CN108779108A - 3- (2,3- dihydro -1H- indenes -5- bases) propanoic derivatives and their purposes as NRF2 conditioning agents - Google Patents

Abstract

The present invention relates to formula (I) and formula (II) compound, wherein B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl, respectively can be by unsubstituted or replaced by 1,2 or 3 substituent group independently selected from the following：–C_1‑3Alkyl ,-O-C_1‑3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂‑OR₄And halogen；D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases or tetrazole radical；And their purposes as NRF2 conditioning agents.

Description

3- (2,3- dihydro -1H- indenes -5- bases) propanoic derivatives are adjusted with them as NRF2 The purposes of agent

Technical field

The present invention relates to aryl analog, the pharmaceutical compositions and their purposes as Nrf2 conditioning agents that contain them.

Background of invention

Nrf2 (NF-E2 correlation factors 2) is the cap and neck of the transcription factor of alkalinity containing characteristic-leucine-zipper motif A member of (cap-n-collar, CNC) family.Under basal conditions, Nrf2 levels are by cytoplasm actin combination repressor The close control of KEAP1 (Kelch- samples ECH relevant albumen 1), KEAP1 combinations Nrf2 simultaneously pass through the E3- ubiquitin based on Cul3 Multienzyme complex targeting Nrf2 is connected to degrade for ubiquitination and proteasome.Under conditions of oxidative stress, DJ1 (PARK7) quilt It activates and stablizes Nrf2 albumen by preventing Nrf2 and KEAP1 from interacting.Equally, the upper reactive cysteines of KEAP1 Modification can lead to conformation change in KEAP1, the variation change Nrf2 combine and Nrf2 promoted to stablize.Therefore, cytosol The level of middle Nrf2 is low under normal operation, but the system is designed to cope with ring rapidly by increasing Nrf2 activity It border stress.

Face continued oxidation stress when inappropriate low Nrf2 activities presents go out for chronic obstructive pulmonary disease (COPD) Potential pathomechanism.This may be Nrf2 conditioning agents and the inappropriate of positive modulators (such as DJ1) lacks and negative regulator The result that balance between the surplus of (such as Keap1 and Bach1) changes.Therefore, Nrf2 is active in COPD patient lung Recovery should can make it is described it is unbalance reparation and mitigate deleterious processes such as Constituent cell (including alveolar epithelial cells and endothelium it is thin Born of the same parents) apoptosis and inflammation.These effects are tied the result is that enhancing cytoprotection, maintenance lung structure and realization in COPD lungs Structure reparation, to slow down progression of disease.Therefore, Nrf2 conditioning agents can treat COPD (Boutten, A., et al. 2011.Trends Mol.Med.17:363-371) and other respiratory diseases, including asthma and pulmonary fibrosis (Cho, H.Y., and Kleeberger, S.R.2010.Toxicol.Appl.Pharmacol.244:43-56).

The inappropriate active example of low Nrf2 is found in the pulmonary macrophage from COPD patient.With It is compared from the similar cell of control patient, these cells have impaired bacterial phagocytosis effect, and this acts through and adds in vitro Add Nrf2 activators and is reversed.Therefore, in addition to effect above-mentioned, the active recoveries of Nrf2 appropriate can also pass through drop Low Lung infection deteriorates to save COPD.This point is proven by Nrf2 activators sulforaphane (Sulforaphane), Lay Fu sulfanes increase from the COPD macrophages for the mouse for being exposed to smoke from cigarette and having for pulmonary alveolar macrophageCollagen structure Macrophage receptor(MARCO) thus expression improves bacterial phagocytosis effect in vitro and in vivo in these cells (pseudomonas aeruginosa (Pseudomonas aeruginosa), non-H. influenzae (non-typable Haemophilus influenzae)) and bacteria clearance (Harvey, C.J., et al. 2011.Sci.Transl.Med.3: 78ra32)。

The treatment potential of Nrf2 in targeting lung is not limited to COPD.More precisely, targeting Nrf2 approach can treat other Be presented the mankind's tuberculosis and respiratory disease of oxidative stress component, for example, chronic and acute asthma, secondary to environmental exposure (packet Include but be not limited to ozone, diesel exhaust and occupational exposure) tuberculosis, fibrosis, acute pulmonary infection (for example, virus (Noah, T.L. et al. 2014.PLoS ONE 9 (6):E98671), bacterium or fungi), chronic pulmonary inflammation, alpha1 Anti-trypsin Disease and cystic fibrosis (CF, Chen, J. et al. 2008.PLoS One.2008；3(10):e3367).

Target the Nrf2 by way for the treatment of also outside lung and respiratory system have a variety of potential uses.Nrf2 activators can Many diseases that can be useful to its are autoimmune disease (psoriasis, IBD, MS), this shows that Nrf2 activators can be used generally In autoimmune disease.

Clinically, targeting Nrf2 approach drug (bardoxolone methyl, bardoxolone methyl) with Shown in the diabetic of nephrosis/chronic kidney disease (CKD) effect (Aleksunes, L.M., et al. 2010.J.Pharmacol.Exp.Ther.335:2-12), but in the patient of the most serious stage with CKD with the drug into The capable III phases, which test, to be terminated.In addition, on evidence the such treatment of guess septicemia-induction 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 the nephrosis or kidney dysfunction observed during kidney transplant in can be effective.

In heart area, currently suffers from and bardoxolone methyl is studied in the patient of pulmonary hypertension, because This drug that Nrf2 is targeted by other mechanism can be also used in the disease.Equally, it can be used in a variety of angiocardiopathies, packet Include but be not limited to atherosclerosis, hypertension and heart failure (Oxidative Medicine and Cellular Longevity Volume 2013 (2013), Article ID pages 104308,10).

Activation Nrf2 by way of drug can also be used for treating serious neurodegenerative disease including Parkinson's disease (PD), A Er Ci Haimo diseases (AD), amyotrophic lateral sclerosis (ALS) (Brain Res.2012Mar 29；1446:109- 18.2011.12.064.Epub 2012Jan 12.) and multiple sclerosis (MS).Multiple In vivo models are it was demonstrated that Nrf2KO is small Mouse is more sensitive to neurotoxic injury compared with their corresponding wild types.In cerebrum ischemia-re-perfusion model, lived with Nrf2 Agent tert-butyl hydroquinone (tBHQ) treatment rat reduces the damage of the cortex in rat, and in Nrf2 wild types rather than KO mouse In, after tBHQ is administered cortex glutathione level increase (Shih, A.Y., et al. 2005.J.Neurosci.25:10321– 10335)。Tecfidera^TM(dimethyl fumarate) (it activates other target spots, including Nrf2) is used for by U.S.'s approval Treat relapsing-remitting multiple hardening (MS).The activation of Nrf2 also helps to treat family ataxia case, In reported the sensibility of oxidative stress is increased and Nrf2 activation it is impaired (Paupe V., et al., 2009.PLoS One；4 (1):e4253)。

Have Preclinical evidence demonstrate Nrf2 approach inflammatory bowel disease (IBD, Crohn's disease and ulcerative colitis) and/ Or in model of colon cancer specific protective effect (Khor, T.O., et al., 2008.Cancer Prev.Res. (Phila) 1: 187-191)。

In the people that the age is more than 50 years old, age-dependent macular degeneration (AMD) is the common cause of blindness.Smoking right and wrong The main risk factor of neovascular (dry type) AMD development, and may be also the main danger of neovascular (wet type) AMD The dangerous factor.Support such viewpoint, i.e. Nrf2 approach that it is thin to be related to skin on the retina with the discovery in preclinical species in vitro The anti-oxidant response of born of the same parents and the adjusting of the inflammation of eye injury preclinical models (Schimel, et al., 2011.Am.J.Pathol.178:2032-2043).Fuchs endothelial dystrophy of cornea (FECD) (Fuchs Endothelial Corneal Dystrophy) it is progressive blinding disease, it is characterized in that endothelial cell apoptosis.This is A kind of disease of old people and increased oxidative stress expressed to low-level Nrf2 and/or function it is related (Bitar, M.S., et al. 2012.Invest Ophthalmol.Vis.Sci.,August 24,2012vol.53no.9 5806-5813).In addition, Nrf2 Activator can be used for uveitis or other inflammatory eye diseases.

Nonalcoholic fatty liver (NASH) is fat deposition, inflammation and the disease of damage in liver, is happened at seldom Drink or the patient of no drinking in.In preclinical models, when being excited with methionine-and the insufficient diet of choline-, lacking In the KO mouse of few Nrf2, the development of NASH greatly accelerated (Chowdhry S., et al. 2010.Free Rad.Biol.& Med.48：357-371).On the feed in the rat of the diet of the insufficient l-amino acid-restriction of choline-, administration Nrf2 activators are difficult to understand For pula and NK-252 significantly weaken the especially liver fibrosis of tissue sexual abnormality progress (Shimozono R. et al. 2012, Molecular Pharmacology.84:62-70).Other hepatopathys that Nrf2 adjustings can be complied with are the hepatopathy (example of toxin-induction Such as, the hepatopathy of paracetamol-induction), virus hepatitis and hepatic sclerosis (Oxidative Medicine and Cellular Longevity Volume 2013 (2013), Article ID pages 763257,9).

Recent research has also started to illustrate effects of the ROS in skin disease such as psoriasis.In psoriatic Carry out researches show that the increase of Serum MDA and nitric oxide final product and red blood cell-superoxide dismutase activity, The reduction of catalase activity and total antioxidation agent state, they are all related to the severity index of disease in each case (Dipali P.K., et al. Indian J Clin Biochem.2010October；25(4):388–392).Equally, Nrf2 tune Section agent can be used for treat dermatitis/radiation local action (Et al. M. 2010.Genes&Devl.24:1045- 1058), and for due to (the Kim JH et al., J.Clin.Invest.2014Feb 3 of immunosupress caused by radioactive exposure； 124(2):730-41)。

Also there is data to suggest that, Nrf2 activators can be beneficial in pre-eclampsia, and the pre-eclampsia is pregnant in 2-5% The disease occurred in crowd of being pregnent and it is related to hypertension and proteinuria (Annals of Anatomy-Anatomischer Anzeiger Volume 196, Issue in September, 5,2014, page 268-277).

Preclinical data is it has been shown that have the compound of Nrf2 activating activities in terms of the damage for reversing High aititude-induction It is more preferable than not having the active compounds of Nrf2, use acute mountain sickness animal and cell model (Lisk C. et al., 2013, Free Radic Biol Med.Oct 2013；63:264–273).

Invention content

In one aspect of the invention, provide aryl analog, pharmaceutically acceptable salt and containing they Pharmaceutical composition.

In the second aspect, the present invention provides the purposes of formula (I) and (II) compound as Nrf2 conditioning agents.

On the other hand, the present invention provides formula (I) and (II) compound and is treating and preventing and the unbalance related illnesss of Nrf2 In purposes.

In an aspect, the present invention provides pharmaceutical composition, and it includes the chemical combination according to formula (I) and (II) of the present invention Object or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.In particular it relates to for treating Nrf2 The disease of adjusting or the pharmaceutical composition of obstacle, wherein the composition includes the compound or its medicine according to formula (I) or (II) Acceptable salt and pharmaceutically acceptable excipient on.

On the other hand, the method for present invention offer treatment following breathing and non-respiratory systemic disease, including COPD, heavy breathing Asthma, fibrosis, chronic and acute asthma, the pulmonary disease secondary to environmental exposure, acute pulmonary infection, chronic lung infection, α 1 antitrypsin disease, cystic fibrosis, autoimmune disease, nephrosis, chronic kidney disease, septicemia induce Nephrosis or renal insufficiency, pulmonary hypertension, Atherosclerosis during acute kidney injury, acute kidney injury (AKI), kidney transplant Change, hypertension, heart failure, Parkinson's disease (PD), Alzheimer disease (AD), family ataxia (FA), flesh Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry type) AMD and new life It is vascular type (wet type) AMD, eye traumas, Fuchs endothelial dystrophy of cornea (FECD), uveitis or other inflammatory eye diseases, non- Alcoholic fatty liver inflammation (NASH), the hepatopathy hepatopathy of induction (such as paracetamol) of toxin-induced, virus hepatitis, Hepatic sclerosis, psoriasis, the local effect of dermatitis/radiation, due to immunosupress caused by radioactive exposure, pre-eclampsia and plateau Disease, the method includes giving the compound of people's formula (I) in need or formula (II).

On the other hand, the present invention provides the use of formula (I) and (II) compound in treatment breathing and non-respiratory systemic disease On the way, including COPD, asthma, fibrosis, chronic and acute asthma, the pulmonary disease secondary to environmental exposure, acute pulmonary infection, Chronic lung infection, alpha1 Anti-trypsin disease, cystic fibrosis, autoimmune disease, nephrosis, chronic renal Nephrosis or renal insufficiency, pulmonary artery are high during disease, the acute kidney injury of septicemia induction, acute kidney injury (AKI), kidney transplant Pressure, atherosclerosis, hypertension, heart failure, Parkinson's disease (PD), Alzheimer disease (AD), nereditary are total Ji imbalance (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, non-neovascular are (dry Type) AMD and neovascular (wet type) AMD, eye traumas, Fuchs endothelial dystrophy of cornea (FECD), uveitis or its Its inflammatory eye disease, nonalcoholic fatty liver disease (NASH), toxin-induced hepatopathy (such as paracetamol induction liver Disease), virus hepatitis, hepatic sclerosis, psoriasis, the local effect of dermatitis/radiation, due to immunosupress caused by radioactive exposure, Pre-eclampsia and altitude sickness.

On the other hand, the present invention relates to formula (I) and (II) compounds or its pharmaceutically acceptable salt to prepare for controlling Treat the purposes in the drug of following breathing and non-respiratory systemic disease, including COPD, asthma, fibrosis, chronic and acute asthma, Pulmonary disease, acute pulmonary infection, chronic lung infection, alpha1 Anti-trypsin disease, capsule fiber secondary to environmental exposure Acute kidney injury, the acute kidney injury that change, autoimmune disease, nephrosis, chronic kidney disease, septicemia induce (AKI), nephrosis or renal insufficiency, pulmonary hypertension, atherosclerosis, hypertension, heart failure, pa gold during kidney transplant It is gloomy disease (PD), Alzheimer disease (AD), family ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple Harden (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry type) AMD and neovascular (wet type) AMD, eye traumas, richness Gram this Fuch's dystrophy (FECD), uveitis or other inflammatory eye diseases, nonalcoholic fatty liver disease (NASH), poison The hepatopathy hepatopathy of induction (such as paracetamol) of element induction, virus hepatitis, hepatic sclerosis, psoriasis, dermatitis/radiation Local effect, due to immunosupress caused by radioactive exposure, pre-eclampsia and altitude sickness.

On the other hand, it the present invention relates to formula (I) and (II) compound or its pharmaceutically acceptable salt, is used to cure Learn treatment.

On the other hand, it the present invention relates to formula (I) and (II) compound or its pharmaceutically acceptable salt, is used to treat and exhale It inhales and non-respiratory systemic disease, including COPD, asthma, fibrosis, chronic and acute asthma, lung's disease secondary to environmental exposure Disease, acute pulmonary infection, chronic lung infection, alpha1 Anti-trypsin disease, cystic fibrosis, autoimmune disease, glycosuria Nephrosis or kidney function during characteristic of disease nephrosis, chronic kidney disease, the acute kidney injury of septicemia induction, acute kidney injury (AKI), kidney transplant Can not complete, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's disease (PD), Alzheimer disease (AD), Family ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, Non- neovascular (dry type) AMD and neovascular (wet type) AMD, eye traumas, Fuchs endothelial dystrophy of cornea (FECD), uveitis or other inflammatory eye diseases, nonalcoholic fatty liver disease (NASH), the hepatopathy of toxin-induced are (such as right The hepatopathy of Paracetamol induction), it is virus hepatitis, hepatic sclerosis, psoriasis, the local effect of dermatitis/radiation, sudden and violent due to radiating Immunosupress, pre-eclampsia and altitude sickness caused by dew.

On the other hand, the purposes the present invention relates to formula (I) or formula (II) compound in treating COPD.

On the other hand, the present invention relates to formulas (I) or formula (II) compound or its pharmaceutically acceptable salt to be used in preparation Treat the purposes in the drug of COPD.

On the other hand, it the present invention relates to the compound or its pharmaceutically acceptable salt of formula (I) and (II), is used to treat COPD。

On the other hand, the present invention relates to the methods for the treatment of COPD comprising formula (I) or formula (II) is administered to the people of needs Compound.

On the other hand, the present invention relates to the purposes that formula (I) or formula (II) compound are used to treat heart failure.

On the other hand, the present invention relates to treatment heart failure method, this method include to the people of needs be administered formula (I) or Formula (II) compound.

On the other hand, the present invention relates to formulas (I) or formula (II) compound or its pharmaceutically acceptable salt to be used in preparation Treat the purposes in the drug of heart failure.

On the other hand, it the present invention relates to formula (I) or formula (II) compound or its pharmaceutically acceptable salt, is used to treat Heart failure.

Formula (I) and (II) compound and its pharmaceutically acceptable salt can be used for combining with one or more other drugs, The other drugs can be used for preventing or treat such as anaphylactia, inflammatory disease, autoimmune disease；Antigen is immune to be treated Method, antihistamine, corticosteroid (for example, fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, cloth how Moral, ciclesonide, momestasone furoate, triamcinolone, flunisolide), NSAID, leukotriene modifer is (for example, montelukast, bundle Lu Site, Pranlukast), iNO inhibitor, tryptase inhibitors, IKK2 inhibitor, p38 inhibitor, Syk inhibitor, egg White enzyme inhibitor such as elastatinal, integrin antagonists (for example, Beta 2 integrin antagonist), Adenosine A2a Agonist, tramsmitter release inhibitor such as nasmil (sodium chromoglycate), 5- lipoxidase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K δ inhibitor, ITK inhibitor, LP (lysophosphatidic acid) inhibitor or FLAP (5- lipoxygenase-activating proteins) inhibitor is (for example, 3- (3- (tert. butyl-sulphenyl) -1- (4- (6- ethoxy pyridine -3- bases) benzyls Base) -5- ((5- picoline -2- bases) methoxyl group) -1H- indoles -2- bases) -2,2- neopentanoic acids sodium), bronchodilators (for example, muscarinic antagonist, β -2 agonist), methotrexate (MTX) and similar drug；Monoclonal antibody therapy is for example anti-IgE, Anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar medicine；Cell factor receptor autogenic therapy such as Yi Naxi General and similar medicine；Antigen-non-specific immunotherapy is (for example, interferon or other cell factor/chemotactic factor (CF), chemotactic factor (CF)s Receptor modulators such as CCR3, CCR4 or CXCR2 antagonist, other cell factors/chemotactic factor (CF) agonist or antagonist, TLR Agonist and similar medicine).

The compound can also be used for and the pharmaceutical composition of transplanting, including cyclosporin, tacrolimus, wheat is contributed to examine phenol Sour not ester, prednisone, imuran, sirolimus, daclizumab, basiliximab or OKT3.

They can also be used for and the pharmaceutical composition for diabetes：Melbine (biguanides), meglitinide, sulfonylureas Class, DPP-4 inhibitor, thiazolidinediones, Alpha-glucosidase inhibitor, amylin analogies, duodenin simulation Object and insulin.

The compound can be used for combining with drug for hypertension, such as the resistance of diuretics, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, ARBS, calcium channel Disconnected agent and Beta receptor blockers.

In one embodiment, the present invention relates to formula (I) or the compounds or its pharmaceutically acceptable salt of formula (II) Purposes, be used as active therapeutic agent.More specifically, the present invention provides compound as described herein for treating respiratory system The purposes of disease and non-respiratory systemic disease, specifically, disease as described herein and obstacle.Therefore, the present invention provide formula (I) or The compound or its pharmaceutically acceptable salt of formula (II) have suffering from for this needs to breathe system as active therapeutic agent in treatment Purposes in the people of disease of uniting and non-respiratory systemic disease, specifically, disease as described herein and obstacle.Specifically, of the invention The compound or its pharmaceutically acceptable salt of offer formula (I) or formula (II), as active therapeutic agent in treating COPD Purposes.

In one embodiment, it the present invention relates to compound as described herein or its pharmaceutically acceptable salt, is making The use being ready for use in treatment respiratory disease and non-respiratory systemic disease, such as the drug of disease as described herein and obstacle On the way.The present invention further provides formula (I) or the compounds or its pharmaceutically acceptable salt of formula (II), are preparing for treating Purposes in respiratory disease and non-respiratory systemic disease, such as the drug of disease as described herein and obstacle.Specifically, originally Invention further provides for the compound or its pharmaceutically acceptable salt of formula (I) or formula (II), is preparing for treating COPD's Purposes in drug.

Other aspects and advantages of the present invention in the detailed description of preferred embodiment below to further describing.

Detailed description of the invention

The present invention provides formula (I) and (II) compound：

Wherein：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂- OR₄And halogen；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases Or tetrazole radical；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group is connected to them Carbon forms cyclopropyl together；

R₄For hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base, imidazolidine and diazacyclo Heptantriene base or Tetrahydro-pyridine and oxaza heptantriene base, all these groups can be unsubstituted or by 1,2 or 3 Substituent group independently selected from the following is replaced：-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃、C_3-6Spiro cycloalkyl group And OH；

N is 1 or 2；

Or its pharmaceutically acceptable salt.

Wherein：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂- OR₄And halogen；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases Or tetrazole radical；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group is connected to them Carbon forms cyclopropyl together；

R₂For=O or hydrogen；

R₄For hydrogen or-C_1-3Alkyl；

Linker is-CH₂、-O-C(O)-、-CH₂-C(O)-、–C(O)-、-CH(CH₃)-C (O)-or-N (CH₃)-C(O)-；

A is cyclohexyl, cyclopenta, phenyl or decahydro naphthalene；All these groups can be it is unsubstituted or independently by Substituent group selected from the following is replaced：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1 or 2；

X is CH₂Or O；

Or its pharmaceutically acceptable salt.

" alkyl " refers to the hydrocarbon chain of the unit price saturation with specified carbon member atoms' number.For example, C_1-4Alkyl refers to having 1 To the alkyl of 4 carbon member atoms.Alkyl can be straight chain or branch.There are one representative branched alkyl tools, two or three A branch.Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl) and butyl (normal-butyl, isobutyl group, sec-butyl and uncle Butyl).

“C_3-6Spiro cycloalkyl group " refers to referring to Spirocyclopropyl, spiro cyclobutyl, spiro cyclopentane and loop coil hexane.

When used in this application, term ' halogen ' and ' it is halogenated ' respectively include fluorine, chlorine, bromine and iodine and fluoro, chlorine Generation, bromo and iodo.

When mentioning group, " substitution " refers to the one or more hydrogen atoms being connected with member atoms in the group It is replaced by the substituent group selected from defined substituent group.It should be understood that term " substitution " includes implicit premise item Part, i.e., the described substitution meets the chemical valence that substituted atom and the substituent group are allowed, and the substitution obtains stablizing chemical combination (that is, the compound will not spontaneously undergo conversion for example by rearrangement, cyclisation or elimination, and the compound is steady enough for object It is separated in ground reaction mixture).When mentioning group and can contain one or more substituent groups, one in the group Or multiple (optionally) member atoms can be substituted.In addition, the single member atom in the group can be by more than one substitution Base replaces, and condition is that such substitution meets the chemical valence that the atom allows.It is each taken if substituent group such as the application appropriate Generation or optional substituted group is defined.

Term refers to " independently " when more than one substituent group is selected from multiple possible substituent groups, those substituent groups can be identical Or it is different.In other words, each substituent group is respectively selected from the entire possible substituent group.

The invention also includes the various isomers and its mixture of formula (I) and (II) compound." isomers " refers to having Same composition and molecular weight but with the Bu Tong physically and/or chemically compound of property.Architectural difference may is that construction (geometry Isomers) or rotatory polarization optical plane ability (stereoisomer).Formula (I) or formula (II) compound contain one or more not Symmetrical centre (also referred to as chiral centre), and therefore can individually enantiomter, diastereoisomer or other solids are different Configuration formula or their mixture exist.All such isomeric forms are included within the scope of the invention, including they Mixture.

Chiral centre also is present in substituent group such as alkyl.When being present in formula (I) and (II) or be present in this Shen When the spatial chemistry of chiral centre in arbitrary chemical constitution that please be described does not illustrate, which is intended to arbitrary solid Isomers and its all mixtures.Therefore, contain the formula (I) of one or more chiral centres and (II) compound can be used as outer disappear Rotation mixture, the mixture rich in enantiomter or the single stereoisomer pure as corresponding isomery use.

The single stereoisomer of formula (I) and (II) compound containing one or more asymmetric centers can pass through ability Method known to field technique personnel is split.For example, such fractionation can carry out in the following way：(1) it is different to form diastereomeric Structure body salt, compound or other derivatives；(2) it is selectively reacted with stereoisomer specific reagent, such as enzymatic oxidation Reaction or reduction reaction；Or (3) in chiral environment by gas-liquid phase or liquid chromatography, for example, in chiral loaded article example It such as combines on the silica gel of chiral ligand or in the presence of chiral solvent.It is understood to one skilled in the art that when by above-mentioned When required stereoisomer is transformed into another chemical entities by one of lock out operation, it is also necessary to which form is another needed for release Step.Selectively, specific stereoisomer can be by using optically active reagent, substrate, catalyst or solvent not A kind of enantiomter is transformed into other enantiomters to synthesize by symmetrical synthesis by asymmetric transformation.

It is used in this application it is " pharmaceutically acceptable " refer to those compounds, substance, composition and dosage form, they are being closed Be suitable for contacting with the tissue of human and animal in the medical judgment scope of reason, without excessive toxicity, stimulation or other problems or Complication matches with rational interests/Hazard ratio.

Technical staff understands, can prepare the pharmaceutically acceptable salt of formula (I) and (II) compound.These pharmacy Upper acceptable salt can be prepared in situ in the final separation of the compound and purification process or respectively with alkali appropriate or acid The purified compound of its free acid or free alkali form is individually handled to prepare.

In some embodiments, formula (I) and (II) compound can contain acidic functionality and therefore can be by with suitable When alkali process form pharmaceutically acceptable base addition salts.The example of such alkali include a) sodium, potassium, lithium, calcium, magnesium, aluminium and Hydroxide, carbonate and the bicarbonate of zinc；And b) primary amine, secondary amine and tertiary amine, including aliphatic amine, aromatic amine, aliphatic Diamines and hydroxy alkyl amine such as methylamine, ethamine, 2 hydroxy ethylamine, diethylamine, triethylamine, ethylenediamine, ethanol amine, diethanol amine And cyclo-hexylamine.

In some embodiments, formula (I) and (II) compound can contain basic functionality and therefore can be by with suitable When sour processing form pharmaceutically acceptable acid-addition salts.It is appropriate sour including pharmaceutically acceptable inorganic acid and organic Acid.It is representative it is pharmaceutically acceptable acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, Phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, lemon Acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, pyrovinic acid, p-methyl benzenesulfonic acid, oleic acid, bay Acid etc..

Term " formula (I) or (II) compound " used in this application or " formula (I) or (II) compound " refer to one kind Or a variety of formulas (I) or (II) compound.The formula (I) and (II) compound may be present in solid or liquid form.In solid-state, It can be crystallized or non-crystalline forms exist or exist with their form of mixtures.It is understood to one skilled in the art that medicine Acceptable solvate can be formed by crystalline compounds on, and wherein solvent molecule combines in crystallization process in lattice. Solvate may include that nonaqueous solvents is such as, but not limited to ethyl alcohol, isopropanol, DMSO, acetic acid, ethanol amine or ethyl acetate, or They may include water as solvent, and the solvent is incorporated in lattice.It is such molten when water is the solvent being incorporated in lattice Agent closes object and is commonly referred to as " hydrate ".Hydrate includes the hydrate of stoichiometry and the composition containing variable water. The present invention includes all these solvates.

Technical staff is further appreciated that, some compounds of the existing present invention, including its various solvent in crystalline form Object is closed, can be existed with polymorphic forms (that is, the ability occurred with different crystalline textures).These different crystal forms usually quilts Referred to as " polymorph ".The present invention includes all such polymorphs.Polymorph chemical composition having the same, but Accumulation, the geometry arrangement of crystalline solid state are different with other descriptive properties.Therefore, polymorph can have different physics Property such as shape, density, hardness, morphotropism, stability and Dissolution behaviours.Polymorph usually has different fusing points, IR Spectrum and X-ray powder diffraction collection, these can be used for differentiating.Technical staff understands that different polymorphs can be such as It prepares the reaction condition used in the compound or reagent by being altered or modified and produces.For example, temperature, pressure or solvent Variation can lead to polymorph.In addition, a kind of polymorph can spontaneously be transformed into another polymorphic under certain conditions Object.

The invention also includes the compounds of isotope labelling, with chemical combination shown in formula (I) and (II) and its attached formula Object is identical, the difference is that one or more atoms are replaced with the atom different from the atomic weight or atomicity being naturally generally found It changes.The example that the isotope in the compounds of this invention and its pharmaceutically acceptable salt can be mixed includes the isotope of hydrogen, carbon The isotope and chlorine of isotope, the isotope of nitrogen, the isotope of oxygen, the isotope of phosphorus, the isotope of sulphur, the isotope of fluorine, iodine Isotope, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I。

The medicine of the compounds of this invention and the compound of other isotopes containing above-mentioned isotope and/or other atoms Acceptable salt is within the scope of the invention on.The compound of the isotope labelling of the present invention, such as wherein mix radioactivity Isotope is for example³H,¹⁴Those of C compounds are used in drug and/or substrate tissue measure of spread.Tritium generation i.e.³H and carbon-14 I.e.¹⁴C isotopes are easily prepared due to it and easily detection property is particularly preferred.¹¹C and¹⁸(positron emission is disconnected in PET for F isotopes Layer imaging) in be it is particularly useful,¹²⁵I isotopes are particularly useful in SPECT (single photon emission computerized tomography) , all of which is used in Brian Imaging.In addition, being with heavier isotope such as deuterium²It is excellent that H substitutions can get some treatments Gesture, this is because higher metabolic stability such as Half-life in vivo increases or volume requirements reduce, therefore in some cases It is preferred.The formula (I) and (II) compound and its attached cpd of the present invention of isotope labelling usually can be by under implementation Prepared by operation described in face scheme and/or embodiment, wherein replaced with the reagent for the isotope labelling being easy to get non-same The reagent of position element label.

Representative embodiment

In an embodiment of formula (I) compound：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂- OR₄And halogen；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases Or tetrazole radical；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group is connected to them Carbon forms cyclopropyl together；

R₄For hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base, imidazolidine and diazacyclo Heptantriene base or Tetrahydro-pyridine and oxaza heptantriene base, all these groups can be unsubstituted or by 1,2 or 3 Substituent group independently selected from the following is replaced：-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃、C_3-6Spiro cycloalkyl group And OH；With

N is 1 or 2；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (I) compound：

B is benzotriazole base or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 independently selected from Substituent group below is replaced：–C_1-3Alkyl and halogen；

D is-C (O) OH；

R₁It independently is hydrogen or methyl or two R₁Group carbon connected to them forms cyclopropyl together；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base or Tetrahydro-pyridine and oxygen azepine Cycloheptatriene base, all these groups can be unsubstituted or be taken by 1,2 or 3 substituent group independently selected from the following Generation：-C_1-3Alkyl, halogen or CN or-O C_1-3Alkyl；With

N is 1 or 2；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (I) compound：

B is benzotriazole base or phenyl, can be respectively unsubstituted or independently selected from the following is taken by 1,2 or 3 Replaced for base：–C_1-3Alkyl, halogen and CN；

D is-C (O) OH；

R₁It independently is hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base, imidazolidine and diazacyclo Heptantriene base or Tetrahydro-pyridine and oxaza heptantriene base, all these groups can be unsubstituted or by 1,2 or 3 Substituent group independently selected from the following is replaced：-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃、C_3-6Spiro cycloalkyl group And OH；With

N is 1；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (I) compound：

B is benzotriazole base, can be unsubstituted or by 1,2 or 3 independently selected from-C_1-3The substituent group institute of alkyl Substitution；

D is-C (O) OH；

R₁It independently is hydrogen or C_1-3Alkyl；

A be tetrahydro benzo oxaza heptantriene base, can be it is unsubstituted or by 1,2 or 3 independently selected from Under substituent group replaced：-C_1-3Alkyl ,-OC_1-3Alkyl, CN and halogen；With

N is 1；

Or its pharmaceutically acceptable salt.

In an embodiment of formula (II) compound：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂- OR₄And halogen；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases Or tetrazole radical；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group is connected to them Carbon forms cyclopropyl together；

R₂For=O or hydrogen；

R₄For hydrogen or C_1-3Alkyl；

Linker is-CH₂-、-O-C(O)-、-CH₂-C(O)-、–C(O)-、-CH(CH₃)-C (O)-or-N (CH₃)-C (O)-；

A is cyclohexyl, cyclopenta, phenyl or decahydro naphthalene；All these groups can be it is unsubstituted or independently by Substituent group selected from the following is replaced：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1 or 2；With

X is CH₂Or O；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (II) compound：

B is benzotriazole base or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 independently selected from Substituent group below is replaced：–C_1-3Alkyl and halogen；

D is-C (O) OH；

R₁It independently is hydrogen or methyl or two R₁Group carbon connected to them forms cyclopropyl together；

R₂For=O or hydrogen；

Linker is-CH₂-、-O-C(O)-、-CH(CH₃)-C (O)-or-N (CH₃)-C(O)-；

A is cyclohexyl or cyclopenta, can be respectively unsubstituted or is independently taken by substituent group selected from the following Generation：C_1-3Alkyl, CN and halogen；

N is 1；With

X is CH₂Or O；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (II) compound：

B is benzotriazole base or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 independently selected from Substituent group below is replaced：–C_1-3Alkyl and-O-C_1-3Alkyl；

D is-C (O) OH；

R₁It independently is hydrogen；

R₂For hydrogen；

Linker is-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydro naphthalene；All these groups can be unsubstituted or independently by selected from following Substituent group replaced：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1；With

X is CH₂；

Or its pharmaceutically acceptable salt.

In another embodiment of formula (II) compound：

B is benzotriazole base or-(CH₂)₂Triazolyl, respectively can be it is unsubstituted or by 1,2 or 3 independently selected from Substituent group below is replaced：–C_1-3Alkyl and-O-C_1-3Alkyl；

D is-C (O) OH；

R₁It independently is hydrogen；

R₂For=O；

Linker is-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydro naphthalene；All these groups can be unsubstituted or independently by selected from following Substituent group replaced：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1；With

X is CH₂Or O；

Or its pharmaceutically acceptable salt.

It should be understood that present invention encompasses all combinations of specific group described above.

The specific example of the compounds of this invention includes following：

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (3,3-3- [(3aR, 8bS) -1- (hexamethylenes Ylmethyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] -3- (1,4- dimethyl -1H-1, 2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 1- [(4- ethylcyclohexyls) methyl] -2- oxygen Generation -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } propionic acid；

3- [(3aR, 8bS) -1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles Cough up -7- bases] -5- (1- ethyl -1H-1,2,3- triazole-4-yls) valeric acid；

3- [1- (decahydronaphthalene -2- ylmethyls) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- Base] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 2- oxos -1- [(4- propylcyclohexyls) first Base] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [1- (2- Cyclohexylacetyls) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- methylvaleryls) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- { 1- [2- (2- chlorphenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } - 3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [2- (2- cyano-phenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- Base } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

Dimethylbutanoyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] propionic acid；

3- { 1- [butyl (methyl) carbamoyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- Base } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (7- Methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1- Ethyl -4- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -5- (1- Ethyl -1H-1,2,3- triazole-4-yls) valeric acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (7- Methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 5H, 9bH- benzo [g] indoles -8- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [3- (cyclohexyl methyl) -2- oxos -2H, 3H, 3aH, 8H, 8aH- indenos [1,2-d] [1,3] oxazole -5- bases] - 3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [3- (the chloro- 2,2- dimethyl -2,3,4,5- tetrahydrochysenes -1,4- benzos oxaza heptantriene -4- bases of 7-) -2,3- Dihydro -1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2,7- trimethyls -2,3,4,5- four Hydrogen -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (dimethyl -2,3 7- methoxyl group -2,2-, 4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2,8- trimethyls -2,3,4,5- four Hydrogen -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (fluoro- 2,2- dimethyl -2,3,4,5- of 8- Tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -3- (4- fluoro-2-methylbenzenes base) -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] -2,2- neopentanoic acids；Formic acid；

3- [3- (7- cyano -2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2, 3- dihydro -1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- Tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } -2,2- neopentanoic acids；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- 3- [methyl -2 (2R) -2-, 3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrroles Pyridine simultaneously [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrroles Pyridine simultaneously [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

3- [3- (8- cyano -2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2, 3- dihydro -1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyls -2H, 3H, 4H, 5H- Pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } -2,2- neopentanoic acids；First Acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- [3- (2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- Dihydro -1H- indenes -5- bases } -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

(3S) -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [(3R) -3- (dimethyl -2,3 2,2-, 4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- { 3- [(2R) -2- methyl - 2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydros - 1H- indenes -5- bases } -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- Tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrroles Pyridine simultaneously [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- { 3- [(2S) -2- methyl - 2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrroles Pyridine simultaneously [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (tetrahydrochysene -1 2,3,4,5-, 4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- methyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- (3- { 2H, 3H, 4H, 5H- pyrroles Pyridine simultaneously [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2S) -2- methyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyls -2H, 3H, 4H, 5H- Pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,3,4,5- tetrahydrochysene -1,4- benzo oxygen nitrogen Heterocycle heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；Formic acid；

3- (4- cyano -2- aminomethyl phenyls) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyridos [3,2-f] [1,4] Oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- methyl -2H, 3H, 4H, 5H- Pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } - 2,3- dihydro -1H- indenes -5- bases) -3- { 3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases } propionic acid；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid；Trifluoroacetic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -5- (2- ethyl -2H-1,2,3,4- tetrazolium -5- bases) -2,2- dimethyl valeric acids；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros - 1H- indenes -5- bases] -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid；

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) propionic acid；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (S) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2-Dimethylpropionic acid, trifluoroacetate；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -- 2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydro pyridos [4,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2-Dimethylpropionic acid, trifluoroacetate；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (S) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydro pyridos [4,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2-Dimethylpropionic acid, trifluoroacetate；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids； Or

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids；

Or its pharmaceutically acceptable salt.

It is prepared by compound

It will be understood by those skilled in the art that if substituent group described herein and synthetic method described herein Incompatible, the available protecting group appropriate to stable reaction conditions of the substituent group is protected.It can react appropriate in reaction sequence Point removes the protecting group, obtains required intermediate or target compound.Protecting group appropriate and the use guarantor appropriate Shield base protection different substituents and the method being deprotected are well known to those skilled in the art；The example of protecting group appropriate Can in T.Greene and P.Wuts,Protecting Groups in Chemical Synthesis(3rd ed.), John Wiley&Sons, NY are found in (1999).In some instances, it is reactivity that can be specifically chosen under used reaction condition Substituent group.In these cases, selected substituent group is converted to another substituent group by the reaction condition, this another Substituent group is used as midbody compound or is a desired substituent group in target compound.

The synthesis of logical formula (I) and (II) compound and its pharmaceutically acceptable derivates and salt can be such as following scheme 1-21 Shown in complete.In the following description, unless otherwise indicated, the group is such as above for formula (I) and (II) compound It is defined.Abbreviation is as defined in embodiment part.Starting material is commercially available or use side well known by persons skilled in the art It is prepared by starting material of the method commercially available from.

Scheme 1

Condition：a)NBS,TFA,H₂SO₄；b)i)MeNH₂(or) EtNH₂THF；ii)Zn,HOAc；iii)NaNO₂,H₂SO₄

Scheme 1 shows the general approach for being used to prepare the bromo- 4- methyl-1s of 5--methyl-1 H- benzos [d] [1,2,3] triazole. Started with the commercially available fluoro- 3- methyl -2- nitrobenzenes of 1-, intermediate 2 is obtained with NBS brominations.Fluorine is replaced with suitable amine, it is then right Nitro carry out zinc metal reduction generate aniline, diazotising and be cyclized obtain required triazole 3.

Scheme 2

Condition：a)K₂CO₃,MeI,DMF；b)Br₂, acetic acid；c)NaH,MeI,DMF；D) zinc, acetic acid；e)NaNO₂,H₂SO₄

Scheme 2 shows the general approach for preparing bromo- 7- methoxyl groups -1- methyl-1s H- benzos [d] [1,2,3] triazoles of 5-.It rises Commercially available 2- amino -3- nitrophenols is started from, K is used₂CO₃Phenol methylates with MeI, and (step a) provides intermediate 2, can be used NBS brominations (step c).By anilinomethyl (step d) and then reduction nitro (step d) and diazotising and cyclisation (step e) Triazole 5 needed for providing.

Scheme 3

Condition：a)NaIO₄/H₂SO₄,I₂,Ac₂O/AcOH；b)CuI,Cs₂CO₃,MeOH；

Scheme 3 shows the general side for preparing bromo- 7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles of 5- Case.This two-step method is since the iodate on the positions C7 of bromo- 1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles of 5-.Use first The iodide displacement that alcohol carries out copper mediation provides required substance.

Scheme 4

Condition：a)H₂O₂,TFA；b)(ii)KNO₃,H₂SO₄；(ii)CH₃NH₂；c)Ni,EtOH,40psi；d)NaNO₂, H₂SO₄

Scheme 4 shows the general approach for preparing chloro- 3- methyl -3H- [1,2,3] triazol [4,5-c] pyridines of 6-.By commercially available The chloro- 5- fluorine pyridines of 2- start, oxidation obtain intermediate 2.It is subsequently converted into nitro intermediate 3.It is set using suitable amine Fluoride is changed, nitro progress nickel metal is then reduced into aniline, obtains intermediate 4.It carries out diazotising and cyclisation provides institute The triazole 5 needed.

Scheme 5

Condition：a)H₂NCH₂C(R₈)(R₉)OH,NaBH₄,NaOH,MeOH；b)Cs₂CO₃,CuI,IPA；Or KO_tBu,DMSO； C) Boc acid anhydrides, Et₃N,THF；D) HCl, dioxanes

Scheme 5 indicates to prepare 2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptan used in the present invention The general approach of triolefin and 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene.In scheme 5, R₇For-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃Or OH；And R₈And R₉For hydrogen, C_1-3Alkyl or C_3-6Spirocyclane Base.It is commercially available to be described as the substituted 2- bromobenzaldehydes of starting material or substituted 2- fluorobenzaldehydes.Reaction condition such as top Described in case；However, it will be understood by those skilled in the art that certain modifications of reaction condition and reagent used are possible.

Aldehyde is originated with suitable amino alcohol reduction amination, bromide or fluoride is then replaced, obtains required intermediate 3.Then it is protected as Boc carbamates to promote to purify.It will be understood to those of skill in the art that replacement can be used Blocking group.Deprotection generates required amine 5.

Scheme 6

Condition：a)H₂NCH₂CH(R₈)OH,NaBH₄,NaOH,MeOH；b)PPh₃,DEAD,THF；C) Boc acid anhydrides, Et₃N, THF；D) HCl, dioxanes

Scheme 6 indicates to prepare (R) -2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen azepine used in the present invention The general approach of cycloheptatriene and 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene.In scheme 6 In, R₇And R₈As defined above.It is commercially available to be described as the substituted Benzaldehyde,2-hydroxy of starting material.Reaction condition such as top Described in case；However, it will be understood by those skilled in the art that certain modifications of reaction condition and/or reagent used are possible.

With suitable amino alcohol reductive amination of aldehydes, Mitsunobo reactions are then carried out, required intermediate 3 is obtained.Then It is protected as Boc carbamates to promote to purify.It will be understood to those of skill in the art that the protecting group substituted can be used Group.Deprotection generates required amine 5.

Scheme 7

Condition：a)K₂CO₃,THF；b)NaOMe,DMF；c)LAH,THF

Scheme 7 indicate prepare the present invention used in replace-tetrahydro benzo [f] [1,4] oxaza heptantriene one As scheme.In scheme 7, R₈As defined above.The 2-Hydroxylbenzamide for being described as starting material is commercially available.Reaction condition Described in scheme as above；However, it will be understood by those skilled in the art that certain modifications of reaction condition and/or reagent used are can Can.

Intermediate 3 is obtained by the reaction in 2-Hydroxylbenzamide and bromacetate appropriate.It is cyclized under alkaline condition, then With the acid imide of LAH reduction gained, required amine 5 is obtained.

Scheme 8

Condition：a)H₂NCH₂C(R₈)(R₉)OH,NaBH₄,NaOH,MeOH；b)Cs₂CO₃,CuI,IPA；Or KO_tBu,DMSO； C) Boc acid anhydrides, Et₃N,THF；D) HCl, dioxanes

Scheme 8 indicates to prepare the general of tetrahydropyridine simultaneously [1,4] oxaza heptatriene hydrochloride used in the present invention Scheme.In scheme 8, R₈And R₉As defined above.The fluoro cigarette aldehyde, chloro cigarette aldehyde or bromo cigarette aldehyde for being described as starting material are can Commercially available.Described in reaction condition scheme as above；However, it will be understood by those skilled in the art that reaction condition and/or examination used Certain modifications of agent are possible.

Aldehyde is originated with suitable amino alcohol reduction amination, bromide or fluoride is then replaced, obtains required intermediate 3.Then it is protected as Boc carbamates to promote to purify.It will be understood to those of skill in the art that replacement can be used Blocking group.Deprotection generates the required amine 5 of hydrochloride form.

Scheme 9

Condition：a)H₂NCH₂CH(R₈)OH,NaBH₄,NaOH,MeOH；b)PPh₃,DEAD,THF；C) Boc acid anhydrides, Et₃N, THF；D) HCl, dioxanes

Scheme 9 indicates to prepare simultaneously [1,4] [2,3-f] of (R) -2- ethyl -2,3,4,5- tetrahydropyridines used in the present invention Oxaza heptatriene hydrochloride and 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [2,3-f] [1,4] oxaza heptantriene The general approach of hydrochloride.In scheme 9, R₈As defined above.3- pyridone -2- the formaldehyde for being described as starting material is can quotient Purchase.Described in reaction condition scheme as above；However, it will be understood by those skilled in the art that reaction condition and/or reagent used Certain modifications be possible.

With the aldehyde commercially available from suitable amino alcohol reduction amination, Mitsunobo reactions are then carried out, required intermediate is obtained 3.Then it is protected as Boc carbamates to promote to purify.It will be understood to those of skill in the art that replacement can be used Blocking group.Deprotection generates required amine 5.

Scheme 10

Condition：a)NH₄OH；B) (R)-(2)-ethyl ethylene oxide, EtOH；c)KO_tBu,DMF

Scheme 10 indicates to prepare simultaneously [1,4] [3,2-f] of (R) -2- ethyl -2,3,4,5- tetrahydropyridines used in the present invention The general approach of oxaza heptantriene.It is commercially available to be described as 2- bromo- 3- (bromomethyl) pyridine of starting material.Reaction condition Described in scheme as above；However, it will be understood by those skilled in the art that certain modifications of reaction condition and/or reagent used are can Can.

Commercially available 2- bromo- 3- (bromomethyl) pyridine, which is handled, with ammonium hydroxide generates primary amine 2.By the way that epoxides is open alkane Base provides intermediate 4 with rear substitution bromide.

Scheme 11

Condition：A) amine, K₂CO₃, THF, water；b)Cs₂CO₃,CuI,IPA

Scheme 11 indicates to prepare 2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptan used in the present invention The general side of three pinene hyhrochlorides and 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptatriene hydrochloride Case.In scheme 11, R₇、R₈And R₉As defined above.Substituted 1- bromo- 2- (bromomethyl) benzene for being described as starting material is can quotient Purchase.Described in reaction condition scheme as above；However, it will be understood by those skilled in the art that reaction condition and/or reagent used Certain modifications be possible.

It is alkylated using amino alcohol appropriate, then replaces bromide, required intermediate 3 is provided.

Scheme 12

Condition：a)POCl₃；b)NaOH,DCM；C) borane dimethylsulf iotade, THF；d)(i)KO_tBu,DMSO；(ii) Boc acid Acid anhydride, Et₃N,THF；D) HCl, dioxanes

Scheme 12 indicate prepare the present invention used in 2,2,8- trimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1, 4] general approach of oxaza heptatriene hydrochloride.In this scenario, being described as the 4- hydroxyl -6- methylnicotinic acids of starting material is It is commercially available.Described in reaction condition scheme as above；However, it will be understood by those skilled in the art that reaction condition used and/or Certain modifications of reagent are possible.

Use POCl₃It is converted to acyl chlorides by commercially available sour 1, amide is subsequently formed, obtains intermediate 3.Use borane dimethylsulfide Ether reducing amide generates amine 4.It uses potassium tert-butoxide to be cyclized as alkali, is then t-butylcarbamate group by amine protection, obtains To compound 5.Deprotection obtains required amine 6 in acid condition.

Scheme 13

Condition：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

13 expression of scheme prepares the general approach of intermediate 4,8 and formula (I) compound.In scheme 13, R₆For C_1-3Alkane Base, halogen or-OC_1-3Alkyl, R₇、R₈And R₉As defined above.Y independently is CH or N.

By commercially available indone 1, NaBH is used₄Reduction generates desired alcohol intermediate 2.2 hydroxyl of intermediate can lead to It crosses and is handled with NaH and PMBCl and protection is PMB ethers, to obtain intermediate 3.It will be understood to those of skill in the art that blocking group It can change and be not limited to PMB.In addition, by converting intermediate 3 in required aldehyde with butyl lithium and DMF processing, generate Required intermediate 4.4 and 5 coupling with tert-butyl lithium and the processing of intermediate 45 by being completed, to form alcohol 6.Pass through first Use Cl₃CCN and DBU processing, then in Tf₂It is handled with required commercially available silicyl ketenes condensed ethandiol to make in the presence of NH Alcohol 6 is converted into 7.Intermediate 7 is deprotected to form intermediate 8 with DDQ.SOCl is used first₂, then use amine 9 and K₂CO₃, NaI processing Intermediate 8, is then hydrolyzed with NaOH, forms final product 10.

Scheme 14

Condition：A) two (pinacol combined) two boron, 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

14 expression of scheme prepare intermediate 2 and 5 and formula (I) compound general approach.In scheme 14, R₆、R₇、R₈、R₉ It is as defined above with Y.Z is CH or N.

Commercially available indone 1 is reduced to hydroxy indene first, is then converted to borate, or by palladium chtalyst It is handled with two (pinacol combined) two boron in the presence of agent and is directly translated into borate, obtain 2.The intermediate 3 under Heck reaction conditions It is converted to 4.(for intermediate 3, in the case of Z=N, in the presence of four (triphenylphosphines) close palladium rather than bromide, chlorine Compound is coupled for Heck.) 2 and 4 carry out rhodium catalysis Michael's additions provide ester 5.If desired, using NaBH₄Reduction can be with Intermediate 5 is converted to hydroxy indene, then by with SOCl₂It handles and is converted to chloride.By with 6 and K₂CO₃, at NaI Chloride is managed, then completes the conversion to final product 7 with NaOH hydrolysis.

Scheme 15

Condition：a)LiHMDS,BrCH₂CO₂Bn,THF；B) two (pinacol combined) two boron, PdCl₂(dppf)-CH₂Cl₂, KOAc, 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)]₂, TEA, 1,4- dioxanes, H₂O；g)(i)Pd/C,H₂,MeOH；(ii)6,T3P, TEA,DCM；h)(i)TFA,Et₃SiH,MeCN；(ii)NaOH,MeOH/H₂O

15 expression of scheme prepares the general approach of intermediate 3,6 and formula (II) compound.In scheme 15, R₆Determine as preceding Justice.R₁₀For C_1-3Alkyl, CN.In the presence of suitable solvent, commercially available indone 1 is made to be reacted with LiHMDS and benzyl acetate bromide, Intermediate 2 needed for generating.In a suitable solvent, by intermediate 2 further with two (pinacol combined) two boron, PdCl₂ (dppf)-CH₂Cl₂It is converted into required intermediate 3 with KOAc.By commercially available ketone 4 and p-TolSO₂CH₂NC, KOBu-t exist Reaction generates required intermediate 5 in suitable solvent, can be restored by LAH and be further converted to amine 6.It is described as starting material Triazole 7 can be by the materials synthesis that is easy to get.Described in reaction condition scheme as above；However, those skilled in the art will Understand that certain modifications of reaction condition used and/or reagent are possible.It is deposited in acid chloride (II) and diisopropyl ethyl amine Under, in the presence of suitable solvent, triazole 7 is handled with ethyl acrylate, generates the product of required Heck cross couplings 8.Under suitable conditions, 3 and 8 with [RhCl (cod)]₂Coupling generates intermediate 9, can be further by hydrocarbon with Pd/ Change and then forms amide using T3P and amine 6 and be converted into 10.Intermediate 10 uses TFA and Et first₃SiH is cyclized, and then uses NaOH Hydrolysis is to generate required product 11.

Scheme 16

Condition：a)LiHMDS,BrCH₂CO₂Me,THF；b)HONH₂.HCl,NaOAc,MeOH；c)(i)Zn,HOAc；(ii) BH₃.Me₂S,THF；d)(i)Boc₂O,TEA,DCM；(ii) two (pinacol combined) two boron, PdCl₂(dppf)-CH₂Cl₂,KOAc,1, 4- dioxanes；E) ethyl acrylate Pd (OAc)₂,P(o-tol)₃,DIEA,DMF；f)[RhCl(cod)]₂, TEA, 1,4- bis- Evil Alkane, H₂O；g)NaOH,MeOH/H₂O

16 expression of scheme prepares the general approach of intermediate 5 and 8.In scheme 16, R₆As defined above.

Commercially available indone 1 is reacted with LiHMDS and methyl bromoacetate in the presence of suitable solvent and generates intermediate 2.? By the hydroxy amine hydrochloric acid salt of intermediate 2 and sodium acetate, further conversion obtains required intermediate 3 in methanol.Intermediate 3 is first The HOAc solution treatments for first using Zn, then use BH₃·Me₂The THF solution of S is handled, and obtains amine 4.Boc is used in DCM first₂O and TEA, then in a suitable solvent with two (pinacol combined) two boron, PdCl₂(dppf)-CH₂Cl₂With KOAc conversions 4, institute is generated The intermediate 5 needed.The triazole 6 for being described as starting material can be by the materials synthesis that is easy to get.Institute in reaction condition scheme as above It states；However, it will be understood by those skilled in the art that certain modifications of reaction condition and/or reagent used are possible.Suitable Solvent in the presence of, in the presence of acid chloride (II) and diisopropyl ethyl amine, triazole 6 is handled with ethyl acrylate, generate The product 7 of required Heck cross couplings.At [RhCl (cod)]₂In the presence of, 5 and 7 couplings are generated 8, it can be by removing ester Protecting group is converted to required product 9.

Scheme 17

Condition：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。

17 expression of scheme prepares the general approach of intermediate 2 and formula (II) compound.In scheme 17, R₆With for example preceding institutes of A Definition.

So that commercially available alcohol 1 is reacted with CDI and DMAP and generates intermediate 2.The intermediate 3 for being described as starting material can be by scheme The materials synthesis being easy to get described in 16.The Boc groups of intermediate 3 are deprotected with the 1,4- dioxane solutions of HCl and are generated Intermediate 4.Ester then can be converted to acid and is converted to amide product 5 by intermediate 4 by using T3P to form amide first. Then urea product 6 can be handled with suitable amine by handling 4 with CDI first, ester be then converted to acid to obtain.Amino Then ester can be converted to acid to obtain by formic acid esters 7 by being handled with intermediate 2.

Scheme 18

Condition：a)LiHMDS,BrCH₂CO₂Et,THF；b)NaOH,MeOH/H₂O；c)C₆H₉CH₂NH₂,T3P,TEA,DCM； d)TFA,Et₃SiH,MeCN；E) two (pinacol combined) two boron, 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。

18 expression of scheme prepares the general approach of intermediate 6 and formula (II) compound.In scheme 18, R₆Determine as preceding Justice.

Commercially available indone 1 reacts the centre needed for generating with LiHMDS and bromoacetate in the presence of suitable solvent Body 2.Intermediate 3 is generated using NaOH hydrolyzing intermediates 2.It is converted into amide, then uses TFA and Et₃SiH is cyclized intermediate 4 and gives birth to At intermediate 5, in a suitable solvent with two (pinacol combined) two boron, PdCl₂(dppf) and during KOAc is further converted to Mesosome 6.The triazole 7 for being described as starting material can be by the materials synthesis that is easy to get.Described in reaction condition scheme as above；So And it will be appreciated by those skilled in the art that certain modifications of reaction condition and/or reagent used are possible.In suitable solvent In the presence of, in the presence of acid chloride (II) and diisopropyl ethyl amine, required Heck is generated with ethyl acrylate processing triazole 7 The product 8 of cross coupling.At [RhCl (cod)]₂In the presence of realize intermediate 6 and intermediate 8 coupling.Ester is converted to sour life At 9.

Scheme 19

Condition：a)C₆H₅I(OAc)₂,KOH,MeOH；b)(i)C₆H₉CH₂NCO,DMAP,PhMe；(ii) 10%HCl；c) TFA,Et₃SiH,MeCN；D) two (pinacol combined) two boron, 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。

19 expression of scheme prepares the general approach of intermediate 5 and formula (II) compound.In scheme 19, R₆Determine as preceding Justice.

Commercially available indone 1 is used into C₆H₅I(OAc)₂MeOH solution oxides generate needed for intermediate 2.It first will be intermediate Body 2 is handled with cyclohexyl methyl isocyanates, is then deprotected with HCl, is obtained required intermediate 3.Intermediate 3 with TFA and Et₃SiH cyclisation generates intermediate 4, in a suitable solvent with two (pinacol combined) two boron, PdCl₂(dppf) and KOAc is into one Step is converted into intermediate 5.The triazole 6 for being described as starting material can be by the materials synthesis that is easy to get.Reaction condition scheme as above Described in；However, it will be understood by those skilled in the art that certain modifications of reaction condition and/or reagent used are possible.? In the presence of suitable solvent, in the presence of acid chloride (II) and diisopropyl ethyl amine, triazole 6 is handled with ethyl acrylate and is given birth to At the product 7 of required Heck cross couplings.Under suitable conditions, with [RhCl (cod)]₂Intermediate 5 and intermediate 7 is even It closes, ester is then converted to acid, to generate 8.

Scheme 20

Condition：a)NaBH₄,THF；b)NaH,PMBCl；c)n-BuLi,THF,DMF,-78℃；d)DCM,40℃；E) four fourth Yl benzoic acid ammonium, THF；f)(i)LiOH,4:2:1THF:MeOH:H₂O；(ii)BH₃·DMS；g)CBr₄, Polymer-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 indicates to prepare the general approach of formula (I) compound.

Required alcohol 2 will be generated with sodium borohydride processing ketone 1, can be used to methoxy-benzyl chlorine and sodium hydride progress Protection, obtains aryl-bromide 3.It is exchanged by carrying out halogen-lithium, aryl-bromide 3 can be converted to aldehyde 4, it can be with Under the conditions of standard Wittig alkylenes α, beta-unsaturated esters 6 are converted into inner salt 5.Ketenes-acetal 7 and α, β-unsaturation The Isosorbide-5-Nitrae addition of ester 6 can be completed by the way that tetrabutyl ammonium benzoate is added in THF, obtain methyl ester 8.People in the art Member will be understood that the selective hydrolysis of methyl ester 8 and the then reduction of corresponding carboxylic acid will generation alcohol 9.Bromide 10 can pass through Alcohol 9 and the triphenylphosphine of carbon tetrabromide and Polymer-supported is set to carry out effect acquisition.By by the tetrahydrofuran of proper proportion, Cymag in water and methanol is heated to suitable temperature, can complete the displacement of bromide 10 to provide cyanide 11.Ability Field technique personnel be appreciated that by microwave reactor in trimethylsilyl azide and tetrabutyl ammonium fluoride three Cyanide 11 is heated in the presence of hydrate, is then alkylated with iodoethane and triethylamine, can be formed tetrazolium 13.Then It is deprotected to obtain benzylalcohol 14.Benzylalcohol is converted to amine and is reacted by bromination and with amine 15 to complete.It then can be in alkali By the aqueous amine solution under the conditions of property microwave reactor, 16 are obtained.

Scheme 21

Condition：a)n-BuLi,THF,DMF,-78℃；b)DCM,40℃；C) tetrabutyl ammonium benzoate, THF；d)Pd (PPh₃)₄, morpholine；e)BH₃·DMS；f)MsCl,Et₃N；g)NaN₃,CuI,DIPEA；h)DDQ；i)(i)PBr₃；(ii)13, DIPEA；(iii)NaOH,120℃

Scheme 21 indicates to prepare the other general approach of formula (I) compound.

It is exchanged by carrying out halogen-lithium, aryl-bromide 1 can be converted to aldehyde 2, it can be in standard Wittig alkene α is converted into inner salt 3, the undersaturated esters of β -4 under the conditions of change.Silicyl ketenes condensed ethandiol 5 and α, β-are undersaturated The Isosorbide-5-Nitrae addition of ester 4 can be completed by the way that the THF solution of tetrabutyl ammonium benzoate is added, and obtain allyl ester 6.This field skill Art personnel will be understood that allyl, which is carried out the deprotection that palladium (0) is catalyzed, obtains carboxylic acid 7, can then be reduced to generate alcohol 8.Mesylation and nucleophilic displacement will cause generate azide, can use copper catalysis azide-alkynes cycloaddition and Alkynes appropriate is converted to triazole 11.After the oxidation deprotection of benzylalcohol, 12 can be and anti-with amine 13 by with phosphorus tribromide bromination Answer, subsequent basic hydrolysis and be converted into amine 14.

Bioactivity

As described above, Formulas I and (II) compound are Nrf2 conditioning agents and oxidative stress group are presented for treating or preventing Point human diseases, such as respiratory disease and non-respiratory systemic disease, including COPD, asthma, fibrosis, chronic and acute Asthma, the tuberculosis secondary to environmental exposure, acute pulmonary infection, chronic pulmonary inflammation, alpha1 Anti-trypsin disease, cystic fibrosis, from Body immunity disease, nephrosis, chronic kidney disease, the acute kidney injury of septicemia-induction, acute kidney injury (AKI), The nephrosis or kidney dysfunction observed during kidney transplant, pulmonary hypertension, atherosclerosis, hypertension, heart failure, It is Parkinson's disease (PD), Alzheimer disease (AD), family ataxia (FA), amyotrophic lateral sclerosis (ALS), more Hair property hardening (MS), inflammatory bowel disease, colon cancer, non-neovascular (dry type) AMD and neovascular (wet type) AMD, eye damage Wound, Fuchs endothelial dystrophy of cornea (FECD), uveitis or other inflammatory eye diseases, nonalcoholic fatty liver disease (NASH), the liver disease (such as hepatopathy of paracetamol-induction), virus hepatitis of toxin-induction, hepatic sclerosis, silver bits Disease, the local action of dermatitis/radiation, due to immunosupress caused by radioactive exposure, pre-eclampsia and altitude sickness.

The bioactivity of formula (I) and II compounds can be used any suitable measurement (for being determined as Nrf2 antagonists Candidate compound activity) and tissue and In vivo model determine.

The bioactivity of formula (I) and (II) compound is proved by following test.

BEAS-2B NQO1 MTT tests

NAD(P)H：Benzoquinones oxidoreducing enzyme 1 (NQO1) is also referred to as DT diaphorase, is the enzyme of the FAD containing homodimeric, What two electron reduction of mandatory NAD (P) H- dependences of the enzymatic quinone and protecting cells from was generated by an electron reduction The toxicity and tumor formation effect of free radical and reactive oxygen species.The transcription of NQO1 is fine-tuned by Nrf2, therefore NQO1 activity It is the good sign object of Nrf2 activation.At first day, the BEAS-2B cells (ATCC) of freezing are thawed in a water bath, are counted simultaneously And it is suspended again with the concentration of 250,000 cell/mL.By 50 microlitres of cell inoculation in the plate at 384 hole black transparent bottoms. By plate at 37 DEG C, 5%CO₂Overnight incubation.Second day, plate is centrifuged and 50nL compounds or reference material are added into cell.So Afterwards by plate at 37 DEG C, 5%CO₂Cultivate 48h.4th day, medium is taken away from the plate and is prepared in the following manner crude Cell lysate：13 μ L 1X Cell Signaling Technologies lysis buffer solutions are added, wherein slow per 10mL lysis Fliud flushing be added 1 it is complete, mini, without EDTA protease inhibitors piece (Roche).After lysis, by plate in incubated at room temperature 20 minutes. 2 microlitres of lysates are taken out to measure in (Promega) for Cell Titer Glo and prepare MTT mixtures (MTT Cocktail) (Prochaska et al. 1998) is for measuring NQO1 activity.50 microlitres of MTT mixtures are added into each hole, Plate is centrifuged and is analyzed 30 minutes using absorbance 570nm labels in Envision plate reader (Perkin Elmer).Product Formation is the pEC that dynamic measures and NQO1 activity specifics induce₅₀It is opposite by the variation (Δ OD/min) that will be absorbed 3- parameter fitting calculating is then carried out in the logarithm mapping of compound concentration.

Beas2B NQO1 MTT tests

All embodiments described herein have NQO1 specific enzymatic activities, wherein EC in BEAS-2B cells₅₀?> 10uM-<Between 1nM, unless otherwise indicated (referring to following table).EC₅₀<1nM (+++ ++), EC₅₀10nM-1nM (++++), EC₅₀ 10-100nM (+++), EC₅₀100nM-1uM (++), EC₅₀1-10uM (+), EC₅₀>10uM (-), or do not determine (ND).

# pEC in some measurement₅₀<170pM

Nrf2-Keap1 FP tests

A model for Nrf2-Keap1 interactions is by the two basic change in the Neh2 structural domains on Nrf2 Site.The two sites are referred to as DLG binding motifs (bolt lock structure domain (latch domain), μM grade compatibility) and ETGE is tied Close motif (hinge domain, nM grades of affinity).The Keap1 albumen is by N- terminal regions (NTR), wide compound (broad Complex), tramtrack and brick a ' brac structural domains (BTB), insert district (intervening region, IVR), double Glycine repetitive structure domain (DGR or Kelch) and C- terminal regions are constituted.DLG the and ETGE motifs of the Neh2 structural domains of Nrf2 It is combined with the Kelch structural domains of Keap1 with different affinity.In Keap1 Kelch fluorescence polarizations (FP) measurement, use The 16mer peptides (AFFAQLQLDEETGEFL) of TAMRA- labels, the peptide contain the ETGE motifs of Nrf2 and the Kelch knots of Keap1 Structure domain (321-609).Between the measurement determines whether compound interferes the peptide that Keap1 (361-609) and TAMRA- is marked In conjunction with.The combination of the Nrf2 peptides and Keap1 (321-609) of TAMRA- labels leads to high FP signals.If described in compound interference Combination between peptide and the albumen, this can cause to measure signal reduction.Therefore, signal is measured to be inversely proportional in conjunction with inhibition.

FP is tested

100X compound dose response curves (continuous 3- times dilution) of the 100nL in DMSO Echo liquid is operated System (Labcyte) is added in the holes 384- low volume black assay plate (Greiner, #784076), and wherein DMSO is in the 6th He In 18th row.The compound of maximum concentration is located in the 1st and 13 row.Keap1 (321-609) is measured into buffer solution (50mM in 1X Tris, pH 8.0,100mM NaCl, 5mM MgCl₂, 1mM DTT, 2mM CHAPS and 0.005%BSA) in be diluted to 40nM (2X) and added with the Multidrop Combi (Thermo Electron Corporation) equipped with metal tip distributor Add in 5ul to all holes of compound plate, except the 18th row.18th row only receive 5ul and measure buffer solution.With that is, by 5 μ L 16nM (2X) Tamra label peptide (AFFAQLQLDEETGEFL, 21^stCentury Biochemicals) add to the plate All holes in.The plate is rotated into 1min with 500rpm, in incubated at room temperature 1 hour and excitation (530/25nm) is being equipped with and is sending out It penetrates on the Analyst GT (Molecular Devices) of (580/10nm) filter and reads, the filter is directed to through design Tamra probes.561nm dichronic mirrors are also used in Analyst.Keap1 (321-609) and Tamra label peptide it is final Measured concentration is respectively 20nM and 8nM.Fluorescence measurements (being indicated with mP) are used in the conversion of data.Compound activity is base It is calculated in suppression percentage, is standardized relative to the control in measurement and (compares 1 and contain Tamra peptides and Keap1 simultaneously (321-609) (0% response), control 2 contain only Tamra peptides (100% response)).Using software package Abase XE (Surrey, United Kingdom) data analysis is processed.% inhibiting values are calculated by following equation：

100- (100* ((compound response-average control 2)/(average control 1- average controls 2))).In order to calculate pIC₅₀, Abase XE use quadruplex parameters.

All embodiments as described herein are all active in Keap1/Nrf2 FP are measured.

NRF2-Keap1 TR-FRET tests

In Nrf2-Keap1TR-FRET (time-resolved fluorescence Resonance energy transfer) measurement, overall length Nrf2 albumen is used With overall length Keap1 albumen (Keap1 is with dimer presence).The measurement detection compound substitutes Keap1 and the life of FlagHis labels The ability of the combination of object element, Avi labels Nrf2 albumen.(detection is mixed with streptavidin-europium by biotin-Nrf2 Close object component) combine, and Keap1-FlagHis by anti-Flag APC (allophycocyanin) antibody (and detection mixture Component) identification.If combined between two kinds of protein, there will be from the Eu+3 (donor) to 665nm from 615nm The energy transfer of the APC (receptor) at place.Potential Keap1 inhibitor will cause TR- by interfering the combination of Keap1 and Nrf2 The reduction of FRET signals.

Using Echo liquid processing systems (Labcyte) by the 100X compound dose responses of 100 nanoliters in DMSO Curve (continuous 3 times dilution) is stamped into 384 hole low capacity black assay plates (Greiner, #784076), DMSO in the 6th row and 18th row.The maximum concentration of compound is located at the 1st row and the 13rd row.All reagents are measuring buffer solution (50mM Tris, pH 8.0,5mM MgCl₂, 100mM NaCl, 0.005%BSA, 1mM DTT and 2mM CHAPS) in dilution.It will on the day of measurement BSA, DTT and CHAPS, which are added to, to be measured in buffer solution.Use the Multidrop Combi for being equipped with ferrule distributor (Thermo Electron Corporation), other than the hole in the 18th column, by 5ul 25nM Keap1-FlagHis albumen It is added in all holes of compound plate.Hole instead reception 5ul in 18th column measure buffer solution.By tablet with 500rpm is centrifuged 1 minute, covers flat plate cover, and cultivate 2.25 hours at 37 DEG C.Then tablet is taken out and is made from incubator It is cooled to room temperature 15 minutes.Then 5 microlitres of 50nM biotin-Nrf2 protein are added in all holes of plate, and should Plate is centrifuged 1 minute with 500rpm, is then cultivated 1.25 hours at 4 DEG C.Then make tablet be warming up to room temperature to be kept for 15 minutes, with Addition 10ul detections mixture (1nM streptavidins Eu+W1024 and 5 μ g/ml and SureLight APC antibody conjugates afterwards The anti-DYKDDDDK IgG of mouse；It is all from Columbia Biosciences) arrive all holes.Tablet is centrifuged with 500rpm 1 minute, emit optical filter in Envision in incubated at room temperature 1 hour, and using 320nm exciter filters and 615nm and 665nm It is read on plate reader.Ratio calculation compound response (% inhibition) based on two kinds of transmittings (665nm/615nm) and efficiency (pIC50), then by the data of conversion, relative to the control normalization in measurement, (control 1=exists in Nrf2 and Keap1 albumen Lower 1%DMSO, control 2=is there is no protein in the case of 1%DMSO).Using software package Abase XE (Surrey, United Kingdom) processing data analysis.By following equation % inhibiting values are calculated from ratio (conversion) data：

100- (100* (compound response-average control 2)/(average control 1- average controls 2)).

Calculating for pIC50, Abase XE use 4 parameter equations.

The low albumen tests of Nrf2-Keap1 TR-FRET

In the low albumen tests of Nrf2-Keap1 TR-FRET (time-resolved fluorescence Resonance energy transfer), overall length is used Nrf2 albumen and overall length Keap1 albumen (Keap1 is with dimer presence).The measurement detection compound substitutes Keap1 FlagHis With the protein bound abilities of biotinylated Avi-Nrf2.Biotin-Nrf2 and streptavidin-europium (detection mixture Component) combine, and Keap1 FlagHis by anti-Flag APC (allophycocyanin) antibody (and detection mixture group Point) identification.If combined between two kinds of protein, there will be from the Eu+3 (donor) from 615nm at 665nm The energy transfer of APC (receptor).Potential Nrf2 inhibitor will cause TR-FRET by interfering the combination of Keap1 and Nrf2 The reduction of signal.

It is using Echo liquid processing systems (Labcyte) that the 100X compounds dose response of 10 nanoliters in DMSO is bent Line (continuous 3 times dilution) is stamped into 384 hole low capacity black assay plates (Greiner, #784076), and DMSO is in the 6th row and the 18 row.Other 90nl DMSO are added per hole, total volume is made to reach every hole 100nl.The maximum concentration of compound is located at the 1st row With the 13rd row, serial dilution is carried out across row.All reagents are measuring buffer solution (50mM Tris, pH 8.0,5mM MgCl₂, 100mM NaCl, 0.005%BSA, 1mM DTT and 2mM CHAPS) in dilution.On the day of measurement by BSA, DTT and CHAPS, which is added to, to be measured in buffer solution.Use the Multidrop Combi (Thermo for being equipped with ferrule distributor Electron Corporation), other than the hole in the 18th column, 5ul 1.25nM Keap1FlagHis albumen is added to In all holes of compound plate.Hole instead reception 5ul in 18th column measure buffer solution.By tablet with 500rpm from The heart 1 minute covers flat plate cover, and is cultivated 2.25 hours at 37 DEG C.Then tablet is taken out and is allowed to cool to from incubator Room temperature 15 minutes.Then 5 microlitres of 2.5nM biotin-Nrf2 protein are added in all holes of plate, and by plate with 500rpm Centrifugation 1 minute, is then cultivated 1.25 hours at 4 DEG C.Then make tablet be warming up to room temperature to be kept for 15 minutes, then add 10ul Detecting mixture, (mouse of 1nM streptavidins Eu+W1024 and 5 μ g/ml and SureLight APC antibody conjugates are anti- DYKDDDDK IgG；It is all from Columbia Biosciences) arrive all holes.Tablet is centrifuged 1 minute with 500rpm, Incubated at room temperature 1 hour, and emit optical filter on Envision plate readers using 320nm exciter filters and 615nm and 665nm Reading.Ratio calculation compound response (% inhibition) based on two kinds of transmittings (665nm/615nm) and efficiency (pIC50), then By the data of conversion relative in measurement control normalization (control 1%DMSOs of 1=in the presence of Nrf2 and Keap1 albumen, Compare 1%DMSOs of the 2=only in the presence of Nrf2 albumen).It uses software package Abase XE (Surrey, United Kingdom) Handle data analysis.By following equation % inhibiting values are calculated from ratio (conversion) data：

100- (100* (compound response-average control 2)/(average control 1- average controls 2)).

Calculating for pIC50, Abase XE use 4 parameter equations.

Application method

The compounds of this invention is Nrf2 conditioning agents and for treating or preventing Respiratory Disturbances, including COPD, asthma, Fibrosis, pulmonary infection, nephrosis/chronic kidney disease, autoimmune disease (such as multiple sclerosis and inflammatory bowel disease), Eye diseases (such as AMD, Fuchs and uveitis), angiocardiopathy, nonalcoholic fatty liver disease (NASH), Parkinson Disease, Alzheimer disease, psoriasis, acute kidney injury, the local effect of radiation and kidney transplant.

Therefore, on the other hand, the present invention relates to the methods for treating the illness.

The therapy of the present invention includes that the compound of formula I or its medicine of safe and effective amount are administered to patient in need Acceptable salt on.

" treatment " used in this application refers to when being related to illness：(1) improve or prevent the illness or the illness One or more biological performances, (2) interference (a) cause or the biological cascade of the illness are caused one or more of to react Point, or (b) one or more biological performances of the illness, (3) mitigate with the relevant one or more symptoms of the illness or Effect, or (4) slow down the progress of one or more biological performances of the illness or the illness.

Technical staff understands that " prevention " is not an absolute terms.On drug, " prevention " is understood to preventative Administration medicine with reduce substantially illness or its biological performance possibility seriousness or for postpone the illness or its biology The morbidity of performance.

" safe and effective amount " used in this application the present invention is concerned compound or whens other forms of pharmacologically active agents refer to In rational medical judgment scope, the amount of the compound is enough to treat the illness of the patient, but be it is sufficiently low to Avoid serious side reaction (there is rational interests/Hazard ratio).The compound of safe and effective amount can be with selected specific Compound (for example, it is contemplated that the potential of the compound, effect and half-life period)；Selected administration route；The illness treated； The seriousness for the illness treated；Age, build, weight and the physiological status of treated patient；The drug of the patient treated History；The duration of the treatment；The property for the therapy being carried out at the same time；Desired therapeutic effect；Change with similar factor, But it still can routinely be determined by technical staff.

" patient " used in this application refers to people or other animals.

The compounds of this invention can be administered by any administration route appropriate, including Formulations for systemic administration and local administration.Whole body Administration includes oral medication, parenteral administration, cutaneous penetration, rectally and passes through inhalation.Parenteral administration refers to non- Intestines, non-transdermal or non-approach by inhalation and usually pass through injection or administered by infusion.Parenteral administration includes vein Interior administration, intramuscular administration and hypodermic injection or infusion.Sucking refers to being administered into the lung of patient, whether by mouth sucking or It is sucked by nasal meatus.Local administration includes being administered to skin and eye drops, ear administration, intravaginal administration and intranasal administration.

The compounds of this invention can be administered primary or more according to being administered with different time intervals wherein in given time period The Dosage Regimens Dosage of secondary dosage.For example, can be administered once daily, twice, three times or four dosage.It can dosage always Until realizing desired therapeutic effect or being irregularly administered to maintain desired therapeutic effect.For the compounds of this invention Appropriate dosage regimen depends on the pharmacokinetic property of the compound, such as absorption, distribution and half-life period, this can be by technology Personnel determine.In addition, for the compounds of this invention suitable dosage regimen (the administration duration for including the program) according to Rely in the illness treated, the severity for the illness treated, the age of the patient treated and physiological status, treat trouble The pharmacohistory of person, the property for the treatment being carried out at the same time, desired therapeutic effect and knowledge and professional knowledge in technical staff Similar factor in range.Technical staff is further appreciated that, suitable dosage regimen may need in view of individual patient to this to The reaction of prescription case and be adjusted, or since the change of individual patient demand is adjusted at any time.

Common daily dosage can change according to selected specific administration route.Usual amounts for oral medication Ranging from daily everyone 1mg to 1,000mg.Preferred dosage is 1-500mg once a day, everyone more preferably daily 1- 100mg.Intravenously (IV) dosage range be 0.1-1,000mg/ day, preferably 0.1-500mg/ days with more preferably 0.1- 100mg/ days.The daily dosage of sucking ranging from 10 μ g-10mg/ days, preferably 10 μ g-2mg/ days and more preferably 50 μ g-500 μ g/ days.

In addition, the compounds of this invention can be used as prodrug administration." prodrug " of the compounds of this invention used in this application is institute The functionality derivative for stating compound finally discharges the compound of the present invention in vivo after being administered to patient.Prodrug is administered The compounds of this invention of form can enable a technician to accomplish one of the following or many aspects:(a) change the chemical combination Object starts the time to play a role in vivo；(b) change the duration that the compound acts in vivo；(c) change institute State the transhipment or distribution of compound in vivo；(d) change the solubility of the compound in vivo；(e) overcome side reaction or Other difficulties that the compound encounters.The common functionality derivative for being used to prepare prodrug includes chemistry or enzyme in vivo The modification of the compound of fracture.Such modification is well known to those skilled in the art, including prepare phosphate, amide, ether, Ester, thioesters, carbonic ester and carbamate.

Composition

Before administered patient, the compounds of this invention is generally but not that can necessarily be formulated into pharmaceutical composition.Therefore, exist Another aspect of the present invention, is related to pharmaceutical composition, and the composition includes the compounds of this invention and one or more pharmacy Upper acceptable excipient.

The pharmaceutical composition of the present invention can be prepared and packed with bulk form, wherein safe and effective amount can be taken out Then the compounds of this invention is given in the form of powder or syrup in the patient.Selectively, the drug of the present invention can be prepared Composition is simultaneously packaged into unit dosage form, wherein each physically discrete unit contains the present invention of safe and effective amount Compound.When preparing in a unit, pharmaceutical composition of the invention usually contains 1mg to 1000mg.

The pharmaceutical composition of the present invention usually contains a kind of the compounds of this invention.However, this hair red in some embodiments Bright pharmaceutical composition contains more than one the compounds of this invention.For example, in some embodiments, pharmaceutical composition of the invention Object is containing there are two types of the compounds of this invention.In addition, the pharmaceutical composition of the present invention optionally can further contain one kind or multiple additional Pharmaceutically active compound.

" pharmaceutically acceptable excipient " used in this application refers to pharmaceutically acceptable substance, composition or medium Object, they are related to that described pharmaceutical composition is made to have form or consistency.When mixing, each excipient must be with the drug The other compositions of composition are compatible, thus avoid interacting, which can substantially reduce the compounds of this invention when administration Effect when patient, and the interaction can obtain acceptable pharmaceutical composition in non-pharmaceutical.In addition, each excipient is worked as Must so have sufficiently high purity so that it is pharmaceutically acceptable.

The compounds of this invention and pharmaceutically acceptable excipient (one or more) are usually formulated as being suitable for passing through institute Desired administration route delivers medicine to the dosage form of the patient.For example, dosage form includes being suitable for those of following situations：(1) take orally to Medicine, such as tablet, capsule, Caplet, pill, dragee, powder, syrup, elixir, suspension, solution, emulsion, anther sac , such as sterile solution agent, suspension and the powder agent for reconstruct (sachet) and cachet (2) parenteral administration；(3) transdermal Administration, such as transdermal patch；(4) rectally, such as suppository；(5) it sucks, such as dry powder, aerosol, suspension and solution Agent；(6) local administration, such as cream, ointment, lotion, solution, paste, spray, foaming agent and gelling agent.

Suitable pharmaceutically acceptable excipient can change according to selected specific dosage form.In addition, suitable medicine Acceptable excipient can be directed to the concrete function that they are played in the composition and be selected on.For example, some pharmacy Upper acceptable excipient is selected as the ability for having the generation for promoting equal one dosage type low temperature due to them.Some are pharmaceutically acceptable Excipient be selected as due to they have promote stabilizer type generation ability.Some pharmaceutically acceptable excipient It is selected as promoting the compounds of this invention after delivering medicine to the patient from an organ of body or position since they have Carry or be transported to another organ of body or the ability at position.Some pharmaceutically acceptable excipient be selected as due to They have the ability of enhancing patient's compliance.

Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, adhesive, collapses filler Solve agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, flavoring Agent, odor mask, colorant, anti-caking agent, moisturizer, chelating agent, plasticizer, tackifier, antioxidant, preservative, stabilizer, Surfactant and buffer.Technical staff understands that some pharmaceutically acceptable excipient can exist according to the excipient Have that how many and which kind of other compositions are present in said preparation and play more than one function and can play replacement work(in preparation Energy.

Technical staff grasps the knowledge and skills of this field, so as to make them select appropriate amount used in this invention Suitable pharmaceutically acceptable excipient.In addition, being technology people there are many data of pharmaceutically acceptable excipient is described Member is obtainable and can be used for selecting suitable pharmaceutically acceptable excipient.Example includesRemington'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 composition of the present invention is prepared using technology and methods well known by persons skilled in the art.Commonly used in the art Some descriptions in method existRemington's Pharmaceutical Sciences(Mack Publishing Company in).

In an aspect, the present invention relates to solid oral dosage form such as tablet or capsule, it includes safe and effective amounts The compounds of this invention and diluent or filler.Suitable diluent and filler include lactose, sucrose, dextrose, mannitol, mountain Pears sugar alcohol, starch (for example, cornstarch, potato starch and pregelatinized starch), cellulose and its derivates are (for example, crystallite Cellulose), calcium sulfate and two basic calcium phosphates.The oral dosage form can further include adhesive.Suitable adhesive Including starch (for example, cornstarch, potato starch and pregelatinized starch), gel, Arabic gum, sodium alginate, alginic acid, Tragacanth, guar gum, povidone and cellulose and its derivates (for example, microcrystalline cellulose).The oral dosage form can Further include disintegrant.Suitable disintegrant includes Crospovidone, primojel, Croscarmellose, alginic acid And sodium carboxy methyl cellulose.The oral dosage form can further include lubricant.Suitable lubricant include stearic acid, Magnesium stearate, calcium stearate and talcum.

On the other hand, the present invention relates to suitable for parenteral administration in patient include subcutaneous administration, intramuscular administration, vein The dosage form of interior administration or intradermal administration.Pharmaceutical preparation suitable for parenteral administration includes aqueous and non-aqueous sterile injection solution, It contains anti-oxidants, buffer, bacteriostatic agent and the solute for keeping the preparation isotonic with the blood of expected recipient；And water Property and non-aqueous sterile suspensions, may include suspending agent and thickener.The preparation may be present in single dose or multi-dose holds It in device, such as in the ampoule bottle and bottle of sealing and can be stored under the conditions of freeze-drying (freeze-drying), it is only necessary to will make With preceding addition sterile liquid carrier such as water for injection.Extemporaneous injection solutions can be prepared by aseptic powdery, particle and tablet and are hanged Supernatant liquid.

On the other hand, the present invention relates to suitable for by inhalation in the dosage form of patient.For example, the compounds of this invention It can be drawn into lung in the form of dry powder, aerosol, suspension or solution.

Chemical combination of the present invention for generally comprising finely pulverized powder type by the dry powder composite of inhalation delivery to lung The pharmaceutically acceptable excipient of object and one or more finely pulverized powder types.The pharmacy being particularly well suited for being used in dry powder Upper acceptable excipient is well known to those skilled in the art and includes lactose, starch, mannitol and monosaccharide, disaccharides and more Sugar.

Dry powder composite used according to the invention can be administered by suction apparatus.It is this as an example Device may include the bubble-cap of the capsule and cylindrantherae such as laminated aluminium foil of such as gelatin.In various embodiments, each Capsule, cylindrantherae or bubble-cap can include multi-dose according to the composition instructed herein.The example of suction apparatus may include purport For those of unit dose or multi-dose delivering compositions, including all devices as described herein.As an example, In the case that multi-dose delivers, preparation can be pre-metered (for example, such asReferring to GB2242134, U.S. Patent number 6,032,666,5,860,419,5,873,360,5,590,645,6,378,519 and 6,536,427 or Diskhaler, referring to GB 2178965,2129691 and 2169265, U.S. Patent number 4,778,054,4,811,731,5,035,237) or metering make With (such as Turbuhaler, referring to EP 69715 or U.S. Patent number 6, the device described in 321,747).Dosage unit is set Standby example is Rotahaler (referring to GB 2064336).In one embodiment,Suction apparatus includes by having What is formed there are many substrate of groove elongated lath (groove is along its length interval) and the cover plate that can be removed that is sealed against, To limit many containers, there is inhalable preparation in each container, compound is contained in preparation, optionally contains and instruct herein Other excipient and additive.Strippable sealing device is engineering sealing device, and in one embodiment, work Journey sealing device is hermetic sealing.Preferably, lath is sufficiently flexible so as to being coiled into scroll.Cover plate and substrate preferably have Fore-end not sealed against one another, and design at least one fore-end and be connected with winding device.It is also preferred that in base Engineering sealing between matter and cover plate expands to its full width.Can preferably cover plate in the head end from the substrate with longitudinal direction Mode is removed from substrate.

Dry powder composite also is present in suction apparatus, allows two kinds of different components for dividually including composition. Thus, for example, these components can be administered simultaneously, but it is stored, for example, in separated pharmaceutical composition, example As described in WO 03/061743A1, WO 2007/012871A1 and/or WO2007/068896.In one embodiment, The suction apparatus for allowing individually to accommodate component is the inhaler device having there are two peelable blister strips, and each item includes along its length Spend the pre-metered dose in the blister pouch of arrangement, such as the multiple containers in each blister strips.Described device has internal index Mechanism, when each device is activated, the pocket of each band of peel-to-open simultaneously positions bubble-cap so that the new exposure of each of each band The neighbouring manifold being connected to the mouthpiece of device of dosage.When patient's air-breathing at mouthpiece, each dosage is relevant from its simultaneously It is extracted out in pocket, the respiratory tract of patient is entered into manifold and via mouthpiece entrainment.Another kind, which allows to separate, accommodates heterogeneity Device be Innovata DUOHALER^TM.In addition, other than delivering simultaneously, the various structures of suction apparatus additionally provide From device sequence or dividually deliver pharmaceutical composition.

Aerosol can be formed by the way that the compounds of this invention to be suspended or dissolved in liquefied propellant.Suitable propellant packet Include halogenated hydrocarbons, hydrocarbon or other liquefied gas.Representative propellant includes:Arcton 11 (propellant 11), dichlorofluoromethane (promote Agent 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- Difluoroethanes (HFA-152a), difluoro Methane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, Butane, iso-butane and pentane.Including the aerosol of the compounds of this invention is usually delivered medicine to by the inhalator of dosing (MDI) Patient.Described device is known to the skilled in the art.

The aerosol contains other pharmaceutically acceptable, commonly used in multi-dose inhaler excipient, such as Surfactant, lubricant, cosolvent and other excipient are to improve the physical stability of the preparation, raising valve performance, carry High-dissolvability improves taste.

Including the suspension and solution of the compounds of this invention also can deliver medicine to patient by atomizer.Solvent for atomization Or suspending agent can be arbitrary pharmaceutically acceptable liquid such as water, saline solution, alcohol or glycol, for example, ethyl alcohol, isopropyl Alcohol, glycerine, propylene glycol, polyethylene glycol etc. or their mixture.The salt that saline solution uses show upon administration seldom or Hardly show pharmacological activity.Organic salt and inorganic salts can be used in the purpose, and inorganic salts are the halogen of such as alkali metal or ammonium Salt, for example, sodium chloride, potassium chloride, organic salt is sylvite, sodium salt and the ammonium salt of such as organic acid, and the organic acid is for example, anti-bad Hematic acid, citric acid, acetic acid, tartaric acid etc..

Other pharmaceutically acceptable excipient can be added into the suspension or solution.The compound of the present invention can Stablized by adding following substance：Inorganic acid, for example, hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid；Organic acid, for example, anti-bad Hematic acid, citric acid, acetic acid and tartaric acid etc.；Complexing agent such as EDTA or citric acid and its salt；Or antioxidant such as vitamin E Or ascorbic acid.These substances be can be used alone or be used together to stablize the compounds of this invention.Preservative such as benzene can be added Prick oronain or benzoic acid and its salt.Surfactant can be specifically added to improve the physical stability of suspension.These include ovum Phosphatide, dioctyl sodium sulfosuccinates acid disodium, oleic acid and sorbitan ester.

Formula (I) and (II) compound and its pharmaceutically acceptable salt can be used for combining with one or more other drugs, The other drugs can be used for preventing or treat such as anaphylactia, inflammatory disease, autoimmune disease；Antigen is immune to be treated Method, antihistamine, corticosteroid, (such as fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, cloth how Moral, ciclesonide, momestasone furoate, triamcinolone, flunisolide), NSAID, leukotriene modifer (prick by such as montelukast Lu Site, Pranlukast), iNOS inhibitor, tryptase inhibitors, IKK2 inhibitor, p38 inhibitor, Syk inhibitor, Protease inhibitors such as elastatinal, integrin antagonists (for example, Beta 2 integrin antagonist), adenosine A2a agonists, tramsmitter release inhibitor such as nasmil, 5- lipoxidase inhibitors (zyflo), DP1 antagonists, DP2 are short of money Anti-agent, PI3K δ inhibitor, ITK inhibitor, LP (lysophosphatidic acid) inhibitor or FLAP (5- lipoxygenase-activating proteins) inhibit Agent (such as 3- (3- (tert. butyl-sulphenyl) -1- (4- (6- ethoxy pyridine -3- bases) benzyl) -5- ((5- picoline -2- bases) first Oxygroup) -1H- indoles -2- bases) -2,2-Dimethylpropionic acid sodium), bronchodilators is (for example, muscarinic antagonist, β -2 are exciting Agent), methotrexate (MTX) and similar medicine；Monoclonal antibody therapy is for example anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL- 12, anti-IL-1 and similar medicine；Cell factor receptor autogenic therapy such as Etanercept and similar medicine；Antigen-non-specific is immune Therapy (for example, interferon or other cell factor/chemotactic factor (CF), chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cell factors/chemotactic factor (CF) agonist or antagonist, TLR agonists and similar medicine).

The compound can also be used for and the pharmaceutical composition of transplanting, including cyclosporin, tacrolimus, wheat is contributed to examine phenol Sour not ester, prednisone, imuran, sirolimus, daclizumab, basiliximab or OKT3.

They can be used for and the pharmaceutical composition for diabetes:Melbine (biguanides), meglitinide, sulfonylureas Class, DPP-4 inhibitor, thiazolidinediones, Alpha-glucosidase inhibitor, Amylin analogies, duodenin, insulin.

The compound can be used for and antihypertensive pharmaceutical composition, such as diuretics, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, ARBS, calcium channel Blocking agent and Beta receptor blockers.

One embodiment of the invention includes combination (combination), and it includes one or two kinds of other therapeutic agents.This Field technology personnel it is clear that in appropriate circumstances, the other treatment ingredient can in a salt form (such as alkali metal or Amine salt) it uses, or as an acid addition salt form or the form of prodrug or the form (such as lower alkyl esters) of ester use, or with molten The form that object (such as hydrate) is closed in agent uses, to make therapeutic component activity and/or stability and/or physical characteristic for example Solubility optimizes.It is also clear that in appropriate circumstances, the therapeutic component can be used in the form of optically pure.

Combination above-mentioned can advantageously be provided to be used in pharmaceutical dosage form, therefore include combination as defined above An additional aspect of the present invention is represented with the pharmaceutical preparation of pharmaceutically acceptable diluent or carrier.

Each compound of the combination can be administered or be administered simultaneously successively in pharmaceutical preparation alone or in combination.One In a embodiment, each compound is administered simultaneously in the pharmaceutical preparation of combination.The suitable dosage of known treatment agent is ability Field technique personnel are readily comprehensible.

Therefore, the present invention provides pharmaceutical composition on the other hand, and it includes the compounds of this invention to treat with another The combination of activating agent.

Embodiment

The present invention is described referring now to embodiment below, these examples are merely illustrative, should not be construed For limitation of the scope of the invention.All temperature all by degree Celsius as unit of provide, all solvents be all highest can get purity And all reactions are optionally in anhydrous conditions in argon gas (Ar) or nitrogen (N₂) carry out in atmosphere.

Analtech Silica Gel GF and E.Merck Silica Gel 60F-254 lamellaes are used for thin layer color Spectrometry.Flash chromatography and gravimetric chromatography method are carried out on silica gel 230-400,100-200&60-120Cilicant Brand 's.It is used for purifying in this applicationSystem is purchased from Isco, Inc.Purifying is to use Silicagel column, the UV wavelength of prepackage are carried out in the detector and multi-solvents or solvent combination of 254nm.

Preparative HPLC is using Gilson the or Waters preparatives system detected with variable wavelength UV or with matter Agilent Mass Directed AutoPrep (MDAP) systems or Shimadzu of amount detection and variable wavelength UV detections What PREP LC 20AP were carried out.A variety of reversed-phase columns for example, Luna C18 (2), SunFire C18, XBridge C18, Atlantics T3, Kromasil C18, Xbridge Phenyl-Hexyl columns are used in the purifying, the selection of column support Dependent on the condition used in the purifying.Use CH₃The gradient elution compound of CN or first alcohol and water.Neutrallty condition uses CH₃CN and water gradient, without additional modifying agent, acid condition uses sour modifying agent, usual 0.1%TFA or 0.1% formic acid, and Alkaline condition uses basic modifier, usually 0.1%NH₄OH (being added to the water) or 10mM ammonium hydrogen carbonate (being added in water), Or 0.05%NH₄HCO₃(being added in water).

Analytic type HPLC be using with 2996PDA detectors Agilent systems or Waters Alliance HPLC, What Waters Acquity UPLC-MS or Agilent Infinity 1290 with PDA were carried out, or in Sunfire C18 It on column, or is carried out using RP chromatography on XSELECT CSH C18 columns, uses CH₃The gradient of CN and water have 0.1% Formic acid modifying agent (is added to each solvent), and alkaline condition uses basic modifier, usually 5mM ammonium hydrogen carbonate or 10mM carbonic acid PH is adjusted to 10 by the aqueous solution of hydrogen ammonium with ammonia solution.Compound by lcms analysis, using Shimadzu LC systems with UV 214nm wavelength detectings and H₂O-CH₃CN gradient elutions (4-95% is through 1.9min.), are acidified to 0.02%TFA.Reversed-phase column is 2.1x20mm Thermo Hypersil Gold C18 (1.9u particles), at 50 DEG C.Single quadrupole MS detectors are with cation Sciex 150EX or the Waters ZQ of operation.Alternatively, LC-MS is to use PE Sciex Single Quadrupole 150EX LC-MS or Waters ZQ Single Quadrupole, Waters 3100Single Quadrupole, Agilent What 6130SQD or Agilent 6120Single Quadrupole LC-MS instruments determined.Use reversed-phase column such as Thermo Hypersil Gold C18 and/or Luna C18 analyze the compound, use CH₃The gradient of CN and water is eluted, wherein Sour modifying agents such as 0.02% containing low percentage or 0.1%TFA.

Preparative chirality SFC be using with single wavelength UV detecting systems Thar/Waters preparative SFC systems into Capable.A variety of chirality SFC columns, such as Chiralpak IA, IC, AY, AD, IF, OJ are used in the purifying.Use shooting flow Body CO₂The compound is eluted with cosolvent, the cosolvent is such as MeOH, and EtOH, IPA and these solvents are based on compound Combination in varing proportions.Modifying agent (0.1% to 0.4% TFA, NH can be used on demand₄OH, DEA, TEA).Using above-mentioned Chiral column and pyridinyl amides carry out normal-phase chromatography, and ethylpyridine achirality column is respectively used to the purifying of chiral and achirality.According to It needs to use modifying agent (0.1% TFA, NH₄OH, DEA).K PREP Lab 100G-YMC instruments are net for positive preparation scale Change.

Analytic type chirality SFC is using the Thar/Waters SFC system operations with variable wavelength UV detections.At this A variety of chirality SFC columns, such as Chiralpak IA, IB, IC, ID, IF, AY, AD, OD, C2, AS, OJ, CCL4 are used in purifying. The compound is to use supercritical fluid CO₂With cosolvent elution, the cosolvent is such as MeOH, EtOH, IPA and this Combination of a little solvents based on compound selectivity in varing proportions.Modifying agent (0.1% to 0.4% can be used as needed TFA、NH₄OH、DEA、TEA)。

It for filter aid, is made of the diatomite of acid elution, and is Manville Corp., Denver, The registered trademark of Colorado.For the absorbent based on functionalized silica gel and it is Biotage AB Corp., The registered trademark of Sweden.

NMR spectrum is using Bruker AVANCE 400 or Brucker DPX400 spectrometers or Varian MR400 spectrometers are recorded in 400MHz.CDCl₃For deuterochloroform, DMSO-D₆It is four for hexadeuterated dimethyl sulfoxide and MeOD Deuterated methanol, CD₂Cl₂For deuterated dichloromethane.Chemical shift is in the downfield from internal standard tetramethylsilane (TMS) (downfield) with parts per million (δ) be unit report and be calibrated in NMR solvents (for example, CHCl₃In CDCl₃ In) residual protons signal.Abbreviation for NMR data is as described below:S=is unimodal, d=doublets, t=triplets, q=tetra- Weight peak, m=multiplets, dd=double doublets, the bis- triplets of dt=, app=be apparent, br=broad peaks.J indicates with Hertz to be single The NMR coupling constants that position measures.

It is in Biotage with microwave radiation heating reaction mixtureIt carries out on microwave reactor, usually adopts It is configured with high-selenium corn.

After cylinder or column equipped with the polymer based on functional group's (acid, alkali, metal-chelator etc.) are used as compound A part for reason.During " amine " column or cylinder are used for and/or alkalization acidic reaction mixture or product.These include NH2 aminopropyls SPE-ed SPE columns (being obtained from Applied Separations) and diethylamino SPE columns (are obtained fromUnited Chemical Technologies, Inc.)。

The table of abbreviation

Intermediate 1

The bromo- 2,3- dihydros -1H- indenes -1- alcohol of 6-

Under nitrogen protection, to bromo- 2, the 3- dihydros -1H- 1-Indanones (5g, 23.69mmol) of 6- in methanol (50mL) Sodium borohydride (0.896g, 23.69mmol) is added in solution.Reaction mixture is stirred at ambient temperature 2 hours.Then subtract Pressure removes solvent.Residue is dissolved in 100mL ethyl acetate and 20mL 1N HCl.By organic layer separation and water layer is used EtOAc (3 × 30mL) is extracted.Combined organic layer is washed with brine (30mL), uses anhydrous Na₂SO₄It is dried and concentrated, obtains The bromo- 2,3- dihydros -1H- indenes -1- alcohol (5.0g, 23.47mmol, 99%) of title compound 6-.LC-MS m/z 195.0(M-OH )⁺, 1.46 minutes (retention time).

Intermediate 2

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes

At 0 DEG C, to bromo- 2, the 3- dihydros -1H- indenes -1- alcohol (7g, 32.9mmol) of 6- in n,N-Dimethylformamide NaH (1.314g, 32.9mmol) is added in solution in (80mL).By reaction mixture in N₂Under protection 30 are stirred at 0 DEG C Minute, 1- (chloromethyl) -4- methoxybenzenes (5.15g, 32.9mmol) are then added into reaction, reaction mixture is in environment temperature It is continuously stirred under degree 2 hours, uses 300mL H later₂O is quenched and EtOAc (3x 100mL) is used to extract.Combined organic layer is used Water (100mL), brine (100mL) washing, use anhydrous Na₂SO₄It is dried and concentrated.Pass through silica gel chromatograph (petrol ether/ethyl acetate =10:1) residue is purified, the bromo- 1- of title compound 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes is obtained (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

The bromo- 2,3- dihydros -1H- indenes -1- alcohol of 6-

At 0 DEG C, to solution of bromo- 2, the 3- dihydros -1H- 1-Indanones (30g, 142mmol) of 6- in methanol (100mL) In NaBH is added portionwise₄(10.76g,284mmol).Reaction mixture is stirred at ambient temperature 1 hour.Reaction is mixed Object is concentrated under reduced pressure and uses the NaHCO of saturation₃Solution quenches, and then EtOAc (2X) is used to extract, uses Na₂SO₄It dries and filters.It will filter Liquid is concentrated under reduced pressure and by using (2:8)EtOAc:The purification by flash chromatography of hexane.Product fraction is concentrated, title compound is obtained Object (23g, 76% yield).¹H NMR(400MHz,CDCl₃) δ ppm=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 alkane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol

Into solution of the bromo- 2,3- dihydros -1H- indenes -1- alcohol (12g, 56.3mmol) of 6- in 1,4- dioxanes (100mL) Two (pinacol combined) two boron (18.59g, 73.2mmol), potassium acetate (13.82g, 141mmol) is added, mixture argon gas is existed It deaerates 20 minutes in seal pipe.PdCl is added₂(dppf) (2.060g, 2.82mmol), and reaction mixture is stirred at 90 DEG C It mixes 2 hours.Reaction mixture is filtered by diatomite and is washed with ethyl acetate.Filtrate decompression is concentrated, thick remnants are obtained Object.Thick residue is purified as the column chromatography of eluant, eluent by using the n-hexane of 20% ethyl acetate.The fraction of elution is subtracted Pressure concentration, obtains title compound (12g, 82% yield).¹H NMR(400MHz,CDCl₃) δ ppm=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- nitroanilines

At 0 DEG C, Br is added into mixtures of the NaOH (2.220g, 55.5mmol) in water (12mL)₂(0.322mL, 6.26mmol).Then 3- methyl -2- nitrobenzamides (1g, 5.55mmol) are added at one time, and in a water bath by mixture Slow heating.The material color is dimmed quickly, and at 50-55 DEG C (internal temperature), oil droplet is initially separated.Temperature is gradually risen It is kept for 1 hour to 70 ° and in this temperature.It is slowly added to solution of the NaOH of 0.7g in 4mL water, and temperature is risen to 80 DEG C again One hour.The reaction is cooled to environment temperature and is extracted with EtOAc (3 × 50mL).Combined organic layer is dried and concentrated, Obtain title compound (0.7g, 90%).LC-MS m/z 153.1(M+H)⁺, 1.65 minutes (retention time).

Intermediate 6

The bromo- 3- methyl -2- nitroanilines of 4-

By the mixed of NBS (51.5g, 289mmol), 3- methyl -2- nitroanilines (44g, 289mmol) and acetic acid (450mL) Object is closed to stir 1 hour at 110 DEG C.The mixture is cooled to environment temperature and is poured into water (100mL).Solid is collected, is obtained To 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- nitroanilines

At 25 DEG C, to the bromo- 3- methyl -2- nitroanilines (20g, 87mmol) of 4- in n,N-Dimethylformamide NaH (3.81g, 95mmol) is added in solution in (200mL).Reaction mixture is stirred 30 minutes at 25 DEG C.Then plus Enter iodomethane (12.90g, 91mmol).Reaction mixture is stirred 12 hours.Reaction mixture is poured into water, solid is collected, Obtain title compound (18g, 59.4%).LC-MS m/z 247.0 (M+H)+, 1.90 minutes (retention time).

Intermediate 8

The bromo- N1,3- dimethyl benzenes -1,2- diamines of 4-

At ambient temperature, to the bromo- N of 4-, 3- dimethyl -2- nitroanilines (65g, 265mmol) in ethyl alcohol (600mL) and Ammonium chloride (142g, 2652mmol) is added in solution in water (300mL), is subsequently added into iron (59.2g, 1061mmol).It will be anti- Mixture is answered to be stirred 4 hours at 90 DEG C.Reaction mixture is cooled to environment temperature and is filtered by Celite pad, is used EtOAc (100mL) is washed, filtrate evaporated in vacuo.By residue NaHCO₃Solution (500mL) dilutes, and EtOAc (2x are used in combination 500mL) extract.Combined organic layer is washed and with saline solution (500mL) through Na₂SO₄It is dry, it filters and is evaporated in vacuo molten Agent.By using EtOAc:Hexane (3:7) column chromatography purifies thick residue.It evaporates the partial vacuum of elution to obtain 4- bromo- N1,3- dimethyl benzene -1,2- diamines (46g, 61.7% yield).LC-MS m/z 214.9(M+H)⁺, 2.54 minutes (when reservation Between).

Intermediate 9

Bromo- 1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles of 5-

At 0 DEG C to the bromo- N1 of 4-, 10%H of 3- dimethyl benzenes -1, the 2- diamines (30g, 139mmol) in 17ml₂SO₄In it is molten Through 20 minutes with aliquot addition sodium nitrite (13.47g, 195mmol) in liquid.After reaction mixture is stirred for 30 minutes, add Add 200mL water.Gained precipitation is collected by filtration, and is washed with water and dries.Mother liquor is stood 16 hours, forms second lot Precipitation collects it before.Combined solid crosses column to remove inorganic salts with EtOAc, obtain 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- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate

To bromo- 1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles (10g, 44.2mmol) of 5- in N, N- dimethyl formyls In solution in amine (20mL) be added tri-o-tolyl phosphine (2.69g, 8.85mmol), methyl acrylate (7.62g, 88mmol) and DIPEA (23.18mL, 133mmol).Then addition Pd (OAc)₂(0.993g, 4.42mmol).By reaction mixture at 100 DEG C Stirring 12 hours.It pours the mixture into water and is extracted with EtOAc (30mL).By organic layer drying and concentration is slightly to be produced Object.It passes through silica gel column chromatography (petroleum ether:EtOAc=4:1) it purifies, obtains 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- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- Base) ethyl propionate

In seal pipe, to (E) -3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate 6- (4,4,5,5- tetramethyls are added in the solution of (3.5g, 14.27mmol) in 1,4- dioxanes (10mL)/water (10.00mL) Base -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol (4.83g, 18.55mmol), 6- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol (4.83g, 18.55mmol). With argon cleaning mixture 20 minutes, be subsequently added into (1,5- cyclo-octadiene) radium chloride (I) dimer (0.704g, 1.427mmol).Reaction mixture is stirred 16 hours at 95 DEG C.Reaction mixture is quenched with cold water, with EtOAc (2X) and Brine extracts.By organic layer through anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and in another experiment with Identical crude Compound prepared by 3.5g scales merges.By combined crude Compound by using EtOAc:Hexane (40:60) Column chromatography purifying, obtain title compound (3g, 55.4% yield).LC-MS m/z 380(M+H)⁺, (retain within 2.09 minutes Time).

Intermediate 12

4- ethyl cyclohexane Ethyl formates

Under nitrogen atmosphere, at ambient temperature, to 4- ethyl cyclohexanes formic acid (15g, 96mmol) in ethyl alcohol (200mL) Solution in be slowly added to H₂SO₄(1mL,18.76mmol).Reaction mixture is stirred 16 hours at 80 DEG C.Then water is used (100mL) diluting reaction is simultaneously extracted with EtOAc (3x 200mL).By mixture under nitrogen flowing in 50 DEG C of concentrations, title is obtained Compound (15g, 76% yield), without further purification i.e. in next step.LC-MS m/z 185(M+H)⁺, 2.32 points Clock (retention time).

Intermediate 13

(4- ethylcyclohexyls) methanol

Under a nitrogen, in 0 DEG C of solution to 4- ethyl cyclohexanes Ethyl formate (15g, 81mmol) in THF (200mL) In be slowly added to LiAlH₄(5g,132mmol).Mixture is stirred at ambient temperature 4 hours.Then the reaction is cooled to 0 DEG C, and reaction is quenched with water (5mL), 10%NaOH (5mL) and water (15mL) successively.Reaction is filtered and concentrated, title is obtained Compound (11.5g, 94% yield).LC-MS m/z 125(M-OH)⁺, 1.94 minutes (retention time).

Intermediate 14

4- toluenesulfonic acids (4- ethylcyclohexyls) methyl ester

Under a nitrogen, at 10 DEG C, to (4- ethylcyclohexyls) methanol (11.5g, 81mmol) in DCM (500mL) 4- methylbenzene -1- sulfonic acid chlorides (15.41g, 81mmol), TEA (22.54mL, 162mmol) and DMAP are slowly added in solution (0.988g,8.09mmol).Reaction mixture is stirred 16 hours at 10 DEG C.Reaction is diluted with water (10mL), is used in combination EtOAc (3X 30mL) is extracted, and Isolute is added in the organic layer of merging, and by mixture in a nitrogen atmosphere at 50 DEG C Lower concentration.By the crude product adsorbed through Isolute by purification by flash chromatography, (hexane is used in combination:Ethyl acetate=20:1) it elutes, Title compound 4- toluenesulfonic acids (4- ethylcyclohexyls) methyl ester (18g, 71.4% yield) is obtained, is solid.LC-MS m/z 319(M+23)⁺, 2.38 minutes (retention time).

Intermediate 15

2- (bromo- -2 (the 3H)-subunits of 1- oxos -1H- indenes of 6-) acetic acid

Under a nitrogen, at ambient temperature, to bromo- 2, the 3- dihydros -1H- 1-Indanones (5g, 23.69mmol) of 6- in Isosorbide-5-Nitrae - 2- Oxoacetic Acids (35.1g, 237mmol), H are slowly added into solution in dioxane (20mL)₂SO₄(5mL,94mmol).It will Reaction mixture stirs 4 hours at 100 DEG C.The reaction is cooled to environment temperature, and water (100mL) is added to the reaction In.Filtering reacts and dries white solid under a high vacuum, obtains title compound (5.6g, 84% yield).LC-MS m/z 268(M+H)⁺, 1.56 minutes (retention time).

Intermediate 16

2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetic acid

Under a nitrogen, at ambient temperature, to 2- (bromo- -2 (the 3H)-subunits of 1- oxos -1H- indenes of 6-) acetic acid (5.6g, 20.97mmol) zinc (3.43g, 52.4mmol) is slowly added into the solution in acetic acid (50mL) and water (15mL).It will reaction Mixture stirs 0.5 hour at 100 DEG C, and water (50mL) is added in reaction, is extracted with EtOAc (3 × 100mL).It will mixing Object in 50 DEG C of concentrations, obtains title compound (5g, 84% yield) under nitrogen flowing, is white solid.LC-MS m/z 269(M +H)⁺, 1.47 minutes (retention time).

Intermediate 17

2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetamide

Under a nitrogen, at 20 DEG C, to 2- (bromo- 1- oxos -2, the 3- dihydro -1H- indenes -2- bases of 6-) acetic acid (24g, 89mmol) oxalyl chloride (78mL, 892mmol) is slowly added into the solution in toluene (200mL).By reaction mixture 20 It is stirred 16 hours at DEG C.It is diluted reaction concentration and with DCM (300mL).Reaction mixture is cooled to 0 DEG C, ammonium hydroxide is added dropwise (50mL, 647mmol), and stir 4 hours at ambient temperature.Then use DCM (3 × 200mL) extraction reactions, concentration organic molten Agent.By residue ethyl acetate and hexane (1:1) it grinds, obtains title compound (14g, 54.4% production for white solid Rate).LC-MS m/z 268(M+H)⁺, 1.63 minutes (retention time).

Intermediate 18

The bromo- 1,3a of 7-, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

Under a nitrogen, at ambient temperature, to 2- (bromo- 1- oxos -2, the 3- dihydro -1H- indenes -2- bases of 6-) acetamide It is slowly added into TFA (20.12mL, 261mmol) and triethyl group silicon in the solution of (14g, 52.2mmol) in acetonitrile (250mL) Alkane (78mL, 522mmol).Reaction mixture is stirred 16 hours at 100 DEG C.It is ground by solvent concentration and by residue with hexane Mill, obtains title compound (9.8g, 63.3% yield), without further purification i.e. in next step.LC-MS m/z 252 (M+H)⁺, 1.60 minutes (retention time).

Intermediate 19

The bromo- 1- of 7- ((4- ethylcyclohexyls) methyl) -1,3a, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

Under a nitrogen, at 10 DEG C, to 7- bromo- 1,3a, 4,8b- tetrahydrochysene indeno [1,2-b] pyrroles -2 (3H) -one (4g, 15.87mmol) NaH (2.54g, 63.5mmol) is slowly added into the solution in N,N-dimethylformamide (100mL).It will Reaction mixture stirs 1 hour at 10 DEG C.Later, by 4- toluenesulfonic acids (4- ethylcyclohexyls) methyl ester (9.41g, It 31.7mmol) is added in the solution in 50mL DMF, and is stirred 4 hours at 80 DEG C.Reaction is dilute with water (100mL) It releases, EtOAc (3X100mL) is used in combination to extract.Isolute is added in the organic layer of merging, and under nitrogen flowing by mixture In 50 DEG C of concentrations.By the crude product adsorbed through Isolute by purification by flash chromatography, (hexane is used in combination:Ethyl acetate=4:1) it washes It is de-, obtain title compound (2.6g, 31.8% yield).LC-MS m/z 376(M+H)⁺, 2.00 minutes (retention time).

Intermediate 20

1- ((4- ethylcyclohexyls) methyl) -7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- Base) -1,3a, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

To the bromo- 3- of 5- ((4- ethylcyclohexyls) methyl) -3,3a, 8,8a- tetrahydro cyclopentyl diene simultaneouslies [a] indenes -2 (1H) -one Potassium acetate (3.37g, 34.4mmol) and two (frequencies are added in the solution of (4.3g, 11.46mmol) in 1,4- dioxanes (50mL) Which alcohol closes) two boron (3.78g, 14.89mmol).By reaction mixture argon-degassed 30 minutes, then into reaction mixture PdCl is added₂(dppf)-CH₂Cl₂Adduct (0.936g, 1.146mmol), and stirred 16 hours at 100 DEG C.It then will be anti- It should cool down and be filtered by diatomite, and filter vacuum is concentrated.By using EtOAc:Hexane (1:2) as the fast of eluent Fast column chromatography purifies crude residue, obtains title compound (3.1g, 59.4% yield).LC-MS m/z 424(M+H)⁺, 2.04 minutes (retention time).

Intermediate 21

4- propyl cyclohexane methyl formates

Under a nitrogen, at ambient temperature, to 4- propyl cyclohexanes formic acid (15g, 88mmol) in methanol (100mL) H is slowly added into solution₂SO₄(1mL,18.76mmol).Reaction mixture is stirred 16 hours at 70 DEG C.Water is added (30mL) extracts reaction EtOAc (3 × 50mL).By mixture under nitrogen flowing in 50 DEG C of concentrations, title compound is obtained (15.2g, 94% yield), without further purification i.e. in next step.LC-MS m/z 185(M+H)⁺, (protect within 2.32 minutes Stay the time).

Intermediate 22

(4- propylcyclohexyls) methanol

Under a nitrogen, molten in THF (200mL) to 4- propyl cyclohexanes methyl formate (15g, 81mmol) at 0 DEG C LiAlH is slowly added into liquid₄(5g,132mmol).The mixture is stirred 4 hours at ambient temperature.The reaction is cooled to 0 DEG C, the reaction is quenched with water (5mL), 10%NaOH (5mL) and water (15mL) successively.Reaction is filtered and concentrated, title is obtained Compound (12g, 90% yield) is grease.LC-MS m/z 139(M+H)⁺, 2.07 minutes (retention time).

Intermediate 23

4- toluenesulfonic acids (4- propylcyclohexyls) methyl ester

Under a nitrogen, molten in DCM (200mL) to (4- propylcyclohexyls) methanol (12g, 77mmol) at 10 DEG C 4- methylbenzene -1- sulfonic acid chlorides (14.64g, 77mmol), TEA (21.41mL, 154mmol) and DMAP are slowly added into liquid (0.938g,7.68mmol).Reaction mixture is stirred 16 hours at 10 DEG C.Water (200mL) is added, and mixture is used EtOAc (3 × 200mL) is extracted.Isolute is added in the organic layer of merging, and by mixture under nitrogen flowing in 50 DEG C Concentration.By the crude product adsorbed through Isolute by purification by flash chromatography, (hexane is used in combination:Ethyl acetate=20:1) it elutes, obtains It is white solid to title compound (15g, 57.9% yield).LC-MS m/z 333(M+23)⁺, 2.02 minutes (when reservation Between).

Intermediate 24

The bromo- 1- of 7- ((4- propylcyclohexyls) methyl) -1,3a, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

Under a nitrogen, at 20 DEG C, to 7- bromo- 1,3a, 4,8b- tetrahydrochysene indeno [1,2-b] pyrroles -2 (3H) -one (5g, 19.83mmol) 60%NaH (3.17g, 79mmol) is slowly added into the solution in N,N-dimethylformamide (50mL). Reaction mixture is stirred 1 hour at 20 DEG C.Then 4- toluenesulfonic acids (4- propylcyclohexyls) methyl ester is added DMF (2mL) solution of (12.31g, 39.7mmol), and stirred 4 hours at 80 DEG C.Water (100mL) is added, and by mixture It is extracted with EtOAc (3 × 100mL).Isolute is added in the organic layer of merging, and by mixture under nitrogen flowing in 50 DEG C concentration.By the crude product adsorbed through Isolute by purification by flash chromatography, (hexane is used in combination:Ethyl acetate=4:1) it elutes, Obtain title compound (3.3g, 31.1% yield).LC-MS m/z 390(M+H)⁺, 2.49 minutes (retention time).

Intermediate 25

1- ((4- propylcyclohexyls) methyl) -7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- Base) -1,3a, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

To the bromo- 3- of 5- ((4- propylcyclohexyls) methyl) -3,3a, 8,8a- tetrahydro cyclopentyl diene simultaneouslies [a] indenes -2 (1H) -one Potassium acetate (2.420g, 24.66mmol) and two are added in the solution of (3.2g, 8.22mmol) in 1,4- dioxanes (50mL) (pinacol combined) two boron (2.71g, 10.68mmol).By reaction mixture argon-degassed 30 minutes, then to reaction mixture Middle addition PdCl₂(dppf)-CH₂Cl₂Adduct (0.671g, 0.822mmol), and stirred 16 hours at 100 DEG C.Then will Reaction is cooling and is filtered by diatomite, and filter vacuum is concentrated.By using EtOAc:Hexane (1:2) as eluent Flash column chromatography crude residue obtains crude product, then crystallizes it by hexane, obtain title compound (2.6g, 67.3% yield), it is white solid.LC-MS m/z 396(M+Na)⁺, 2.11 minutes (retention time).

Intermediate 26

2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetic acid benzyl ester

In N₂Under atmosphere, at -78 DEG C, to 6- bromo- 2,3- dihydro -1H- 1-Indanones (2.0g, 9.48mmol) are in THF LiHMDS (11.37mL, 11.37mmol) is added dropwise in solution in (10mL).After addition, reaction mixture is made to be to slowly warm up to 0 DEG C and at this temperature stir 8 hours.Mixture is cooled to -78 DEG C, be added dropwise 2- Bromoacetic acid benzyl esters (1.651mL, 10.42mmol).Reaction mixture is stirred 30 minutes, and is to slowly warm up to environment temperature.Reaction is quenched with water and with acetic acid second Ester extracts.Organic layer water and salt water washing, are dried and concentrated.By with petroleum ether:EtOAc(10:1) flash chromatography eluted Thick residue is purified, title compound (700mg, 20.56% yield) is obtained.LC-MS m/z 359(M+H)⁺, 1.78 minutes (retention time).

Intermediate 27

2- (1- oxos -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydros -1H- Indenes -2- bases) acetic acid benzyl ester

To 2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetic acid benzyl esters (8.51g, 23.69mmol) 1, In solution in 4- dioxanes (100mL) be added potassium acetate (5.81g, 59.2mmol) and two (pinacol combined) two boron (7.82g, 30.8mmol).By reaction mixture argon-degassed 30 minutes, PdCl is then added into reaction mixture₂(dppf)- CH₂Cl₂Adduct (1.935g, 2.369mmol), and stirred 16 hours at 100 DEG C.Then it will react cooling and pass through diatom Soil filtering, and filter vacuum is concentrated.By using EtOAc:Hexane (1:3) as the flash column chromatography crude product of eluent Residue obtains crude product, then crystallizes it by hexane, obtains title compound (5.0g, 46.8% yield), solid for white Body.LC-MS m/z 407(M+H)⁺, 1.94 minutes (retention time).

Intermediate 28

The bromo- 1,2,3,3a of 7-, 4,8b- hexahydros indeno [1,2-b] pyrroles

At 0 DEG C, to 7- bromo- 1,3a, 4,8b- tetrahydrochysene indeno [1,2-b] pyrroles -2 (3H) -one (3.5g, 13.88mmol) 2M BH are added in solution in THF (60mL)₃·DMS(48.6mL,97mmol).Reaction mixture return stirring is stayed overnight, It is subsequently cooled to 0 DEG C.By being slowly added to MeOH (2mL) and then reaction mixture being quenched with 3N HCl.Reaction mixture is returned Stream stirring 3 hours, then concentrates.Water is added into residue, the pH of solution is adjusted to pH with 4N NaOH>9.The solution is used Ether extracts.Organic layer is merged, Na is used₂SO₄It is dried, filtered and concentrated, obtains title compound (3.05g, 92% yield). LC-MS m/z 238(M+H)⁺, 1.15 minutes (retention time).

Intermediate 29

The bromo- 2,3,3a of 7-, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate

To the bromo- 1,2,3,3a of 7-, 4,8b- hexahydros indeno [1,2-b] pyrroles (3.05g, 12.81mmol) is at DCM (30mL) In solution in TEA (3.57mL, 25.6mmol) and Boc is added₂O(4.46mL,19.21mmol).By reaction mixture in ring It is stirred 6 hours at a temperature of border.The reaction is cooled to environment temperatures, and water is added, mixture is extracted with ethyl acetate.Organic layer water It with salt water washing, is dried and concentrated, obtains title compound (2.5g, 57.7% yield).LC-MS m/z 360(M+H)⁺, 2.04 minutes (retention time).

Intermediate 30

7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysene indenos [1,2- B] pyrroles -1 (8bH)-carboxylate

To the bromo- 2,3,3a of 7-, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (2.9g, Potassium acetate (2.104g, 21.43mmol) and two (pinacols 8.57mmol) are added in the solution in 1,4- dioxanes (200mL) Close) two boron (2.83g, 11.15mmol).By reaction mixture argon-degassed 30 minutes, then it is added into reaction mixture PdCl₂(dppf)-CH₂Cl₂Adduct (0.350g, 0.429mmol), and stirred 16 hours at 100 DEG C.Then it will react cold But it and by diatomite filters, and filter vacuum is concentrated.By using EtOAc:Hexane (15:1) as the quick of eluent Column chromatography purify crude residue, obtain crude product, then crystallize it by hexane, obtain title compound (2.05g, 56.1% yield), it is white solid.LC-MS m/z 408(M+H)⁺, 1.99 minutes (retention time).

Intermediate 31

The bromo- 5- fluoro-2-methylbenzenes amine of 4-

By NBS (14.22g, 80mmol), 5- fluoro-2-methylbenzenes amine (10g, 80mmol) and N,N-dimethylformamide The mixture of (200mL) stirs 12 hours at 25 DEG C.Then filter solid is poured the mixture into water and crossed, title compound is obtained Object (13g, 71% yield) is yellow solid.LC-MS m/z204(M+H)⁺, 1.68 minutes (retention time).

Intermediate 32

N- (the bromo- 5- fluoro-2-methylbenzenes bases of 4-) acetamide

In N₂Under atmosphere, at 25 DEG C, to the addition fluoro- 2- methyl of the bromo- 5- of 4- in pure acetic anhydride (4.62mL, 49.0mmol) Aniline (1g, 4.90mmol).Reaction is stirred 30 minutes at 25 DEG C.Filter solid is poured the mixture into water and crossed, is marked Compound (1.1g, 4.02mmol) is inscribed, is yellow solid.LC-MS m/z 246(M+H)⁺, 1.57 minutes (retention time).

Intermediate 33

N- (the fluoro- 6- methyl -2- nitrobenzophenones of the bromo- 3- of 4-) acetamide

By nitric acid (200mL, 4475mmol), N- (the bromo- 5- fluoro-2-methylbenzenes bases of 4-) acetamides (30g, 122mmol) and H₂SO₄The mixture of (200mL, 3752mmol) is at 0 DEG C, in N₂It is stirred under atmosphere, and it is small that mixture is stirred at 0 DEG C to 2 When.Reaction is poured into water, solid is filtered out, obtains title compound, is faint yellow solid (30.1g, 72% yield).LC-MS m/z 291(M+H)⁺, 1.53 minutes (retention time).

Intermediate 34

The fluoro- 6- methyl -2- nitroanilines of the bromo- 3- of 4-

HCl (10.44mL, 344mmol) is added to N- (the fluoro- 6- methyl -2- nitrobenzophenones of the bromo- 3- of 4-) acetamide In (20g, 68.7mmol).The mixture of generation is stirred 4 hours at 100 DEG C.Then solvent is removed, NaHCO is used in combination₃Aqueous solution Residue is adjusted to pH~8.Aqueous mixture is extracted with EtOAc (3 × 50mL), and solvent in vacuo is concentrated.It will be remaining Object is through with (petroleum ether:EtOAc=10:1) silica gel chromatography eluted, obtains title compound (5g, 20% yield).LC- MS m/z 249(M+H)⁺, 1.71 minutes (retention time).

Intermediate 35

The bromo- 3- of 4- fluoro- N, 6- dimethyl -2- nitroanilines

At 0 DEG C, to the fluoro- 6- methyl -2- nitroanilines (15g, 60.2mmol) of the bromo- 3- of 4- in n,N-Dimethylformamide Sodium hydride (2.168g, 90mmol) is added in solution in (50mL).Mixture is stirred 10 minutes at 0 DEG C, then by iodine Methane (4.52mL, 72.3mmol) is added in reaction.The mixture of generation is stirred 20 minutes at 0 DEG C, is then added NH₄Cl (aqueous solution) is extracted water layer with EtOAc (3 × 50mL) with consuming excessive NaH, and solvent in vacuo is concentrated, and is obtained To title compound (16g, 31% yield).LC-MS m/z 263(M+H)⁺, 1.84 minutes (retention time).

Intermediate 36

The fluoro- N1,6- dimethyl benzenes -1,2- diamines of the bromo- 3- of 4-

Into solution of the bromo- 3- of 4- fluoro- N, the 6- dimethyl -2- nitroanilines (16g, 60.8mmol) in acetic acid (4mL) Zinc (150mg, 2.294mmol) is added.Mixture is stirred 2 hours at 65 DEG C.Then filtering is reacted and is concentrated in vacuo.It will be residual Excess is through with (petroleum ether:EtOAc=10:1) silica gel chromatography eluted, obtains title compound (5.3g, 36% yield). LC-MS m/z 233(M+H)⁺, 1.45 minutes (retention time).

Intermediate 37

Fluoro- 1,7- dimethyl -1H- benzos [d] [1,2,3] triazoles of the bromo- 4- of 5-

By the fluoro- N1,6- dimethyl benzenes -1,2- diamines (5g, 21.45mmol) of the bromo- 3- of 4- sulfuric acid (4.57mL, Water (30mL) solution treatment of stirred suspension sodium nitrite solution (1.480g, 21.45mmol) in 85.8mmol).It will Mixture stirs 2 hours at 0 DEG C, then filters, and obtains title compound (2g, 36.7% yield).¹H-NMR(400MHz, CDCl3) δ ppm 7.30-7.28 (m, 1H), 4.49 (s, 3H), 2.71 (q, J=1.2,3H).

Intermediate 38

(E) -3- (fluoro- 1,7- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases of 4-) ethyl acrylate

To fluoro- 1,7- dimethyl -1H- benzos [d] [1,2,3] triazoles (2g, 8.19mmol) of the bromo- 4- of 5-, 3- ethyoxyls -3- Oxo propyl- 1- alkene -1- (1.624g, 16.39mmol), triphenylphosphine (0.430g, 1.639mmol) and TEA (2.284mL, 16.39mmol) be added in the mixture in n-methyl-2-pyrrolidone (NMP) (20mL) diacetoxy palladium (0.368g, 1.639mmol).The mixture of generation is stirred overnight at 135 DEG C.Then the reaction is cooled to environment temperature, filtering is used in combination EtOAc (3 × 50mL) is extracted, and is then concentrated in vacuo.Residue passes through silica gel chromatograph (petroleum ether:EtOAc=3:1) it purifies, obtains To title compound (1g, 38.7% yield).LC-MS m/z 234(M+H)⁺, 1.66 minutes (retention time).

Intermediate 39

1- ((2,3- difluorobenzyls) amino) -2- methyl propan-2-ols

1- amino -2- first is added into solution of the 2,3- difluorobenzaldehydes (10g, 70.4mmol) in methanol (100mL) Base propan-2-ol (6.27g, 70.4mmol) and NaOH (7.04mL, 7.04mmol).It stirs to 1 hour in a nitrogen atmosphere, so NaBH is added portionwise in 10 minutes afterwards₄(1.065g,28.1mmol).Reaction is stirred 24 hours at ambient temperature.It will be thick Product silica gel chromatography.Fraction is concentrated, title compound (10g, 44.0mmol, 62.5% yield) is obtained, is greyish white Color solid.LC-MS：m/z：216.13(M+H)⁺, 1.915 minutes (retention time).

Intermediate 40

Fluoro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] the oxaza heptantrienes of 9-

To 1- ((2,3- difluorobenzyls) amino) -2- methyl propan-2-ol (2g, 9.29mmol) at dimethyl sulfoxide (DMSO) (DMSO) Potassium tert-butoxide (2.085g, 18.58mmol) is added in solution in (20mL), and it is small that reaction mixture is stirred at 80 DEG C to 2 When.Reaction mixture is poured into ice water (100mL), is extracted with ethyl acetate (2 × 100mL).Combined organic layer water (2 × 100mL), brine (100mL) washing, then use Na₂SO₄It is dry.It is filtered and is concentrated.By crude residue silica gel color Spectrum purifying, obtains title compound (2g, 5.77mmol, 62.1% yield), is gumminess liquid.LC-MS：m/z：196.09(M +H)⁺, 1.875 minutes (retention time).

Intermediate 41

Fluoro- -4 (the 5H)-carboxylates of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene of 9-

At 0 DEG C, to fluoro- 2, the 2- dimethyl -2,3 of 9-, 4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene (5g, TEA (7.14mL, 51.2mmol) and Boc- acid anhydrides 25.6mmol) are added in the solution in dichloromethane (DCM) (50mL) (7.73mL,33.3mmol).Will reaction at ambient temperature stir 3 hours, with water (100mL) dilute and with ethyl acetate (2 × It 100mL) extracts, is washed with saline solution (100mL), use anhydrous Na₂SO₄It is dried, filtered and concentrated.By crude residue silicon Glue chromatogram purification obtains title compound (6.5g, 21.47mmol, 84% yield), is pale solid.LC-MS：m/z： 239.94(M-56)⁺, 6.256 minutes (retention time).

Intermediate 42

Fluoro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] the oxaza heptatriene hydrochlorides of 9-

At 10 DEG C, to fluoro- 2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H)-of 9- The 1,4- bis- of 4M HCl is added in solution of the carboxylate (6.5g, 22.01mmol) in dichloromethane (DCM) (20mL) Oxane solution (16.51mL, 66.0mmol).It is stirred for 1 hour.The precipitation being obtained by filtration, it is fully dry with hexanes trituration It is pale solid to title compound (4.47g, 18.99mmol, 86% yield).LC-MS m/z：196.0(M-HCl)⁺, 3.335 minutes (retention time).

Compound in the following table 1 be by be similar to prepare 9- fluoro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1, 4] prepared by the method for oxaza heptatriene hydrochloride.It will be understood by those skilled in the art that these similar embodiments may include The variation of usual reaction condition.

Table 1

Embodiment 1

3- [(3aR, 8bS) -1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles Cough up -7- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetic acid benzyl ester

At -78 DEG C, in N₂Under atmosphere, to bromo- 2, the 3- dihydros -1H- 1-Indanones (2.0g, 9.48mmol) of 6- in THF LiHMDS (11.37mL, 11.37mmol) is added dropwise in solution in (10mL).After addition, reaction mixture is made to be to slowly warm up to 0 DEG C and at this temperature stir 8 hours.The mixture is cooled to -78 DEG C, be added dropwise 2- Bromoacetic acid benzyl esters (1.651mL, 10.42mmol).Reaction mixture is stirred 30 minutes, and is to slowly warm up to environment temperature.Reaction is quenched with water and uses acetic acid Ethyl ester extracts.Organic layer water and salt water washing, are dried and concentrated.By with petroleum ether:EtOAc(10:1) the quick color eluted Spectrum purifying crude residue, obtains title compound (700mg, 20.56% yield).LC-MS m/z 359(M+H)⁺, 1.78 points Clock (retention time).

2- (1- oxos -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydros -1H- Indenes -2- bases) acetic acid benzyl ester

To 2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) acetic acid benzyl esters (8.51g, 23.69mmol) 1, In solution in 4- dioxanes (100mL) be added potassium acetate (5.81g, 59.2mmol) and two (pinacol combined) two boron (7.82g, 30.8mmol).By reaction mixture argon-degassed 30 minutes, PdCl is then added into reaction mixture₂(dppf)- CH₂Cl₂Adduct (1.935g, 2.369mmol), and stirred 16 hours at 100 DEG C.Then it will react cooling and pass through diatom Soil filtering, and filter vacuum is concentrated.By using EtOAc:Hexane (1:3) as the flash column chromatography crude product of eluent Residue obtains crude product, then crystallizes it by hexane, obtains title compound (5.0g, 46.8% yield), solid for white Body.LC-MS m/z 407(M+H)⁺, 1.94 minutes (retention time).

3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- diformazans Base -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (1.0g, 2- (1- oxos -6- (4,4,5,5- tetramethyls 4.08mmol) are added in the solution in 1,4- dioxanes (30mL) and water (10mL) Base -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -2- bases) acetic acid benzyl ester (1.656g, 4.08mmol), TEA (1.705mL, 12.23mmol) and [Rh (cod) Cl]₂(0.101g,0.204mmol).Gained reaction is mixed Object is closed to stir 18 hours at 90 DEG C.Reaction mixture is extracted with EtOAc (3 × 30mL).By combined organic layer MgSO₄It is dry It is dry, it filters, is concentrated under reduced pressure, through silica gel chromatography, obtains required product 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxygen Generation -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (2.1099g, 2.128mmol, 52.2% yield).LC-MS m/z 526.5(M+H)⁺, 1.12 minutes (retention time).

3- (2- (2- ((cyclohexyl methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- bis- Methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) in solution of the ethyl propionate (298mg, 0.3mmol) in methanol (15mL) 10%Pd/C (63.9mg, 0.060mmol) is added.By gained suspension at ambient temperature in H₂It is stirred 90 minutes under atmosphere. Reaction mixture is filtered, filter cake is washed with MeOH (2x 5mL).Combined filtrate is concentrated under reduced pressure, is then dissolved in DCM (6mL) In, be then added cyclohexylmethylamine (0.078mL, 0.600mmol), TEA (0.084mL, 0.600mmol) and T3P (50%wt's EtOAc solution) (0.179mL, 0.600mmol).Gained reaction mixture is stirred 17 hours at ambient temperature.Reaction is mixed It closes object to be concentrated under reduced pressure, through silica gel chromatography, obtains required product 3- (2- (2- ((cyclohexyl methyl) amino) -2- oxo second Base) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) 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- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles Cough up -7- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (2- (2- ((cyclohexyl methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) - 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (150mg, 0.283mmol) is in acetonitrile In solution in (2.0mL) and THF (1.0mL) be added triethylsilane (0.226mL, 1.413mmol) and TFA (0.065mL, 0.848mmol).Gained reaction mixture was used into microwave heating 1 at 120 DEG C again at 100 DEG C with microwave heating 1 hour Hour.Reaction mixture is concentrated under reduced pressure, is dissolved in methanol (3mL), then be added NaOH (3.0N) (0.754mL, 2.261mmol).By reaction mixture in 80 DEG C of microwave heatings 20 minutes.Reaction mixture is concentrated under reduced pressure, reversed-phase HPLC is used in combination Purifying, obtains required product 3- (1- (cyclohexyl methyl) -2- oxos -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles - 7- yls) (64.5mg, 0.133mmol, 46.9% are produced -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid Rate).LC-MS m/z 487.4(M+H)⁺, 0.89 minute (retention time)

Embodiment 2

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 1- [(4- ethylcyclohexyls) methyl] -2- oxygen Generation -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } propionic acid

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (2- (2- (((4- ethylcyclohexyls) first Base) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- bis- Methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (298mg, 0.3mmol) is in methanol (15mL) and THF (5mL) In solution in be added 10%Pd/C (63.9mg, 0.060mmol).By gained suspension at ambient temperature in H₂It is stirred under atmosphere It mixes 30 minutes.Reaction mixture is filtered, filter cake is washed with MeOH (2x 5mL).Combined filtrate is concentrated under reduced pressure, obtains in crude product Mesosome.The intermediate is dissolved in DCM (6mL), (4- ethylcyclohexyls) methylamine (85mg, 0.600mmol), TEA is then added T3P (the EtOAc solution of 50%wt) (0.179mL, 0.600mmol) is then added in (0.084mL, 0.600mmol).By gained Reaction mixture stirs 43 hours at ambient temperature, be then added TEA (0.042mL, 0.300mmol) and T3P (50%wt's EtOAc solution) (0.089mL, 0.300mmol), and stir at ambient temperature other 94 hours.Reaction mixture is depressurized dense Contracting, through silica gel chromatography, obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (2- (2- (((4- ethylcyclohexyls) methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (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- benzotriazole -5- bases) -3- { 1- [(4- ethylcyclohexyls) methyl] -2- oxygen Generation -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (2- (2- (((4- ethylcyclohexyls) Methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (130mg, 0.233mmol) exists Triethylsilane (0.186mL, 1.163mmol) and TFA (0.054mL, 0.698mmol) are added in solution in acetonitrile (2mL). By gained reaction mixture with microwave heating 2 hours at 100 DEG C.Reaction mixture is concentrated under reduced pressure, methanol (3mL) is dissolved in In, NaOH (3.0N) (0.620mL, 1.861mmol) is then added, by mixture at 80 DEG C with microwave heating 20 minutes.It will be anti- It answers mixture to be concentrated under reduced pressure, is purified with reversed-phase HPLC, obtain required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (1- ((4- ethylcyclohexyls) methyl) -2- oxos -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles Cough up -7- bases) propionic acid (64.5mg, 0.125mmol, 53.9% yield).LC-MS m/z 515.4(M+H)⁺, (retain within 0.99 minute Time).

Embodiment 3

3- [(3aR, 8bS) -1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles Cough up -7- bases] -5- (1- ethyl -1H-1,2,3- triazole-4-yls) valeric acid

(E)-hept-2-ene" -6- ynoic acid ethyl esters

Sodium hydride (1.056g, 26.4mmol) point is added to 2- (diethoxy phosphoryl) ethyl acetate in small batches In the solution of (3.03mL, 14.4mmol) in DCM (15mL).Mixture is stirred 5 minutes at 23 DEG C, is slowly added to The amyl- 4- alkynes aldehyde of crude product (~1mL, 12mmol) in DCM (10mL), and mixture is stirred 30 minutes at 23 DEG C.It is added NH₄Cl (saturated aqueous solution), and solution is extracted with DCM.Then by crude product flash chromatography on silica column (12g) Purifying, with 30mL/min speed 0-60%EtOAc/ hexanes gradient elutions 20 minutes.Fraction containing product is merged, decompression removes Solvent is removed, the title compound of 1.32g (72%) is obtained.LC-MS m/z 153.0(M+H)⁺, 0.82 (retention time).

(E) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) amyl- 2- olefin(e) acids ethyl ester

By NaN₃(0.085g, 1.31mmol), CuI (0.25mg, 1.31umol) and iodoethane (0.090mL, It 1.31mmol) is added in solution of (E)-hept-2-ene" -6- ynoic acid ethyl esters (0.2g, 1.31mmol) in water (5mL), will mix Object is closed to stir 14 hours at 70 DEG C.Mixture is concentrated and on silica gel (12g) through purification by flash chromatography, with 30mL/min speed Degree uses 0-30%MeOH/DCM gradient elutions 20 minutes, obtains title compound (100mg, 34%).LC-MS m/z 224.1(M +H)⁺, 0.65 minute (retention time).

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- (hydroxymethyl) -4- aminomethyl phenyls) ethyl valerate

By (3- (hydroxymethyl) -4- aminomethyl phenyls) boric acid (0.11g, 0.67mmol), TEA (0.094mL, 0.67mmol) [RhCl (cod)]₂(11mg, 0.022mmol) is added to (E) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) amyl- 2- alkene In solution of the acetoacetic ester (0.1g, 0.45mmol) in 1,4- dioxanes (1mL) and water (0.5mL).It will react (high at 140 DEG C Absorb) microwave in heat 4 hours.Mixture is concentrated, and through purification by flash chromatography on silica gel (12g), with 30mL/min Speed 0-10%MeOH/DCM gradient elutions 20 minutes obtain (E)-of the title compound and 50mg recycling of 64mg (41%) 5- (1- ethyl -1H-1,2,3- triazole-4-yls) amyl- 2- olefin(e) acids ethyl ester.LC-MS m/z 346.2(M+H)⁺, (protect within 0.81 minute Stay the time).

3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -5- (1- ethyls - 1H-1,2,3- triazole-4-yls) ethyl valerate

To (E) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) amyl- 2- olefin(e) acids ethyl ester (0.3g, 1.344mmol) 1, 2- (1- oxos -6- (4,4,5,5- tetramethyl -1,3,2- dioxas are added in solution in 4- dioxanes (12mL) and water (4mL) Boron heterocycle pentane -2- bases) -2,3- dihydro -1H- indenes -2- bases) acetic acid benzyl ester (0.819g, 2.015mmol), TEA (0.562mL, 4.03mmol) and [Rh (cod) Cl]₂(0.033g,0.067mmol).Gained reaction mixture is stirred at 90 DEG C It mixes 17 hours.Reaction mixture is extracted with EtOAc (3 × 30mL).Combined organic layer MgSO₄Dry, filtering is depressurized dense Contracting, through silica gel chromatography, obtains required product 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxos -2,3- dihydros - 1H- indenes -5- bases) (403.9mg, 0.802mmol, 59.7% are produced -5- (1- ethyl -1H-1,2,3- triazole-4-yls) ethyl valerate Rate).LC-MS m/z 504.1(M+H)⁺, 1.05 minutes (retention time).

3- (2- (2- ((cyclohexyl methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) ethyl valerate

To 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -5- (1- ethyls - 1H-1,2,3- triazole-4-yls) 10%Pd/ is added in solution of the ethyl valerate (0.20g, 0.397mmol) in methanol (15mL) C(0.085g,0.079mmol).By gained suspension at ambient temperature in H₂It is stirred 66 hours under atmosphere.Filtering reaction mixing Object.10%Pd/C (0.085g, 0.079mmol) is added into filtrate, by suspension at ambient temperature in H₂It is stirred under atmosphere 90 minutes.Reaction mixture is filtered, filter cake is washed with MeOH (2x 5mL).Combined filtrate decompression is concentrated.By the intermediate It is dissolved in DCM (6mL), cyclohexylmethylamine (0.103mL, 0.794mmol), TEA (0.111mL, 0.794mmol) is then added, Then T3P (the EtOAc solution of 50%wt) (0.236mL, 0.794mmol) is added.By gained reaction mixture in environment temperature Lower stirring 19 hours.More cyclohexylmethylamines (0.052mL, 0.397mmol), TEA are added into reaction mixture (0.055mL, 0.397mmol) and T3P (the EtOAc solution of 50%wt) (0.236mL, 0.397mmol).Gained is reacted and is mixed Object is stirred for 5 hours at ambient temperature.By reaction mixture through silica gel chromatography, required product 3- (2- (2- ((rings are obtained Hexyl methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -5- (1- ethyls -1H-1,2,3- three Azoles -4- bases) ethyl valerate (119.8mg, 0.236mmol, 59.3% yield).LC-MS m/z 509.3(M+H)⁺, 0.99 minute (retention time).

3- [(3aR, 8bS) -1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles Cough up -7- bases] -5- (1- ethyl -1H-1,2,3- triazole-4-yls) valeric acid

To 3- (2- (2- ((cyclohexyl methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) - 5- (1- ethyl -1H-1,2,3- triazole-4-yls) ethyl valerate (119mg, 0.234mmol) is in acetonitrile (2.0mL) and THF Triethylsilane (0.187mL, 1.170mmol) and TFA (0.054mL, 0.702mmol) are added in solution in (1.0mL).It will Gained reaction mixture is at 120 DEG C with microwave heating 1 hour；Again with microwave heating 2 hours at 120 DEG C；At 130 DEG C Microwave heating 1 hour is used again.Reaction mixture is concentrated under reduced pressure, is dissolved in methanol (3mL), NaOH (3.0N) is then added (0.624mL,1.872mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C.By reaction mixture true Sky is lower to be concentrated under reduced pressure, and is purified with reversed-phase HPLC, obtain required product 3- (1- (cyclohexyl methyl) -2- oxos -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) valeric acid (57.5mg, 0.124mmol, 52.9% yield).LC-MS m/z 465.2(M+H)⁺, 0.86 minute (retention time).

Embodiment 4

3- [1- (decahydronaphthalene -2- ylmethyls) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- Base] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

Decahydronaphthalene -2- formonitrile HCNs

At 0 DEG C, to 2- decalones (2.332mL, 15mmol) and p-toluenesulfonyl methyl isocyanide (3.51g, 18.00mmol) KOtBu (3.37g, 30.0mmol) is slowly added into the solution in THF (50mL).Gained is reacted and is mixed Object stirs 1 hour at 0 DEG C, then stirs 2 hours at ambient temperature.Reaction mixture is concentrated under reduced pressure, is then added Enter water (150mL), then hexane (3 × 100mL) is used to extract.By combined organic layer MgSO₄It is dry, it filters, is concentrated under reduced pressure, And by silica gel chromatography, obtain required product decahydronaphthalene -2- formonitrile HCNs (1.9881g, 12.18mmol, 81% yield). LC-MS m/z 164.3(M+H)⁺, 1.05 minutes (retention time).

(decahydronaphthalene -2- bases) methylamine

At ambient temperature, ten are slowly added in the suspension to LAH (0.690g, 18.19mmol) in THF (40mL) THF (5mL) solution of hydrogen naphthalene -2- formonitrile HCNs (1.98g, 12.13mmol).It is small that gained reaction mixture stirs 1 at ambient temperature When.By reaction mixture Na₂SO₄(saturated aqueous solution) is slowly quenched, and filters, and is concentrated under reduced pressure, obtains required product (decahydronaphthalene- 2- yls) methylamine (1.9205g, 11.48mmol, 95% yield).LC-MS m/z 168.1(M+H)⁺, 0.69 minute (when reservation Between).

3- (2- (2- (((decahydronaphthalene -2- bases) methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes - 5- yls) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- bis- Methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) in solution of the ethyl propionate (298mg, 0.3mmol) in methanol (15mL) 10%Pd/C (63.9mg, 0.060mmol) is added.By gained suspension at ambient temperature in H₂It is stirred 30 minutes under atmosphere. Reaction mixture is filtered, and filter cake is washed with MeOH (2x 5mL).Combined filtrate is evaporated under vacuum.Among this Body is dissolved in DCM (6mL), then be added (decahydronaphthalene -2- bases) methylamine (100mg, 0.600mmol), TEA (0.084mL, 0.600mmol), and T3P (the EtOAc solution of 50%wt) (0.357mL, 0.600mmol) is then added.Gained is reacted and is mixed Object stirs 2 hours at ambient temperature, be then added more T3P (the EtOAc solution of 50%wt) (0.179mL, 0.300mmol) and TEA (0.042mL, 0.300mmol).Gained reaction mixture is stirred for 30 minutes at ambient temperature. Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, obtains required product 3- (2- (2- (((decahydronaphthalene -2- bases) Methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (156.4mg, 0.267mmol, 89% yield).LC-MS m/z 585.4(M+H)⁺, 1.26 minutes (retention time).

3- [1- (decahydronaphthalene -2- ylmethyls) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- Base] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (2- (2- (((decahydronaphthalene -2- bases) methyl) amino) -2- oxoethyls) -3- oxo -2,3- dihydros -1H- Indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (150mg, 0.257mmol) exists Triethylsilane (0.205mL, 1.283mmol) and TFA (0.059mL, 0.770mmol) are added in solution in acetonitrile (3mL). By gained reaction mixture with microwave heating 1 hour at 120 DEG C.Reaction mixture is concentrated under reduced pressure, methanol (3mL) is dissolved in In, and NaOH (3.0N) (0.684mL, 2.052mmol) is then added.Gained reaction mixture is used into microwave heating at 80 DEG C 20 minutes.Reaction mixture is concentrated under reduced pressure, is purified with reversed-phase HPLC, required product 3- (1- ((decahydronaphthalene -2- are obtained Base) methyl) -2- oxos -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (85.2mg, 0.158mmol, 61.4% yield).LC-MS m/z 541.4(M+H)⁺, 1.04 minutes (retention time).

Embodiment 5

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 2- oxos -1- [(4- propylcyclohexyls) first Base] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } propionic acid

4- propyl cyclohexane formonitrile HCNs

At 0 DEG C, to 4- propylcyclohexanones (2.319mL, 15mmol) and p-toluenesulfonyl methyl isocyanide (3.51g, 18.00mmol) KOtBu (3.37g, 30.0mmol) is slowly added into the solution in THF (50mL).The reaction of generation is mixed It closes object to stir at 0 DEG C 1 hour, then stir 2 hours at ambient temperature.Reaction mixture is concentrated under reduced pressure, water is used (100mL) dilutes, and then hexane (3x 80mL) is used to extract.By combined organic layer MgSO₄Dry, filtering is dense under reduced pressure Contracting, and by silica gel chromatography, obtain required product 4- propyl cyclohexane formonitrile HCNs (1.2419g, 8.21mmol, 54.7% Yield).¹H NMR (400MHz, chloroform-d) δ 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- propylcyclohexyls) methylamine

At ambient temperature, it is slowly added into the suspension to LAH (0.452g, 11.90mmol) in THF (20mL) THF (5mL) solution of 4- propyl cyclohexanes formonitrile HCN (1.2g, 7.93mmol).Gained reaction mixture is stirred at ambient temperature It mixes 1 hour.By reaction mixture Na₂SO₄(aqueous solution of saturation) is slowly quenched, filtering, and is concentrated under reduced pressure, and obtains Required product (4- propylcyclohexyls) methylamine (1.1512g, 7.41mmol, 93% yield).LC-MS m/z 156.0(M+H )⁺, 0.69 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxos -2- (2- oxo -2- (((4- Propylcyclohexyl) methyl) amino) ethyl) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To 3- (2- (2- (benzyloxy) -2- oxoethyls) -3- oxo -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- bis- Methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) in solution of the ethyl propionate (298mg, 0.3mmol) in methanol (15mL) 10%Pd/C (63.9mg, 0.060mmol) is added.By gained suspension at ambient temperature in H₂It is stirred 30 minutes under atmosphere. Reaction mixture is filtered, and filter cake is washed with MeOH (2x 5mL).Combined filtrate is evaporated under vacuum.Among this Body is dissolved in DCM (6mL), then be added (4- propylcyclohexyls) methylamine (93mg, 0.600mmol), TEA (0.084mL, 0.600mmol), and T3P (the EtOAc solution of 50%wt) (0.357mL, 0.600mmol) is then added.Gained is reacted and is mixed Object stirs 2 hours at ambient temperature, be then added more T3P (the EtOAc solution of 50%wt) (0.179mL, 0.300mmol) and TEA (0.042mL, 0.300mmol).Gained reaction mixture is stirred for 68 hours at ambient temperature. Be added into the reaction mixture more (4- propylcyclohexyls) methylamines (46.6mg, 0.300mmol), T3P (50%wt's EtOAc solution) (0.179mL, 0.300mmol) and TEA (0.042mL, 0.300mmol).By gained reaction mixture in environment At a temperature of stir 6 hours, more T3P (the EtOAc solution of 50%wt) (0.179mL, 0.300mmol) and TEA is then added (0.042mL,0.300mmol).Gained reaction mixture is stirred for 19 hours at ambient temperature.Reaction mixture is passed through Silica gel chromatography obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxygen Generation -2- (2- oxos -2- (((4- propylcyclohexyls) methyl) amino) ethyl) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (146.2mg, 0.255mmol, 85% yield).LC-MS m/z 573.4(M+H)⁺, 1.25 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (2- oxos -1- ((4- propylcyclohexyls) Methyl) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxos -2- (2- oxos -2- (((4- propylcyclohexyls) methyl) amino) ethyl) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (145mg, 0.253mmol) In solution in acetonitrile (3mL) be added triethylsilane (0.202mL, 1.266mmol) and TFA (0.059mL, 0.760mmol).By gained reaction mixture with microwave heating 1 hour at 120 DEG C.Reaction mixture is concentrated under reduced pressure, is dissolved in In methanol (3mL), NaOH (3.0N) (0.675mL, 2.025mmol) is then added.Gained reaction mixture is used at 80 DEG C Microwave heating 20 minutes.Reaction mixture is concentrated under reduced pressure, is purified with reversed-phase HPLC, required product 3- (Isosorbide-5-Nitraes-two are obtained Methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) -3- (2- oxos -1- ((4- propylcyclohexyls) methyl) -1,2,3,3a, 4, 8b- hexahydros indeno [1,2-b] pyrroles -7- bases) propionic acid (83.2mg, 0.157mmol, 62.2% yield).LC-MS m/z 529.3 (M+H)⁺, 1.06 minutes (retention time).

Embodiment 6

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) methyl acetate

It is molten in THF (300mL) to bromo- 2, the 3- dihydros -1H- 1-Indanones (15g, 71.1mmol) of 6- at -78 DEG C LiHMDS (85mL, 85mmol) is added dropwise in liquid.Then reaction mixture is warmed to 0 DEG C, and is cooled to -78 DEG C again.- 78 2- methyl bromoacetates (7.38mL, 78mmol) are added dropwise at DEG C.Reaction mixture is warmed to environment temperature.Water is added, second is used in combination Acetoacetic ester extracts.By organic layer water and salt water washing, through MgSO₄It is dry, and concentrate, product is obtained, silicagel column is passed through Chromatography (petroleum ether:Ethyl acetate=10:1) it purifies, obtains 2- (bromo- 1- oxos -2, the 3- dihydro -1H- indenes -2- bases of 6-) acetic acid first Ester (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- (oxyimino) -2,3- dihydro -1H- indenes -2- bases) methyl acetate

To 2- (the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- bases of 6-) methyl acetate (8.1g, 28.6mmol) in methanol Hydroxy amine hydrochloric acid salt (2.98g, 42.9mmol) and sodium acetate (3.52g, 42.9mmol) are added in solution in (100mL).It will Reaction mixture stirs 6 hours at 65 DEG C.Water is added, and mixture is extracted with ethyl acetate, by organic layer water and salt Water washing, through Na₂SO₄It is dried and concentrated, obtains (Z) -2- (the bromo- 1- of 6- (oxyimino) -2,3- dihydro -1H- indenes -2- bases) Methyl acetate (7.6g, 25.5mmol, 89% yield).LC-MS m/z 300.0(M+H)⁺, 1.59 minutes (retention time).

The bromo- 1,3a of 7-, 4,8b- tetrahydrochysenes indeno [1,2-b] pyrroles -2 (3H) -one

At ambient temperature, to (Z) -2- (the bromo- 1- of 6- (oxyimino) -2,3- dihydro -1H- indenes -2- bases) acetic acid first Zinc (8.3g, 127mmol) is added in solution of the ester (7.6g, 25.5mmol) in acetic acid (100mL).By reaction mixture 60 DEG C stirring 1 hour, is then cooled to environment temperature, filters, and concentrate.Water is added, and mixture ethyl acetate is extracted It takes, by organic layer water and salt water washing, through Na₂SO₄It is dried and concentrated, obtains crude product, it is passed through into silica gel chromatograph (oil Ether:Ethyl acetate=1:2) purify, obtain 7- bromo- 1,3a, 4,8b- tetrahydrochysene indeno [1,2-b] pyrroles -2 (3H) -one (3.5g, 13.88mmol, 54.5% yield).LC-MS m/z 253.9(M+H)⁺, 1.09 minutes (retention time).

The bromo- 1,2,3,3a of 7-, 4,8b- hexahydros indeno [1,2-b] pyrroles

At 0 DEG C, to 7- bromo- 1,3a, 4,8b- tetrahydrochysene indeno [1,2-b] pyrroles -2 (3H) -one (3.5g, 13.88mmol) BH is added in solution in THF (60mL)₃.DMS(48.6mL,97mmol).It is small that reaction mixture is stirred to 16 under reflux When, and it is subsequently cooled to 0 DEG C.By reaction mixture by being slowly added to MeOH (2mL), 3N HCl are then added to be quenched.It will Reaction mixture is stirred for 3 hours under reflux, is then concentrated.It adds water in residue, is used in combination 4N NaOH by solution PH is adjusted to>9.The solution is extracted with ether.By organic layer through Na₂SO₄It is dried and concentrated, obtains 7- bromo- 1,2,3,3a, 4, 8b- hexahydros indeno [1,2-b] pyrroles (3.05g, 12.81mmol, 92% yield).LC-MS m/z 238.0(M+H)⁺, 1.12 points Clock (retention time).

The bromo- 2,3,3a of 7-, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate

To the bromo- 1,2,3,3a of 7-, 4,8b- hexahydros indeno [1,2-b] pyrroles (3.05g, 12.81mmol) is at DCM (30mL) In solution in TEA (3.57mL, 25.6mmol) and Boc is added₂O(4.46mL,19.21mmol).By reaction mixture in ring It is stirred 6 hours at a temperature of border.Water is added, and mixture is extracted with ethyl acetate, by organic layer water and salt water washing, warp Na₂SO₄It is dried and concentrated, obtains bromo- 2,3,3a, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (the 8bH)-carboxylates of 7- (2.5g, 7.39mmol, 57.7% yield).LC-MS m/z 260.0(M+H)⁺, 2.04 minutes (retention time).

7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysene indenos [1,2- B] pyrroles -1 (8bH)-carboxylate

To the bromo- 2,3,3a of 7-, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (2.9g, Potassium acetate (2.104g, 21.43mmol), two (pinacols 8.57mmol) are added in the solution in 1,4- dioxanes (200mL) Close) two boron (2.83g, 11.15mmol), and by reaction mixture argon-degassed 30 minutes, PdCl is then added₂(dppf)- CH₂Cl₂Adduct (0.350g, 0.429mmol).The reaction mixture is stirred 16 hours at 100 DEG C, is cooled to environment temperature Degree, and filtered by diatomite.Filter vacuum is concentrated.By using EtOAc:Hexane (15:1) silica gel chromatography crude product Residue obtains crude product, it is crystallized by hexane, obtains 7- (4,4,5,5- tetramethyls -1,3,2- dioxaborolans Alkane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (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- benzos [d] [1,2,3] triazole -5- bases) -3- ethyoxyl -3- oxopropyls) -2, 3,3a, 4- tetrahydrochysene indeno [1,2-b] pyrroles -1 (8bH)-carboxylate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (0.491g, 7- (4,4,5,5- tetramethyl -1,3,2- dioxas 2mmol) are added in the solution in 1,4- dioxanes (12mL) and water (4mL) Boron heterocycle pentane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (1.156g, 3.00mmol), TEA (1.115mL, 8.00mmol) and [Rh (cod) Cl]₂(0.049g,0.100mmol).By the reaction of generation Mixture stirs 65 hours at 90 DEG C.Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, is obtained required Product 7- (1- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- ethyoxyl -3- oxopropyls) -2,3,3a, 4- tetrahydrochysenes indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (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, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 7- (1- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- ethyoxyl -3- oxopropyls) - 2,3,3a, 4- tetrahydrochysene indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (30mg, 0.059mmol) is in methanol (1mL) Solution in be added NaOH (3.0N) (0.099mL, 0.297mmol).Gained reaction mixture is used into microwave heating at 80 DEG C 20 minutes.Reaction mixture is slowly acidified to pH~3 with HCl (3N), is then concentrated under reduced pressure, is used in combination reversed-phase HPLC pure Change, obtains required product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) - 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (24.6mg, 0.052mmol, 87% yield).LC- MS m/z 421.2(M+H)⁺, 0.98 minute (retention time).

Embodiment 7

3- [1- (2- Cyclohexylacetyls) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) propionate hydrochloride

To 7- (1- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- ethyoxyl -3- oxopropyls) - 2,3,3a, 4- tetrahydrochysene indeno [1,2-b] pyrroles -1 (8bH)-carboxylate (970mg, 1.922mmol) is in 1,4- dioxanes HCl (the 1,4- dioxane solutions of 4M) (2.403mL, 9.61mmol) is added in solution in (2.5mL).Gained is reacted and is mixed Object stirs 1 hour at ambient temperature.Reaction mixture is concentrated under reduced pressure, required product 3- (Isosorbide-5-Nitraes-dimethyl-are obtained 1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) propionic acid second Ester hydrochloride (971.6mg, 2.203mmol, 115% yield).LC-MS m/z 405.4(M+H)⁺, 0.73 minute (when reservation Between).

3- [1- (2- Cyclohexylacetyls) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- hexamethylenes are added in solution of the propionate hydrochloride (50mg, 0.113mmol) in THF (2mL) Guanidine-acetic acid (17.74mg, 0.125mmol), TEA (0.047mL, 0.340mmol), and the T3P (EtOAc of 50%wt are then added Solution) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 70 minutes at ambient temperature, is then added more T3P (the EtOAc solution of 50%wt) (0.034mL, 0.113mmol) and TEA (0.016mL, 0.113mmol).Gained is anti- Mixture is answered to be stirred at ambient temperature 3 hours.More T3P are added into the reaction mixture, and (EtOAc of 50%wt is molten Liquid) (0.034mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained reaction mixture is stirred at ambient temperature It mixes more than 50 minutes, more 2- cyclohexyl-acetic acids (17.74mg, 0.125mmol) is then added.By gained reaction mixture in ring It is stirred at a temperature of border 18 hours.Reaction mixture is concentrated under reduced pressure, is dissolved in methanol (2.000mL), NaOH is then added (3N)(0.378mL,1.134mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C.It is mixed to the reaction More NaOH (3N) (0.378mL, 1.134mmol) are added in object.Gained reaction mixture is added at 80 DEG C with microwave again Heat 20 minutes.More NaOH (3N) (0.113mL, 0.340mmol) are added into the reaction mixture.Gained is reacted and is mixed Object, with microwave heating 20 minutes, is heated 20 minutes with microwave at 80 DEG C again at 80 DEG C.By reaction mixture HCl (3N) acid Change to pH 3~4, is concentrated under reduced pressure, is purified with reversed-phase HPLC, obtain required product 3- (1- (2- cyclohexyl acetyl Base) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] three Azoles -5- bases) propionic acid (20.7mg, 0.041mmol, 36.5% yield).LC-MS m/z 501.4(M+H)⁺, (retain within 1.03 minutes Time).

Embodiment 8

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- phenyl is added in solution of the propionate hydrochloride (50mg, 0.113mmol) in THF (2mL) Propionic acid (0.017mL, 0.125mmol), TEA (0.047mL, 0.340mmol), and then (EtOAc of 50%wt is molten by addition T3P Liquid) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 50 minutes at ambient temperature.To the reaction mixture It is middle be added more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.016mL, 0.113mmol).Gained reaction mixture is stirred for 3 hours at ambient temperature.It is added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained is reacted Mixture is stirred for 50 minutes at ambient temperature.Be added into the reaction mixture more 2- phenylpropionic acids (0.017mL, 0.125mmol).Gained reaction mixture is stirred for 18 hours at ambient temperature.Then by reaction mixture 80 DEG C with Microwave heating 30 minutes.Be added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained reaction mixture is stirred for 71 hours at ambient temperature. Then by reaction mixture at 80 DEG C with microwave heating 30 minutes.Reaction mixture is concentrated under reduced pressure, methanol (2.000mL) is dissolved in In, NaOH (3N) (0.756mL, 2.268mmol) is then added.Gained reaction mixture is divided at 80 DEG C with microwave heating 20 Clock.More NaOH (3N) (0.378mL, 1.134mmol) are added into the reaction mixture.By gained reaction mixture 80 With microwave heating 20 minutes at DEG C.Reaction mixture is acidified to pH 3~4 with HCl (3N), is then concentrated under reduced pressure, is used in combination Reversed-phase HPLC purifies, and obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenyl Propiono) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] propionic acid (isomers 1) (8.4mg, 0.017mmol, 14.57% yield).LC-MS m/z 509.3(M+H)⁺, 0.96 minute (retention time).

Embodiment 9

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- phenyl is added in solution of the propionate hydrochloride (50mg, 0.113mmol) in THF (2mL) Propionic acid (0.017mL, 0.125mmol), TEA (0.047mL, 0.340mmol), and then (EtOAc of 50%wt is molten by addition T3P Liquid) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 50 minutes at ambient temperature.To the reaction mixture It is middle be added more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.016mL, 0.113mmol).Gained reaction mixture is stirred for 3 hours at ambient temperature.It is added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained is reacted Mixture is stirred for 50 minutes at ambient temperature.Be added into the reaction mixture more 2- phenylpropionic acids (0.017mL, 0.125mmol).Gained reaction mixture is stirred for 18 hours at ambient temperature.Then by reaction mixture 80 DEG C with Microwave heating 30 minutes.Be added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained reaction mixture is stirred for 71 hours at ambient temperature. Then by reaction mixture at 80 DEG C with microwave heating 30 minutes.Reaction mixture is concentrated under reduced pressure, methanol (2.000mL) is dissolved in In, NaOH (3N) (0.756mL, 2.268mmol) is then added.Gained reaction mixture is divided at 80 DEG C with microwave heating 20 Clock.More NaOH (3N) (0.378mL, 1.134mmol) are added into the reaction mixture.By gained reaction mixture 80 With microwave heating 20 minutes at DEG C.Reaction mixture is acidified to pH 3~4 with HCl (3N), is concentrated under reduced pressure, reverse phase is used in combination HPLC is purified, and obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyls Base) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] propionic acid (isomers 2) (15.1mg, 0.030mmol, 26.2% yield).LC-MS m/z 509.3(M+H)⁺, 1.01 minutes (retention time).

Embodiment 10

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- methylvaleryls) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- methyl is added in solution of the propionate hydrochloride (50mg, 0.113mmol) in THF (2mL) Valeric acid (0.016mL, 0.125mmol), TEA (0.047mL, 0.340mmol), and then (EtOAc of 50%wt is molten by addition T3P Liquid) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 70 minutes at ambient temperature.To the reaction mixture It is middle be added more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.016mL, 0.113mmol).Gained reaction mixture is stirred 3 hours at ambient temperature.It is added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol) and TEA (0.032mL, 0.227mmol).Gained is reacted Mixture stirs 50 minutes at ambient temperature.Be added into the reaction mixture more 2 methyl valeric acids (0.016mL, 0.125mmol).Gained reaction mixture is stirred 18 hours at ambient temperature.Then by reaction mixture at 80 DEG C with micro- Wave heating 30 minutes (33-8).Be added into the reaction mixture more T3P (the EtOAc solution of 50%wt) (0.067mL, 0.113mmol),TEA(0.032mL,0.227mmol).Gained reaction mixture is stirred 71 hours at ambient temperature.It will be anti- Answer mixture to be concentrated under reduced pressure, be subsequently solubolized in methanol (2.000mL), then be added NaOH (3N) (0.756mL, 2.268mmol).More NaOH (3N) are then added with microwave heating 20 minutes at 80 DEG C in gained reaction mixture (0.378mL, 1.134mmol), then with microwave heating 20 minutes at 80 DEG C.Reaction mixture is acidified to HCl (3N) PH 3~4, is concentrated under reduced pressure, and is purified with reversed-phase HPLC, obtains required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1- (2- methylvaleryls) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) Propionic acid (16.6mg, 0.035mmol, 30.8% yield).LC-MS m/z 475.3(M+H)⁺, 0.96/0.98 minutes (when reservation Between).

Embodiment 11

3- { 1- [2- (2- chlorphenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } - 3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- (2- are added in solution of the propionate hydrochloride (50mg, 0.113mmol) in DCM (2mL) Chlorphenyl) acetic acid (23.21mg, 0.136mmol), TEA (0.063mL, 0.454mmol), and then be added T3P (50%wt's EtOAc solution) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 40 minutes at ambient temperature.Reaction is mixed It closes object to be concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) (0.378mL, 1.134mmol) is then added.It will Gained reaction mixture is at 80 DEG C with microwave heating 20 minutes.Reaction mixture is acidified to pH 3~4 with HCl (3N), so After be concentrated under reduced pressure, purified with reversed-phase HPLC, obtain required product 3- (1- (2- (2- chlorphenyls) acetyl group) -1,2, 3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) Propionic acid (31.8mg, 0.060mmol, 53.0% yield).LC-MS m/z 529.2(M+H)⁺, 0.97 minute (retention time).

Embodiment 12

3- { 1- [2- (2- cyano-phenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- Base } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 2- (2- are added in solution of the propionate hydrochloride (50mg, 0.113mmol) in DCM (2mL) Cyano-phenyl) acetic acid (21.93mg, 0.136mmol), TEA (0.063mL, 0.454mmol), then be added T3P (50%wt's EtOAc solution) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 30 minutes at ambient temperature.Reaction is mixed It closes object to be concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) (0.378mL, 1.134mmol) is then added.It will Gained reaction mixture is at 100 DEG C with microwave heating 20 minutes.Reaction mixture is acidified to pH 3~4 with HCl (3N), so After be concentrated under reduced pressure, purified with reversed-phase HPLC, obtain required product 3- (1- (2- (2- cyano-phenyls) acetyl group) -1, 2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) propionic acid (32.4mg, 0.062mmol, 55.0% yield).LC-MS m/z 520.3(M+H)⁺, 0.90 minute (when reservation Between).

Embodiment 13

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (3,3- dimethylbutanoyls) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) 3,3- bis- is added in solution of the propionate hydrochloride (50mg, 0.113mmol) in DCM (2mL) Methylbutanoic acid (0.017mL, 0.136mmol), TEA (0.063mL, 0.454mmol), and then be added T3P (50%wt's EtOAc solution) (0.101mL, 0.170mmol).Gained reaction mixture is stirred 30 minutes at ambient temperature.Reaction is mixed It closes object to be concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) (0.378mL, 1.134mmol) is then added.It will Gained reaction mixture is at 80 DEG C with microwave heating 20 minutes.Reaction mixture is acidified to pH 3~4 with HCl (3N), so After be concentrated under reduced pressure, purified with reversed-phase HPLC, obtain required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (1- (3,3- dimethylbutanoyls) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) third Sour (26.0mg, 0.055mmol, 48.3% yield).LC-MS m/z 475.2(M+H)⁺, 0.94 minute (retention time).

Embodiment 14

3- { 1- [butyl (methyl) carbamoyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- Base } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (1,2,3,3a, 4,8b- hexahydro indenos [1,2-b] pyrroles -7- bases) CDI is added in solution of the propionate hydrochloride (50mg, 0.113mmol) in DCM (2mL) (22.06mg,0.136mmol),TEA(0.032mL,0.227mmol).Gained reaction mixture is stirred 1 at ambient temperature Hour, N- methyl butyl- 1- amine (0.020mL, 0.170mmol) is then added.Gained reaction mixture is stirred at ambient temperature 100 minutes are mixed, then at 80 DEG C with microwave heating 30 minutes.More N- methyl butyl- 1- amine are added into the reaction mixture (0.027mL, 0.227mmol), then at 80 DEG C with microwave heating 30 minutes.Reaction mixture is concentrated under reduced pressure, Isosorbide-5-Nitrae-is dissolved in In dioxane (0.5mL), more N- methyl butyl- 1- amine (0.5mL, 4.22mmol) are then added.By gained reaction mixture With microwave heating 30 minutes at 80 DEG C；It is heated again with microwave 30 minutes at 100 DEG C；60 are heated again with microwave at 120 DEG C Minute；It is heated again with microwave 60 minutes at 130 DEG C.Reaction mixture is concentrated under reduced pressure, and is dissolved in methanol (2.000mL) In, NaOH (3N) (0.227mL, 0.680mmol) is then added.Gained reaction mixture is divided at 80 DEG C with microwave heating 20 More NaOH (3N) (0.227mL, 0.680mmol) are then added in clock, then with microwave heating 20 minutes at 80 DEG C.It will Reaction mixture is acidified to pH 3~4 with HCl (3N), is then concentrated under reduced pressure, is purified with reversed-phase HPLC, obtains required Product 3- (1- (butyl (methyl) carbamoyl) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) -3- (1, 4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (23.3mg, 0.048mmol, 42.0% yield).LC-MS m/z 490.4(M+H)⁺, 0.97 minute (retention time).

Embodiment 15

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (7- Methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid

2- methoxyl group -6- nitroanilines

To 2- amino-3-nitro phenols (2.55g, the 16.55mmol) solution for being dissolved in N,N-dimethylformamide (35mL) Middle addition potassium carbonate (2.52g, 18.20mmol).Stir the mixture for 5 minutes, be then added iodomethane (1.138mL, 18.20mmol), and by the reaction it stirs at ambient temperature 2 hours.Water (75mL) is added so that the reaction is quenched, is collected by filtration Precipitated product is washed with water, and obtains title compound 2- methoxyl group -6- nitroanilines (2.26g, 81%).LC-MS m/z 168.9(M+H)⁺, 0.74 minute (retention time)

The bromo- 2- methoxyl groups -6- nitroanilines of 4-

Second is added into 2- methoxyl group -6- nitroanilines (2.26g, the 13.44mmol) solution being dissolved in acetic acid (50mL) Sour sodium (1.654g, 20.16mmol) and bromine (0.762mL, 14.78mmol), and mixture is stirred to 30 points at ambient temperature Clock.Water (75mL) is added so that the reaction is quenched, and the product of precipitation is collected by filtration, is washed with water and is dried in vacuo, obtain The bromo- 2- methoxyl groups -6- nitroanilines (84%) of 4- of 2.78g.LC-MS m/z 246.9/248.9(M+H)⁺, (protect within 0.93 minute Stay the time).

The bromo- 2- methoxy-. N-methyls -6- nitroanilines of 4-

At 0 DEG C, to the bromo- 2- methoxyl groups -6- nitroanilines of 4- being dissolved in n,N-Dimethylformamide (50mL) It is slowly added into sodium hydride (300mg, 12.50mmol) in (2.76g, 11.17mmol) solution, and reaction mixture is stirred 30 Minute.Then iodomethane (0.768mL, 12.29mmol) is added.Water (60mL) is added to be quenched the reaction, and by the production of precipitation Object is collected by filtration, and is washed with water and is dried in vacuo, and obtains the bromo- 2- methoxy-. N-methyls -6- nitroanilines of title compound 4- (2.82g, 97%).LC-MS m/z260.9/263(M+H)⁺, 1.03 minutes (retention time).

Bromo- 7- methoxyl groups -1- methyl-1s H- benzos [d] [1,2,3] triazoles of 5-

To the bromo- 2- methoxy-. N-methyls -6- nitroanilines of 4- being dissolved in glacial acetic acid (100ml, 1747mmol) Zinc (4.94g, 76mmol) is added in (2.82g, 10.80mmol) solution, and it is small that reaction mixture is stirred to 2 at ambient temperature When 30 minutes.Zinc (150mg, 2.294mmol) is added in the mixture, and by solution stirring until orange color dissipated is (big About 30 minutes).Mixture is filtered, solid is washed with ethyl acetate, then concentrates filtrate.By crude product vitriolization (10%) In (50mL, 10.80mmol), sodium nitrite (0.745g, 10.80mmol) is added with small lot at 0 DEG C, and mixture is existed It is stirred 45 minutes 1 hour at 0 DEG C.Water (100mL) is added so that the reaction is quenched, and the product of precipitation is collected by filtration, is washed with water Wash and be dried in vacuo, obtain bromo- 7- methoxyl groups -1- methyl-1s H- benzos [d] [1,2, the 3] triazoles of title compound 5- (1.28g, 49%).LC-MS m/z 241.9/243.9(M+H)⁺, 0.83 minute (retention time).

(E) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate

To be dissolved in DMF (15mL) bromo- 7- methoxyl groups -1- methyl-1s H- benzos [d] [1,2,3] triazoles of 5- (974mg, DIPEA (2.108mL, 12.07mmol), ethyl acrylate (4.29mL, 40.2mmol), diethyl 4.02mmol) are added in solution Acyloxy palladium (271mg, 1.207mmol) and tri-o-tolyl phosphine (980mg, 3.22mmol), and reaction mixture is placed in 150 It is kept for 2 hours in DEG C microwave.Water (50mL) is added so that the reaction is quenched.Ethyl acetate is added and detaches each layer.Then by water layer It is extracted with ethyl acetate twice, and by combined organic layer through MgSO₄Dry, concentration then by silica gel chromatography, obtains (E) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (820mg, 78%).LC- MS m/z 262(M+H)⁺, 0.90 minute (retention time).

3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (7- methoxies Base -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

To 7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1, 2-b] pyrroles -1 (8bH)-carboxylate (66.4mg, 0.172mmol) is in 1,4- dioxanes (2mL) and water (0.7mL) Solution in be added (E) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (30mg, 0.115mmol), TEA (0.048mL, 0.344mmol) and [RhCl (cod)]₂(2.83mg,5.74μmol).It will generate Reaction mixture in 90 DEG C heat 100 minutes.Reaction mixture is concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) (0.306mL, 0.919mmol) is then added.By gained reaction mixture with microwave heating 20 minutes at 80 DEG C. Reaction mixture is acidified to pH 3~4 with HCl (3N), is then concentrated under reduced pressure, is purified with reversed-phase HPLC, is obtained required Product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (7- methoxies Base -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (35.8mg, 0.073mmol, 63.3% yield).LC-MS m/z 493.3(M+H)⁺, 1.00 minutes (retention time).

Embodiment 16

3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (1- second Base -4- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

To 7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1, 2-b] pyrroles -1 (8bH)-carboxylate (66.9mg, 0.174mmol) is in 1,4- dioxanes (2mL) and water (0.7mL) Solution in be added (E) -3- (1- ethyls -4- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (30mg, 0.116mmol), TEA (0.048mL, 0.347mmol) and [RhCl (cod)]₂(2.85mg,5.78μmol).By the reaction of generation Mixture heats 100 minutes in 90 DEG C.Reaction mixture is concentrated under reduced pressure, and is dissolved in methanol (2.000mL), is then added Enter NaOH (3N) (0.309mL, 0.926mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C.It will reaction Mixture is acidified to pH 3~4 with HCl (3N), is then concentrated under reduced pressure, is purified with reversed-phase HPLC, obtains required product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (1- ethyl -4- methyl - 1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (25.3mg, 0.052mmol, 44.6% yield).LC-MS m/z 435.3 (M+H)⁺, 1.02 minutes (retention time).

Embodiment 17

3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -5- (1- second Base -1H-1,2,3- triazole-4-yls) valeric acid

To 7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1, 2-b] pyrroles -1 (8bH)-carboxylate (78mg, 0.202mmol) is in 1,4- dioxanes (2mL) and water (0.7mL) The amyl- 2- olefin(e) acids ethyl esters (30mg, 0.134mmol) of (E) -5- (1- ethyl -1H-1,2,3- triazole-4-yls), TEA are added in solution (0.056mL, 0.403mmol) and [RhCl (cod)]₂(3.31mg,6.72μmol).The reaction mixture of generation is added in 90 DEG C Heat 100 minutes.Reaction mixture is concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) is then added (0.358mL,1.075mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C.Reaction mixture is used HCl (3N) is acidified to pH 3~4, is then concentrated under reduced pressure, is purified with reversed-phase HPLC, obtains required product 3- (1- (uncles Butoxy carbonyl) -1,2,3,3a, 4,8b- hexahydros indeno [1,2-b] pyrroles -7- bases) -5- (1- ethyl -1H-1,2,3- triazoles - 4- yls) valeric acid (32.4mg, 0.071mmol, 53.0% yield).LC-MS m/z 455.2(M+H)⁺, 0.94 minute (when reservation Between).

Embodiment 18

3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (7- methoxies Base -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

To 7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3,3a, 4- tetrahydrochysenes indeno [1, 2-b] pyrroles -1 (8bH)-carboxylate (66.4mg, 0.172mmol) is in 1,4- dioxanes (2mL) and water (0.7mL) Solution in be added (E) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl acrylate (30mg, 0.115mmol), TEA (0.048mL, 0.344mmol) and [RhCl (cod)]₂(2.83mg,5.74μmol).It will generate Reaction mixture in 90 DEG C heat 66 hours.Reaction mixture is concentrated under reduced pressure, and is dissolved in methanol (2.000mL), NaOH (3N) (0.306mL, 0.919mmol) is then added.By gained reaction mixture with microwave heating 20 minutes at 80 DEG C. Reaction mixture is acidified to pH 3~4 with HCl (3N), is then concentrated under reduced pressure, is purified with reversed-phase HPLC, is obtained required Product 3- (1- (tert-butoxycarbonyl) -1,2,3,3a, 4,8b- hexahydro indeno [1,2-b] pyrroles -7- bases) -3- (7- methoxies Base -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid (35.9mg, 0.071mmol, 61.7% yield). LC-MS m/z 507.2(M+H)⁺, 1.01 minutes (retention time).

Embodiment 19

3- (1- (cyclohexyl methyl) -2- oxos -2,3,3a, 4,5,9b- hexahydro -1H- benzos [g] indoles -8- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-) ethyl acetate

At -78 DEG C, it is bromo- that LiHMDS (THF solution of 1.0M) (11.00mL, 11.00mmol) is slowly added into 7- In solution of 3,4- dihydronaphthalene -1 (2H) -one (2.251g, 10mmol) in THF (10mL) (time with 10 minutes).It will give birth to At reaction mixture be warmed to 0 DEG C, and stir 30 minutes at such a temperature, be subsequently cooled to -78 DEG C.At -78 DEG C, to this THF (2mL) solution of 2- bromoacetates (1.391mL, 11.00mmol) is slowly added into reaction mixture.By generation Mixture stirs 1 hour at -78 DEG C, is then warmed to environment temperature, and stir 18 hours.Reaction mixture 10mL is satisfied The NH of sum₄Cl solution is quenched, and H is used in combination₂O (10mL) dilutes.Mixture is extracted with EtOAc (3x 30mL).By the organic of merging Layer is washed with brine (30mL), through MgSO₄Dry, filtering is concentrated under reduced pressure, and by silica gel chromatography, obtain title Compound (1.6881g, 2.170mmol, 21.70% yield) is colorless oil.LC-MS m/z 310.9(M+H)⁺,1.09 Minute (retention time).

2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-) acetic acid

To 2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-) ethyl acetate (1.6881g, 5.42mmol) in methanol The 2M NaOH (20.0mmol) of 10mL are added in solution in (5mL).The solution of generation is heated by microwave irradiation at 80 DEG C 30 minutes.Reaction mixture is acidified to pH~5 with HCl (1N), EtOAc (3x 40mL) is used in combination to extract.By combined organic phase Be concentrated under reduced pressure, obtain title compound 2- (the bromo- 1- oxos -1,2 of 7-, 3,4- naphthane -2- bases) acetic acid (1.4661g, 3.26mmol, 60.1% yield), it is solid.LC-MS m/z 282.9(M+H)⁺, 0.86 minute (retention time).

2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-)-N- (cyclohexyl methyl) acetamide

To 2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-) acetic acid (0.400g, 1.413mmol) at DCM (3mL) In solution in be added TEA (0.788ml, 5.65mmol), T3P (the EtOAc solution of 50%wt) (1.682ml, 2.826mmol) With cyclohexylmethylamine (0.552ml, 4.245mmol).The mixture of generation is stirred 3 hours at ambient temperature.Reaction is mixed It closes object to be concentrated under reduced pressure, and by silica gel chromatography, obtaining title compound, (0.2483g, 0.446mmol, 31.6% are produced Rate), it is solid.LC-MS m/z 378.1(M+H)⁺, 1.14 minutes (retention time).

8- bromo- 1- (cyclohexyl methyl) -3,3a, 4,5- tetrahydrochysene -1H- benzos [g] indoles -2 (9bH) -one

To 2- (the bromo- 1- oxos -1,2,3,4- naphthanes -2- bases of 7-)-N- (cyclohexyl methyl) acetamide (0.2483g, 0.656mmol) in the solution in acetonitrile (8mL) be added triethylsilane (0.524ml, 3.28mmol) and TFA (0.152ml, 1.969mmol).The solution of generation is heated 2 hours by microwave irradiation at 100 DEG C.Reaction mixture is concentrated under reduced pressure, and is led to Silica gel chromatography is crossed, title compound (0.1449g, 0.400mmol, 60.9% yield) is obtained, is colorless oil.LC- MS m/z 362.0(M+H)⁺, 1.24 minutes (retention time).

1- (cyclohexyl methyl) -8- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -3,3a, 4, 5- tetrahydrochysene -1H- benzos [g] indoles -2 (9bH) -one

To 8- bromo- 1- (cyclohexyl methyl) -3,3a, 4,5- tetrahydrochysene -1H- benzos [g] indoles -2 (9bH) -one (0.1449g, 0.400mmol) in the solution in N,N-dimethylformamide (2mL) be added two (pinacol combined) two boron (0.152g, 0.600mmol), KOAc (0.079g, 0.800mmol) and PdCl₂(dppf)(0.015g,0.020mmol).By the solution of generation It is heated 1 hour at 100 DEG C by microwave irradiation.Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, obtains title Compound (0.1287g, 0.314mmol, 79% yield) is grease.LC-MS m/z 410.3(M+H)⁺, (protect within 1.32 minutes Stay the time).

3- (1- (cyclohexyl methyl) -2- oxos -2,3,3a, 4,5,9b- hexahydro -1H- benzos [g] indoles -8- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (0.049g, 0.2mmol) in the solution in 1,4- dioxanes (1.5mL) and water (0.5mL) be added 1- (cyclohexyl methyl) -8- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -3,3a, 4,5- tetrahydrochysene -1H- benzos [g] indoles -2 (9bH) -one (0.1287g, 0.314mmol), TEA (0.084ml, 0.600mmol) and [Rh (cod) Cl]₂(4.93mg,10.00μmol).It will The solution of generation stirs 5 hours at 90 DEG C.Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, obtains intermediate 3- (1- (cyclohexyl methyl) -2- oxos -2,3,3a, 4,5,9b- hexahydro -1H- benzos [g] indoles -8- bases) -3- (1,4- diformazans Base -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate.The intermediate is re-dissolved in methanol (2mL).To acquired solution Middle addition 2M NaOH (0.5mL, 1.000mmol).After being heated 30 minutes at 80 DEG C by microwave radiation, reaction mixture is used HCl (1N) be acidified at pH~5, be concentrated under reduced pressure, purified with preparative HPLC, obtain title compound (20mg, 0.040mmol, 19.97% yield), it is white solid.LC-MS m/z 501.3(M+H)⁺, 0.90 minute (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).

Embodiment 20

3- (3- (cyclohexyl methyl) -2- oxos -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

The bromo- 1,1- dimethoxys -2,3- dihydros -1H- indenes -2- alcohol of 6-

By the bromo- 2,3- dihydros -1H- 1-Indanones (1.055g, 5mmol) of 6- and KOH (3.09g, 55.0mmol) in methanol Solution in (25mL) stirs 10 minutes at 0 DEG C, and (diacetoxy iodine) benzene (1.933g, 6.00mmol) is then added.It will The solution of generation stirs 1 hour at 0 DEG C, and stirs 2 hours at ambient temperature.Then reaction mixture is dense under reduced pressure Contracting, and by silica gel chromatography, title compound (0.7734g, 2.61mmol, 52.1% yield) is obtained, it is kermesinus tree Colloid substance.LC-MS m/z 273.0(M+H)⁺, 0.84 minute (retention time).

The bromo- 1- oxos -2,3- dihydros -1H- indenes -2- base esters of (cyclohexyl methyl) carbamic acid 6-

To the bromo- 1,1- dimethoxys -2,3- dihydros -1H- indenes -2- alcohol (0.3385g, 1.239mmol) of 6- and DMAP In the solution of (0.227g, 1.859mmol) in toluene (12mL) be added dropwise (isocyanatomethyl) hexamethylene (0.443mL, 3.10mmol).The solution of generation is heated 5 hours by microwave irradiation at 100 DEG C.Reaction mixture is dense under reduced pressure Contracting, obtains bromo- 1,1- dimethoxys -2, the 3- dihydro -1H- indenes -2- base esters of crude intermediate (cyclohexyl methyl) carbamic acid 6-. The crude intermediate is re-dissolved in the 10%HCl solution of 10mL.The mixture of generation is stirred 3 hours at ambient temperature. Reaction mixture is concentrated under reduced pressure and by silica gel chromatography, obtain title compound (0.5234g, 1.429mmol, 115% yield), it is white solid.LC-MS m/z 366.0(M+H)⁺, 1.17 minutes (retention time).

5- bromo- 3- (cyclohexyl methyl) -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -2- ketone

To the bromo- 1- oxos -2,3- dihydros -1H- indenes -2- base esters of (cyclohexyl methyl) carbamic acid 6- (0.5234g, Triethylsilane (2.283ml, 14.29mmol) and TFA 1.429mmol) are added in the solution in acetonitrile (12mL) (0.330ml,4.29mmol).The solution of generation is heated 4 hours by microwave irradiation at 120 DEG C.Reaction mixture is being subtracted Pressure concentrates and by silica gel chromatography, obtains title compound (0.3618g, 1.033mmol, 72.3% yield), is nothing Color grease.LC-MS m/z 349.9(M+H)⁺, 1.16 minutes (retention time).

3- (cyclohexyl methyl) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -3,3a, 8, 8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -2- ketone

To 5- bromo- 3- (cyclohexyl methyl) -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -2- ketone (0.3618g, 1.033mmol) in the solution in N,N-dimethylformamide (5mL) be added two (pinacol combined) two boron (0.393g, 1.549mmol), KOAc (0.203g, 2.066mmol) and PdCl₂(dppf)(0.038g,0.052mmol).By the solution of generation It is heated 1 hour at 100 DEG C by microwave irradiation.Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, obtains title Compound (0.298g, 0.750mmol, 72.6% yield) is colorless oil.LC-MS m/z 398.2(M+H)⁺, 1.30 points Clock (retention time).

3- (3- (cyclohexyl methyl) -2- oxos -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (0.120g, 3- (cyclohexyl methyl) -5- (4,4,5,5- 0.489mmol) are added in the solution in 1,4- dioxanes (3mL) and water (1mL) Tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -2- ketone (0.298g, 0.750mmol), TEA (0.205ml, 1.468mmol) and [Rh (cod) Cl]₂(0.012g,0.024mmol).It will The solution of generation stirs 3 hours in 90 DEG C.Reaction mixture is concentrated under reduced pressure, and by silica gel chromatography, obtains intermediate 3- (3- (cyclohexyl methyl) -2- oxos -3,3a, 8,8a- tetrahydrochysene -2H- indenos [1,2-d] oxazole -5- bases) -3- (1,4- diformazans Base -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate.The intermediate is dissolved in methanol (4mL), is then added The 2M NaOH solutions (2.00mmol) of 1.0mL.After being heated 30 minutes at 80 DEG C by microwave radiation, by reaction mixture HCl (1N) be acidified at pH~5, be concentrated under reduced pressure, purified with preparative HPLC, obtain title compound (58.1mg, 0.119mmol, 24.31% yield), it is solid.LC-MS m/z 489.2(M+H)⁺, 0.90 minute (retention time).¹H NMR (400MHz, chloroform-d) δ=0.90 (q, J=11.80Hz, 2H), 1.09-1.27 (m, 3H), 1.48 (d, J=12.55Hz, 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)。

Embodiment 21

3- (3- (chloro- -4 (the 5H)-yls of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene of 7-) -2, 3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

Bis- bromo- 2,3- dihydros -1H- indenes of 1,6-

At 0 DEG C, into solution of bromo- 2, the 3- dihydros -1H- indenes -1- alcohol (3g, 14.08mmol) of 6- in DCM (30mL) PBr is added₃(1.726mL,18.30mmol).The reaction is stirred 30 minutes at ambient temperature.Then reaction mixture is cold But to 0 DEG C, with saturation NaHCO₃It is quenched, is extracted with DCM (2X).By combined organic matter aqueous salt solu-tion, by organic layer Through anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and title compound (3g, 77% yield) is obtained.¹H NMR(400MHz, CDCl₃) δ ppm=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- ((the bromo- 5- chlorobenzyls of 2-) amino) -2- methyl propan-2-ols

Under a nitrogen, 1- ammonia is added in the solution to the bromo- 5- chlorobenzaldehydes (1g, 4.56mmol) of 2- in methanol (20mL) Base -2- methyl propan-2-ol (0.406g, 4.56mmol) and 1N NaOH (0.5mL, 0.500mmol).With 10 minutes at 0 DEG C NaBH is added portionwise in time₄(0.345g, 9.11mmol), and stir 72 hours at ambient temperature.Reaction mixture is depressurized Evaporation, then use purification by flash chromatography, obtain 1- ((the bromo- 5- chlorobenzyls of 2-) amino) -2- methyl propan-2-ol (1g, 3.39mmol, 74.4% yield).LC-MS m/z 291.9(M+H)⁺, 1.62 minutes (retention time).

Chloro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] the oxaza heptantrienes of 7-

To 1- ((the bromo- 5- chlorobenzyls of 2-) amino) -2- methyl propan-2-ol (500mg, 1.709mmol) at isopropanol (8mL) In solution in Cs is added₂CO₃(472mg, 3.42mmol) and cuprous iodide (I) (32.5mg, 0.171mmol), and reaction is mixed Object is closed to stir 1 hour in microwave reactor at 130 DEG C.Reaction mixture is quenched with water, is extracted twice and is used in combination with EtOAc Salt water washing.By organic layer anhydrous Na₂SO₄It dries and filters.Filtrate is concentrated to and used purification by flash chromatography, is obtained required Chloro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] the oxaza heptantrienes of product 7- (450mg, 1.213mmol, 71.0% yield).LC-MS m/z 212.0(M+H)⁺, 3.49 minutes (retention time).

Compound in the following table 2 be by be similar to prepare 7- chloro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1, 4] prepared by the method for oxaza heptantriene.It will be understood by those skilled in the art that these similar embodiments may include usually instead Answer the variation of condition.

Table 2

The chloro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] of 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -7- Oxaza heptantriene

At ambient temperature, to 1,6-, bis- bromo- 2,3- dihydros -1H- indenes (500mg, 1.812mmol) and chloro- 2, the 2- of 7- bis- DIPEA is added in the solution of methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (384mg, 1.812mmol) (0.633mL,3.62mmol).Reaction mixture is stirred 1 hour in microwave reactor at 90 DEG C.Reaction mixture is cold But it to 0 DEG C, is quenched with cold water, EtOAc (2X) is used in combination to extract.By combined organic matter aqueous salt solu-tion, organic layer is used Anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and by crude residue by with EtOAc:Hexane (4:96) it elutes Purification by flash chromatography obtains title compound (500mg, 67.8% yield).¹H NMR(400MHz,CDCl₃) δ ppm=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).

The chloro- 2,2- dimethyl -4- of 7- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2, 3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To the chloro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] of 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -7- [1, 4] two (pinacol combined) are added in solution of the oxaza heptantriene (500mg, 1.229mmol) in 1,4- dioxanes (10mL) Two boron (375mg, 1.475mmol) and potassium acetate (241mg, 2.459mmol).By reaction mixture argon-degassed 10 minutes, Then PdCl is added₂(dppf)-CH₂Cl₂Adduct (50.2mg, 0.061mmol), and reaction mixture is heated 16 in 90 DEG C Hour.Reaction mixture is cooled to 0 DEG C, is quenched with cold water, EtOAc (2X) is used in combination to extract.By combined organic matter brine Solution washs, by organic layer anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and crude residue is passed through into use EtOAc:Hexane (5:95) purification by flash chromatography eluted, obtains title compound (350mg, 62.7% yield).¹H NMR (400MHz,CDCl₃) δ ppm 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- (chloro- -4 (the 5H)-yls of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene of 7-) -2, 3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

In seal pipe, to (E) -3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (200mg, 0.815mmol) in the solution in the mixture of 1,4- dioxanes (4mL) and water (4mL) be added TEA (0.334mL, 2.446mmol).Reaction nitrogen is deaerated 20 minutes, (1,5- cyclo-octadiene) radium chloride (I) dimer is then added (40.2mg,0.082mmol).Reaction mixture is stirred 4 hours at 90 DEG C.Reaction mixture is quenched with cold water, is used in combination EtOAc (2X) is extracted.By combined organic matter aqueous salt solu-tion, by organic layer anhydrous Na₂SO₄It dries and filters.It will filter Liquid is evaporated under reduced pressure, and obtains title compound (250mg, 53.5% yield).LC-MS m/z 573(M+H)⁺, (retain within 4.52 minutes Time).

3- (3- (chloro- -4 (the 5H)-yls of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene of 7-) -2, 3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

At 0 DEG C, to 3- (3- (chloro- 2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes of 7- -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid second 10%NaOH (10mL, 0.436mmol) is added in solution of the ester (250mg, 0.436mmol) in ethyl alcohol (10mL).This is anti- It should stir at ambient temperature 16 hours.Reaction mixture is evaporated under reduced pressure, is neutralized with 2N HCl, DCM (2X) is used in combination to extract.It will Combined organic matter aqueous salt solu-tion, by organic layer anhydrous Na₂SO₄It dries and filters.Filtrate is evaporated, preparative is used HPLC is purified, and obtains title compound (23mg, 9.56% yield).LC-MS m/z 545(M+H)⁺, 3.27 minutes (when reservation Between).

Embodiment 22

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,7- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

1- ((the bromo- 5- methylbenzyls of 2-) amino) -2- methyl propan-2-ols

1- amino -2- first is added into solution of the bromo- 5- tolyl aldehydes (2g, 10.05mmol) of 2- in methanol (5mL) Base propan-2-ol (0.896g, 10.05mmol) and NaOH (1.005mL, 1.005mmol).By the reaction mixture of generation in nitrogen It is stirred 1 hour under atmosphere, is then slowly added into NaBH₄(0.266g, 7.03mmol), and the reaction is stirred at ambient temperature It mixes 72 hours.The reaction is evaporated under vacuum, is diluted with water (30mL), DCM (2x 20mL) is used in combination to extract.By having for merging Machine layer is washed with brine (20mL), uses Na₂SO₄It is dry, it filters and is evaporated in vacuo, obtain required product 1- ((the bromo- 5- methyl of 2- Benzyl) amino) -2- methyl propan-2-ol (2.4g, 5.84mmol, 58.2% yield).LC-MS m/z 272.2(M+H)⁺,1.28 Minute (retention time).

2,2,7- trimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To 1- ((the bromo- 5- methylbenzyls of 2-) amino) -2- methyl propan-2-ol (1.2g, 4.41mmol) in isopropanol Cs is added in solution in (10mL)₂CO₃(2.011g, 6.17mmol) and cuprous iodide (I) (0.084g, 0.441mmol), and Reaction mixture is stirred 1 hour at 130 DEG C in microwave reactor.Reaction mixture is filtered, and by filter cake isopropyl Alcohol (10mL) washs.Combined filter vacuum is concentrated, then through purification by flash chromatography, obtains required 2,2,7- front three of product Base -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (500mg, 1.354mmol, 30.7% yield).LC-MS m/z 192.1(M+H)⁺, 3.39 minutes (retention time).

4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2,7- trimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen Azepine cycloheptatriene

To 2,2,7- trimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (832mg, 4.35mmol) 1,6-, bis- bromo- 2,3- dihydros -1H- indenes (600mg, 2.174mmol) are added in solution in acetonitrile (20mL), are then added DIPEA(1.139mL,6.52mmol).Reaction mixture is stirred 1 hour in microwave reactor at 120 DEG C.Then should Reaction is diluted with ice water, and EtOAc (2x 20mL) is used in combination to extract.Combined organic layer is washed with saline solution (30mL), and is passed through Anhydrous Na₂SO₄It is dry, filtering, and solvent in vacuo is evaporated.By crude residue by with EtOAc:Hexane (1:9) elution is fast Fast column chromatography purifying.The fraction of elution is concentrated in vacuo, title compound (600mg, 68.8% yield) is obtained.LC-MS m/z 386(M+H)⁺, 2.41 minutes (retention time).

2,2,7- trimethyls -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- two Hydrogen -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2,7- trimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] Two (pinacol combined) two are added in solution of the oxaza heptantriene (600mg, 1.553mmol) in 1,4- dioxanes (10mL) Boron (473mg, 1.864mmol) and potassium acetate (305mg, 3.11mmol).By reaction mixture argon-degassed 10 minutes, then PdCl is added₂(dppf)-CH₂Cl₂Adduct (127mg, 0.155mmol), and reaction mixture is heated 3 hours in 90 DEG C.It will Reaction mixture is filtered by diatomite, and EtOAc (100mL) is used in combination to wash.Filtrate is concentrated under reduced pressure, crude residue is obtained Object.Crude residue is purified by column chromatography, the hexanes of 10% ethyl acetate are used in combination.The fraction of elution is depressurized Concentration, obtains title compound (500mg, 62.9% yield).LC-MS m/z 434(M+H)⁺, 2.33 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,7- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (250mg, 1.019mmol) and 2,2,7- trimethyls -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2, 3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (574mg, 1.325mmol) exists TEA (0.426mL, 3.06mmol) and (1,5- rings pungent two are added in solution in 1,4- dioxanes (5mL) and water (5.00mL) Alkene) radium chloride (I) dimer (50.3mg, 0.102mmol).By reaction mixture argon-degassed 10 minutes, then at 100 DEG C Lower stirring 2 hours.Reaction mixture is cooled to environment temperature, is diluted with water, EtOAc (2x 20mL) is used in combination to extract.It will merge Organic layer washed with saline solution (20mL), and through Na₂SO₄It is dry, it filters and is evaporated in vacuo.By crude residue by making Use EtOAc:Hexane (5:5) as the flash column chromatography of eluent, title compound (200mg, 29.3% yield) is obtained. LC-MS m/z 553(M+H)⁺, 2.09 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,7- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

At 0 DEG C, to 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,7- front threes - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate The aqueous solution (10mL, 10.00mmol) of 1M NaOH is added in the solution of (200mg, 0.362mmol) in ethyl alcohol (10mL).It will The reaction is stirred 4 hours at ambient temperature.Reaction mixture is concentrated under reduced pressure, is neutralized, is extracted with DCM, and pass through with 1N HCl Na₂SO₄It is dry.Filtrate decompression is evaporated, and is purified using reversed-phase HPLC, title compound (120mg, 61.0% yield) is obtained. LC-MS m/z5253(M+H)⁺, 1.81 minutes (retention time).

Embodiment 23

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (7- methoxyl group -2,2- dimethyl - - 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -7- methoxyl group -2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

At ambient temperature, to 1,6-, bis- bromo- 2,3- dihydros -1H- indenes (500mg, 1.812mmol), 7- methoxyl groups -2,2- Dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (376mg, 1.812mmol) is in acetonitrile (10mL) Solution in be added DIPEA (0.633mL, 3.62mmol).By reaction mixture, stirring 1 is small at 90 DEG C in microwave reactor When.Reaction mixture is cooled to 0 DEG C, is quenched with cold water, EtOAc (2X) is used in combination to extract.Combined organic layer salt is water-soluble Liquid washs, by organic layer through anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and by crude residue by using EtOAc:Hexane (4:96) as the purification by flash chromatography of eluent, title compound (400mg, 54.9% yield) is obtained.¹H NMR(400MHz,CDCl₃) δ ppm=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- methoxyl group -2,2- dimethyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- Base) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -7- methoxyl group -2,2- dimethyl -2,3,4,5- tetrahydro benzos Two (frequencies are added in solution of [f] [1,4] the oxaza heptantriene (400mg, 0.994mmol) in 1,4- dioxanes (10mL) Which alcohol closes) two boron (303mg, 1.193mmol) and potassium acetate (195mg, 1.988mmol).By reaction mixture argon-degassed 10 minutes, PdCl is then added₂(dppf)-CH₂Cl₂Adduct (40.6mg, 0.050mmol), and by reaction mixture in 90 DEG C Heating 4 hours.Reaction mixture is cooled to 0 DEG C, is quenched with cold water, EtOAc (2x) is used in combination to extract.Combined organic layer is used Aqueous salt solu-tion, by organic layer through anhydrous Na₂SO₄It dries and filters.Filtrate decompression is evaporated, and crude residue is passed through Use EtOAc:Hexane (5:95) as the flash column chromatography of eluent, title compound (300mg, 67.1% production are obtained Rate).¹H NMR(400MHz,CDCl₃) δ ppm=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- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (7- methoxyl group -2,2- dimethyl - - 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (200mg, 0.815mmol) in the solution in the mixture of 1,4- dioxanes (4mL) and water (4mL) be added TEA (0.334mL, 2.446mmol).Solution nitrogen is deaerated 20 minutes, (1,5- cyclo-octadiene) radium chloride (I) dimer is then added (40.2mg,0.082mmol).Reaction mixture is stirred 4 hours at 90 DEG C.Then reaction mixture is quenched with cold water, It is used in combination EtOAc (2X) to extract.By combined organic matter aqueous salt solu-tion, by organic layer through anhydrous Na₂SO₄It dries and filters. Filtrate decompression is evaporated, crude title compound is obtained, can be used to without further purification next step (300mg, 64.7% yield).LC-MS m/z 569(M+H)⁺, 4.42 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (7- methoxyl group -2,2- dimethyl - - 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

At 0 DEG C, to 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (methoxyl group -2 7-, - 4 (5H)-yl of 2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third 10%NaOH (10mL, 0.528mmol) is added in solution of the acetoacetic ester (300mg, 0.528mmol) in ethyl alcohol (10mL).It will The reaction is stirred 16 hours at ambient temperature.Reaction mixture is evaporated under reduced pressure, is neutralized with 2N HCl, DCM (2X) is used in combination to extract It takes.By combined organic layer aqueous salt solu-tion, by organic layer through anhydrous Na₂SO₄It dries and filters.Filtrate is evaporated and led to Preparative HPLC purifying is crossed, title compound (57mg, 19.94% yield) is obtained.LC-MS m/z 541(M+H)⁺, 1.78 points Clock (retention time).

Embodiment 24

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,8- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2,8- trimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen Azepine cycloheptatriene

At ambient temperature, to 2,2,8- trimethyls -2,3,4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene Bis- bromo- 2,3- dihydros -1H- indenes (289mg, 1.046mmol) of (200mg, 1.046mmol) and 1,6- is molten in acetonitrile (10mL) DIPEA (0.365mL, 2.091mmol) is added in liquid.Reaction mixture is stirred 16 hours at 70 DEG C.Then reaction is mixed It closes object to be concentrated under reduced pressure, be diluted with water, and be extracted with ethyl acetate.By organic layer aqueous salt solu-tion, through Na₂SO₄It is dry And it filters.Filtrate is concentrated, and by using (5:95)EtOAc:Hexane is purified as the column chromatography of eluant, eluent.Solvent is dense Contracting, obtains title compound (220mg, 54.5% yield).¹H NMR(400MHz,CDCl₃) δ ppm=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- trimethyls -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- two Hydrogen -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

In seal pipe, to 4- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 6-) -2,2,8- trimethyls -2,3,4,5- tetrahydrochysene benzene And it is added two in solution of [f] [1,4] the oxaza heptantriene (300mg, 0.777mmol) in 1,4- dioxanes (10mL) (pinacol combined) two boron (256mg, 1.010mmol) and potassium acetate (191mg, 1.941mmol).By reaction argon-degassed 20 Minute, PdCl is then added₂(dppf)(28.4mg,0.039mmol).Reaction mixture is stirred 2 hours at 90 DEG C.It will be thick Product residue is purified by using the hexane solution of 20% ethyl acetate as the column chromatography of eluent.The fraction of elution is depressurized Concentration, obtains title compound (250mg, 69.2% yield).LC-MS m/z 434(M+H)⁺, 4.97 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,8- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

In seal pipe, to (E) -3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate 2,2,8- trimethyls -4- is added in the solution of (50mg, 0.204mmol) in 1,4- dioxanes (10mL) and water (10.00mL) (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- Tetrahydro benzo [f] [1,4] oxaza heptantriene (115mg, 0.265mmol).By reaction argon-degassed 20 minutes, then (1,5- cyclo-octadiene) radium chloride (I) dimer (10.05mg, 0.020mmol) is added.Reaction mixture is stirred at 95 DEG C 16 hours.Then reaction mixture is filtered by diatomite, ethyl acetate is used in combination to wash.Filtrate is concentrated under reduced pressure, and Crude residue is purified by using the hexane solution of 20% ethyl acetate as the column chromatography of eluent.By the fraction of elution It is concentrated under reduced pressure, obtains title compound (120mg, 56.2% yield).LC-MS m/z 553(M+H)⁺, 2.12 minutes (when reservation Between).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,8- trimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

At 0 DEG C, to 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2,8- front threes - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate 1M NaOH (10mL, 10.00mmol) are added in the solution of (120mg, 0.217mmol) in ethyl alcohol (10mL).The reaction is existed Stirred at ambient temperature 4 hours.Reaction mixture is concentrated under reduced pressure, is neutralized with 1N HCl, is used in combination (1:1)MeOH:DCM is extracted. By organic layer through Na₂SO₄It is dry.Filtrate decompression is evaporated, and is purified by preparative HPLC, obtain title compound (56mg, 48% yield).LC-MS m/z 525(M+H)⁺, 1.85 minutes (retention time).

Embodiment 25

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (the fluoro- 2,2- dimethyl -2,3- of 8- - 4 (5H)-yl of dihydrobenzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

The fluoro- 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] of 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -8- Oxaza heptantriene

At ambient temperature, to fluoro- 2, the 2- dimethyl -2,3 of 8-, 4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene Bis- bromo- 2,3- dihydros -1H- indenes (212mg, 0.768mmol) of (150mg, 0.768mmol) and 1,6- is molten in acetonitrile (10mL) DIPEA (0.268mL, 1.537mmol) is added in liquid.Reaction mixture is stirred 4 hours at 70 DEG C.Reaction mixture is subtracted Pressure concentration, is diluted with water, and be extracted with ethyl acetate.By organic layer aqueous salt solu-tion, through Na₂SO₄It dries and filters.It will Filter vacuum evaporates, and by using EtOAc:Hexane (5:95) it is purified as the column chromatography of eluent.The fraction of elution is dense Contracting, obtains title compound (200mg, 66.7% yield).¹H NMR(400MHz,CDCl₃) δ ppm=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).

The fluoro- 2,2- dimethyl -4- of 8- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2, 3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

In seal pipe, to 4- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 6-) fluoro- 2, the 2- dimethyl -2,3 of -8-, 4,5- tetra- Hydrogen benzo [f] [1,4] oxaza heptantriene (200mg, 0.512mmol) is added in the solution in 1,4- dioxanes (10mL) Two (pinacol combined) two boron (169mg, 0.666mmol) and potassium acetate (126mg, 1.281mmol).By the reaction argon-degassed 20 minutes, PdCl is then added₂(dppf)(18.75mg,0.026mmol).Reaction mixture is stirred 4 hours at 90 DEG C. By reaction mixture by diatomite, ethyl acetate is used in combination to wash.The reaction is diluted with water, EtOAc is used in combination to extract.It will be organic Layer is through Na₂SO₄It dries and filters.Filtrate is concentrated under reduced pressure, and by using (5:95)EtOAc:Hexane is as eluant, eluent Column chromatography purifies.The fraction of elution is evaporated, title compound (215mg, 87% yield) is obtained.LC-MS m/z 438(M+H )⁺, 4.80 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (the fluoro- 2,2- dimethyl -2,3- of 8- - 4 (5H)-yl of dihydrobenzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

In seal pipe, to (E) -3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate The fluoro- 2,2- dimethyl-of 8- is added in the solution of (50mg, 0.204mmol) in 1,4- dioxanes (10mL) and water (10.00mL) 4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- bases) -2,3,4, 5- tetrahydro benzos [f] [1,4] oxaza heptantriene (116mg, 0.265mmol).By reaction argon-degassed 20 minutes, with (1,5- cyclo-octadiene) radium chloride (I) dimer (10.05mg, 0.020mmol) is added afterwards.Reaction mixture is stirred at 95 DEG C It mixes 16 hours.Reaction mixture is filtered by diatomite, ethyl acetate is used in combination to wash.Filtrate is concentrated under reduced pressure, and will Crude residue is purified by using the hexane solution of 20% ethyl acetate as the column chromatography of eluent.The fraction of elution is subtracted Pressure concentration, obtains title compound (150mg, 42.7% yield).LC-MS m/z 557(M+H)⁺, 4.97 minutes (when reservation Between).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (the fluoro- 2,2- dimethyl -2,3- of 8- - 4 (5H)-yl of dihydrobenzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

At 0 DEG C, to 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (fluoro- 2,2- of 8- bis- - 4 (5H)-yl of methyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid second The aqueous solution (10.78mg, 0.269mmol) of NaOH is added in solution of the ester (150mg, 0.269mmol) in ethyl alcohol (10mL). Reaction mixture is stirred at ambient temperature 16 hours.Then reaction mixture is concentrated under reduced pressure, is quenched with 1N HCl, MeOH is used in combination:DCM(1:9) it extracts.By organic layer through Na₂SO₄It dries and filters.Filter vacuum is evaporated, and residue is passed through Preparative HPLC purifies, and obtains title compound (60mg, 41.6% yield).LC-MS m/z 529(M+H)⁺, 3.19 minutes (retention time).

Embodiment 26

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) -2,2- neopentanoic acids

4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen nitrogen Heterocycle heptantriene

To bis- bromo- 2,3- dihydros -1H- indenes (800mg, 2.90mmol) of 1,6- and 2,2- dimethyl -2,3,4,5- tetrahydrochysene benzene And DIPEA is added in solution of [f] [1,4] the oxaza heptantriene (617mg, 3.48mmol) in acetonitrile (15mL) (0.506mL, 2.90mmol), and microwave stirs 1 hour at 90 DEG C by reaction mixture.Reaction mixture ice water is dilute It releases, EtOAc is used in combination to extract.By combined organic layer aqueous salt solu-tion, and through anhydrous Na₂SO₄It dries and filters.By solvent It is evaporated in vacuo, and by crude residue by using EtOAc:Hexane (2:8) as the purification by flash chromatography of eluent.By solvent It is concentrated in vacuo, obtains title compound (600mg, 54.8% yield).LC-MS m/z 374(M+H)⁺, 2.50 minutes (when reservation Between).

(3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydros - 1H- indenes -5- bases) (4- fluoro-2-methylbenzenes base) methanol

At -78 DEG C, to 4- (bromo- 2, the 3- dihydros -1H- indenes -1- bases of 6-) -2,2- dimethyl -2,3,4,5- tetrahydro benzos Oneself of 1.6M BuLi is added in solution of [f] [1,4] the oxaza heptantriene (600mg, 1.612mmol) in THF (25mL) Alkane solution (1.309mL, 2.095mmol).Reaction mixture is stirred 30 minutes at -78 DEG C.Then the 4- in THF is added Fluoro-2-methylbenzene formaldehyde (245mg, 1.773mmol), and reaction mixture is stirred at ambient temperature 1 hour.Reaction is mixed Close the NH of object saturation₄Cl is quenched, and is diluted with ice water, and EtOAc is used in combination to extract.By combined organic layer aqueous salt solu-tion, And through anhydrous Na₂SO₄It is dry, it filters and is evaporated in vacuo.By crude residue by using EtOAc:Hexane (2:8) as elution The purification by flash chromatography of liquid.Solvent in vacuo is concentrated, title compound (300mg, 31.1% yield) is obtained.LC-MS m/z 432(M+H)⁺, 4.34 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) -2,2- dimethylated methyl propionates

To (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) it is added in solution of (the 4- fluoro-2-methylbenzenes base) methanol (180mg, 0.417mmol) in DCM (10mL) ((1- methoxyl group -2- methyl propyl- 1- alkene -1- bases) oxygroup) trimethyl silane (218mg, 1.251mmol), is then added TiCl₄ (6mL, 6.00mmol), and stirred 30 minutes at 0 DEG C.The NaHCO that reaction mixture is saturated₃Dilution, is used in combination EtOAc to extract It takes.By combined organic layer aqueous salt solu-tion, and through anhydrous Na₂SO₄It is dried, filtered and concentrated.Crude residue is passed through Use EtOAc:Hexane (2:8) as the purification by flash chromatography of eluent.Solvent in vacuo is concentrated, title compound is obtained (150mg, 67.1% yield).LC-MS m/z 516(M+H)⁺, 4.83 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) -2,2- neopentanoic acids

To 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) -2,2- dimethylated methyl propionates (150mg, 0.291mmol) are two 2N NaOH (3mL, 0.291mmol) and methanol (3mL) are added in solution in methyl sulfoxide (DMSO) (3mL), and reaction is mixed Object is closed to heat 18 hours at 100 DEG C.After the completion of reaction, vacuum evaporating solvent, residue is diluted with ice water, is acidified to 1N HCl PH is 3.The solid of generation is filtered, and is purified by preparative HPLC, title compound (52mg, 35.1% yield) is obtained. LC-MS m/z 502(M+H)⁺, 3.68 minutes (retention time).

Embodiment 27

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, 2 formic acid Salt

3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- formaldehyde

At -78 DEG C, to the bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes (3.33g, Butyl lithium (4.80mL, 11.99mmol) 9.99mmol) is added in the solution in THF (70mL).In N₂Under atmosphere, it will mix Object stirs half an hour at -78 DEG C, and then DMF (3.87mL, 50.0mmol) is slowly added into reaction.By the reaction of generation Mixture stirs 2 hours at -78 DEG C, then with the NH of saturation₄Cl solution is quenched.Mixture is extracted with ethyl acetate three It is secondary.Combined organic layer is washed with brine, through anhydrous Na₂SO₄It is dry, it filters, evaporation, and by purification by flash chromatography, obtain (2.3g, 8.15mmol, 82% are produced required product 3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- formaldehyde Rate).LC-MS m/z 305.2(M+H)⁺, 2.07 minutes (retention time).

(1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) (3- ((4- methoxy-benzyls) oxygroup) -2,3- two Hydrogen -1H- indenes -5- bases) methanol

At -78 DEG C, in N₂Under atmosphere, to the bromo- Isosorbide-5-Nitraes of 5--dimethyl -1H- benzos [d] [1,2,3] triazole (2.26g, Tert-butyl lithium (9.23mL, 12.00mmol) 10.00mmol) is added in the solution in THF (60mL).By reaction mixture- In N at 78 DEG C₂It is stirred under atmosphere one hour, then by 3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- formaldehyde The 20ml THF solutions of (2.82g, 10.00mmol) are slowly added into the reaction.By the reaction mixture of generation at -78 DEG C Then lower stirring 2 hours is to slowly warm up to environment temperature and stirs 8 hours.The NH that reaction mixture is saturated₄Cl solution is quenched It goes out, and is extracted with ethyl acetate three times.Combined organic layer is washed with brine, anhydrous Na is used in combination₂SO₄It is dry.It filters and concentrates Afterwards, residue is obtained into required product (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- through purification by flash chromatography Base) (3.2g, 7.45mmol, 74.5% are produced (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) methanol Rate).LC-MS m/z 514.2(M+H)⁺, 2.24 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((4- methoxy-benzyls) oxygroup) - 2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates

In N₂Under protection, to (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) (3- ((4- methoxybenzyls Base) oxygroup) -2,3- dihydro -1H- indenes -5- bases) and in solution of the methanol (1g, 2.328mmol) in anhydrous acetonitrile (40mL) slowly DBU (7.02 μ L, 0.047mmol) and 2,2,2- Tritoxes (0.403g, 2.79mmol) is added in ground.The mixture of generation is existed ((1- methoxyl group -2- methyl propyl- 1- alkene -1- bases) oxygroup) trimethyl silane is then added in stirred at ambient temperature half an hour (1.015g, 5.82mmol), be then added three fluoro- N- ((trifluoromethyl) sulfonyl) Methanesulfomides (0.033g, 0.116mmol).Reaction mixture is stirred at ambient temperature 2 hours, then uses EtOAc (10ml) extractions three times, and will have Machine layer is washed with brine, and is filtered and is evaporated, and required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole-are obtained 5- yls) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates (1.1g, 2.14mmol, 92% yield).LC-MS m/z 514.2(M+H)⁺, 2.24 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- Base) -2,2- dimethylated methyl propionates

At 0 DEG C, to 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((4- methoxybenzyls Base) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates (5.9g, 11.49mmol) are at chloroform (64mL) With addition DDQ (2.61g, 11.49mmol) in the solution in water (4mL).The mixture of generation is stirred 2 hours at 0 DEG C, with EtOAc (120mL) and NaHCO is added afterwards₃(70mL, the aqueous solution of saturation).By organic layer separation, aqueous layer with ethyl acetate extraction Three times, and by combined organic layer the NaHSO being saturated₃Aqueous solution and salt water washing.By the solution through anhydrous Na₂SO₄It is dry, Filtering, evaporation, through purification by flash chromatography, obtains required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) (2.7g, 6.70mmol, 97.7% are produced -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates Rate).LC-MS m/z 394.2(M+H)⁺, 1.86 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, 2 formic acid Salt

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (79mg, 0.2mmol) in DCM (1.0mL)₂ (0.029mL,0.400mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, is evaporated in vacuo and is dissolved in acetonitrile In (3mL).2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloric acid are added into the solution Salt (85mg, 0.400mmol), sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(83mg,0.600mmol).By the anti-of generation Mixture is answered to be heated 68 hours in 40 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).By combined filtrate Evaporation, is dissolved in methanol (3mL), and NaOH (3N) (0.533mL, 1.600mmol) is then added.Gained reaction mixture is existed With microwave heating 1 hour at 130 DEG C.Reaction mixture is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pass through Reversed-phase HPLC purifies, and obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base propionic acid, 2 formates (21.6mg, 0.034mmol, 17.12% yield).LC-MS m/z 539.5(M+H)⁺, 0.80 minute (retention time).

Embodiment 28

3- (3- (- 4 (5H)-yl of 7- cyano -2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

Bromo- -4 (the 5H)-carboxylates of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene of 7-

At ambient temperature, to bromo- 2, the 2- dimethyl -2,3 of 7-, 4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene TEA (0.381mL, 2.73mmol) is added in the solution of (700mg, 2.73mmol) in DCM (5mL).Two carbon are added at 0 DEG C Sour tertiary butyl ester (596mg, 2.73mmol).Reaction mixture is stirred at ambient temperature 1 hour.It is diluted with water, and It is extracted with ethyl acetate, through Na₂SO₄It is dried, filtered and concentrated.Crude residue is used into silica gel chromatography, is obtained titled Object (900mg, 2.444mmol, 89% yield) is closed, is liquid.LC-MS m/z 300.13(M+H)⁺, 4.23 minutes (when reservation Between)

2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene -7- formonitrile HCNs

At ambient temperature, to bromo- 2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes of 7- -4 Zn is added in the solution in N,N-dimethylformamide (5mL) in (5H)-carboxylate (300mg, 0.842mmol) (CN)₂(99mg,0.842mmol).Reaction mixture is deaerated 20 minutes, four (triphenylphosphines) are then added and close palladium (0) (97mg,0.084mmol).Reaction mixture is heated 1 hour at 95 DEG C in microwave reactor.Reaction mixture is dense Contracting, and silica gel chromatography is used, title compound (90mg, 0.101mmol, 12.02% yield) is obtained, is liquid.LC-MS m/z 203.21(M+H)⁺, 1.22 minutes (retention time).

Compound in table 3 is to prepare 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen nitrogen by being similar to Prepared by the method for heterocycle heptantriene -7- formonitrile HCNs.It will be understood by those skilled in the art that these similar embodiments may include usually instead Answer the variation of condition.

Table 3

3- (3- (- 4 (5H)-yl of 7- cyano -2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene -7- carbonitrile hydrochlorides K is added in the solution of (95mg, 0.400mmol) in methanol (3mL)₂CO₃(55.3mg,0.400mmol).Gained reaction is mixed It closes object to stir at ambient temperature 30 minutes, be evaporated in vacuo.Acetonitrile (3mL) is added into gained residue, and in environment temperature Lower stirring 10 minutes, then filters, obtains acetonitrile solution A.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (76mg, 0.2mmol) in DCM (1.000mL)₂(0.029mL, 0.400mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, is then evaporated in vacuo, above-mentioned second is then added Nitrile solution A, sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).Gained reaction mixture is existed It is heated 22 hours at 40 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, It is dissolved in methanol (3mL).NaOH (3N) (0.533mL, 1.600mmol) is added.By gained reaction mixture with micro- at 80 DEG C Wave heating 20 minutes.Reaction mixture is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pure by reversed-phase HPLC Change, obtains product 3- (3- (7- cyano -2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates (36.3mg, 0.064mmol, 32.0% yield).LC-MS m/z 536.4(M+H)⁺, 0.80 minute (retention time).

Embodiment 29

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

Iodo- 1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles of the bromo- 7- of 5-

Sodium metaperiodate (0.378g, 1.769mmol) is suspended in acetic acid (2mL) and Ac₂O's (2.98mL, 31.5mmol) It stirs in mixture, is cooled to 5-10 DEG C.Dense H is very slowly added dropwise₂SO₄(1.792mL,33.6mmol).5- bromo- 1 is added, 4- dimethyl -1H- benzos [d] [1,2,3] triazole (1g, 4.42mmol), and continue stirring 16 hours at ambient temperature.It will be anti- Mixture is answered to pour into containing the Na dissolved in advance₂SO₃Ice water in.After 15 minutes, the precipitation EtOAc and Na of collection₂SO₃It is molten Liquid processing.Then use Combiflash Companion purification of crude product on silica column (40g), with 40mL/min by 100% hexane obtains title compound (286mg, 18.34%) to the gradient elution 35 minutes of 80%EtOAc/ hexanes.LC-MS m/z 351.9,353.9(M+H)⁺, 1.03 (retention times).

Bromo- 7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles of 5-

At ambient temperature, to the iodo- Isosorbide-5-Nitraes of the bromo- 7- of 5--dimethyl -1H- benzos [d] [1,2,3] triazole (286mg, Cuprous iodide (I) (77mg, 0.406mmol) and Cs 0.813mmol) are added in the solution in methanol (5mL)₂CO₃(530mg, 1.625mmol).Reaction mixture is stirred 40 minutes at 110 DEG C.The solvent was evaporated under reduced pressure.Then Combiflash is used Companion purification of crude product on silica column (12g), with 20mL/min by 100% hexane to 80%EtOAc/ hexanes Gradient elution 35 minutes, obtain title compound (68mg, 32.7%).LC-MS m/z 256.1,258.0(M+H)⁺,0.91 (retention time).

(E) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate

To bromo- 7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles (88mg, 0.344mmol) of 5- in N, In solution in dinethylformamide (1mL) be added ethyl acrylate (206mg, 2.062mmol), DIPEA (0.240mL, 1.374mmol) and acid chloride (II) (11.57mg, 0.052mmol).Reaction mixture is heated 1 hour for 110 DEG C in microwave.Add Enter water so that the reaction is quenched.Ethyl acetate is added, and detaches each layer.Once by aqueous layer with ethyl acetate extraction, merging is organic Layer is washed with brine primary.Organic layer is concentrated.Then use Combiflash Companion pure on silica column (40g) Change crude product, with 40mL/min by the gradient elution 35 minutes of 100% hexane to 80%EtOAc/ hexanes, obtains title compound (90mg, 95%).LC-MS m/z 276.1(M+H)⁺, 0.93 (retention time).

3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2, 3] triazole -5- bases) methyl propionate

To (E) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl acrylate 6- (4,4,5,5- tetramethyls-are added in the solution of (0.653g, 2.50mmol) in 1,4- dioxanes (12mL) and water (4mL) 1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol (0.976g, 3.75mmol), TEA (1.045mL, 7.50mmol) and [Rh (cod) Cl]₂(0.062g,0.125mmol).The reaction mixture of generation is stirred at 90 DEG C It mixes 2 hours.Reaction mixture is evaporated in vacuo, and by purification by flash chromatography, obtains product 3- (3- hydroxyls -2,3- dihydros - 1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (0.2238g, 0.566mmol, 22.64% yield).LC-MS m/z 396.1(M+H)⁺, 0.92 minute (retention time).

3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) methyl propionate

To 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) SOCl is added in solution of the methyl propionate (0.158g, 0.4mmol) in DCM (2mL)₂(0.058mL, 0.800mmol).Gained reaction mixture is stirred 2 hours at ambient temperature.The reaction is evaporated in vacuo, product 3- is obtained (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) Methyl propionate (0.1959g, 0.473mmol, 118% yield).LC-MS m/z 410.1(M-Cl+MeOH)⁺, (protect within 1.07 minutes Stay the time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (73.6mg, 0.344mmol) and K₂CO₃In the solution of (127mg, 0.918mmol) in acetonitrile (2mL) be added sodium iodide (17.20mg, 0.115mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) methyl propionate (95mg, 0.230mmol).Acquired solution is heated 16 hours at 50 DEG C.Reaction is mixed Object filters.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, then methanol (2.000mL) is used to dilute, so NaOH (2N) (0.552mL, 0.230mmol) is added afterwards.By gained reaction mixture with microwave heating 15 minutes at 80 DEG C.It will Reaction mixture is acidified to HCl (1N)_pH~5 are evaporated under vacuum, and are purified by reversed-phase HPLC, and product 3- (3- are obtained (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates (51.8mg, 0.096mmol, 41.7% yield).LC-MS m/z 541.4(M+H)⁺, 0.79 minute (retention time).

Embodiment 30

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, formates

3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) -2,2- dimethylated methyl propionates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (550mg, 1.398mmol) in DCM (3mL)₂ (0.306mL,4.19mmol).Gained reaction mixture is stirred 2 hours at ambient temperature.The reaction is evaporated in vacuo, is obtained To product 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) - 2,2- dimethylated methyl propionates (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- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates

To (R) -2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (125mg, K 0.583mmol) is added in the solution in acetonitrile (2mL)₂CO₃(215mg,1.554mmol).By acquired solution in environment temperature Lower stirring 20 minutes, is then added sodium iodide (18.19mg, 0.121mmol) and 3- (chloro- 2, the 3- dihydros -1H- indenes -5- bases of 3-) - 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (160mg, 0.388mmol) Solution in acetonitrile (2mL).The solution of generation is heated 19 hours at 50 DEG C.Reaction mixture is filtered.Filter cake is used MeCN (3mL) is washed.

(R) -2- ethyls -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (78mg, 0.364mmol) K is added in another reaction in acetonitrile (2.5mL)₂CO₃(134m_g,0.971mmol).By acquired solution in ring It is stirred 20 minutes at a temperature of border, and sodium iodide (18.19mg, 0.121mmol) and 3- (chloro- 2, the 3- dihydros -1H- indenes -5- of 3- is added Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).The solution of generation is heated 16 hours in 50 DEG C, is then filtered.

Combined filter vacuum is evaporated.By residue by purification by flash chromatography, product 3- (Isosorbide-5-Nitraes-dimethyl-are obtained 1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptan three Alkene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) (202.5mg, 0.366mmol, 39% are produced -2,2- dimethylated methyl propionates Rate).LC-MS m/z 553.3(M+H)⁺, 0.96 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated methyl propionates NaOH (2N) (73.3mg, 1.832mmol) is added in the solution of (202.5mg, 0.366mmol) in methanol (5mL).It will generate Solution microwave heated 5 hours at 120 DEG C.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid (34mg, 0.063mmol, 17.23% yield).LC-MS m/z 539.5(M+H)⁺, 0.85 minute (when reservation Between).

Embodiment 31

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2,7- dimethyl -2,3- two - 4 (5H)-yl of hydrogen benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, first Hydrochlorate

(R) -2,7- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

It is bromo- that 2- is added into solution of (the R) -1- amino propan-2-ol (0.394mL, 5.00mmol) in methanol (25mL) 5- tolyl aldehydes (995mg, 5mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, is then slowly added Enter NaBH₄(76mg,2.000mmol).Gained reaction mixture is stirred 67 hours at ambient temperature, is evaporated under vacuum, It is re-dissolved in DCM (20mL), through MgSO₄It is dry, it filters, is evaporated in vacuo, and be dissolved in isopropanol (20mL).Cuprous iodide is added (I) (95mg, 0.500mmol) and K₂CO₃(1382mg,10.00mmol).By gained reaction mixture in 130 DEG C of microwave heatings 60 Minute.Reaction mixture is evaporated in vacuo, is re-dissolved in DCM (20mL), through MgSO₄It is dry, it filters, is evaporated in vacuo, is produced Object (R) -2,7- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (727.0mg, 4.10mmol, 82% Yield).LC-MS m/z 178.0(M+H)⁺, 0.50 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2,7- dimethyl -2,3- two - 4 (5H)-yl of hydrogen benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, first Hydrochlorate

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (79mg, 0.2mmol) in DCM (1.000mL)₂ (0.029mL,0.400mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, evaporates, is dissolved under vacuum In acetonitrile (2mL), (R) -2,7- dimethyl -2,3,4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene is then added (70.9mg, 0.400mmol), sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).By generation Reaction mixture heats 92 hours at 40 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).By combined filter Liquid is evaporated in vacuo, and is dissolved in methanol (2mL).NaOH (3N) (0.533mL, 1.600mmol) is added.Gained reaction mixture is existed With microwave heating 2 hours at 120 DEG C.Reaction mixture is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pass through Reversed-phase HPLC purifies, and obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2,7- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid, formates (36.8mg, 0.065mmol, 32.5% yield).LC-MS m/z 539.5(M+H)⁺, 0.82 minute (retention time).

Embodiment 32

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formic acid Salt

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) methyl propionate

To (R) -2- methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (72.7mg, K 0.364mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(134mg,0.971mmol).By acquired solution in environment temperature The lower stirring of degree 20 minutes, is then added sodium iodide (18.19mg, 0.121mmol) and 3- (3- chloro- 2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).Acquired solution is heated 16 hours at 50 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL). Combined filter vacuum is evaporated, and residue is obtained into product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos by purification by flash chromatography [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- methyl -2,3- dihydrobenzos [f] [1,4] oxazas Heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) methyl propionate (98.4mg, 0.183mmol, 75% yield).LC- MS m/z 539.2(M+H)⁺, 0.93 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) methyl propionate NaOH (2N) (36.4mg, 0.910mmol) is added in the solution of (98mg, 0.182mmol) in methanol (3mL).By generation Solution microwave heats 7 hours at 120 DEG C.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- diformazans Base -3- (3- (- 4 (5H)-yl of (R) -2- methyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) propionic acid (46.2mg, 0.088mmol), 48.4% yield.LC-MS m/z 525.6(M+H)⁺, (retain within 0.78 minute Time).

Embodiment 33

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [Isosorbide-5-Nitrae] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2-Dimethylpropionic acid, Trifluoroacetate

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the solution of (86mg, 0.400mmol) in methanol (3mL)₂CO₃(83mg,0.600mmol).Gained is reacted and is mixed Object stirs 50 minutes at ambient temperature, is evaporated in vacuo, and acetonitrile (3mL) is then added, and filtering obtains acetonitrile solution A.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (79mg, 0.2mmol) in DCM (1.0mL)₂ (0.029mL,0.400mmol).Gained reaction mixture is stirred 25 minutes at ambient temperature, is evaporated in vacuo, is then added Above-mentioned acetonitrile solution A, sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(83mg,0.600mmol).Gained is reacted and is mixed Object heats 20 hours at 40 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is steamed Hair, is then re-dissolved in methanol (3mL), and NaOH (3N) (0.533mL, 1.600mmol) is then added.By gained reaction mixture With microwave heating 1 hour at 130 DEG C, it then is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pass through reverse phase HPLC is purified, and obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- bis- - 4 (5H)-yl of methyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) - 2,2-Dimethylpropionic acid, trifluoroacetate (56.9mg, 0.105mmol, 52.7% yield).LC-MS m/z 540.4(M+H)⁺, 0.85 minute (retention time).

Embodiment 34

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, Formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (79mg, 0.2mmol) in DCM (1.0mL)₂ (0.029mL,0.400mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, is evaporated in vacuo, it is then molten again In acetonitrile (3mL), it is added 2,2- dimethyl -2,3 later, 4,5- tetrahydropyridines simultaneously [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantriene (71.3mg, 0.400mmol), sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).By generation Reaction mixture heats 20 hours in 40 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).Combined filtrate is true Sky evaporation, be then re-dissolved in methanol (3mL), and NaOH (3N) (0.533mL, 1.600mmol) is added, then 140 DEG C with Microwave heating 60 minutes is acidified to pH 4~5 with HCl (3N), is evaporated in vacuo and is purified by reversed-phase HPLC, obtain product 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2- F] -4 (5H)-yl of [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, formates (9.4mg, 0.017mmol, 8.42% yield).LC-MS m/z 540.2(M+H)⁺, 0.80 minute (retention time).

Embodiment 35

3- (3- (- 4 (5H)-yl of 8- cyano -2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene -8- carbonitrile hydrochlorides K is added in the solution of (0.063g, 0.264mmol) in methanol (2mL)₂CO₃(0.036g,0.264mmol).Gained is reacted Mixture stirs 30 minutes at ambient temperature, is evaporated in vacuo, and acetonitrile (2mL) is then added, and stir 10 at ambient temperature Minute, it then filters, obtains acetonitrile solution A.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (0.050g, 0.132mmol) in DCM (1.0mL)₂(0.019mL, 0.264mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, evaporate, be then added above-mentioned acetonitrile solution A, Sodium iodide (9.88mg, 0.066mmol) and K₂CO₃(0.036g,0.264mmol).The reaction mixture of generation is heated at 40 DEG C It 19 hours, is then filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, methanol is then re-dissolved in In (2mL), NaOH (3N) (0.351mL, 1.054mmol) is then added.Gained reaction mixture is added at 80 DEG C with microwave Heat 20 minutes, is then acidified to pH 4~5 with HCl (3N), evaporates under vacuum, and purified by reversed-phase HPLC, obtain product 3- (3- (- 4 (5H)-yl of 8- cyano -2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates (8.5mg, 0.015mmol, 11.55% yield).LC-MS m/z 536.1(M+H)⁺, 0.82 minute (retention time).

Embodiment 36

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, Formates

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid first Ester

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride (73.9mg, 0.344mmol) and K₂CO₃Sodium iodide is added in the solution of (127mg, 0.918mmol) in acetonitrile (2mL) (17.20mg, 0.115mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1,4- dimethyl -1H- Benzo [d] [1,2,3] triazole -5- bases) methyl propionate (95mg, 0.230mmol).The solution microwave of generation is heated at 50 DEG C 16 hours.Reaction mixture is evaporated in vacuo, and through purification by flash chromatography, obtains required product 3- (3- (2,2- dimethyl- - 4 (5H)-yl of 2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -3- (7- Methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (41.9mg, 0.075mmol, 32.9% Yield).LC-MS m/z 556.2(M+H)⁺, 0.96 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, Formates

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) third NaOH (2N) (15.08mg, 0.377mmol) is added in solution of the sour methyl esters (41.9mg, 0.075mmol) in methanol (2mL). The solution microwave of generation is heated 15 minutes at 80 DEG C, then pH~5 is acidified to HCl (1N), evaporates under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyrido [3,4-f] [Isosorbide-5-Nitrae] oxazas Heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2, 3] triazole -5- bases) propionic acid, formates (32.9mg, 0.061mmol, 81% yield).LC-MS m/z 542.5(M+H)⁺,0.82 Minute (retention time).

Embodiment 37

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl 15 third Acid, formates

To (R) -2- ethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the solution of (86mg, 0.400mmol) in methanol (3mL)₂CO₃(55.3mg,0.400mmol).Gained reaction is mixed It closes object to stir at ambient temperature 30 minutes, be evaporated in vacuo, acetonitrile (3mL) is then added, and stir 20 points at ambient temperature Clock then filters, obtains acetonitrile solution A.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (79mg, 0.2mmol) in DCM (1.000mL)₂ (0.029mL,0.400mmol).Gained reaction mixture is stirred 10 minutes at ambient temperature, is evaporated in vacuo, is then added Above-mentioned acetonitrile solution A, sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).By the reaction of generation Mixture heats 20 hours at 40 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is steamed Hair, is then re-dissolved in methanol (3mL), and NaOH (3N) (0.533mL, 1.600mmol) is then added.

By gained reaction mixture in 140 DEG C of microwave heatings 60 minutes, it then is acidified to pH 4~5 with HCl (3N), true The lower evaporation of sky, and purified by reversed-phase HPLC, obtain product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) -3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids, formates (53.8mg, 0.095mmol, 47.4% yield).LC-MS m/z 540.5(M+H)⁺, 0.69,0.73 minutes (retention time).

Embodiment 38

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- neopentanoic acids, formates

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates

To 2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (54.3mg, 0.364mmol) in acetonitrile K is added in solution in (2.5mL)₂CO₃(101mg,0.728mmol).Acquired solution is stirred at ambient temperature 20 minutes, Sodium iodide (18.19mg, 0.121mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- diformazans are then added Base -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).By acquired solution It heats 16 hours at 50 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, is passed through Purification by flash chromatography obtains product 3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (71mg, 0.135mmol, 55.7% yield).LC-MS m/z 525.1(M+H)⁺, 0.90,0.91 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- neopentanoic acids

To 3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes - 5- yls) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (71mg, NaOH (2N) (27.1mg, 0.677mmol) 0.135mmol) is added in the solution in methanol (2mL).By acquired solution 120 With microwave heating 6 hours at DEG C, pH~5 then are acidified to HCl (1N), are evaporated under vacuum, and purified by reversed-phase HPLC, Obtain product 3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- neopentanoic acids (56.4mg, 0.110mmol, 82% yield).LC-MS m/z 511.5(M+H)⁺, 0.74 minute (retention time).

Embodiment 39

3- (3- (- 4 (5H)-yl of (R) -2,7- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2, 3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, first Hydrochlorate

To 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) SOCl is added in solution of the ethyl propionate (0.050g, 0.122mmol) in DCM (0.60mL)₂ (0.018mL,0.244mmol).Gained reaction mixture is stirred 10 minutes at ambient temperature, is evaporated in vacuo, and be dissolved in second In nitrile (1.5mL), (R) -2,7- dimethyl -2,3,4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene is then added (0.043g, 0.244mmol), sodium iodide (9.15mg, 0.061mmol) and K₂CO₃(0.034g,0.244mmol).Gained is anti- It answers mixture to be heated 18 hours at 40 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).By combined filter vacuum Evaporation, is then re-dissolved in methanol (1.5mL), and NaOH (3N) (0.204mL, 0.611mmol) is then added.Gained reaction is mixed Object is closed at 80 DEG C with microwave heating 20 minutes, then pH 4~5 is acidified to HCl (3N), evaporates under vacuum, and by anti- Phase HPLC purifying, obtains product 3- (3- ((R) -2,7- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) propionic acid, formates (41.2mg, 0.072mmol, 58.9% yield).LC-MS m/z 541.4(M+H)⁺, (protect within 0.84 minute Stay the time).

Embodiment 40

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) ethyl propionate (100mg, 0.264mmol) DCM (0.5mL) solution in be added thionyl chloride (0.038mL, 0.527mmol).Gained reaction mixture is stirred 55 minutes at ambient temperature, is evaporated in vacuo, is then dissolved in acetonitrile In (2.5mL), 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene, hydrochloride is then added (113mg,0.527mmol)、K₂CO₃(109mg, 0.791mmol), sodium iodide (7.90mg, 0.053mmol).By the reaction of generation Mixture stirs 69 hours at 40 DEG C.Then filtered, be evaporated in vacuo, then be added NaOH (3N) (0.439mL, 1.318mmol).Then gained reaction mixture is acidified to pH~6 with microwave heating 20 minutes at 80 DEG C with HCl (3N), It evaporates, is purified by reversed-phase HPLC under vacuum, obtain product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) -3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydros - 1H- indenes -5- bases) propionic acid (76.1mg, 0.149mmol, 56.6% yield).LC-MS m/z 511.5(M+H)⁺, 0.70 minute (retention time).

Embodiment 41

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- 1-Indanones

To the bromo- 2,3- dihydros -1H- 1-Indanones (1.688g, 8mmol) of 6- in N,N-dimethylformamide (16mL) Two (pinacol combined) two boron (3.05g, 12.00mmol), KOAc (1.570g, 16.00mmol) and PdCl are added in solution₂ (dppf)(0.293g,0.400mmol).By gained reaction mixture with microwave heating 1 hour at 100 DEG C.Reaction is mixed Object H₂O (20mL) and EtOAc (40mL) dilutions, stir and filter.By organic layer separation, and by water layer EtOAc (2x 30mL) extract.Combined organic layer is washed with brine (40mL), through MgSO₄Dry, filtering is evaporated, under vacuum through quick Chromatogram purification obtains required product 6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) -2,3- bis- Hydrogen -1H- 1-Indanones (1.9623g, 7.60mmol, 95% yield).LC-MS m/z 259.1(M+H)⁺, (retain within 1.03 minutes Time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydro -1H- indenes -5- Base) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (0.564g, 6- (4,4,5,5- tetramethyl -1,3,2- dioxies 2.3mmol) are added in the solution in 1,4- dioxanes (13mL) and water (4ml) Miscellaneous boron heterocycle pentane -2- bases) -2,3- dihydro -1H- 1-Indanones (0.891g, 3.45mmol), TEA (1.282mL, 9.20mmol) [Rh (cod) Cl]₂(0.057g,0.115mmol).The reaction mixture of generation is stirred 1 hour at 90 DEG C.Reaction is mixed Object is evaporated in vacuo, and through purification by flash chromatography, obtains required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole - 5- yls) -3- (3- oxo -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (0.6070g, 1.608mmol, 69.9% yield). LC-MS m/z 378.3(M+H)⁺, 0.87 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydro -1H- indenes -5- Base) ethyl propionate

By 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydro -1H- indenes - 5- yls) ethyl propionate (0.800g, 2.120mmol) purified by chiral SFC, obtain the product 3- (Isosorbide-5-Nitraes-diformazan of enantiomer-pure Base -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (0.3393g, 0.899mmol, 42.4% yield).LC-MS m/z 378.3(M+H)⁺, 0.88 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- Base) ethyl propionate

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydro -1H- indenes - 5- yls) NaBH is added in solution of the ethyl propionate (339mg, 0.898mmol) in methanol (5mL)₄(34.0mg, 0.898mmol).Gained reaction mixture is stirred 140 minutes at ambient temperature, more NaBH are then added₄ (34.0mg,0.898mmol).Gained reaction mixture is stirred 90 minutes at ambient temperature, more NaBH are then added₄ (68.0mg,1.796mmol).Gained reaction mixture is stirred 1 hour at ambient temperature, is evaporated under vacuum, by fast Fast chromatogram purification obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyls -2,3- bis- Hydrogen -1H- indenes -5- bases) ethyl propionate (0.3120g, 0.822mmol, 92% yield).LC-MS m/z 380.2(M+H)⁺,0.87 Minute (retention time).

3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) ethyl propionate

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (120mg, 0.316mmol) in DCM (2mL)₂(0.069mL, 0.949mmol).Gained reaction mixture is stirred 5 hours at ambient temperature, be evaporated in vacuo, obtain product 3- (3- chloro- 2, 3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (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- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (101mg, 0.474mmol) and K₂CO₃In the solution of (175mg, 1.265mmol) in acetonitrile (3mL) be added sodium iodide (23.70mg, 0.158mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles - 5- yls) ethyl propionate (125.8mg, 0.316mmol).Acquired solution is evaporated in vacuo at 60 DEG C with microwave heating 16 hours, Then by purification by flash chromatography, product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- are obtained (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) Ethyl propionate (118.4mg, 0.220mmol, 69.5% yield).LC-MS m/z 539.2(M+H)⁺, 0.94 minute (when reservation Between).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (118.4mg, NaOH (2N) (44.0mg, 1.099mmol) 0.220mmol) is added in the solution in methanol (3mL).The solution of generation is used Microwave heats 15 minutes at 80 DEG C, is then acidified to pH~5 with HCl (1N), evaporates under vacuum, and by reversed-phase HPLC, Then purified with chirality SFC, obtain product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2, - 4 (5H)-yl of 2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Acid, formates (20mg, 0.039mmol, 17.82% yield).LC-MS m/z 511.6(M+H)⁺, 0.70 minute (when reservation Between).

Embodiment 42

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Acid, formates

(R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol

(R) -1- amino propan-2-ols are added into solution of the 2- chlorine cigarette aldehyde (0.708g, 5mmol) in methanol (10mL) (0.488g,6.50mmol).Reaction mixture is stirred at ambient temperature 1 hour, is then slowly added into NaBH₄ (0.378g, 10.00mmol) is then stirred for 1 hour at ambient temperature.By reaction mixture NaHCO₃(the water of saturation Solution) (0.5mL) be quenched, be then evaporated in vacuo.Residue is diluted with DCM (50mL), through MgSO₄It is dry, filter simultaneously vacuum Evaporation, obtains product (R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol (1.3176g, 6.57mmol, 131% Yield).LC-MS m/z 200.9(M+H)⁺, 0.24 minute (retention time).

(R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

To (R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol (1.2176g, 6.07mmol) in N, N- bis- KOtBu (2.043g, 18.20mmol) is added in solution in methylformamide (60mL).The solution of generation is heated 4 in 80 DEG C Hour, it then evaporates under a high vacuum, then DCM (50mL) is used to dilute, filtering.The solution is evaporated in vacuo, product is obtained (R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (0.7899g, 4.81mmol, 79% Yield).LC-MS m/z165.0(M+H)⁺, 0.16 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Sour methyl esters

To (R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (80mg, K 0.486mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(101mg,0.728mmol).By acquired solution in environment temperature The lower stirring of degree 20 minutes, is then added sodium iodide (18.19mg, 0.121mmol) and 3- (3- chloro- 2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).The solution of generation is heated 23 hours in 50 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).It will merge Filter vacuum evaporation, and by purification by flash chromatography, obtain product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] three Azoles -5- bases) -2,2- dimethyl -3- (3- ((R) -2- methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptan three Alkene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) methyl propionate (73.8mg, 0.137mmol, 56.3% yield).LC-MS m/z 540.2(M+H)⁺, 0.87 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third NaOH (2N) (27.1mg, 0.676mmol) is added in solution of the sour methyl esters (73mg, 0.135mmol) in methanol (2.5mL). The solution microwave of generation is heated 7 hours at 120 DEG C, then pH~5 is acidified to HCl (1N), evaporates under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- diformazans Base -3- (3- (- 4 (5H)-yl of (R) -2- methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) propionic acid, formates (51.6mg, 0.098mmol, 72.6% yield).LC-MS m/z 526.6(M+H)⁺, 0.68 minute (retention time).

Embodiment 43

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] three Azoles -5- bases) ethyl propionate

To (E) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (653mg, 6- (4,4,5,5- tetramethyls -1,3,2- two 2.50mmol) are added in the solution in 1,4- dioxanes (12mL) and water (4mL) Oxa- boron heterocycle pentane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol (976mg, 3.75mmol), TEA (1.045mL, 7.50mmol) and [Rh (cod) Cl]₂(61.6mg,0.125mmol).The reaction mixture of generation is stirred 3 hours at 90 DEG C, It is evaporated in vacuo, and by purification by flash chromatography, obtains product 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxies Base -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (334.1mg, 0.845mmol, 33.8% yield). LC-MS m/z 396.1(M+H)⁺, 0.90 minute (retention time).

3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] three Azoles -5- bases) ethyl propionate

To 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] Triazole -5- bases) SOCl is added in solution of the ethyl propionate (280mg, 0.708mmol) in DCM (3mL)₂(0.103mL, 1.416mmol).Gained reaction mixture is stirred 2 hours at ambient temperature, be evaporated in vacuo, obtain product 3- (3- chloro- 2, 3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (0.3455g, 0.835mmol, 118% yield).LC-MS m/z 396.0(M-Cl+H₂O)⁺, 0.95 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (69.7mg, 0.326mmol) and K₂CO₃In the solution of (90mg, 0.652mmol) in acetonitrile (2mL) be added sodium iodide (16.30mg, 0.109mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] Triazole -5- bases) ethyl propionate (90mg, 0.217mmol).The solution microwave of generation is heated 15 hours at 50 DEG C, true The lower evaporation of sky, by purification by flash chromatography, obtains product 3- (3- (2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxygen azepines Cycloheptatriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] Triazole -5- bases) ethyl propionate (58.1mg, 0.105mmol, 48.2% yield).LC-MS m/z 555.2(M+H)⁺, 0.95 point Clock (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate NaOH (2N) (20.95mg, 0.524mmol) is added in the solution of (58.1mg, 0.105mmol) in methanol (2mL).It will generate Solution microwave heated at 80 DEG C 15 minutes, be then acidified to pH~5 with HCl (1N), evaporate under vacuum, and by anti- Phase HPLC purifying, obtains product 3- (3- (2,2- dimethyl -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, Formates (20.86mg, 0.037mmol, 35.0% yield).LC-MS m/z 527.2(M+H)⁺, 0.82 minute (when reservation Between).

Embodiment 44

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, Formates

1- (((2- chloropyridine -3- bases) methyl) amino) -2- methyl propan-2-ols

1- amino-2-methyl propyl-s 2- is added into solution of the 2- chlorine cigarette aldehyde (1.132g, 8mmol) in methanol (20mL) Alcohol (0.927g, 10.40mmol).Reaction mixture is stirred at ambient temperature 1 hour.Then by NaBH₄(0.605g, It 16.00mmol) is added in reaction solution, and acquired solution is stirred at ambient temperature 1 hour with two batches.Reaction is mixed Close object NaHCO₃(saturation) (0.7ml) is quenched, and is then evaporated in vacuo.Residue is dissolved in DCM, through MgSO₄It is dry, mistake It filters and is evaporated in vacuo, obtain required product 1- (((2- chloropyridine -3- bases) methyl) amino) -2- methyl propan-2-ols (1.8329g, 8.54mmol, 107% yield).LC-MS m/z 214.9(M+H)⁺, 0.30 minute (retention time).

2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

To 1- (((2- chloropyridine -3- bases) methyl) amino) -2- methyl propan-2-ol (1.6575g, 7.72mmol) in N, N- NaH (0.371g, 15.44mmol) is added in solution in dimethylformamide (75mL).The solution of generation is heated 1 at 80 DEG C Hour, then concentration is used DCM (50ml) to dilute, and is filtered.The solution is evaporated in vacuo, required product 2,2- diformazans are obtained Base -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (1.3823g, 7.76mmol, 100% yield). LC-MS m/z 179.0(M+H)⁺, 0.21 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid first Ester

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (134mg, K 0.750mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(69.1mg, 0.500mmol), sodium iodide (18.74mg, 0.125mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) methyl propionate (103mg, 0.25mmol).The solution microwave of generation is heated 3 hours at 60 DEG C, then It is evaporated in vacuo, by purification by flash chromatography, obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [Isosorbide-5-Nitrae] Oxaza heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (43.1mg, 0.078mmol, 31.0% yield).LC-MS m/z 556.2(M+ H)⁺, 0.82 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, Formates

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) third NaOH (2N) (15.48mg, 0.387mmol) is added in solution of the sour methyl esters (43mg, 0.077mmol) in methanol (1.5mL). The solution microwave of generation is heated 15 minutes at 80 DEG C, then pH~5 is acidified to HCl (1N), evaporates under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyrido [3,2-f] [Isosorbide-5-Nitrae] oxazas Heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H- benzos [d] [1,2, 3] triazole -5- bases) propionic acid, formates (14.1mg, 0.026mmol, 33.6% yield).LC-MS m/z 542.3(M+H)⁺, 0.75 minute (retention time).

Embodiment 45

3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate

To (R) -2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (85mg, K 0.399mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(147mg,1.063mmol).By acquired solution in environment temperature The lower stirring of degree 20 minutes, is then added sodium iodide (19.92mg, 0.133mmol) and 3- (3- chloro- 2,3- dihydro -1H- indenes -5- Base) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (110mg, 0.266mmol).The solution of generation is heated 19 hours at 50 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).It will Combined filter vacuum evaporation, and residue is obtained into product 3- (3- ((R) -2- ethyls -2,3- bis- by purification by flash chromatography - 4 (5H)-yl of hydrogen benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- Dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (104.7mg, 0.189mmol, 71.0% yield).LC- MS m/z 555.2(M+H)⁺, 0.97 minute (retention time).

3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate NaOH (2N) (37.5mg, 0.937mmol) is added in the solution of (104mg, 0.187mmol) in methanol (3mL).By generation Solution microwave heats 15 minutes at 80 DEG C, is then acidified to pH~5 with HCl (1N), evaporates under vacuum, and pass through reverse phase HPLC is purified, and obtains product 3- (3- ((R) -2- ethyls -2,3- dihydrobenzo [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) third Acid, formates (36.8mg, 0.068mmol, 36.3% yield).LC-MS m/z 541.4(M+H)⁺, 0.80 minute (when reservation Between).

Embodiment 46

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formic acid Salt

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the solution of (124mg, 0.580mmol) in acetonitrile (2.0mL)₂CO₃(214mg,1.546mmol).By acquired solution It stirs at ambient temperature 20 minutes, sodium iodide (29.0mg, 0.193mmol) and 3- (chloro- 2, the 3- dihydros -1H- of 3- is then added Indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (160mg, Acetonitrile (2.0mL) solution 0.387mmol).The solution microwave of generation is heated 14 hours at 50 DEG C, is then filtered.It will Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, and by residue by purification by flash chromatography, is obtained required Product 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2, 3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (17.6mg, 0.032mmol, 8.19% yield).LC-MS m/z 556.2(M+H)⁺, 1.02 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formic acid Salt

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid second NaOH (2N) (9.21mg, 0.230mmol) is added in solution of the ester (25.6mg, 0.046mmol) in methanol (1mL).It will give birth to At solution microwave heated at 80 DEG C 15 minutes, be then acidified to pH~5 with HCl (1N), evaporate under vacuum, and pass through Reversed-phase HPLC purifies, and obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyrido [3,4-f] [Isosorbide-5-Nitrae] oxaza heptan three Alkene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- Base) propionic acid, formates (8.4mg, 0.016mmol, 34.6% yield).LC-MS m/z 528.2(M+H)⁺, (protect within 0.84 minute Stay the time).

Embodiment 47

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2,7- dimethyl -2,3- two - 4 (5H)-yl of hydrogen benzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (76mg, 0.2mmol) in DCM (1.000mL)₂(0.029mL, 0.400mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, be evaporated in vacuo and is dissolved in acetonitrile (2mL), Then be added (R) -2,7- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (70.9mg, 0.400mmol), sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).The reaction of generation is mixed Object heats 92 hours at 40 DEG C, then filters.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, and is dissolved in In methanol (2mL), NaOH (3N) (0.333mL, 1.000mmol) is then added.By gained reaction mixture with micro- at 80 DEG C Wave heating 20 minutes is then acidified to pH 4~5 with HCl (3N), evaporates, and purified by reversed-phase HPLC, obtain under vacuum Required product 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2,7- dimethyl -2,3- - 4 (5H)-yl of dihydrobenzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (60.4mg, 0.113mmol, 56.4% yield).LC-MS m/z 511.5(M+H)⁺, 0.75 minute (retention time).

Embodiment 48

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene (67.1mg, K 0.376mmol) is added in the solution in acetonitrile (3mL)₂CO₃(96mg, 0.691mmol), sodium iodide (25.9mg, 0.173mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles - 5- yls) ethyl propionate (137.5mg, 0.346mmol).The solution microwave of generation is heated 5 hours at 60 DEG C, then vacuum steaming Hair, by purification by flash chromatography, obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) - 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydros - 1H- indenes -5- bases) ethyl propionate (17mg, 0.032mmol, 9.12% yield).LC-MS m/z 540.2(M+H)⁺, 0.89 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (17mg, NaOH (2N) (6.30mg, 0.158mmol) 0.032mmol) is added in the solution in methanol (1mL).The solution of generation is used Microwave heats 15 minutes at 80 DEG C, is then acidified to pH~5 with HCl (1N), evaporates under vacuum, and pure by reversed-phase HPLC Change, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- bis- Pyridinium hydroxide simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (10.5mg, 0.021mmol, 65.2% yield).LC-MS m/z 512.2(M+H)⁺, 0.78 minute (retention time).

Embodiment 49

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((S) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Acid, formates

(S) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol

(S) -1- amino propan-2-ols are added into solution of the 2- chlorine cigarette aldehyde (0.708g, 5mmol) in methanol (10mL) (0.488g,6.50mmol).Reaction mixture is stirred at ambient temperature 1 hour, is then slowly added into NaBH₄ (0.378g, 10.00mmol), and the solution of generation is stirred for 1 hour at ambient temperature, then use NaHCO₃(saturation) It is quenched, is diluted with DCM (20mL), through MgSO₄It is dry, it filters, is evaporated in vacuo, obtains product (S) -1- (((2- chloropyridines -3- Base) methyl) amino) propan-2-ol (1.0291g, 5.13mmol, 103% yield).LC-MS m/z 200.9(M+H)⁺, 0.19 point Clock (retention time).

(S) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

To (S) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol (1.026g, 5.11mmol) in N, N- diformazans KOtBu (1.721g, 15.34mmol) is added in solution in base formamide (50mL).It is small that the solution of generation is heated at 80 DEG C to 4 When, it evaporates under a high vacuum, then DCM (50mL) is used to dilute, filter, be evaporated in vacuo, obtain product (S) -2- methyl -2,3,4, 5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (0.8617g, 5.25mmol, 103% yield).LC-MS m/z 164.9(M+H)⁺, 0.10 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((S) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Sour methyl esters

To (S) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (80mg, K 0.486mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(101mg,0.728mmol).By acquired solution in environment temperature The lower stirring of degree 20 minutes, is then added sodium iodide (18.19mg, 0.121mmol) and 3- (3- chloro- 2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).The solution of generation is heated 21 hours at 50 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).It will Combined filter vacuum evaporation, then by purification by flash chromatography, obtains required product 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((S) -2- methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxygen Azepine cycloheptatriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) (78.9mg, 0.146mmol, 60.2% are produced methyl propionate Rate).LC-MS m/z 540.2(M+H)⁺, 0.85 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((S) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third Acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- ((S) -2- first - 4 (5H)-yl of base -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) third NaOH (2N) (28.9mg, 0.723mmol) is added in solution of the sour methyl esters (78mg, 0.145mmol) in methanol (2.5mL). The solution microwave of generation is heated 7 hours at 120 DEG C, then pH~5 is acidified to HCl (1N), evaporates under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- diformazans Base -3- (3- (- 4 (5H)-yl of (S) -2- methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) propionic acid, formates (54mg, 0.103mmol, 71.1% yield).LC-MS m/z 526.5(M+H)⁺, 0.69 minute (retention time).

Embodiment 50

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) ethyl propionate (0.050g, 0.132mmol) DCM (0.50mL) solution in SOCl is added₂(0.019mL, 0.264mmol).Gained reaction mixture is stirred 15 minutes at ambient temperature, evaporates under vacuum, is dissolved in acetonitrile In (1.5mL), (R) -2- ethyls -2,3,4,5- tetrahydro benzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene, hydrochloride is then added (0.042g, 0.198mmol), sodium iodide (9.88mg, 0.066mmol) and K₂CO₃(0.055g,0.395mmol).By generation Reaction mixture heats 17 hours at 40 DEG C, then filters.Filter cake is washed with MeCN (2mL).Combined filter vacuum is steamed Hair, and be dissolved in methanol (1.5mL), NaOH (3N) (0.220mL, 0.659mmol) is then added.Gained reaction mixture is existed With microwave heating 20 minutes at 80 DEG C, it then is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pass through reversed-phase HPLC Purifying, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyls -2,3- - 4 (5H)-yl of dihydrobenzo [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (22.7mg, 0.042mmol, 32.0% yield) (78.7mg, 0.158mmol, 67.5% yield).LC-MS m/z 511.5(M+ H)⁺, 0.75 minute (retention time).

Embodiment 51

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((2,2- dimethyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,2-f] [1,4] oxaza heptantriene) methyl) -4- aminomethyl phenyls) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (76mg, 0.2mmol) in DCM (1.000mL)₂(0.029mL, 0.400mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, is evaporated in vacuo, is then re-dissolved in acetonitrile In (3mL), it is then added 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantriene (71.3mg, 0.400mmol), sodium iodide (14.99mg, 0.100mmol) and K₂CO₃(55.3mg,0.400mmol).By generation Reaction mixture heats 21 hours at 40 DEG C, is then filtered.Filter cake is washed with MeCN (2mL).Combined filtrate is true Sky evaporation, and be dissolved in methanol (3mL), NaOH (3N) (0.533mL, 1.600mmol) is then added.By gained reaction mixture With microwave heating 20 minutes at 80 DEG C, it then is acidified to pH 4~5 with HCl (3N), is evaporated under vacuum, and pass through reverse phase HPLC is purified, and obtains required product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- bis- - 4 (5H)-yl of methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) Propionic acid (40.5mg, 0.079mmol, 39.6% yield).LC-MS m/z 512.1(M+H)⁺, 0.72 minute (retention time).

Embodiment 52

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate

To 2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (59.5mg, 0.399mmol) in acetonitrile K is added in solution in (2.5mL)₂CO₃(110mg,0.797mmol).Acquired solution is stirred at ambient temperature 20 minutes, Sodium iodide (19.92mg, 0.133mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl groups-are then added 1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (110mg, 0.266mmol).By the solution of generation It is heated 19 hours in 50 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).Combined filter vacuum is evaporated, And residue is obtained into product 3- (3- (2,3- dihydrobenzos [f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 by purification by flash chromatography (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) methyl propionate (50.8mg, 0.096mmol, 36.3% yield).LC-MS m/z 527.3(M+H)⁺, (retain within 0.82 minute Time).

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes - 5- yls) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) methyl propionate (50.8mg, NaOH (2N) (19.29mg, 0.482mmol) 0.096mmol) is added in the solution in methanol (2mL).The solution of generation is existed 80 DEG C with microwave heating 15 minutes.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, and pass through reverse phase HPLC purify, obtain required product 3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [Isosorbide-5-Nitrae] oxaza heptantriene) -2, 3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, first Hydrochlorate (39.8mg, 0.078mmol, 80% yield).LC-MS m/z 513.6(M+H)⁺, 0.71 minute (retention time).

Embodiment 53

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

The chloro- 2,3- dihydros -1H- indenes of the bromo- 1- of 6-

It is added into solution of the bromo- 2,3- dihydros -1H- indenes -1- alcohol (1.50g, 7.04mmol) of 6- in DCM (3.5mL) Thionyl chloride (1.028mL, 14.08mmol).Gained reaction mixture is stirred 1 hour at ambient temperature.Reaction is mixed Object is evaporated in vacuo, and obtains chloro- 2, the 3- dihydros -1H- indenes of the bromo- 1- of product 6- (1.6225g, 7.01mmol, 100% yield).¹H NMR (400MHz, chloroform-d) δ ppm 2.33-2.44 (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=8.03Hz, 1H) 7.39 (d, J=8.03Hz, 1H) 7.57 (s, 1H).

((2R) -4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2- methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen Azepine cycloheptatriene

It is added into solution of the chloro- 2,3- dihydros -1H- indenes (185mg, 0.8mmol) of the bromo- 1- of 6- in acetonitrile (8mL) (R) -2- methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (261mg, 1.600mmol), K₂CO₃ (221mg, 1.600mmol) and sodium iodide (23.98mg, 0.160mmol).The reaction mixture of generation is small in 60 DEG C of heating 68 When.Reaction mixture is evaporated in vacuo, by purification by flash chromatography, obtains product (2R) -4- (bromo- 2,3- dihydros -1H- indenes-of 6- 1- yls) -2- methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (191.5mg, 0.535mmol, 66.8% Yield).LC-MS m/z358.1(M+H)⁺, 0.77 minute (retention time).

(2R) -2- methyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- two Hydrogen -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To (2R) -4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2- methyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen Two (pinacols are added in solution of the azepine cycloheptatriene (190mg, 0.530mmol) in N,N-dimethylformamide (3mL) Close) two boron (202mg, 0.795mmol), KOAc (104mg, 1.061mmol) and PdCl₂(dppf)(19.40mg, 0.027mmol).By gained reaction mixture with microwave heating 1 hour at 100 DEG C.Reaction mixture is evaporated in vacuo, is passed through Purification by flash chromatography obtains product (2R) -2- methyl -4- (6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolans alkane - 2- yls) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (164.1mg, 0.405mmol, 76% yield).LC-MS m/z 406.2(M+H)⁺, 0.94 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

To (2R) -2- methyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- Dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (165mg, 0.408mmol) 1, (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] three are added in solution in 4- dioxanes (2mL) and water (0.7mL) Azoles -5- bases) ethyl acrylate (50mg, 0.204mmol), TEA (0.085mL, 0.612mmol) and [RhCl (cod)]₂ (5.03mg,10.19μmol).The reaction mixture of generation is heated 90 minutes in 90 DEG C.Reaction mixture is evaporated in vacuo, with After be re-dissolved in methanol (2mL), then be added NaOH (3N) (0.340mL, 1.019mmol).By gained reaction mixture 80 With microwave heating 20 minutes at DEG C.Reaction mixture is acidified to pH 3~4 with HCl (3N), is evaporated under vacuum, and by anti- Phase HPLC purifying, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- first - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid (11.0mg, 0.022mmol, 10.87% yield).LC-MS m/z 497.2(M+H)⁺, 0.74 minute (retention time).

Embodiment 54

3- (3- (- 4 (5H)-yl of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- neopentanoic acids, formates, formic acid Salt

2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

Be added into solution of the 2- chlorine cigarette aldehyde (425mg, 3mmol) in methanol (5mL) 2- ethylaminoethanols (476mg, 3.90mmol).Reaction mixture is stirred at ambient temperature 1 hour, NaBH is then added₄(227mg,6.00mmol).It will The solution of generation is stirred for 1 hour at ambient temperature.By reaction mixture NaHCO₃(saturation) (0.5mL) is quenched and steams Hair.Residue is diluted with DCM (20mL), through MgSO₄It is dry, filtering, and be then evaporated in vacuo, then use N, N- dimethyl methyls Amide (30.00mL) dilutes, and KOtBu (673mg, 6.00mmol) is then added.The solution of generation is heated 4 hours in 80 DEG C, More KOtBu (337mg, 3.00mmol) are then added, are then reheated 3 hours in 80 DEG C.Reaction mixture is filtered, and Filter cake is washed with N,N-dimethylformamide (5.00mL).Combined filter vacuum is evaporated.By residue with DCM (30mL) Dilution, through MgSO₄It is dried and evaporated, obtains 2,3,4,5- tetrahydropyridine of product simultaneously [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantriene (679mg, 4.52mmol, 151% yield).LC-MS m/z 150.8(M+H)⁺, 0.11 minute (retention time).

- 4 (5H)-carboxylate of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene

Under an argon, in the solution to two dimethyl dicarbonate butyl esters (2.099mL, 9.04mmol) in THF (5.0mL) The THF (5.0mL) of 2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (679mg, 4.52mmol) is added Solution.The solution of generation is stirred 21 hours at ambient temperature.Then the reaction is evaporated in vacuo, it is pure by flash chromatography Change, obtains product 2, -4 (5H)-carboxylate of 3- dihydro pyridos [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantriene (390.8mg, 1.561mmol, 34.5% yield).LC-MS m/z 250.9(M+H)⁺, 0.69 minute (retention time).

2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene, hydrochloride

To -4 (5H)-carboxylate of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene (390mg, 1.558mmol) in the solution in 1,4- dioxanes (3mL) be added HCl (the 1,4- dioxane solutions of 4M) (1.169mL, 4.67mmol).The solution of generation is stirred 2 hours at ambient temperature, more HCl (- dioxanes of Isosorbide-5-Nitrae of 4M are then added Solution) (2.73mL, 10.91mmol).The solution of generation is stirred for 20 hours at ambient temperature.By the reaction solution vacuum Evaporation, obtains 2,3,4,5- tetrahydropyridine of product simultaneously [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantriene, hydrochloride (290.4mg, 1.556mmol, 100% yield).LC-MS m/z 150.8(M+H)⁺, 0.13 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates

To 2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene, hydrochloride (68.0mg, K 0.364mmol) is added in the solution in acetonitrile (2.5mL)₂CO₃(134mg,0.971mmol).By acquired solution in environment temperature The lower stirring of degree 20 minutes, is then added sodium iodide (18.19mg, 0.121mmol) and 3- (3- chloro- 2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (100mg, 0.243mmol).Acquired solution is heated 16 hours at 50 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL). Combined filter vacuum is evaporated, and residue is obtained into product 3- (3- (2,3- dihydro pyridos by purification by flash chromatography - 4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzene And [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates (64.2mg, 0.122mmol, 50.3% yield).LC-MS m/z 526.2(M+H)⁺, 0.79 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- neopentanoic acids, formates

To 3- (3- (- 4 (5H)-yl of 2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros - 1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethylated methyl propionates NaOH (2N) (24.35mg, 0.609mmol) is added in the solution of (64mg, 0.122mmol) in methanol (2.5mL).It will generate Solution microwave heated 7 hours at 120 DEG C.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, It is purified by reversed-phase HPLC, obtains product 3- (3- (2,3- dihydro pyridos [3,2-f] [Isosorbide-5-Nitrae] oxaza heptantrienes -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- Neopentanoic acid, formates (24.5mg, 0.048mmol, 39.3% yield).LC-MS m/z 512.6(M+H)⁺, 0.66 minute (retention time).

Embodiment 55

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formic acid Salt

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene, hydrochloride (93mg, 0.435mmol) and K₂CO₃Sodium iodide is added in the solution of (120mg, 0.870mmol) in acetonitrile (3mL) (21.73mg, 0.145mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (120mg, 0.290mmol).The solution microwave of generation is heated 19 at 50 DEG C Hour.Reaction mixture is evaporated in vacuo, by purification by flash chromatography, obtains product 3- (3- (2,2- dimethyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups - 1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) ethyl propionate (62.6mg, 0.113mmol, 38.9% yield).LC-MS m/z 556.3(M+H)⁺, 0.84 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formic acid Salt

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl groups -1- methyl-1 H- benzos [d] [1,2,3] triazole -5- bases) propionic acid second NaOH (2N) (22.53mg, 0.563mmol) is added in solution of the ester (62.6mg, 0.113mmol) in methanol (2mL).It will give birth to At solution at 80 DEG C with microwave heating 15 minutes.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, And purified by reversed-phase HPLC, obtain product 3- (3- (2,2- dimethyl -2,3- dihydro pyrido [3,2-f] [Isosorbide-5-Nitrae] oxygen azepines Cycloheptatriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H- benzos [d] [1,2,3] Triazole -5- bases) propionic acid, formates (38mg, 0.072mmol, 63.9% yield).LC-MS m/z 528.3(M+H)⁺, 0.68 point Clock (retention time).

Embodiment 56

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((S) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) (S) -2- methyl -2,3,4,5- tetrahydrochysene benzene is added in solution of the ethyl propionate (40mg, 0.101mmol) in acetonitrile (1mL) And [f] [1,4] oxaza heptantriene (32.8mg, 0.201mmol), K₂CO₃(27.8mg, 0.201mmol) and sodium iodide (3.01mg,0.020mmol).The reaction mixture of generation is stirred 23 hours at 40 DEG C.Reaction mixture is filtered.By filter cake It is washed with MeCN (1mL).Combined filter vacuum is evaporated, is dissolved in methanol (1.5mL), NaOH (3N) is then added (0.168mL,0.503mmol).Then gained reaction mixture was used into HCl (3N) acid at 80 DEG C with microwave heating 20 minutes Change to pH~6, evaporate under vacuum, and purified by reversed-phase HPLC, obtain product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) -3- (3- (- 4 (5H)-yl of (S) -2- methyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (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).

Embodiment 57

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To (R) -2- ethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the solution of (86mg, 0.400mmol) in methanol (3mL)₂CO₃(55.3mg,0.400mmol).Gained reaction is mixed It closes object to stir at ambient temperature 30 minutes, be evaporated in vacuo.Acetonitrile (3mL) is added into the residue of generation, and in environment temperature The lower stirring of degree 10 minutes, is then filtered as acetonitrile solution A for subsequently using.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in solution of the ethyl propionate (76mg, 0.2mmol) in DCM (1.000mL)₂(0.029mL, 0.400mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, be evaporated in vacuo and is dissolved in acetonitrile (3mL). Previous acetonitrile solution A, sodium iodide (14.99mg, 0.100mmol) and K are added into the solution₂CO₃(55.3mg, 0.400mmol).The reaction mixture of generation is heated 22 hours at 40 DEG C, is then filtered.By filter cake with MeCN (2mL) Washing.Combined filter vacuum is evaporated, is subsequently solubolized in methanol (3mL), be then added NaOH (3N) (0.533mL, 1.600mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C.Reaction mixture is acidified with HCl (3N) To pH 4~5, evaporate, and purified by reversed-phase HPLC under vacuum, obtain product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1, 2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantrienes -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (33.2mg, 0.061mmol, 30.5% yield).LC-MS m/z 512.6(M+H)⁺, 0.69 minute (retention time).

Embodiment 58

3- (3- (- 4 (5H)-yl of 2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) propionic acid, formates

To 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) 2,3,4,5- tetrahydro benzos [f] [1,4] are added in solution of the ethyl propionate (40mg, 0.101mmol) in acetonitrile (1mL) Oxaza heptantriene (30.0mg, 0.201mmol), K₂CO₃(27.8mg, 0.201mmol) and sodium iodide (7.53mg, 0.050mmol).The reaction mixture of generation is stirred 21 hours at 40 DEG C.Reaction mixture is filtered.By filter cake MeCN (1mL) is washed.Combined filter vacuum is evaporated, is dissolved in methanol (1.5mL), be then added NaOH (3N) (0.168mL, 0.503mmol).Gained reaction mixture is then acidified to pH~6 with microwave heating 20 minutes at 80 DEG C with HCl (3N), It evaporates, and is purified by reversed-phase HPLC under vacuum, obtain product 3- (3- (2,3- dihydrobenzos [f] [Isosorbide-5-Nitrae] oxaza heptan Triolefin -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) Propionic acid, formates (15.0mg, 0.029mmol, 28.7% yield).LC-MS m/z 483.4(M+H)⁺, (retain within 0.66 minute Time).

Embodiment 59

3- (4- cyano -2- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxygen nitrogen Heterocycle heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1, 4] oxaza heptantriene

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (0.927g, K 5.20mmol) is added in the solution in acetonitrile (40mL)₂CO₃(1.382g, 10.00mmol), sodium iodide (0.300g, 2.000mmol) and the chloro- 2,3- dihydros -1H- indenes (0.926g, 4.00mmol) of the bromo- 1- of 6-.By the solution of generation in 60 DEG C of heating It 21 hours, evaporates under vacuum, by purification by flash chromatography, obtains required product 4- (bromo- 2, the 3- dihydros -1H- indenes -1- of 6- Base) -2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (1.159g, 3.10mmol, 78% yield).LC-MS m/z 373.1(M+H)⁺, 0.87 minute (retention time).

2,2- dimethyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- two Hydrogen -1H- indenes -1- bases) -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

To 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-), -2,2- dimethyl -2,3,4,5- tetrahydropyridines are simultaneously [3,2-f] [1,4] two are added in solution of the oxaza heptantriene (1.158g, 3.10mmol) in N,N-dimethylformamide (10mL) (pinacol combined) two boron (1.182g, 4.65mmol), PdCl₂(dppf) (0.113g, 0.155mmol) and KOAc (0.609g, 6.20mmol).Gained reaction mixture is evaporated with microwave heating 1 hour at 100 DEG C, passed through flash chromatography under vacuum Purifying, obtains product 2,2- dimethyl -4- (6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) -2, 3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (1.527g, 3.63mmol, 117% yield).LC-MS m/z 421.2(M+H)⁺, 0.87 minute (retention time).

(E) -3- (4- cyano -2- aminomethyl phenyls) methyl acrylate

It is added into solution of the bromo- 3- methyl-benzonitriles (0.784g, 4mmol) of 4- in N,N-dimethylformamide (20mL) Methyl acrylate (1.812mL, 20.00mmol), DIPEA (1.747mL, 10.00mmol), acid chloride (II) (0.090g, 0.400mmol) and tri-o-tolyl phosphine (0.243g, 0.800mmol).Then by reaction mixture microwave at 150 DEG C N₂It is heated 1 hour under atmosphere.Reaction mixture is evaporated in vacuo to remove remaining methyl acrylate, then uses H₂O (20mL) is dilute It releases, is extracted with EtOAc (3x40mL).Combined organic layer is washed with brine (50ml), through MgSO₄It is dry, filtering, in vacuum Lower evaporation obtains required product (E) -3- (4- cyano -2- aminomethyl phenyls) methyl acrylate through purification by flash chromatography (0.8815g, 4.38mmol, 110% yield).¹H-NMR (400MHz, chloroform-d) δ ppm 2.47 (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- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxygen nitrogen Heterocycle heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) methyl propionate

To (E) -3- (4- cyano -2- aminomethyl phenyls) methyl acrylate (0.101g, 0.5mmol) in 1,4- dioxanes 2,2- dimethyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxas are added in solution in (1.5mL) and water (0.5mL) Boron heterocycle pentane -2- bases) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza Heptantriene (0.420g, 1.000mmol), TEA (0.209mL, 1.500mmol) and [Rh (cod) Cl]₂(0.012g, 0.025mmol).The reaction mixture of generation is stirred 1 hour in 90 DEG C, is evaporated in vacuo, and by purification by flash chromatography, obtain 3- (4- cyano -2- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptan three Alkene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) methyl propionate (0.1297g, 0.262mmol, 52.3% yield).LC-MS m/z 496.3(M+H)⁺, 0.92 minute (retention time).

3- (4- cyano -2- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxygen nitrogen Heterocycle heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (4- cyano -2- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxygen Azepine cycloheptatriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) methyl propionate (129.7mg, 0.254mmol) is in methanol NaOH (2N) (50.9mg, 1.272mmol) is added in solution in (3mL).By the solution of generation at 80 DEG C with microwave heating 15 Minute.Reaction mixture is acidified to pH~5 with HCl (1N), evaporates, and purified by reversed-phase HPLC, is produced under vacuum Object 3- (4- cyano -2- aminomethyl phenyls) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptan Triolefin -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates (51.5mg, 0.107mmol, 42.0% yield). LC-MS m/z 482.2(M+H)⁺, 0.76 minute (retention time).

Embodiment 60

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) propionic acid, formates

(E) -3- (4- fluoro-2-methylbenzenes base) methyl acrylate

Into solution of the bromo- 4- fluoro-2-methylbenzenes (0.756g, 4mmol) of 1- in N,N-dimethylformamide (10mL) Be added methyl acrylate (1.812mL, 20.00mmol), DIPEA (1.747mL, 10.00mmol), acid chloride (II) (0.090g, 0.400mmol) and tri-o-tolyl phosphine (0.243g, 0.800mmol).By reaction mixture microwave in argon gas at 130 DEG C It is heated 6 hours under atmosphere.Reaction mixture is concentrated, then EtOAc (20ml) is used to dilute, uses H₂O is washed, and EtOAc (20ml are used in combination X 3) extraction.Organic phase is concentrated, and through purification by flash chromatography, obtains required product (E) -3- (4- fluoro-2-methylbenzenes base) Methyl acrylate (0.5479g, 2.82mmol, 70.5% yield).LC-MS m/z 195.0(M+H)⁺, 1.01 minutes (when reservation Between).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) methyl propionate

To (E) -3- (4- fluoro-2-methylbenzenes base) methyl acrylate (104mg, 0.5mmol) at 1,4- dioxanes (1.5mL) With addition 2,2- dimethyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolans in the solution in water (0.5mL) Alkane -2- bases) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (420mg, 1.000mmol), TEA (0.209mL, 1.500mmol) and [Rh (cod) Cl]₂(12.33mg,0.025mmol).It will The reaction mixture of generation stirs 1 hour in 90 DEG C, is evaporated in vacuo, and by purification by flash chromatography, obtain product 3- (3- (2, - 4 (5H)-yl of 2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -3- (4- fluoro-2-methylbenzenes base) methyl propionate (52.3mg, 0.104mmol, 20.81% yield).LC-MS m/z 489.4 (M+H)⁺, 1.00 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) propionic acid, formates

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) methyl propionate (52.3mg, 0.104mmol) is in methanol NaOH (2N) (20.81mg, 0.520mmol) is added in solution in (1.5mL).The solution microwave of generation is heated at 80 DEG C 15 minutes, then HCl (1N) is used to be acidified into pH~5, evaporate under vacuum, and purified by reversed-phase HPLC, obtain product 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) propionic acid, formates (34.4mg, 0.072mmol, 69.7% yield).LC-MS m/ z 475.2(M+H)⁺, 0.81 minute (retention time).

Embodiment 61

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

(R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol

(R) -1- amino propan-2-ols are added into solution of the 2- chlorine cigarette aldehyde (0.708g, 5mmol) in methanol (10mL) (0.488g,6.50mmol).Reaction mixture is stirred at ambient temperature 1 hour, NaBH is then added₄(0.378g, 10.00mmol), it is then stirred at ambient temperature 1 hour.NaHCO is added into the reaction mixture₃(saturation) (0.5mL), is then evaporated in vacuo.Residue is diluted with DCM (50mL), through MgSO₄It is dry, it filters and is evaporated in vacuo, obtain Product (R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol (1.3176g, 6.57mmol, 131% yield).LC- MS m/z 200.9(M+H)⁺, 0.18 minute (retention time).

(R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene

To (R) -1- (((2- chloropyridine -3- bases) methyl) amino) propan-2-ol (100mg, 0.5mmol) in N, N- dimethyl KOtBu (168mg, 1.500mmol) is added in solution in formamide (5mL), and the solution microwave of generation is added at 80 DEG C Heat 2 hours.Then reaction mixture is evaporated in vacuo, is diluted and filtered with DCM (20mL), is then evaporated in vacuo, obtains product (R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (71.2mg, 0.434mmol, 87% Yield).LC-MS m/z164.9(M+H)⁺, 0.10 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate

To (R) -2- methyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (71.2mg, K 0.434mmol) is added in the solution in acetonitrile (3mL)₂CO₃(120mg, 0.867mmol), sodium iodide (13.00mg, 0.087mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazoles - 5- yls) ethyl propionate (173mg, 0.434mmol).The solution microwave of generation is heated 2 hours at 60 DEG C, is steamed under vacuum Hair, by purification by flash chromatography, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (- 4 (5H)-yl of (R) -2- methyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) ethyl propionate (57mg, 0.108mmol, 25.01% yield).LC-MS m/z 526.1(M+H)⁺, 0.77 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formates

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) ethyl propionate (57mg, NaOH (2N) (21.69mg, 0.542mmol) 0.108mmol) is added in the solution in methanol (1.500mL).By the molten of generation Liquid microwave heats 15 minutes at 80 DEG C, is then acidified to pH~5 with HCl (1N), evaporates under vacuum, and pass through reversed-phase HPLC Purifying, obtains product 3- (Isosorbide-5-Nitrae-dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- methyl -2,3- - 4 (5H)-yl of dihydro pyrido [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid, formic acid Salt (41.6mg, 0.084mmol, 77% yield).LC-MS m/z 498.2(M+H)⁺, 0.65 minute (retention time).

Embodiment 62

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) propionic acid, formates

The chloro- 5- fluorine pyridine 1- oxides of 2-

Under a nitrogen, molten in trifluoroacetic acid (150mL) to the fluoro- pyridines of the chloro- 5- of 2- (20g, 152mmol) at 70 DEG C H is slowly added into liquid₂O₂(78mL,760mmol).Reaction mixture is stirred 16 hours and concentrated at 70 DEG C.By water and DCM is added in residue.It is adjusted into pH to 7 with 28% Ammonia, is used in combination DCM to extract, through MgSO₄It is dry, it is dense Contracting, obtains the fluoro- pyridine 1- oxides of the chloro- 5- of title compound 2- (20.1g, 136mmol, 90% yield), without further Purifying is with regard to carrying out in next step.LC-MS m/z 147.6(M+H)⁺, 0.78 minute (retention time).

The fluoro- 4- nitropyridines 1- oxides of the chloro- 5- of 2-

Under a nitrogen, at ambient temperature, to the H of the fluoro- pyridine 1- oxides (5g, 33.9mol) of the chloro- 5- of 2-₂SO₄ Potassium nitrate (13.71g, 136mol) is slowly added into (50mL, 938mmol) solution.Reaction mixture is stirred at 110 DEG C 16 hours.Then it is poured into 50 milliliters of ice/waters.The solid is filtered, and is dried under a high vacuum, it is fluoro- to obtain the chloro- 5- of 2- 3- methyl -4- nitropyridine 1- oxides (5.1g, 21.99mmol, 64.9% yield) are yellow solid.LC-MS m/z 203.9(M+H)⁺, 1.29 minutes (retention time).

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

By the mixed of the fluoro- 4- nitropyridines 1- oxides (5.3g, 27.5mmol) of the chloro- 5- of 2- and methylamine (50mL, 425mmol) Object is closed to stir 3 hours in 20 DEG C.After evaporation of the solvent, 50mL water is added.The solid is filtered, and is dried under a high vacuum, is obtained Title compound 2- chloro- 5- (methylamino) -4- nitropyridine 1- oxides (5.1g, 18.54mmol, 67.3% yield) are Yellow solid.LC-MS_m/z 203.9(M+H)⁺, 1.29 minutes (retention time).

The chloro- N3- picolines -3,4- diamines of 6-

Under a nitrogen, at 20 DEG C, to 2- chloro- 5- (methylamino) -4- nitropyridine 1- oxides (160mg, 0.786mmol) nickel (46.1mg, 0.786mmol) is slowly added into the solution in ethyl alcohol (10mL).By it in environment temperature Under in Parr containers with 40psi hydrogenate 16 hours.Mixture is filtered, and filtrate is concentrated, it is chloro- to obtain title compound 6- N3- picolines -3,4- diamines (120mg, 0.647mmol, 82% yield) is dark solid.LC-MS m/z 158.0(M+ H)⁺, 0.68 minute (retention time).

Chloro- 3- methyl -3H- [1,2,3] triazol [4,5-c] pyridines of 6-

Under a nitrogen, at 0 DEG C, to chloro- N3- picolines -3, the 4- diamines (3.2g, 20.30mmol) of 6- in H₂SO₄ The water of sodium nitrite (2.80g, 40.6mmol) is slowly added into solution in the 50mL aqueous solutions of (3mL, 56.3mmol) (30mL) solution.Reaction mixture is stirred 4 hours at 0 DEG C, then uses Na₂CO₃PH is adjusted to 8 by (aqueous solution).This is consolidated Body filter, obtain chloro- 3- methyl -3H- [1,2,3] triazol [4, the 5-c] pyridines of title compound 6- (3.2g, 18.98mmol, 93% yield), it is transferred to without further purification in next step.LC-MS m/z 169.0(M+H)⁺, 1.33 minutes (when reservation Between).

(E) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) ethyl acrylate

By chloro- 3- methyl -3H- [1,2,3] triazol [4,5-c] pyridines (3.000g, 17.80mmol) of 6-, (E) -3- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) ethyl acrylate (9.90mL, 89mmol), TEA (12.40mL, 89mmol), four (triphenylphosphines) close palladium (0) (1.453g, 1.780mmol) in N,N-dimethylformamide Mixture in (50mL) stirs 12 hours at 140 DEG C.Reaction mixture is filtered, and filtrate is passed through into silica gel chromatograph (hexane: Ethyl acetate=4:1) it purifies, obtains title compound (E) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- Base) ethyl acrylate (710mg, 2.97mmol, 16.66% yield).LC-MS m/z 233.0(M+H)⁺, (retain within 1.51 minutes Time).

3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridines - 6- yls) ethyl propionate

To (E) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) ethyl acrylate (0.232g, 6- (4,4,5,5- tetramethyl -1,3,2- dioxas 1mmol) are added in the solution in 1,4- dioxanes (9mL) and water (3mL) Boron heterocycle pentane -2- bases) -2,3- dihydro -1H- indenes -1- alcohol (0.390g, 1.500mmol), TEA (0.418mL, 3.00mmol) [Rh (cod) Cl]₂(0.025g,0.050mmol).The reaction mixture of generation is stirred 3 hours at 90 DEG C, is steamed under vacuum Hair, by purification by flash chromatography, obtain product 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2, 3] triazol [4,5-c] pyridine -6- bases) ethyl propionate (0.1139g, 0.311mmol, 31.1% yield).LC-MS m/z 367.0(M+H)⁺, 0.79 minute (retention time).

3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- Base) ethyl propionate

To 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyrroles Pyridine -6- bases) SOCl is added in solution of the ethyl propionate (0.1139g, 0.311mmol) in DCM (1.5mL)₂(0.045mL, 0.622mmol).Gained reaction mixture is stirred 3 hours at ambient temperature, be evaporated in vacuo, obtain product 3- (3- chloro- 2, 3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) ethyl propionate (0.1349g, 0.351mmol, 113% yield).LC-MS m/z381.1(M-Cl+MeOH)⁺, 0.95 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) ethyl propionate

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,2-f] [1,4] oxaza heptantriene (0.222g, K 1.247mmol) is added in the solution in acetonitrile (3mL)₂CO₃(0.086g, 0.624mmol), sodium iodide (9.35mg, 0.062mmol) and 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyrroles Pyridine -6- bases) ethyl propionate (0.12g, 0.312mmol).By the solution of generation at 60 DEG C with microwave heating 2 hours.It then will be anti- It answers mixture to be evaporated in vacuo, and by purification by flash chromatography, obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyridos - 4 (5H)-yl of [3,2-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2, 3] triazol [4,5-c] pyridine -6- bases) ethyl propionate (0.1253g, 0.238mmol, 76% yield).LC-MS m/z 527.3 (M+H)⁺, 0.77 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantriene) - 2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) propionic acid, formates

To 3- (3- (2,2- dimethyl -2,3- dihydro pyridos [3,2-f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases) ethyl propionate NaOH (2N) (47.6mg, 1.190mmol) is added in the solution of (125.3mg, 0.238mmol) in methanol (4mL).It will generate Solution at 80 DEG C with microwave heating 15 minutes.Reaction mixture is acidified to pH~5 with HCl (1N), is evaporated under vacuum, and It is purified by reversed-phase HPLC, obtains product 3- (3- (2,2- dimethyl -2,3- dihydro pyrido [3,2-f] [Isosorbide-5-Nitrae] oxazas Heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -3- (3- methyl -3H- [1,2,3] triazol [4,5-c] pyridines - 6- yls) propionic acid, formates (52.9mg, 0.102mmol, 42.7% yield).LC-MS m/z 499.5(M+H)⁺, 0.57 minute (retention time).

Embodiment 63

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid, trifluoroacetate

3- ((t-butyldimethylsilyl) oxygroup) propyl- 1- alcohol

THF (200mL) is added into the argon cleaning flask containing NaH-60% dispersion oils (4.4g).This is anti- It should be vigorously stirred, propylene glycol (7.61g, 100mmol) is slowly added at 0 DEG C.The reaction is stirred 45 points at ambient temperature Clock, initial grey suspension become white.Then, TBSCl (16.58g, 110mmol) is added to several in flask, it is small The heart avoids overflowing due to violent gas release.Then reaction is stirred for 45 minutes.By reaction 50mL 10% Na₂CO₃Aqueous solution is slowly quenched, and is formed two layers.Two layers of separation, and by water layer Et₂O is extracted.By combined organic matter brine Washing, and through Na₂SO₄It is dry.After being concentrated under reduced pressure, thick title compound (21g, 110% yield) has enough purity.¹H NMR (400MHz, chloroform-d) δ ppm 0.10 (s, 6H) 0.87-0.97 (m, 9H) 1.76-1.85 (m, 2H) 3.79-3.94 (m,4H)

3- ((t-butyldimethylsilyl) oxygroup) propionic aldehyde

At 22 DEG C, by 3- ((t-butyldimethylsilyl) oxygroup) propyl- 1- alcohol (4.48mL, 21.01mmol) and Solution of the TEA (29.1mL, 210mmol) in dimethyl sulfoxide (DMSO) (DMSO) (10mL) with pyridine. sulfur trioxide (10.03g, Dimethyl sulfoxide (DMSO) (DMSO) (10mL) solution treatment 63.0mmol), and the reaction is stirred 4 hours under argon gas.This is anti- It should be mixed with 1M HCl (1x 100mL), EtOAc (2x 100mL) is used in combination to extract.By combined EtOAc water (2x 100mL), Brine (100mL) washs, through Na₂SO₄It is dry, and be concentrated under reduced pressure.Crude title compound (4.13g, 104% yield) is received Integrate as gold oil, uses without further purification.¹H NMR (400MHz, chloroform-d) δ ppm 0.06 (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- ((t-butyldimethylsilyl) oxygroup) amyl- 2- olefin(e) acids ethyl ester

By DCM (10mL) solution of 3- ((t-butyldimethylsilyl) oxygroup) propionic aldehyde (2.667g, 14.16mmol) It is mixed with 2- (triphenylphosphine alkene) ethyl acetate (5.30g, 15.21mmol), and mixture is flowed back 22 hours, and then cooled down To 22 DEG C.After reflux 25 minutes, reaction becomes light red from golden yellow.The reaction is diluted with DCM (1x 100mL), uses water (2x 50mL), brine (50mL) wash, through Na₂SO₄It is dry, and be concentrated under reduced pressure.By crude product at silica column (40g) It is upper to use purification by flash chromatography, with 0-25%EtOAc/ hexanes gradient elutions, obtain title compound (1.197g, 32.7% production Rate), it is weak yellow liquid.LC-MS m/z 259.1(M+H)⁺, 1.43 minutes (retention time).

(E) -5- ((mesyl) oxygroup) amyl- 2- olefin(e) acids ethyl ester

Under argon gas, to (E) -5- ((t-butyldimethylsilyl) oxygroup) amyl- 2- olefin(e) acids ethyl ester (1.391g, The THF solution (5.87mL, 5.87mmol) of 1M TBAF 5.38mmol) is added in the solution in THF (15.00mL), and stirs 45 minutes.It is dissolved in DCM (15mL) by solvent concentration, and by crude residue.TEA (0.970mL, 7.00mmol) is added, and Mixture is cooled to 0 DEG C.Mesyl chloride (0.583mL, 7.54mmol) is added, and reaction mixture is stirred 4 hours.Again plus Enter 0.5mL mesyl chlorides, reaction stirring 17 hours.Add 2.5 milliliters of mesyl chlorides and 3 milliliters of TEA, reaction stirring 1 hour. Then the reaction is diluted with DCM (60mL), is washed with water (4x 50mL), brine (25mL), through Na₂SO₄It is dry, and depressurizing Lower concentration obtains title compound (2.168g, 65% yield), uses without further purification.LC-MS m/z of 245.0(M+Na)⁺, 0.71 minute (retention time).

(E) -5- (4- propyl -1H-1,2,3- triazol-1-yls) amyl- 2- olefin(e) acids ethyl ester

Crude product (E) -5- ((mesyl) oxygroup) amyl- 2- olefin(e) acids ethyl ester (2.168g, 9.75mmol) is dissolved in N, N- bis- In methylformamide (25mL), and sodium azide (0.761g, 11.71mmol) is added, and reaction mixture is stirred at 70 DEG C It mixes 2 hours.Reaction mixture is set to be cooled to environment temperature.Water (25.00mL) is added in reaction mixture, and by mixture It is placed under nitrogen atmosphere.Copper sulphate (II) (1.401g, 8.78mmol), pentyne are added into the reaction mixture of stirring (1.346mL, 13.66mmol) and sodium ascorbate (1.739g, 8.78mmol).Reaction mixture is concentrated under reduced pressure.Add Enter EtOAc, and by the reaction by disposable frit to remove desalination.Crude mixture is used into Reverse phase preparative HPLC Purifying, obtains title compound (120mg, 5.18% yield), is weak 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 alkane -2- bases) -2,3- two Hydrogen -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene

To 4- (the bromo- 2,3- dihydros -1H- indenes -1- bases of 6-) -2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen Two (pinacol combined) two boron are added in solution of the azepine cycloheptatriene (3.5g, 9.40mmol) in 1,4- dioxanes (35mL) (2.86g, 11.28mmol) and potassium acetate (1.845g, 18.80mmol).By reaction mixture argon-degassed 10 minutes, then PdCl is added₂(dppf)-CH₂Cl₂(0.384g, 0.470mmol), and heated 16 hours in 90 DEG C.Reaction mixture is passed through into silicon Diatomaceous earth filters, and EtOAc (2x 100ml) is used in combination to wash.Filtrate is concentrated under reduced pressure, then by purification by flash chromatography, is obtained 2,2- dimethyl -4- (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes - 1- yls) -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene (2.52g, 5.98mmol, 63.6% yield).LC-MS m/z 420.3(M+H)⁺, 4.80 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -5- (4- propyl -1H-1,2,3- triazol-1-yls) ethyl valerate

To (E) -5- (4- propyl -1H-1,2,3- triazol-1-yls) amyl- 2- olefin(e) acids ethyl ester (35mg, 0.147mmol) 1, Be added in solution in 4- dioxanes (2mL) and water (1.000mL) 2,2- dimethyl -4- (6- (tetramethyl -1,3 4,4,5,5-, 2- dioxaborolan alkane -2- bases) -2,3- dihydro -1H- indenes -1- bases) -2,3,4,5- tetrahydro benzos [f] [1,4] oxygen azepine Cycloheptatriene (93mg, 0.221mmol), (1,5- cyclo-octadiene) radium chloride (I) dimer (3.86mg, 7.83 μm of ol) and TEA (0.020mL,0.147mmol).Ar air-flows are made to pass through mixture about 5 minutes, then heating 2.5 is small at 90 DEG C of Ar by reaction When.Mixture is slowly cooled to 23 DEG C in 16 hours.Residue is mixed with EtOAc (5mL) and water (5mL).By water layer It uses EtOAc (10mL) to extract again, and combined EtOAc layers is concentrated.Crude product is purified on Reverse phase preparative HPLC, is obtained It is dark orange oil to title compound (12mg, 15.33% yield).LC-MS m/z 531.4(M+H)⁺, 0.95 minute (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid, trifluoroacetate

By 3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- Dihydro -1H- indenes -5- bases) -5- (4- propyl -1H-1,2,3- triazol-1-yls) ethyl valerate (22mg, 0.041mmol) is dissolved in THF In (1.4mL), and water (1.400mL) solution of lithium hydroxide (2.98mg, 0.124mmol) is added.Methanol (0.5mL) is added, And the reaction is stirred 16 hours at 23 DEG C.Then by solvent concentration, and the crude product is pure on Reverse phase preparative HPLC Change, obtains title compound (31mg, 121% yield).LC-MS m/z 503.3(M+H)⁺, 0.91 (retention time).

Embodiment 64

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -5- (2- ethyl -2H- tetrazolium -5- bases) -2,2- dimethyl valeric acids, trifluoroacetate

The bromo- 2,3- dihydros -1H- indenes -1- alcohol of 6-

In the case where ice bath cools down (10 DEG C), NaBH4 (1.344g, 35.5mmol) is added to bromo- 2, the 3- dihydros-of 6- with a batch In solution of the 1H- 1-Indanones (5.0g, 23.69mmol) in methanol (100mL).Ice bath is removed, and reaction stirring 3 is small When.The reaction is poured into water (250mL), EtOAc (250mL and 100mL) is used in combination to extract.By combined extract liquor water The washing of the NaCl aqueous solutions (50mL) of (100mL) and saturation, and through Na₂SO₄It is dry, and it is condensed into small size, precipitation is filtered out, Linen solid is obtained, it is fully washed with several hexanes, obtains first substance.Filtrate is concentrated.It is formed in filtrate More precipitations, are diluted with hexane and refilter, obtain more pale solids.Two batches substance is merged, is obtained titled Object (4.15g, 82%) is closed, is pale solid.LC-MS m/z 194(M-OH)⁺, 0.84 minute (retention time).

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes

The bromo- 2,3- dihydros -1H- indenes -1- alcohol (4.1g, 19.24mmol) of 6- are dissolved in N,N-dimethylformamide (22mL) In, and 60% sodium hydride (1.539g, 38.5mmol) is added by (10 DEG C) cooling solution of ice-water bath, and with a batch.Reaction production Anger bubble simultaneously spontaneous is warmed to 15 DEG C.Ice bath is removed, and is stirred the mixture for 1 hour, 10 DEG C are cooled in ice-water bath, is added 1- (chloromethyl) -4- methoxybenzenes (3.93mL, 28.9mmol).The mixture of generation is stirred 2 hours at 23 DEG C.Pass through dropwise addition Water (5mL) carefully quenches excessive NaH, and it is diluted with EtOAc (200mL) and water (75mL), by phase oscillations and divides From with more EtOAc (75mL) and then with NaCl aqueous solutions (25mL) extraction water of saturation, dry (Na₂SO₄), and vacuum Concentration, obtains yellow oil.By mixture it is pure be injected into hexane balance silicagel column (120g) on, flash chromatography is used in combination Purifying obtains title compound with 85mL/ minutes speed hexanes to 10%EtOAc/ hexanes gradient elutions 25 minutes (5.85g, 91%) is transparent oil.¹H NMR(400MHz,CDCl₃)δppm 2.09-2.20(m,1H)2.33-2.44(m, 1H) 4.62 (d, J=of 2.71-2.82 (m, 1H) 2.99-3.09 (m, 1H) 3.84 (s, 3H) 4.56 (d, J=12.0Hz, 1H) 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- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- formaldehyde

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes (5.85g, 17.56mmol) is dissolved in anhydrous In THF (140mL), and it is cooling in dry ice acetone bath.2M n-BuLis (10.97mL, 21.94mmol) are added, and this is anti- It is 0.5 hour cooling using dry ice acetone stirring.DMF (6.80mL, 88mmol) is added, and the reaction is stirred 2 hours.This is anti- Using the NH of saturation₄It Cl aqueous solutions (10mL) and then is diluted with other water (50mL) and EtOAc (100mL).By water layer with separately Outer a batch EtOAc (50mL) extraction, and the NaCl aqueous solutions (50mL) of combined EtOAc water (50mL) and saturation are washed, Through Na₂SO₄It is dried and concentrated.Crude product is used into purification by flash chromatography on silica column (120g), with 85mL/ minutes speed Degree hexane was to 50%EtOAc/ hexanes gradient elutions 30 minutes.According to tlc (4:1 heptane/EtOAc), by the required grade of elution Divide and collect, and concentrate, obtain 4.1g (83%) title compound, is faint yellow clear oily matter.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) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) methyl acrylate

By 2- (triphenylphosphine alkene) methyl acetate (5.34g, 15.97mmol) and 3- ((4- methoxy-benzyls) oxygroup) -2, 3- dihydro -1H- indenes -5- formaldehyde (4.1g, 14.52mmol) is dissolved in DCM (105mL), and is heated to reflux 16 hours.By the reaction It is cooled to 23 DEG C and stirs 2 days.Crude product is adsorbed on isolute in advance, and with quick on silica column (120g) Chromatogram purification, with 85mL/ minutes speed hexanes to 30%EtOAc/ hexanes gradient elutions 25 minutes.Required fraction is mixed Merge concentration, obtains the title compound of 4.94g (101%).LC-MS m/z 339(M+H)⁺, 1.20 minutes (retention time).

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated pentanedioic acid dimethyl esters

(E) -3- (3- ((4- methoxy-benzyls) the oxygroup) -2,3- dihydro -1H- indenes -5- bases) acrylic acid cooled down to ice water It is added in methyl esters (4.9g, 14.48mmol), tetrabutyl ammonium benzoate (0.263g, 0.724mmol) and THF (72mL) solution ((1- methoxyl group -2- methyl propyl- 1- alkene -1- bases) oxygroup) trimethyl silane (5.05g, 29.0mmol).Ice bath is removed, and will be molten Liquid stirs 3 hours.The reaction is concentrated, and is adsorbed on isolute in advance, and by crude product on silica column (120g) With purification by flash chromatography, with 85mL/ minutes speed hexanes to 100%EtOAc gradient elutions 30 minutes.By required fraction It mixes and concentrates, obtain the title compound of 6.4g (100%).LC-MS m/z 463(M+Na)⁺, 1.26 minutes (when reservation Between).

5- hydroxyls -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids Methyl esters

At 23 DEG C, to 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl Dimethyl glutarate (5.2639g, 11.95mmol) is molten in THF (72.4mL), water (18.10mL) and methanol (36.2mL) LiOH (2.86g, 119mmol) is added in liquid.After stirring 18 hours, reaction is diluted with DCM, 1N HCl is used in combination to wash.By water Layer is extracted with DCM (3x).The NaCl aqueous solutions of combined organic layer water and saturation are washed, through MgSO₄It is dry, and vacuum is dense Contracting.At 23 DEG C, crude product is dissolved in THF (72.4mL) and trimethylborate (4.01mL, 35.8mmol).With 60 minutes Time, 2M BH were added dropwise into the solution₃·DMS(29.9mL,59.7mmol).After being further stirred for 1 hour, methanol is added (36.2mL) and reaction is stirred for 1 hour.Solvent in vacuo is removed, and residue is dissolved in EtOAc.Organic layer is used full The NaHCO of sum₃The NaCl aqueous solutions of aqueous solution, water and saturation wash.By organic layer through MgSO₄It is dry, and be concentrated in vacuo.Then Crude product is used into purification by flash chromatography on silica column (40g), with the speed of 40mL/min 100% hexane to 80% EtOAc/ hexanes gradient elutions 25 minutes, obtain the title compound of 4.12g (84%).LC-MS m/z 435(M+Na)⁺, 1.17 minutes (retention time).

The bromo- 3- of 5- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acid first Ester

Under ice cooling, 4, by the triphenylphosphine of Polymer-supported (2.71g, 5.20mmol) and carbon tetrabromide (1.812g, 5.47mmol) it is added sequentially to 5- hydroxyls -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- In solution of the dimethyl methyl (2.1471g, 5.20mmol) in DCM (26.0mL).After 18 hours, pass through disposable glass The filtering reaction of glass material, is removed in vacuum volatile matter.Then crude product is adsorbed on isolute in advance, and in silica column Purification by flash chromatography is used on (24g), obtains 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- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids Methyl esters

NaCN (0.173g, 3.54mmol) is added to the bromo- 3- of 5- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydros - 1H- indenes -5- bases) -2,2- dimethyl methyls (1.5299g, 3.22mmol) are in ethyl alcohol (6.03mL)/water (2.011mL) Solution in.The reaction is warmed to 75 DEG C to be kept for 3 days.Then by the NaHCO of the reaction water and saturation₃Aqueous solution dilutes, It is used in combination EtOAc to extract.By organic layer through MgSO₄It is dry, and be dried in vacuo.Then by crude product on silica column (40g) Using purification by flash chromatography, title compound (927.2mg, 68.4%) is obtained.LC-MS m/z 444(M+Na)⁺, 1.26 minutes (retention time).

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -5- (2H- tetrazoliums - 5- yls) methyl valerate

In seal pipe, by TMS-N₃(1.168mL, 8.80mmol) and TBAF3H₂O (398mg, 1.523mmol) is added To pure 5- cyano -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids In methyl esters (917.2mg, 2.176mmol).After being stirred 45 minutes at 23 DEG C, do not react, therefore reaction is heated to 130 ℃.Reaction is cooled to 23 DEG C after 4 hours, and reaction mixture is dissolved in EtOAc, and the NaCl aqueous solutions of water and saturation is used in combination to wash It washs.Water layer is extracted with EtOAc (3x), and by organic layer through MgSO₄It is dry, and be concentrated in vacuo, obtain title compound (1.18g, 117%).LC-MS m/z 487(M+Na)⁺, 1.15 minutes (retention time).

5- (2- ethyl -2H- tetrazolium -5- bases) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- Base) -2,2- dimethyl methyls

Iodoethane (261 μ L, 3.26mmol) is added to 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydros -1H- Indenes -5- bases) -2,2- dimethyl -5- (1H-TETRAZOLE -5- bases) methyl valerates (1011mg, 2.176mmol) and TEA (531 μ L, In THF (11mL) solution 3.81mmol).This is reacted on 50 DEG C to heat 21 hours.The reaction is quenched by the way that water is added, It is used in combination EtOAc (3x) to extract.By organic layer through MgSO₄It is dry, and be concentrated in vacuo.Then by crude product in silica column Purification by flash chromatography is used on (24g), is divided with the speed of 35mL/min 100% hexane to 100%EtOAc gradient elutions 20 Clock obtains title compound (480.9mg, 44.9%).LC-MS m/z 493(M+H)⁺, 1.27 minutes (retention time).

5- (2- ethyl -2H- tetrazolium -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids Methyl esters

At 23 DEG C, to 5- (2- ethyl -2H- tetrazolium -5- bases) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- bis- Hydrogen -1H- indenes -5- bases) -2,2- dimethyl methyls (480.9mg, 0.976mmol) are in DCM (4.768mL) and water DDQ (244mg, 1.074mmol) is added in solution in (0.238mL).After forty minutes, the NaHCO of saturation is added₃Aqueous solution is quenched It goes out the reaction, DCM is used in combination to extract 3 times.By organic layer through MgSO₄It is dry, and be concentrated in vacuo.Then by crude product in silica Purification by flash chromatography is used on column (12g), is divided with the speed of 20mL/min 100% hexane to 100%EtOAc gradient elutions 20 Clock obtains title compound (224.9mg, 61.9%).LC-MS m/z 395(M+Na)⁺, 1.00 minutes (retention time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -5- (2- ethyl -2H- tetrazolium -5- bases) -2,2- dimethyl valeric acids, trifluoroacetate

At -10 DEG C, by PBr₃(0.057mL, 0.601mmol) is added to 5- (2- ethyl -2H- tetrazolium -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl methyls (112mg, 0.301mmol) are in DCM In solution in (1.203mL).The reaction is stirred 20 minutes at -10 DEG C.After twenty minutes, TLC analyses are any without showing Initial substance, and the NaHCO that the reaction is saturated₃Aqueous solution is quenched.Water layer is extracted with DCM (3x), and will be organic laminated And the NaCl aqueous solutions washing of saturation is used in combination.By organic layer through MgSO₄It is dry, and be concentrated in vacuo, obtain clear yellow oily Object.The crude residue is dissolved in acetonitrile (1.203mL), and is transferred in Biotage microwave vials.By 2,2- diformazans Base -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptatriene hydrochloride (77mg, 0.361mmol) and DIPEA (0.158mL, 0.902mmol) is added in the solution, and heats 1 hour (height at 90 DEG C in Biotage microwave reactors It absorbs).Volatile matter is removed in vacuum, and mixture is dissolved in methanol (0.601mL), and is transferred in Biotage microwave vials. Be added 3M NaOH (0.501mL, 1.504mmol), and by the reaction in Biotage microwave reactors with high-selenium corn at 120 DEG C Heating 3 hours.The DMSO of 1mL is added, volatile matter is removed in vacuum.DMSO solution is acidified to~pH 5 with 1N HCl.It is removed in vacuum Water, and mixture is filled by 0.45 micrometer syringe formula filter in clean bottle.By product in Gilson HPLC It is purified on (Sunfire C18,5m 19X 100mm), with the speed 15%CH of 18mL/min₃CN/H₂O (0.1%TFA) is extremely 55%CH₃CN/H₂The linear gradient elution of O (0.1%TFA), obtains the title compound of 18mg (10%).LC-MS m/z 518 (M+H)⁺, 0.82 minute (retention time).

Embodiment 65

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid, trifluoroacetate

3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- formaldehyde

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes (3.4g, 10.20mmol) is dissolved in anhydrous In THF (80mL), and -78 DEG C are cooled in dry ice acetone bath.2M n-BuLis (6.38mL, 12.75mmol) are added, and will The reaction is stirred 0.5 hour at -78 DEG C.DMF (3.95mL, 51.0mmol) is added, and the reaction is stirred 2 at -78 DEG C Hour.The NH that the reaction is saturated₄Cl aqueous solutions (10mL), and it is then dilute with other water (50mL) and EtOAc (100mL) It releases.Water layer is extracted with another batch of EtOAc (50mL), and the NaCl of combined EtOAc layers water (50mL) and saturation is water-soluble Liquid (50mL) washs, through Na₂SO₄It is dry, and be concentrated in vacuo.Crude product is pure using flash chromatography on silica column (80g) Change, with the speed hexane of 65mL/min to 50%EtOAc/ hexanes gradient elutions 30 minutes, obtain title compound (2.4g, 83%).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) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) allyl acrylate

By 2- (triphenylphosphine alkene) allyl acetate (3.19g, 8.84mmol) and 3- ((4- methoxy-benzyls) oxygroup)- 2,3- dihydro -1H- indenes -5- formaldehyde (2.269g, 8.04mmol) are dissolved in DCM (65mL), and are heated to reflux 23 hours.It will slightly produce Object is adsorbed on isolute in advance, and purification by flash chromatography is used on silica column (80g), is used with the speed of 65mL/min Hexane obtained title compound (2.71g, 93%) to 25%EtOAc/ hexanes gradient elutions 25 minutes.LC-MS m/z 430(M +H₂O)⁺, 1.17 minutes (retention time).

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethylated pentanedioic acid 5- allyls Base 1- methyl esters

At 0 DEG C, to (E) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) acrylic acid alkene Propyl diester (2.8128g, 7.72mmol) and tetrabutyl ammonium benzoate (0.101g, 0.278mmol) are molten in THF (31.5mL) ((1- methoxyl group -2- methyl propyl- 1- alkene -1- bases) oxygroup) trimethyl silane (1.882mL, 9.26mmol) is added in liquid.4 hours Afterwards, reaction is diluted with water, water layer is extracted with EtOAc, uses Na₂SO₄Be dried and concentrated, obtain title compound (3.48g, 97%).LC-MS m/z 489(M+Na)⁺, 1.37 minutes (retention time).

5- methoxyl groups -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -4,4- dimethyl -5- Oxopentanoic acid

Under argon gas, to 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl The four (three of 0.120g is added in solution of the glutaric acid 5- allyl 1- methyl esters (3.60g, 7.72mmol) in THF (386mL) Phenylphosphine) close palladium (0) (0.270g, 0.234mmol).Morpholine (6.66mL, 77mmol) is added dropwise thereto.React not complete after 3 days At other 150mg tetra- (triphenylphosphine) is added and closes palladium (0).After 5 days, solvent is removed in vacuum.Residue is dissolved in EtOAc, It is washed twice, is washed with water primary with 1N HCl.By organic layer through MgSO₄It is dry, and be concentrated in vacuo, obtain title compound (3.49g, 106%).LC-MS m/z 444(M+H₂O)⁺449(M+Na)⁺, 1.15 minutes (retention time).

5- hydroxyls -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids Methyl esters

At 23 DEG C, to 5- methoxyl groups -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -4, Trimethylborate is added in the solution in THF (18.00mL) in 4- dimethyl -5- oxopentanoic acids (3.29g, 7.72mmol) (2.58mL,23.16mmol).With 60 minutes time, BH is added dropwise into the solution₃·DMS(19.30mL,38.6mmol).It stirs After mixing 1 hour, methanol (9.00mL) is added, and the reaction is stirred 1 hour.Solvent in vacuo is removed, and residue is dissolved in In EtOAc.The NaHCO that organic layer is saturated₃Aqueous solution, H₂The NaCl aqueous solutions of O and saturation wash.By organic layer through MgSO₄ It is dry, and be concentrated in vacuo.Then crude product is used to purification by flash chromatography on silica column (40g), with 40mL/min's Speed 100% hexane to 50%EtOAc/ hexanes gradient elutions 25 minutes, obtains title compound (1.61g, 50.6%). LC-MS m/z 430(M+H₂O)⁺, 1.17 minutes (retention time).

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -5- ((methylsulfonyls Base) oxygroup) methyl valerate

At 0 DEG C, to 5- hydroxyls -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- In solution of the dimethyl methyl (833.3mg, 2.020mmol) in DCM (10.100mL) be added TEA (0.366mL, 2.63mmol) and mesyl chloride (0.173mL, 2.222mmol).The reaction is slowly heated up, it is after sixty minutes that reaction is dilute with DCM It releases, with 1N HCl, H₂The NaCl aqueous solutions of O and saturation wash.Combined water layer is extracted with DCM (3x).Organic layer is merged, Through MgSO₄It is dry, and be loaded on Isolute.Then crude product is pure using flash chromatography on silica column (12g) Change, with the speed of 20mL/min 100% hexane to 50%EtOAc/ hexanes gradient elutions 22 minutes, obtains title compound (752.8mg, 76%).LC-MS m/z 513(M+Na)⁺, 1.22 minutes (retention time).

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -5- (4- propyl - 1H-1,2,3- triazol-1-yls) methyl valerate

To 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -5- ((methylsulphurs Acyl group) oxygroup) sodium azide is added in solution of the methyl valerate (752.8mg, 1.534mmol) in DMF (12.787mL) Reaction is heated to 60 DEG C by (110mg, 1.688mmol).After 2 hours, DMF is removed under vacuum, and crude residue is dissolved in In THF (12.79mL).Be added pentyne (0.756mL, 7.67mmol), N- ethyl-N-iospropyl propyl- 2- amine (0.080mL, 0.460mmol) and cuprous iodide (I) (58.4mg, 0.307mmol), and the reaction is stirred at ambient temperature.18 hours Afterwards, THF is removed under reduced pressure.Then crude product is used to purification by flash chromatography on silica column (24g), with the speed of 35mL/min With 100% hexane to 100%EtOAc gradient elutions 20 minutes, title compound (259mg, 33.4%) is obtained.LC-MS m/z 506(M+H)⁺, 1.34 minutes (retention time).

3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazoles -1- Base) methyl valerate

At 23 DEG C, to 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl - 5- (4- propyl -1H-1,2,3- triazol-1-yls) methyl valerate (259mg, 0.512mmol) is in DCM (2.567mL) and water DDQ (128mg, 0.563mmol) is added in solution in (0.128mL).After 45 minutes, by the reaction by the way that saturation is added NaHCO₃Aqueous solution is quenched, and DCM is used in combination to extract.By organic layer through MgSO₄It is dry, and volume is reduced in a vacuum.Then it will slightly produce Object uses purification by flash chromatography on silica column (4g), with the speed of 18mL/min 100% hexane to 100%EtOAc Gradient elution 20 minutes obtains title compound (89.5mg, 45.3%).LC-MS m/z 384(M+H)⁺, (protect within 0.99 minute Stay the time).

3- (3- (- 4 (5H)-yl of 2,2- dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- two Hydrogen -1H- indenes -5- bases) -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid, trifluoroacetate

At -10 DEG C, by PBr₃(0.066ml, 0.698mmol) is added to 3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- Base) -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazol-1-yls) methyl valerate (134.5mg, 0.349mmol) DCM In (1.133mL) solution.The reaction is stirred 20 minutes at -10 DEG C.After twenty minutes, TLC analyses are without showing any starting Substance, and by reaction NaHCO₃It is quenched.Water layer is extracted with DCM (3x), and organic layer is merged, the NaCl of saturation is used in combination Washing.By organic layer through MgSO₄It is dry, and concentrate, clear yellow oil is obtained, is dissolved in acetonitrile (1.133mL), And it is transferred in microwave vial.By 2,2- dimethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptatriene hydrochloride (89mg, 0.419mmol) and DIPEA (0.183ml, 1.047mmol) are added in the solution, and under high-selenium corn in microwave It is heated 1 hour in 90 DEG C.After 1 hour, LC-MS shows that there is no initial substances and product to form (545 (M+H of LC-MS m/z )⁺, 1.01 minutes (retention time)).Solvent in vacuo is removed, and mixture is dissolved in methanol (1.133mL), and is transferred to In microwave vial.3M NaOH (0.581mL, 1.744mmol) are added, and the reaction is heated 3 hours in microwave in 120 DEG C. The DMSO of 1mL is added, and volatile matter is removed in vacuum.DMSO solution is acidified to~pH 5 with 1N HCl.Water is removed in vacuum, and Mixture is filled by 0.45 micrometer syringe formula filter in clean bottle.By the product in Gilson HPLC It is purified on (Sunfire C18,5m 19X 100mm), 20%CH is used with 18mL/min speed₃CN/H₂O (0.1%TFA) is extremely 50%CH₃CN/H₂O (0.1%TFA) linear gradient elution obtains title compound (18mg, 10%).LC-MS m/z 531(M+ H)⁺, 0.81 minute (retention time).

Embodiment 66

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) propionic acid

The bromo- 1,2,3,4- naphthanes -1- alcohol of 7-

At 25 DEG C, to bromo- -1 (2H) -one (2000mg, 8.89mmol) of 3,4- dihydronaphthalene of 7- in methanol (20mL) NaBH is added in solution₄(672mg,17.77mmol).After reaction mixture is stirred 2 hours, 1N HCl solutions are added to be quenched The reaction is used in combination ethyl acetate (3x 50mL) to extract.Combined organic layer is washed with brine (50mL), through MgSO₄It is dry, And it is concentrated to give bromo- 1,2,3,4- naphthane -1- alcohol (1800mg, 7.93mmol, 89% yield) of title compound 7-, it is oily Object.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 alkane -2- bases) -1,2,3,4- naphthane -1- alcohol

Under a nitrogen, to bromo- 1,2,3,4- naphthane -1- alcohol (1000mg, 4.40mmol) of 7- in-dioxane of Isosorbide-5-Nitrae 4,4,4', 4', 5,5,5' are slowly added into solution in (20mL), 5'- prestoxs -2,2'- is bis-, and (1,3,2- dioxa boron is miscellaneous Penta ring) (1342mg, 5.28mmol), potassium acetate (648mg, 6.61mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (180mg, 0.220mmol).Reaction mixture is stirred 16 hours at 90 DEG C.Water (50mL) is added, and by mixture ethyl acetate (3x 50mL) is extracted.By combined organic layer through MgSO₄It is dry, and in 50 DEG C of concentrations under stream of nitrogen gas.Crude product is passed through Silica gel chromatograph (hexane:Ethyl acetate=1:1) it purifies, obtains title compound 7- (4,4,5,5- tetramethyls -1,3,2- dioxas Boron heterocycle pentane -2- bases) -1,2,3,4- naphthane -1- alcohol (800mg, 2.92mmol, 66.3% yield) are 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- benzos [d] [1,2,3] triazole -5- bases) -3- (8- hydroxyl -5,6,7,8- naphthanes -2- Base) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (300mg, 7- (4,4,5,5- tetramethyls -1,3,2- two 1.223mmol) are added in the solution in 1,4- dioxanes (10mL) and water (5mL) Oxa- boron heterocycle pentane -2- bases) -1,2,3,4- naphthane -1- alcohol (800mg, 2.92mmol) and TEA (0.341mL, 2.446mmol).Under nitrogen protection, reaction mixture is stirred 10 minutes, (1,5- cyclo-octadiene) radium chloride is then added (I) dimer (30.2mg, 0.061mmol).Reaction mixture is stirred 16 hours at 90 DEG C.Then reaction mixture is used EtOAc (3x 10mL) is extracted.By combined organic layer through MgSO₄It is dry, and concentrate.Crude product is passed through into silica gel chromatograph (oil Ether/ethyl acetate=1:1) it purifies, obtains title compound 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] triazole -5- Base) -3- (8- hydroxyls -5,6,7,8- naphthane -2- bases) ethyl propionate (300mg, 0.762mmol, 62.3% yield) is solid Body.LCMS m/z 394.2(M+H)⁺, 1.85 minutes (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) ethyl propionate

By 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- hydroxyl -5,6,7,8- naphthanes - 2- yls) ethyl propionate (250mg, 0.635mmol), DIPEA (0.222mL, 1.271mmol) is at dichloromethane (DCM) (10mL) In mixture in 0 DEG C stirring.Mesyl chloride (0.074mL, 0.953mmol) is added, and stirs 2 hours.By reaction mixture Concentration.Residue is dissolved in n,N-Dimethylformamide (DMF) (2mL), and (R) -2- methyl -2,3 is added, 4,5- tetrahydrochysene benzene And [f] [1,4] oxaza heptantriene (311mg, 1.906mmol).Then it is stirred 2 hours in 90 DEG C.Reaction is mixed Object is poured into ice-water, is used in combination ethyl acetate (3x 30mL) to extract, through MgSO₄It is dry, and concentrate.Crude product is passed through into silica gel Chromatography (petrol ether/ethyl acetate=1:1) it purifies, obtains title compound 3- (Isosorbide-5-Nitraes-dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (8- (- 4 (5H)-yl of (R) -2- methyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -5,6, 7,8- naphthane -2- bases) ethyl propionate (300mg, 0.557mmol, 88% yield) is grease, without further purification With regard to carrying out in next step.LCMS m/z 539.2(M+H)⁺, 1.70 minutes (retention time)

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzenes And -4 (5H)-yl of [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) propionic acid

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydros - 4 (5H)-yl of benzo [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) ethyl propionate (200mg, NaOH (59.4mg, 1.485mmol) and water (2.0mL) 0.371mol) are added in the solution in MeOH (2mol).Reaction is mixed Object is closed to stir 2 hours at 50 DEG C.Mixture is concentrated, and is dissolved in water (5mL).Then it is neutralized to 1N HCl/water solution pH 6.Residue is concentrated, and passes through reversed-phase HPLC (20%MeCN/H₂O it) purifies, obtains title compound 3- (Isosorbide-5-Nitraes-diformazan Base -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzos [f] [1,4] oxazas Heptantriene -4 (5H)-yl) -5,6,7,8- naphthane -2- bases) propionic acid (100mg, 0.186mmol, 50.1% yield) is solid. LCMS m/z 511.2(M+H)⁺, 1.5 minutes (retention time).

Embodiment 67

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (S) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2-Dimethylpropionic acid, trifluoroacetate

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) it is added in the mixture of -2,2- dimethylated methyl propionates (0.060g, 0.152mmol) in dichloromethane (0.50mL) SOCl₂(0.022mL,0.305mmol).Gained reaction mixture is stirred 10 minutes at ambient temperature, then under reduced pressure Concentration.The residue is dissolved in acetonitrile (1.5mL) and tetrahydrofuran (0.50mL), is then added 2,2- dimethyl -2,3,4, 5- tetrahydropyridines simultaneously [2,3-f] [1,4] oxaza heptantriene, hydrochloride (0.049g, 0.229mmol), sodium iodide (0.011g, 0.076mmol) and K₂CO₃(0.063g,0.457mmol).The reaction mixture of generation is small in 40 DEG C of heating 24 When.Reaction mixture is filtered.Filter cake is washed with MeCN (2mL).Combined filtrate is concentrated under reduced pressure.Residue is molten In methanol (1.5mL), NaOH (3N) (0.254mL, 0.762mmol) is then added.By gained reaction mixture 130 DEG C with Microwave heating 60 minutes then uses HCl (3N) (0.254mL, 0.762mmol) to be acidified.Reaction mixture is concentrated under reduced pressure, And purified by reversed-phase HPLC, title compound (9.3mg, 0.014mmol, 9.33% yield) is obtained, is solid.LCMS m/z 540.5(M+H)⁺, 0.84min (retention time).

Table 4In compound be by be similar to prepare rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (rac- (S) -3- (2,2- dimethyl -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantrienes - 4 (5H)-yls) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids method prepare.Those skilled in the art should manage Solution, these similar embodiments may include the variation of usual reaction condition.

Table 4

Embodiment 69

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- dimethylated methyl propionates

To (R) -2- ethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the mixture of (344mg, 1.600mmol) in methanol (12mL)₂CO₃(332mg,2.400mmol).Gained is reacted Mixture stirs 60 minutes at ambient temperature, then filters, concentration, and is dissolved in acetonitrile (12mL), obtains midbody solution.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the solution of -2,2- dimethylated methyl propionates (315mg, 0.8mmol) in DCM (4.0mL)₂ (0.117mL,1.600mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, is then concentrated under reduced pressure, Above-mentioned midbody solution, sodium iodide (60.0mg, 0.400mmol) and K is then added₂CO₃(332mg,2.400mmol).It will generate Reaction mixture in 40 DEG C heat 20 hours, then filter.Filter cake is washed with MeCN (6mL).Combined filtrate is being subtracted Pressure concentration is then purified by reversed-phase HPLC (TFA modifying agent) by purification by flash chromatography, then uses chirality SFC (columns： Chiralpak AD 20x250mm,5u；Cosolvent：25%EtOH；Flow velocity：50g/min；Back pressure：100Bar) it is further purified, Obtain title compound (42.3mg, 0.076mmol, 9.55% yield).LCMS m/z 554.3(M+H)⁺, (protect within 0.91 minute Stay the time).

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids

To rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydros -1H- Indenes -5- bases) it is added in the mixture of -2,2- dimethylated methyl propionates (42.3mg, 0.076mmol) in methanol (1.5mL) NaOH(3.0N)(0.127mL,0.382mmol).The reaction mixture microwave of generation heats at 120 DEG C to continue 14 times small When, then HCl (3.0N) (0.127mL, 0.382mmol) is used to be acidified, reaction mixture is concentrated under reduced pressure, and pass through reversed-phase HPLC (formic acid modifying agent) purifies, and obtains title compound (28.6mg, 0.049mmol, 63.9% yield).LCMS m/z 540.5(M +H)⁺, 0.82 minute (retention time).

Table 5In compound be by be similar to prepare rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (rel- (R) -3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantrienes - 4 (5H)-yls) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids method prepare.Those skilled in the art should manage Solution, these similar embodiments may include the variation of usual reaction condition.

Table 5

Embodiment 70

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- oxos -2,3- two Hydrogen -1H- indenes -5- bases) methyl propionate

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) Dai Si-is added in the solution of -2,2- dimethylated methyl propionates (650mg, 1.652mmol) in dichloromethane (50mL) Martin's oxidant (1401mg, 3.30mmol) and a drop water.Reaction mixture is stirred 8 hours at 25 DEG C, then filtering should Mixture, and filtrate is concentrated.Crude product is passed through into silica gel chromatograph (petroleum ether:Ethyl acetate=1:1) it purifies, obtains titled Close object 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- oxo -2,3- dihydros - 1H- indenes -5- bases) methyl propionate (570mg) is yellow oil.LC/MS m/z 392.2(M+H)⁺, 1.65 (retention times).

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- oxygen Generation -2,3- dihydro -1H- indenes -5- bases) methyl propionate

By 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- oxos -2,3- Dihydro -1H- indenes -5- bases) methyl propionate (0.57g, 1.456mmol) passes through chiral SFC (columns：Chiralpak IA 20x250mm,5u；Cosolvent：20%EtOH；Flow velocity：50g/min；Back pressure：It 100Bar) purifies, obtains title compound (177.9mg, 0.454mmol, 31.2% yield).LCMS m/z 392.2(M+H)⁺, 0.99 minute (retention time).

Rel- (3S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyls -2,3- two Hydrogen -1H- indenes -5- bases) -2,2- dimethylated methyl propionates

To rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -2,2- dimethyl -3- (3- Oxo -2,3- dihydro -1H- indenes -5- bases) it is added in solution of the methyl propionate (177mg, 0.452mmol) in methanol (3.5mL) NaBH₄(17.11mg,0.452mmol).The reaction is stirred 30 minutes at ambient temperature, is then concentrated under reduced pressure, is used DCM (2x 5mL) is extracted, through Na₂SO₄It is dry, filtering, and being concentrated under reduced pressure, obtain title compound (203.9mg, 0.518mmol, 115% yield).LCMS m/z 394.2(M+H)⁺, 0.96 minute (retention time).

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- - 4 (5H)-yl of dimethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- Neopentanoic acid

To rel- (3S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyls -2,3- two Hydrogen -1H- indenes -5- bases) the mixture of -2,2- dimethylated methyl propionates (100mg, 0.254mmol) in dichloromethane (1.0mL) Middle addition SOCl2 (0.037mL, 0.508mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature, is then existed The lower concentration of decompression.The residue is dissolved in acetonitrile (3.0mL) and tetrahydrofuran (1.0mL), dimethyl -2 2,2- are then added, 3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (109mg, 0.508mmol), sodium iodide (19.05mg, 0.127mmol) and K2CO3 (140mg, 1.017mmol).The reaction mixture of generation is heated 17 hours in 40 DEG C, then mistake Filter.Filter cake is washed with MeCN (3mL).Combined filtrate is concentrated under reduced pressure, and is dissolved in methanol (3.0mL).It is added NaOH(3N)(0.678mL,2.033mmol).The reaction mixture of generation heats at 130 DEG C with microwave to continue 1 twice small When, then HCl (3N) (0.678mL, 2.033mmol) is used to be acidified, is concentrated under reduced pressure, and purified by reversed-phase HPLC, obtains Title compound (28.7mg, 0.053mmol, 20.96% yield).LCMS m/z 539.4(M+H)⁺, 0.86 minute (when reservation Between).

Table 6In compound be by be similar to prepare rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (rel- (R) -3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantrienes - 4 (5H)-yls) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids method prepare.Those skilled in the art should manage Solution, these similar embodiments may include the variation of usual reaction condition.

Table 6

Embodiment 71

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxo -2,3- dihydros - 1H- indenes -5- bases) ethyl propionate

To (E) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) ethyl acrylate (564mg, 6- (4,4,5,5- tetramethyls -1,3,2- two 2.3mmol) are added in the mixture in 1,4- dioxanes (13mL) and water (4ml) Oxa- boron heterocycle pentane -2- bases) -2,3- dihydro -1H- 1-Indanones (891mg, 3.45mmol), triethylamine (1.282mL, 9.20mmol) and [Rh (cod) Cl]₂(56.7mg,0.115mmol).The reaction mixture of generation is stirred 17 hours in 90 DEG C, Then it is concentrated under reduced pressure, by purification by flash chromatography, and (column is then purified by chiral SFC：Chiralpak AD, 20x250,5u；Cosolvent：30% reagent alcohol (90%EtOH, 5%MeOH, 5%IPA)；Overall flow rate：50g/min；Back pressure： It 100bar) is further purified, obtains title compound (168.0mg, 0.445mmol, 19.35% yield).LCMS m/z 378.3(M+H)⁺, 0.88 minute (retention time).

Rel- (3R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyls -2,3- two Hydrogen -1H- indenes -5- bases) ethyl propionate

To rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- oxos -2,3- two Hydrogen -1H- indenes -5- bases) NaBH is added in solution of the ethyl propionate (168mg, 0.445mmol) in methanol (3.0mL)₄ (16.84mg,0.445mmol).Gained reaction is stirred 2 hours at ambient temperature, more NaBH are then added₄ (8.42mg,0.223mmol).After 1 hour, reaction mixture is concentrated under reduced pressure, by purification by flash chromatography, obtains title Compound (127.3mg, 0.335mmol, 75% yield).LCMS m/z 380.3(M+H)⁺, 0.90 minute (retention time).

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid Ethyl ester

To (R) -2- ethyl -2,3,4,5- tetrahydro benzos [f] [1,4] oxaza heptantriene, hydrochloride (141mg, K 0.659mmol) is added in the mixture in methanol (5.0mL)₂CO₃(91mg,0.659mmol).By gained reaction mixture It stirs 30 minutes, then filters, and filtrate is concentrated under reduced pressure at ambient temperature.Gained residue is dissolved in acetonitrile In (5.0mL), midbody solution is obtained.

To rel- (3R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyls -2,3- two Hydrogen -1H- indenes -5- bases) SOCl is added in mixture of the ethyl propionate (125mg, 0.329mmol) in dichloromethane (1.5mL)₂ (0.048mL,0.659mmol).Gained reaction mixture is stirred 10 minutes at ambient temperature, is then concentrated under reduced pressure. Above-mentioned midbody solution, sodium iodide (24.69mg, 0.165mmol), sodium and K is added₂CO₃(91mg,0.659mmol).By gained Reaction mixture heats 18 hours at 40 DEG C, then filters.Filter cake is washed with MeCN (2mL).Combined filtrate is being depressurized Then lower concentration is further purified by chiral HPLC by purification by flash chromatography, obtain title compound (48.0mg, 0.089mmol, 27.0% yield).LCMS m/z 539.5 (M+H)+, 0.93 minute (retention time).

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid

To rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) In solution of the ethyl propionate (48mg, 0.089mmol) in methanol (2.0mL) be added NaOH (3.0N) (0.149mL, 0.446mmol).By gained reaction mixture with microwave heating 20 minutes at 80 DEG C, then use HCl (3.0N) (0.149mL, 0.446mmol) it is acidified.Reaction mixture is concentrated under reduced pressure, DCM (3x 2mL) is used in combination to extract.By combined organic layer through MgSO4 It is dry, filtering, and be concentrated under reduced pressure, obtain title compound (42.7mg, 0.084mmol, 94% yield).LCMS m/z 511.5(M+H)⁺, 0.80 minute (retention time).

Table 7In compound be by be similar to prepare rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] Triazole -5- bases) -3- (rel- (S) -3- ((R) -2- ethyl -2,3- dihydrobenzos [f] [1,4] oxaza heptantrienes -4 (5H) - Base) -2,3- dihydro -1H- indenes -5- bases) propionic acid method prepare.It will be understood by those skilled in the art that these similar embodiments It may include the variation of usual reaction condition.

Table 7

Embodiment 85

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- dimethylated methyl propionates

To (R) -2- ethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the mixture of (344mg, 1.600mmol) in methanol (12mL)₂CO₃(332mg,2.400mmol).Gained is reacted Mixture stirs 60 minutes and filters at ambient temperature, and filtrate is concentrated, and residue is dissolved in acetonitrile (12mL), obtains Midbody solution.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) SOCl is added in the mixture of -2,2- dimethylated methyl propionates (315mg, 0.8mmol) in dichloromethane (4.0mL)₂ (0.117mL,1.600mmol).Gained reaction mixture is stirred 20 minutes at ambient temperature and is then concentrated.It is added among the above Between liquid solution, sodium iodide (60.0mg, 0.400mmol) and K₂CO₃(332mg,2.400mmol).By the reaction mixture of generation in 40 DEG C are heated 20 hours, are then filtered.Filter cake is washed with MeCN (6mL).Combined filtrate is concentrated, and passes through flash chromatography Purifying is then purified by reversed-phase HPLC (TFA modifying agent), and chirality SFC (columns are then used：Chiralpak AD 20x250mm, 5u；Cosolvent：25%EtOH；Flow velocity：50g/min；Back pressure：100Bar) be further purified, obtain title compound (49.1mg, 0.089mmol, 11.08% yield).LC/MS：m/z 554.3(M+H)⁺, 0.88 minute (retention time).

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) - - 4 (5H)-yl of 2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- Base) -2,2- neopentanoic acids

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- ((R) -2- ethyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl propylenes In solution of the sour methyl esters (49mg, 0.088mmol) in methanol (1.5mL) be added NaOH (3.0N) (0.147mL, 0.442mmol).The reaction mixture of generation is heated by microwave at 120 DEG C and continues 1 hour twice, then uses HCl (3.0N) (0.147mL, 0.442mmol) is acidified, and concentration and is purified by reverse phase, obtain title compound (6.9mg, 0.013mmol, 14.45% yield).LC/MS：m/z540.5(M+H)⁺, 0.76 minute (retention time).

Embodiment 86

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids Methyl esters

To 2,2- dimethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene, hydrochloride K is added in the mixture of (0.344g, 1.600mmol) in methanol (12mL)₂CO₃(0.332g,2.400mmol).Gained is anti- It answers mixture to stir 60 minutes at ambient temperature and filters.Filtrate is concentrated, and residue is dissolved in acetonitrile (12mL), is obtained To midbody solution.

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- hydroxyl -2,3- dihydro -1H- indenes - 5- yls) it is added in the mixture of -2,2- dimethylated methyl propionates (0.315g, 0.8mmol) in dichloromethane (4.0mL) SOCl₂(0.117mL,1.600mmol).Gained reaction mixture is stirred 40 minutes at ambient temperature, is then added above-mentioned Midbody solution, sodium iodide (0.060g, 0.400mmol) and K₂CO₃(0.332g,2.400mmol).The reaction of generation is mixed Object heats 67 hours in 40 DEG C.Reaction mixture is filtered.Filter cake is washed with MeCN (6mL).Combined filtrate is concentrated, and It is purified with reversed-phase HPLC (TFA modifying agent), chirality SFC (columns is used in combination：Chiralpak AD 20x250mm,5u；Cosolvent：5% EtOH；Flow velocity：50g/min；Back pressure：100Bar) be further purified, obtain title compound (52.9mg, 0.096mmol, 11.94% yield).LC/MS：m/z 554.4(M+H)⁺, 0.96 minute (retention time).

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyrroles Pyridine simultaneously -4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids

To 3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydros - 4 (5H)-yl of pyrido [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl propylenes In solution of the sour methyl esters (52.9mg, 0.096mmol) in methanol (1.2mL) be added NaOH (3.0N) (0.159mL, 0.478mmol), and by reaction continue 1 hour 3 times by microwave heating at 130 DEG C.By reaction mixture with HCl (3.0N) (0.159mL, 0.478mmol) is acidified, and concentration is used in combination reversed-phase HPLC (formic acid modifying agent) to purify, obtains title compound (35.8mg, 0.061mmol, 64.0% yield).LC/MS：m/z 540.5(M+H)⁺, 0.97 minute (retention time).

Embodiment 87

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes

Bromo- 2, the 3- dihydros -1H- indenes -1- alcohol (8.6g, 40.4mmol) of 6- are dissolved in DMF (50mL), and are cooled to 4 DEG C, 60% sodium hydride (3.23g, 81mmol) is added with a batch.It is stirred 1 hour at 23 DEG C, is then cooled to~10 again with ice bath DEG C, 1- (chloromethyl) -4- methoxybenzenes (9.48g, 60.5mmol) are added.It is stirred 14 hours at 23 DEG C.By the reaction water (25mL) is quenched, and stirs 3 minutes, EtOAc (200mL) and more water (25mL) is then used to dilute.Detach each layer, and by water layer With other 2X 75mL EtOAc extractions.By combined EtOAc water (75mL) and then with the NaCl aqueous solutions of saturation (50mL) is washed, dry (Na₂SO₄), concentration, and by remaining amber grease on ISCO silica columns (120g) It is purified using Combiflash Companion, is divided with 85mL/min speed hexane to 10%EtOAc/ hexanes gradient elutions 30 Clock.By required fraction collector, obtain the bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes (11.76g, 35.3mmol, 87% yield), it is clear grease.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- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -5- (trimethyl silyl) is amyl- 4- alkynes -1- alcohol

The bromo- 1- of 6- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes (3.3005g, 9.90mmol) is dissolved in THF In (66.0ml), and it is cooled to -70 DEG C.1.6M butyl lithiums (8.05ml, 12.88mmol) are added dropwise.By the mixture of generation in -65 It is stirred 30 minutes to -75 DEG C, the THF of 5- (trimethyl silyl) amyl- 4- alkynes aldehyde (2.978g, 19.30mmol) is then added (3mL) solution (T<- 65 DEG C), and mixture is stirred 2 hours in -75 DEG C.The reaction water and EtOAc are diluted.By each phase It vibrates together, uses EtOAc aqueous phase extracteds again, combined EtOAc water and saturation NaCl aqueous solutions are washed, it is dry (MgSO₄) and filter.Filtrate is concentrated, and uses ISCO Combiflash on ISCO silica columns (40g) Companion is purified, with hexane to 30%EtOAc/ hexanes gradient elutions 20 minutes.Required fraction is merged, 1- (3- are obtained ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) the amyl- 4- alkynes -1- alcohol of -5- (trimethyl silyl) (3.6339g, 8.89mmol, 90% yield) is 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)。

(the bromo- 5- of 5- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) amyl- 1- alkynes -1- bases) front three Base silane

To 1- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -5- (trimethyl silyl) Amyl- 4- alkynes -1- alcohol (3.6339g, 8.89mmol) is continuously added to the PPh of polymer combination in the solution in DCM (44.5ml)₃ (2.39mmol/g) (3.72g, 8.89mmol) and carbon tetrabromide (3.54g, 10.67mmol).It stirs 3 days and is added more CBr₄(2.95g,8.89mmol).After other 1 hour, which is concentrated, and filters, by crude product in ISCO silica columns Purification by flash chromatography is used on (40g), with 35mL/min speed hexane to 10%EtOAc/ hexanes gradient elutions 35 minutes.It will Required fraction collector and concentration, obtain (the bromo- 5- of 5- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) Amyl- 1- alkynes -1- bases) trimethyl silane (1.31g, 2.78mmol, 31.2% yield) is clear oily matter.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)。

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -7- (trimethyl first Silylation) hept- 6- acetylenic acid benzyl esters

By THF (23.75ml) the solution 1.6M n-BuLis of -70 DEG C of diisopropylamines (4.06ml, 28.5mmol) (8.91ml, 14.25mmol) processing, and stirred 15 minutes at -70 DEG C.By isobutyric acid benzyl ester (4.22ml, 23.75mmol) It is added drop-wise in -70 DEG C of solution.It is stirred 45 minutes at -70 DEG C, is then warmed to -45C and continues 5 minutes, and cool back -70 ℃.By (the bromo- 5- of 5- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) amyl- 1- alkynes -1- bases) trimethyl THF (3mL) solution of silane (2.24g, 4.75mmol) is added drop-wise in enolate, and anhydrous 1,3- dimethyl tetrahydros are then added Pyrimidine -2 (1H) -one (5.06ml, 42.0mmol).After being stirred 1 hour at -78 DEG C, which is warmed to -45 DEG C.- 45 At DEG C after 2.5 hours, by the reaction by the way that NH is added₄Cl is quenched, and water layer EtOAc is extracted 3 times.Thick grease is existed Use 0-20% hexanes/(3:1EtOAc:EtOH it is purified 20 minutes on 24g silica columns).Using 0-20% hexanes/ Second 24g silica column of EtOAc carries out chromatogram purification 20 minutes again, the 3- purified (3- ((4- methoxybenzyls Base) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl -7- (trimethyl silyl) hept- 6- acetylenic acid benzyl esters (1.2886g, 2.265mmol, 47.7% yield) is clear grease.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)

3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl-g -6- acetylenic acid benzyls Base ester

By K₂CO₃(1.230g, 8.90mmol) is added to 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydros -1H- Indenes -5- bases) -2,2- dimethyl -7- (trimethyl silyl) hept- 6- acetylenic acids benzyl ester (1.260g, 2.215mmol) methanol In (11.08ml) solution.After 3 hours, which is diluted with water, DCM is used in combination to extract 3 times.By organic layer through MgSO₄It is dry, And concentrate, obtain 3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl-g -6- acetylenic acids Benzyl ester (1.11g, 2.235mmol, 101% yield) is colorless oil.LC/MS(ES⁺)[M+Na]⁺=519.3 (1.61min)。

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydros -1H- Indenes -5- bases) -2,2- dimethyl acid benzyl esters

By sodium azide (0.363g, 5.59mmol), iodoethane (0.449ml, 5.59mmol), cuprous iodide (I) (0.064g, 0.335mmol) and N- ethyl-N-iospropyl propyl- 2- amine (0.078ml, 0.447mmol) are added to 3- (3- ((4- Methoxy-benzyl) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl-g -6- acetylenic acids benzyl ester (1.11g, In the tert-butyl alcohol (5.6ml) 2.235mmol)/water (5.6ml) solution.The mixture is heated 1 hour by microwave in 70 DEG C, The reaction water and EtOAc are diluted.Water layer EtOAc is extracted 3 times, and by combined organic layer MgSO₄It is dry and dense Contracting, and crude oil is eluted 20 minutes in ISCO24g purified on silica column with 0-90% hexanes/EtOAc.It will be required Fraction collector obtains 5- (1- ethyls -1H-1,2,3- triazole-4-yls) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- bis- Hydrogen -1H- indenes -5- bases) -2,2- dimethyl acid benzyl ester (1.0147g, 1.787mmol, 80% yield) is yellow oil. LC/MS(ES⁺)[M+H]⁺=568.4 (1.46min).

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base acid benzyl ester

Ammonium ceric nitrate (1.936g, 3.53mmol) is added to 5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((4- methoxy-benzyls) oxygroup) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl acid benzyl ester (1.0023g, In acetonitrile (7.94ml) and water (0.883ml) solution 1.765mmol).After 18 hours, by mixture DCM and NaHCO₃It is dilute It releases.Water layer DCM is extracted 3 times.By combined organic layer through MgSO₄It is dry, and concentrate.By crude oil in 24g ISCO It is purified on silica column (0-100% hexanes/EtOAc), obtains 5- (1- ethyls -1H-1,2,3- triazole-4-yls) -3- (3- hydroxyls Base -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl acid benzyl ester (150mg, 0.335mmol, 18.98% yield).LC/ MS (ES+) [M-OH] +=430.2 (1.04min).

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids

By K₂CO₃(46.3mg, 0.335mmol) be added to (R) -2- ethyl -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1, 4] in solution of the oxaza heptatriene hydrochloride (39.8mg, 0.223mmol) in methanol (1mL).Stir the mixture for 20 Minute, and filter out solid.Then filtrate is concentrated under vacuum.Then the free alkali of concentration is dissolved in acetonitrile (2.000mL), Obtain solution A.By SOCl₂(8.15 μ l, 0.112mmol) is added to 5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- Hydroxyl -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl acid benzyl ester (50mg, 0.112mmol) is at DCM (1.000mL) In solution in.After twenty minutes, which is concentrated in vacuo, obtains intermediate 3- (chloro- 2, the 3- dihydros -1H- indenes -5- bases of 3-) - 5- (1- ethyl -1H-1,2,3- triazole-4-yls) -2,2- dimethyl acid benzyl esters.By acetonitrile (2.000mL) and free alkali (R) -2- ethyls -2,3,4,5- tetrahydropyridines simultaneously [3,4-f] [1,4] oxaza heptantriene (39.8mg, 0.223mmol) solution (solution A) is added to 3- (the chloro- 2,3- dihydros -1H- indenes -5- bases of 3-) -5- (1- ethyl -1H-1,2,3- triazole-4-yls) -2,2- Dimethyl acid benzyl ester intermediate and K₂CO₃In (46.3mg, 0.335mmol) and sodium iodide (8.37mg, 0.056mmol).It will Mixture is warmed to 40 DEG C, and the reaction is stirred 18 hours, which is diluted with water, and water layer EtOAc is extracted 3 It is secondary.By organic layer through MgSO₄It is dry, and concentrate.Crude residue is dissolved in the MeOH of 10mL, 3M NaOH are added (0.186mL, 0.559mmol), and the reaction is heated 5 hours in microwave in 100 DEG C, 1mL DMSO are added, and depressurize and remove Remove volatile matter.DMSO solution is acidified to~pH5 with 1N HCl.Water is removed under reduced pressure, and mixture is passed through 0.45 micron Syringe filter filters, and passes through reverse phase preparative HPLC using neutrallty condition.The product formic acid that gained is purified Reverse phase preparative HPLC as solvent modified dose is further purified, and obtains 5- (1- ethyls -1H-1,2,3- triazole-4-yls) -3- (3- (- 4 (5H)-yl of (R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydros - 1H- indenes -5- bases) -2,2- dimethyl valeric acid (4mg, 7.73 μm of ol, 6.92% yield).LC/MS(ES⁺)[M+H]⁺=518.4 (0.78min)。

Claims (18)

1. formula (I) compound or its pharmaceutically acceptable salt,

Wherein：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂-OR₄And halogen Element；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases or four Oxazolyl；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group carbon one connected to them It rises and forms cyclopropyl；

R₄For hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base, imidazolidine and diaza cycloheptyl three Alkenyl or Tetrahydro-pyridine and oxaza heptantriene base, all these groups can be unsubstituted or by 1,2 or 3 independences Ground substituent group selected from the following is replaced：-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃、C_3-6Spiro cycloalkyl group and OH；

N is 1 or 2.

2. formula (II) compound or its pharmaceutically acceptable salt,

Wherein：

B is benzotriazole base, phenyl, triazolo pyridyl or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 substituent groups independently selected from the following are replaced：–C_1-3Alkyl ,-O-C_1-3Alkyl, CN ,-(CH₂)₂–O–(CH₂)₂-OR₄And halogen Element；

D is-C (O) OH ,-C (O) NHSO₂CH₃、–SO₂NHC(O)CH₃, 5- (trifluoromethyl) -4H-1,2,4- triazole -2- bases or four Oxazolyl；

R₁It independently is hydrogen, C_1-3Alkyl, F, C_3-6Spiro cycloalkyl group, propylene oxide or two R₁Group carbon one connected to them It rises and forms cyclopropyl；

R₂For=O or hydrogen；

R₄For hydrogen or C_1-3Alkyl；

Linker is-CH₂、-O-C(O)-、-CH₂-C(O)-、–C(O)-、-CH(CH₃)-C (O)-or-N (CH₃)-C(O)-；

A is cyclohexyl, cyclopenta, phenyl or decahydro naphthalene；All these groups can be it is unsubstituted or independently by selected from Substituent group below is replaced：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1 or 2；

X is CH₂Or O.

3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 independently selected from following Substituent group replaced：–C_1-3Alkyl and halogen；

D is-C (O) OH；

R₁It independently is hydrogen or methyl or two R₁Group carbon connected to them forms cyclopropyl together；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base or Tetrahydro-pyridine and oxaza heptan Trialkenyl, all these groups can be unsubstituted or be replaced by 1,2 or 3 substituent group selected from the following：-C_1-3Alkyl, Halogen, CN and-OC_1-3Alkyl；With

N is 1 or 2.

4. compound according to claim 1 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base or phenyl, can be respectively unsubstituted or by 1,2 or 3 substituent group independently selected from the following Replaced：–C_1-3Alkyl, halogen and CN；

D is-C (O) OH；

R₁It independently is hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, tetrahydro benzo azepine cycloheptatriene base, imidazolidine and diaza cycloheptyl three Alkenyl or Tetrahydro-pyridine and oxaza heptantriene base, all these groups can be unsubstituted or by 1,2 or 3 independences Ground substituent group selected from the following is replaced：-C_1-3Alkyl, halogen, CN ,-OC_1-3Alkyl ,-CH₂-O-CH₃、C_3-6Spiro cycloalkyl group and OH；With

N is 1.

5. compound according to claim 1 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base, can be unsubstituted or by 1,2 or 3 independently selected from-C_1-3The substituent group of alkyl is replaced；

D is-C (O) OH；

R₁It independently is hydrogen or C_1-3Alkyl；

A is tetrahydro benzo oxaza heptantriene base, can be unsubstituted or independently selected from the following by 1,2 or 3 Substituent group is replaced：-C_1-3Alkyl ,-OC_1-3Alkyl, CN and halogen；With

N is 1.

6. compound according to claim 2 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 independently selected from following Substituent group replaced：–C_1-3Alkyl and halogen；

D is-C (O) OH；

R₁It independently is hydrogen or methyl or two R₁Group carbon connected to them forms cyclopropyl together；

R₂For=O or hydrogen；

Linker is-CH₂-、-O-C(O)-、-CH(CH₃)-C (O)-or-N (CH₃)-C(O)-；

A is cyclohexyl or cyclopenta, and all these groups can be unsubstituted or independently by substituent group institute selected from the following Substitution：C_1-3Alkyl, CN and halogen；

N is 1；With

X is CH₂Or O.

7. compound according to claim 2 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 independently selected from following Substituent group replaced：–C_1-3Alkyl and-O-C_1-3Alkyl；

D is-C (O) OH；

R₁It independently is hydrogen；

R₂For hydrogen；

Linker is-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydro naphthalene；All these groups can be unsubstituted or independently be taken by selected from the following Replaced for base：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1；With

X is CH₂。

8. compound according to claim 2 or its pharmaceutically acceptable salt, wherein：

B is benzotriazole base or-(CH₂)₂Triazolyl can be respectively unsubstituted or by 1,2 or 3 independently selected from following Substituent group replaced：–C_1-3Alkyl and-O-C_1-3Alkyl；

D is-C (O) OH；

R₁It independently is hydrogen；

R₂For=O；

Linker is-CH₂-、-O-C(O)-、-CH₂-C(O)-；

A is cyclohexyl, phenyl or decahydro naphthalene；All these groups can be unsubstituted or independently be taken by selected from the following Replaced for base：C_1-3Alkyl, CN and halogen；

Or A is C_4-5Alkyl, can be by-OC_1-3Alkyl is replaced；

N is 1；With

X is CH₂Or O.

9. compound is：

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (3,3-3- [(3aR, 8bS) -1- (cyclohexyl first Base) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] -3- (1,4- dimethyl -1H-1,2,3- Benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 1- [(4- ethylcyclohexyls) methyl] -2- oxos - 1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases } propionic acid；

3- [(3aR, 8bS) -1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- Base] -5- (1- ethyl -1H-1,2,3- triazole-4-yls) valeric acid；

3- [1- (decahydronaphthalene -2- ylmethyls) -2- oxos -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] - 3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 2- oxos -1- [(4- propylcyclohexyls) methyl] - 1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases } propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1,4- bis- Methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [1- (2- Cyclohexylacetyls) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] -3- (1,4- bis- Methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- phenylpropionyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [1- (2- methylvaleryls) -1H, 2H, 3H, 3aH, 4H, 8bH- indeno [1,2-b] pyrroles -7- bases] propionic acid；

3- { 1- [2- (2- chlorphenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1, 4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [2- (2- cyano-phenyls) acetyl group] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

Dimethylbutanoyl) -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases] propionic acid；

3- { 1- [butyl (methyl) carbamoyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (7- methoxies Base -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (1- second Base -4- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -5- (1- second Base -1H-1,2,3- triazole-4-yls) valeric acid；

3- { 1- [(tert-butoxy) carbonyl] -1H, 2H, 3H, 3aH, 4H, 8bH- indenos [1,2-b] pyrroles -7- bases } -3- (7- methoxies Base -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [1- (cyclohexyl methyl) -2- oxos -1H, 2H, 3H, 3aH, 4H, 5H, 9bH- benzo [g] indoles -8- bases] -3- (1,4- Dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [3- (cyclohexyl methyl) -2- oxos -2H, 3H, 3aH, 8H, 8aH- indeno [1,2-d] [1,3] oxazole -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- [3- (the chloro- 2,2- dimethyl -2,3,4,5- tetrahydrochysenes -1,4- benzos oxaza heptantriene -4- bases of 7-) -2,3- dihydros - 1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (tetrahydrochysene -1 2,2,7- trimethyl -2,3,4,5-, 4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (7- methoxyl group -2,2- dimethyl -2,3,4,5- Tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (tetrahydrochysene -1 2,2,8- trimethyl -2,3,4,5-, 4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (fluoro- 2,2- dimethyl -2,3,4,5- tetrahydrochysenes-of 8- 1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -3- (4- fluoro-2-methylbenzenes base) -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] -2,2- neopentanoic acids；Formic acid；

3- [3- (7- cyano -2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- two Hydrogen -1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } -2,2- neopentanoic acids；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- 3- [methyl -2,3,4 (2R) -2-, 5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyridos [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyridos [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

3- [3- (8- cyano -2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- two Hydrogen -1H- indenes -5- bases] -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyls -2H, 3H, 4H, 5H- pyridines And [3,4-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases -2,2- neopentanoic acids；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- [3- (2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydros - 1H- indenes -5- bases } -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

(3S) -3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [(3R) -3- (2,2- dimethyl -2,3,4,5- Tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- 3- [(2R) -2- methyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid；

3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydros -1H- Indenes -5- bases } -3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) propionic acid

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2,7- dimethyl -2,3,4,5- tetrahydrochysenes - 1,4- benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyridos [3,4-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- 3- [(2S) -2- methyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyridos [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (7- methoxyl group -1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,3,4,5- tetrahydrochysene -1,4- benzene And oxaza heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- methyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -2,2- dimethyl -3- (3- { 2H, 3H, 4H, 5H- pyridos [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- (7- methoxyl group -1- methyl-1 H-1,2,3- benzotriazole -5- bases) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2S) -2- methyl -2,3,4,5- tetrahydrochysenes -1,4- Benzo oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases } propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- ethyls -2H, 3H, 4H, 5H- pyridines And [3,4-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases propionic acid；Formic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- [3- (2,3,4,5- tetrahydrochysene -1,4- benzo oxazas Heptantriene -4- bases) -2,3- dihydro -1H- indenes -5- bases] propionic acid；Formic acid；

3- (4- cyano -2- aminomethyl phenyls) -3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxygen nitrogen Heterocycle heptantriene -4- bases } -2,3- dihydro -1H- indenes -5- bases) propionic acid；

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- (4- fluoro-2-methylbenzenes base) propionic acid；

3- (1,4- dimethyl -1H-1,2,3- benzotriazole -5- bases) -3- { 3- [(2R) -2- methyl -2H, 3H, 4H, 5H- pyridines And [3,2-f] [1,4] oxaza heptantriene -4- bases] -2,3- dihydro -1H- indenes -5- bases propionic acid

3- (3- { 2,2- dimethyl -2H, 3H, 4H, 5H- pyrido [3,2-f] [1,4] oxaza heptantriene -4- bases } -2,3- Dihydro -1H- indenes -5- bases) -3- { 3- methyl -3H- [1,2,3] triazol [4,5-c] pyridine -6- bases } propionic acid；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid；Trifluoroacetic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -5- (2- ethyl -2H-1,2,3,4- tetrazolium -5- bases) -2,2- dimethyl valeric acids；Formic acid；

3- [3- (2,2- dimethyl -2,3,4,5- tetrahydrochysene -1,4- benzo oxaza heptantriene -4- bases) -2,3- dihydros -1H- Indenes -5- bases] -2,2- dimethyl -5- (4- propyl -1H-1,2,3- triazol-1-yls) valeric acid；

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (8- ((R) -2- methyl -2,3- dihydrobenzos - 4 (5H)-yl of [f] [1,4] oxaza heptantriene) -5,6,7,8- naphthane -2- bases) propionic acid；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (S) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids, trifluoroacetate；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (R) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydro pyridos [2,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -- 2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (R) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydro pyridos [4,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids, trifluoroacetate；

Rac- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rac- (S) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydro pyridos [4,3-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids, trifluoroacetate；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- (2,2- diformazans - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- diformazans Base propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (R) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (R) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydrobenzos [f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) propionic acid；

Rel- (S) -3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (rel- (S) -3- ((R) -2- second - 4 (5H)-yl of base -2,3- dihydro pyridos [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2, 2- neopentanoic acids；

3- (1,4- dimethyl -1H- benzos [d] [1,2,3] triazole -5- bases) -3- (3- (2,2- dimethyl -2,3- dihydro pyridos - 4 (5H)-yl of [3,4-f] [1,4] oxaza heptantriene) -2,3- dihydro -1H- indenes -5- bases) -2,2- neopentanoic acids；Or

5- (1- ethyl -1H-1,2,3- triazole-4-yls) -3- (3- ((R) -2- ethyl -2,3- dihydro pyridos [3,4-f] [1,4] Oxaza heptantriene -4 (5H)-yl) -2,3- dihydro -1H- indenes -5- bases) -2,2- dimethyl valeric acids；

Or its pharmaceutically acceptable salt.

10. pharmaceutical composition, it includes the compound of any one of claim 1-9 and pharmaceutically acceptable carrier or figurations Agent.

11. treatment breathing or non-respiratory systemic disease, including COPD, asthma, fibrosis, chronic asthma, acute asthma, secondary to The pulmonary disease of environmental exposure, acute pulmonary infection, chronic lung infection, alpha1 Anti-trypsin disease, cystic fibrosis, itself Immunity disease, nephrosis, chronic kidney disease, the acute kidney injury of septicemia induction, acute kidney injury (AKI), kidney move Nephrosis or renal insufficiency during plant, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's disease (PD), Alzheimer disease (AD), family ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Inflammatory bowel disease, colon cancer, non-neovascular (dry type) AMD and neovascular (wet type) AMD, eye traumas, Fuchs cornea Endothelium malnutrition (FECD), uveitis or other inflammatory eye diseases, nonalcoholic fatty liver disease (NASH), toxin-induced Hepatopathy (such as hepatopathy of paracetamol induction), virus hepatitis, hepatic sclerosis, psoriasis, the part effect of dermatitis/radiation It answers, due to the method for immunosupress caused by radioactive exposure, pre-eclampsia and altitude sickness, it is in need the method includes giving The compound of any one of people's claim 1-10.

12. method according to claim 11, wherein the compound oral administration.

13. method according to claim 11, wherein the compound is through intravenous administration.

14. method according to claim 11, wherein the compound passes through inhalation.

15. method according to claim 11, wherein the disease is COPD.

16. compound as claimed in one of claims 1-10 or its pharmaceutically acceptable salt are being prepared for treating breathing With non-respiratory systemic disease, including COPD, asthma, fibrosis, chronic asthma, acute asthma, the lung secondary to environmental exposure Disease, acute pulmonary infection, chronic lung infection, alpha1 Anti-trypsin disease, cystic fibrosis, autoimmune disease, sugar Nephrosis or kidney during urine characteristic of disease nephrosis, chronic kidney disease, the acute kidney injury of septicemia induction, acute kidney injury (AKI), kidney transplant Insufficiency, pulmonary hypertension, atherosclerosis, hypertension, heart failure, Parkinson's disease (PD), Alzheimer disease (AD), family ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, knot Intestinal cancer, non-neovascular (dry type) AMD and neovascular (wet type) AMD, eye traumas, Fuchs endothelial dystrophy of cornea (FECD), uveitis or other inflammatory eye diseases, nonalcoholic fatty liver disease (NASH), the hepatopathy of toxin-induced are (such as right The hepatopathy of Paracetamol induction), it is virus hepatitis, hepatic sclerosis, psoriasis, the local effect of dermatitis/radiation, sudden and violent due to radiating Purposes in the drug of immunosupress, pre-eclampsia and altitude sickness caused by dew.

17. compound as claimed in one of claims 1-10 or its pharmaceutically acceptable salt are being prepared for treating COPD Drug in purposes.

18. compound as claimed in one of claims 1-10 is used to treat.