CN108349974A - A kind of substituted pyridine amides and its application - Google Patents

Abstract

A kind of substituted pyridine amides and its application.Specifically disclose formula（I）Shown in deuterated pyridine amides and contain the compound or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvate pharmaceutical composition.The compound can be used as JAK inhibitor, and then can be used conveniently to prepare treatment JAK relevant diseases（Such as autoimmune disease）Drug.

Description

A kind of substituted pyridine amides and its application Technical field

The invention belongs to field of medicaments.In particular it relates to a kind of deuterated pyridine amides compound and application thereof, more specifically, it is related to pyridine amides and its as JAK inhibitor, or for treating and preventing and JAK enzyme related disease.

Background technique

Janus kinases (JAK) is transducer cell factor signal from membrane receptor to the cytoplasmic tyrosine kinase of STAT transcription factor.Four kinds of JAK family members: JAK1, JAK2, JAK3 and TYK2 have been described in the prior art.When cell factor is in conjunction with its receptor, JAK family member autophosphorylation and/or turn phosphorylation each other, subsequent STATs phosphorylation, then migrate in nucleus to adjust transcription.JAK-STAT intracellular signal transduction is suitable for interferon, most of interleukins and cytokine profiles and endocrine factor, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL.

Cartilage degeneration is the mark of many diseases, and wherein rheumatoid arthritis and osteoarthritis are most important.Rheumatoid arthritis (Rheumatoid Arthritis, abbreviation RA) is chronic joint degenerative disease, it is characterised in that the inflammation and destruction of joint structure.When disease is not suppressed, since the forfeiture of function of joint leads to substantive disability and pain or even premature death.Therefore, the purpose of RA treatment, which is not only in that, delays disease, and is to be mitigated, to terminate destruction of joint.In addition to the seriousness of disease outcome, the universal RA of height (adult of the whole world~0.8% is perplexed) means very high social economy's impact.

Osteoarthritis (Osteoarthritis, abbreviation OA) is the most common arthritis form, it is characterised in that the loss of articular cartilage, usually with hyperostosis and pain.

Osteoarthritis is difficult to treat.Currently, being not possible to cure, treatment, which concentrates on, to relieve pain and prevents diseased joints from deforming.Common treatment includes applying non-steroidal anti-inflammatory drugs.Although being identified it is safely and effectively to select for treatment the nutrient and healthcare products such as chondroitin and glucosamine sulfate of osteoarthritis, nearest clinical test shows that both treatments cannot reduce pain related with osteoarthritis.Filgotinib is a kind of in the high selectivity JAK1 inhibitor ground, it is found by Galapagos and is developed, from the point of view of the comprehensive clinical data obtained, Filgotinib treats rheumatoid arthritis (RA) and Crohn disease (Crohn's disease, CD) working, rapid, curative effect is high, while having good safety and tolerance.

Therefore there is still a need for new compound is developed, for treating degenerative joint disease.Compound of the present invention can be used for treating degenerative joint disease, such as osteoarthritis, rheumatic arthritis and osteoporosis, especially osteoarthritis.In addition, the present invention provides compound, its preparation method and the pharmaceutical composition comprising the compounds of this invention and suitable pharmaceutical carriers.The present invention also provides the compounds of this invention to prepare the purposes in the drug for treating degenerative joint disease.

Summary of the invention

The object of the present invention is to provide a kind of new compounds and preparation method thereof with the effect of JAK inhibitor.

The present invention provides deuterated pyridine amides compounds shown in a kind of formula (I), and its physiologically acceptable salt, solvate, hydrate, prodrug, tautomer and stereoisomer, the mixture formed including these compounds with all proportions.

In formula:

Each R is independently selected from the group being made of " hydrogen (H), deuterium (D) "；

And its physiologically acceptable salt, solvate, hydrate, prodrug, tautomer and stereoisomer, the mixture formed including these compounds with all proportions.

It is selected in example another, deuterium isotopic content of the deuterium in deuterated position is at least greater than natural deuterium isotopic content (0.015%), is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 99%.

Specifically, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²Deuterium isotopic content is at least 5% in each deuterated position, it is preferably greater than 10%, even more preferably greater than 15%, even more preferably greater than 20%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than 35%, even more preferably greater than 40%, even more preferably greater than 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than 60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than 85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.

It is selected in example another, the R of compound in formula (I)¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹And R²², at least one of which R contains deuterium, more preferably two R contain deuterium, more preferably three R contain deuterium, more preferably four R contain deuterium, more preferably five R contain deuterium, more preferably six R contain deuterium, more preferably seven R contain deuterium, more preferably eight R contain deuterium, more preferably nine R contain deuterium, more preferably ten R contain deuterium, more preferably 11 R contain deuterium, more preferably 12 R contain deuterium, more preferably 13 R contain deuterium, more preferably 14 R contain deuterium, more preferably 15 R contain deuterium, more preferably 16 R contain deuterium, more preferably 17 R contain deuterium, more preferably 18 R contain deuterium, more preferably 19 R contain deuterium, more preferably 20 R contain deuterium.

It is selected in example another, R¹、R²、R³、R⁴、R⁵It is each independently deuterium or hydrogen.

Preferably, R¹、R²、R³、R⁴And R⁵It is deuterium.

It is selected in example another, R⁶、R⁷、R⁸It is each independently deuterium or hydrogen

Preferably, R⁶It is deuterium.

Preferably, R⁷It is deuterium.

Preferably, R⁸It is deuterium.

It is selected in example another, R⁹、R¹⁰、R¹¹、R¹²It is each independently deuterium or hydrogen.

Preferably, R⁹It is deuterium.

Preferably, R¹¹It is deuterium.

It is selected in example another, R¹³、R¹⁴It is each independently deuterium or hydrogen.

Preferably, R¹³、R¹⁴It is deuterium.

It is selected in example another, R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²It is each independently deuterium or hydrogen.

Preferably, R¹⁵、R¹⁶It is deuterium.

Preferably, R¹⁷、R¹⁸It is deuterium.

Preferably, R¹⁹、R²⁰It is deuterium.

Preferably, R²¹、R²²It is deuterium.

Preferably, R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²It is deuterium.

It is selected in example another, the compound is selected from such as the following group compound or its pharmaceutically acceptable salt, but is not limited to following compounds:

The compounds of this invention does not include non-deuterated compound.

The compound of the present invention is novel JAK inhibitor, with structure compared with similar compound, shows the efficiency significantly improved in vivo.In a specific embodiment, the compounds of this invention is JAK1 and JAK2 inhibitor.

On the other hand, the present invention provides the pharmaceutical composition containing the compounds of this invention and pharmaceutical carrier, excipient or diluent.Moreover, the compounds of this invention used in pharmaceutical composition disclosed in the text and treatment method is pharmaceutically acceptable for making and using.In this aspect of the invention, described pharmaceutical composition is also containing the other active components being suitable for the compounds of this invention use in conjunction.

In another aspect of this invention, the present invention provides the methods for treating susceptible or infection those listed herein illness mammal, illness especially relevant to abnormal J AK activity, such as inflammation, autoimmune disease, proliferative diseases, graft rejection, be related to cartilage and update impaired disease, congenital cartilage deformity and/or disease relevant to IL6 hypersecretion, this method includes applying the pharmaceutical composition or compound of the invention of therapeutically effective amount described herein.In a specific embodiment, the illness is relevant to abnormal J AK1 and JAK2 activity.

On the other hand, the present invention provides the compounds of this invention for treating or preventing illness, the illness is selected from those listed herein, those of especially may be related to abnormal J AK activity illness, such as inflammation, autoimmune disease, proliferative diseases, graft rejection, be related to cartilage and update impaired disease, congenital cartilage deformity and/or disease relevant to IL6 hypersecretion.

Also in terms of another treatment method, the present invention provides the method for the mammal for treating as described herein susceptible or infection illness relevant to abnormal J AK activity, this method includes the invention described herein pharmaceutical composition or compound for the amount applied effectively treatment illness or prevent illness.In a specific aspect, the illness is relevant to abnormal JAK1 and JAK2 activity in the cause of disease.

On the other hand, the present invention is provided to treat or prevent the compounds of this invention of illness relevant to abnormal J AK activity.

On the other hand, the present invention provides the method using disclosed representative synthetic schemes herein below and route synthesis the compounds of this invention.

Therefore, the main object of the present invention is to provide new compound, can correct the activity of JAK, to prevent or treat any possible relative disease.In a specific aspect, the activity of the compounds of this invention adjustable JAK1 and JAK2.

It is a further object of the present invention to provide the compounds that can treat or alleviate disease or disease symptoms, the disease or disease are such as inflammation, autoimmune disease, proliferative diseases, graft rejection, are related to the impaired disease of cartilage update, congenital cartilage deformity and disease relevant to IL6 hypersecretion, these diseases may be related to JAK, particularly JAK1 and JAK2 activity.

It is a further object of the present invention to provide the pharmaceutical compositions that can be used to treat or prevent various disease states, the morbid state include to the relevant disease of JAK activity, such as inflammation, autoimmune disease, proliferative diseases, graft rejection, be related to cartilage and update impaired disease, congenital cartilage deformity and disease relevant to IL6 hypersecretion.In a specific embodiment, the disease is especially relevant to JAK1 and JAK2 activity.

Specific implementation step

Detailed description of the invention

Definition

Following term is intended to have meaning given below and for understanding description and the scope of the present invention herein.

It when describing the invention, may include the method for compound, the pharmaceutical composition comprising such compound and application such compound and composition, unless otherwise stated, following term, if it exists, then having following meanings.It is to be further understood that any group described herein can be replaced by a variety of substituent groups, and the group replaced includes as defined in the range of it is respectively.Unless otherwise stated, term " substituted " is as defined below.It is to be further understood that term " base " and " group " used herein can be interchanged.

Indefinite article "one" and "an" can be used to indicate that the referents of the grammatical of one (kind) or more than one (kind) (i.e. at least one (kind)) article, such as " (kind) analog " one (kind) analog of expression or more than one (kind) analog herein.

The term as used herein " JAK " is related to Janus kinases (JAKs) family, is the cytoplasmic tyrosine kinase from membrane receptor to STAT transcription factor transducer cell factor signal.Prior art describes four kinds of JAK family members: JAK1, JAK2, JAK3 and TYK2, and term JAK can indicate all JAK family members of entirety shown in context or one or more JAK family members.

Term " pharmaceutically acceptable " means that corresponding mechanism national except federal or continent government management organization or the U.S. has been approved by or listed in authorizable or United States Pharmacopeia or other universally recognized pharmacopeia for animal and is more particularly for people's.

Term " pharmaceutically acceptable salt " means that the salt of the compounds of this invention, the salt are required pharmacological activities pharmaceutically acceptable and with parent compound.Specifically, such salt is nontoxic, can be inorganic or organic acid addition salt and base addition salts.Especially, such salt includes: (1) and the acid-addition salts that inorganic acid is formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.；Or the acid-addition salts formed with organic acid, the organic acids such as acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4- hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2- ethionic acid, 2- ethylenehydrinsulfonic acid, benzene sulfonic acid, 4- chlorobenzenesulfonic acid, 2- naphthalene sulfonic acids, 4- toluenesulfonic acid, camphorsulfonic acid, 4- methyl bicyclic [2.2.2]-oct-2-ene -1- formic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.；Or (2) when in parent compound there are when acid proton, the salt that metal ion replaces the acid proton to be formed, the metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion；Or it is coordinated with organic base, described organic bases such as ethanol amine, diethanol amine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..Salt further comprises the salt such as sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium；And when compound includes basic functionality, form non-toxic organic or the salt, such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalates of inorganic acid etc..

The acceptable cation counterbalancing ion of term " pharmaceutically acceptable cation " expression acidic functionality.This cationoid such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cation etc..

" pharmaceutically acceptable medium " indicates diluent, adjuvant, excipient or the carrier applied together with the compounds of this invention.

" solvate " indicates the compound form usually by solvolytic reaction and solvent association.The association of this physics includes hydrogen bond.Conventional solvent includes water, ethyl alcohol, acetic acid etc..The compounds of this invention can be prepared into such as crystal form and can be with solvation or aquation.Suitable solvate includes pharmaceutically acceptable solvate, such as hydrate, and further includes the solvate and non-stoichiometric solvate of stoichiometry.In some cases, solvate can separate, such as when in the lattice of one or more solvent molecules incorporation crystalline solid." solvate " includes solution phase and separable solvate.Representative solvate includes hydrate, alcoholate and methylate.

" therapeutically effective amount " means effective when being applied to the treatment that amount of the individual for compound when treating disease is enough to disease." therapeutically effective amount " can be according to the variation such as compound, disease and its severity, age, the weight for the treatment of individual.

" preventing " or " prevention " indicates to reduce the risk for obtaining or developing into disease or illness, even if the clinical symptoms of at least one disease do not develop in individual, the individual is likely to be exposed at pathogenic agent or is susceptible to suffer from the disease before seizure of disease.Term " prevention " is related to " preventing ", indicates measure or method, and its object is to prevent and non-treatment or healing disease.

The invention also includes the compound of isotope labelling, the example that can be classified as the compound of the present invention isotope includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,³¹P,³²P,³⁵S,¹⁸F and³⁶Cl.Compound or enantiomer in the present invention, diastereomer, isomers or pharmaceutically acceptable salt or solvate, wherein being within the scope of the present invention containing the isotope of above compound or other other isotope atoms.Certain compound isotopically labelleds in the present invention, such as³H and¹⁴The radioactive isotope of C is also useful in the experiment of the Tissue distribution of drug and substrate wherein.Tritium, i.e.,³H and carbon-14, i.e.,¹⁴C, their preparation and detection are easier, and are the first choices in isotope.The compound of isotope labelling can use general method that can be prepared by replacing with non isotopic reagent with the isotope labeling reagent being easy to get with the scheme in example.

The non-limiting example of precautionary measures includes application vaccine；Such as due to not moving and to there are the patient in hospital of thrombosis risk to apply low molecular weight heparin；And Anti-Malarial, such as chloroquine are applied before going to malaria prevalence or the very high geographic area of risk of being infected with malaria.

In one embodiment, " treatment " of any disease or illness indicates to improve disease or illness (prevent disease or mitigate the presentation, degree or seriousness of its at least one clinical symptoms).In another embodiment, " treatment " indicates to improve at least one body index, which may not be that individual is perceptible.In another embodiment, " treatment " indicates to adjust disease or obstacle, (such as stablizing perceptible symptom) on body, physiologically (such as stable body index) or both.

In a further embodiment, " treatment " indicates to slow down the process of disease.

The term as used herein " inflammation " indicates one group of illness, including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway diseases (such as asthma, rhinitis), inflammatory bowel disease (such as clone disease, colitis), endotoxin driving morbid state (such as the complication after bypass surgery or chronic endotoxin state due to caused by such as chronic heart failure) and be related to the related disease of cartilage, such as joint disease.The term particularly shows rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma) and inflammatory bowel disease.

The term as used herein " autoimmune disease " indicates one group of disease, including obstructive airway diseases, packet Include illness such as COPD, asthma (such as intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), asthma (such as late asthma and airway hyperreactivity) that is especially chronic or being formed for a long time, bronchitis (including bronchial asthma), systemic loupus erythematosus (SLE), multiple sclerosis, type-1 diabetes mellitus and its relevant complication, atopic eczema (atopic dermatitis), contact dermatitis, it further include eczematous dermatitis, inflammatory bowel disease (such as clone's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.The term particularly shows COPD, asthma, systemic loupus erythematosus, type-1 diabetes mellitus and inflammatory bowel disease.

The term as used herein " proliferative diseases " indicates illness, such as cancer (such as leiomyosarcoma of uterus or prostate cancer), bone marrow proliferation sexual dysfunction (such as thrombocythemia and myelofibrosis of polycythemia vera, primary), leukaemia (such as acute myeloid leukaemia and acute lymphoblastic leukemia), Huppert's disease, psoriasis, restenosis, sclerodermatitis or fibrosis.The term particularly shows cancer, leukaemia, Huppert's disease and psoriasis.

The term as used herein " cancer " indicates that the pernicious or benign growths of cell in skin or biological organs, the organ are to be such as, but not limited to breast, prostate, lung, kidney, pancreas, stomach or intestines.Cancer is easy to invade adjacent tissue and farther away organ, such as bone, liver, lung or brain are arrived in diffusion (transfer).The term as used herein cancer includes metastatic tumour cellular type, such as, but not limited to melanoma, lymthoma, leukaemia, fibrosarcoma, rhabdomyosarcoma and mastocytoma, and organize cancer type, such as, but not limited to colorectal cancer, prostate cancer, Small Cell Lung Cancer and non-small cell lung cancer, breast cancer, cancer of pancreas, bladder cancer, kidney, gastric cancer, glioblastoma, primary carcinoma of liver, oophoroma, prostate cancer and leiomyosarcoma of uterus.

The tumor disease of the term as used herein " leukaemia " expression blood and blood forming organ.Such disease can lead to marrow and immune system dysfunction, this infects host easily and bleeding.Term leukaemia particularly shows acute myeloid leukaemia and acute lymphoblastic leukemia.

The term as used herein " graft rejection " indicates such as cell of pancreas islet, stem cell, marrow, skin, muscle, cornea tissue, neuronal tissue, heart, lung, cardiopulmonary joint, kidney, liver, intestines, pancreas, tracheae or esophagus, the allograft of tissue or solid organ or the acute or chronic repulsion of xenograft or graft versus host disease(GVH disease).

The term as used herein " be related to cartilage and update impaired disease " includes illness, such as osteoarthritis, psoriatic arthritis, Rheumatoid Arthritis, urarthritis, septic or infectional arthritis, adjuvant arthritis, reflex sympathetic dystrophy, algodystrophy, tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, the arthritis of region form such as Kashin-Beck's disease, Mseleni disease and Handigodu disease, denaturation caused by fibromyalgia, systemic loupus erythematosus, chorionitis and ankylosing spondylitis.

The term as used herein " congenital cartilage deformity " includes illness, such as heredity chondrolysis, osteochondrodysplasia and pseudoachondroplasia, is especially but not limited to microtia, earless, metaphysial chondrodysplasia and associated disease.

The term as used herein " disease relevant to IL6 hypersecretion " includes illness, such as Castleman disease, Huppert's disease, psoriasis, Kaposi sarcoma and/or Pathology of Mesangial Proliferative Glomerulonephritis.

" the compounds of this invention " and equivalents indicate the compound including structural formula described in text, which includes pharmaceutically acceptable salt and solvate, such as the solvate of hydrate and pharmaceutically acceptable salt, as long as allowing in context.Similarly, refer to intermediate (no matter whether themselves is claimed) When include their salt and solvate, as long as allowing in context.

The acid of other derivatives of the compounds of this invention and sour derivative form all have activity, but acid-sensitive form can usually provide more favorable dissolubility, histocompatbility in mammalian organism or delay to discharge (Bundgard, H.Design of Prodrugs (design of prodrug), 7-9,21-24 pages, Elsevier, Amsterdam 1985).

The compounds of this invention is new JAK inhibitor.In particular, the compound is effective JAK1 and JAK2 inhibitor.

Pharmaceutical composition

When as medicinal application, the compounds of this invention is applied usually in the form of pharmaceutical composition.Such composition can be with the well-known method preparation of pharmaceutical field, and includes at least one reactive compound.In general, the compounds of this invention is applied with medicinal effective quantity.For the amount for the compound actually applied usually by doctor depending on correlation circumstance, the correlation circumstance includes treated illness, selected administration method, the practical compound applied, age, weight and the response of individual patient, the severity of patient symptom etc..

Pharmaceutical composition of the invention can be applied through a variety of ways, including oral, rectum, percutaneous, subcutaneous, intra-articular, intravenous, intramuscular and intranasal.According to expected route of delivery, the compounds of this invention is preferably configured to Injectable composition or Orally administered composition or all ointment for being used for transdermal administration, lotion or patch.

The composition of oral administration can be using a large amount of aqueous agents or the form of suspension or a large amount of powders.However, it is much more common that composition is to be accurately administered existing for unit dosage forms.Term " unit dosage forms " indicates physically separated unit, it is suitable as the unit administration of individual human and other mammals, each unit includes the active material (required therapeutic effect can be generated by being computed) and suitable drug excipient, medium or carrier of predetermined amount.Typical unit dosage forms include the ampoule or syringe of liquid composition that is pre-filled, measuring in advance, or include pill, tablet, capsule etc. in the case where solid composite.In such composition, the compounds of this invention is usually less component (about 0.1 weight % to about 50 weight %, for preferably from about 1 weight % to about 40 weight %), remainder is a variety of media or carrier and processing aid to contribute to form required form of medication.

Liquid form suitable for oral administration may include the suitable aqueous or non-aqueous medium containing buffer, suspending agent and dispersing agent, colorant, corrigent etc..Solid form may include the compound of for example any following component or similarity: adhesive, such as microcrystalline cellulose, bassora gum or gelatin；Excipient such as starch or lactose；Disintegrating agent, such as alginic acid, Primogel or cornstarch；Lubricant, such as magnesium stearate；Glidant, such as colloidal silicon dioxide；Sweetener, such as sucrose or saccharin；Or corrigent, such as peppermint, gaultherolin or orange flavor.

Injectable composition is normally based on injectable Sterile Saline or phosphate buffered saline (PBS) or other injectable carriers known in the art.As described above, reactive compound is usually less component in the composition, for typically about 0.05 weight % to 10 weight %, remainder is injectable carrier etc..

Transdermal composition is typically formulated as topical ointments or cream containing active constituent, and the amount of active constituent generally ranges from about 0.01% to about 20% weight, preferably from about 0.1% to about 20% weight, preferably from about 0.1 to about 10% weight and more preferably from about 0.5 to about 15% weight.When being formulated as ointment, active constituent ointment bases usually miscible with paraffin or water is mixed.Alternatively, active constituent can be prepared together with such as oil-in-water type cream base in cream.Such percutaneous preparation be it is well-known in the art and generally comprise it is other at Divide to enhance the cuticular penetration stability of active constituent or preparation.All such known percutaneous preparations and ingredient are included within the scope of the invention.

The compounds of this invention can also be applied by transcutaneous device.Therefore, transdermal administration can be realized using the patch of storage cavern or porous film type or solid matrix variant.

It is above-mentioned it is oral can apply, the component for the composition that injectable or part can apply is only representative.Other materials and processing technique etc. are in Remington ' s Pharmaceutical Sciences (Remington materia medica), and the 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvanian 8th part are described, and which is incorporated herein by reference.

The compounds of this invention can also be applied with sustained release forms or from slow releasing pharmaceutical delivery system.The description of representative sustained-release materials is referring to Remington ' s Pharmaceutical Sciences (Remington materia medica).

Following example of formulations explanation can be with representative pharmaceutical composition prepared in accordance with the present invention.But the present invention is not limited to following pharmaceutical compositions.

1 tablet of preparation

The compounds of this invention can be mixed as dry powder with dry gelatin adhesive with about 1:2 weight ratio.A small amount of magnesium stearate is added as lubricant.240-270mg tablet (the every active amide compound containing 80-90mg) is made in mixture in tablet press machine.

2 capsule of preparation

The compounds of this invention can be mixed as dry powder with starch diluent with about 1:1 weight ratio.Mixture is packed into 250mg capsule (the active amide compound that each capsule contains 125mg).

3 liquid of preparation

The compounds of this invention (125mg) can be mixed with sucrose (1.75g) and xanthan gum (4mg), and the mixture of generation can be mixed, pass through the U.S. sieve of No. 10 mesh numbers, then it is mixed with the aqueous solution of the microcrystalline cellulose and sodium carboxymethylcellulose (11:89,50mg) that previously prepared.Sodium benzoate (10mg), corrigent and colorant are diluted with water and are added under stiring.Then enough water can be added under stiring.Then enough water is added so that total volume is made as 5mL.

4 tablet of preparation

The compounds of this invention can be mixed as dry powder with dry gelatin adhesive with about 1:2 weight ratio.A small amount of magnesium stearate is added as lubricant.450-900mg tablet (the active amide compound of 150-300mg) is made in mixture in tablet press machine.

5 injection of preparation

The compounds of this invention can be dissolved in or be suspended in the Sterile Saline injectable aqueous medium of buffering to concentration is about 5mg/mL.

6 part of preparation

Stearyl alcohol (250g) and albolene (250g) are melted at about 75 DEG C, then be added be dissolved in water (about 370g) the compounds of this invention (50g), methyl p-hydroxybenzoate (0.25g), propylparaben (0.25g), lauryl sodium sulfate (10g) and propylene glycol (120g) mixture, and by the mixture of generation stirring until condensation.

Treatment method

It is relevant to JAK abnormal activity in mammal for treating that the compounds of this invention may be used as therapeutic agent Or the illness due to caused by JAK abnormal activity.Specifically, such illness is related to JAK1 and/or JAK2 abnormal activity.Thus, it is found that the compounds of this invention and pharmaceutical composition of the present invention are used to prevent and/or treat the inflammation, autoimmune disease, proliferative diseases, graft rejection that mammal includes people, are related to the impaired disease of cartilage update, congenital cartilage deformity and disease relevant to IL6 hypersecretion as therapeutic agent.

In terms of other treatment method, the present invention provides treat it is susceptible or infection be related to inflammation mammal method.This method includes the pharmaceutical composition or compound for the one or more invention described hereins applied effectively treatment illness or prevent illness amount.In specific embodiments, inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma) and inflammatory bowel disease.

On the other hand, it the present invention provides the compounds of this invention, is used to treat, prevent or prevention of inflammation.In special embodiment, inflammation is selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma) and inflammatory bowel disease.

In terms of other treatment method, the present invention provides the methods for treating susceptible or infection autoimmune disease mammal.This method includes the pharmaceutical composition or compound for the one or more invention described hereins applied effectively treatment illness or prevent illness amount.In specific embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, type-1 diabetes mellitus and inflammatory bowel disease.

On the other hand, the present invention provides the compounds of this invention, is used to treat, prevent or preventing autoimmune disease.In special embodiment, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, type-1 diabetes mellitus and inflammatory bowel disease.

In terms of further treatment method, the present invention provides the method for treating the mammal of susceptible or infection development disease, particularly cancer (such as solid tumor such as leiomyosarcoma of uterus or prostate cancer), leukaemia (such as AML or ALL), Huppert's disease and/or psoriasis.

On the other hand, the present invention provides the compounds of this invention, it is used to treat, prevents or prevent proliferative diseases, especially cancer (such as solid tumor such as leiomyosarcoma of uterus or prostate cancer), leukaemia (such as AML or ALL), Huppert's disease and/or psoriasis.

In terms of other treatment method, the present invention provides the methods for treating susceptible or infection graft rejection mammal.In special embodiment, the present invention provides the methods for the treatment of organs graft rejection.

On the other hand, the present invention provides the compounds of this invention, is used to treat, prevents or prevent graft rejection.In special embodiment, the present invention provides the methods for the treatment of organs graft rejection.

In terms for the treatment of method, the present invention provides the method for being related in the mammal that cartilage updates impaired disease treating, prevent or prevent in susceptible or infection, this method include the invention described herein of application therapeutically effective amount compound or one or more pharmaceutical compositions of the present invention.

On the other hand, the present invention provides the compounds of this invention, is used to treat, prevent or prevents to be related to the impaired disease of cartilage update.

The present invention also provides the method for treating congenital cartilage deformity, this method includes applying a effective amount of one or more pharmaceutical compositions of the present invention described herein or compound.

On the other hand, the present invention provides the compounds of this invention, is used to treat, prevents or prevent congenital cartilage deformity.

As further aspect of the present invention, the present invention provides the compounds of this invention, are used as drug and are particularly useful for the treatment of or prevent above-mentioned illness and disease.The compounds of this invention is also provided herein in preparation for treating or pre- Prevent the purposes in the drug of one of above-mentioned illness and disease.

The special scheme of one of this method includes applying a effective amount of the compounds of this invention for a period of time to the individual for being related to inflammation, and the time is enough to reduce the level of inflammation of patient, and preferably terminates the process of the inflammation.The special embodiment of this method includes to suffering from or the susceptible individual patient that rheumatoid arthritis occurs applies a effective amount of the compounds of this invention for a period of time, the time is enough to reduce or prevent the arthritis of the patient respectively, and preferably terminates the process of the inflammation.

Another special projects of this method include applying a effective amount of the compounds of this invention for a period of time to the individual with the disease case (such as rheumatic arthritis and/or osteoarthritis) characterized by cartilage or joint degeneration, and the time is enough to reduce and preferably terminate the process of the degeneration itself continued to develop.The special embodiment of this method includes to suffering from or the susceptible individual patient that osteoarthritis occurs applies a effective amount of the compounds of this invention for a period of time, the time is enough to reduce or prevent the cartilage degradation of the patient articular respectively, and preferably terminates the process of the degeneration itself continued to develop.In special embodiment, the compound can show cartilage anabolic and/or Anticatabolism property.

Injection dosage horizontal extent is about 0.1mg/kg/ hours at least 10mg/kg/ hours, be the entire process have about 1 to about 120 hour, especially 24 to 96 hours.Agent is injected in the prepackage that about 0.1mg/kg can also be applied to about 10mg/kg or more, to obtain enough steady-state levels.Estimated maximum accumulated dose no more than about 2g/ days for 40 to 80kg human patient.

For preventing and/or treating long-term illness, such as neuodegenerative disorder, therapeutic scheme usually continues several months or several years, therefore for the convenience and tolerance of patient, is preferably administered orally.For oral administration, representative scheme is daily 1 to 5, particularly 2 to 4, is usually 3 oral doses.Using these administration modes, the compounds of this invention of each dosage offer about 0.01 to about 20mg/kg is each to provide about 0.1 to about 10mg/kg, particularly about 1 to about 5mg/kg for special dosage.

Percutaneous dosing is generally selected to provide than with drug administration by injection is obtained similar or lower blood level.

When the breaking-out for prevention of inflammatory conditions, the compounds of this invention is applied to above-mentioned dosage level in the patient occurred in disease risk usually under the informing of doctor and supervision.Those of illness family history has been generally included in the patient occurred in special disease risk, or those of especially susceptible generation illness is determined as by genetic testing or screening.

The compounds of this invention can be used as individual activating agent application or they and can be administered in combination with other activating agents, including be determined as safe and efficient other compounds with same or similar therapeutic activity and for such combined administration.In special embodiment, the co-administration of two kinds of (or a variety of) activating agents allows to significantly reduce the dosage of every kind of activating agent used, to reduce seen side effect.

In one embodiment, the compounds of this invention and other therapeutic agent are co-administered for treatment and/or prevention of inflammation disease, special activating agent includes but is not limited to immunomodulator, such as imuran, corticosteroid (such as prednisolone or dexamethasone), cyclophosphamide, ciclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, such as), ATG, aspirin, paracetamol, brufen, naproxen and piroxicam.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treating and/or preventing arthritis (such as rheumatoid arthritis), special activating agent include but is not limited to antalgesic, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthesis DMARDS (such as, but not limited to methotrexate (MTX), carry out fluorine Meter Te, sulfasalazine, Anranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, imuran and cyclosporine) and biological products be such as, but not limited to infliximab, Etanercept, adalimumab, Rituximab and Abatace.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treating and/or preventing proliferative disorders, specific activating agent includes but is not limited to: methotrexate (MTX), folinic acid, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 FU 5 fluorouracil, taxol, docetaxel, vincristine, vincaleukoblastinum, vinorelbine, Doxorubicin, tamoxifen, Toremifene, megestrol acetate, Anastrozole, Goserelin, anti- HER2 monoclonal antibody (such as Herceptin (TM)), capecitabine, RALOXIFENE HCL, EGFR inhibitor (such as Tarceva^TM、Erbitux^TM), VEGF inhibitor (such as Avastin^TM), proteasome inhibitor (such as Velcade^TM) or hsp90 inhibitor (such as 17-AAG).In addition, the compounds of this invention can be applied with other therapeutic combinations, other treatments include but is not limited to radiotherapy or operation.In special embodiment, proliferative disorder is selected from cancer, bone marrow proliferative diseases or leukaemia.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treatment and/or preventing autoimmune disease, special activating agent includes but is not limited to: glucocorticoid, inhibition of cell proliferation (such as purine analogue), alkylating agent (such as mustargen (cyclophosphamide), nitroso ureas, platinum compounds etc., antimetabolite (such as methotrexate (MTX), imuran and mercaptopurine), cytotoxic antibiotic (such as dactinomycin D anthracene nucleus, mitomycin C, bleomycin and plicamycin), antibody (such as anti-CD 20, anti- CD25 or anti-CD3 (OTK3) monoclonal antibody, cyclosporine, tacrolimus, rapamycin, interferon, TNF binding protein, Etanercept or adalimumab, Mycophenolate Mofetil, fingomode and myriocin.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treating and/or preventing graft rejection, special activating agent includes but is not limited to: the plain inhibitor of calcium nerve (such as cyclosporine or tacrolimus, mTOR inhibitors (such as sirolimus, everolimus), antiproliferative agents (such as imuran, Mycophenolic Acid), corticosteroid (such as prednisolone, hydrocortisone), antibody (such as the anti-IL-2R α receptor antibody of monoclonal, basiliximab, daclizumab), Anti-TNF-α-T- cell antibody (such as antithymocyte globulin (ATG), antilymphocyte globulin (ALG).

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treatment and/or prevention of asthma and/or rhinitis and/or COPD, and special activating agent includes but is not limited to: β₂Adrenoceptor agonists (such as salbutamol, Levalbuterol, Terbutaline and bitolterol), adrenaline (such as sucking or tablet), anticholinergic drug (such as Ipratropium Bromide), glucocorticoid (such as oral or sucking), long-acting beta₂Agonist (such as salmeterol, Formoterol, bambuterol and release oral salbutamol), combination (such as fluticasone/salmeterol of the steroids of sucking and long-acting bronchodilator, Budesonide/formoterol), leukotriene antagonist and synthetic inhibitor (such as montelukast, zafirlukast and Zileuton), mediator release inhibitor (such as cromoglycate and Ketotifen), the biological regulator (such as omalizumab) of IgE response, antihistamine (such as cetirizine, cinnarizine, fexofenadine and vasoconstrictor (such as oxymetazoline, Xylometazoline, naphazoline and Tramazoline).

In addition, the compounds of this invention can be administered in combination with emergency treatment and be used for asthma and/or COPD, such treatment includes the (example of oxygen or helium-oxygen gas mixture application, spraying salbutamol or Terbutaline (optionally combine with anticholinergic drug), the steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone or hydrocortisone) of synthesis, intravenous salbutamol, non-specificity beta-2-agonists, injection or sucking Such as adrenaline, Isoetharine, isoprel, orciprenaline), anticholinergic drug (such as glycopyrronium bromide, atropine, ipratropium), methyl xanthine (theophylline, aminophylline, bamiphylline), inhalation anesthetic (isoflurane, fluothane, enflurane), ketamine and intravenous magnesium sulfate.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treatment and/or prophylaxis of inflammatory bowel disease (IBD), and special activating agent includes but is not limited to: glucocorticoid (such as prednisone, budesonide), the immunomodulator (such as methotrexate (MTX), leflunomide, sulfasalazine, Mesalazine, imuran, Ismipur and cyclosporine) of the alleviation disease synthesized and biological products alleviate the immunomodulator (such as infliximab, adalimumab, Rituximab and Abatace) of disease.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treatment and/or prevention system lupus erythematosus, and special activating agent includes but is not limited to: alleviating antirheumatic drug such as Anti-Malarial (such as hydroxychloroquine, hydroxychloroquine), immunosuppressor (such as methotrexate (MTX) and imuran), cyclophosphamide and the Mycophenolic Acid of disease；Immunosuppressive drug and antalgesic, such as non-steroidal anti-inflammatory drugs, anesthetic (such as dextropropoxyphene and compound codeine paracetamol), opium (such as hydrocodone, Oxycodone, Morphine or methadone) and Duragesic.

In one embodiment, the compounds of this invention and other therapeutic agents are co-administered for treating and/or preventing psoriasis, special activating agent includes but is not limited to: local treatment such as body wash solution agent, wetting agent, the cream of drug containing and ointment containing coal tar, Dithranol, corticosteroid such as Desoximetasone, Fluocinonide, novel vitamin D analogues (such as Calcipotriol), Arganoiland retinoid (etretinate, Acitretin, tazarotene), constitutional treatment such as methotrexate (MTX), cyclosporine, retinoid, thioguanine, hydroxycarbamide, sulfasalazine, mycophenolate mofetil, imuran, tacrolimus, fumarate or biological products such as Ah method's Saite, Etanercept, adalimumab, infliximab, auspicious body skin and excellent spy gram monoclonal antibody (IL-12 and IL- 23 blocking agents).In addition, the compounds of this invention can be administered in combination with other therapies, the therapy includes but is not limited to light therapy or photochemotherapy.

Co-administration includes the part that any modes of two or more therapeutic agents is delivered to patient as identical treatment scheme, this is obvious for technicians.Although two or more activating agents can be administered simultaneously with single preparation, this is not required.Activating agent can be applied with different preparations and in different times.

Synthetic method

General rule

The compounds of this invention is prepared by easily available starting materials using following universal method and operation.It should be understood that when providing typical or preferred process conditions (i.e. reaction temperature, time, the molar ratio of reactant, solvent, pressure etc.) unless otherwise stated, other process conditions can also be applied.Optimum reaction condition may be different and different due to specific reactant used or solvent, but these conditions are that those skilled in the art are confirmable by routine optimisation procedures.

In addition, it is obvious to the skilled person that GPF (General Protection False base may be needed to prevent certain functional groups from carrying out undesirable reaction.The protecting group of the suitable specific functional group of selection and the suitable condition of protection and deprotection are well-known in the art.For example, T.W.Greene and P.G.M.Wuts, Protecting Groups in Organic Synthesis (protecting group in organic synthesis); the second edition; Wiley, New York, 1991 and text in describe many protecting groups and its introducing and removing in the document that is drawn.

The compound for preparing the compounds of this invention listed above and comparative example is described in detail in following methods.The compounds of this invention and the compound of comparative example can be prepared by the technical staff of organic synthesis field with known or commercially available raw materials and reagents.

Unless otherwise stated, all reagents are commerical grades and use after receiving without being further purified.Commercial anhydrous solvent is used for the reaction carried out under inert atmosphere.Unless otherwise stated, the solvent of SILVER REAGENT is used for all other situation.

Under be classified as breviary vocabulary used in test portion:

DCM methylene chloride

DiPEA N, N- diisopropyl ethyl amine

MeCN acetonitrile

BOC tert-butoxycarbonyl

DMF n,N-Dimethylformamide

TFA trifluoroacetic acid

THF tetrahydrofuran

NMR nuclear magnetic resonance

DMSO dimethyl sulfoxide

DPPA diphenyl phosphoryl azide

LC-MS liquid chromatography-mass spectrography

Ppm a few millionths

EtOA_cEthyl acetate

PdCl₂Dppf [1,1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II)

TEA triethylamine

The preparation method of formula (I) structural compounds of the present invention is more described more particularly below below, but these specific methods do not form any restrictions to the present invention.Various synthetic methods describing in the present specification or known in the art can also optionally be combined and are easily made by the compounds of this invention, and such combination can readily be carried out by those skilled in the art in the invention.

The compound of the present invention has series of advantages compared with non-deuterated compound well known in the prior art.Main advantages of the present invention include: that (1) the compounds of this invention has excellent inhibition to jak kinase；(2) metabolism of the compound in organism is changed by this technology of deuterate, makes compound that there is better pharmacokinetic parameter characteristic, in such a case, it is possible to change dosage and form durative action preparation, improve applicability；(3) drug concentration of compound in animal body can be improved, to improve curative effect of medication due to its deuterium isotope effect with the hydrogen atom in deuterium substituted compound；The safety of compound may be improved since certain metabolites are suppressed with the hydrogen atom in deuterium substituted compound.

Present invention will be further explained below with reference to specific examples.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages are parts by weight and weight percent.

Embodiment 1N- (5- (4- ((1,1- dioxo-thio thiomorpholine -2,2,6,6-d4) methyl) phenyl)-[1,2,4] three Azoles simultaneously [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 13)

Step 1:1- (6- bromopyridine -2- base) -3- ethoxycarbonyl-thiocarbamide (compound 3) synthesis.

At 5 DEG C, by ethoxycarbonyl isothiocyanate (6.80mL, 2- amido -6- bromopyridine (10.0g 57.8mmol) is slowly dropped in 15 minutes, in methylene chloride (100mL) solution 57.8mmol), after being added dropwise, reaction solution is being warming up to room temperature, is stirred to react overnight.Solvent is removed under reduced pressure, solid filtering, with petroleum ether, vacuum drying obtains 16.9g yellow solid, yield: 96.1%.

The synthesis of bromo- [1,2,4] triazol [1,5-a] pyridine -2- amido (compound 4) of step 2:5-.

DIPEA (27.0mL, 165.6mmol) is added drop-wise in the solution of ethyl alcohol/methanol (v:v=1:1,170mL) of hydroxylamine hydrochloride (19.2g, 276.0mmol) at room temperature, is reacted after room temperature is to be stirred to react 1h.It is slowly added to 1- (6- bromopyridine -2- base) -3- ethoxycarbonyl-thiocarbamide (16.8g, 55.2mmol) in batches, reacts back flow reaction 3 hours.Reaction solution is cooled to room temperature, solid filtering.Filtrate decompression concentration, is added the water of 30mL.Obtain sediment filtering.Solid merges, and uses water (30mL) respectively, and ethyl alcohol/methanol (v/v=1:1,60mL) washing, vacuum drying obtains 9.8g white solid, yield: 83.3%.¹H NMR(300MHz,DMSO-d₆): δ 7.40-7.30 (m, 2H), 7.21 (dd, J=6.5,2.2Hz, 1H), 6.29 (s, 2H).

The synthesis of step 3:N- (bromo- [1,2,4] triazol [1,5-a] pyridine -2- base of 5-) cyclopropyl carboxamide (compound 6).

At 5 DEG C, by triethylamine (5.80mL, 41.0mmol) and cyclopropyl formyl chloride (3.80mL, it 41mmol) is slowly dropped to 5- bromo- [1 respectively, 2,4] in the anhydrous acetonitrile solvent (75mL) of triazol [1,5-a] pyridine -2- amido (3.5g, 16.4mmol).Reaction solution is warming up to room temperature, is stirred to react to raw material fully reacting (12h).Solvent is removed under reduced pressure, the methanol solution (7N, 30mL) of ammonia is added in residue, and hydrolysis bisacylation product (6h) is stirred at room temperature.Solvent is removed under reduced pressure, ether (20mL) and acetone (20mL), solid filtering is added, with water (20mL), acetone (20mL), ether (20mL) washing, vacuum drying obtains 2.7g brown solid, yield: 58.7%.LC-MS (APCI): m/z=281.1 (M+H)⁺。

The synthesis of step 4:4- (4- bromobenzyl) 1,1- Dioxo-thiomorpholin (compound 9).

Triethylamine (2.18mL, 15.7mmol) is added drop-wise to 1 pair of bromobenzyl bromine (1.28g, 5.10mmol) and thiomorpholine 1, DMF (15mL) mixture of 1- dioxide. HCl (944mg, 5.50mmol) In, reaction solution reacts at room temperature to be stirred to react overnight.Ethyl acetate (50mL) diluting reaction is added, is washed respectively with water (30mL x 3) and saturated salt solution (30mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure to give 1.0g white solid, yield: 64.5%.It is directly used in and reacts in next step.¹H NMR(300MHz,MeOD-d₄):δ7.53–7.47(m,2H),7.34–7.27(m,2H),4.90(s,2H),3.16–3.06(m,4H),3.00–2.93(m,4H)。

The synthesis of step 5:4- (4- (penta ring -2- base of 4,4,5,5- tetramethyl-dioxy boron) benzyl) thiomorpholine 1,1- dioxide (compound 10).

DMSO (15mL) is added to 4- (4- bromobenzyl) 1 under nitrogen protection; 1- Dioxo-thiomorpholin (1.00g; 3.30mmol) and connection boric acid pinacol ester (1.00g; 3.90mmol), potassium acetate (970mg, 9.86mmol), Pd (dppf) Cl₂(170mg), under nitrogen protection, 100 DEG C are stirred to react overnight for reaction.It is cooled to room temperature, water (25mL) is added to dilute, extracted with ethyl acetate (30mL x 2), organic layer is washed with saturated salt solution (20mL), the white brown solid of anhydrous slufuric acid, yield: 47.4%.LC-MS (APCI): m/z=352.2 (M+H)⁺。

The synthesis of step 6:N- [5- [4- [(1,1- dioxo-thiomorpholinyl) methyl] phenyl]-[1,2,4] triazol [1,5-a] pyridine -2- base] cyclopropane carboxamide (compound 11).

In N₂Under protection; Isosorbide-5-Nitrae-dioxane (6mL) and water (1.5mL) are injected into N- (5- bromo- [1,2; 4] triazol [1; 5-a] pyridine -2- base) cyclopropyl carboxamide (140mg, 0.50mmol), 4- (4- (4,4; 5; penta ring -2- base of 5- tetramethyl-dioxy boron) benzyl) thiomorpholine 1,1- dioxide (210mg, 0.60mmol), Pd (dppf) Cl₂In the mixture of (15mg), potassium carbonate (207mg, 1.50mmol), reaction is reacted overnight at 100 DEG C.It is cooled to greenhouse, diatom filtering washs filter cake with methylene chloride, filtrate is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), 140mg brown solid is obtained, yield: 65.8%.LC-MS (APCI): m/z=426.5 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆): δ 11.05 (s, 1H), 7.99 (d, J=8.3Hz, 2H), 7.75-7.66 (m, 2H), 7.52 (d, J=8.2Hz, 2H), 7.29 (dd, J=6.1,2.4Hz, 1H), 3.77 (s, 2H), 3.21-3.08 (m, 4H), 2.99-2.85 (m, 4H), 2.14-1.88 (m, 1H), 0.81 (d, J=6.2Hz, 4H).

The synthesis of step 7:4- (4- (2- amido-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) thiomorpholine -1,1- dioxo -2,2,6,6-d4 (compound 12).

By sodium methoxide (30mg, 0.50mmol) it is added to N- [5- [4- [(1,1- dioxo -4- thio-morpholinyl) methyl] phenyl]-[1,2,4] triazol [1,5-a] pyridine -2- base] cyclopropyl carboxamide (35mg, 0.08mmol) deuterated methanol (CD₃OD-d₄, 5mL), back flow reaction is stayed overnight under nitrogen protection.Aggravate water (10mL) quenching reaction, (10mL x 4) is extracted with dichloromethane, organic phase is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=10:1), obtains buff white solid 28mg, yield: 96.8%.LC-MS (APCI): m/z=362.2 (M+H)⁺。

Step 8:N- (5- (4- ((1,1- dioxo-thio thiomorpholine -2,2,6,6-d₄) methyl) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl formyl (compound 13) synthesis.

At 5 DEG C, by triethylamine (32mg, 0.31mmol) and cyclopropyl formyl chloride (35mg, 0.31mmol) is slowly dropped to 4- (4- (2- amido-[1,2 respectively, 4] triazol [1,5-a] pyridine -5- base) phenyl) thiomorpholine -1,1- dioxo -2,2,6,6-d₄The anhydrous methylene chloride (5mL) of (28mg, 0.08mmol), it is complete (16h) to reactant reaction that reaction solution is warming up to room temperature.Reaction dissolvent is removed under reduced pressure, the methanol solution (7M, 5mL) of ammonia is added in residue, and hydrolysis bisacylation product (6h) is stirred at room temperature and obtains monoacylated object.Add water (20 ML) quenching reaction, (20mL x 3) is extracted with dichloromethane, organic phase is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out preparative thin layer chromatography separation (solvent: methylene chloride/methanol (v/v)=12:1/15:1), obtains buff white solid 22mg, yield: 64.2%.LC-MS (APCI): m/z=430.10 (M+H)⁺。¹H NMR(300MHz,DMSO-d₄): δ 11.06 (s, 1H), 8.00 (d, J=8.2Hz, 2H), 7.76-7.65 (m, 2H), 7.53 (d, J=8.2Hz, 2H), 7.30 (dd, J=6.2,2.3Hz, 1H), 3.77 (s, 2H), 2.92 (s, 4H), 2.04-1.96 (m, 1H), 0.82 (d, J=6.2Hz, 4H).

Embodiment 2N- (5- (4- ((1,1- dioxo -4- thio-morpholinyl) methyl-d) phenyl-[1,2,4] triazol [1,5-a] Pyridine -2- base) cyclopropyl carboxamide (compound 18)

The synthesis of step 1:N- (5- (4- Fonnylphenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 15).

N₂Under protection; by 1; 4- dioxane (12mL) and water (4mL) are injected into N- (5- bromo- [1; 2; 4] triazol [1; 5-a] pyridine -2- base) cyclopropyl carboxamide (560mg, 2.00mmol), (4- Fonnylphenyl) boric acid (360mg, 2.40mmol), Pd (dppf) Cl₂In the mixture of (70mg, 0.10mmol), potassium carbonate (850mg, 6.00mmol), reaction is reacted overnight (16h) at 90 DEG C.It is cooled to greenhouse, diatom filtering washs filter cake with methylene chloride, filtrate is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), 450mg buff white solid is obtained, yield: 73.5%.LC-MS (APCI): m/z=307.1 (M+H)⁺。

The synthesis of step 2:N- (5- (4- (methylol-d) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 16).

Under ice bath; by boron deuterate sodium (74mg; N- (5- (4- Fonnylphenyl)-[1 1.76mmol) is added portionwise; 2; 4] triazol [1; 5-a] pyridine -2- base) cyclopropyl carboxamide (450mg, 1.47mmol) anhydrous methanol (5mL) solution in, reaction be warming up to room temperature reaction 1.5h.Heavy water (10mL) quenching reaction is added, it is extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, remove solvent, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), obtains 400mg buff white solid, yield: 88.1%.LC-MS (APCI): m/z=310.2 (M+H)⁺；¹HNMR(300MHz,DMSO-d₆): δ 11.05 (s, 1H), 7.97 (d, J=8.2Hz, 2H), 7.76-7.63 (m, 2H), 7.50 (d, J=8.1Hz, 2H), 7.28 (dd, J=6.3,1.8Hz, 1H), 5.33 (d, J=5.7Hz, 1H), 4.58 (d, J=5.7Hz, 1H), 2.12-1.92 (m, 1H), 0.81 (d, J=6.1Hz, 4H).

Step 3:(4- (2- (cyclopropyl carboxamide)-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) methyl-d- methane sulfonic acid (compound 17) synthesis.

Under ice bath, by triethylamine (0.15mL, 1.00mmol) and MsCl (methylsufonyl chloride, 0.05mL, 0.58mmol) successively it is slowly dropped to N- (5- (4- (methylol-d) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (150mg, 0.49mmol) anhydrous methylene chloride (10mL) solution in, reaction solution be warming up to room temperature reaction 2h.Add water (25mL) quenching reaction, extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure to give 190mg grease, is directly used in and reacts in next step, yield: 100%.LC-MS (APCI): m/z=388.1 (M+H)⁺。

Step 4:N- (5- (4- ((1,1- dioxo -4- thio-morpholinyl) methyl-d) phenyl-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 18) synthesis.

Under ice bath, by triethylamine (0.25mL, 1.50mmol) and thiomorpholine 1,1- dioxide. HCl (125mg, 0.75mmol) is successively added to (4- (2- (cyclopropyl carboxamide)-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) and methyl-d- methane sulfonic acid (190mg, 0.49mmol) anhydrous tetrahydro furan (5mL) solution in, reaction solution be warming up at room temperature reaction overnight.Add water (25mL) quenching reaction, it is extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), obtain buff white solid, (solvent: methylene chloride/methanol (v/v)=12:1/15:1) is further purified with preparative thin layer chromatography again and obtains white solid 70mg, yield: 33.5%.LC-MS (APCI): m/z=427.0 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆): δ 11.06 (s, 1H), 7.99 (d, J=8.2Hz, 2H), 7.78-7.64 (m, 2H), 7.52 (d, J=8.2Hz, 2H), 7.29 (dd, J=6.1,2.4Hz, 1H), 3.74 (s, 1H), 3.19-3.08 (m, J=4.8Hz, 4H), 2.99-2.85 (m, J=2.5Hz, 4H), 2.06-1.90 (m, J=30.2Hz, 1H), 0.82 (d, J=6.2Hz, 4H).

Embodiment 3N- (5- (4- ((1,1- dioxo-thio thiomorpholine) methyl-d2) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 24)

The synthesis of step 1:4- carboxylate methyl ester phenyl boric acid (compound 20).

The concentrated sulfuric acid (0.5mL) is added drop-wise to the anhydrous methanol (50mL) of 4- Carboxybenzeneboronic acid (3.50g, 21.09mmol), back flow reaction is stayed overnight under nitrogen protection.Reaction solution is concentrated under reduced pressure, and the water of 50mL is added, (50x 3) is extracted with ethyl acetate, organic layer water (50mL) and the saline solution (50mL) of saturation wash, and anhydrous sodium sulfate is dry, are concentrated under reduced pressure, white solid 4.1g is obtained, yield: 100%.LC-MS (APCI): m/z=181.1 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆):δ7.89(s,4H),7.52(s,4H),3.83(s,3H)。

The synthesis of step 2:4- (2- (cyclopropyl carboxamide)-[1,2,4] triazol [1,5-a] pyridine -5- base) methyl benzoate (compound 21).

N₂Under protection; by 1; 4- dioxane (9mL) and water (3mL) are injected into N- (5- bromo- [1; 2; 4] triazol [1; 5-a] pyridine -2- base) cyclopropyl carboxamide (282mg, 1.00mmol), (4- carboxylate methyl ester phenyl boric acid (220mg, 1.20mmol), Pd (dppf) Cl₂In the mixture of (40mg, 0.05mmol), potassium carbonate (420mg, 3.00mmol), reaction is reacted overnight (16h) under nitrogen protection at 90 DEG C.It is cooled to greenhouse, diatom filtering washs filter cake with methylene chloride, filtrate is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), 230mg buff white solid is obtained, yield: 68.4%.LC-MS (APCI): m/z=337.2 (M+H)⁺。

Step 3:N- (5- (4- (methylol-d₂) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 22) synthesis.

Under ice bath, by four deuterium aluminium lithium (27mg, 4- (2- (cyclopropyl carboxamide)-[1 0.63mmol) is added portionwise, 2,4] triazol [1,5-a] pyridine -5- base) methyl benzoate (200mg, 0.60mmol) anhydrous tetrahydro furan (10mL) solution in, reaction be warming up to room temperature reaction 1.5h.Heavy water (10mL) quenching reaction is added, it is extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, remove solvent, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=15:1), obtains 143mg white solid, yield: 77.2%.LC-MS (APCI): m/z=311.2 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆): δ 11.03 (s, 1H), 7.95 (d, J=8.2Hz, 2H), 7.69 (m, 2H), 7.48 (d, J=8.2Hz, 2H), 7.27 (dd, J=6.4,2.0Hz, 1H), 5.29 (s, 1H), 2.02 (m, 1H), 0.80 (d, J=6.2Hz, 4H)

Step 4:(4- (2- (cyclopropyl carboxamide)-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) methyl-d₂The synthesis of methane sulfonic acid (compound 23).

Under ice bath, triethylamine (0.12mL, 0.86mmol) and MsCl (methylsufonyl chloride, 0.04mL, 0.52mmol) are successively slowly dropped to N- (5- (4- (methylol-d₂) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (135mg, 0.43mmol) anhydrous methylene chloride (10mL) solution in, reaction solution be warming up to room temperature reaction 2h.Add water (25mL) quenching reaction, extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure to give 170mg grease, is directly used in and reacts in next step, yield: 100%.LC-MS (APCI): m/z=388.1 (M+H)⁺。

Step 5:N- (5- (4- ((1,1- dioxo-thio thiomorpholine) methyl-d₂) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 24) synthesis.

Under ice bath, by triethylamine (0.25mL, 1.74mmol) and thiomorpholine 1,1- dioxide. HCl (120mg, 0.70mmol) successively it is added to (4- (2- (cyclopropyl carboxamide)-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) methyl-d₂In anhydrous tetrahydro furan (5mL) solution of methane sulfonic acid (225mg, 0.58mmol), reaction solution is warming up to reaction at room temperature overnight, then is warming up to 85 DEG C of back flow reactions and stays overnight.Add water (25mL) quenching reaction, it is extracted with methylene chloride (30mL x 3), organic layer is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), obtains white solid, white solid 160mg is obtained, yield: 64.6%.LC-MS (APCI): m/z=427.0 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆): δ 11.05 (s, 1H), 7.99 (d, J=8.1Hz, 2H), 7.70 (m, 2H), 7.52 (d, J=8.0Hz, 2H), 7.29 (dd, J=6.0,2.1Hz, 1H), 3.15 (m, 4H), 2.94 (m, 4H), 1.99 (m, 1H), 0.80 (d, J=6.1Hz, 4H).

Embodiment 4N- (5- (4- ((1,1- dioxo-thio thiomorpholine -2,2,6,6-d4) methyl-d2) benzene Base)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 26)

Step 1:4- ((4- (2- amido-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) methyl-d₂) thiomorpholine 1,1- dioxide -2,2,6,6-d₄The synthesis of (compound 25).

Sodium methoxide (120mg, 2.10mmol) is added to N- (5- (4- ((1,1- dioxo-thio thiomorpholine) methyl-d₂) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (89mg, 0.21mmol) deuterated methanol (CD₃OD-d₄, 5mL), tube sealing reaction is stayed overnight under nitrogen protection.Aggravate water (10mL) quenching reaction, (10mL x 4) is extracted with dichloromethane, organic phase is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=10:1), obtains buff white solid 70mg, yield: 92.0%.ESI-MS m/z:364.2(M+H)⁺。

Step 2:N- (5- (4- ((1,1- dioxo-thio thiomorpholine -2,2,6,6-d₄) methyl-d₂) phenyl)-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 26) synthesis.

At 5 DEG C, by triethylamine (80mg, 0.76mmol) and cyclopropyl formyl chloride (80mg, 0.76mmol) successively it is slowly dropped to 4- ((4- (2- amido-[1,2,4] triazol [1,5-a] pyridine -5- base) phenyl) methyl-d₂) thiomorpholine 1,1- dioxide -2,2,6,6-d₄The anhydrous methylene chloride (5mL) of (70mg, 0.19mmol), it is complete (16h) to reactant reaction that reaction solution is warming up to room temperature.Reaction dissolvent is removed under reduced pressure, the methanol solution (7M, 5mL) of ammonia is added in residue, and hydrolysis bisacylation product (6h) is stirred at room temperature and obtains monoacylated object.Add water (20mL) quenching reaction, (20mL x 3) is extracted with dichloromethane, organic phase is washed with saturated salt solution (15mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out preparative thin layer chromatography separation, obtains buff white solid 50m_g, yield: 61.0%.LC-MS (APCI): m/z=432.1 (M+H)⁺；¹HNMR (300MHz, DMSO-d6): δ 11.05 (s, 1H), 7.99 (d, J=8.1Hz, 2H), 7.69 (m, 2H), 7.53 (d, J=8.0Hz, 2H), 7.29 (dd, J=6.0,2.3Hz, 1H), 2.95 (m, 4H), 2.00 (m, 1H), 0.80 (d, J=6.2Hz, 4H).

((4- ((1,1- dioxo-thio thiomorpholine) methyl) phenyl -2,6-d2)-[1,2,4] 5- embodiment 5N- Triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (compound 33)

Step 1:4- methylaniline -2,6-d₂The synthesis of (compound 28).

At room temperature, by dense deuterated hydrochloric acid (1.70mL, it 20.00mmol) is added drop-wise in heavy water (10mL) turbid solution of para-totuidine (2.14g, 20.00mmol) and is allowed to after being completely dissolved, be stirred to react 45min at 180 DEG C of reaction solution microwave.It is cooled to room temperature, is adjusted to neutral meta-alkali, methylene chloride (30mL x 3) extraction with the sodium bicarbonate solution of saturation, organic layer is washed with saturated salt solution (20mL), and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtain brownish black solid 1.80g, yield: 84.1%.LC-MS (APCI): m/z=110.1 (M+H)⁺；¹H NMR(300MHz,CDCl₃):δ7.01(s,2H),2.28(s,3H)。

Step 2:2,6-d₂The synthesis of -4- toluene bromide (compound 29).

HBr (40wt% aqueous solution, 22mL) is slowly dropped to 4- methylaniline -2,6-d₂In water (16mL) solution of (3.60g, 33.0mmol).After greenhouse stirs 15min, ice salt bath is cooled to -5 DEG C.Then the water (10mL) of sodium nitrite (2.67g, 38.6mmol) is slowly dropped into, reaction temperature is maintained at 0 DEG C once, stirs 30min.Reaction solution is slowly dropped in the suspension of HBr (40wt% aqueous solution, 30mL) of cuprous bromide (6.86g, 47.8mmol) again, is added dropwise, reaction reacts 2h at 50 DEG C.It is cooled to greenhouse, with petroleum ether extraction (100mL x 3), merge organic layer, with saturated sodium bicarbonate solution, water (100mL) washing, anhydrous sodium sulfate drying, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=1:0), obtains 840mg colourless liquid, yield: 12.0%.

Step 3:1- bromo- 4- (bromomethyl) benzene -2,6-d₂The synthesis of (compound 30).

Azodiisobutyronitrile (AIBN, 45mg, 0.24mmol) is added to 2,6-d at room temperature₂In carbon tetrachloride (15mL) solvent of -4- toluene bromide (840mg, 4.85mmol) and N- bromo-succinimide (NBS, 900mg, 5.09mmol), under nitrogen protection, back flow reaction is overnight for reaction.Reaction solution is concentrated under reduced pressure, the water of 20mL is added, with methylene chloride (20mLx 3), organic layer is washed with saturated sodium bicarbonate (30mL) and saturated salt solution (30mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and concentrate carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=2:1), pale tan oil 700mg is obtained, yield: 57.9%.LC-MS (APCI): m/z=251.0 (M+H)⁺。

Step 4:4- (4- bromobenzyl -3,5-d₂) 1,1- Dioxo-thiomorpholin (compound 31) synthesis.

Triethylamine (850mg, 8.34mmol) is added drop-wise to 1- bromo- 4- (bromomethyl) benzene -2,6-d₂(700mg, 2.78mmol) and thiomorpholine 1, in n,N-Dimethylformamide (DMF, 15mL) mixture of 1- dioxide. HCl (477mg, 2.78mmol), reaction solution reacts at room temperature to be stirred to react overnight.Ethyl acetate (50mL) diluting reaction is added, it is washed respectively with water (20mL x 3) and saturated salt solution (20mL), anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, concentrate carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=2:1), 270mg white solid is obtained, yield: 31.7%.ESI-MS m/z:306.1(M+H)⁺。

Step 5: compound 4- (3,5-d₂- 4- (penta ring -2- base of 4,4,5,5- tetramethyl-dioxy boron) benzyl) thiomorpholine 1,1- dioxide (compound 32) synthesis

DMSO (5mL) is added to 4- (4- bromobenzyl -3,5-d under nitrogen protection₂) 1,1- Dioxo-thiomorpholin (270mg, 0.88mmol) and connection boric acid pinacol ester (270mg, 1.06mmol), potassium acetate (260mg, 2.64mmol), Pd (dppf) Cl₂(36mg, 0.04mmol), under nitrogen protection, 100 DEG C are stirred to react overnight for reaction.It is cooled to room temperature, water (25mL) is added to dilute, it is extracted with ethyl acetate (30mL x 2), organic layer is washed with saturated salt solution (20mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and concentrate carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=2:1), 240mg white solid is obtained, yield: 77.0%.LC-MS (APCI): m/z=354.2 (M+H)⁺。

Step 6:N- (5- (4- ((1,1- dioxo-thiomorpholinyl) methyl] phenyl -2,6-d₂)-[1,2,4] triazol [1,5-a] pyridine -2- base] cyclopropane carboxamide (compound 33) synthesis.

In N₂Under protection, Isosorbide-5-Nitrae-dioxane (6mL) and water (1.5mL) are injected into N- (5- bromo- [1; 2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide (80mg; 0.30mmol), (3,5-d 4-₂- 4- (4,4,5,5- tetramethyls-dioxy boron, penta ring -2- base) benzyl) thiomorpholine 1,1- dioxide (115mg, 0.33mmol), Pd (dppf) Cl₂In the mixture of (15mg, 0.02mmol), potassium carbonate (130mg, 0.90mmol), reaction is reacted overnight at 90 DEG C.It is cooled to greenhouse, diatom filtering washs filter cake with methylene chloride, filtrate is dry with anhydrous sodium sulfate, removes solvent, and concentrate carries out post separation (eluent: methylene chloride/methanol (v/v)=25:1), 50mg buff white solid is obtained, yield: 68.4%.LC-MS (APCI): m/z=428.2 (M+H)⁺；¹H NMR(300MHz,DMSO-d₆): δ 11.04 (s, 1H), 7.69 (m, 2H), 7.51 (s, 2H), 7.29 (m, 1H), 3.76 (s, 2H), 3.14 (m, 4H), 2.92 (m, 4H), 2.00 (m, 1H), 0.80 (d, J=6.0Hz, 4H).

Embodiment 6JAK kinase inhibitory activity

Institute's reagent and consumptive material:

Recombined human JAK1 catalytic domain (Carna, Cat.No 08-144), recombined human JAK2 catalytic domain (Carna, Cat.No 08-045), recombined human JAK3 catalytic domain (Carna, Cat.No 08-046) ATP (Sigma, Cat.No.A7699-1G), DMSO (Sigma, Cat.No.D2650), 96 orifice plate (Corning, Cat.No.3365), 384 orifice plates (Greiner, Cat.No.784076), HTRF Kinase TK kit (Cisbio, Cat.No.62TK0PEB).Experimental method:

Compound is prepared: test-compound is dissolved in DMSO and is made into 20mM mother liquor.Using preceding compound is diluted to 0.1mM (dilution of 100 times of final concentrations) in DMSO, and does 3 times of gradient dilutions, 11 concentration.The dilution of 4 times of final concentrations is diluted to when dosing with buffer.

Kinase assay: after preparing buffer, enzyme is mixed with the various concentration compound that beforehand dilution is prepared, is placed at room temperature for 30 minutes, each concentration duplicate hole.Corresponding substrate and ATP is added, reacts at room temperature 60 minutes (being provided with yin and yang attribute control).Antibody test is added in end of reaction, and Evnvision is detected after sixty minutes for incubation at room temperature, acquires data.Data analysis and quasi- figure are carried out according to XLfit5 software.Wherein, A indicates IC₅₀≤0.04μM；B indicates 0.04 μM < IC₅₀≤0.1μM；C indicates 0.1 μM < IC₅₀≤1μM；D indicates IC₅₀>1μM；

Kinase inhibitory activity IC in embodiment₅₀(μM) is summarized in as in the following table 1

The kinase inhibitory activity of 1 embodiment compound of table

Embodiment number	JAK1IC50(μM)	JAK2IC50(μM)	JAK3IC50(μM)
Filgotinib	B	C	D
Embodiment 1	B	C	D
Embodiment 2	B	C	D
Embodiment 3	B	C	D
Embodiment 4	A	B	D
Embodiment 5	A	B	D

As shown in table 1, the compounds of this invention has the inhibiting effect of excellent selectivity to JAK enzyme, to the inhibiting effect of JAK1 (embodiment 1,2,3 is suitable with Filgotinib activity, embodiment 4 and 5 it is active even Better than Filgotinib) better than the inhibiting effect to JAK2, better than to the inhibiting effect of JAK3.Therefore, the compound of the present invention can be used for treating the relevant illness of abnormal J AK activity while its toxic side effect is effectively reduced.

The evaluation of 7 metabolic stability of embodiment

Microsomal assay: people's hepatomicrosome: 0.5mg/mL, Xenotech；Rat liver microsomes: 0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH): 1mM, Sigma Life Science；Magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).

The preparation of stock solution: precision weighs a certain amount of embodiment compound, and is dissolved to 5mM respectively with DMSO.

Phosphate buffer (100mM, pH7.4 preparation): the 0.5M dipotassium hydrogen phosphate solution of the 0.5M potassium dihydrogen phosphate 150mL and 700mL that prepare in advance is taken to mix, mixed liquor pH value is adjusted to 7.4 with 0.5M dipotassium hydrogen phosphate solution again, 5 times are diluted with ultrapure water using preceding, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM magnesium chloride, pH 7.4.

Prepare NADPH regenerative system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride), using it is preposition in it is wet on ice.

Prepare terminate liquid: the acetonitrile solution containing 50ng/mL Propranolol Hydrochloride and 200ng/mL orinase (internal standard).It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L people's hepatomicrosomes, mix, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L SD rat liver microsomes, mix, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.

The incubation of sample: being diluted to 0.25mM for the stock solution of respective compound with the aqueous solution containing 70% acetonitrile respectively, spare as working solution.It takes people's hepatomicrosome of 398 μ L or rat liver microsomes dilution that 96 holes are added respectively to be incubated in plate (N=2), is separately added into the working solution of 2 μ L 0.25mM, mixes.

The measurement of metabolic stability: the terminate liquid of 300 μ L pre-cooling is added in every hole of 96 hole deep-well plates, is placed on ice, as termination plate.96 holes are incubated for plate and NADPH regenerative system is placed in 37 DEG C of water baths, 5min is incubated in 100 revs/min of concussions in advance.80 μ L Incubating Solutions addition termination plate is taken out from the every hole of plate is incubated for, mixes, 20 μ L NADPH regenerative system solution is supplemented, as 0min sample.Again to the NADPH regenerative system solution for being incubated for 80 μ L of the every hole addition of plate, starting reaction starts timing.The reaction density of respective compound is 1 μM, protein concentration 0.5mg/mL.When reacting 10,30,90min, 100 μ L reaction solutions are respectively taken, are added in termination plate, vortex 3min terminates reaction.Termination plate is centrifuged 10min under the conditions of 5000 × g, 4 DEG C.It takes 100 μ L supernatants to being previously added in 96 orifice plates of 100 μ L distilled water, mixes, sample analysis is carried out using LC-MS/MS.

Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, compound and internal standard peak area ratio are calculated.Slope is measured by the natural logrithm of the percentage of compound surplus and time mapping, and calculates t according to the following formula_1/2And CL_int, wherein V/M is equal to 1/ protein concentration.

Experimental result is as shown in table 2 below, and the compounds of this invention all shows splendid metabolic stability in people's hepatomicrosome and rat liver microsomes experiment.

The liver particle metabolic evaluation of 2 embodiment compound of table

Pharmacokinetic Evaluation in 8 rat of embodiment

8 male Sprague-Dawley rats, 7-8 week old, weight about 210g, it is divided into 2 groups, every group 4, single oral gives (a) control group of 5mg/kg dosage: N- (5- (4- ((1,1- dioxo -4- thio-morpholinyl) methyl) phenyl-[1,2,4] triazol [1,5-a] pyridine -2- base) cyclopropyl carboxamide；(b) test group: embodiment 1-5 compares its pharmacokinetic difference.

Rat is raised using standard feed, gives water.Test is fasted for first 16 hours.Drug is dissolved with PEG400 and dimethyl sulfoxide.Eye socket blood sampling, the time point of blood sampling are 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.

Rat sucks of short duration anesthesia after ether, and eye socket acquires 300 μ L sample of blood in test tube.There are 30 μ L1% heparin salting liquids in test tube.Before use, test tube is stayed overnight in 60 DEG C of drying.After being completed with the latter time point blood specimen collection, put to death after rat etherization.

It after blood specimen collection, leniently overturns test tube at least 5 times, is placed on ice after guaranteeing mixing sufficiently immediately.Blood sample is centrifuged 5 minutes in 4 DEG C of 5000rpm, and blood plasma is separated with red blood cell.100 μ L blood plasma are sucked out into clean plastic centrifuge tube with pipettor, show title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.With the concentration of the compounds of this invention in LC-MS/MS measurement blood plasma.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.

The experimental results showed that the compounds of this invention has better pharmacokinetics in animal body, thus has better pharmacodynamics and therapeutic effect relative to control compound.

It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, test method without specific conditions in embodiment, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages are parts by weight and weight percent.

The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, without departing from the inventive concept of the premise, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to protection scope of the present invention.

Claims (10)

1. Deuterated pyridine amides or its crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds shown in logical formula (I):

   In formula:

   Each R is independently selected from the group being made of " hydrogen (H), deuterium (D) "；

   And its physiologically acceptable salt, solvate, hydrate, prodrug, tautomer and stereoisomer, the mixture formed including these compounds with all proportions.
2. Compound as described in claim 1, which is characterized in that R¹、R²、R³、R⁴、R⁵It is each independently deuterium or hydrogen.
3. Compound as described in claim 1, which is characterized in that R⁶、R⁷、R⁸It is each independently deuterium or hydrogen.
4. Compound as described in claim 1, which is characterized in that R⁹、R¹⁰、R¹¹、R¹²It is each independently deuterium or hydrogen.
5. Compound as described in claim 1, which is characterized in that R¹³、R¹⁴It is each independently deuterium or hydrogen.
6. Compound as described in claim 1, which is characterized in that R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²²It is each independently deuterium or hydrogen.
7. Compound as described in claim 1, which is characterized in that selected from the deuterated pyridine amides compound or its pharmaceutically acceptable salt in the following group, but be not limited to following compound:
8. A kind of pharmaceutical composition comprising compound according to claim 1 or its pharmaceutically-acceptable salts and pharmaceutically acceptable carrier, it is characterized in that, contain deuterated pyridine amides compound or its pharmaceutically acceptable salt described in claim 1 as effective component, and contains conventional pharmaceutical carrier.
9. Pharmaceutical composition as claimed in claim 19, which is characterized in that the pharmaceutical composition can be used for treating, prevent or eliminate various JAK associated diseases.Pharmaceutical composition comprising these compounds is used to treat in different therapy fields such as cancer, prevents disease or obstacle or slow down the disease or obstacle process.
10. A method of disease being treated, including to needing the patient of this treatment to apply composition described in compound described in claim 1 or claim 19, the disease is related to JAK enzyme, such as rheumatoid arthritis.