting material can be synthesized from readily available materials. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible. Triazole 6 is treated with ethyl acrylate in the presence of palladium (II) acetate and diisopropylethylamine in the presence of a suitable solvent to give the desired Heck cross-coupled product 7. In [ RhCl (cod) ] ]₂In the presence of coupling 5 with 7 gives 8, which can be converted to the desired product 9 by removal of the ester protecting group.

Scheme 17

Conditions are as follows: a) CDI, DMAP, DCM; b) HCl,1, 4-dioxane; c) (i) R₂CO₂H,T3P,TEA,DCM；(ii)NaOH,MeOH/H₂O；d)(i)CDI,CH₃a-NH,1, 4-dioxane; (ii) NaOH, MeOH/H₂O；e)(i)2,MeCN；(ii)NaOH,MeOH/H₂O。

Scheme 17 represents a general scheme for the preparation of intermediate 2 and compounds of formula (II). In scheme 17, R₆And A is as previously defined.

Commercial alcohol 1 was reacted with CDI and DMAP to produce intermediate 2. Intermediate 3, described as the starting material, can be synthesized from readily available materials as depicted in scheme 16. Deprotection of the Boc group of intermediate 3 with HCl in 1, 4-dioxane yielded intermediate 4. Intermediate 4 can be converted to amide product 5 by first forming an amide using T3P, followed by conversion of the ester to the acid. The urea product 6 may be obtained by first treating 4 with CDI, then with the appropriate amine, and then converting the ester to the acid. Carbamate 7 may be obtained by treatment with intermediate 2 followed by conversion of the ester to the acid.

Scheme 18

Conditions are as follows: a) LiHMDS, BrCH₂CO₂Et,THF；b)NaOH,MeOH/H₂O；c)C₆H₉CH₂NH₂,T3P,TEA,DCM；d)TFA,Et₃SiH, MeCN; e) bis (pinacolato) diboron, PdCl₂(dppf), KOAc, DMF; f) ethyl acrylate, Pd (OAc)₂,P(o-tol)₃,DIEA,DMF；g)(i)[RhCl(cod)]₂,TEA,H₂O,1, 4-dioxane; (ii) NaOH, MeOH/H₂O。

Scheme 18 represents a general scheme for the preparation of intermediate 6 and compounds of formula (II). In scheme 18, R ₆As previously defined.

Commercially available indanone 1 is reacted with LiHMDS and ethyl bromoacetate in the presence of a suitable solvent to yield the desired intermediate 2. Hydrolysis of intermediate 2 using NaOH yielded intermediate 3. Conversion to the amide followed by TFA and Et₃SiH cyclization of intermediate 4 to intermediate 5 with bis (pinacolato) diboron, PdCl in a suitable solvent₂(dppf) and KOAc were further converted to intermediate 6. The triazole 7 described as the starting material can be synthesized from readily available materials. The reaction conditions are as described in the above scheme; however, those skilled in the art will understand thatSome modifications of the reaction conditions and/or reagents used are possible. Treatment of triazole 7 with ethyl acrylate in the presence of palladium (II) acetate and diisopropylethylamine in the presence of a suitable solvent yields the desired Heck cross-coupled product 8. In [ RhCl (cod) ]]₂Coupling of intermediate 6 and intermediate 8 is effected in the presence. Conversion of the ester to the acid yields 9.

Scheme 19

Conditions are as follows: a) c₆H₅I(OAc)₂,KOH,MeOH；b)(i)C₆H₉CH₂NCO,DMAP,PhMe；(ii)10％HCl；c)TFA,Et₃SiH, MeCN; d) bis (pinacolato) diboron, PdCl₂(dppf), KOAc, DMF; e) ethyl acrylate, Pd (OAc)₂,P(o-tol)₃,DIEA,DMF；f)(i)[RhCl(cod)]₂,TEA,H₂O,1, 4-dioxane; (ii) NaOH, MeOH/H₂O。

Scheme 19 represents a general scheme for the preparation of intermediate 5 and compounds of formula (II). In scheme 19, R ₆As previously defined.

Commercial indanone 1 as C₆H₅I(OAc)₂To yield the desired intermediate 2. Intermediate 2 was first treated with cyclohexylmethyl isocyanate and then deprotected with HCl to give the desired intermediate 3. Intermediate 3 with TFA and Et₃SiH cyclization to give intermediate 4 using bis (pinacolato) diboron, PdCl in a suitable solvent₂(dppf) and KOAc were further converted to intermediate 5. The triazole 6 described as the starting material can be synthesized from readily available materials. The reaction conditions are as described in the above scheme; however, those skilled in the art will appreciate that certain modifications of the reaction conditions and/or reagents used are possible. Treatment of triazole 6 with ethyl acrylate in the presence of palladium (II) acetate and diisopropylethylamine in the presence of a suitable solvent yields the desired Heck cross-coupled product 7. Under appropriate conditions with [ RhCl (cod) ]]₂Intermediate 5 and intermediate 7 were coupled, and the ester was then converted to the acid, thereby generating 8.

Scheme 20

Conditions are as follows: a) NaBH₄,THF；b)NaH,PMBCl；c)n-BuLi,THF,DMF,-78℃；d)DCM,40℃(ii) a e) Tetrabutylammonium benzoate, THF; f) (i) LiOH,4:2:1THF: MeOH: H₂O；(ii)BH₃·DMS；g)CBr₄Polymer supported PPh₃；h)NaCN,3:1EtOH:H₂O；i)TMSN₃,TBAF·3H₂O；j)EtI,Et₃N；k)DDQ；l)(i)PBr₃；(ii)DIPEA,15,90℃；(iii)NaOH,120℃

Scheme 20 represents a general scheme for preparing compounds of formula (I).

Treatment of ketone 1 with sodium borohydride will yield the desired alcohol 2, which can be protected with p-methoxybenzyl chloride and sodium hydride to give aryl-bromide 3. Aryl-bromide 3 can be converted to aldehyde 4 by performing a halogen-lithium exchange, which can be converted to α, β -unsaturated ester 6 with ylide 5 under standard Wittig olefination conditions. The 1,4 addition of ketene-acetal 7 with α, β -unsaturated ester 6 can be accomplished by adding tetrabutylammonium benzoate to THF to give methyl ester 8. It will be appreciated by those skilled in the art that selective hydrolysis of the methyl ester 8 and subsequent reduction of the corresponding carboxylic acid will yield the alcohol 9. The bromide 10 may be obtained by reacting the alcohol 9 with carbon tetrabromide and polymer-supported triphenylphosphine. Displacement of bromide 10 to provide cyanide 11 may be accomplished by heating sodium cyanide in the appropriate proportions of tetrahydrofuran, water and methanol to a suitable temperature. It will be appreciated by those skilled in the art that tetrazole 13 can be formed by heating cyanide 11 in the presence of trimethylsilyl azide and tetrabutylammonium fluoride trihydrate in a microwave reactor, followed by alkylation with iodoethane and triethylamine. Subsequent deprotection affords benzyl alcohol 14. Conversion of benzyl alcohol to amine is accomplished by bromination and reaction with amine 15. The amine can then be hydrolyzed under basic microwave reactor conditions to afford 16.

Scheme 21

Conditions are as follows: a) n-BuLi, THF, DMF, -78 deg.C; b) DCM,40 ℃; c) tetrabutylammonium benzoate, THF; d) pd (PPh)₃)₄Morpholine; e) BH₃·DMS；f)MsCl,Et₃N；g)NaN₃,CuI,DIPEA；h)DDQ；i)(i)PBr₃；(ii)13,DIPEA；(iii)NaOH,120℃

Scheme 21 represents an additional general scheme for the preparation of compounds of formula (I).

Aryl-bromide 1 can be converted to aldehyde 2 by performing a halogen-lithium exchange, which can be converted to the α, β -unsaturated ester 4 with ylide 3 under standard Wittig olefination conditions. 1,4 addition of silylketene acetal 5 to the α, β -unsaturated ester 4 can be accomplished by adding a THF solution of tetrabutylammonium benzoate to afford allyl ester 6. It will be appreciated by those skilled in the art that palladium (0) catalyzed deprotection of the allyl group affords carboxylic acid 7, which can then be reduced to produce alcohol 8. Mesylation and nucleophilic displacement will result in the formation of an azide which can be converted to the triazole 11 using a copper-catalyzed azide-alkyne cycloaddition and the appropriate alkyne. Following oxidative deprotection of the benzyl alcohol, 12 can be converted to amine 14 by bromination with phosphorous tribromide and reaction with amine 13 followed by basic hydrolysis.

Biological activity

As described above, compounds of formula I and (II) are Nrf2 modulators and are useful in the treatment or prevention of human diseases exhibiting oxidative stress components, such as respiratory and non-respiratory diseases, including COPD, asthma, fibrosis, chronic and acute asthma, lung diseases secondary to environmental exposure, acute lung infections, chronic lung infections, alpha 1 antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), kidney disease or renal dysfunction observed during kidney transplantation, pulmonary arterial hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Friedreich's Ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, Colon cancer, non-neovascular (dry) AMD and neovascular (wet) AMD, ocular injury, fukes corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced liver disease), viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia, and altitude sickness.

The biological activity of the compounds of formulae (I) and II can be determined using any suitable assay for determining the activity of candidate compounds as Nrf2 antagonists, as well as tissue and in vivo models.

The biological activity of the compounds of formulae (I) and (II) was demonstrated by the following tests.

BEAS-2B NQO1 MTT test

NAD (P) H: benzoquinone oxidoreductase 1(NQO1), also known as DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes the obligatory nad (p) H-dependent two-electron reduction of quinones and protects cells from the toxic and neoplastic effects of free radicals and reactive oxygen species generated by one-electron reduction. Transcription of NQO1 is finely regulated by Nrf2, so NQO1 activity is a good marker of Nrf2 activation. On the first day, frozen BEAS-2B cells (ATCC) were thawed in a water bath, counted and resuspended at a concentration of 250,000 cells/mL. 50 microliters of cells were seeded in 384-well black clear-bottom plates. The plates were incubated at 37 ℃ with 5% CO₂The culture was carried out overnight. The next day, plates were centrifuged and 50nL of compound or control was added to the cells. The plates were then incubated at 37 ℃ with 5% CO₂Culturing for 48 h. On day four, the medium was aspirated from the plate and a crude cell lysate was prepared by: 13 μ L of 1X Cell Signaling Technologies lysis buffer was added, wherein 1 complete, mini, EDTA-free protease inhibitor tablet (Roche) was added per 10mL of lysis buffer. After lysis, the plates were incubated at room temperature for 20 minutes. 2 microliters of lysate were removed for use in the Cell Titer Glo assay (Promega) and a MTT mixture (MTT cocktail) was prepared (Prochaska et al 1998) for measuring NQO1 activity. To each well 50 microliters of MTT mix was added, the plates were centrifuged and analyzed on an Envision plate reader (Perkin Elmer) for 30 minutes using absorbance 570nm tags. Product formation pEC which is dynamically measured and induced by NQO1 specific activity ₅₀Was calculated by plotting the change in absorption (. DELTA.OD/min) against the logarithm of the compound concentration and then performing a 3-parameter fit.

Beas2B NQO1 MTT test

All examples described herein have NQO1 specificity in BEAS-2B cellsSexual enzyme activity, wherein EC₅₀In that>10uM-<1nM unless otherwise indicated (see table below). EC (EC)₅₀<1nM(+++++)，EC₅₀ 10nM-1nM(++++)，EC₅₀10-100nM(+++)，EC₅₀100nM-1uM(++)，EC₅₀1-10uM(+)，EC₅₀>10uM (-), or undetermined (ND).

^#pEC in some assays₅₀<170pM

Nrf2-Keap1 FP test

One model for Nrf2-Keap1 interaction is through two binding sites in the Neh2 domain on Nrf 2. These two sites are called the DLG binding motif (latch domain, affinity of μ M class) and the ETGE binding motif (hinge domain, affinity of nM class). The Keap1 protein consists of an N-terminal region (NTR), a broad complex (broad complex), a tramtramtrack and brick a' brac domain (BTB), an intervening region (IVR), a double glycine repeat domain (DGR or Kelch), and a C-terminal region. The DLG and ETGE motifs of the Neh2 domain of Nrf2 bound with different affinities to the Kelch domain of Keap 1. In the Keap1 Kelch Fluorescence Polarization (FP) assay, a TAMRA-labeled 16mer peptide (AFFAQLQLDEETGEFL) containing the ETGE motif of Nrf2 and the Kelch domain of Keap1(321-609) was used. This assay determines whether the compound interferes with the binding between Keap1(361-609) and the TAMRA-labeled peptide. Binding of the TAMRA-labeled Nrf2 peptide to Keap1 (321-. If the compound interferes with the binding between the peptide and the protein, this will result in a decrease in the assay signal. Thus, the assay signal is inversely proportional to the inhibition of binding.

FP test

100nL of 100X compound dose-response curve in DMSO (serial 3-fold dilutions) was usedThe Echo liquid handling system (Labcyte) was added to 384-well low volume black assay plates (Greiner, #784076) with DMSO in columns 6 and 18. The highest concentration of compound is in columns 1 and 13. Keap1(321-609) was assayed in 1 Xassay buffer (50mM Tris, pH 8.0, 100mM NaCl, 5mM MgCl)₂1mM DTT, 2mM CHAPS and 0.005% BSA) to 40nM (2X) and 5ul was added to all wells of the compound plate with a Multidrop Combi (Thermo Electron Corporation) equipped with a metal tip dispenser, except column 18. Column 18 received only 5ul of assay buffer. Subsequently, 5. mu.L of 16nM (2X) Tamra-labeled peptide (AFFAQLQLDEETGEFL, 21)^stCentury Biochemicals) were added to all wells of the plate. The plate was spun at 500rpm for 1min, incubated at room temperature for 1 hour and read on an analysis GT (Molecular Devices) equipped with excitation (530/25nm) and emission (580/10nm) filters designed for Tamra probes. A 561nm dichroic mirror is also used in the analysis. The final assay concentrations of the Keap1(321-609) and Tamra-labeled peptides were 20nM and 8nM, respectively. Fluorescence measurements (expressed in mP) were used in the transformation of the data. Compound activity was calculated based on percent inhibition, normalized to the control in the assay (control 1 containing both Tamra peptide and Keap1(321-609) (0% response), control 2 containing only Tamra peptide (100% response)). The data analysis was processed using the software package Abase XE (Surrey, United Kingdom). The% inhibition value is calculated by the following equation:

100- (100 ((compound response-mean control 2)/(mean control 1-mean control 2))). To calculate pIC₅₀Abase XE uses a four parameter equation.

All examples described herein were active in the Keap1/Nrf2 FP assay.

NRF2-Keap1TR-FRET test

In the Nrf2-Keap1TR-FRET (time-resolved fluorescence resonance energy transfer) assay, the full-length Nrf2 protein and the full-length Keap1 protein (Keap1 exists as a dimer) were used. This assay detects the ability of compounds to replace FlagHis-tagged Keap1 to bind to biotinylated, Avi-tagged Nrf2 protein. biotin-Nrf 2 was bound to streptavidin-europium (a component of the assay mixture) and Keap1-FlagHis was recognized by anti-Flag APC (allophycocyanin) antibodies (also a component of the assay mixture). If binding occurs between the two proteins, there will be an energy transfer from Eu +3 (donor) at 615nm to APC (acceptor) at 665 nm. Potential Keap1 inhibitors will cause a reduction in TR-FRET signals by interfering with Keap1 binding to Nrf 2.

100 nanoliters of 100X compound dose response curves (serial 3-fold dilutions) in DMSO in columns 6 and 18 were stamped into 384-well low-volume black assay plates (Greiner, #784076) using the Echo liquid handling system (labcell). The highest concentrations of compounds are located in columns 1 and 13. All reagents were in assay buffer (50mM Tris, pH 8.0,5mM MgCl) ₂100mM NaCl, 0.005% BSA, 1mM DTT and 2mM CHAPS). BSA, DTT and CHAPS were added to assay buffer on the day of assay. Using a Multidrop comb (Thermo Electron Corporation) equipped with a metal head dispenser, 5ul of 25nM Keap1-FlagHis protein was added to all wells of the compound plate except the wells in column 18. The wells in column 18 instead receive 5ul of assay buffer. The plate was centrifuged at 500rpm for 1 minute, the plate cover was closed, and the plate was incubated at 37 ℃ for 2.25 hours. The plate was then removed from the incubator and allowed to cool to room temperature for 15 minutes. Then 5 microliters of 50nM biotin-Nrf 2 protein was added to all wells of the plate and the plate was centrifuged at 500rpm for 1 minute and then incubated at 4 ℃ for 1.25 hours. The plates were then allowed to warm to room temperature for 15 minutes, followed by the addition of 10ul of the assay mix (1nM streptavidin Eu + W1024 and 5. mu.g/ml mouse anti-DYKDDDDK IgG conjugated to SureLight APC antibody; both from Columbia Biosciences) to all wells. The plates were centrifuged at 500rpm for 1 minute, incubated at room temperature for 1 hour, and read on an Envision plate reader using a 320nm excitation filter and 615nm and 665nm emission filters. Compound responses (% inhibition) and potency (pIC50) were calculated based on the ratio of the two emissions (665nm/615nm), and the transformed data were then normalized to the controls in the assay (control 1 ═ 1% DMSO in the presence of Nrf2 and Keap1 proteins, control 2 ═ 1% DMSO in the absence of protein). Data analysis was processed using the software package Abase XE (Surrey, United Kingdom) . The% inhibition value was calculated from the ratio (converted) data by the following equation:

100- (100 × (compound response-mean control 2)/(mean control 1-mean control 2)).

For calculation of pIC50, Abase XE uses a 4 parameter equation.

Nrf2-Keap1 TR-FRET low protein assay

In the Nrf2-Keap1 TR-FRET (time-resolved fluorescence resonance energy transfer) low protein assay, the full-length Nrf2 protein and the full-length Keap1 protein (Keap1 is present as a dimer) were used. This assay detects the ability of compounds to bind biotinylated Avi-Nrf2 protein instead of Keap1 FlagHis. biotin-Nrf 2 was bound to streptavidin-europium (a component of the assay mixture) and Keap1 FlagHis was recognized by anti-Flag APC (allophycocyanin) antibodies (also a component of the assay mixture). If binding occurs between the two proteins, there will be an energy transfer from Eu +3 (donor) at 615nm to APC (acceptor) at 665 nm. A potential Nrf2 inhibitor would cause a reduction in TR-FRET signal by interfering with the binding of Keap1 to Nrf 2.

A 10 nanoliter dose response curve of 100X compound (serial 3-fold dilutions) in DMSO in columns 6 and 18 was stamped into 384-well low-volume black assay plates (Greiner, #784076) using the Echo liquid handling system (labcell). An additional 90nl of DMSO was added per well to bring the total volume to 100nl per well. The highest concentration of compound was located in columns 1 and 13, with serial dilutions across rows. All reagents were in assay buffer (50mM Tris, pH 8.0,5mM MgCl) ₂100mM NaCl, 0.005% BSA, 1mM DTT and 2mM CHAPS). BSA, DTT and CHAPS were added to assay buffer on the day of assay. Using a Multidrop Combi (Thermo Electron Corporation) equipped with a metal head dispenser, 5ul of 1.25nM Keap1 flag his protein was added to all wells of the compound plate except for the wells in column 18. The wells in column 18 instead receive 5ul of assay buffer. The plate was centrifuged at 500rpm for 1 minute, the plate cover was closed, and the plate was incubated at 37 ℃ for 2.25 hours. The plate was then removed from the incubator and allowed to cool to room temperature for 15 minutes. Then 5 microliters of 2.5nM biotin-Nrf 2 protein was added to the plateAnd the plate was centrifuged at 500rpm for 1 minute, and then incubated at 4 ℃ for 1.25 hours. The plates were then allowed to warm to room temperature for 15 minutes, followed by the addition of 10ul of the assay mix (1nM streptavidin Eu + W1024 and 5. mu.g/ml mouse anti-DYKDDDDK IgG conjugated to SureLight APC antibody; both from Columbia Biosciences) to all wells. The plates were centrifuged at 500rpm for 1 minute, incubated at room temperature for 1 hour, and read on an Envision plate reader using a 320nm excitation filter and 615nm and 665nm emission filters. Compound responses (% inhibition) and potency (pIC50) were calculated based on the ratio of the two emissions (665nm/615nm) and the transformed data were then normalized to the controls in the assay (control 1 ═ 1% DMSO in the presence of Nrf2 and Keap1 proteins, control 2 ═ 1% DMSO in the presence of Nrf2 protein only). Data analysis was processed using the software package Abase XE (Surrey, United Kingdom). The% inhibition value was calculated from the ratio (converted) data by the following equation:

100- (100 × (compound response-mean control 2)/(mean control 1-mean control 2)).

For calculation of pIC50, Abase XE uses a 4 parameter equation.

Application method

The compounds of the invention are Nrf2 modulators and are useful in the treatment or prevention of respiratory disorders including COPD, asthma, fibrosis, lung infections, diabetic nephropathy/chronic kidney disease, autoimmune diseases (e.g. multiple sclerosis and inflammatory bowel disease), ocular diseases (e.g. AMD, fukes and uveitis), cardiovascular diseases, non-alcoholic steatohepatitis (NASH), parkinson's disease, alzheimer's disease, psoriasis, acute kidney injury, local effects of radiation and kidney transplantation.

Thus, in another aspect, the invention relates to a method of treating said disorder.

The treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

As used herein, "treating" when referring to a condition means: (1) ameliorating or preventing the disorder or one or more biological manifestations of the disorder, (2) interfering with (a) one or more points in a biological cascade that causes or accounts for the disorder, or (b) one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The skilled person understands that "prevention" is not an absolute term. Pharmaceutically, "preventing" is understood as the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or biological manifestation thereof or to delay the onset of said condition or biological manifestation thereof.

As used herein, a "safe and effective amount" in reference to a compound of the present invention or other pharmaceutically active agent means an amount of the compound that is sufficient to treat the condition of the subject patient, but low enough to avoid serious side effects (with a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound selected (e.g., taking into account the potency, and half-life of the compound); the chosen route of administration; the condition being treated; the severity of the condition being treated; the age, size, weight and physiological condition of the patient being treated; the drug history of the patient treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and the like, but can nevertheless be routinely determined by the skilled artisan.

As used herein, "patient" refers to a human or other animal.

The compounds of the invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, rectal and administration by inhalation. Parenteral administration refers to the parenteral, non-transdermal or non-inhalation route and is usually administered by injection or infusion. Parenteral administration includes intravenous administration, intramuscular administration, and subcutaneous injection or infusion. Inhalation refers to administration into the lungs of a patient, whether by mouth or nasal inhalation. Topical administration includes application to the skin as well as intraocular, otic, intravaginal and intranasal administration.

The compounds of the present invention may be administered once or according to a dosing regimen wherein multiple doses are administered at different time intervals over a given period of time. For example, one, two, three or four doses per day may be administered. The dosage may be administered until the desired therapeutic effect is achieved or may be administered sporadically to maintain the desired therapeutic effect. Suitable dosing regimens for the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, a suitable dosing regimen for a compound of the invention (including the duration of administration of the regimen) will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of the skilled artisan. The skilled artisan also understands that a suitable dosing regimen may need to be adjusted in view of the individual patient's response to the dosing regimen, or over time as the individual patient's needs change.

The usual daily dosage may vary depending on the particular route of administration selected. Common dosage ranges for oral administration are from 1mg to 1,000mg per person per day. The preferred dosage is 1-500mg once daily, more preferably 1-100mg per person daily. The Intravenous (IV) dose ranges from 0.1 to 1,000 mg/day, preferably from 0.1 to 500 mg/day and more preferably from 0.1 to 100 mg/day. The daily dose for inhalation is in the range of 10. mu.g to 10 mg/day, preferably 10. mu.g to 2 mg/day and more preferably 50. mu.g to 500. mu.g/day.

In addition, the compounds of the present invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the present invention is a functional derivative of the compound that, upon administration to a patient, ultimately releases the compound of the present invention in vivo. Administration of a compound of the invention in prodrug form may enable the skilled person to (a) alter the time at which the compound begins to act in vivo; (b) altering the duration of action of the compound in vivo; (c) altering the transport or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side reactions or other difficulties encountered with the compounds. Common functional derivatives used to prepare prodrugs include modifications of the compounds that are cleaved chemically or enzymatically in vivo. Such modifications are well known to those skilled in the art and include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates and carbamates.

Composition comprising a metal oxide and a metal oxide

The compounds of the present invention will generally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Thus, in another aspect of the invention, it relates to a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form, wherein a safe and effective amount of a compound of the present invention may be removed and then administered to the patient in the form of a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention will generally contain from 1mg to 1000 mg.

The pharmaceutical compositions of the invention will generally contain one compound of the invention. However, in some embodiments, the pharmaceutical compositions of the present invention contain more than one compound of the present invention. For example, in some embodiments, a pharmaceutical composition of the invention contains two compounds of the invention. In addition, the pharmaceutical compositions of the present invention may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition or vehicle involved in imparting form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed, thereby avoiding interactions that would substantially reduce the efficacy of the compounds of the invention when administered to a patient and that would result in a non-pharmaceutically acceptable pharmaceutical composition. Furthermore, each excipient must of course be of sufficiently high purity to be pharmaceutically acceptable.

The compounds of the present invention and pharmaceutically acceptable excipient(s) are generally formulated in a dosage form suitable for administration to the patient by the desired route of administration. For example, dosage forms include those suitable for: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets (sachets) and cachets (2) parenteral administration, such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the specific function they serve in the composition. For example, some pharmaceutically acceptable excipients are selected for their ability to facilitate the production of a uniform dosage form. Some pharmaceutically acceptable excipients are chosen for their ability to facilitate the production of stable dosage forms. Some pharmaceutically acceptable excipients are selected for their ability to facilitate the transport or transport of the compounds of the present invention from one organ or site of the body to another organ or site of the body after administration to the patient. Some pharmaceutically acceptable excipients are selected for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan understands that some pharmaceutically acceptable excipients may perform more than one function and may perform alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Furthermore, there is a lot of information describing pharmaceutically acceptable excipients available to the skilled person and can be used to select suitable pharmaceutically acceptable excipients. Examples includeRemington's Pharmaceutical Sciences(Mack Publishing Company)，The Handbook of Pharmaceutical Additives(Gower Publishing Limited) andThe Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

the pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described inRemington's Pharmaceutical Sciences(Mack Publishing Company).

In one aspect, the present invention relates to solid oral dosage forms, such as tablets or capsules, comprising a safe and effective amount of a compound of the present invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starches (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starches (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and derivatives thereof (e.g., microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

In another aspect, the invention relates to a dosage form suitable for parenteral administration to a patient, including subcutaneous, intramuscular, intravenous, or intradermal administration. Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidizing agents, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

In another aspect, the invention relates to a dosage form suitable for administration to a patient by inhalation. For example, the compounds of the invention may be inhaled into the lungs in the form of a dry powder, aerosol, suspension or solution.

Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of the invention in the form of a finely divided powder and one or more pharmaceutically acceptable excipients in the form of a finely divided powder. Pharmaceutically acceptable excipients that are particularly suitable for use in dry powders are well known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides.

The dry powder compositions for use according to the invention may be administered by inhalation devices. As an example, such devices may include capsules and cartridges of, for example, gelatin, or blisters of, for example, laminated aluminum foil. In various embodiments, each capsule, cartridge, or blister may contain multiple doses of a composition according to the teachings herein. Examples of inhalation devices may include those intended for unit-dose or multi-dose delivery of compositions, including all devices described herein. As one example, in the case of multiple dose delivery, the formulation may be pre-metered (e.g., asSee GB2242134, U.S. patent nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and 6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. patent nos. 4,778,054, 4,811,731, 5,035,237) or metered use (e.g. Turbuhaler, see EP 69715, or the devices described in U.S. patent No. 6,321,747). An example of a unit dose device is Rotahaler (see GB 2064336). In one embodiment of the process of the present invention,the inhalation device comprises an elongate strip of base sheet having a plurality of recesses spaced along its length and a peelable cover sheet sealing the same to define a plurality of receptacles each having an inhalable formulation therein containing a compound, optionally with other excipients and additives as taught herein. The peelable sealing device is an engineered sealing device, and in one embodiment, the engineered sealing device is a hermetic seal. Preferably, the slats are sufficiently flexible to be wound into a roll. The cover sheet and the base sheet preferably have front end portions which are not sealed to each other, and at least one of said front end portions is designed to be connected to a winding device. It is also preferred that the engineered seal between the base and cover sheets extends to its full width. It may be preferred that the cover sheet is peeled from the base sheet in a longitudinal manner from the head end of the base sheet.

The dry powder composition may also be present in an inhalation device, which allows two different components of the composition to be contained separately. Thus, for example, the components may be administered simultaneously, but stored separately, e.g. in separate pharmaceutical compositions, e.g. as described in WO 03/061743a1, WO 2007/012871a1 and/or WO 2007/068896. In one embodiment, the inhalation device allowing for separate containment of the components is an inhaler device having two peelable blister strips, each strip containing a pre-metered dose in a blister pocket arranged along its length, e.g. a plurality of containers within each blister strip. The device has an internal indexing mechanism that peels open the pockets of each strip and positions the blisters so that each newly exposed pocket of each stripThe dose is adjacent to a manifold that communicates with the mouthpiece of the device. As the patient inhales at the mouthpiece, each dose is simultaneously withdrawn from its associated pocket, enters the manifold and is entrained via the mouthpiece into the patient's respiratory tract. Another device that allows separate containment of different components is the DuOHALER of Innovata^TM. In addition, in addition to simultaneous delivery, various configurations of inhalation devices provide for sequential or separate delivery of pharmaceutical compositions from the device.

An aerosol can be formed by suspending or dissolving a compound of the present invention in a liquefied propellant. Suitable propellants include halogenated hydrocarbons, hydrocarbons or other liquefied gases. Representative propellants include trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds of the invention are typically administered to a patient by means of a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art.

The aerosol may contain other pharmaceutically acceptable excipients commonly used in multi-dose inhalers, such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility or to improve taste.

Suspensions and solutions containing the compounds of the invention may also be administered to a patient by nebulizer. The solvent or suspending agent used for aerosolization can be any pharmaceutically acceptable liquid such as water, saline solution, alcohol or glycol, e.g., ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, and the like, or mixtures thereof. Saline solutions use salts that exhibit little or no pharmacological activity after administration. Both organic salts such as halogen salts of alkali metals or ammonium, e.g., sodium chloride, potassium chloride, and inorganic salts such as potassium salts, sodium salts, and ammonium salts of organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, and the like, can be used for this purpose.

Other pharmaceutically acceptable excipients may be added to the suspension or solution. The compounds of the invention can be stabilized by the addition of: inorganic acids, for example, hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid, and the like; complexing agents such as EDTA or citric acid and salts thereof; or an antioxidant such as vitamin E or ascorbic acid. These substances may be used alone or together to stabilize the compounds of the present invention. Preservatives such as benzalkonium chloride or benzoic acid and salts thereof may be added. Surfactants may be added specifically to improve the physical stability of the suspension. These include lecithin, disodium dioctyl sulfosuccinate, oleic acid, and sorbitan esters.

The compounds of formulae (I) and (II) and pharmaceutically acceptable salts thereof are useful in combination with one or more other drugs useful in the prevention or treatment of, for example, allergic diseases, inflammatory diseases, autoimmune diseases; antigen immunotherapy, antihistamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), iNOS inhibitors, tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, transmitter release inhibitors such as cromolyn sodium, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic acid) inhibitors, or FLAP (5-lipase activator) inhibitors (e.g., 3- (3- (tert-butylsulfanyl) -1- (4- (6) s-th-yl-amino acid -ethoxypyridin-3-yl) benzyl) -5- ((5-methylpyridin-2-yl) methoxy) -1H-indol-2-yl) -2, 2-dimethylpropionic acid sodium), bronchodilators (e.g., muscarinic antagonists, β -2 agonists), methotrexate and the like; monoclonal antibody therapies such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and the like; cytokine receptor therapies such as etanercept and similar drugs; antigen non-specific immunotherapy (e.g., interferons or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists, and similar drugs).

The compounds may also be used in combination with drugs that aid in transplantation, including cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, daclizumab, basiliximab, or OKT 3.

They can also be used in combination with drugs for diabetes mellitus, metformin (biguanides), meglitinide, sulfonylureas, DPP-4 inhibitors, thiazolidinediones, alpha-glucosidase inhibitors, Amylin mimetics, incretins, insulin.

The compounds are useful in combination with antihypertensive drugs, such as diuretics, ACE inhibitors, ARBS, calcium channel blockers and beta blockers.

One embodiment of the present invention includes a combination comprising one or two additional therapeutic agents. It will be clear to the skilled person that, where appropriate, the other therapeutic ingredients may be used in the form of salts (e.g. alkali metal or amine salts), or acid addition salts or prodrugs or esters (e.g. lower alkyl esters), or solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical properties of the therapeutic ingredient, e.g. solubility. It is also clear that the therapeutic ingredients may be used in optically pure form where appropriate.

The above-mentioned combinations may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of the combination may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate dosages of known therapeutic agents are readily understood by those skilled in the art.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention in combination with another therapeutically active agent.

Examples

The invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention. All temperatures are given in degrees Celsius, all solvents are of the highest achievable purity and all reactions are optionally carried out under anhydrous conditions under argon (Ar) or nitrogen (N)₂) Is carried out in an atmosphere.

Analtech Silica Gel GF and E.Merck Silica Gel 60F-254 thin layer plates were used for thin layer chromatography. The flash chromatography and the gravity chromatography are carried out on silica gel 230-400, 100-200 &60-120Cilicant Brand. For purification in this applicationSystems are available from Isco, Inc.Purification was performed using a pre-loaded silica gel column, a detector with a UV wavelength of 254nm, and various solvents or solvent combinations.

Preparative HPLC was performed using Gilson or Waters preparative systems with variable wavelength UV detection or Agilent Mass Directed AutoPrep (MDAP) systems with quality detection and variable wavelength UV detection or Shimadzu PREP LC 20 AP. Various reverse phase columns such as, for example, Luna C18(2), SunFire C18, Xbridge C18, Atlantics T3, Kromasil C18, Xbridge Phenyl-Hexyl columns are used in the purification, the choice of column support depending on the conditions used in the purification. Using CH₃CN or methanol and water gradient elution of compounds. Neutral condition using CH₃CN and water gradient, no additional modifier, acidic conditions with acid modifier, typically 0.1% TFA or 0.1% formic acid, and basic conditions with basic modifier, typically 0.1% NH₄OH (added to water) or 10mM ammonium bicarbonate (added to water), or 0.05% NH₄HCO₃(addition to water).

Analytical HPLC is usedAgilent system with 2996PDA detector or Waters Alliance HPLC, Waters Acquity UPLC-MS or Agilent Infinity 1290 with PDA, or on a Sunfire C18 column or on an XSELECT CSH C18 column using reverse phase chromatography with CH ₃CN and water gradient with 0.1% formic acid modifier (added to each solvent) and alkaline conditions pH adjusted to 10 with ammonia solution using alkaline modifier, typically 5mM ammonium bicarbonate or 10mM aqueous ammonium bicarbonate solution. Compounds were analyzed by LCMS using a Shimadzu LC system with UV 214nm wavelength detection and H₂O-CH₃Gradient elution with CN (4-95% over 1.9min.) acidified to 0.02% TFA. The reverse phase column was 2.1X20 mm Thermo Hypersil Gold C18(1.9u particles) at 50 ℃. The single quadrupole MS detector was Sciex 150EX or Waters ZQ operated with cations. Alternatively, the LC-MS is determined using a PE Sciex Single Quadrupole 150EX LC-MS, or a Waters ZQ Single Quadrupole, Waters 3100Single Quadrupole, Agilent 6130SQD, or Agilent 6120Single Quadrupole LC-MS instrument. The compounds are analyzed using reverse phase columns such as Thermo Hypersil Gold C18 and/or Luna C18, using CH₃A gradient of CN and water is eluted with a low percentage of acid modifier such as 0.02% or 0.1% TFA.

Preparative chiral SFC was performed using a Thar/Waters preparative SFC system with a single wavelength UV detection system. Various chiral SFC columns are used in this purification, such as Chiralpak IA, IC, AY, AD, IF, OJ. Using supercritical fluid CO ₂And co-solvents such as MeOH, EtOH, IPA and combinations of these solvents in different ratios based on the compound. Modifiers (0.1% to 0.4% TFA, NH) may be used as desired₄OH, DEA, TEA). Normal phase chromatography was performed using the above chiral column and pyridylamide, with an ethylpyridine achiral column for chiral and achiral purification, respectively. If desired, modifiers (0.1% TFA, NH)₄OH, DEA). The K PREP Lab 100G-YMC instrument was used for normal phase preparative scale purification.

Analytical chiral SFC was run using a Thar/Waters SFC system with variable wavelength UV detection. In this purification, chiral SFC columns of various kinds are used, for exampleChiralpak IA, IB, IC, ID, IF, AY, AD, OD, C2, AS, OJ, CCL 4. The compound is prepared by using supercritical fluid CO₂And co-solvents such as MeOH, EtOH, IPA and combinations of these solvents in different ratios based on compound selectivity. Modifiers (0.1% to 0.4% TFA, NH) may be used as required₄OH、DEA、TEA)。

As a filter aid, it consists of acid-washed diatomaceous earth and is a registered trademark of Manville corp.Is a functionalized silica gel based absorbent and is a registered trademark of Biotage AB corp.

The nuclear magnetic resonance spectra were recorded at 400MHz using either a Bruker AVANCE 400 or Brucker DPX400 spectrometer or a Varian MR400 spectrometer. CDCl₃Is deuterated chloroform, DMSO-D₆Is hexadeuterated dimethyl sulfoxide and MeOD is tetradeuterated methanol and CD₂Cl₂Deuterated dichloromethane. Chemical shifts are reported in parts per million (δ) from the low magnetic field (downfield) of internal Tetramethylsilane (TMS) and calibrated to be in NMR solvents (e.g., CHCl)₃In CDCl₃Middle) of the proton signal. Abbreviations used for NMR data are as follows, s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, m ═ multiplet, dd ═ doublet, dt ═ doublet, app ═ appearance, br ═ broad. J denotes the NMR coupling constant measured in Hertz.

Heating the reaction mixture with microwave radiation was at BiotageCarried out on a microwave reactor, usually with a high absorption configuration.

Cartridges or columns containing polymers based on functional groups (acids, bases, metal chelators, etc.) can be used as part of the post-treatment of the compounds. "amine"columns or cartridges are used to neutralize or alkalize the acidic reaction mixture or product. These include NH₂Aminopropyl SPE-ed SPE cartridges (obtained from Applied Separations) and diethylamino SPE cartridges (obtained from Applied Separations) United Chemical Technologies，Inc.)。

Table of abbreviations

Intermediate 1

6-bromo-2, 3-dihydro-1H-inden-1-ol

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (5g, 23.69mmol) in methanol (50mL) under nitrogen was added sodium borohydride (0.896g, 23.69 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed under reduced pressure. The residue was dissolved in 100mL ethyl acetate and 20mL 1N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (30mL) and anhydrous Na₂SO₄Drying and concentration gave the title compound 6-bromo-2, 3-dihydro-1H-inden-1-ol (5.0g,23.47mmol, 99%). LC-MS M/z 195.0(M-OH)⁺1.46 minutes (retention time).

Intermediate 2

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-ol (7g,32.9mmol) in N, N-dimethylformamide (80mL) at 0 deg.C was added NaH (1.314g,32.9 mmol). The reaction mixture is stirred under N₂Stirring was carried out at 0 ℃ for 30 minutes under protection, then 1- (chloromethyl) -4-methoxybenzene (5.15g,32.9mmol) was added to the reaction and the reaction mixture was stirred continuously for 2 hours at ambient temperature, after which 300mL of H were used₂O was quenched and extracted with EtOAc (3x100 mL). The combined organic layers were washed with water (100mL), brine (100mL), and anhydrous Na ₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 10:1) to give the title compound 6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (9.2g,27.1mmol, 82%).¹H NMR(400MHz,CDCl₃)δ＝7.48(s,1H),7.35-7.28(m,3H),7.10(d,J＝8Hz,1H),6.88(d,J＝8.4Hz,2H),4.95(t,J＝6Hz,1H),4.59-4.51(q,J＝21.6Hz,J＝11.4Hz,2H),3.79(s,3H),2.99-2.97(m,1H),2.74-2.73(m,1H),2.35-2.32(m,1H),2.11-2.04(m,1H)。

Intermediate 3

6-bromo-2, 3-dihydro-1H-inden-1-ol

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (30g,142mmol) in methanol (100mL) at 0 deg.C was added NaBH in portions₄(10.76g,284 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and saturated NaHCO₃The solution was quenched and then extracted with EtOAc (2X) and Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography using (2:8) EtOAc: hexanes. The product fractions were concentrated to give the title compound (23g, 76% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.54(s,1H),7.37(dd,J＝1.8,7.9Hz,1H),7.11(d,J＝7.9Hz,1H),5.22(q,J＝5.8Hz,1H),2.99(ddd,J＝4.5,8.6,16.1Hz,1H),2.76(td,J＝7.7,15.9Hz,1H),2.51(dddd,J＝4.6,7.0,8.3,13.2Hz,1H),2.00-1.90(m,1H),1.73(br d,J＝6.4Hz,1H),0.51-0.51(m,1H)。

Intermediate 4

6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-ol (12g,56.3mmol) in 1, 4-dioxane (100mL) was added bis (pinacolato) diboron (18.59g,73.2mmol), potassium acetate (13.82g,141mmol) and the mixture was degassed with argon in a sealed tube for 20 minutes. Adding PdCl₂(dppf) (2.060g,2.82mmol) and the reaction mixture was stirred at 90 ℃ for 2 h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give a crude residue. The crude residue was purified by column chromatography using 20% ethyl acetate in n-hexane as eluent. The eluted fractions were concentrated under reduced pressure to give the title compound (12g, 82% yield). ¹H NMR(400MHz,CDCl₃)δppm＝7.88(s,1H),7.72(d,J＝7.7Hz,1H),7.28(s,1H),5.25(br t,J＝5.8Hz,1H),3.08(ddd,J＝5.0,8.4,16.4Hz,1H),2.88-2.78(m,1H),2.51-2.41(m,1H),2.01-1.91(m,1H),1.68(br s,1H),1.37-1.27(m,12H)。

Intermediate 5

3-methyl-2-nitroaniline

To a mixture of NaOH (2.220g,55.5mmol) in water (12mL) at 0 deg.C was added Br₂(0.322mL,6.26 mmol). 3-methyl-2-nitrobenzamide (1g,5.55mmol) was then added in one portion and the mixture was slowly heated in a water bath. The substance darkened quickly and at 50-55 ℃ (internal temperature) the oil droplets started to separate. The temperature was gradually raised to 70 ℃ and maintained at this temperature for 1 hour. A solution of 0.7g of NaOH in 4mL of water was slowly added and the temperature was raised to 80 ℃ for another hour. The reaction was cooled to ambientTemperature and extract with EtOAc (3X 50 mL). The combined organic layers were dried and concentrated to give the title compound (0.7g, 90%). LC-MS M/z 153.1(M + H)⁺1.65 minutes (retention time).

Intermediate 6

4-bromo-3-methyl-2-nitroaniline

A mixture of NBS (51.5g,289mmol), 3-methyl-2-nitroaniline (44g,289mmol) and acetic acid (450mL) was stirred at 110 ℃ for 1 hour. The mixture was cooled to ambient temperature and poured into water (100 mL). The solid was collected to give the title compound (55g, 78%). LC-MS M/z 230.9(M + H)⁺1.78 minutes (retention time).

Intermediate 7

4-bromo-N, 3-dimethyl-2-nitroaniline

To a solution of 4-bromo-3-methyl-2-nitroaniline (20g,87mmol) in N, N-dimethylformamide (200mL) at 25 deg.C was added NaH (3.81g,95 mmol). The reaction mixture was stirred at 25 ℃ for 30 minutes. Methyl iodide (12.90g,91mmol) was then added. The reaction mixture was stirred for 12 hours. The reaction mixture was poured into water and the solid was collected to give the title compound (18g, 59.4%). LC-MS M/z 247.0(M + H) +,1.90 min (retention time).

Intermediate 8

4-bromo-N1, 3-dimethylbenzene-1, 2-diamine

To a solution of 4-bromo-N, 3-dimethyl-2-nitroaniline (65g,265mmol) in ethanol (600mL) and water (300mL) at ambient temperature was added ammonium chloride (142g,2652mmol) followed by iron (59.2g,1061 mmol). Will be provided withThe reaction mixture was stirred at 90 ℃ for 4 hours. The reaction mixture was cooled to ambient temperature and filtered through a pad of celite, washing with EtOAc (100mL) and the filtrate was evaporated in vacuo. The residue is taken up in NaHCO₃The solution (500mL) was diluted and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine solution (500mL) and Na₂SO₄Dry, filter and evaporate the solvent in vacuo. The crude residue was purified by column chromatography using EtOAc: hexane (3: 7). The eluted fractions were evaporated in vacuo to give 4-bromo-N1, 3-dimethylbenzene-1, 2-diamine (46g, 61.7% yield). LC-MS M/z 214.9(M + H)⁺2.54 minutes (retention time).

Intermediate 9

5-bromo-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazole

4-bromo-N1, 3-dimethylbenzene-1, 2-diamine (30g, 139mmol) in 17ml of 10% H at 0 deg.C₂SO₄Sodium nitrite (13.47g, 195mmol) was added in small portions over 20 minutes. After stirring the reaction mixture for another 30 minutes, 200mL of water was added. The resulting precipitate was collected by filtration, washed with water and dried. The mother liquor was allowed to stand for 16 hours and a second batch of precipitate formed, which was collected as before. The combined solids were passed through a column with EtOAc to remove inorganic salts to give the title compound (10g, 21.57%). LC-MS M/z 226.0(M + H) ⁺1.71 minutes (retention time).

Intermediate 10

(E) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) acrylic acid ethyl ester

To 5-bromo-1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazole (10g,44.2mmol) in N, N-dimethylformamide (20mL) was added tri-o-tolylphosphine (2.69g,8.85mmol), methyl acrylate (7.62g, 88mmol) and DIPEA (23.18mL, 133 mmol). Then P is addedd(OAc)₂(0.993g, 4.42 mmol). The reaction mixture was stirred at 100 ℃ for 12 hours. The mixture was poured into water and extracted with EtOAc (30 mL). The organic layer was dried and concentrated to give the crude product. It was purified by silica gel column chromatography (petroleum ether: EtOAc ═ 4:1) to give the title compound (8.2g, 76%). LC-MS M/z 246.1(M + H)⁺1.68 minutes (retention time).

Intermediate 11

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

In a sealed tube to (E) -3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (3.5g,14.27mmol) in 1, 4-dioxane (10 mL)/water (10.00mL) was added 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol (4.83g,18.55mmol), 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol (4.83g,18.55 mmol). The mixture was flushed with argon for 20 minutes, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (0.704g,1.427 mmol). The reaction mixture was stirred at 95 ℃ for 16 hours. The reaction mixture was quenched with cold water and extracted with EtOAc (2 ×) and brine. Subjecting the organic layer to anhydrous Na ₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure and combined with the same crude compound prepared on a 3.5g scale in another experiment. The combined crude compounds were purified by column chromatography using EtOAc: hexanes (40:60) to give the title compound (3g, 55.4% yield). LC-MS M/z 380(M + H)⁺2.09 minutes (retention time).

Intermediate 12

4-Ethylcyclohexanecarboxylic acid ethyl ester

The reaction mixture was heated in a nitrogen atmosphere, at ambient temperature,to a solution of 4-ethylcyclohexanecarboxylic acid (15g,96mmol) in ethanol (200mL) was slowly added H₂SO₄(1mL,18.76 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours. The reaction was then diluted with water (100mL) and extracted with EtOAc (3 × 200 mL). The mixture was concentrated under a stream of nitrogen at 50 ℃ to give the title compound (15g, 76% yield), which was used in the next step without further purification. LC-MS M/z 185(M + H)⁺2.32 minutes (retention time).

Intermediate 13

(4-ethylcyclohexyl) methanol

To a solution of 4-ethylcyclohexanecarboxylic acid ethyl ester (15g,81mmol) in THF (200mL) at 0 deg.C under nitrogen was slowly added LiAlH₄(5g,132 mmol). The mixture was stirred at ambient temperature for 4 hours. The reaction was then cooled to 0 ℃ and quenched with water (5mL), 10% NaOH (5mL), and water (15mL) in that order. The reaction was filtered and concentrated to give the title compound (11.5g, 94% yield). LC-MS M/z 125(M-OH) ⁺1.94 minutes (retention time).

Intermediate 14

4-Methylbenzenesulfonic acid (4-ethylcyclohexyl) methyl ester

To a solution of (4-ethylcyclohexyl) methanol (11.5g,81mmol) in DCM (500mL) under nitrogen at 10 deg.C was slowly added 4-methylbenzene-1-sulfonyl chloride (15.41g,81mmol), TEA (22.54mL,162mmol), and DMAP (0.988g,8.09 mmol). The reaction mixture was stirred at 10 ℃ for 16 hours. The reaction was diluted with water (10mL) and extracted with EtOAc (3X30mL), Isolute was added to the combined organic layers, and the mixture was concentrated at 50 ℃ under a nitrogen atmosphere. The crude product adsorbed by Isolute was purified by flash chromatography eluting with (hexane: ethyl acetate ═ 20:1) to give the title compound 4-methylbenzeneSulfonic acid (4-ethylcyclohexyl) methyl ester (18g, 71.4% yield) as a solid. LC-MS M/z 319(M +23)⁺2.38 minutes (retention time).

Intermediate 15

2- (6-bromo-1-oxo-1H-inden-2 (3H) -ylidene) acetic acid

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (5g,23.69mmol) in 1, 4-dioxane (20mL) under nitrogen at ambient temperature was slowly added 2-oxoacetic acid (35.1g,237mmol), H₂SO₄(5mL,94 mmol). The reaction mixture was stirred at 100 ℃ for 4 hours. The reaction was cooled to ambient temperature and water (100mL) was added to the reaction. The reaction was filtered and the white solid was dried under high vacuum to give the title compound (5.6g, 84% yield). LC-MSm/z 268(M + H) ⁺1.56 minutes (retention time).

Intermediate 16

2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetic acid

To a solution of 2- (6-bromo-1-oxo-1H-inden-2 (3H) -ylidene) acetic acid (5.6g,20.97mmol) in acetic acid (50mL) and water (15mL) at ambient temperature under nitrogen was slowly added zinc (3.43g,52.4 mmol). The reaction mixture was stirred at 100 ℃ for 0.5 h, water (50mL) was added to the reaction and extracted with EtOAc (3X 100 mL). The mixture was concentrated under a stream of nitrogen at 50 ℃ to give the title compound (5g, 84% yield) as a white solid. LC-MS M/z 269(M + H)⁺1.47 minutes (retention time).

Intermediate 17

2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetamide

To a solution of 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetic acid (24g,89mmol) in toluene (200mL) under nitrogen at 20 ℃ was slowly added oxalyl chloride (78mL,892 mmol). The reaction mixture was stirred at 20 ℃ for 16 hours. The reaction was concentrated and diluted with DCM (300 mL). The reaction mixture was cooled to 0 ℃, aqueous ammonia (50mL, 647mmol) was added dropwise, and stirred at ambient temperature for 4 hours. The reaction was then extracted with DCM (3X 200mL) and the organic solvent was concentrated. The residue was triturated with ethyl acetate and hexane (1:1) to give the title compound as a white solid (14g, 54.4% yield). LC-MS M/z 268(M + H) ⁺1.63 minutes (retention time).

Intermediate 18

7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To a solution of 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetamide (14g,52.2mmol) in acetonitrile (250mL) under nitrogen at ambient temperature was slowly added TFA (20.12mL,261mmol) and triethylsilane (78mL,522 mmol). The reaction mixture was stirred at 100 ℃ for 16 hours. The solvent was concentrated and the residue triturated with hexanes to give the title compound (9.8g, 63.3% yield) which was used in the next step without further purification. LC-MS M/z 252(M + H)⁺1.60 minutes (retention time).

Intermediate 19

7-bromo-1- ((4-ethylcyclohexyl) methyl) -1,3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To 7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] at 10 ℃ under nitrogen]To a solution of pyrrol-2 (3H) -one (4g,15.87mmol) in N, N-dimethylformamide (100mL) was slowly added NaH (2.54g,63.5 mmol). The reaction mixture is added inThe mixture was stirred at 10 ℃ for 1 hour. Thereafter, methyl 4-methylbenzenesulfonate (4-ethylcyclohexyl) ester (9.41g,31.7mmol) was added to a solution in 50mL of DMF and stirred at 80 ℃ for 4 hours. The reaction was diluted with water (100mL) and extracted with EtOAc (3X100 mL). Isolute was added to the combined organic layers and the mixture was concentrated under a stream of nitrogen at 50 ℃. The crude adsorbed by Isolute was purified by flash chromatography eluting with (hexane: ethyl acetate 4:1) to give the title compound (2.6g, 31.8% yield). LC-MS M/z 376(M + H) ⁺2.00 minutes (retention time).

Intermediate 20

1- ((4-ethylcyclohexyl) methyl) -7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To 5-bromo-3- ((4-ethylcyclohexyl) methyl) -3,3a,8,8 a-tetrahydrocyclopenta [ a ]]To a solution of inden-2 (1H) -one (4.3g,11.46mmol) in 1, 4-dioxane (50mL) was added potassium acetate (3.37g,34.4mmol) and bis (pinacolato) diboron (3.78g,14.89 mmol). The reaction mixture was degassed with argon for 30 minutes, and then PdCl was added to the reaction mixture₂(dppf)-CH₂Cl₂Adduct (0.936g,1.146mmol) and stirred at 100 ℃ for 16 h. The reaction was then cooled and filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexanes (1:2) as eluent to give the title compound (3.1g, 59.4% yield). LC-MS M/z 424(M + H)⁺2.04 min (retention time).

Intermediate 21

4-Propylcyclohexanecarboxylic acid methyl ester

To 4-propylcyclohexanecarboxylic acid (15g,88mmol) in methanol under nitrogen at ambient temperature(100mL) to the solution was added H slowly₂SO₄(1mL,18.76 mmol). The reaction mixture was stirred at 70 ℃ for 16 hours. Water (30mL) was added and the reaction extracted with EtOAc (3X 50 mL). The mixture was concentrated under a stream of nitrogen at 50 ℃ to give the title compound (15.2g, 94% yield), which was used in the next step without further purification. LC-MS M/z 185(M + H) ⁺2.32 minutes (retention time).

Intermediate 22

(4-Propylcyclohexyl) methanol

To a solution of methyl 4-propylcyclohexanecarboxylate (15g,81mmol) in THF (200mL) at 0 deg.C under nitrogen was slowly added LiAlH₄(5g,132 mmol). The mixture was stirred at ambient temperature for 4 hours. The reaction was cooled to 0 ℃ and quenched with water (5mL), 10% NaOH (5mL), and water (15mL) in that order. The reaction was filtered and concentrated to give the title compound (12g, 90% yield) as an oil. LC-MS M/z 139(M + H)⁺2.07 minutes (retention time).

Intermediate 23

4-Methylbenzenesulfonic acid (4-propylcyclohexyl) methyl ester

To a solution of (4-propylcyclohexyl) methanol (12g,77mmol) in DCM (200mL) under nitrogen at 10 deg.C was slowly added 4-methylbenzene-1-sulfonyl chloride (14.64g,77mmol), TEA (21.41mL,154mmol), and DMAP (0.938g,7.68 mmol). The reaction mixture was stirred at 10 ℃ for 16 hours. Water (200mL) was added and the mixture was extracted with EtOAc (3X 200 mL). Isolute was added to the combined organic layers and the mixture was concentrated under a stream of nitrogen at 50 ℃. The crude adsorbed by Isolute was purified by flash chromatography eluting with (hexane: ethyl acetate ═ 20:1) to give the title compound (15g, 57.9% yield) as a white solid. LC-M Sm/z 333(M+23)⁺2.02 minutes (retention time).

Intermediate 24

7-bromo-1- ((4-propylcyclohexyl) methyl) -1,3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To 7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] at 20 ℃ under nitrogen]To a solution of pyrrol-2 (3H) -one (5g,19.83mmol) in N, N-dimethylformamide (50mL) was slowly added 60% NaH (3.17g,79 mmol). The reaction mixture was stirred at 20 ℃ for 1 hour. Then a solution of methyl 4-methylbenzenesulfonate (4-propylcyclohexyl) ester (12.31g,39.7mmol) in DMF (2mL) was added and stirred at 80 ℃ for 4 hours. Water (100mL) was added and the mixture was extracted with EtOAc (3X 100 mL). Isolute was added to the combined organic layers and the mixture was concentrated under a stream of nitrogen at 50 ℃. The crude adsorbed by Isolute was purified by flash chromatography eluting with (hexane: ethyl acetate ═ 4:1) to give the title compound (3.3g, 31.1% yield). LC-MS M/z 390(M + H)⁺2.49 minutes (retention time).

Intermediate 25

1- ((4-Propylcyclohexyl) methyl) -7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To 5-bromo-3- ((4-propylcyclohexyl) methyl) -3,3a,8,8 a-tetrahydrocyclopenta [ a ] ]To a solution of inden-2 (1H) -one (3.2g,8.22mmol) in 1, 4-dioxane (50mL) was added potassium acetate (2.420g,24.66mmol) and bis (pinacolato) diboron (2.71g,10.68 mmol). The reaction mixture was degassed with argon for 30 minutes, and then PdCl was added to the reaction mixture₂(dppf)-CH₂Cl₂Adduct (0.671g,0.822mmol) and stirred at 100 ℃ for 16 h. The reaction is then cooled and filtered through celite, anThe filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexane (1:2) as eluent to give the crude product, which was then crystallized from hexane to give the title compound (2.6g, 67.3% yield) as a white solid. LC-MS M/z 396(M + Na)⁺2.11 minutes (retention time).

Intermediate 26

Benzyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate

In N₂LiHMDS (11.37mL,11.37mmol) was added dropwise to a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (2.0g,9.48mmol) in THF (10mL) at-78 ℃ under an atmosphere. After the addition, the reaction mixture was slowly warmed to 0 ℃ and stirred at this temperature for 8 hours. The mixture was cooled to-78 deg.C again and benzyl 2-bromoacetate (1.651mL,10.42mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and slowly warmed to ambient temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The crude residue was purified by flash chromatography eluting with petroleum ether, EtOAc (10:1) to give the title compound (700mg, 20.56% yield). LC-MS M/z 359(M + H) ⁺1.78 minutes (retention time).

Intermediate 27

Benzyl 2- (1-oxo-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-2-yl) acetate

To a solution of benzyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate (8.51g,23.69mmol) in 1, 4-dioxane (100mL) was added potassium acetate (5.81g,59.2mmol) and bis (pinacolato) diboron (7.82g,30.8 mmol). The reaction mixture was degassed with argon for 30 minutes, and then PdCl was added to the reaction mixture₂(dppf)-CH₂Cl₂An adduct (1.935g,2.369mmol) and stirred at 100 ℃ for 16 h. The reaction was then cooled and filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexane (1:3) as eluent to give the crude product, which was then crystallized from hexane to give the title compound (5.0g, 46.8% yield) as a white solid. LC-MS M/z 407(M + H)⁺1.94 minutes (retention time).

Intermediate 28

7-bromo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrole

To 7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] at 0 deg.C]To a solution of pyrrol-2 (3H) -one (3.5g,13.88mmol) in THF (60mL) was added 2M BH₃DMS (48.6mL,97 mmol). The reaction mixture was stirred at reflux overnight and then cooled to 0 ℃. The reaction mixture was quenched by slow addition of MeOH (2mL) followed by 3N HCl. The reaction mixture was stirred at reflux for 3 hours and then concentrated. Water was added to the residue and the pH of the solution was adjusted to pH with 4N NaOH >9. The solution was extracted with diethyl ether. The organic layers were combined and washed with Na₂SO₄Dried, filtered and concentrated to give the title compound (3.05g, 92% yield). LC-MS M/z 238(M + H)⁺1.15 minutes (retention time).

Intermediate 29

7-bromo-2, 3,3a, 4-tetrahydroindeno [1,2-b ] pyrrole-1 (8bH) -carboxylic acid tert-butyl ester

To 7-bromo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrole (3.05g,12.81mmol) in DCM (30mL) was added TEA (3.57mL,25.6mmol) and Boc₂O (4.46mL,19.21 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction was cooled to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and driedDrying and concentration gave the title compound (2.5g, 57.7% yield). LC-MS M/z 360(M + H)⁺2.04 min (retention time).

Intermediate 30

7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ] pyrrole-1 (8bH) -carboxylic acid tert-butyl ester

To 7-bromo-2, 3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (2.9g,8.57mmol) in 1, 4-dioxane (200mL) was added potassium acetate (2.104g,21.43mmol) and bis (pinacolato) diboron (2.83g,11.15 mmol). The reaction mixture was degassed with argon for 30 minutes, and then PdCl was added to the reaction mixture ₂(dppf)-CH₂Cl₂Adduct (0.350g,0.429mmol) and stirred at 100 ℃ for 16 h. The reaction was then cooled and filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexane (15:1) as eluent to give the crude product, which was then crystallized from hexane to give the title compound (2.05g, 56.1% yield) as a white solid. LC-MS M/z 408(M + H)⁺1.99 minutes (retention time).

Intermediate 31

4-bromo-5-fluoro-2-methylaniline

A mixture of NBS (14.22g,80mmol), 5-fluoro-2-methylaniline (10g,80mmol) and N, N-dimethylformamide (200mL) was stirred at 25 ℃ for 12 h. The mixture was then poured into water and the solid filtered to give the title compound (13g, 71% yield) as a yellow solid. LC-MS M/z204(M + H)⁺1.68 minutes (retention time).

Intermediate 32

N- (4-bromo-5-fluoro-2-methylphenyl) acetamide

In N₂To neat acetic anhydride (4.62mL,49.0mmol) was added 4-bromo-5-fluoro-2-methylaniline (1g,4.90mmol) under an atmosphere at 25 ℃. The reaction was stirred at 25 ℃ for 30 minutes. The mixture was poured into water and the solid was filtered to give the title compound (1.1g,4.02mmol) as a yellow solid. LC-MS M/z 246(M + H) ⁺1.57 minutes (retention time).

Intermediate 33

N- (4-bromo-3-fluoro-6-methyl-2-nitrophenyl) acetamide

Nitric acid (200mL,4475mmol), N- (4-bromo-5-fluoro-2-methylphenyl) acetamide (30g,122mmol) and H₂SO₄(200mL,3752mmol) of the mixture at 0 ℃ in N₂Stirring was carried out under an atmosphere, and the mixture was stirred at 0 ℃ for 2 hours. The reaction was poured into water and the solid filtered off to give the title compound as a pale yellow solid (30.1g, 72% yield). LC-MS M/z 291(M + H)⁺1.53 minutes (retention time).

Intermediate 34

4-bromo-3-fluoro-6-methyl-2-nitroaniline

HCl (10.44mL,344mmol) was added to N- (4-bromo-3-fluoro-6-methyl-2-nitrophenyl) acetamide (20g,68.7 mmol). The resulting mixture was stirred at 100 ℃ for 4 hours. Then the solvent is removed and NaHCO is used₃The aqueous solution adjusted the residue to pH 8. The aqueous mixture was extracted with EtOAc (3X 50mL) and the solvent was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with (petroleum ether: EtOAc ═ 10:1) to give the title compound (5g, 20% yield). LC-MS M/z 249(M + H)⁺,1.71Minutes (retention time).

Intermediate 35

4-bromo-3-fluoro-N, 6-dimethyl-2-nitroaniline

To a solution of 4-bromo-3-fluoro-6-methyl-2-nitroaniline (15g,60.2mmol) in N, N-dimethylformamide (50mL) was added sodium hydride (2.168g,90mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 10 minutes, then methyl iodide (4.52mL, 72.3mmol) was added to the reaction. The resulting mixture was stirred at 0 ℃ for 20 minutes, then NH was added ₄Cl (aq) to consume excess NaH, and the aqueous layer was extracted with EtOAc (3 × 50mL), and the solvent was concentrated in vacuo to give the title compound (16g, 31% yield). LC-MS M/z 263(M + H)⁺1.84 minutes (retention time).

Intermediate 36

4-bromo-3-fluoro-N1, 6-dimethylbenzene-1, 2-diamine

To a solution of 4-bromo-3-fluoro-N, 6-dimethyl-2-nitroaniline (16g,60.8mmol) in acetic acid (4mL) was added zinc (150mg,2.294 mmol). The mixture was stirred at 65 ℃ for 2 hours. The reaction was then filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with (petroleum ether: EtOAc ═ 10:1) to give the title compound (5.3g, 36% yield). LC-MS M/z 233(M + H)⁺1.45 minutes (retention time).

Intermediate 37

5-bromo-4-fluoro-1, 7-dimethyl-1H-benzo [ d ] [1,2,3] triazole

A solution of 4-bromo-3-fluoro-N1, 6-dimethylbenzene-1, 2-diamine (5g,21.45mmol) in sulfuric acid (4.57mL,85.8mmol)The stirred suspension was treated with a solution of sodium nitrite solution (1.480g,21.45mmol) in water (30 mL). The mixture was stirred at 0 ℃ for 2 hours and then filtered to give the title compound (2g, 36.7% yield).¹H-NMR(400MHz,CDCl3)δppm 7.30-7.28(m,1H),4.49(s,3H),2.71(q,J＝1.2,3H)。

Intermediate body 38

(E) -3- (4-fluoro-1, 7-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) acrylic acid ethyl ester

To 5-bromo-4-fluoro-1, 7-dimethyl-1H-benzo [ d ][1,2,3]To a mixture of triazole (2g,8.19mmol), 3-ethoxy-3-oxoprop-1-en-1-ium (1.624g,16.39mmol), triphenylphosphine (0.430g,1.639mmol) and TEA (2.284mL,16.39mmol) in N-methyl-2-pyrrolidone (NMP) (20mL) was added diacetoxypalladium (0.368g,1.639 mmol). The resulting mixture was stirred at 135 ℃ overnight. The reaction was then cooled to ambient temperature, filtered and extracted with EtOAc (3 × 50mL) and then concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: EtOAc ═ 3:1) to give the title compound (1g, 38.7% yield). LC-MS M/z 234(M + H)⁺1.66 minutes (retention time).

Intermediate 39

1- ((2, 3-difluorobenzyl) amino) -2-methylpropan-2-ol

To a solution of 2, 3-difluorobenzaldehyde (10g,70.4mmol) in methanol (100mL) was added 1-amino-2-methylpropan-2-ol (6.27g,70.4mmol) and NaOH (7.04mL,7.04 mmol). It was stirred under nitrogen for 1 hour and then NaBH was added in portions over 10 minutes₄(1.065g,28.1 mmol). The reaction was stirred at ambient temperature for 24 hours. The crude product was purified by silica gel chromatography. The fractions were concentrated to give the title compound (10g,44.0mmol, 62.5% yield) as an off-white solid. LC-MS: m/z: 216.13(M + H)⁺1.915 minutes (retention time).

Intermediate 40

9-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene

To a solution of 1- ((2, 3-difluorobenzyl) amino) -2-methylpropan-2-ol (2g,9.29mmol) in dimethyl sulfoxide (DMSO) (20mL) was added potassium tert-butoxide (2.085g,18.58mmol) and the reaction mixture was stirred at 80 ℃ for 2 h. The reaction mixture was poured into ice-water (100mL) and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with water (2X 100mL), brine (100mL), then Na₂SO₄And (5) drying. It was filtered and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (2g,5.77mmol, 62.1% yield) as a gummy liquid. LC-MS: m/z: 196.09(M + H)⁺1.875 minutes (retention time).

Intermediate 41

9-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepine-4 (5H) -carboxylic acid tert-butyl ester

To 9-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at 0 deg.C][1,4]To a solution of oxazepine triene (5g,25.6mmol) in Dichloromethane (DCM) (50mL) was added TEA (7.14mL,51.2mmol) and Boc-anhydride (7.73mL,33.3 mmol). The reaction was stirred at ambient temperature for 3 hours, diluted with water (100mL) and extracted with ethyl acetate (2X 100mL), washed with brine solution (100mL), and dried over anhydrous Na ₂SO₄Dried, filtered and concentrated. The crude residue was purified by silica gel chromatography to give the title compound (6.5g,21.47mmol, 84% yield) as an off-white solid. LC-MS: m/z: 239.94(M-56)⁺6.256 minutes (retention time).

Intermediate body 42

9-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene hydrochloride

At 10 deg.C, to 9-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f][1,4]To a solution of oxazepine-4 (5H) -carboxylic acid tert-butyl ester (6.5g,22.01mmol) in Dichloromethane (DCM) (20mL) was added a 4M HCl solution in 1, 4-dioxane (16.51mL,66.0 mmol). It was stirred for 1 hour. The resulting precipitate was filtered, triturated with hexanes and dried well to give the title compound (4.47g,18.99mmol, 86% yield) as an off-white solid. LC-MS m/z: 196.0(M-HCl)⁺3.335 minutes (retention time).

The compounds in Table 1 below were prepared by a method similar to that for the preparation of 9-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine hydrochloride. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 1

Example 1

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

Benzyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate

At-78 ℃ under N₂To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (2.0g,9.48mmol) under an atmosphereLiHMDS (11.37mL,11.37mmol) was added dropwise to a solution in THF (10 mL). After the addition, the reaction mixture was slowly warmed to 0 ℃ and stirred at this temperature for 8 hours. The mixture was cooled to-78 deg.C again and benzyl 2-bromoacetate (1.651mL, 10.42mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and slowly warmed to ambient temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The crude residue was purified by flash chromatography eluting with petroleum ether, EtOAc (10:1) to give the title compound (700mg, 20.56% yield). LC-MS M/z 359(M + H)⁺1.78 minutes (retention time).

Benzyl 2- (1-oxo-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-2-yl) acetate

To a solution of benzyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate (8.51g,23.69mmol) in 1, 4-dioxane (100mL) was added potassium acetate (5.81g,59.2mmol) and bis (pinacolato) diboron (7.82g,30.8 mmol). The reaction mixture was degassed with argon for 30 minutes, and then PdCl was added to the reaction mixture ₂(dppf)-CH₂Cl₂Adduct (1.935g,2.369mmol) and stirred at 100 ℃ for 16 h. The reaction was then cooled and filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexane (1:3) as eluent to give the crude product, which was then crystallized from hexane to give the title compound (5.0g, 46.8% yield) as a white solid. LC-MS M/z 407(M + H)⁺1.94 minutes (retention time).

3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (1.0g,4.08mmol) in 1, 4-dioxane (30mL) and water (10mL) was added benzyl 2- (1-oxo-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-2-yl) acetate (1.656g,4.08mmol), TEA (1.705mL,12.23mmol) and [ Rh (cod) Cl]₂(0.101g,0.204 mmol). The resulting reaction mixture was stirred at 90 ℃ for 18 hours. The reaction mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with MgSO₄Drying, filtering, concentrating under reduced pressure, and purifying by silica gel chromatography to obtain the desired product 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] ][1,2,3]Triazol-5-yl) propionic acid ethyl ester (2.1099g,2.128mmol, 52.2% yield). LC-MS M/z 526.5(M + H)⁺1.12 minutes (retention time).

3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (298mg,0.3mmol) in methanol (15mL) was added 10% Pd/C (63.9mg,0.060 mmol). The resulting suspension is brought to ambient temperature under H₂Stirred under atmosphere for 90 minutes. The reaction mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The combined filtrates were concentrated under reduced pressure and then dissolved in DCM (6mL) and cyclohexylmethylamine (0.078mL,0.600mmol), TEA (0.084mL,0.600mmol) and T3P (50% wt in EtOAc) (0.179mL,0.600mmol) were added. The resulting reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the desired product 3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (103.5mg,0.195mmol, 65.0% yield). LC-MS M/z 531.3(M + H) ⁺1.06 minutes (retention time).

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

To 3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (150mg,0.283mmol) in acetonitrile (2.0mL) and THF (1.0mL) was added triethylsilane (0.226mL,1.413mmol) and TFA (0.065mL,0.848 mmol). The resulting reaction mixture was heated at 100 ℃ for 1 hour with a microwave and again at 120 ℃ for 1 hour with a microwave. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (3mL), and NaOH (3.0N) (0.754mL,2.261mmol) was added. The reaction mixture was heated at 80 ℃ for 20 minutes with a microwave. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1- (cyclohexylmethyl) -2-oxo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (64.5mg,0.133mmol, 46.9% yield). LC-MS M/z 487.4(M + H)⁺0.89 minute (retention time)

Example 2

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {1- [ (4-ethylcyclohexyl) methyl ] -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (2- (2- (((4-ethylcyclohexyl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

To 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (298mg,0.3mmol) in methanol (15mL) and THF (5mL) was added 10% Pd/C (63.9mg,0.060 mmol). The resulting suspension is brought to ambient temperature under H₂Stirred under atmosphere for 30 minutes. The reaction mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The combined filtrates were concentrated under reduced pressure to give a crude intermediate. This intermediate was dissolved in DCM (6mL) and then (4-ethylcyclohexyl) methylamine (85mg,0.600mmol), TEA (0.084mL,0.600mmol) and then T3P (50% wt in EtOAc) (0.179mL,0.600mmol) were added. The resulting reaction mixture was stirred at ambient temperature for 43 hours, then TEA (0.042mL,0.300mmol) and T3P (50% wt in EtOAc) (0.089mL,0.300mmol) were added and stirred at ambient temperature for an additional 94 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (2- (2- (((4-ethylcyclohexyl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (136.7mg,0.245mmol, 82% yield). LC-MS M/z 559.3(M + H) ⁺1.08 minutes (retention time).

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {1- [ (4-ethylcyclohexyl) methyl ] -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (2- (2- (((4-ethylcyclohexyl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (130mg,0.233mmol) in acetonitrile (2mL) was added triethylsilane (0.186mL,1.163mmol) and TFA (0.054mL,0.698 mmol). The resulting reaction mixture was heated at 100 ℃ for 2 hours with a microwave. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (3mL), then NaOH (3.0N) (0.620mL, 1.861mmol) was added and the mixture was heated at 80 ℃ with microwave for 20 min. Mixing the reactionThe mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1- ((4-ethylcyclohexyl) methyl) -2-oxo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid (64.5mg,0.125mmol, 53.9% yield). LC-MS M/z 515.4(M + H)⁺0.99 minutes (retention time).

Example 3

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid

(E) -hept-2-en-6-ynoic acid ethyl ester

Sodium hydride (1.056g,26.4mmol) was added in small portions to a solution of ethyl 2- (diethoxyphosphoryl) acetate (3.03mL,14.4mmol) in DCM (15 mL). The mixture was stirred at 23 ℃ for 5 minutes, crude pent-4-ynal (. about.1 mL,12mmol) in DCM (10mL) was added slowly, and the mixture was stirred at 23 ℃ for 30 minutes. Addition of NH₄Cl (saturated aqueous solution), and the solution was extracted with DCM. The crude product was then purified by flash chromatography on a silica column (12g) eluting with a gradient of 0-60% EtOAc/hexane at 30mL/min for 20 minutes. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 1.32g (72%) of the title compound. LC-MS M/z 153.0(M + H)⁺0.82 (retention time).

(E) -5- (1-Ethyl-1H-1, 2, 3-triazol-4-yl) pent-2-enoic acid ethyl ester

Adding NaN₃(0.085g,1.31mmol), CuI (0.25mg,1.31umol) and iodoethane (0.090mL,1.31mmol) were added to (E) -hept-2-en-6-yneTo a solution of ethyl acetate (0.2g,1.31mmol) in water (5mL) the mixture was stirred at 70 ℃ for 14 h. The mixture was concentrated and purified by flash chromatography on silica gel (12g) eluting with a gradient of 0-30% MeOH/DCM at 30mL/min for 20 min to give the title compound (100mg, 34%). LC-MS M/z 224.1(M + H) ⁺0.65 minutes (retention time).

5- (1-Ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- (hydroxymethyl) -4-methylphenyl) pentanoic acid ethyl ester

(3- (hydroxymethyl) -4-methylphenyl) boronic acid (0.11g,0.67mmol), TEA (0.094mL,0.67mmol) and [ RhCl (cod)]₂(11mg,0.022mmol) was added to a solution of (E) -ethyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pent-2-enoate (0.1g,0.45mmol) in 1, 4-dioxane (1mL) and water (0.5 mL). The reaction was heated in a microwave at 140 deg.C (high absorption) for 4 hours. The mixture was concentrated and purified by flash chromatography on silica gel (12g) eluting with a gradient of 0-10% MeOH/DCM at 30mL/min for 20 min to give 64mg (41%) of the title compound and 50mg of recovered ethyl (E) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pent-2-enoate. LC-MS M/z 346.2(M + H)⁺0.81 minutes (retention time).

3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid ethyl ester

To a solution of ethyl (E) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pent-2-enoate (0.3g,1.344mmol) in 1, 4-dioxane (12mL) and water (4mL) was added benzyl 2- (1-oxo-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-2-yl) acetate (0.819g,2.015mmol), TEA (0.562mL,4.03mmol) and [ Rh (cod) Cl ]₂(0.033g,0.067 mmol). The resulting reaction mixture was stirred at 90 ℃ for 17 hours. The reaction mixture was extracted with EtOAc (3X 30mL)A compound (I) is provided. The combined organic layers were over MgSO₄Drying, filtration, concentration under reduced pressure and purification by silica gel chromatography gave the desired product ethyl 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoate (403.9mg,0.802mmol, 59.7% yield). LC-MS M/z 504.1(M + H)⁺1.05 minutes (retention time).

3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid ethyl ester

To a solution of ethyl 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoate (0.20g,0.397mmol) in methanol (15mL) was added 10% Pd/C (0.085g,0.079 mmol). The resulting suspension is brought to ambient temperature under H₂Stirred under atmosphere for 66 hours. The reaction mixture was filtered. To the filtrate was added 10% Pd/C (0.085g,0.079mmol) and the suspension was brought to ambient temperature under H₂Stirred under atmosphere for 90 minutes. The reaction mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The combined filtrates were concentrated under reduced pressure. This intermediate was dissolved in DCM (6mL), then cyclohexylmethylamine (0.103mL,0.794mmol), TEA (0.111mL,0.794mmol) were added, followed by T3P (50% wt in EtOAc) (0.236mL,0.794 mmol). The resulting reaction mixture was stirred at ambient temperature for 19 hours. More cyclohexylmethylamine (0.052mL,0.397mmol), TEA (0.055mL,0.397mmol) and T3P (50% wt in EtOAc) (0.236mL,0.397mmol) were added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for an additional 5 hours. The reaction mixture was purified by silica gel chromatography to give the desired product ethyl 3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoate (119.8mg,0.236mmol, 59.3% yield). LC-MS M/z 509.3(M + H) ⁺0.99 minutes (retention time).

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid

To a solution of ethyl 3- (2- (2- ((cyclohexylmethyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoate (119mg,0.234mmol) in acetonitrile (2.0mL) and THF (1.0mL) was added triethylsilane (0.187mL,1.170mmol) and TFA (0.054mL,0.702 mmol). Heating the resulting reaction mixture at 120 ℃ for 1 hour with microwaves; heating again at 120 deg.C for 2 hr with microwave; the mixture was heated again with microwaves at 130 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (3mL), and NaOH (3.0N) (0.624mL,1.872mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was concentrated under reduced pressure in vacuo and purified by reverse phase HPLC to give the desired product 3- (1- (cyclohexylmethyl) -2-oxo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid (57.5mg,0.124mmol, 52.9% yield). LC-MSm/z 465.2(M + H)⁺0.86 minutes (retention time).

Example 4

3- [1- (decahydronaphthalen-2-ylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

Decahydronaphthalene-2-carbonitrile

To a solution of 2-decalinone (2.332mL,15mmol) and p-toluenesulfonylmethylisonitrile (3.51g,18.00mmol) in THF (50mL) at 0 deg.C was slowly added KOtBu (3.37g,30.0 mmol). Subjecting the resulting reaction mixture to 0 deg.CStir at ambient temperature for 1 hour, then for 2 hours. The reaction mixture was concentrated under reduced pressure, then water (150mL) was added, followed by extraction with hexane (3X 100 mL). The combined organic layers were washed with MgSO₄Drying, filtration, concentration under reduced pressure, and purification by silica gel chromatography gave the desired product, decahydronaphthalene-2-carbonitrile (1.9881g,12.18mmol, 81% yield). LC-MS M/z 164.3(M + H)⁺1.05 minutes (retention time).

(decahydronaphthalen-2-yl) methylamines

To a suspension of LAH (0.690g,18.19mmol) in THF (40mL) at ambient temperature was slowly added a solution of decalin-2-carbonitrile (1.98g,12.13mmol) in THF (5 mL). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with Na₂SO₄(saturated aqueous solution) was slowly quenched, filtered, and concentrated under reduced pressure to give the desired product (decahydronaphthalen-2-yl) methylamine (1.9205g,11.48mmol, 95% yield). LC-MS M/z 168.1(M + H) ⁺0.69 minutes (retention time).

3- (2- (2- (((decahydronaphthalen-2-yl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (298mg,0.3mmol) in methanol (15mL) was added 10% Pd/C (63.9mg,0.060 mmol). The resulting suspension is brought to ambient temperature under H₂Stirred under atmosphere for 30 minutes. The reaction mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The combined filtrates were evaporated in vacuo. This intermediate was dissolved in DCM (6mL), followed by the addition of (decahydronaphthalen-2-yl) methylamine (100mg,0.600mmol), TEA (0.084mL,0.600mmol), and thenT3P (50% wt in EtOAc) was added (0.357mL,0.600 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours, then more T3P (50% wt in EtOAc) (0.179mL,0.300mmol) and TEA (0.042mL,0.300mmol) were added. The resulting reaction mixture was stirred at ambient temperature for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the desired product 3- (2- (2- (((decahydronaphthalen-2-yl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d) ][1,2,3]Triazol-5-yl) propionic acid ethyl ester (156.4mg,0.267mmol, 89% yield). LC-MS M/z 585.4(M + H)⁺1.26 minutes (retention time).

3- [1- (decahydronaphthalen-2-ylmethyl) -2-oxo-1H, 2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

To 3- (2- (2- (((decahydronaphthalen-2-yl) methyl) amino) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (150mg,0.257mmol) in acetonitrile (3mL) was added triethylsilane (0.205mL,1.283mmol) and TFA (0.059mL,0.770 mmol). The resulting reaction mixture was heated at 120 ℃ for 1 hour with a microwave. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (3mL), and then NaOH (3.0N) (0.684mL,2.052mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1- ((decahydronaphthalen-2-yl) methyl) -2-oxo-1, 2,3,3a,4,8 b-hexahydroindeno [1, 2-b)]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (85.2mg,0.158mmol, 61.4% yield). LC-MS M/z 541.4(M + H)⁺1.04 min (retention time).

Example 5

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- { 2-oxo-1- [ (4-propylcyclohexyl) methyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid

4-Propylcyclohexanecarbonitrile

To a solution of 4-propylcyclohexanone (2.319mL,15mmol) and p-toluenesulfonylmethylisonitrile (3.51g,18.00mmol) in THF (50mL) at 0 deg.C was slowly added KOtBu (3.37g,30.0 mmol). The resulting reaction mixture was stirred at 0 ℃ for 1 hour, then at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (100mL) and extracted with hexane (3 × 80 mL). The combined organic layers were washed with MgSO₄Drying, filtration, concentration under reduced pressure, and purification by silica gel chromatography gave the desired product, 4-propylcyclohexanecarbonitrile (1.2419g,8.21mmol, 54.7% yield).¹H NMR (400MHz, chloroform-d) delta ppm 0.84-0.94(m,4H),1.13-1.39(m,6H),1.49-1.56(m,1H),1.57-1.61(m,1H),1.67-1.87(m,2H),1.93-2.15(m,2H),2.29-2.94(m, 1H).

(4-propylcyclohexyl) methylamine

To a suspension of LAH (0.452g,11.90mmol) in THF (20mL) at ambient temperature was slowly added a solution of 4-propylcyclohexanecarbonitrile (1.2g,7.93mmol) in THF (5 mL). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with Na ₂SO₄(saturated aqueous solution) was slowly quenched, filtered, and concentrated under reduced pressure to give the desired product (4-propylcyclohexyl) methylamine (1.1512g,7.41mmol, 93% yield). LC-MS M/z 156.0(M + H)⁺0.69 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-oxo-2- (2-oxo-2- (((4-propylcyclohexyl) methyl) amino) ethyl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

To 3- (2- (2- (benzyloxy) -2-oxoethyl) -3-oxo-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (298mg,0.3mmol) in methanol (15mL) was added 10% Pd/C (63.9mg,0.060 mmol). The resulting suspension is brought to ambient temperature under H₂Stirred under atmosphere for 30 minutes. The reaction mixture was filtered and the filter cake was washed with MeOH (2 × 5 mL). The combined filtrates were evaporated in vacuo. This intermediate was dissolved in DCM (6mL), followed by the addition of (4-propylcyclohexyl) methylamine (93mg,0.600mmol), TEA (0.084mL,0.600mmol), and then T3P (50% wt in EtOAc) (0.357mL,0.600 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours, then more T3P (50% wt in EtOAc) (0.179mL,0.300mmol) and TEA (0.042mL,0.300mmol) were added. The resulting reaction mixture was stirred at ambient temperature for an additional 68 hours. To the reaction mixture was added more (4-propylcyclohexyl) methylamine (46.6mg,0.300mmol), T3P (50% wt in EtOAc) (0.179mL,0.300mmol) and TEA (0.042mL,0.300 mmol). The resulting reaction mixture was stirred at ambient temperature for 6 hours, then more T3P (50% wt in EtOAc) (0.179mL,0.300mmol) and TEA (0.042mL,0.300mmol) were added. The resulting reaction mixture was stirred at ambient temperature for an additional 19 hours. The reaction mixture was purified by silica gel chromatography to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ] ][1,2,3]Triazol-5-yl) -3- (3-oxo-2- (2-oxo-2- (((4-propylcyclohexyl) methyl) amino) ethyl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (146.2mg,0.255mmol, 85% yield). LC-MS M/z 573.4(M + H)⁺1.25 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (2-oxo-1- ((4-propylcyclohexyl) methyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-oxo-2- (2-oxo-2- (((4-propylcyclohexyl) methyl) amino) ethyl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (145mg,0.253mmol) in acetonitrile (3mL) was added triethylsilane (0.202mL,1.266mmol) and TFA (0.059mL,0.760 mmol). The resulting reaction mixture was heated at 120 ℃ for 1 hour with a microwave. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (3mL), and NaOH (3.0N) (0.675mL,2.025mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (2-oxo-1- ((4-propylcyclohexyl) methyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] ]Pyrrol-7-yl) propionic acid (83.2mg,0.157mmol, 62.2% yield). LC-MS M/z529.3(M + H)⁺1.06 minutes (retention time).

Example 6

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetic acid methyl ester

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (15g,71.1mmol) in THF (300mL) at-78 deg.C was added LiHMDS (85mL,85mmol) dropwise. The reaction mixture was then warmed to 0 ℃ and cooled again to-78 ℃. Methyl 2-bromoacetate (7.38mL,78mmol) was added dropwise at-78 ℃. The reaction mixture was warmed to ambient temperature. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, over MgSO₄Drying and concentrating to obtain the product, passing it throughPurification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) gave methyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate (8.1g,28.6mmol, 40.3% yield). LC-MS M/z 285.0(M + H)⁺1.68 minutes (retention time).

(Z) -2- (6-bromo-1- (hydroxyimino) -2, 3-dihydro-1H-inden-2-yl) acetic acid methyl ester

To a solution of methyl 2- (6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl) acetate (8.1g,28.6mmol) in methanol (100mL) was added hydroxylamine hydrochloride (2.98g,42.9mmol) and sodium acetate (3.52g,42.9 mmol). The reaction mixture was stirred at 65 ℃ for 6 hours. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and then washed with Na ₂SO₄Drying and concentration gave methyl (Z) -2- (6-bromo-1- (hydroxyimino) -2, 3-dihydro-1H-inden-2-yl) acetate (7.6g,25.5mmol, 89% yield). LC-MS M/z 300.0(M + H)⁺1.59 minutes (retention time).

7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] pyrrol-2 (3H) -one

To a solution of methyl (Z) -2- (6-bromo-1- (hydroxyimino) -2, 3-dihydro-1H-inden-2-yl) acetate (7.6g,25.5mmol) in acetic acid (100mL) at ambient temperature was added zinc (8.3g,127 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour, then cooled to ambient temperature, filtered, and concentrated. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and then washed with Na₂SO₄Drying and concentration gave the crude product which was purified by silica gel chromatography (petroleum ether: ethyl acetate ═ 1:2) to give 7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ═ b]Pyrrol-2 (3H) -one (3.5g,13.88mmol, 54.5% yield). LC-MS M/z 253.9(M + H)⁺1.09 minutes (retention time).

7-bromo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrole

To 7-bromo-1, 3a,4,8 b-tetrahydroindeno [1,2-b ] at 0 deg.C]Pyrrole-2 (3H) -one (3.5g,13.88mmol) in THF (60mL) was added BH₃DMS (48.6mL,97 mmol). The reaction mixture was stirred at reflux for 16 hours and then cooled to 0 ℃. The reaction mixture was quenched by slow addition of MeOH (2mL) followed by addition of 3N HCl. The reaction mixture was stirred under reflux for a further 3 hours and then concentrated. Water was added to the residue and the pH of the solution was adjusted to 4N NaOH >9. The solution was extracted with diethyl ether. Subjecting the organic layer to Na₂SO₄Drying and concentrating to obtain 7-bromo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrole (3.05g,12.81mmol, 92% yield). LC-MS M/z 238.0(M + H)⁺1.12 minutes (retention time).

7-bromo-2, 3,3a, 4-tetrahydroindeno [1,2-b ] pyrrole-1 (8bH) -carboxylic acid tert-butyl ester

To 7-bromo-1, 2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrole (3.05g,12.81mmol) in DCM (30mL) was added TEA (3.57mL,25.6mmol) and Boc₂O (4.46mL,19.21 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. Water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and then washed with Na₂SO₄Drying and concentrating to obtain 7-bromo-2, 3,3a, 4-tetrahydroindeno [1,2-b]Pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (2.5g,7.39mmol, 57.7% yield). LC-MS M/z 260.0(M + H)⁺2.04 min (retention time).

7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ] pyrrole-1 (8bH) -carboxylic acid tert-butyl ester

To 7-bromo-2, 3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (2.9g,8.57mmol) in 1, 4-dioxane (200mL) was added potassium acetate (2.104g,21.43mmol), bis (pinacolato) diboron (2.83g,11.15mmol), and the reaction mixture was degassed with argon for 30 min, then PdCl was added ₂(dppf)-CH₂Cl₂Adduct (0.350g,0.429 mmol). The reaction mixture was stirred at 100 ℃ for 16 h, cooled to ambient temperature, and filtered through celite. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography using EtOAc: hexane (15:1) to give the crude product, which was crystallized from hexane to give 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]Pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (2.05g,4.81mmol, 56.1% yield). LC-MS M/z 408.2(M + H)⁺1.99 minutes (retention time).

7- (1- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3-ethoxy-3-oxopropyl) -2,3,3a, 4-tetrahydroindeno [1,2-b ] pyrrole-1 (8bH) -carboxylic acid tert-butyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (0.491g,2mmol) in 1, 4-dioxane (12mL) and water (4mL) was added 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]Pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (1.156g,3.00mmol), TEA (1.115mL,8.00mmol) and [ Rh (cod) Cl]₂(0.049g,0.100 mmol). The resulting reaction mixture was stirred at 90 ℃ for 65 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the desired product 7- (1- (1, 4-dimethyl-1H-benzo [ d) ][1,2,3]Triazol-5-yl) -3-ethoxy-3-oxopropyl) -2,3,3a, 4-tetrahydroindeno [1,2-b]Pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (1.0056g,1.993mmol, 100% yield). LC-MS M/z 505.3(M + H)⁺1.19 minutes (retention time).

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

To 7- (1- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3-ethoxy-3-oxopropyl) -2,3,3a, 4-tetrahydroindeno [1,2-b]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (30mg,0.059mmol) in methanol (1mL) was added NaOH (3.0N) (0.099mL,0.297 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was slowly acidified to pH-3 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (24.6mg,0.052mmol, 87% yield). LC-MS M/z421.2(M + H)⁺0.98 minutes (retention time).

Example 7

3- [1- (2-Cyclohexylacetyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

Ethyl 3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) propionate hydrochloride

To 7- (1- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3-ethoxy-3-oxopropyl) -2,3,3a, 4-tetrahydroindeno [1,2-b]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (970mg,1.922mmol) in 1, 4-dioxane (2.5mL) was added HCl (4M in 1, 4-dioxane) (2.403mL,9.61 mmol). Subjecting the obtained product toThe reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid ethyl ester hydrochloride (971.6mg,2.203mmol, 115% yield). LC-MS M/z 405.4(M + H)⁺0.73 minute (retention time).

3- [1- (2-Cyclohexylacetyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrole-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) to a solution in THF (2mL) was added 2-cyclohexylacetic acid (17.74mg,0.125mmol), TEA (0.047mL,0.340mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 70 min, then more T3P (50% wt in EtOAc) (0.034mL,0.113mmol) and TEA (0.016mL,0.113mmol) were added. The resulting reaction mixture was stirred at ambient temperature for an additional 3 hours. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.034mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for 50 more minutes, then more 2-cyclohexylacetic acid (17.74mg,0.125mmol) was added. The resulting reaction mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (2.000mL), and NaOH (3N) (0.378mL,1.134mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. More NaOH (3N) (0.378mL,1.134mmol) was added to the reaction mixture. The resulting reaction mixture was heated at 80 ℃ with microwaves for a further 20 minutes. More NaOH (3N) (0.113mL,0.340mmol) was added to the reaction mixture. The resulting reaction mixture was heated at 80 ℃ for 20 minutes with microwaves and heated again at 80 ℃ for 20 minutes with microwaves. Acidifying the reaction mixture with HCl (3N) to pH 3-4, concentrating under reduced pressure Condensation and purification by reverse phase HPLC to afford the desired product 3- (1- (2-cyclohexylacetyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (20.7mg,0.041mmol, 36.5% yield). LC-MS M/z501.4(M + H)⁺1.03 minutes (retention time).

Example 8

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) to a solution in THF (2mL) was added 2-phenylpropionic acid (0.017mL,0.125mmol), TEA (0.047mL,0.340mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 50 minutes. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.016mL,0.113 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 3 hours. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 50 minutes. To the reaction mixture was added more 2-phenylpropionic acid (0.017mL,0.125 mmol). The resulting reaction mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was then heated at 80 ℃ with microwaves for 30 minutes. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 71 hours. The reaction mixture was then heated at 80 ℃ with microwaves for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (2.000mL), and NaOH (3N) (0.756mL,2.268mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. More NaOH (3N) (0) was added to the reaction mixture. 378mL,1.134 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture is acidified with HCl (3N) to pH 3-4, then concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b [ ] -]Pyrrol-7-yl]Propionic acid (isomer 1) (8.4mg,0.017mmol, 14.57% yield). LC-MS M/z 509.3(M + H)⁺0.96 minutes (retention time).

Example 9

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) to a solution in THF (2mL) was added 2-phenylpropionic acid (0.017mL,0.125mmol), TEA (0.047mL,0.340mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 50 minutes. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.016mL,0.113 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 3 hours. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 50 minutes. To the reaction mixture was added more 2-phenylpropionic acid (0.017mL,0.125 mmol). The resulting reaction mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was then heated at 80 ℃ with microwaves for 30 minutes. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for an additional 71 hours. The reaction mixture was then heated at 80 ℃ with microwaves for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (2.000mL), NaOH (3N) (0.756mL,2.268mmol) was then added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. More NaOH (3N) (0.378mL,1.134mmol) was added to the reaction mixture. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture is acidified to pH 3-4 with HCl (3N), concentrated under reduced pressure, and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ]]Pyrrol-7-yl]Propionic acid (isomer 2) (15.1mg,0.030mmol, 26.2% yield). LC-MS M/z 509.3(M + H)⁺1.01 minutes (retention time).

Example 10

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-methylpentanoyl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) to a solution in THF (2mL) was added 2-methylpentanoic acid (0.016mL,0.125mmol), TEA (0.047mL,0.340mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 70 minutes. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.016mL,0.113 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol) and TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for 50 minutes. To the reaction mixture was added more 2-methylvaleric acid (0.016mL,0.125 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then heated at 80 ℃ with microwaves for 30 minutes (33-8). To the reaction mixture was added more T3P (50% wt EtOAc solution) (0.067mL,0.113mmol), TEA (0.032mL,0.227 mmol). Subjecting the resulting reaction mixture to ambient conditions Stirred at temperature for 71 hours. The reaction mixture was concentrated under reduced pressure, then dissolved in methanol (2.000mL), and NaOH (3N) (0.756mL,2.268mmol) was added. The resulting reaction mixture was heated at 80 ℃ with microwaves for 20 minutes, followed by addition of more NaOH (3N) (0.378mL,1.134mmol) and then heating at 80 ℃ with microwaves for 20 minutes. The reaction mixture is acidified to pH 3-4 with HCl (3N), concentrated under reduced pressure, and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1- (2-methylpentanoyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) propionic acid (16.6mg,0.035mmol, 30.8% yield). LC-MS M/z 475.3(M + H)⁺0.96/0.98 min (retention time).

Example 11

3- {1- [2- (2-chlorophenyl) acetyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) in DCM (2mL) was added 2- (2-chlorophenyl) acetic acid (23.21mg,0.136mmol), TEA (0.063mL,0.454mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by the addition of NaOH (3N) (0.378mL,1.134 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product 3- (1- (2- (2-chlorophenyl) acetyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] ]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (31.8mg,0.060mmol, 53.0% yield). LC-MS M/z 529.2(M + H)⁺0.97 min (retention time).

Example 12

3- {1- [2- (2-cyanophenyl) acetyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) in DCM (2mL) was added 2- (2-cyanophenyl) acetic acid (21.93mg,0.136mmol), TEA (0.063mL,0.454mmol) followed by T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by the addition of NaOH (3N) (0.378mL,1.134 mmol). The resulting reaction mixture was heated at 100 ℃ for 20 minutes with a microwave. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product 3- (1- (2- (2-cyanophenyl) acetyl) -1,2,3,3a,4,8 b-hexahydroindeno [1, 2-b)]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d ][1,2,3]Triazol-5-yl) propionic acid (32.4mg,0.062mmol, 55.0% yield). LC-MS M/z 520.3(M + H)⁺0.90 minutes (retention time).

Example 13

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (3, 3-dimethylbutyryl) -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) in DCM (2mL) was added 3, 3-dimethylbutyric acid (0.017mL,0.136mmol), TEA (0.063mL,0.454mmol), and then T3P (50% wt in EtOAc) (0.101mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes. Mixing the reactionThe material was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by the addition of NaOH (3N) (0.378mL,1.134 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was acidified with HCl (3N) to pH 3-4, then concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d [)][1,2,3]Triazol-5-yl) -3- (1- (3, 3-dimethylbutyryl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b]Pyrrol-7-yl) propionic acid (26.0mg,0.055mmol, 48.3% yield). LC-MS M/z475.2(M + H) ⁺0.94 minute (retention time).

Example 14

3- {1- [ butyl (methyl) carbamoyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]To a solution of pyrrol-7-yl) propionic acid ethyl ester hydrochloride (50mg,0.113mmol) in DCM (2mL) was added CDI (22.06mg,0.136mmol), TEA (0.032mL,0.227 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 hour, followed by the addition of N-methylbutan-1-amine (0.020mL,0.170 mmol). The resulting reaction mixture was stirred at ambient temperature for 100 minutes and then heated with microwaves at 80 ℃ for 30 minutes. More N-methylbutan-1-amine (0.027mL,0.227mmol) was added to the reaction mixture, which was then heated with microwaves at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in 1, 4-dioxane (0.5mL) and more N-methylbutan-1-amine (0.5mL,4.22mmol) was added. Heating the reaction mixture at 80 deg.C with microwave for 30 min; reheating the mixture at 100 ℃ for 30 minutes by microwaves; reheating with microwave at 120 deg.C for 60 min; the mixture was heated again with microwaves at 130 ℃ for 60 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by the addition of NaOH (3N) (0.227mL,0.680 mmol). The resulting reaction mixture was heated at 80 ℃ with microwaves for 20 minutes, then more NaOH (3N) (0.227mL,0.680mmol) was added, followed by microwaves at 80 ℃ Heat for 20 minutes. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1- (butyl (methyl) carbamoyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (23.3mg,0.048mmol, 42.0% yield). LC-MS M/z 490.4(M + H)⁺0.97 min (retention time).

Example 15

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H,3H,3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid

2-methoxy-6-nitroaniline

To a solution of 2-amino-3-nitrophenol (2.55g,16.55mmol) in N, N-dimethylformamide (35mL) was added potassium carbonate (2.52g,18.20 mmol). The mixture was stirred for 5 minutes, followed by the addition of methyl iodide (1.138mL,18.20mmol), and the reaction was stirred at ambient temperature for 2 hours. Water (75mL) was added to quench the reaction, and the precipitated product was collected by filtration and washed with water to give the title compound, 2-methoxy-6-nitroaniline (2.26g, 81%). LC-MS M/z 168.9(M + H)⁺0.74 minutes (Retention time)

4-bromo-2-methoxy-6-nitroaniline

To a solution of 2-methoxy-6-nitroaniline (2.26g,13.44mmol) in acetic acid (50mL) was added sodium acetate (1.654g,20.16mmol) and bromine (0.762mL,14.78mmol) and the mixture was stirred at ambient temperature for 30 min. Water (75mL) was added to quench the reaction and the precipitated product was removed Collected by filtration, washed with water and dried under vacuum to give 2.78g of 4-bromo-2-methoxy-6-nitroaniline (84%). LC-MS M/z 246.9/248.9(M + H)⁺0.93 minutes (retention time).

4-bromo-2-methoxy-N-methyl-6-nitroaniline

To a solution of 4-bromo-2-methoxy-6-nitroaniline (2.76g,11.17mmol) in N, N-dimethylformamide (50mL) was slowly added sodium hydride (300mg,12.50mmol) at 0 deg.C, and the reaction mixture was stirred for 30 min. Methyl iodide (0.768mL,12.29mmol) was then added. Water (60mL) was added to quench the reaction, and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound 4-bromo-2-methoxy-N-methyl-6-nitroaniline (2.82g, 97%). LC-MS M/z260.9/263(M + H)⁺1.03 minutes (retention time).

5-bromo-7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazole

To a solution of 4-bromo-2-methoxy-N-methyl-6-nitroaniline (2.82g,10.80mmol) in glacial acetic acid (100ml,1747mmol) was added zinc (4.94g,76mmol) and the reaction mixture was stirred at ambient temperature for 2 h 30 min. Zinc (150mg,2.294mmol) was added to the mixture and the solution was stirred until the orange colour disappeared (approximately 30 min). The mixture was filtered, the solid was washed with ethyl acetate, and the filtrate was concentrated. The crude product was dissolved in sulfuric acid (10%) (50mL,10.80mmol), sodium nitrite (0.745g,10.80mmol) was added in small portions at 0 deg.C, and the mixture was stirred at 0 deg.C for 1 hour 45 minutes. Water (100mL) was added to quench the reaction, and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound 5-bromo-7-methoxy-1-methyl-1H-benzo [ d ][1,2,3]Triazole (1.28g, 49%). LC-MS M/z 241.9/243.9(M + H)⁺0.83 minute (Bao)Time left).

(E) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) acrylic acid ethyl ester

To 5-bromo-7-methoxy-1-methyl-1H-benzo [ d ] in DMF (15mL)][1,2,3]To a solution of triazole (974mg,4.02mmol) were added DIPEA (2.108mL,12.07mmol), ethyl acrylate (4.29mL,40.2mmol), diacetoxypalladium (271mg,1.207mmol) and tri-o-tolylphosphine (980mg,3.22mmol), and the reaction mixture was placed in a microwave at 150 ℃ for 2 hours. Water (50mL) was added to quench the reaction. Ethyl acetate was added and the layers were separated. The aqueous layer was then extracted twice with ethyl acetate and the combined organic layers were over MgSO₄Drying, concentrating, and purifying by silica gel chromatography to obtain (E) -3- (7-methoxy-1-methyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) acrylic acid ethyl ester (820mg, 78%). LC-MS M/z 262(M + H)⁺0.90 minutes (retention time).

3- (1- (tert-Butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid

To 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (66.4mg,0.172mmol) in 1, 4-dioxane (2mL) and water (0.7mL) was added (E) -3- (7-methoxy-1-methyl-1H-benzo [ d ][1,2,3]Triazol-5-yl) acrylic acid Ethyl ester (30mg,0.115mmol), TEA (0.048mL,0.344mmol) and [ RhCl (cod))]₂(2.83mg, 5.74. mu. mol). The resulting reaction mixture was heated at 90 ℃ for 100 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL), followed by the addition of NaOH (3N) (0.306mL,0.919 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. Acidifying the reaction mixture with HCl (3N) to pH 3-4, thenThen concentrated under reduced pressure and purified by reverse phase HPLC to give the desired product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (35.8mg,0.073mmol, 63.3% yield). LC-MS M/z 493.3(M + H)⁺1.00 min (retention time).

Example 16

3- (1- (tert-Butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) -3- (1-ethyl-4-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid

To 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (66.9mg,0.174mmol) in 1, 4-dioxane (2mL) and water (0.7mL) was added (E) -3- (1-ethyl-4-methyl-1H-benzo [ d |) ][1,2,3]Triazol-5-yl) acrylic acid Ethyl ester (30mg,0.116mmol), TEA (0.048mL,0.347mmol) and [ RhCl (cod))]₂(2.85mg, 5.78. mu. mol). The resulting reaction mixture was heated at 90 ℃ for 100 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by the addition of NaOH (3N) (0.309mL,0.926 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (1-ethyl-4-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (25.3mg,0.052mmol, 44.6% yield). LC-MS M/z 435.3(M + H)⁺1.02 minutes (retention time).

Example 17

3- (1- (tert-Butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid

To 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (78mg,0.202mmol) in 1, 4-dioxane (2mL) and water (0.7mL) were added (E) -ethyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pent-2-enoate (30mg,0.134mmol), TEA (0.056mL,0.403mmol) and [ RhCl (cod) ]₂(3.31mg, 6.72. mu. mol). The resulting reaction mixture was heated at 90 ℃ for 100 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL) followed by addition of NaOH (3N) (0.358mL,1.075 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid (32.4mg,0.071mmol, 53.0% yield). LC-MS M/z455.2(M + H)⁺0.94 minute (retention time).

Example 18

3- (1- (tert-Butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ] pyrrol-7-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid

To 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,3a, 4-tetrahydroindeno [1,2-b ]]To a solution of pyrrole-1 (8bH) -carboxylic acid tert-butyl ester (66.4mg,0.172mmol) in 1, 4-dioxane (2mL) and water (0.7mL) was added (E) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d [ -c][1,2,3]Triazol-5-yl) acrylic acid methyl ester (30mg,0.115mmol), TEA (0.048mL,0.344mmol) and [ RhCl (cod)) ]₂(2.83mg, 5.74. mu. mol). The resulting reaction mixture was heated at 90 ℃ for 66 hours. The reaction mixture was concentrated under reduced pressure and dissolved in methanol (2.000mL), followed by the addition of NaOH (3N) (0.306mL,0.919 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. The reaction mixture was acidified to pH 3-4 with HCl (3N), then concentrated under reduced pressure and washed with waterPurification by reverse phase HPLC to give the desired product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a,4,8 b-hexahydroindeno [1,2-b ]]Pyrrol-7-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid (35.9mg,0.071mmol, 61.7% yield). LC-MS M/z 507.2(M + H)⁺1.01 minutes (retention time).

Example 19

3- (1- (cyclohexylmethyl) -2-oxo-2, 3,3a,4,5,9 b-hexahydro-1H-benzo [ g ] indol-8-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid

2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetic acid ethyl ester

LiHMDS (1.0M in THF) (11.00mL,11.00mmol) was slowly added to a solution of 7-bromo-3, 4-dihydronaphthalen-1 (2H) -one (2.251g,10mmol) in THF (10mL) at-78 deg.C (over a 10 minute period). The resulting reaction mixture was warmed to 0 ℃ and stirred at this temperature for 30 minutes and then cooled to-78 ℃. To the reaction mixture was slowly added a solution of ethyl 2-bromoacetate (1.391mL,11.00mmol) in THF (2mL) at-78 ℃. The resulting mixture was stirred at-78 ℃ for 1 hour, then warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with 10mL of saturated NH ₄Quenched with Cl solution and H₂Dilution with O (10 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30mL) over MgSO₄Drying, filtration, concentration under reduced pressure, and purification by silica gel chromatography gave the title compound (1.6881g,2.170mmol, 21.70% yield) as a colorless oil. LC-MS M/z 310.9(M + H)⁺1.09 minutes (retention time).

2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetic acid

To a solution of ethyl 2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetate (1.6881g,5.42mmol) in methanol (5mL) was added 10mL of 2M NaOH (20.0 mmol). The resulting solution was heated by microwave irradiation at 80 ℃ for 30 minutes. The reaction mixture was acidified to pH-5 with HCl (1N) and extracted with EtOAc (3 × 40 mL). The combined organic phases were concentrated under reduced pressure to give the title compound 2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetic acid (1.4661g,3.26mmol, 60.1% yield) as a solid. LC-MS M/z 282.9(M + H)⁺0.86 minutes (retention time).

2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) -N- (cyclohexylmethyl) acetamide

To a solution of 2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) acetic acid (0.400g,1.413mmol) in DCM (3mL) were added TEA (0.788mL,5.65mmol), T3P (50% wt in EtOAc) (1.682mL,2.826mmol) and cyclohexylmethylamine (0.552mL,4.245 mmol). The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.2483g,0.446mmol, 31.6% yield) as a solid. LC-MS M/z 378.1(M + H) ⁺1.14 minutes (retention time).

8-bromo-1- (cyclohexylmethyl) -3,3a,4, 5-tetrahydro-1H-benzo [ g ] indol-2 (9bH) -one

To a solution of 2- (7-bromo-1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) -N- (cyclohexylmethyl) acetamide (0.2483g,0.656mmol) in acetonitrile (8mL) was added triethylsilane (0.524mL,3.28mmol) and TFA (0.152mL,1.969 mmol). The resulting solution was heated at 100 ℃ for 2 hours by microwave irradiation. The reaction mixture was decompressedConcentration and purification by silica gel chromatography gave the title compound (0.1449g,0.400mmol, 60.9% yield) as a colorless oil. LC-MS M/z 362.0(M + H)⁺1.24 minutes (retention time).

1- (cyclohexylmethyl) -8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,4, 5-tetrahydro-1H-benzo [ g ] indol-2 (9bH) -one

To 8-bromo-1- (cyclohexylmethyl) -3,3a,4, 5-tetrahydro-1H-benzo [ g]To a solution of indol-2 (9bH) -one (0.1449g,0.400mmol) in N, N-dimethylformamide (2mL) were added bis (pinacolato) diboron (0.152g,0.600mmol), KOAc (0.079g,0.800mmol) and PdCl₂(dppf) (0.015g,0.020 mmol). The resulting solution was heated at 100 ℃ for 1 hour by microwave irradiation. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.1287g,0.314mmol, 79% yield) as an oil. LC-MS M/z 410.3(M + H) ⁺1.32 minutes (retention time).

3- (1- (cyclohexylmethyl) -2-oxo-2, 3,3a,4,5,9 b-hexahydro-1H-benzo [ g ] indol-8-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (0.049g,0.2mmol) in 1, 4-dioxane (1.5mL) and water (0.5mL) was added 1- (cyclohexylmethyl) -8- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,4, 5-tetrahydro-1H-benzo [ g []Indol-2 (9bH) -one (0.1287g,0.314mmol), TEA (0.084ml,0.600mmol) and [ Rh (cod) Cl]₂(4.93mg, 10.00. mu. mol). The resulting solution was stirred at 90 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give intermediate 3- (1- (cyclohexylmethyl) -2-oxo-2, 3,3a,4,5,9 b-hexahydro-1H-benzo [ g)]Indol-8-yl) -3- (1, 4-dimethyl-1H-Benzo [ d ] carbonyl][1,2,3]Triazol-5-yl) propionic acid ethyl ester. This intermediate was redissolved in methanol (2 mL). To the resulting solution was added 2M NaOH (0.5mL,1.000 mmol). After heating by microwave irradiation at 80 ℃ for 30 min, the reaction mixture was acidified to pH-5 with HCl (1N), concentrated under reduced pressure and purified by preparative HPLC to give the title compound (20mg,0.040mmol, 19.97% yield) as a white solid. LC-MSm/z501.3(M + H) ⁺0.90 minutes (retention time).¹H NMR (400MHz, chloroform-d) δ 0.53-0.74(m,2H),0.89-1.33(m,6H),1.44-1.60(m,3H),1.73(br.s.,2H),2.19-2.96(m,10H),3.05-3.23(m,3H),4.27(d, J ═ 2.76Hz,3H),4.58(t, J ═ 7.78Hz,1H),4.95-5.07(m,1H),6.94-7.06(m,1H),7.12(dd, J ═ 13.30,7.78Hz,1H),7.21(dd, J ═ 19.07,7.78Hz,1H),7.31(s,1H),7.33-7.45(m, 1H).

Example 20

3- (3- (cyclohexylmethyl) -2-oxo-3, 3a,8,8 a-tetrahydro-2H-indeno [1,2-d ] oxazol-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid

6-bromo-1, 1-dimethoxy-2, 3-dihydro-1H-inden-2-ol

A solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (1.055g,5mmol) and KOH (3.09g,55.0mmol) in methanol (25mL) was stirred at 0 deg.C for 10 min, followed by the addition of (diacetoxyiodo) benzene (1.933g,6.00 mmol). The resulting solution was stirred at 0 ℃ for 1 hour and at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.7734g,2.61mmol, 52.1% yield) as a dark red gum. LC-MS M/z 273.0(M + H)⁺0.84 minutes (retention time).

(Cyclohexylmethyl) carbamic acid 6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl ester

To a solution of 6-bromo-1, 1-dimethoxy-2, 3-dihydro-1H-inden-2-ol (0.3385g,1.239mmol) and DMAP (0.227g,1.859mmol) in toluene (12mL) was added (isocyanoylmethyl) cyclohexane (0.443mL,3.10mmol) dropwise. The resulting solution was heated at 100 ℃ for 5 hours by microwave irradiation. The reaction mixture was concentrated under reduced pressure to give the crude intermediate (cyclohexylmethyl) carbamic acid 6-bromo-1, 1-dimethoxy-2, 3-dihydro-1H-inden-2-yl ester. The crude intermediate was redissolved in 10mL of 10% HCl solution. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.5234g,1.429mmol, 115% yield) as a white solid. LC-MS M/z 366.0(M + H)⁺1.17 minutes (retention time).

5-bromo-3- (cyclohexylmethyl) -3,3a,8,8 a-tetrahydro-2H-indeno [1,2-d ] oxazol-2-one

To a solution of (cyclohexylmethyl) carbamic acid 6-bromo-1-oxo-2, 3-dihydro-1H-inden-2-yl ester (0.5234g,1.429mmol) in acetonitrile (12mL) was added triethylsilane (2.283mL,14.29mmol) and TFA (0.330mL,4.29 mmol). The resulting solution was heated at 120 ℃ for 4 hours by microwave irradiation. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.3618g,1.033mmol, 72.3% yield) as a colorless oil. LC-MSm/z 349.9(M + H) ⁺1.16 minutes (retention time).

3- (cyclohexylmethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,8,8 a-tetrahydro-2H-indeno [1,2-d ] oxazol-2-one.

To 5-bromo-3- (cyclohexylmethyl) -3,3a,8,8 a-tetrahydro-2H-indeno [1,2-d]To a solution of oxazol-2-one (0.3618g,1.033mmol) in N, N-dimethylformamide (5mL) were added bis (pinacolato) diboron (0.393g,1.549mmol), KOAc (0.203g,2.066mmol) and PdCl₂(dppf) (0.038g,0.052 mmol). The resulting solution was heated at 100 ℃ for 1 hour by microwave irradiation. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.298g,0.750mmol, 72.6% yield) as a colorless oil. LC-MS M/z 398.2(M + H)⁺1.30 minutes (retention time).

3- (3- (cyclohexylmethyl) -2-oxo-3, 3a,8,8 a-tetrahydro-2H-indeno [1,2-d ] oxazol-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (0.120g,0.489mmol) in 1, 4-dioxane (3mL) and water (1mL) was added 3- (cyclohexylmethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3,3a,8,8 a-tetrahydro-2H-indeno [1,2-d ] ]Oxazol-2-one (0.298g,0.750mmol), TEA (0.205ml,1.468mmol) and [ Rh (cod) Cl]₂(0.012g,0.024 mmol). The resulting solution was stirred at 90 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to give intermediate 3- (3- (cyclohexylmethyl) -2-oxo-3, 3a,8,8 a-tetrahydro-2H-indeno [1,2-d ]]Oxazol-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid ethyl ester. This intermediate was dissolved in methanol (4mL) followed by the addition of 1.0mL of 2M NaOH solution (2.00 mmol). After heating by microwave irradiation at 80 ℃ for 30 min, the reaction mixture was acidified to pH-5 with HCl (1N), concentrated under reduced pressure and purified by preparative HPLC to give the title compound (58.1mg,0.119mmol, 24.31% yield) as a solid. LC-MS M/z 489.2(M + H)⁺0.90 minutes (retention time).¹H NMR (400MHz, chloroform-d) δ 0.90(q, J11.80 Hz,2H),1.09-1.27(m,3H),1.48(d, J12.55 Hz,1H),1.61-1.76(m,5H),2.76-2.87(m,4H),3.03-3.29(m,4H),3.34-3.46(m,1H),4.23-4.30(m,3H),4.96-5.07(m,2H),5.29(td,J＝7.47,2.64Hz,1H),7.03-7.15(m,1H),7.18-7.28(m,2H),7.29-7.42(m,2H)。

Example 21

3- (3- (7-chloro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

1, 6-dibromo-2, 3-dihydro-1H-indene

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-ol (3g,14.08mmol) in DCM (30mL) at 0 deg.C was added PBr₃(1.726mL,18.30 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to 0 ℃ with saturated NaHCO₃Quench and extract with DCM (2 ×). The combined organics were washed with brine solution and the organic layer was washed with anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure to give the title compound (3g, 77% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.55(d,J＝1.5Hz,1H),7.36(dd,J＝1.8,8.1Hz,1H),7.12(d,J＝7.9Hz,1H),5.48(dd,J＝2.4,6.6Hz,1H),3.12(td,J＝7.8,16.0Hz,1H),2.83(ddd,J＝2.7,7.7,16.1Hz,1H),2.67-2.45(m,2H)。

1- ((2-bromo-5-chlorobenzyl) amino) -2-methylpropan-2-ol

To a solution of 2-bromo-5-chlorobenzaldehyde (1g,4.56mmol) in methanol (20mL) under nitrogen was added 1-amino-2-methylpropan-2-ol (0.406g,4.56mmol) and 1N NaOH (0.5mL,0.500 mmol). Add NaBH portionwise over a period of 10 minutes at 0 deg.C₄(0345g,9.11mmol) and stirred at ambient temperature for 72 hours. The reaction mixture was evaporated under reduced pressure and then purified by flash chromatography to give 1- ((2-bromo-5-chlorobenzyl) amino) -2-methylpropan-2-ol (1g,3.39mmol, 74.4% yield). LC-MS M/z 291.9(M + H)⁺1.62 minutes (retention time).

7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene

To a solution of 1- ((2-bromo-5-chlorobenzyl) amino) -2-methylpropan-2-ol (500mg,1.709mmol) in isopropanol (8mL) was added Cs ₂CO₃(472mg,3.42mmol) and copper (I) iodide (32.5mg,0.171mmol), and the reaction mixture was stirred in a microwave reactor at 130 ℃ for 1 hour. The reaction mixture was quenched with water, extracted twice with EtOAc and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated and purified by flash chromatography to give the desired product 7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazacycloheptatriene (450mg,1.213mmol, 71.0% yield). LC-MS M/z 212.0(M + H)⁺3.49 minutes (retention time).

The compounds in Table 2 below were prepared by a method similar to that for the preparation of 7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 2

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 1, 6-dibromo-2, 3-dihydro-1H-indene (500mg,1.812mmol) and 7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at ambient temperature][1,4]DIPEA (0.633mL,3.62mmol) was added to a solution of oxazepine (384mg,1.812 mmol). The reaction mixture was stirred in a microwave reactor at 90 ℃ for 1 hour. The reaction mixture was cooled to 0 ℃, quenched with cold water, and extracted with EtOAc (2 ×). The combined organics were washed with brine solution and the organic layer was washed with anhydrous Na ₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography eluting with EtOAc: hexane (4:96) to give the title compound (500mg, 67.8% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.39(s,1H),7.34(br d,J＝7.9Hz,1H),7.12-7.07(m,2H),6.94(d,J＝2.4Hz,1H),6.84(d,J＝8.3Hz,1H),4.48(br t,J＝7.9Hz,1H),3.58(s,2H),2.94-2.86(m,1H),2.81-2.67(m,3H),2.22-2.12(m,1H),2.04(qd,J＝8.8,12.9Hz,1H),1.24(d,J＝5.7Hz,6H)。

7-chloro-2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (500mg,1.229mmol) in 1, 4-dioxane (10mL) was added bis (pinacolato) diboron (375mg,1.475mmol) and potassium acetate (241mg,2.459 mmol). The reaction mixture was degassed with argon for 10 min, then PdCl was added₂(dppf)-CH₂Cl₂Adduct (50.2mg,0.061mmol) and the reaction mixture was heated at 90 ℃ for 16 h. The reaction mixture was cooled to 0 ℃, quenched with cold water, and extracted with EtOAc (2 ×). Dissolving the combined organic with brineWashing the organic layer with anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography eluting with EtOAc: hexane (5:95) to give the title compound (350mg, 62.7% yield).¹H NMR(400MHz,CDCl₃)δppm 7.73(s,1H),7.68(d,J＝7.5Hz,1H),7.15(br dd,J＝7.2,19.3Hz,1H),7.08(dd,J＝2.5,8.4Hz,1H),6.93(d,J＝2.4Hz,1H),6.83(d,J＝8.3Hz,1H),4.50(br t,J＝7.7Hz,1H),3.65-3.54(m,2H),3.00-2.91(m,1H),2.88-2.71(m,2H),2.21-2.12(m,1H),2.06-1.96(m,2H),1.35-1.27(m,12H),1.24(d,J＝11.0Hz,6H)。

3- (3- (7-chloro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

In a sealed tube to (E) -3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (200mg,0.815mmol) in a mixture of 1, 4-dioxane (4mL) and water (4mL) was added TEA (0.334mL,2.446 mmol). The reaction was degassed with nitrogen for 20 minutes, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (40.2mg,0.082 mmol). The reaction mixture was stirred at 90 ℃ for 4 hours. The reaction mixture was quenched with cold water and extracted with EtOAc (2 ×). The combined organics were washed with brine solution and the organic layer was washed with anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure to give the title compound (250mg, 53.5% yield). LC-MS M/z 573(M + H)⁺4.52 minutes (retention time).

3- (3- (7-chloro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3- (7-chloro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] at 0 DEG C][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (250mg,0.436mmol) in ethanol (10mL) was added 10% NaOH (10mL,0.436 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, neutralized with 2N HCl and extracted with DCM (2 ×). The combined organics were washed with brine solution and the organic layer was washed with anhydrous Na ₂SO₄Dried and filtered. The filtrate was evaporated and purified by preparative HPLC to give the title compound (23mg, 9.56% yield). LC-MS M/z 545(M + H)⁺3.27 minutes (retention time).

Example 22

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 7-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

1- ((2-bromo-5-methylbenzyl) amino) -2-methylpropan-2-ol

To a solution of 2-bromo-5-methylbenzaldehyde (2g,10.05mmol) in methanol (5mL) was added 1-amino-2-methylpropan-2-ol (0.896g,10.05mmol) and NaOH (1.005mL,1.005 mmol). The resulting reaction mixture was stirred under nitrogen for 1 hour, then NaBH was added slowly₄(0.266g,7.03mmol) and the reaction stirred at ambient temperature for 72 hours. The reaction was evaporated in vacuo, diluted with water (30mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄Drying, filtration and evaporation in vacuo gave the desired product 1- ((2-bromo-5-methylbenzyl) amino) -2-methylpropan-2-ol (2.4g,5.84mmol, 58.2% yield). LC-MS M/z 272.2(M + H)⁺,1.28 minutes (retention time).

2,2, 7-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene

To a solution of 1- ((2-bromo-5-methylbenzyl) amino) -2-methylpropan-2-ol (1.2g,4.41mmol) in isopropanol (10mL) was added Cs₂CO₃(2.011g,6.17mmol) and copper (I) iodide (0.084g,0.441mmol) and the reaction mixture was stirred in a microwave reactor at 130 ℃ for 1 hour. The reaction mixture was filtered and the filter cake was washed with isopropanol (10 mL). The combined filtrates were concentrated in vacuo and then purified by flash chromatography to give the desired product 2,2, 7-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f [ -f ] -][1,4]Oxazacycloheptatriene (500mg,1.354mmol, 30.7% yield). LC-MS M/z 192.1(M + H)⁺3.39 minutes (retention time).

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2,2, 7-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

To 2,2, 7-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine triene (832mg,4.35mmol) in acetonitrile (20mL) was added 1, 6-dibromo-2, 3-dihydro-1H-indene (600mg,2.174mmol), followed by DIPEA (1.139mL,6.52 mmol). The reaction mixture was stirred in a microwave reactor at 120 ℃ for 1 hour. The reaction was then diluted with ice water and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine solution (30mL) and over anhydrous Na ₂SO₄Dried, filtered and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography eluting with EtOAc: hexanes (1: 9). The eluted fractions were concentrated in vacuo to give the title compound (600mg, 68.8% yield). LC-MS M/z 386(M + H)⁺2.41 minutes (retention time).

2,2, 7-trimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2,2, 7-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (600mg,1.553mmol) in 1, 4-dioxane (10mL) was added bis (pinacolato) diboron (473mg,1.864mmol) and potassium acetate (305mg,3.11 mmol). The reaction mixture was degassed with argon for 10 min, then PdCl was added₂(dppf)-CH₂Cl₂Adduct (127mg,0.155mmol) and the reaction mixture was heated at 90 ℃ for 3 h. The reaction mixture was filtered through celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a crude residue. The crude residue was purified by column chromatography eluting with 10% ethyl acetate in hexane. The eluted fractions were concentrated under reduced pressure to give the title compound (500mg, 62.9% yield). LC-MS M/z 434(M + H) ⁺2.33 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 7-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) acrylic acid ethyl ester (250mg,1.019mmol) and 2,2, 7-trimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (574mg,1.325mmol) in 1, 4-dioxane (5mL) and water (5.00mL) was added TEA (0.426mL,3.06mmol) and (1, 5-cyclooctadiene) rhodium (I) chloride dimer (50.3mg,0.102 mmol). The reaction mixture was degassed with argon for 10 minutes and then stirred at 100 ℃ for 2 hours. The reaction mixture was cooled to ambient temperature and washed with waterDiluted and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine solution (20mL) and Na₂SO₄Dried, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography using EtOAc: hexanes (5:5) as eluent to give the title compound (200mg, 29.3% yield). LC-MS M/z 553(M + H)⁺2.09 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 7-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ] at 0 DEG C][1,2,3]Triazol-5-yl) -3- (3- (2,2, 7-trimethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (200mg,0.362mmol) in ethanol (10mL) was added 1M aqueous NaOH solution (10mL,10.00 mmol). The reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 1N HCl, extracted with DCM, and taken over Na₂SO₄And (5) drying. The filtrate was evaporated under reduced pressure and purified using reverse phase HPLC to give the title compound (120mg, 61.0% yield). LC-MSm/z 5253(M + H)⁺1.81 minutes (retention time).

Example 23

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (7-methoxy-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -7-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 1, 6-dibromo-2, 3-dihydro-1H-indene (500mg,1.812mmol), 7-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at ambient temperature][1,4]DIPEA (0.633mL,3.62mmol) was added to a solution of oxazepine (376mg,1.812mmol) in acetonitrile (10 mL). The reaction mixture was stirred in a microwave reactor at 90 ℃ for 1 hour. The reaction mixture was cooled to 0 ℃, quenched with cold water, and extracted with EtOAc (2 ×). The combined organic layers were washed with brine solution and the organic layer was washed with anhydrous Na ₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure and the crude residue was purified by flash chromatography using EtOAc: hexanes (4:96) as eluent to give the title compound (400mg, 54.9% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.42(s,1H),7.33(br d,J＝8.3Hz,1H),7.09(d,J＝7.9Hz,1H),6.83(d,J＝8.8Hz,1H),6.66(dd,J＝3.1,8.6Hz,1H),6.48(d,J＝3.1Hz,1H),4.48(br t,J＝8.0Hz,1H),3.76(s,3H),3.56(s,2H),2.95-2.85(m,1H),2.82-2.70(m,3H),2.23-2.13(m,1H),2.11-2.02(m,1H),1.24(d,J＝18.2Hz,6H)。

7-methoxy-2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -7-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (400mg,0.994mmol) in 1, 4-dioxane (10mL) was added bis (pinacolato) diboron (303mg,1.193mmol) and potassium acetate (195mg,1.988 mmol). The reaction mixture was degassed with argon for 10 min, then PdCl was added₂(dppf)-CH₂Cl₂Adduct (40.6mg,0.050mmol) and the reaction mixture was heated at 90 ℃ for 4 hours. The reaction mixture was cooled to 0 ℃, quenched with cold water, and extracted with EtOAc (2 ×). The combined organic layers are washed with brine solution, andorganic layer warp anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure and the crude residue was purified by flash column chromatography using EtOAc: hexane (5:95) as eluent to give the title compound (300mg, 67.1% yield). ¹H NMR(400MHz,CDCl₃)δppm＝7.76(s,1H),7.67(d,J＝7.5Hz,1H),7.15(br dd,J＝7.2,19.3Hz,1H),6.82(d,J＝8.6Hz,1H),6.65(dd,J＝3.0,8.7Hz,1H),6.52(d,J＝2.9Hz,1H),4.51(br t,J＝7.6Hz,1H),3.74(s,3H),3.69-3.58(m,2H),3.00-2.90(m,1H),2.82(td,J＝8.4,16.4Hz,1H),2.69(q,J＝12.6Hz,2H),2.22-2.12(m,1H),2.09-2.00(m,1H),1.32-1.26(m,12H),1.22(d,J＝6.4Hz,6H)。

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (7-methoxy-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (200mg,0.815mmol) in a mixture of 1, 4-dioxane (4mL) and water (4mL) was added TEA (0.334mL,2.446 mmol). The solution was degassed with nitrogen for 20 minutes, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (40.2mg,0.082 mmol). The reaction mixture was stirred at 90 ℃ for 4 hours. The reaction mixture was then quenched with cold water and extracted with EtOAc (2 ×). The combined organics were washed with brine solution and the organic layer was washed with anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated under reduced pressure to give the crude title compound which was used in the next step without further purification (300mg, 64.7% yield). LC-MS M/z 569(M + H)⁺4.42 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (7-methoxy-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ] at 0 DEG C ][1,2,3]Triazol-5-yl) -3- (3- (7-methoxy-2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (300mg,0.528mmol) in ethanol (10mL) was added 10% NaOH (10mL,0.528 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated under reduced pressure, neutralized with 2N HCl and extracted with DCM (2 ×). The combined organic layers were washed with brine solution and the organic layer was washed with anhydrous Na₂SO₄Dried and filtered. The filtrate was evaporated and purified by preparative HPLC to give the title compound (57mg, 19.94% yield). LC-MS M/z 541(M + H)⁺1.78 minutes (retention time).

Example 24

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 8-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2,2, 8-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

To 2,2, 8-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at ambient temperature][1,4]To a solution of oxazepine heptatriene (200mg,1.046mmol) and 1, 6-dibromo-2, 3-dihydro-1H-indene (289mg,1.046mmol) in acetonitrile (10mL) was added DIPEA (0.365mL,2.091 mmol). The reaction mixture was stirred at 70 ℃ for 16 hours. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine solution and Na ₂SO₄Dried and filtered. The filtrate was concentrated and purified by using (5:95) EtOAc: hexaneColumn chromatography as eluent. The solvent was concentrated to give the title compound (220mg, 54.5% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.41(s,1H),7.32(dd,J＝1.3,8.1Hz,1H),7.08(d,J＝7.9Hz,1H),6.86-6.72(m,3H),4.48(t,J＝8.0Hz,1H),3.58(s,2H),2.93-2.83(m,1H),2.79-2.67(m,3H),2.28(s,3H),2.21-2.04(m,2H),1.25(d,J＝10.7Hz,6H)。

2,2, 8-trimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2,2, 8-trimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] in a sealed tube][1,4]To a solution of oxazepine (300mg,0.777mmol) in 1, 4-dioxane (10mL) was added bis (pinacolato) diboron (256mg,1.010mmol) and potassium acetate (191mg,1.941 mmol). The reaction was degassed with argon for 20 min, followed by addition of PdCl₂(dppf) (28.4mg,0.039 mmol). The reaction mixture was stirred at 90 ℃ for 2 hours. The crude residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent. The eluted fractions were concentrated under reduced pressure to give the title compound (250mg, 69.2% yield). LC-MS M/z 434(M + H)⁺4.97 min (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 8-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

In a sealed tube to (E) -3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (50mg,0.204mmol) in 1, 4-dioxane (10mL) and water (10.00mL) was added 2,2, 8-trimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepine triene (115mg,0.265 mmol). The reaction was degassed with argon for 20 min, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (10.05mg,0.020 mmol). The reaction mixture was stirred at 95 ℃ for 16 hours. The reaction mixture was then filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent. The eluted fractions were concentrated under reduced pressure to give the title compound (120mg, 56.2% yield). LC-MS M/z 553(M + H)⁺2.12 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2,2, 8-trimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ] at 0 DEG C ][1,2,3]Triazol-5-yl) -3- (3- (2,2, 8-trimethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (120mg,0.217mmol) in ethanol (10mL) was added 1M NaOH (10mL,10.00 mmol). The reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 1N HCl, and extracted with (1:1) MeOH: DCM. Subjecting the organic layer to Na₂SO₄And (5) drying. The filtrate was evaporated under reduced pressure and purified by preparative HPLC to give the title compound (56mg, 48% yield). LC-MS M/z 525(M + H)⁺1.85 minutes (retention time).

Example 25

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (8-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -8-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 8-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at ambient temperature][1,4]To a solution of oxazepine (150mg,0.768mmol) and 1, 6-dibromo-2, 3-dihydro-1H-indene (212mg,0.768mmol) in acetonitrile (10mL) was added DIPEA (0.268mL,1.537 mmol). The reaction mixture was stirred at 70 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine solution and Na ₂SO₄Dried and filtered. The filtrate was evaporated in vacuo and purified by column chromatography using EtOAc: hexane (5:95) as eluent. The eluted fractions were concentrated to give the title compound (200mg, 66.7% yield).¹H NMR(400MHz,CDCl₃)δppm＝7.40(s,1H),7.35-7.31(m,1H),7.09(d,J＝7.9Hz,1H),6.87-6.80(m,2H),6.65(dd,J＝2.9,8.6Hz,1H),4.48(t,J＝7.9Hz,1H),3.57(s,2H),2.93-2.85(m,1H),2.81-2.71(m,3H),2.22-2.13(m,1H),2.10-2.01(m,1H),1.30-1.27(m,2H),1.24(dd,J＝2.2,9.9Hz,H)。

8-fluoro-2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -8-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] in a sealed tube][1,4]To a solution of oxazepine (200mg,0.512mmol) in 1, 4-dioxane (10mL) was added bis (pinacolato) diboron (169mg,0.666mmol) and potassium acetate (126mg,1.281 mmol). The reaction was degassed with argon for 20 min, followed by addition of PdCl₂(dppf) (18.75mg,0.026 mmol). The reaction mixture was stirred at 90 ℃ for 4 hours.The reaction mixture was passed through celite and washed with ethyl acetate. The reaction was diluted with water and extracted with EtOAc. Subjecting the organic layer to Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography using (5:95) EtOAc: hexane as eluent. The eluted fractions were evaporated to give the title compound (215mg, 87% yield). LC-MS M/z 438(M + H) ⁺4.80 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (8-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

In a sealed tube to (E) -3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (50mg,0.204mmol) in 1, 4-dioxane (10mL) and water (10.00mL) was added 8-fluoro-2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepine triene (116mg,0.265 mmol). The reaction was degassed with argon for 20 min, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (10.05mg,0.020 mmol). The reaction mixture was stirred at 95 ℃ for 16 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography using 20% ethyl acetate in hexane as eluent. The eluted fractions were concentrated under reduced pressure to give the title compound (150mg, 42.7% yield). LC-MS M/z 557(M + H)⁺4.97 min (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (8-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ] at 0 DEG C][1,2,3]Triazol-5-yl) -3- (3- (8-fluoro-2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (150mg,0.269mmol) in ethanol (10mL) was added aqueous NaOH (10.78mg,0.269 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure, quenched with 1N HCl, and extracted with MeOH: DCM (1: 9). Subjecting the organic layer to Na₂SO₄Dried and filtered. The filtrate was evaporated in vacuo and the residue was purified by preparative HPLC to give the title compound (60mg, 41.6% yield). LC-MS M/z 529(M + H)⁺3.19 minutes (retention time).

Example 26

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropionic acid

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

To a mixture of 1, 6-dibromo-2, 3-dihydro-1H-indene (800mg,2.90mmol) and 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine triene (617mg,3.48mmol) in acetonitrile (15mL) was added DIPEA (0.506mL,2.90mmol) and the reaction mixture was stirred with a microwave at 90 ℃ for 1 h. The reaction mixture was diluted with ice water and extracted with EtOAc. The combined organic layers were washed with brine solution and over anhydrous Na ₂SO₄Dried and filtered. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography using EtOAc: hexane (2:8) as eluent. The solvent was concentrated in vacuo to give the title compound (600mg, 54.8% yield))。LC-MS m/z 374(M+H)⁺2.50 minutes (retention time).

(3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) (4-fluoro-2-methylphenyl) methanol

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at-78 deg.C][1,4]To a solution of oxazepine (600mg,1.612mmol) in THF (25mL) was added a 1.6M solution of BuLi in hexane (1.309mL,2.095 mmol). The reaction mixture was stirred at-78 ℃ for 30 minutes. 4-fluoro-2-methylbenzaldehyde (245mg,1.773mmol) in THF was then added and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated NH₄Quench Cl, dilute with ice water, and extract with EtOAc. The combined organic layers were washed with brine solution and over anhydrous Na₂SO₄Dried, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using EtOAc: hexanes (2:8) as eluent. The solvent was concentrated in vacuo to give the title compound (300mg, 31.1% yield). LC-MS M/z 432(M + H) ⁺4.34 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropionic acid methyl ester

To (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) (4-fluoro-2-methylphenyl) methanol (180mg,0.417mmol) in DCM (10mL) was added ((1-methoxy-2-methylpropan-1-en-1-yl) oxy) trimethylsilane (218mg,1.251mmol) followed by TiCl₄(6mL,6.00mmol) and stirred at 0 ℃ for 30 min. The reaction mixture was washed with saturated NaHCO₃Diluted and extracted with EtOAc. The combined organic layers were washed with brine solution and over anhydrous Na₂SO₄Dried, filtered and concentrated. The crude residue was purified by flash chromatography using EtOAc: hexanes (2:8) as eluent. The solvent was concentrated in vacuo to give the title compound (150mg, 67.1% yield). LC-MSm/z 516(M + H)⁺4.83 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropionic acid

To 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f) ][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropionate (150mg,0.291mmol) in dimethyl sulfoxide (DMSO) (3mL) was added 2N NaOH (3mL,0.291mmol) and methanol (3mL), and the reaction mixture was heated at 100 ℃ for 18 hours. After completion of the reaction, the solvent was evaporated in vacuo and the residue was diluted with ice water and acidified with 1N HCl to pH 3. The resulting solid was filtered and purified by preparative HPLC to give the title compound (52mg, 35.1% yield). LC-MS M/z 502(M + H)⁺3.68 minutes (retention time).

Example 27

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, 2-formate salt

3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde

To a solution of 6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (3.33g,9.99mmol) in THF (70mL) at-78 deg.C was added butyllithium (4.80mL,11.99 mmol). In N₂The mixture was stirred at-78 ℃ for half an hour under an atmosphere, and then DMF (3.87mL,50.0mmol) was added slowly to the reaction. The resulting reaction mixture was stirred at-78 ℃ for 2 hours, followed by saturated NH ₄And (4) quenching the Cl solution. The mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Drying, filtration, evaporation and purification by flash chromatography gave the desired product 3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde (2.3g,8.15mmol, 82% yield). LC-MS M/z 305.2(M + H)⁺2.07 minutes (retention time).

(1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) methanol

At-78 ℃ under N₂To 5-bromo-1, 4-dimethyl-1H-benzo [ d ] under an atmosphere][1,2,3]To a solution of triazole (2.26g,10.00mmol) in THF (60mL) was added tert-butyllithium (9.23mL,12.00 mmol). The reaction mixture was heated at-78 ℃ under N₂After stirring for one hour under atmosphere, a solution of 3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde (2.82g,10.00mmol) in 20ml THF was slowly added to the reaction. The resulting reaction mixture was stirred at-78 ℃ for 2 hours, then slowly warmed to ambient temperature and stirred for 8 hours. The reaction mixture was washed with saturated NH₄The Cl solution was quenched and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue is purified by flash chromatography to give the desired product (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) methanol (3.2g,7.45mmol, 74.5% yield). LC-MS M/z 514.2(M + H)⁺2.24 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

In N₂Protected with (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) methanol (1g,2.328mmol) in dry acetonitrile (40mL) was slowly added DBU (7.02. mu.L, 0.047mmol) and 2,2, 2-trichloroacetonitrile (0.403g,2.79 mmol). The resulting mixture was stirred at ambient temperature for half an hour, followed by addition of ((1-methoxy-2-methylprop-1-en-1-yl) oxy) trimethylsilane (1.015g,5.82mmol) followed by trifluoro-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (0.033g,0.116 mmol). The reaction mixture was stirred at ambient temperature for 2H, then extracted three times with EtOAc (10ml) and the organic layer was washed with brine, filtered and evaporated to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d [) ][1,2,3]Methyl triazol-5-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (1.1g,2.14mmol, 92% yield). LC-MS M/z 514.2(M + H)⁺2.24 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To 3- (1, 4-dimethyl-1H-benzo [ d ] at 0 DEG C][1,2,3]To a solution of methyl triazol-5-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (5.9g,11.49mmol) in chloroform (64mL) and water (4mL) was added DDQ (2.61g,11.49 mmol). The resulting mixture was stirred at 0 ℃ for 2 h, followed by the addition of EtOAc (120mL) and NaHCO₃(70mL, saturated aqueous solution). Will be organicThe layers were separated, the aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were extracted with saturated NaHSO₃Aqueous solution and brine. Subjecting the solution to anhydrous Na₂SO₄Drying, filtering, evaporating, and purifying by flash chromatography to obtain the desired product 3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester (2.7g,6.70mmol, 97.7% yield). LC-MS M/z 394.2(M + H)⁺1.86 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, 2-formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (79mg,0.2mmol) in DCM (1.0mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, evaporated in vacuo and dissolved in acetonitrile (3 mL). To this solution was added 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepin, hydrochloride (85mg,0.400mmol), sodium iodide (14.99mg,0.100mmol) and K₂CO₃(83mg,0.600 mmol). The resulting reaction mixture was heated at 40 ℃ for 68 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated, dissolved in methanol (3mL), followed by addition of NaOH (3N) (0.533mL,1.600 mmol). The resulting reaction mixture was heated at 130 ℃ with a microwave for 1 hour. Acidifying the reaction mixture with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f) ][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropanoic acid, 2-carboxylic acid salt (21.6mg,0.034mmol, 17.12% yield). LC-MS M/z 539.5(M + H)⁺0.80 minutes (retention time).

Example 28

3- (3- (7-cyano-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

7-bromo-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepine-4 (5H) -carboxylic acid tert-butyl ester

To 7-bromo-2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] at ambient temperature][1,4]TEA (0.381mL,2.73mmol) was added to a solution of oxazepine (700mg,2.73mmol) in DCM (5 mL). Tert-butyl dicarbonate (596mg,2.73mmol) was added at 0 ℃. The reaction mixture was stirred at ambient temperature for 1 hour. It was diluted with water and extracted with ethyl acetate, over Na₂SO₄Dried, filtered and concentrated. The crude residue was purified using silica gel chromatography to give the title compound (900mg,2.444mmol, 89% yield) as a liquid. LC-MS M/z 300.13(M + H)⁺4.23 minutes (Retention time)

2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine-7-carbonitrile

To 7-bromo-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] at ambient temperature][1,4]To a solution of oxazepine-4 (5H) -carboxylic acid tert-butyl ester (300mg,0.842mmol) in N, N-dimethylformamide (5mL) was added Zn (CN)₂(99mg,0.842 mmol). The reaction mixture was degassed for 20 min, then tetrakis (triphenylphosphine) palladium (0) (97mg,0.084mmol) was added. The reaction mixture was heated at 95 ℃ for 1 hour in a microwave reactor. Will be provided withThe reaction mixture was concentrated and purified using silica gel chromatography to give the title compound (90mg,0.101mmol, 12.02% yield) as a liquid. LC-MS M/z 203.21(M + H)⁺1.22 minutes (retention time).

The compounds in Table 3 were prepared by a method similar to that for the preparation of 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine-7-carbonitrile. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 3

3- (3- (7-cyano-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazacycloheptatriene-7-carbonitrile hydrochloride (95mg,0.400mmol) in methanol (3mL) was added K ₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes and evaporated in vacuo. To the resulting residue was added acetonitrile (3mL) and stirred at ambient temperature for 10 minutes, followed by filtration to give acetonitrile solution a.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (76mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes and then evaporated in vacuo before adding acetonitrile solution A as described above, sodium iodide (14.99mg,0.100mmol) andK₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 22 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and dissolved in methanol (3 mL). NaOH (3N) (0.533mL,1.600mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. Acidifying the reaction mixture with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (3- (7-cyano-2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] ][1,2,3]Triazol-5-yl) propionic acid, formate (36.3mg,0.064mmol, 32.0% yield). LC-MS M/z 536.4(M + H)⁺0.80 minutes (retention time).

Example 29

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

5-bromo-7-iodo-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazole

Sodium periodate (0.378g,1.769mmol) was suspended in acetic acid (2mL) and Ac₂To a stirred mixture of O (2.98mL,31.5mmol) was cooled to 5-10 ℃. Very slowly adding concentrated H dropwise₂SO₄(1.792mL,33.6 mmol). Adding 5-bromo-1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazole (1g,4.42mmol) and stirring was continued at ambient temperature for 16 h. The reaction mixture was poured into a flask containing pre-dissolved Na₂SO₃In the ice water. After 15 min, the collected precipitate was washed with EtOAc and Na₂SO₃And (4) solution treatment. The crude product was then purified by Combiflash company on a silica column (40g) at 40mL/min from 100% hexane to 80%Gradient of EtOAc/hexanes over 35 min afforded the title compound (286mg, 18.34%). LC-MS M/z 351.9,353.9(M + H)⁺1.03 (retention time).

5-bromo-7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazole

To 5-bromo-7-iodo-1, 4-dimethyl-1H-benzo [ d ] at ambient temperature][1,2,3]To a solution of triazole (286mg,0.813mmol) in methanol (5mL) was added copper (I) iodide (77mg,0.406mmol) and Cs₂CO₃(530mg,1.625 mmol). The reaction mixture was stirred at 110 ℃ for 40 minutes. The solvent was evaporated under reduced pressure. The crude product was then purified by Combiflash company on a silica column (12g) eluting with a gradient of 100% hexane to 80% EtOAc/hexane at 20mL/min for 35 minutes to give the title compound (68mg, 32.7%). LC-MS M/z 256.1,258.0(M + H)⁺0.91 (retention time).

(E) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) acrylic acid ethyl ester

To 5-bromo-7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]To a solution of triazole (88mg,0.344mmol) in N, N-dimethylformamide (1mL) were added ethyl acrylate (206mg,2.062mmol), DIPEA (0.240mL,1.374mmol) and palladium (II) acetate (11.57mg,0.052 mmol). The reaction mixture was heated at microwave 110 ℃ for 1 hour. Water was added to quench the reaction. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed once with brine. The organic layer was concentrated. The crude product was then purified by Combiflash company on a silica column (40g) eluting with a gradient of 100% hexane to 80% EtOAc/hexane at 40mL/min for 35 minutes to give the title compound (90mg, 95%). LC-MS M/z 276.1(M + H) ⁺0.93 (retention time).

3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To (E) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d)][1,2,3]To a solution of methyl triazol-5-yl) acrylate (0.653g,2.50mmol) in 1, 4-dioxane (12mL) and water (4mL) was added 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol (0.976g,3.75mmol), TEA (1.045mL,7.50mmol) and [ Rh (cod) Cl]₂(0.062g,0.125 mmol). The resulting reaction mixture was stirred at 90 ℃ for 2 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the product 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (0.2238g,0.566mmol, 22.64% yield). LC-MS M/z 396.1(M + H)⁺0.92 minutes (retention time).

3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of methyl triazol-5-yl) propionate (0.158g,0.4mmol) in DCM (2mL) was added SOCl₂(0.058mL,0.800 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction was evaporated in vacuo to give the product 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ][1,2,3]Triazol-5-yl) propionic acid methyl ester (0.1959g,0.473mmol, 118% yield). LC-MS M/z 410.1(M-Cl + MeOH)⁺1.07 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepin, hydrochloride (73.6mg,0.344mmol) and K₂CO₃(127mg,0.918mmol) in acetonitrile (2mL) was added sodium iodide (17.20mg,0.115mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (95mg,0.230 mmol). The resulting solution was heated at 50 ℃ for 16 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo, then diluted with methanol (2.000mL) and NaOH (2N) (0.552mL,0.230mmol) was added. The resulting reaction mixture was heated at 80 ℃ with a microwave for 15 minutes. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f/]][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ][1,2,3]Triazol-5-yl) propionic acid, formate (51.8mg,0.096mmol, 41.7% yield). LC-MS M/z 541.4(M + H)⁺0.79 minutes (retention time).

Example 30

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt

3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (550mg,1.398mmol) in DCM (3mL) was added SOCl₂(0.306mL,4.19 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction was evaporated in vacuo to give the product 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (598.6mg,1.453mmol, 104% yield). LC-MS M/z 408.1(M-Cl + MeOH)⁺1.11 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To (R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]To a solution of oxazepine, hydrochloride salt (125mg,0.583mmol) in acetonitrile (2mL) was added K₂CO₃(215mg,1.554 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d ] ]][1,2,3]A solution of methyl triazol-5-yl) -2, 2-dimethylpropionate (160mg,0.388mmol) in acetonitrile (2 mL). The resulting solution was heated at 50 ℃ for 19 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (3 mL).

(R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Another reaction of oxazepine, hydrochloride salt (78mg,0.364mmol) in acetonitrile (2.5mL) added K₂CO₃(134mg,0.971 mmol). The resulting solution was stirred at ambient temperature for 20 minutes and sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] were added][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 16 hours, and then filtered.

The combined filtrates were evaporated in vacuo. Mixing the residuePurifying by flash chromatography to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d) ][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester (202.5mg,0.366mmol, 39% yield). LC-MS M/z 553.3(M + H)⁺0.96 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (202.5mg,0.366mmol) in methanol (5mL) was added NaOH (2N) (73.3mg,1.832 mmol). The resulting solution was heated at 120 ℃ for 5 hours with a microwave. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropanoic acid (34mg,0.063mmol, 17.23% yield). LC-MS M/z 539.5(M + H)⁺0.85 minutes (retention time).

Example 31

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt

(R) -2, 7-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene

To a solution of (R) -1-aminopropan-2-ol (0.394mL,5.00mmol) in methanol (25mL) was added 2-bromo-5-methylbenzaldehyde (995mg,5 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, followed by slow addition of NaBH₄(76mg,2.000 mmol). The resulting reaction mixture was stirred at ambient temperature for 67 hours, evaporated in vacuo, and redissolved in DCM (20mL) over MgSO₄Dried, filtered, evaporated in vacuo, and dissolved in isopropanol (20 mL). Copper (I) iodide (95mg,0.500mmol) and K were added₂CO₃(1382mg,10.00 mmol). The resulting reaction mixture was heated at 130 ℃ for 60 minutes with a microwave. The reaction mixture was evaporated in vacuo, redissolved in DCM (20mL) and over MgSO₄Drying, filtering and vacuum evaporating to obtain the product (R) -2, 7-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]Oxazepine triene (727.0mg,4.10mmol, 82% yield). LC-MS M/z 178.0(M + H)⁺0.50 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (79mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, evaporated in vacuo, dissolved in acetonitrile (2mL) and then (R) -2, 7-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ] was added][1,4]Oxazepine (70.9mg,0.400mmol), sodium iodide (14.99mg,0.100mmol) and K₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 92 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL).The combined filtrates were evaporated in vacuo and dissolved in methanol (2 mL). NaOH (3N) (0.533mL,1.600mmol) was added. The resulting reaction mixture was heated at 120 ℃ for 2 hours with a microwave. Acidifying the reaction mixture with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f) ][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt (36.8mg,0.065mmol, 32.5% yield). LC-MS M/z 539.5(M + H)⁺0.82 minutes (retention time).

Example 32

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester

To (R) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]To a solution of oxazepine, hydrochloride salt (72.7mg,0.364mmol) in acetonitrile (2.5mL) was added K₂CO₃(134mg,0.971 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d ] ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 16 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and the residue was purified by flash chromatography to give the product 3- (1, 4-dimethyl-1H-benzo [ d) ][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester (98.4mg,0.183mmol, 75% yield). LC-MS M/z 539.2(M + H)⁺0.93 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionate (98mg,0.182mmol) in methanol (3mL) was added NaOH (2N) (36.4mg,0.910 mmol). The resulting solution was heated at 120 ℃ for 7 hours with a microwave. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid (46.2mg,0.088mmol), 48.4% yield. LC-MS M/z 525.6(M + H)⁺0.78 minutes (retention time).

Example 33

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate

F₃CCOOH

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ]][1,4]To a solution of oxazepine, hydrochloride salt (86mg,0.400mmol) in methanol (3mL) was added K₂CO₃(83mg,0.600 mmol). Will be provided withThe resulting reaction mixture was stirred at ambient temperature for 50 minutes, evaporated in vacuo, followed by addition of acetonitrile (3mL) and filtration to give acetonitrile solution a.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (79mg,0.2mmol) in DCM (1.0mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 25 minutes, evaporated in vacuo and the above acetonitrile solution A, sodium iodide (14.99mg,0.100mmol) and K were added₂CO₃(83mg,0.600 mmol). The resulting reaction mixture was heated at 40 ℃ for 20 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and then redissolved in methanol (3mL) followed by the addition of NaOH (3N) (0.533mL,1.600 mmol). Heating the reaction mixture at 130 ℃ with microwaves for 1 hour, acidifying with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the desired product 3- (1, 4-dimethyl-1H-benzo [ d [) ][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate salt (56.9mg,0.105mmol, 52.7% yield). LC-MS M/z 540.4(M + H)⁺0.85 minutes (retention time).

Example 34

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (79mg,0.2mmol) in DCM (1.0mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, evaporated in vacuo and then redissolved in acetonitrile (3mL) before the addition of 2, 2-dimethyl-2,3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine (71.3mg,0.400mmol), sodium iodide (14.99mg,0.100mmol) and K₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 20 hours, followed by filtration. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and subsequently redissolved in methanol (3mL) and NaOH (3N) (0.533mL,1.600mmol) was added, followed by microwave heating at 140 ℃ for 60 min, acidification to pH 4-5 with HCl (3N), evaporation in vacuo and purification by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d [) ][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate (9.4mg,0.017mmol, 8.42% yield). LC-MS M/z 540.2(M + H)⁺0.80 minutes (retention time).

Example 35

3- (3- (8-cyano-2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine-8-carbonitrile hydrochloride (0.063g,0.264mmol) in methanol (2mL) was added K₂CO₃(0.036g,0.264 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes, evaporated in vacuo, then acetonitrile (2mL) was added and stirred at ambient temperature for 10 minutes, then filtered to give acetonitrile solution a.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (0.050g,0.132mmol) in DCM (1.0mL) was added SOCl₂(0.019mL,0.264 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, evaporated and the above acetonitrile solution A, sodium iodide (9.88mg,0.066mmol) and K were added ₂CO₃(0.036g,0.264 mmol). The resultant reaction mixture is mixed withHeated at 40 ℃ for 19 hours and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and subsequently re-dissolved in methanol (2mL) followed by addition of NaOH (3N) (0.351mL,1.054 mmol). Heating the obtained reaction mixture at 80 ℃ for 20 minutes by microwave, acidifying with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (3- (8-cyano-2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid, formate (8.5mg,0.015mmol, 11.55% yield). LC-MS M/z 536.1(M + H)⁺0.82 minutes (retention time).

Example 36

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ] ][1,4]Oxazepin, hydrochloride (73.9mg,0.344mmol) and K₂CO₃(127mg,0.918mmol) in acetonitrile (2mL) was added sodium iodide (17.20mg,0.115mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (95mg,0.230 mmol). The resulting solution was heated with a microwave at 50 ℃ for 16 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the desired product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]OxazazemCycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (41.9mg,0.075mmol, 32.9% yield). LC-MS M/z 556.2(M + H)⁺0.96 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]To a solution of methyl triazol-5-yl) propionate (41.9mg,0.075mmol) in methanol (2mL) was added NaOH (2N) (15.08mg,0.377 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (32.9mg,0.061mmol, 81% yield). LC-MS M/z 542.5(M + H)⁺0.82 minutes (retention time).

Example 37

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate salt

To (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f][1,4]To a solution of oxazepine, hydrochloride salt (86mg,0.400mmol) in methanol (3mL) was added K₂CO₃(55.3mg,0.400 mmol). Subjecting the obtained product toThe reaction mixture was stirred at ambient temperature for 30 minutes, evaporated in vacuo, followed by addition of acetonitrile (3mL) and stirring at ambient temperature for 20 minutes, followed by filtration to give acetonitrile solution a.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (79mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 10 minutes, evaporated in vacuo and the above acetonitrile solution A, sodium iodide (14.99mg,0.100mmol) and K were added ₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 20 hours, followed by filtration. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and subsequently re-dissolved in methanol (3mL) followed by addition of NaOH (3N) (0.533mL,1.600 mmol).

Heating the obtained reaction mixture at 140 ℃ for 60 minutes by microwave, then acidifying with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reversed phase HPLC to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d [)][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, formate (53.8mg,0.095mmol, 47.4% yield). LC-MS M/z 540.5(M + H)⁺0.69,0.73 minutes (retention time).

Example 38

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid, formate salt

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester

To 2,3,4, 5-tetrahydrobenzo [ f)][1,4]To a solution of oxazepine triene (54.3mg,0.364mmol) in acetonitrile (2.5mL) was added K ₂CO₃(101mg,0.728 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d ] ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 16 hours, and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and purified by flash chromatography to give the product 3- (3- (2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (71mg,0.135mmol, 55.7% yield). LC-MS M/z 525.1(M + H)⁺0.90,0.91 minutes (retention time).

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid

To 3- (3- (2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of methyl triazol-5-yl) -2, 2-dimethylpropionate (71mg,0.135mmol) in methanol (2mL) was added NaOH (2N) (27.1mg,0.677 mmol). The resulting solution was heated at 120 ℃ for 6 hours with microwave followed by acidification to pH 5 with HCl (1N), evaporation under vacuum and purification by reverse phase HPLC to give the product 3- (3- (2, 3-dihydrobenzo [ f ] f ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid (56.4mg,0.110mmol, 82% yield). LC-MS M/z 511.5(M + H)⁺0.74 minutes (retention time).

Example 39

3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (0.050g,0.122mmol) in DCM (0.60mL) was added SOCl₂(0.018mL,0.244 mmol). The resulting reaction mixture was stirred at ambient temperature for 10 minutes, evaporated in vacuo, and dissolved in acetonitrile (1.5mL) followed by addition of (R) -2, 7-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f [ -j][1,4]Oxazepinotriene (0.043g,0.244mmol), sodium iodide (9.15mg,0.061mmol) and K₂CO₃(0.034g,0.244 mmol). The resulting reaction mixture was heated at 40 ℃ for 18 hours, and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and then redissolved in methanol (1.5mL) followed by the addition of NaOH (3N) (0.204mL,0.611 mmol). Heating the resulting reaction mixture at 80 ℃ with microwaves for 20 minutes, then acidifying with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to give the product 3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f [ -f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (41.2mg,0.072mmol, 58.9% yield). LC-MS M/z 541.4(M + H)⁺0.84 minutes (retention time).

Example 40

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (100mg,0.264mmol) in DCM (0.5mL) was added thionyl chloride (0.038mL,0.527 mmol). The resulting reaction mixture was stirred at ambient temperature for 55 minutes, evaporated in vacuo, then dissolved in acetonitrile (2.5mL) followed by the addition of 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepin, hydrochloride (113mg,0.527mmol), K₂CO₃(109mg,0.791mmol), sodium iodide (7.90mg,0.053 mmol). The resulting reaction mixture was stirred at 40 ℃ for 69 hours. It was then filtered, evaporated in vacuo and NaOH (3N) was added (0.439mL,1.318 mmol). The resulting reaction mixture was heated at 80 ℃ for 20 minutes with microwaves, then acidified to pH 6 with HCl (3N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ], ][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid (76.1mg,0.149mmol, 56.6% yield). LC-MS M/z 511.5(M + H)⁺0.70 minutes (retention time).

EXAMPLE 41

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (1.688g,8mmol) in N, N-dimethylformamide (16mL) was added bis (pinacolato) diboron (3.05g,12.00mmol), KOAc (1.570g,16.00mmol) and PdCl₂(dppf) (0.293g,0.400 mmol). The resulting reaction mixture was heated at 100 ℃ for 1 hour with a microwave. Subjecting the reaction mixture to hydrogenation with H₂O (20mL) and EtOAc (40mL) were diluted, stirred and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (40mL) over MgSO₄Drying, filtration, evaporation under vacuum, and purification by flash chromatography gave the desired product 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (1.9623g,7.60mmol, 95% yield). LC-MS M/z 259.1(M + H) ⁺1.03 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (0.564g,2.3mmol) in 1, 4-dioxane (13mL) and water (4mL) were added 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (0.891g,3.45mmol), TEA (1.282mL,9.20mmol) and [ Rh (cod) Cl]₂(0.057g,0.115 mmol). The resulting reaction mixture was stirred at 90 ℃ for 1 hour. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (0.6070g,1.608mmol, 69.9% yield). LC-MS M/z 378.3(M + H)⁺0.87 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

Reacting 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Ethyl triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionate (0.800g,2.120mmol) was purified by chiral SFC to give the enantiomerically pure product 3- (1, 4-dimethyl-1H-benzo [ d [ -d)][1,2,3]Triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl ) Ethyl propionate (0.3393g,0.899mmol, 42.4% yield). LC-MS M/z 378.3(M + H)⁺0.88 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (339mg,0.898mmol) in methanol (5mL) was added NaBH₄(34.0mg,0.898 mmol). The resulting reaction mixture was stirred at ambient temperature for 140 minutes, followed by the addition of more NaBH₄(34.0mg,0.898 mmol). The resulting reaction mixture was stirred at ambient temperature for 90 minutes, followed by the addition of more NaBH₄(68.0mg,1.796 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 hour, evaporated in vacuo and purified by flash chromatography to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (0.3120g,0.822mmol, 92% yield). LC-MS M/z 380.2(M + H)⁺0.87 minutes (retention time).

3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (120mg,0.316mmol) in DCM (2mL) was added SOCl ₂(0.069mL,0.949 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 hours and evaporated in vacuo to give the product 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (125.8mg,0.316mmol, 100% yield). LC-MS M/z 394.2(M-Cl + MeOH)⁺1.01 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazacycloheptatriene, hydrochloride (101mg,0.474mmol) and K₂CO₃(175mg,1.265mmol) in acetonitrile (3mL) was added sodium iodide (23.70mg,0.158mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d ] in][1,2,3]Triazol-5-yl) propionic acid ethyl ester (125.8mg,0.316 mmol). The resulting solution was heated at 60 ℃ for 16H with microwave, evaporated in vacuo and then purified by flash chromatography to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (118.4mg,0.220mmol, 69.5% yield). LC-MS M/z 539.2(M + H) ⁺0.94 minute (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (118.4mg,0.220mmol) in methanol (3mL) was added NaOH (2N) (44.0mg,1.099 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified with HCl (1N) to pH-5, evaporated in vacuo and purified by reverse phase HPLC followed by chiral SFC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ],][1,2,3]triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxygen and nitrogenCycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (20mg,0.039mmol, 17.82% yield). LC-MS M/z 511.6(M + H)⁺0.70 minutes (retention time).

Example 42

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

(R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol

To a solution of 2-chloronicotinaldehyde (0.708g,5mmol) in methanol (10mL) was added (R) -1-aminopropan-2-ol (0.488g,6.50 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, followed by slow addition of NaBH₄(0.378g,10.00mmol) and then stirred at ambient temperature for an additional 1 hour. The reaction mixture was washed with NaHCO₃(saturated aqueous) (0.5mL) and evaporated in vacuo. The residue was diluted with DCM (50mL) over MgSO₄Drying, filtration and evaporation in vacuo gave the product (R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (1.3176g,6.57mmol, 131% yield). LC-MS M/z 200.9(M + H)⁺0.24 minutes (retention time).

(R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine

To a solution of (R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (1.2176g,6.07mmol) in N, N-dimethylformamide (60mL) was added KOtBu (2.043g,18.20 mmol). The resulting solution was heated at 80 ℃ for 4 hours,it was then evaporated under high vacuum, then diluted with DCM (50mL) and filtered. The solution was evaporated in vacuo to give the product (R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (0.7899g,4.81mmol, 79% yield). LC-MS M/z 165.0(M + H) ⁺0.16 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid methyl ester

To (R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]To a solution of oxazepine (80mg,0.486mmol) in acetonitrile (2.5mL) was added K₂CO₃(101mg,0.728 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d [ -d ] ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 23 hours and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and purified by flash chromatography to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester (73.8mg,0.137mmol, 56.3% yield). LC-MS M/z 540.2(M + H)⁺0.87 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazole-5-yl-2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoate (73mg,0.135mmol) in methanol (2.5mL) was added NaOH (2N) (27.1mg,0.676 mmol). The resulting solution was heated with microwaves at 120 ℃ for 7 hours, then acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ] b][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (51.6mg,0.098mmol, 72.6% yield). LC-MS M/z 526.6(M + H)⁺0.68 minutes (retention time).

Example 43

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To (E) -3- (7-methoxy-1-methyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (653mg,2.50mmol) in 1, 4-dioxane (12mL) and water (4mL) was added 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol (976mg,3.75mmol), TEA (1.045mL,7.50mmol) and [ Rh (cod) Cl ]₂(61.6mg,0.125 mmol). The resulting reaction mixture was stirred at 90 ℃ for 3 hours, evaporated in vacuo and purified by flash chromatography to give the product 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (334.1mg,0.845mmol, 33.8% yield). LC-MS M/z 396.1(M + H)⁺0.90 minutes (retention time).

3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d)][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (280mg,0.708mmol) in DCM (3mL) was added SOCl₂(0.103mL,1.416 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours and evaporated in vacuo to give the product 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (0.3455g,0.835mmol, 118% yield). LC-MS M/z 396.0(M-Cl + H)₂O)⁺0.95 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepin, hydrochloride (69.7mg,0.326mmol) and K₂CO₃(90mg,0.652mmol) in acetonitrile (2mL) was added sodium iodide (16.30mg,0.109mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d [ -d ] in][1,2,3]Triazol-5-yl) propionic acid ethyl ester (90mg,0.217 mmol). Heating the resulting solution with microwaves at 50 ℃ for 15 hours, evaporating under vacuum, and purifying by flash chromatography to obtain the product 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (58.1mg,0.105mmol, 48.2% yield). LC-MS M/z 555.2(M + H)⁺0.95 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (58.1mg,0.105mmol) in methanol (2mL) was added NaOH (2N) (20.95mg,0.524 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] f ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (20.86mg,0.037mmol, 35.0% yield). LC-MS M/z 527.2(M + H)⁺0.82 minutes (retention time).

Example 44

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

1- (((2-chloropyridin-3-yl) methyl) amino) -2-methylpropan-2-ol

To a solution of 2-chloronicotinaldehyde (1.132g,8mmol) in methanol (20mL) was added 1-amino-2-methylpropan-2-ol (0.927g,10.40 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Then will beNaBH₄(0.605g,16.00mmol) was added to the reaction solution in two portions and the resulting solution was stirred at ambient temperature for an additional 1 hour. The reaction mixture was washed with NaHCO₃(saturated) (0.7ml) quench then evaporate in vacuo. The residue was dissolved in DCM, over MgSO₄Drying, filtration and evaporation in vacuo gave the desired product 1- (((2-chloropyridin-3-yl) methyl) amino) -2-methylpropan-2-ol (1.8329g,8.54mmol, 107% yield). LC-MS M/z 214.9(M + H)⁺0.30 minutes (retention time).

2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine

To a solution of 1- (((2-chloropyridin-3-yl) methyl) amino) -2-methylpropan-2-ol (1.6575g,7.72mmol) in N, N-dimethylformamide (75mL) was added NaH (0.371g,15.44 mmol). The resulting solution was heated at 80 ℃ for 1 hour, concentrated, then diluted with DCM (50ml) and filtered. The solution was evaporated in vacuo to give the desired product 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (1.3823g,7.76mmol, 100% yield). LC-MSm/z 179.0(M + H)⁺0.21 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ]][1,4]To a solution of oxazepine (134mg,0.750mmol) in acetonitrile (2.5mL) was added K₂CO₃(69.1mg,0.500mmol), sodium iodide (18.74mg,0.125mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d [ -d)][1,2,3]Triazol-5-yl) propionic acid methyl ester (103mg,0.25 mmol). Subjecting the resultant solution to microwaveHeating at 60 deg.C for 3 hr, vacuum evaporating, and purifying by flash chromatography to obtain 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (43.1mg,0.078mmol, 31.0% yield). LC-MS M/z 556.2(M + H)⁺0.82 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]To a solution of methyl triazol-5-yl) propionate (43mg,0.077mmol) in methanol (1.5mL) was added NaOH (2N) (15.48mg,0.387 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (14.1mg,0.026mmol, 33.6% yield). LC-MS M/z 542.3(M + H) ⁺0.75 minutes (retention time).

Example 45

3- (3- ((R) -2-Ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

3- (3- ((R) -2-Ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To (R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]To a solution of oxazepine, hydrochloride salt (85mg,0.399mmol) in acetonitrile (2.5mL) was added K₂CO₃(147mg,1.063 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (19.92mg,0.133mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d [ -d ] ] -methyl][1,2,3]Triazol-5-yl) propionic acid methyl ester (110mg,0.266 mmol). The resulting solution was heated at 50 ℃ for 19 hours, and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and the residue was purified by flash chromatography to give the product 3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ][1,2,3]Triazol-5-yl) propionic acid methyl ester (104.7mg,0.189mmol, 71.0% yield). LC-MS M/z 555.2(M + H)⁺0.97 min (retention time).

3- (3- ((R) -2-Ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propanoic acid, formate salt

To 3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]To a solution of methyl triazol-5-yl) propionate (104mg,0.187mmol) in methanol (3mL) was added NaOH (2N) (37.5mg,0.937 mmol). The resulting solution was heated with microwave at 80 ℃ for 15 min, then acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- ((R)-2-ethyl-2, 3-dihydrobenzo [ f][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (36.8mg,0.068mmol, 36.3% yield). LC-MS M/z 541.4(M + H)⁺0.80 minutes (retention time).

Example 46

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ]][1,4]To a solution of oxazepine, hydrochloride salt (124mg,0.580mmol) in acetonitrile (2.0mL) was added K₂CO₃(214mg,1.546 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (29.0mg,0.193mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d [ -d ] ] -methyl][1,2,3]Triazol-5-yl) propionic acid ethyl ester (160mg,0.387mmol) in acetonitrile (2.0 mL). The resulting solution was heated at 50 ℃ for 14 hours with a microwave and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and the residue was purified by flash chromatography to give the desired product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (17.6mg,0.032mmol, 8.19% yield). LC-MS M/z 556.2(M + H)⁺1.02 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (25.6mg,0.046mmol) in methanol (1mL) was added NaOH (2N) (9.21mg,0.230 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (8.4mg,0.016mmol, 34.6% yield). LC-MS M/z 528.2(M + H)⁺0.84 minutes (retention time).

Example 47

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (76mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, evaporated in vacuo and dissolved in acetonitrile (2mL) followed by addition of (R) -2, 7-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f [ ][1,4]Oxazepine (70.9mg,0.400mmol), sodium iodide (14.99mg,0.100mmol) and K₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 92 hours and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and dissolved in methanol (2mL) followed by addition of NaOH (3N) (0.333mL,1.000 mmol). The resulting reaction mixture was heated at 80 ℃ with microwave for 20 min, then acidified to pH 4-5 with HCl (3N), evaporated in vacuo and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ] b][1,2,3]Triazol-5-yl) -3- (3- ((R) -2, 7-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (60.4mg,0.113mmol, 56.4% yield). LC-MS M/z 511.5(M + H)⁺0.75 minutes (retention time).

Example 48

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ]][1,4]To a solution of oxazepine triene (67.1mg,0.376mmol) in acetonitrile (3mL) was added K₂CO₃(96mg,0.691mmol), sodium iodide (25.9mg,0.173mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (137.5mg,0.346 mmol). The resulting solution was heated with microwave at 60 ℃ for 5 hours, then evaporated in vacuo and purified by flash chromatography to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-)Dihydropyrido [3,4-f ]][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (17mg,0.032mmol, 9.12% yield). LC-MS M/z 540.2(M + H)⁺0.89 minute (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (17mg,0.032mmol) in methanol (1mL) was added NaOH (2N) (6.30mg,0.158 mmol). The resulting solution was heated with microwaves at 80 ℃ for 15 minutes, then acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ] b ][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (10.5mg,0.021mmol, 65.2% yield). LC-MS M/z 512.2(M + H)⁺0.78 minutes (retention time).

Example 49

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

(S) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol

To a solution of 2-chloronicotinaldehyde (0.708g,5mmol) in methanol (10mL) was added (S) -1-aminopropan-2-ol (0.488g,6.50 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, followed by slow addition of NaBH₄(0.378g,10.00mmol) and the resulting solution stirred at ambient temperature for a further 1h, then with NaHCO₃(saturated) quench, dilution with DCM (20mL), MgSO₄Drying, filtration and evaporation in vacuo afforded the product (S) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (1.0291g,5.13mmol, 103% yield). LC-MS M/z 200.9(M + H)⁺0.19 minutes (retention time).

(S) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine

To a solution of (S) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (1.026g,5.11mmol) in N, N-dimethylformamide (50mL) was added KOtBu (1.721g,15.34 mmol). The resulting solution was heated at 80 ℃ for 4 h, evaporated under high vacuum, then diluted with DCM (50mL), filtered, and evaporated in vacuo to give the product (S) -2-methyl-2, 3,4, 5-tetrahydropyrido [3, 2-f)][1,4]Oxazepine triene (0.8617g,5.25mmol, 103% yield). LC-MS M/z 164.9(M + H)⁺0.10 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid methyl ester

To (S) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]To a solution of oxazepine (80mg,0.486mmol) in acetonitrile (2.5mL) was added K₂CO₃(101mg,0.728 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (18.19mg,0.121mmol)And 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 21 hours, and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and then purified by flash chromatography to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ] ][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester (78.9mg,0.146mmol, 60.2% yield). LC-MS M/z 540.2(M + H)⁺0.85 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionate (78mg,0.145mmol) in methanol (2.5mL) was added NaOH (2N) (28.9mg,0.723 mmol). The resulting solution was heated with microwaves at 120 ℃ for 7 hours, then acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ] b][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3- ((S) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (54mg,0.103mmol, 71.1% yield). LC-MS M/z 526.5(M + H) ⁺0.69 minutes (retention time).

Example 50

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (0.050g,0.132mmol) in DCM (0.50mL) was added SOCl₂(0.019mL,0.264 mmol). The resulting reaction mixture was stirred at ambient temperature for 15 minutes, evaporated in vacuo, dissolved in acetonitrile (1.5mL) and (R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f ] was added][1,4]Oxazacycloheptatriene, hydrochloride (0.042g,0.198mmol), sodium iodide (9.88mg,0.066mmol) and K₂CO₃(0.055g,0.395 mmol). The resulting reaction mixture was heated at 40 ℃ for 17 hours and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and dissolved in methanol (1.5mL) followed by addition of NaOH (3N) (0.220mL,0.659 mmol). Heating the resulting reaction mixture at 80 ℃ with microwaves for 20 minutes, then acidifying with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ] b][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f) ][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (22.7mg,0.042mmol, 32.0% yield) (78.7mg,0.158mmol, 67.5% yield). LC-MS M/z 511.5(M + H)⁺0.75 minutes (retention time).

Example 51

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) methyl) -4-methylphenyl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (76mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, evaporated in vacuo and then redissolved in acetonitrile (3)mL), then 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] is added][1,4]Oxazepine (71.3mg,0.400mmol), sodium iodide (14.99mg,0.100mmol) and K₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 21 hours, followed by filtration. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and dissolved in methanol (3mL) followed by addition of NaOH (3N) (0.533mL,1.600 mmol). The resulting reaction mixture was heated at 80 ℃ with microwave for 20 min, then acidified to pH 4-5 with HCl (3N), evaporated in vacuo and purified by reverse phase HPLC to give the desired product 3- (1, 4-dimethyl-1H-benzo [ d ] b ][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid (40.5mg,0.079mmol, 39.6% yield). LC-MS M/z 512.1(M + H)⁺0.72 minutes (retention time).

Example 52

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

3- (3- (2, 3-Dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid methyl ester

To 2,3,4, 5-tetrahydrobenzo [ f)][1,4]To a solution of oxazepine triene (59.5mg,0.399mmol) in acetonitrile (2.5mL) was added K₂CO₃(110mg,0.797 mmol). The resulting solution was stirred at ambient temperature for 20 minutes, followed by the addition of sodium iodide (19.92mg,0.133mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d [ -d ] ] -methyl][1,2,3]Triazol-5-yl) propionic acid methyl ester (110mg,0.266mmol). The resulting solution was heated at 50 ℃ for 19 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and the residue was purified by flash chromatography to give the product 3- (3- (2, 3-dihydrobenzo [ f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid methyl ester (50.8mg,0.096mmol, 36.3% yield). LC-MS M/z 527.3(M + H)⁺0.82 minutes (retention time).

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3- (2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]To a solution of methyl triazol-5-yl) propionate (50.8mg,0.096mmol) in methanol (2mL) was added NaOH (2N) (19.29mg,0.482 mmol). The resulting solution was heated at 80 ℃ with a microwave for 15 minutes. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the desired product 3- (3- (2, 3-dihydrobenzo [ f ] b][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (39.8mg,0.078mmol, 80% yield). LC-MS M/z 513.6(M + H)⁺0.71 minutes (retention time).

Example 53

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

6-bromo-1-chloro-2, 3-dihydro-1H-indene

To a solution of 6-bromo-2, 3-dihydro-1H-inden-1-ol (1.50g,7.04mmol) in DCM (3.5mL) was added thionyl chloride (1.028mL,14.08 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo to give the product 6-bromo-1-chloro-2, 3-dihydro-1H-indene (1.6225g,7.01mmol, 100% yield).¹H NMR (400MHz, chloroform-d) δ ppm2.33-2.44(m,1H)2.63(dq, J-14.24, 7.22Hz,1H)2.86(ddd, J-16.00, 7.97,4.14Hz,1H)3.13(dt, J-15.81, 7.65Hz,1H)5.37(dd, J-6.53, 3.51Hz,1H)7.14(d, J-8.03 Hz,1H)7.39(d, J-8.03 Hz,1H)7.57(s, 1H).

((2R) -4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

To a solution of 6-bromo-1-chloro-2, 3-dihydro-1H-indene (185mg,0.8mmol) in acetonitrile (8mL) was added (R) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f/]][1,4]Oxazepinotriene (261mg,1.600mmol), K₂CO₃(221mg,1.600mmol) and sodium iodide (23.98mg,0.160 mmol). The resulting reaction mixture was heated at 60 ℃ for 68 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the product (2R) -4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f ][1,4]Oxazepine triene (191.5mg,0.535mmol, 66.8% yield). LC-MS M/z 358.1(M + H)⁺0.77 minutes (retention time).

(2R) -2-methyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine

To (2R) -4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (190mg,0.530mmol) in N, N-dimethylformamide (3mL) were added bis (pinacolato) diboron (202mg,0.795mmol), KOAc (104mg,1.061mmol) and PdCl₂(dppf) (19.40mg,0.027 mmol). The resulting reaction mixture was heated at 100 ℃ for 1 hour with a microwave. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the product (2R) -2-methyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepine triene (164.1mg,0.405mmol, 76% yield). LC-MS M/z 406.2(M + H)⁺0.94 minute (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To (2R) -2-methyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]To a solution of oxazepine (165mg,0.408mmol) in 1, 4-dioxane (2mL) and water (0.7mL) was added (E) -3- (1, 4-dimethyl-1H-benzo [ d [, d ]][1,2,3]Triazol-5-yl) acrylic acid Ethyl ester (50mg,0.204mmol), TEA (0.085mL,0.612mmol) and [ RhCl (cod))]₂(5.03mg, 10.19. mu. mol). The resulting reaction mixture was heated at 90 ℃ for 90 minutes. The reaction mixture was evaporated in vacuo and then redissolved in methanol (2mL) followed by the addition of NaOH (3N) (0.340mL,1.019 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. Acidifying the reaction mixture with HCl (3N) to pH 3-4, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid (11.0mg,0.022mmol, 10.87% yield). LC-MS M/z 497.2(M + H)⁺0.74 minutes (Retention time)。

Example 54

3- (3- (2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid, formate salt

2,3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine triene

To a solution of 2-chloronicotinaldehyde (425mg,3mmol) in methanol (5mL) was added 2-aminoethanol (476mg,3.90 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then NaBH was added₄(227mg,6.00 mmol). The resulting solution was stirred at ambient temperature for an additional 1 hour. The reaction mixture was washed with NaHCO₃(saturated) (0.5mL) quench and evaporate. The residue was diluted with DCM (20mL) over MgSO₄Dried, filtered and then evaporated in vacuo, followed by dilution with N, N-dimethylformamide (30.00mL) and addition of KOtBu (673mg,6.00 mmol). The resulting solution was heated at 80 ℃ for 4 hours, followed by the addition of more KOtBu (337mg,3.00mmol) and then a further 3 hours at 80 ℃. The reaction mixture was filtered, and the filter cake was washed with N, N-dimethylformamide (5.00 mL). The combined filtrates were evaporated in vacuo. The residue was diluted with DCM (30mL) over MgSO₄Drying and evaporating to obtain the product 2,3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (679mg,4.52mmol, 151% yield). LC-MS M/z 150.8(M + H)⁺0.11 minutes (retention time).

2, 3-Dihydropyrido [3,2-f ] [1,4] Oxazepinotriene-4 (5H) -carboxylic acid tert-butyl ester

To a solution of di-tert-butyl dicarbonate (2.099mL,9.04mmol) in THF (5.0mL) under argon was added 2,3,4, 5-tetrahydropyrido [3,2-f][1,4]A solution of oxazepine triene (679mg,4.52mmol) in THF (5.0 mL). The resulting solution was stirred at ambient temperature for 21 hours. The reaction was then evaporated in vacuo and purified by flash chromatography to give the product 2, 3-dihydropyrido [3,2-f][1,4]Oxazepin-4 (5H) -carboxylic acid tert-butyl ester (390.8mg,1.561mmol, 34.5% yield). LC-MS M/z 250.9(M + H)⁺0.69 minutes (retention time).

2,3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine, hydrochloride

To 2, 3-dihydropyrido [3,2-f ]][1,4]To a solution of oxazepine-4 (5H) -carboxylic acid tert-butyl ester (390mg,1.558mmol) in 1, 4-dioxane (3mL) was added HCl (4M in 1, 4-dioxane) (1.169mL,4.67 mmol). The resulting solution was stirred at ambient temperature for 2 hours, then more HCl (4M in 1, 4-dioxane) was added (2.73mL,10.91 mmol). The resulting solution was stirred at ambient temperature for an additional 20 hours. The reaction solution was evaporated in vacuo to give the product 2,3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine, hydrochloride salt (290.4mg,1.556mmol, 100% yield). LC-MS M/z 150.8(M + H) ⁺0.13 minutes (retention time).

3- (3- (2, 3-Dihydropyrido [3,2-f ] [1,4] Oxazepinepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-Dimethylpropionic acid methyl ester

To 2,3,4, 5-tetrahydropyrido [3,2-f][1,4]To a solution of oxazepine, hydrochloride salt (68.0mg,0.364mmol) in acetonitrile (2.5mL) was added K₂CO₃(134mg,0.971 mmol). Placing the obtained solution in the ringStirring was carried out at ambient temperature for 20 min, followed by addition of sodium iodide (18.19mg,0.121mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] -, sodium iodide][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (100mg,0.243 mmol). The resulting solution was heated at 50 ℃ for 16 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and the residue was purified by flash chromatography to give the product 3- (3- (2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid methyl ester (64.2mg,0.122mmol, 50.3% yield). LC-MS M/z 526.2(M + H)⁺0.79 minutes (retention time).

3- (3- (2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethylpropionic acid, formate salt

To 3- (3- (2, 3-dihydropyrido [3, 2-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of methyl triazol-5-yl) -2, 2-dimethylpropionate (64mg,0.122mmol) in methanol (2.5mL) was added NaOH (2N) (24.35mg,0.609 mmol). The resulting solution was heated at 120 ℃ for 7 hours with a microwave. The reaction mixture was acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethylpropionic acid, formate (24.5mg,0.048mmol, 39.3% yield). LC-MS M/z 512.6(M + H)⁺0.66 minutes (retention time).

Example 55

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] ][1,4]Oxazepin, hydrochloride (93mg,0.435mmol) and K₂CO₃(120mg,0.870mmol) in acetonitrile (3mL) was added sodium iodide (21.73mg,0.145mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d [ -d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (120mg,0.290 mmol). The resulting solution was heated with a microwave at 50 ℃ for 19 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid ethyl ester (62.6mg,0.113mmol, 38.9% yield). LC-MS M/z 556.3(M + H)⁺0.84 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (62.6mg,0.113mmol) in methanol (2mL) was added NaOH (2N) (22.53mg,0.563mmol) . The resulting solution was heated at 80 ℃ with a microwave for 15 minutes. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-benzo [ d][1,2,3]Triazol-5-yl) propionic acid, formate (38mg,0.072mmol, 63.9% yield). LC-MS M/z 528.3(M + H)⁺0.68 minutes (retention time).

Example 56

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((S) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (40mg,0.101mmol) in acetonitrile (1mL) was added (S) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepinotriene (32.8mg,0.201mmol), K₂CO₃(27.8mg,0.201mmol) and sodium iodide (3.01mg,0.020 mmol). The resulting reaction mixture was stirred at 40 ℃ for 23 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (1 mL). The combined filtrates were evaporated in vacuo, dissolved in methanol (1.5mL) and NaOH (3N) (0.168mL,0.503mmol) was added. The resulting reaction mixture was heated at 80 ℃ with microwave for 20 min, then acidified to pH-6 with HCl (3N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (1, 4-dimethyl-1H-benzo [ d ] b ][1,2,3]Triazol-5-yl) -3- (3- ((S) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (26.5mg,0.049mmol, 48.6% yield) (40.5mg,0.079mmol, 39.6% yield). LC-MS M/z 497.2(M + H)⁺0.73 minute (retention time).

Example 57

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f][1,4]To a solution of oxazepine, hydrochloride salt (86mg,0.400mmol) in methanol (3mL) was added K₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes and evaporated in vacuo. To the resulting residue was added acetonitrile (3mL) and stirred at ambient temperature for 10 minutes, followed by filtration as acetonitrile solution a for subsequent use.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (76mg,0.2mmol) in DCM (1.000mL) was added SOCl₂(0.029mL,0.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, evaporated in vacuo and dissolved in acetonitrile (3 mL). To this solution was added the previous acetonitrile solution A, sodium iodide (14.99mg,0.100mmol) and K ₂CO₃(55.3mg,0.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 22 hours, and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were evaporated in vacuo and subsequently dissolved in methanol (3mL) followed by addition of NaOH (3N) (0.533mL,1.600 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes. Acidifying the reaction mixture with HCl (3N) to pH 4-5, evaporating under vacuum, and purifying by reverse phase HPLC to obtain the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (33.2mg,0.061mmol, 30.5% yield). LC-MS M/z 512.6(M + H)⁺0.69 minutes (retention time).

Example 58

3- (3- (2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) propionic acid, formate salt

To 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) propionic acid ethyl ester (40mg,0.101mmol) in acetonitrile (1mL) was added 2,3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepinotriene (30.0mg,0.201mmol), K₂CO₃(27.8mg,0.201mmol) and sodium iodide (7.53mg,0.050 mmol). The resulting reaction mixture was stirred at 40 ℃ for 21 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (1 mL). The combined filtrates were evaporated in vacuo, dissolved in methanol (1.5mL) and NaOH (3N) (0.168mL,0.503mmol) was added. The resulting reaction mixture was heated at 80 ℃ with microwave for 20 min, then acidified to pH-6 with HCl (3N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 3-dihydrobenzo [ f ] benzo [ f ] ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid, formate (15.0mg,0.029mmol, 28.7% yield). LC-MS M/z 483.4(M + H)⁺0.66 minutes (retention time).

Example 59

3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine triene

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ]][1,4]To a solution of oxazepine triene (0.927g,5.20mmol) in acetonitrile (40mL) was added K₂CO₃(1.382g,10.00mmol), sodium iodide (0.300g,2.000mmol) and 6-bromo-1-chloro-2, 3-dihydro-1H-indene (0.926g,4.00 mmol). The resulting solution was heated at 60 ℃ for 21H, evaporated in vacuo and purified by flash chromatography to give the desired product 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (1.159g,3.10mmol, 78% yield). LC-MS M/z 373.1(M + H)⁺0.87 minutes (retention time).

2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine triene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]To a solution of oxazepine (1.158g,3.10mmol) in N, N-dimethylformamide (10mL) were added bis (pinacolato) diboron (1.182g,4.65mmol) and PdCl₂(dppf) (0.113g,0.155mmol) and KOAc (0.609g,6.20 mmol). The resulting reaction mixture was heated at 100 ℃ for 1 hour with microwaves, evaporated in vacuo and purified by flash chromatography to give the product 2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (1.527g,3.63mmol, 117% yield). LC-MS M/z 421.2(M + H)⁺0.87 minutes (retention time).

(E) -3- (4-cyano-2-methylphenyl) acrylic acid methyl ester

To a solution of 4-bromo-3-methylbenzonitrile (0.784g,4mmol) in N, N-dimethylformamide (20mL) were added methyl acrylate (1.812mL,20.00mmol), DIPEA (1.747mL,10.00mmol), palladium (II) acetate (0.090g,0.400mmol), and tri-o-tolylphosphine (0.243g,0.800 mmol). Then mixing the reactionThe composition was microwaved at 150 ℃ under N₂Heat for 1 hour under atmosphere. The reaction mixture was evaporated in vacuo to remove residual methyl acrylate and then washed with H ₂Diluted O (20mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (50ml), over MgSO₄Drying, filtration, evaporation under vacuum and purification by flash chromatography gave the desired product methyl (E) -3- (4-cyano-2-methylphenyl) acrylate (0.8815g,4.38mmol, 110% yield).¹H-NMR (400MHz, chloroform-d) δ ppm2.47(s,3H)3.84(s,3H)6.43(d, J ═ 15.81Hz,1H)7.47-7.55(m,2H)7.61(d, J ═ 8.53Hz,1H)7.92(d, J ═ 15.81Hz, 1H).

3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester

To a solution of methyl (E) -3- (4-cyano-2-methylphenyl) acrylate (0.101g,0.5mmol) in 1, 4-dioxane (1.5mL) and water (0.5mL) was added 2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydropyrido [3, 2-f-inden-1-yl ] -2,3,4, 5-tetrahydropyrido [3,2][1,4]Oxazacycloheptatriene (0.420g,1.000mmol), TEA (0.209mL,1.500mmol), and [ Rh (cod) Cl]₂(0.012g,0.025 mmol). The resulting reaction mixture was stirred at 90 ℃ for 1 hour, evaporated in vacuo, and purified by flash chromatography to give 3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester (0.1297g,0.262mmol, 52.3% yield). LC-MS M/z 496.3(M + H)⁺0.92 minutes (retention time).

3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate salt

To 3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionate (129.7mg,0.254mmol) in methanol (3mL) was added NaOH (2N) (50.9mg,1.272 mmol). The resulting solution was heated at 80 ℃ with a microwave for 15 minutes. The reaction mixture was acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (4-cyano-2-methylphenyl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (51.5mg,0.107mmol, 42.0% yield). LC-MS M/z 482.2(M + H)⁺0.76 min (retention time).

Example 60

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid, formate salt

(E) -3- (4-fluoro-2-methylphenyl) acrylic acid methyl ester

To a solution of 1-bromo-4-fluoro-2-methylbenzene (0.756g,4mmol) in N, N-dimethylformamide (10mL) were added methyl acrylate (1.812mL,20.00mmol), DIPEA (1.747mL,10.00mmol), palladium (II) acetate (0.090g,0.400mmol), and tri-o-tolylphosphine (0.243g,0.800 mmol). The reaction mixture was heated with a microwave at 130 ℃ for 6 hours under argon atmosphere. The reaction mixture was concentrated and then diluted with EtOAc (20mL) and H₂O wash and extract with EtOAc (20ml x 3). The organic phase was concentrated and purified by flash chromatography to give the desired product methyl (E) -3- (4-fluoro-2-methylphenyl) acrylate (0.5479g,2.82mmol, 70.5% yield). LC-MS M/z 195.0(M + H)⁺1.01 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid methyl ester

To a solution of methyl (E) -3- (4-fluoro-2-methylphenyl) acrylate (104mg,0.5mmol) in 1, 4-dioxane (1.5mL) and water (0.5mL) was added 2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydropyrido [3,2-f ] and ][1,4]Oxazacycloheptatriene (420mg,1.000mmol), TEA (0.209mL,1.500mmol), and [ Rh (cod) Cl]₂(12.33mg,0.025 mmol). The resulting reaction mixture was stirred at 90 ℃ for 1 hour, evaporated in vacuo and purified by flash chromatography to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid methyl ester (52.3mg,0.104mmol, 20.81% yield). LC-MS M/z 489.4(M + H)⁺1.00 min (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f))][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propanoate (52.3mg,0.104mmol) in methanol (1.5mL) was added NaOH (2N) (20.81mg,0.520 mmol). The resulting solution was heated with microwave at 80 ℃ for 15 min, then acidified to pH 5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propane Acid, formate (34.4mg,0.072mmol, 69.7% yield). LC-MS M/z 475.2(M + H)⁺0.81 minutes (retention time).

Example 61

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

(R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol

To a solution of 2-chloronicotinaldehyde (0.708g,5mmol) in methanol (10mL) was added (R) -1-aminopropan-2-ol (0.488g,6.50 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, followed by the addition of NaBH₄(0.378g,10.00mmol) and then stirred at ambient temperature for an additional 1 hour. To the reaction mixture was added NaHCO₃(saturated) (0.5mL) and then evaporated in vacuo. The residue was diluted with DCM (50mL) over MgSO₄Drying, filtration and evaporation in vacuo gave the product (R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (1.3176g,6.57mmol, 131% yield). LC-MS M/z 200.9(M + H)⁺0.18 minutes (retention time).

(R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f ] [1,4] oxazepine

To a solution of (R) -1- (((2-chloropyridin-3-yl) methyl) amino) propan-2-ol (100mg,0.5mmol) in N, N-dimethylformamide (5mL) was added KOtBu (168mg,1.500mmol), and the resulting solution was heated with a microwave at 80 ℃ for 2 hours. The reaction mixture was then evaporated in vacuo, diluted with DCM (20mL) and filtered, then Vacuum evaporation to obtain the product (R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]Oxazepine triene (71.2mg,0.434mmol, 87% yield). LC-MS M/z 164.9(M + H)⁺0.10 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To (R) -2-methyl-2, 3,4, 5-tetrahydropyrido [3,2-f][1,4]To a solution of oxazepine triene (71.2mg,0.434mmol) in acetonitrile (3mL) was added K₂CO₃(120mg,0.867mmol), sodium iodide (13.00mg,0.087mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) propionic acid ethyl ester (173mg,0.434 mmol). Heating the resulting solution with microwaves at 60 ℃ for 2 hours, evaporating under vacuum, and purifying by flash chromatography to give the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (57mg,0.108mmol, 25.01% yield). LC-MS M/z 526.1(M + H)⁺0.77 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid, formate salt

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (57mg,0.108mmol) in methanol (1.500mL) was added NaOH (2N) (21.69mg,0.542 mmol). Heating the resultant solution with microwave at 80 deg.C for 15 minSubsequent acidification to pH 5 with HCl (1N), evaporation under vacuum, and purification by reverse phase HPLC afforded the product 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-methyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid, formate (41.6mg,0.084mmol, 77% yield). LC-MS M/z 498.2(M + H)⁺0.65 minutes (retention time).

Example 62

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) propionic acid, formate salt

2-chloro-5-fluoropyridine 1-oxide

To a solution of 2-chloro-5-fluoro-pyridine (20g,152mmol) in trifluoroacetic acid (150mL) under nitrogen at 70 ℃ was slowly added H₂O₂(78mL,760 mmol). The reaction mixture was stirred at 70 ℃ for 16 hours and concentrated. Water and DCM were added to the residue. It was adjusted to pH 7 with 28% ammonium hydroxide solution and extracted with DCM, over MgSO ₄Drying and concentration gave the title compound 2-chloro-5-fluoro-pyridine 1-oxide (20.1g,136mmol, 90% yield), which was carried on to the next step without further purification. LC-MS M/z 147.6(M + H)⁺0.78 minutes (retention time).

2-chloro-5-fluoro-4-nitropyridine 1-oxide

To 2-chloro-5-fluoro-pyridine 1-oxide (5g,33.9mol) in H under nitrogen at ambient temperature₂SO₄Potassium nitrate (13.71g,136mol) was slowly added to the solution (50mL,938 mmol). The reaction mixture was stirred at 110 ℃ for 16 hours. It was then poured into 50ml of ice/water. The solid was filtered and dried under high vacuum to give 2-chloro-5-fluoro-3-methyl-4-nitropyridine 1-oxide (5.1g,21.99mmol, 64.9% yield) as a yellow solid. LC-MS M/z 203.9(M + H)⁺1.29 minutes (retention time).

2-chloro-5- (methylamino) -4-nitropyridine 1-oxide

A mixture of 2-chloro-5-fluoro-4-nitropyridine 1-oxide (5.3g,27.5mmol) and methylamine (50mL,425mmol) was stirred at 20 ℃ for 3 hours. After evaporation of the solvent, 50mL of water was added. The solid was filtered and dried under high vacuum to give the title compound 2-chloro-5- (methylamino) -4-nitropyridine 1-oxide (5.1g,18.54mmol, 67.3% yield) as a yellow solid. LC-MS _m/z 203.9(M+H)⁺1.29 minutes (retention time).

6-chloro-N3-methylpyridine-3, 4-diamine

To a solution of 2-chloro-5- (methylamino) -4-nitropyridine 1-oxide (160mg,0.786mmol) in ethanol (10mL) was slowly added nickel (46.1mg,0.786mmol) under nitrogen at 20 ℃. It was hydrogenated at 40psi in a Parr vessel at ambient temperature for 16 hours. The mixture was filtered and the filtrate was concentrated to give the title compound 6-chloro-N3-methylpyridine-3, 4-diamine (120mg,0.647mmol, 82% yield) as a dark solid. LC-MS M/z 158.0(M + H)⁺0.68 minutes (retention time).

6-chloro-3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridines

To 6-chloro-N3-methylpyridine-3, 4-diamine (3.2g,20.30mmol) in H under nitrogen at 0 deg.C₂SO₄To a solution of (3mL,56.3mmol) in 50mL of aqueous solution was slowly added a solution of sodium nitrite (2.80g,40.6mmol) in water (30 mL). The reaction mixture was stirred at 0 ℃ for 4 hours, followed by Na₂CO₃The pH was adjusted to 8 (aqueous solution). The solid was filtered to give the title compound 6-chloro-3-methyl-3H- [1,2,3]Triazolo [4,5-c]Pyridine (3.2g,18.98mmol, 93% yield), which was carried forward without further purification. LC-MS M/z 169.0(M + H)⁺1.33 minutes (retention time).

(E) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) acrylic acid ethyl ester

Reacting 6-chloro-3-methyl-3H- [1,2,3]Triazolo [4,5-c]A mixture of pyridine (3.000g,17.80mmol), ethyl (E) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate (9.90mL,89mmol), TEA (12.40mL,89mmol), tetrakis (triphenylphosphine) palladium (0) (1.453g,1.780mmol) in N, N-dimethylformamide (50mL) was stirred at 140 ℃ for 12 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (hexane: ethyl acetate ═ 4:1) to give the title compound (E) -3- (3-methyl-3H- [1,2, 3)]Triazolo [4,5-c]Pyridin-6-yl) acrylic acid ethyl ester (710mg,2.97mmol, 16.66% yield). LC-MS M/z 233.0(M + H)⁺1.51 minutes (retention time).

3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) propionic acid ethyl ester

To (E) -3- (3-methyl-3H- [1,2, 3)]Triazolo [4,5-c]To a solution of pyridin-6-yl) acrylic acid ethyl ester (0.232g,1mmol) in 1, 4-dioxane (9mL) and water (3mL) was added 6- (4,4,5, 5-tetramethyl-1, 3, 2-bisOxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-ol (0.390g,1.500mmol), TEA (0.418mL,3.00mmol) and [ Rh (cod) Cl]₂(0.025g,0.050 mmol). The resulting reaction mixture was stirred at 90 ℃ for 3 hours, evaporated in vacuo and purified by flash chromatography to give the product 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2, 3) ]Triazolo [4,5-c]Pyridin-6-yl) propionic acid ethyl ester (0.1139g,0.311mmol, 31.1% yield). LC-MS M/z 367.0(M + H)⁺0.79 minutes (retention time).

3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) propionic acid ethyl ester

To 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2, 3)]Triazolo [4,5-c]To a solution of pyridin-6-yl) propionic acid ethyl ester (0.1139g,0.311mmol) in DCM (1.5mL) was added SOCl₂(0.045mL,0.622 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 hours and evaporated in vacuo to give the product 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3]Triazolo [4,5-c]Pyridin-6-yl) propionic acid ethyl ester (0.1349g,0.351mmol, 113% yield). LC-MS M/z381.1(M-Cl + MeOH)⁺0.95 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) propionic acid ethyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,2-f ]][1,4]To a solution of oxazepine triene (0.222g,1.247mmol) in acetonitrile (3mL) was added K₂CO₃(0.086g,0.624mmol), sodium iodide (9.35mg,0.062mmol) and 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2, 3) ]Triazolo [4,5-c]Pyridin-6-yl) propionic acid ethyl ester (0.12g,0.312 mmol). To be generatedThe solution was heated at 60 ℃ for 2 hours with microwaves. The reaction mixture was then evaporated in vacuo and purified by flash chromatography to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3]Triazolo [4,5-c]Pyridin-6-yl) propionic acid ethyl ester (0.1253g,0.238mmol, 76% yield). LC-MS M/z 527.3(M + H)⁺0.77 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,2-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl) propionic acid, formate salt

To 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f))][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3]Triazolo [4,5-c]To a solution of pyridin-6-yl) propionic acid ethyl ester (125.3mg,0.238mmol) in methanol (4mL) was added NaOH (2N) (47.6mg,1.190 mmol). The resulting solution was heated at 80 ℃ with a microwave for 15 minutes. The reaction mixture was acidified to pH-5 with HCl (1N), evaporated in vacuo and purified by reverse phase HPLC to give the product 3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 2-f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -3- (3-methyl-3H- [1,2,3]Triazolo [4,5-c]Pyridin-6-yl) propionic acid, formate (52.9mg,0.102mmol, 42.7% yield). LC-MS M/z 499.5(M + H)⁺0.57 minutes (retention time).

Example 63

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid, trifluoroacetate salt

F₃CCOOH

3- ((tert-butyldimethylsilyl) oxy) propan-1-ol

THF (200mL) was added to an argon-flushed flask containing NaH-60% dispersion in mineral oil (4.4 g). The reaction was stirred vigorously and propylene glycol (7.61g,100mmol) was added slowly at 0 ℃. The reaction was stirred at ambient temperature for 45 minutes and the initial grey suspension turned white. TBSCl (16.58g,110mmol) was then added to the flask in several batches, taking care to avoid spillage due to vigorous gas evolution. The reaction was then stirred for an additional 45 minutes. The reaction was performed with 50mL of 10% Na₂CO₃The aqueous solution was slowly quenched to form two layers. The two layers were separated and the aqueous layer was washed with Et₂And (4) extracting. The combined organics were washed with brine and over Na₂SO₄And (5) drying. After concentration under reduced pressure, the crude title compound (21g, 110% yield) was of sufficient purity. ¹H NMR (400MHz, chloroform-d) delta ppm 0.10(s,6H)0.87-0.97(m,9H)1.76-1.85(m,2H)3.79-3.94(m,4H)

3- ((tert-butyldimethylsilyl) oxy) propanal

A solution of 3- ((tert-butyldimethylsilyl) oxy) propan-1-ol (4.48mL,21.01mmol) and TEA (29.1mL,210mmol) in dimethyl sulfoxide (DMSO) (10mL) was treated with a solution of pyridine sulfur trioxide (10.03g,63.0mmol) in dimethyl sulfoxide (DMSO) (10mL) at 22 deg.C and the reaction was stirred under argon for 4 hours. The reaction was mixed with 1M HCl (1x100mL) and extracted with EtOAc (2x100 mL). The combined EtOAc was washed with water (2 × 100mL), brine (100mL), over Na₂SO₄Dried and concentrated under reduced pressure. The crude title compound (4.13g, 104% yield) was collected as a golden yellow oil, which was used without purification.¹H NMR (400MHz, chloroform-d) delta ppm0.06(br.s.,6H)0.89(s,9H)2.54-2.59(m,2H)3.94-3.99(m,2H)9.73-9.81(m, 1H).

(E) -5- ((tert-butyldimethylsilyl) oxy) pent-2-enoic acid ethyl ester

A solution of 3- ((tert-butyldimethylsilyl) oxy) propanal (2.667g,14.16mmol) in DCM (10mL) was combined with ethyl 2- (triphenylphosphine ene) acetate (5.30g,15.21mmol) and the mixture was refluxed for 22 h and then cooled to 22 ℃. After refluxing for 25 minutes, the reaction turned from golden yellow to light red. The reaction was diluted with DCM (1 × 100mL), washed with water (2 × 50mL), brine (50mL), and taken over Na ₂SO₄Dried and concentrated under reduced pressure. The crude product was purified on a silica column (40g) using flash chromatography eluting with a 0-25% EtOAc/hexanes gradient to give the title compound (1.197g, 32.7% yield) as a light yellow liquid. LC-MSm/z 259.1(M + H)⁺1.43 minutes (retention time).

(E) -5- ((methylsulfonyl) oxy) pent-2-enoic acid ethyl ester

To a solution of ethyl (E) -5- ((tert-butyldimethylsilyl) oxy) pent-2-enoate (1.391g,5.38mmol) in THF (15.00mL) under argon was added a 1M solution of TBAF in THF (5.87mL,5.87mmol) and stirred for 45 min. The solvent was concentrated and the crude residue was dissolved in DCM (15 mL). TEA (0.970mL,7.00mmol) was added and the mixture was cooled to 0 ℃. Methanesulfonyl chloride (0.583mL,7.54mmol) was added and the reaction mixture was stirred for 4 hours. Then, 0.5mL of methanesulfonyl chloride was added, and the reaction was stirred for 17 hours. Then, 2.5 ml of methanesulfonyl chloride and 3ml of TEA were added, and the reaction was stirred for 1 hour. The reaction was then diluted with DCM (60mL), washed with water (4 × 50mL), brine (25mL), and taken over Na₂SO₄Dried and concentrated under reduced pressure to give the title compound (2.168g, 65% yield), which was used without further purification. LC-MSm/z of 245.0(M + Na) ⁺0.71 minutes (retention time).

(E) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pent-2-enoic acid ethyl ester

Crude ethyl (E) -5- ((methanesulfonyl) oxy) pent-2-enoate (2.168g,9.75mmol) was dissolved in N, N-dimethylformamide (25mL) and sodium azide (0.761g,11.71mmol) was added and the reaction mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was allowed to cool to ambient temperature. Water (25.00mL) was added to the reaction mixture, and the mixture was placed under a nitrogen atmosphere. To the stirred reaction mixture was added copper (II) sulfate (1.401g,8.78mmol), pentyne (1.346mL,13.66mmol), and sodium ascorbate (1.739g,8.78 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc was added and the reaction was filtered through a disposable frit to remove salts. The crude mixture was purified using reverse phase preparative HPLC to give the title compound (120mg, 5.18% yield) as a light yellow liquid. LC-MS M/z 238.0(M + H)⁺,260.1(M+Na)⁺0.78 (retention time).

2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ] [1,4] oxazepine heptatriene

To 4- (6-bromo-2, 3-dihydro-1H-inden-1-yl) -2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f ][1,4]To a solution of oxazepine (3.5g,9.40mmol) in 1, 4-dioxane (35mL) was added bis (pinacolato) diboron (2.86g,11.28mmol) and potassium acetate (1.845g,18.80 mmol). The reaction mixture was degassed with argon for 10 min, then PdCl was added₂(dppf)-CH₂Cl₂(0.384g,0.470mmol) and heated at 90 ℃ for 16 hours. The reaction mixture was filtered through celite and washed with EtOAc (2 × 100 ml). The filtrate was concentrated under reduced pressure, followed by purification by flash chromatography to give 2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan)Pentan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepine triene (2.52g,5.98mmol, 63.6% yield). LC-MSm/z420.3(M + H)⁺4.80 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid ethyl ester

To a solution of ethyl (E) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pent-2-enoate (35mg,0.147mmol) in 1, 4-dioxane (2mL) and water (1.000mL) was added 2, 2-dimethyl-4- (6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) -2,3,4, 5-tetrahydrobenzo [ f ][1,4]Oxazepine heptatriene (93mg,0.221mmol), (1, 5-cyclooctadiene) rhodium (I) chloride dimer (3.86mg, 7.83. mu. mol), and TEA (0.020mL,0.147 mmol). A stream of Ar gas was passed through the mixture for about 5 minutes, and then the reaction was heated at 90 ℃ for 2.5 hours under Ar. The mixture was slowly cooled to 23 ℃ over 16 hours. The residue was combined with EtOAc (5mL) and water (5 mL). The aqueous layer was extracted again with EtOAc (10mL) and the combined EtOAc layers were concentrated. The crude product was purified on reverse phase preparative HPLC to give the title compound (12mg, 15.33% yield) as a dark orange oil. LC-MS M/z 531.4(M + H)⁺0.95 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid, trifluoroacetate salt

F₃CCOOH

Reacting 3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid ethyl ester (22mg,0.041mmol) was dissolved in THF (1.4mL) and lithium hydroxide (2.98mg, 0.041mmol) was added124mmol) of water (1.400 mL). Methanol (0.5mL) was added and the reaction was stirred at 23 ℃ for 16 h. The solvent was then concentrated and the crude product was purified on reverse phase preparative HPLC to give the title compound (31mg, 121% yield). LC-MS M/z 503.3(M + H) ⁺0.91 (retention time).

Example 64

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (2-ethyl-2H-tetrazol-5-yl) -2, 2-dimethylpentanoic acid, trifluoroacetate salt

F₃CCOOH

6-bromo-2, 3-dihydro-1H-inden-1-ol

NaBH4(1.344g,35.5mmol) was added in one portion to a solution of 6-bromo-2, 3-dihydro-1H-inden-1-one (5.0g,23.69mmol) in methanol (100mL) with ice-bath cooling (10 ℃). The ice bath was removed and the reaction was stirred for 3 hours. The reaction was poured into water (250mL) and extracted with EtOAc (250mL and 100 mL). The combined extracts were washed with water (100mL) and saturated aqueous NaCl (50mL) and Na₂SO₄Dried and concentrated to a small volume and the precipitate filtered off to give an off-white solid which was washed well with several batches of hexane to give the first material. The filtrate was concentrated. More precipitate formed in the filtrate, which was diluted with hexane and refiltered to give more off-white solid. The two batches were combined to give the title compound (4.15g, 82%) as an off-white solid. LC-MSm/z 194(M-OH)⁺0.84 minutes (retention time).

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene

6-bromo-2, 3-dihydro-1H-inden-1-ol (4.1g,19.24mmol) was dissolved in N, N-dimethylformamide (22mL) and the solution was cooled by an ice-water bath (10 ℃) and 60% sodium hydride (1.539g,38.5mmol) was added in one portion. The reaction bubbled and spontaneously warmed to 15 ℃. The ice bath was removed and the mixture was stirred for 1h, cooled to 10 ℃ in an ice-water bath and 1- (chloromethyl) -4-methoxybenzene (3.93mL,28.9mmol) was added. The resulting mixture was stirred at 23 ℃ for 2 hours. Excess NaH was carefully quenched by dropwise addition of water (5mL) and diluted with EtOAc (200mL) and water (75mL), the phases were shaken and separated, the water was extracted with more EtOAc (75mL) followed by saturated aqueous NaCl (25mL), dried (Na) ₂SO₄) And concentrated in vacuo to give a yellow oil. The mixture was injected neat onto a hexane equilibrated silica gel column (120g) and purified by flash chromatography eluting with a gradient of hexane to 10% EtOAc/hexane at 85 mL/min for 25 min to give the title compound (5.85g, 91%) as a clear oil.¹H NMR(400MHz,CDCl₃)δppm 2.09-2.20(m,1H)2.33-2.44(m,1H)2.71-2.82(m,1H)2.99-3.09(m,1H)3.84(s,3H)4.56(d,J＝12.0Hz,1H)4.62(d,J＝12.0Hz,1H)4.98(t,J＝5.7Hz,1H)6.93(d,J＝8.4Hz,2H)7.13(d,J＝8.0Hz,1H)7.34(d,J＝8.4Hz,2H)7.38(d,J＝8.0Hz,1H)7.52(s,1H)。

3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (5.85g,17.56mmol) was dissolved in anhydrous THF (140mL) and cooled in a dry ice acetone bath. 2M n-butyllithium (10.97mL,21.94mmol) was added and the reaction stirred with dry ice acetone for 0.5 h. DMF (6.80mL,88mmol) was added and the reaction stirred for 2 hours. The reaction is carried out with saturated NH₄Aqueous Cl (10mL), then diluted with additional water (50mL) and EtOAc (100 mL). The aqueous layer was extracted with another batch of EtOAc (50mL), and the combined EtOAc was washed with water (50mL) and saturated aqueous NaCl solution (50mL)Over Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography on a silica column (120g) eluting with a gradient of hexane to 50% EtOAc in hexane for 30 minutes at 85 mL/min. The eluted desired fractions were collected according to tlc (4:1 heptane/EtOAc) and concentrated to give 4.1g (83%) of the title compound as a light yellow clear oil. ¹H NMR(400MHz,CDCl₃)δppm 2.13-2.26(m,1H)2.36-2.49(m,1H)2.82-2.94(m,1H)3.10-3.24(m,1H)3.82(s,3H)4.58(d,J＝12.0Hz,1H)4.64(d,J＝12.0Hz,1H)5.04(dd,J＝5.6Hz,1H)6.91(d,J＝8.4Hz,2H)7.33(d,J＝8.4Hz,2H)7.40(d,J＝7.8Hz,1H)7.79(d,J＝7.8Hz,1H)7.90(s,1H)10.00(s,1H)。

(E) -methyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) acrylate

Methyl 2- (triphenylphosphine ene) acetate (5.34g,15.97mmol) and 3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde (4.1g,14.52mmol) were dissolved in DCM (105mL) and heated to reflux for 16H. The reaction was cooled to 23 ℃ and stirred for 2 days. The crude product was pre-adsorbed on isolute and purified by flash chromatography on a silica column (120g) eluting with a gradient of hexane to 30% EtOAc/hexane at 85 mL/min for 25 min. The desired fractions were combined and concentrated to yield 4.94g (101%) of the title compound. LC-MS M/z 339(M + H)⁺1.20 minutes (retention time).

3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylglutaric acid dimethyl ester

To a ice water cooled solution of methyl (E) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) acrylate (4.9g,14.48mmol), tetrabutylammonium benzoate (0.263g,0.724mmol) and THF (72mL) was added ((1-methoxy-2-methylprop-1-en-1-yl) oxy) trisMethylsilane (5.05g,29.0 mmol). The ice bath was removed and the solution was stirred for 3 hours. The reaction was concentrated and pre-adsorbed on isolute and the crude product was purified by flash chromatography on a silica column (120g) eluting with a gradient of hexane to 100% EtOAc at 85 mL/min for 30 min. The desired fractions were combined and concentrated to yield 6.4g (100%) of the title compound. LC-MS M/z 463(M + Na) ⁺1.26 minutes (retention time).

5-hydroxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

To a solution of 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylglutarate dimethyl ester (5.2639g,11.95mmol) in THF (72.4mL), water (18.10mL) and methanol (36.2mL) at 23 deg.C was added LiOH (2.86g,119 mmol). After stirring for 18 h, the reaction was diluted with DCM and washed with 1N HCl. The aqueous layer was extracted with DCM (3 ×). The combined organic layers were washed with water and saturated aqueous NaCl solution over MgSO₄Dried and concentrated in vacuo. The crude product was dissolved in THF (72.4mL) and trimethyl borate (4.01mL,35.8mmol) at 23 ℃. To this solution was added 2M BH dropwise over a period of 60 minutes₃DMS (29.9mL,59.7 mmol). After stirring for an additional 1 hour, methanol (36.2mL) was added and the reaction was stirred for an additional 1 hour. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO₃Aqueous solution, water and saturated aqueous NaCl solution. The organic layer was purified over MgSO₄Dried and concentrated in vacuo. The crude product was then purified by flash chromatography on a silica column (40g) eluting at 40mL/min with a gradient of 100% hexanes to 80% EtOAc/hexanes over 25 minutes to give 4.12g (84%) of the title compound. LC-MSm/z 435(M + Na) ⁺1.17 minutes (retention time).

5-bromo-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

Polymer-supported triphenylphosphine (2.71g,5.20mmol) and carbon tetrabromide (1.812g,5.47mmol) were added sequentially to a solution of methyl 5-hydroxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (2.1471g,5.20mmol) in DCM (26.0mL) with cooling in an ice bath. After 18 hours, the reaction was filtered through a disposable frit and the volatiles were removed in vacuo. The crude product was then pre-adsorbed on isolute and purified by flash chromatography on a silica column (24g) to give the title compound (1.5299g,3.22mmol, 61.8% yield). LC-MS M/z 497(M + Na)⁺1.50 minutes (retention time).

5-cyano-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

NaCN (0.173g,3.54mmol) was added to a solution of methyl 5-bromo-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (1.5299g,3.22mmol) in ethanol (6.03 mL)/water (2.011 mL). The reaction was warmed to 75 ℃ for 3 days. The reaction was then quenched with water and saturated NaHCO₃The aqueous solution was diluted and extracted with EtOAc. The organic layer was purified over MgSO ₄Drying and vacuum drying. The crude product was then purified on a silica column (40g) using flash chromatography to give the title compound (927.2mg, 68.4%). LC-MS M/z 444(M + Na)⁺1.26 minutes (retention time).

3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (2H-tetrazol-5-yl) pentanoic acid methyl ester

In a sealed tube, TMS-N is added₃(1.168mL,8.80mmol) and TBAF 3H₂O (398mg,1.523mmol) was added to neat methyl 5-cyano-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (917.2mg,2.176 mmol). After stirring at 23 ℃ for 45 minutes, no reaction occurred, so the reaction was heated to 130 ℃. After 4 h the reaction was cooled to 23 ℃ and the reaction mixture was dissolved in EtOAc and washed with water and saturated aqueous NaCl solution. The aqueous layer was extracted with EtOAc (3X) and the organic layer was MgSO₄Dried and concentrated in vacuo to give the title compound (1.18g, 117%). LC-MS M/z 487(M + Na)⁺1.15 minutes (retention time).

5- (2-Ethyl-2H-tetrazol-5-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

Iodothane (261. mu.L, 3.26mmol) was added to a solution of methyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (1H-tetrazol-5-yl) pentanoate (1011mg,2.176mmol) and TEA (531. mu.L, 3.81mmol) in THF (11 mL). The reaction was heated at 50 ℃ for 21 hours. The reaction was quenched by addition of water and extracted with EtOAc (3 ×). The organic layer was purified over MgSO ₄Dried and concentrated in vacuo. The crude product was then purified on a silica column (24g) using flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc at 35mL/min for 20 minutes to give the title compound (480.9mg, 44.9%). LC-MS M/z 493(M + H)⁺1.27 minutes (retention time).

5- (2-Ethyl-2H-tetrazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

To methyl 5- (2-ethyl-2H-tetrazol-5-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (480.9mg,0.976mmol) in DCM (4.768mL) and water at 23 deg.CTo the solution in (0.238mL) was added DDQ (244mg,1.074 mmol). After 40 minutes, saturated NaHCO was added₃The reaction was quenched with aqueous solution and extracted 3 times with DCM. The organic layer was purified over MgSO₄Dried and concentrated in vacuo. The crude product was then purified on a silica column (12g) using flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc at 20mL/min for 20 minutes to give the title compound (224.9mg, 61.9%). LC-MS M/z 395(M + Na)⁺1.00 min (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -5- (2-ethyl-2H-tetrazol-5-yl) -2, 2-dimethylpentanoic acid, trifluoroacetate salt

F₃CCOOH

PBr is treated at-10 DEG C₃(0.057mL,0.601mmol) was added to a solution of methyl 5- (2-ethyl-2H-tetrazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (112mg,0.301mmol) in DCM (1.203 mL). The reaction was stirred at-10 ℃ for 20 minutes. After 20 min, TLC analysis did not show any starting material and the reaction was run with saturated NaHCO₃And (4) quenching the aqueous solution. The aqueous layer was extracted with DCM (3 ×), and the organic layers were combined and washed with saturated aqueous NaCl solution. The organic layer was purified over MgSO₄Dried and concentrated in vacuo to give a clear yellow oil. The crude residue was dissolved in acetonitrile (1.203mL) and transferred to a Biotage microwave vial. 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]Oxazepine hydrochloride (77mg,0.361mmol) and DIPEA (0.158mL,0.902mmol) were added to the solution and heated in a Biotage microwave reactor at 90 ℃ for 1 hour (high absorption). Volatiles were removed in vacuo and the mixture was dissolved in methanol (0.601mL) and transferred to a Biotage microwave vial. 3M NaOH (0.501mL,1.504mmol) was added and the reaction was heated in a Biotage microwave reactor with high absorption at 120 ℃ for 3 hours. 1mL of DMSO was added and the volatiles were removed in vacuo. The DMSO solution was acidified to pH 5 with 1N HCl. Removing water under vacuum, and mixing The compound was filtered through a 0.45 micron syringe filter into a clean vial. The product was purified on a Gilson HPLC (Sunfire C18,5m 19X100mm) using 15% CH at 18mL/min₃CN/H₂O (0.1% TFA) to 55% CH₃CN/H₂Elution with a linear gradient of O (0.1% TFA) provided 18mg (10%) of the title compound. LC-MS M/z 518(M + H)⁺0.82 minutes (retention time).

Example 65

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid, trifluoroacetate salt

F₃CCOOH

3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (3.4g,10.20mmol) was dissolved in anhydrous THF (80mL) and cooled to-78 ℃ in a dry ice acetone bath. 2M n-butyllithium (6.38mL,12.75mmol) was added and the reaction was stirred at-78 ℃ for 0.5 h. DMF (3.95mL,51.0mmol) was added and the reaction stirred at-78 deg.C for 2 h. The reaction is carried out with saturated NH₄Aqueous Cl (10mL) and then diluted with additional water (50mL) and EtOAc (100 mL). The aqueous layer was extracted with another batch of EtOAc (50mL), and the combined EtOAc layers were washed with water (50mL) and saturated aqueous NaCl solution (50mL) over Na ₂SO₄Dried and concentrated in vacuo. The crude product was purified by flash chromatography on a silica column (80g) eluting with a gradient of hexane to 50% EtOAc/hexane at 65mL/min for 30 minutes to give the title compound (2.4g, 83%).¹H NMR(400MHz,CDCl₃)δppm2.13-2.26(m,1H)2.36-2.49(m,1H)2.82-2.94(m,1H)3.10-3.24(m,1H)3.82(s,3H)4.58(d,J＝12.0Hz,1H)4.64(d,J＝12.0Hz,1H)5.04(dd,J＝5.6Hz,1H)6.91(d,J＝8.4Hz,2H)7.33(d,J＝8.4Hz,2H)7.40(d,J＝7.8Hz,1H)7.79(d,J＝7.8Hz,1H)7.90(s,1H)10.00(s,1H)。

(E) Allyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) acrylate

Allyl 2- (triphenylphosphine ene) acetate (3.19g,8.84mmol) and 3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene-5-carbaldehyde (2.269g,8.04mmol) were dissolved in DCM (65mL) and heated to reflux for 23H. The crude product was pre-adsorbed on isolute and purified by flash chromatography on a silica column (80g) eluting with a gradient of hexane to 25% EtOAc/hexane at 65mL/min for 25 min to give the title compound (2.71g, 93%). LC-MS M/z 430(M + H)₂O)⁺1.17 minutes (retention time).

3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylglutaric acid 5-allyl 1-methyl ester

To a solution of allyl (E) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) acrylate (2.8128g,7.72mmol) and tetrabutylammonium benzoate (0.101g,0.278mmol) in THF (31.5mL) at 0 deg.C was added ((1-methoxy-2-methylprop-1-en-1-yl) oxy) trimethylsilane (1.882mL,9.26 mmol). After 4 h, the reaction was diluted with water, the aqueous layer was extracted with EtOAc and Na ₂SO₄Dried and concentrated to give the title compound (3.48g, 97%). LC-MS M/z 489(M + Na)⁺1.37 minutes (retention time).

5-methoxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -4, 4-dimethyl-5-oxopentanoic acid

To a solution of 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylglutaric acid 5-allyl 1-methyl ester (3.60g,7.72mmol) in THF (386mL) under argon was added 0.120g of tetrakis (triphenylphosphine) palladium (0) (0.270g,0.234 mmol). Morpholine (6.66mL,77mmol) was added dropwise thereto. After 3 days the reaction was incomplete and an additional 150mg of tetrakis (triphenylphosphine) palladium (0) was added. After 5 days, the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed twice with 1N HCl and once with water. The organic layer was purified over MgSO₄Dried and concentrated in vacuo to give the title compound (3.49g, 106%). LC-MS M/z 444(M + H)₂O)⁺449(M+Na)⁺1.15 minutes (retention time).

5-hydroxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid methyl ester

To a solution of 5-methoxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -4, 4-dimethyl-5-oxopentanoic acid (3.29g,7.72mmol) in THF (18.00mL) at 23 ℃ was added trimethyl borate (2.58mL,23.16 mmol). To this solution was added dropwise BH over a period of 60 minutes ₃DMS (19.30mL,38.6 mmol). After stirring for 1 hour, methanol (9.00mL) was added and the reaction was stirred for 1 hour. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO₃Aqueous solution, H₂And washing with saturated NaCl aqueous solution. The organic layer was purified over MgSO₄Dried and concentrated in vacuo. The crude product was then purified on a silica column (40g) using flash chromatography eluting with a gradient of 100% hexane to 50% EtOAc/hexane at 40mL/min for 25 minutes to give the title compound (1.61g, 50.6%). LC-MS M/z 430(M + H)₂O)⁺1.17 minutes (retention time).

3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- ((methanesulfonyl) oxy) pentanoic acid methyl ester

To a solution of methyl 5-hydroxy-3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (833.3mg,2.020mmol) in DCM (10.100mL) at 0 ℃ were added TEA (0.366mL,2.63mmol) and methanesulfonyl chloride (0.173mL,2.222 mmol). The reaction was slowly warmed up, diluted with DCM after 60 min, and 1N HCl, H₂And washing with saturated NaCl aqueous solution. The combined aqueous layers were extracted with DCM (3 ×). The organic layers were combined and MgSO₄Dried and loaded onto Isolute. The crude product was then purified on a silica column (12g) using flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc/hexanes at 20mL/min for 22 minutes to give the title compound (752.8mg, 76%). LC-MS M/z 513(M + Na) ⁺1.22 minutes (retention time).

3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid methyl ester

To a solution of methyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- ((methanesulfonyl) oxy) pentanoate (752.8mg,1.534mmol) in DMF (12.787mL) was added sodium azide (110mg,1.688mmol) and the reaction was heated to 60 ℃. After 2 hours, the DMF was removed in vacuo and the crude residue was dissolved in THF (12.79 mL). Pentyne (0.756mL,7.67mmol), N-ethyl-N-isopropylpropan-2-amine (0.080mL,0.460mmol) and copper (I) iodide (58.4mg,0.307mmol) were added and the reaction stirred at ambient temperature. After 18 hours, THF was removed under reduced pressure. The crude product was then purified by flash chromatography on a silica column (24g) eluting with a gradient of 100% hexanes to 100% EtOAc at 35mL/min for 20 minutes to give the title compound (259mg, 33.4%). LC-MS M/z 506(M + H)⁺1.34 minutes (retention time).

3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid methyl ester

To a solution of methyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoate (259mg,0.512mmol) in DCM (2.567mL) and water (0.128mL) was added DDQ (128mg,0.563mmol) at 23 ℃. After 45 minutes, the reaction was quenched by addition of saturated NaHCO ₃The aqueous solution was quenched and extracted with DCM. The organic layer was purified over MgSO₄Dried and reduced in volume in vacuo. The crude product was then purified on a silica column (4g) using flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc at 18mL/min for 20 minutes to give the title compound (89.5mg, 45.3%). LC-MS M/z 384(M + H)⁺0.99 minutes (retention time).

3- (3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid, trifluoroacetate salt

F₃CCOOH

PBr is treated at-10 DEG C₃(0.066mL,0.698mmol) was added to a solution of methyl 3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoate (134.5mg,0.349mmol) in DCM (1.133 mL). The reaction was stirred at-10 ℃ for 20 minutes. After 20 minutes, TLC analysis did not show any starting material and the reaction was quenched with NaHCO₃And (4) quenching. The aqueous layer was extracted with DCM (3 ×), and the organic layers were combined and washed with saturated NaCl. The organic layer was purified over MgSO₄Dried and concentrated to give a clear yellow oil, which was dissolved in acetonitrile (1.133mL) and transferred to a microwave vial. 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f) ][1,4]Oxazacycloheptatriene hydrochloride (89mg,0.419mmol) and DIPEA (0.183ml,1.047mmol) were added to the solution and heated in a microwave at 90 ℃ for 1 hour under high absorption. After 1 hour, LC-MS showed no more starting material and product formation (LC-MSm/z 545(M + H)⁺1.01 minutes (retention time)). The solvent was removed in vacuo and the mixture was dissolved in methanol (1.133mL) and transferred to a microwave vial. 3M NaOH (0.581mL,1.744mmol) was added and the reaction was heated in a microwave at 120 ℃ for 3 hours. 1mL of DMSO was added and the volatiles were removed in vacuo. The DMSO solution was acidified to pH 5 with 1N HCl. The water was removed in vacuo and the mixture was filtered through a 0.45 micron syringe filter into a clean vial. The product was purified on a Gilson HPLC (Sunfire C18,5m 19X100mm) using 20% CH at 18mL/min₃CN/H₂O (0.1% TFA) to 50% CH₃CN/H₂Elution with a linear gradient of O (0.1% TFA) gave the title compound (18mg, 10%). LC-MS M/z 531(M + H)⁺0.81 minutes (retention time).

Example 66

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid

7-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ol

To a solution of 7-bromo-3, 4-dihydronaphthalen-1 (2H) -one (2000mg,8.89mmol) in methanol (20mL) at 25 deg.C was added NaBH₄(672mg,17.77 mmol). After stirring the reaction mixture for 2 hours, the reaction was quenched by addition of 1N HCl solution and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50mL) over MgSO₄Dried and concentrated to give the title compound 7-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ol (1800 m)g,7.93mmol, 89% yield) as an oil.¹H NMR(400MHz,CDCl₃)δ＝7.58(d,J＝1.2Hz,1H),7.3-7.26(m,1H),6.97(d,J＝7.2Hz 1H),4.72(s,1H),2.74(m,2H),2.04-1.87(m,5H)。

7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-ol

To a solution of 7-bromo-1, 2,3, 4-tetrahydronaphthalen-1-ol (1000mg,4.40mmol) in 1, 4-dioxane (20mL) under nitrogen was slowly added 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan) (1342mg,5.28mmol), potassium acetate (648mg,6.61mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (180mg,0.220 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. Water (50mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over MgSO₄Dried and concentrated at 50 ℃ under a stream of nitrogen. The crude product was purified by silica gel chromatography (hexane: ethyl acetate ═ 1:1) to give the title compound 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-ol (800mg,2.92mmol, 66.3% yield) as a solid. ¹H NMR(400MHz,CDCl₃)δ＝7.87(d,J＝1.2Hz,1H),7.62(d,J＝1.2Hz,1H),7.08(d,J＝7.2Hz 1H),4.80(t,1H),2.83–2.73(m,2H),1.95–1.76(m,4H),1.34(s,12H)。

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8-hydroxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) acrylic acid ethyl ester (300mg,1.223mmol) in 1, 4-dioxane (10mL) and water (5mL) were added 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydronaphthalen-1-ol (800mg,2.92mmol) and TEA (0.341mL,2.446mmol). The reaction mixture was stirred for 10 minutes under nitrogen, followed by addition of (1, 5-cyclooctadiene) rhodium (I) chloride dimer (30.2mg,0.061 mmol). The reaction mixture was stirred at 90 ℃ for 16 hours. The reaction mixture was then extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO₄Dried and concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 1:1) to give the title compound 3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) -3- (8-hydroxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) propionic acid ethyl ester (300mg,0.762mmol, 62.3% yield) as a solid. LCMS M/z 394.2(M + H)⁺1.85 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid ethyl ester

Reacting 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]A mixture of triazol-5-yl) -3- (8-hydroxy-5, 6,7, 8-tetrahydronaphthalen-2-yl) propionic acid ethyl ester (250mg,0.635mmol), DIPEA (0.222mL,1.271mmol) in Dichloromethane (DCM) (10mL) was stirred at 0 ℃. Methanesulfonyl chloride (0.074mL,0.953mmol) was added and stirred for 2 hours. The reaction mixture was concentrated. The residue was dissolved in N, N-Dimethylformamide (DMF) (2mL) and (R) -2-methyl-2, 3,4, 5-tetrahydrobenzo [ f ] was added][1,4]Oxazepine triene (311mg,1.906 mmol). It was then stirred at 90 ℃ for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate (3 × 30mL) over MgSO₄Dried and concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 1:1) to give the title compound 3- (1, 4-dimethyl-1H-benzo [ d)][1,2,3]Triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propionic acid ethyl ester (300mg,0.557mmol, 88% yield) as an oil, which was carried on to the next step without further purification. LCMS M/z 539.2(M + H)⁺1.70 minutes (Retention time)

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propionic acid ethyl ester (200mg,0.371mol) in MeOH (2mol) was added NaOH (59.4mg,1.485mmol) and water (2.0 mL). The reaction mixture was stirred at 50 ℃ for 2 hours. The mixture was concentrated and dissolved in water (5 mL). It was then neutralized to pH 6 with 1N aqueous HCl. The residue was concentrated and subjected to reverse phase HPLC (20% MeCN/H)₂O) purification to give the title compound 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propionic acid (100mg,0.186mmol, 50.1% yield) as a solid. LCMS M/z 511.2(M + H)⁺1.5 minutes (retention time).

Example 67

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate

F₃CCOOH

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a mixture of methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (0.060g,0.152mmol) in dichloromethane (0.50mL) was added SOCl ₂(0.022mL,0.305 mmol). The resulting reaction mixture was stirred at ambient temperature for 10 minutes and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (1.5mL) and tetrahydrofuran (0.50mL), followed by the addition of 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [2,3-f ]][1,4]Oxazepin, hydrochloride (0.049g,0.229mmol), sodium iodide (0.011g,0.076mmol) and K₂CO₃(0.063g,0.457 mmol). The resulting reaction mixture was heated at 40 ℃ for 24 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were concentrated under reduced pressure. The residue was dissolved in methanol (1.5mL) followed by the addition of NaOH (3N) (0.254mL,0.762 mmol). The resulting reaction mixture was heated at 130 ℃ with microwaves for 60 minutes and then acidified with HCl (3N) (0.254mL,0.762 mmol). The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (9.3mg,0.014mmol, 9.33% yield) as a solid. LCMS M/z 540.5(M + H)⁺0.84min (retention time).

TABLE 4The compound (B) is prepared by analogy with the preparation of rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2, 3-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 4

Example 69

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f][1,4]To a mixture of oxazepine, hydrochloride salt (344mg,1.600mmol) in methanol (12mL) was added K₂CO₃(332mg,2.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 60 minutes, then filtered, concentrated, and dissolved in acetonitrile (12mL) to give an intermediate solution.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (315mg,0.8mmol) in DCM (4.0mL) was added SOCl₂(0.117mL,1.600 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, then concentrated under reduced pressure, followed by addition of the above intermediate solution, sodium iodide (60.0mg,0.400mmol) and K ₂CO₃(332mg,2.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 20 hours and then filtered. The filter cake was washed with MeCN (6 mL). The combined filtrates were concentrated under reduced pressure and purified by flash chromatography followed by reverse phase HPLC (TFA modifier) and then further purified using chiral SFC (column: Chiralpak AD 20X250mm,5 u; co-solvent: 25% EtOH; flow rate: 50 g/min; back pressure: 100Bar) to give the title compound (42.3mg,0.076mmol, 9.55% yield). LCMS M/z 554.3(M + H)⁺0.91 minute (retention time).

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

To rel- (S) -3- (1, 4-dimethylradical-1H-benzo [ d][1,2,3]Triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f)][1,4]To a mixture of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (42.3mg,0.076mmol) in methanol (1.5mL) was added NaOH (3.0N) (0.127mL,0.382 mmol). The resulting reaction mixture was heated 4 times with microwave at 120 ℃ for 1 hour, followed by acidification with HCl (3.0N) (0.127mL,0.382mmol), the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC (formic acid modifier) to give the title compound (28.6mg,0.049mmol, 63.9% yield). LCMS M/z 540.5(M + H) ⁺0.82 minutes (retention time).

TABLE 5The compound (B) is prepared by an analogous method to that for the preparation of rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 5

Example 70

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (650mg,1.652mmol) in dichloromethane (50mL) was added dess-martin oxidant (1401mg,3.30mmol) and one drop of water. The reaction mixture was stirred at 25 ℃ for 8 hours, then the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound 3- (1, 4-dimethyl-1H-benzo [ d) ][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester (570mg) as a yellow oil. LC/MS M/z 392.2(M + H)⁺1.65 (retention time).

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -2, 2-dimethyl-3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid methyl ester

Reacting 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -2, 2-dimethyl-3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propanoate (0.57g,1.456mmol) was purified by passage through chiral SFC (column: chiralpak IA 20x250mm,5 u; co-solvent: 20% EtOH; flow rate: 50 g/min; back pressure: 100Bar) to yield the title compound (177.9mg,0.454mmol, 31.2% yield). LCMS M/z 392.2(M + H)⁺0.99 minutes (retention time).

rel- (3S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -2, 2-dimethyl-3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propanoic acid methyl esterTo a solution of the ester (177mg,0.452mmol) in methanol (3.5mL) was added NaBH₄(17.11mg,0.452 mmol). The reaction was stirred at ambient temperature for 30 min, then concentrated under reduced pressure, extracted with DCM (2 × 5mL), and taken over Na ₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound (203.9mg,0.518mmol, 115% yield). LCMS M/z 394.2(M + H)⁺0.96 minutes (retention time).

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

To rel- (3S) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (100mg,0.254mmol) in dichloromethane (1.0mL) was added SOCl₂(0.037mL,0.508 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (3.0mL) and tetrahydrofuran (1.0mL), followed by the addition of 2, 2-dimethyl-2, 3,4, 5-tetrahydrobenzo [ f][1,4]Oxazepin, hydrochloride (109mg,0.508mmol), sodium iodide (19.05mg,0.127mmol) and K₂CO₃(140mg,1.017 mmol). The resulting reaction mixture was heated at 40 ℃ for 17 hours and then filtered. The filter cake was washed with MeCN (3 mL). The combined filtrates were concentrated under reduced pressure and dissolved in methanol (3.0 mL). NaOH (3N) (0.678mL,2.033mmol) was added. The resulting reaction mixture was heated twice with microwave at 130 ℃ for 1 hour, then acidified with HCl (3N) (0.678mL,2.033mmol), concentrated under reduced pressure, and purified by reverse phase HPLC to give the title compound (28.7mg,0.053mmol, 20.96% yield). LCMS M/z 539.4(M + H) ⁺0.86 minutes (retention time).

TABLE 6The compound (B) is prepared by an analogous method to that for the preparation of rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-)2, 3-dihydropyrido [3,4-f ]][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 6

Example 71

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To (E) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Ethyl triazol-5-yl) acrylate (564mg,2.3mmol) to a mixture of 1, 4-dioxane (13mL) and water (4mL) was added 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one (891mg,3.45mmol), triethylamine (1.282mL,9.20mmol) and [ Rh (cod) Cl]₂(56.7mg,0.115 mmol). The resulting reaction mixture was stirred at 90 ℃ for 17 hours, then concentrated under reduced pressure, purified by flash chromatography and then further purified by chiral SFC (column: Chiralpak AD,20X250,5 u; co-solvent: 30% reagent alcohol (90% EtOH, 5% MeOH, 5% IPA); total flow: 50 g/min; back pressure: 100bar) To give the title compound (168.0mg,0.445mmol, 19.35% yield). LCMS M/z 378.3(M + H)⁺0.88 minutes (retention time).

rel- (3R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester

To rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a solution of triazol-5-yl) -3- (3-oxo-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (168mg,0.445mmol) in methanol (3.0mL) was added NaBH₄(16.84mg,0.445 mmol). The resulting reaction was stirred at ambient temperature for 2 hours, followed by the addition of more NaBH₄(8.42mg,0.223 mmol). After 1h, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give the title compound (127.3mg,0.335mmol, 75% yield). LCMS M/z 380.3(M + H)⁺0.90 minutes (retention time).

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid ethyl ester

To (R) -2-ethyl-2, 3,4, 5-tetrahydrobenzo [ f)][1,4]To a mixture of oxazepine, hydrochloride (141mg,0.659mmol) in methanol (5.0mL) was added K₂CO₃(91mg,0.659 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (5.0mL) to give an intermediate solution.

To rel- (3R) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]To a mixture of triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (125mg,0.329mmol) in dichloromethane (1.5mL) was added SOCl₂(0.048mL,0.659 mmol). Mixing the obtained reactionThe compound was stirred at ambient temperature for 10 minutes and then concentrated under reduced pressure. The above intermediate solution, sodium iodide (24.69mg,0.165mmol), sodium and K were added₂CO₃(91mg,0.659 mmol). The resulting reaction mixture was heated at 40 ℃ for 18 hours and then filtered. The filter cake was washed with MeCN (2 mL). The combined filtrates were concentrated under reduced pressure, purified by flash chromatography, and then further purified by chiral HPLC to give the title compound (48.0mg,0.089mmol, 27.0% yield). LCMS M/z 539.5(M + H) +,0.93 min (retention time).

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid

To rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]To a solution of oxiazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid ethyl ester (48mg,0.089mmol) in methanol (2.0mL) was added NaOH (3.0N) (0.149mL,0.446 mmol). The resulting reaction mixture was heated at 80 ℃ with a microwave for 20 minutes and then acidified with HCl (3.0N) (0.149mL,0.446 mmol). The reaction mixture was concentrated under reduced pressure and extracted with DCM (3 × 2 mL). The combined organic layers were dried over MgSO ₄Drying, filtration and concentration under reduced pressure gave the title compound (42.7mg,0.084mmol, 94% yield). LCMS M/z 511.5(M + H)⁺0.80 minutes (retention time).

TABLE 7The compound (B) is prepared by an analogous method to that for the preparation of rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f)][1,4]Oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propionic acid. It will be appreciated by those skilled in the art that these similar examples may include variations in the usual reaction conditions.

TABLE 7

Example 85

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f][1,4]To a mixture of oxazepine, hydrochloride salt (344mg,1.600mmol) in methanol (12mL) was added K₂CO₃(332mg,2.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 60 minutes and filtered, the filtrate was concentrated, and the residue was dissolved in acetonitrile (12mL) to give an intermediate solution.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (315mg,0.8mmol) in dichloromethane (4.0mL) was added SOCl₂(0.117mL,1.600 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes and then concentrated. The above intermediate solution, sodium iodide (60.0mg,0.400mmol) and K were added₂CO₃(332mg,2.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 20 hours and then passedAnd (5) filtering. The filter cake was washed with MeCN (6 mL). The combined filtrates were concentrated and purified by flash chromatography followed by reverse phase HPLC (TFA modifier) and then further purified with chiral SFC (column: Chiralpak AD 20X250mm,5 u; co-solvent: 25% EtOH; flow rate: 50 g/min; back pressure: 100Bar) to give the title compound (49.1mg,0.089mmol, 11.08% yield). LC/MS: m/z 554.3(M + H)⁺0.88 minutes (retention time).

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f) ][1,4]To a solution of methyl oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (49mg,0.088mmol) in methanol (1.5mL) was added NaOH (3.0N) (0.147mL,0.442 mmol). The resulting reaction mixture was heated twice by microwave at 120 ℃ for 1 hour, then acidified with HCl (3.0N) (0.147mL,0.442mmol), concentrated, and purified by reverse phase to give the title compound (6.9mg,0.013mmol, 14.45% yield). LC/MS: m/z540.5(M + H)⁺0.76 min (retention time).

Example 86

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester

To 2, 2-dimethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ]][1,4]To a mixture of oxazepine, hydrochloride salt (0.344g,1.600mmol) in methanol (12mL) was added K₂CO₃(0.332g,2.400 mmol). The resulting reaction mixture was stirred at ambient temperature for 60 minutes and filtered. The filtrate was concentrated, and the residue was dissolved in acetonitrile (12mL) to give an intermediate solution.

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Methyl triazol-5-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionate (0.315g,0.8mmol) in dichloromethane (4.0mL) was added SOCl₂(0.117mL,1.600 mmol). The resulting reaction mixture was stirred at ambient temperature for 40 minutes, followed by addition of the above intermediate solution, sodium iodide (0.060g,0.400mmol) and K₂CO₃(0.332g,2.400 mmol). The resulting reaction mixture was heated at 40 ℃ for 67 hours. The reaction mixture was filtered. The filter cake was washed with MeCN (6 mL). The combined filtrates were concentrated and purified by reverse phase HPLC (TFA modifier) and further purified by chiral SFC (column: Chiralpak AD 20X250mm,5 u; co-solvent: 5% EtOH; flow rate: 50 g/min; back pressure: 100Bar) to give the title compound (52.9mg,0.096mmol, 11.94% yield). LC/MS: m/z 554.4(M + H)⁺0.96 minutes (retention time).

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid

To 3- (1, 4-dimethyl-1H-benzo [ d ]][1,2,3]Triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3, 4-f) ][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid methyl ester (52.9 m)g,0.096mmol) in methanol (1.2mL) NaOH (3.0N) (0.159mL,0.478mmol) was added and the reaction was heated by microwave at 130 ℃ 3 times for 1 hour. The reaction mixture was acidified with HCl (3.0N) (0.159mL,0.478mmol), concentrated, and purified by reverse phase HPLC (formic acid modifier) to give the title compound (35.8mg,0.061mmol, 64.0% yield). LC/MS: m/z 540.5(M + H)⁺0.97 min (retention time).

Example 87

5- (1-Ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene

6-bromo-2, 3-dihydro-1H-inden-1-ol (8.6g,40.4mmol) was dissolved in DMF (50mL) and cooled to 4 ℃ and 60% sodium hydride (3.23g,81mmol) was added in one portion. Stirring was carried out at 23 ℃ for 1 hour, then cooled again to-10 ℃ with ice bath and 1- (chloromethyl) -4-methoxybenzene (9.48g,60.5mmol) was added. Stirring was carried out at 23 ℃ for 14 hours. The reaction was quenched with water (25mL), stirred for 3 min, then diluted with EtOAc (200mL) and more water (25 mL). The layers were separated and the aqueous layer was extracted with additional 2X75mL EtOAc. The combined EtOAc was washed with water (75mL) and then saturated aqueous NaCl solution (50mL) and dried (Na) ₂SO₄) Concentrated and the residual amber oil was purified on an ISCO silica column (120g) using the Combiflash company eluting with a gradient of hexane to 10% EtOAc in hexane at 85mL/min for 30 minutes. The desired fractions were collected to give 6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (11.76g,35.3mmol, 87% yield) as a clear oil.¹H NMR (400MHz, chloroform-d) d 7.46-7.61(m,1H),7.23-7.44(m,3H),7.06-7.18(m,1H),6.81-7.00(m,2H),4.89-5.08(m,1H),4.38-4.74(m,2H),3.84(s,3H),2.95-3.18(m,1H),2.92-3.15(m,1H),2.65-2.89(m,1H),2.30-2.50(m,1H),2.05-2.22(m,1H)。

1- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -5- (trimethylsilyl) pent-4-yn-1-ol

6-bromo-1- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene (3.3005g,9.90mmol) was dissolved in THF (66.0ml) and cooled to-70 ℃. 1.6M butyllithium (8.05ml,12.88mmol) was added dropwise. The resulting mixture was stirred at-65 to-75 deg.C for 30 minutes, then a solution of 5- (trimethylsilyl) pent-4-ynal (2.978g,19.30mmol) in THF (3mL) (T<-65 ℃) and the mixture was stirred at-75 ℃ for 2 hours. The reaction was diluted with water and EtOAc. The phases were shaken together, the aqueous phase was extracted again with EtOAc, the combined EtOAc was washed with water and saturated aqueous NaCl and dried (MgSO 4)₄) And filtered. The filtrate was concentrated and purified on an ISCO silica column (40g) using an ISCO Combiflash company eluting with a gradient of hexane to 30% EtOAc in hexane for 20 minutes. The desired fractions were combined to give 1- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -5- (trimethylsilyl) pent-4-yn-1-ol (3.6339g,8.89mmol, 90% yield) as a yellow oil. ¹H NMR (400MHz, chloroform-d) d 7.39-7.44(m,1H),7.31-7.37(m,2H),7.15-7.30(m,2H),6.76-6.96(m,2H),4.98-5.08(m,1H),4.76-4.90(m,1H),4.53-4.68(m,2H),3.81-3.88(m,3H),3.02-3.19(m,1H),2.75-2.90(m,1H),2.26-2.47(m,3H),2.08-2.19(m,4H),0.19(s, 9H).

(5-bromo-5- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) pent-1-yn-1-yl) trimethylsilane

To 1- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-indene(iii) -5-yl) -5- (trimethylsilyl) pent-4-yn-1-ol (3.6339g,8.89mmol) in DCM (44.5ml) and polymer-bound PPh were added continuously₃(2.39mmol/g) (3.72g,8.89mmol) and carbon tetrabromide (3.54g,10.67 mmol). Stir for 3 days and add more CBr₄(2.95g,8.89 mmol). After an additional 1 hour, the reaction was concentrated and filtered and the crude product was purified on an ISCO silica column (40g) using flash chromatography eluting with a gradient of hexane to 10% EtOAc/hexane at 35mL/min for 35 minutes. The desired fractions were collected and concentrated to give (5-bromo-5- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) pent-1-yn-1-yl) trimethylsilane (1.31g,2.78mmol, 31.2% yield) as a clear oil.¹H NMR (400MHz, chloroform-d) d 7.17-7.50(m,5H),6.85-7.00(m,2H),5.10-5.21(m,1H),4.92-5.04(m,1H),4.51-4.70(m,2H),3.72-3.92(m,3H),3.01-3.17(m,1H),2.72-2.90(m,1H),2.22-2.60(m,5H),2.06-2.21(m, 1H).

Benzyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-7- (trimethylsilyl) hept-6-ynoate

A solution of diisopropylamine (4.06ml,28.5mmol) in THF (23.75ml) at-70 deg.C was treated with 1.6M n-butyllithium (8.91ml,14.25mmol) and stirred at-70 deg.C for 15 min. Benzyl isobutyrate (4.22ml,23.75mmol) was added dropwise to the-70 ℃ solution. Stir at-70 ℃ for 45 minutes, then warm to-45 ℃ for 5 minutes and cool back to-70 ℃. A solution of (5-bromo-5- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) pent-1-yn-1-yl) trimethylsilane (2.24g,4.75mmol) in THF (3mL) was added dropwise to the enolate followed by the addition of anhydrous 1, 3-dimethyltetrahydropyrimidin-2 (1H) -one (5.06mL,42.0 mmol). After stirring at-78 ℃ for 1 hour, the reaction was warmed to-45 ℃. After 2.5 hours at-45 ℃ the reaction was quenched by addition of NH₄The Cl was quenched and the aqueous layer was extracted 3 times with EtOAc. The crude oil was purified on a 24g silica column using 0-20% hexane/(3: 1EtOAc: EtOH) for 20 minutes. Second Using 0-20% Hexane/EtOAcThe column of 24g silica was chromatographed again for 20 min to give purified benzyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-7- (trimethylsilyl) hept-6-ynoate (1.2886g,2.265mmol, 47.7% yield) as a clear oil. ¹H NMR (400MHz, chloroform-d) d7.26-7.45(m,9H),7.12-7.23(m,2H),7.02-7.10(m,1H),6.85-6.96(m,2H),5.02-5.15(m,2H),4.94-5.00(m,1H),4.40-4.66(m,2H),3.74-3.95(m,3H),3.02-3.17(m,2H),2.68-2.90(m,1H),2.28-2.43(m,1H),1.76-2.21(m,5H),1.18-1.25(m,3H),1.06-1.16(m,3H),0.10-0.32(m, 9H); LC/MS (ES)⁺)[M+Na]⁺＝591.3(1.82min)

Benzyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylhept-6-ynoate

Will K₂CO₃(1.230g,8.90mmol) was added to a solution of benzyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethyl-7- (trimethylsilyl) hept-6-ynoate (1.260g,2.215mmol) in methanol (11.08 ml). After 3 hours, the reaction was diluted with water and extracted 3 times with DCM. The organic layer was purified over MgSO₄Dried and concentrated to give benzyl 3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylhept-6-ynoate (1.11g,2.235mmol, 101% yield) as a colorless oil. LC/MS (ES)⁺)[M+Na]⁺＝519.3(1.61min)。

Benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate

Sodium azide (0.363g,5.59mmol), iodoethane (0.449ml,5.59mmol), copper (I) iodide (0.064g,0.335mmol) and N-ethyl-N-isopropylpropan-2-amine (0.078ml,0.447mmol) were added to 3- (3- ((4-methoxybenzyl) salt ) Oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylhept-6-ynoic acid benzyl ester (1.11g,2.235mmol) in tert-butanol (5.6 ml)/water (5.6 ml). The mixture was heated by microwave at 70 ℃ for 1 hour, and the reaction was diluted with water and EtOAc. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were MgSO₄Dried and concentrated, and the crude oil was purified on an ISCO24g silica gel column eluting with 0-90% hexanes/EtOAc for 20 min. The desired fractions were collected to give benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (1.0147g,1.787mmol, 80% yield) as a yellow oil. LC/MS (ES)⁺)[M+H]⁺＝568.4(1.46min)。

Benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate

Ammonium cerium nitrate (1.936g,3.53mmol) was added to a solution of benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((4-methoxybenzyl) oxy) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (1.0023g,1.765mmol) in acetonitrile (7.94ml) and water (0.883 ml). After 18 hours, the mixture was washed with DCM and NaHCO₃And (6) diluting. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSO ₄Dried and concentrated. The crude oil was purified on a 24g ISCO silica column (0-100% hexanes/EtOAc) to give benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (150mg,0.335mmol, 18.98% yield). LC/MS (ES +) [ M-OH ]]+＝430.2(1.04min)。

5- (1-Ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid

Will K₂CO₃(46.3mg,0.335mmol) was added to (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f][1,4]Oxazacycloheptatriene hydrochloride (39.8mg,0.223mmol) in methanol (1 mL). The mixture was stirred for 20 minutes and the solid was filtered off. The filtrate was then concentrated under vacuum. The concentrated free base was then dissolved in acetonitrile (2.000mL) to give solution a. Adding SOCl₂(8.15. mu.l, 0.112mmol) was added to a solution of benzyl 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3-hydroxy-2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoate (50mg,0.112mmol) in DCM (1.000 mL). After 20 min, the solution was concentrated in vacuo to give the intermediate benzyl 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -2, 2-dimethylpentanoate. Acetonitrile (2.000mL) and free base (R) -2-ethyl-2, 3,4, 5-tetrahydropyrido [3,4-f ][1,4]A solution of oxazepine heptatriene (39.8mg,0.223mmol) (solution A) was added to the benzyl 3- (3-chloro-2, 3-dihydro-1H-inden-5-yl) -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -2, 2-dimethylpentanoate intermediate with K₂CO₃(46.3mg,0.335mmol) and sodium iodide (8.37mg,0.056 mmol). The mixture was warmed to 40 ℃ and the reaction was stirred for 18 h, diluted with water and the aqueous layer extracted 3 times with EtOAc. The organic layer was purified over MgSO₄Dried and concentrated. The crude residue was dissolved in 10mL MeOH, 3M NaOH (0.186mL,0.559mmol) was added, and the reaction was heated in a microwave at 100 ℃ for 5h, 1mL DMSO was added, and the volatiles were removed under reduced pressure. The DMSO solution was acidified to pH 5 with 1N HCl. Water was removed under reduced pressure and the mixture was filtered through a 0.45 micron syringe filter and purified by reverse phase preparative HPLC using neutral conditions. The resulting purified product was further purified by reverse phase preparative HPLC using formic acid as solvent modifier to give 5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3, 4-f)][1,4]Oxazacycloheptatrien-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid (4mg, 7.73. mu. mol, 6.92% yield). LC/MS (ES) ⁺)[M+H]⁺＝518.4(0.78min)。

Claims (11)

1. A compound which is:

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (3,3-3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {1- [ (4-ethylcyclohexyl) methyl ] -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid;

3- [ (3aR,8bS) -1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid;

3- [1- (decahydronaphthalen-2-ylmethyl) -2-oxo-1H, 2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- { 2-oxo-1- [ (4-propylcyclohexyl) methyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } propanoic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- [1- (2-cyclohexylacetyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-phenylpropionyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (2-methylpentanoyl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- {1- [2- (2-chlorophenyl) acetyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [2- (2-cyanophenyl) acetyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [1- (3, 3-dimethylbutyryl) -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl ] propionic acid;

3- {1- [ butyl (methyl) carbamoyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (1-ethyl-4-methyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) pentanoic acid;

3- {1- [ (tert-butoxy) carbonyl ] -1H,2H, 3aH,4H,8 bH-indeno [1,2-b ] pyrrol-7-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- [1- (cyclohexylmethyl) -2-oxo-1H, 2H, 3aH,4H,5H,9 bH-benzo [ g ] indol-8-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- [3- (cyclohexylmethyl) -2-oxo-2H, 3aH,8H,8 aH-indeno [1,2-d ] [1,3] oxazol-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- [3- (7-chloro-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,2, 7-trimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (7-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,2, 8-trimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (8-fluoro-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -2, 2-dimethylpropionic acid, formate;

3- [3- (7-cyano-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid, formate;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2R) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- [3- (8-cyano-2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid, formate;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -2, 2-dimethylpropionic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propionic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

(3S) -3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [ (3R) -3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2R) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- {3- [ (2R) -2-Ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } -3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2, 7-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- {3- [ (2S) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (7-methoxy-1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -2, 2-dimethyl-3- (3- {2H,3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (7-methoxy-1-methyl-1H-1, 2, 3-benzotriazol-5-yl) propanoic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2S) -2-methyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid, formate salt;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-ethyl-2H, 3H,4H, 5H-pyrido [3,4-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid; formic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- [3- (2,3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] propionic acid, formate salt;

3- (4-cyano-2-methylphenyl) -3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) propionic acid;

3- (1, 4-dimethyl-1H-1, 2, 3-benzotriazol-5-yl) -3- {3- [ (2R) -2-methyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl ] -2, 3-dihydro-1H-inden-5-yl } propanoic acid

3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- { 3-methyl-3H- [1,2,3] triazolo [4,5-c ] pyridin-6-yl } propanoic acid; formic acid;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid, trifluoroacetate salt;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -5- (2-ethyl-2H-1, 2,3, 4-tetrazol-5-yl) -2, 2-dimethylpentanoic acid, formate;

3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -2, 2-dimethyl-5- (4-propyl-1H-1, 2, 3-triazol-1-yl) pentanoic acid;

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (8- ((R) -2-methyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -5,6,7, 8-tetrahydronaphthalen-2-yl) propanoic acid;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (R) -3- (2, 2-dimethyl-2, 3-dihydropyrido [2,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (R) -3- (2, 2-dimethyl-2, 3-dihydropyrido [4,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rac- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rac- (S) -3- (2, 2-dimethyl-2, 3-dihydropyrido [4,3-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid, trifluoroacetate;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- (2, 2-dimethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (R) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (R) -3- ((R) -2-ethyl-2, 3-dihydrobenzo [ f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) propanoic acid;

rel- (S) -3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (rel- (S) -3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid;

3- (1, 4-dimethyl-1H-benzo [ d ] [1,2,3] triazol-5-yl) -3- (3- (2, 2-dimethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpropionic acid; or

5- (1-ethyl-1H-1, 2, 3-triazol-4-yl) -3- (3- ((R) -2-ethyl-2, 3-dihydropyrido [3,4-f ] [1,4] oxazepin-4 (5H) -yl) -2, 3-dihydro-1H-inden-5-yl) -2, 2-dimethylpentanoic acid;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

3. A compound which is 3- (3- {2, 2-dimethyl-2H, 3H,4H, 5H-pyrido [3,2-f ] [1,4] oxazepin-4-yl } -2, 3-dihydro-1H-inden-5-yl) -3- (4-fluoro-2-methylphenyl) propionic acid,

4. A pharmaceutical composition comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. A compound which is 3- [3- (2, 2-dimethyl-2, 3,4, 5-tetrahydro-1, 4-benzoxazepin-4-yl) -2, 3-dihydro-1H-inden-5-yl ] -3- (4-fluoro-2-methylphenyl) -2, 2-dimethylpropionic acid or a pharmaceutically acceptable salt thereof,

6. a pharmaceutical composition comprising a compound of claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

7. Use of a compound according to any one of claims 1, 3 and 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD, asthma, fibrosis, chronic asthma, acute asthma, a pulmonary disease secondary to environmental exposure, an acute pulmonary infection, a chronic pulmonary infection, an α 1 antitrypsin disease, cystic fibrosis, an autoimmune disease, diabetic nephropathy, chronic nephropathy, sepsis-induced acute kidney injury, Acute Kidney Injury (AKI), renal or renal insufficiency during kidney transplantation, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's Disease (PD), Alzheimer's Disease (AD), Friedreich's Ataxia (FA), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry) AMD and neovascular (wet) AMD, Eye trauma, Fuchs corneal endothelial dystrophy (FECD), uveitis or other inflammatory eye disease, nonalcoholic steatohepatitis (NASH), toxin-induced liver disease, viral hepatitis, cirrhosis, psoriasis, local effects of dermatitis/radiation, immunosuppression due to radiation exposure, preeclampsia and altitude sickness.

8. Use according to claim 7, wherein the medicament is an oral medicament.

9. Use according to claim 7, wherein the medicament is an intravenous medicament.

10. Use according to claim 7, wherein the medicament is an inhalation medicament.

11. Use of a compound according to any one of claims 1, 3 and 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.