CN104059054B - Three-level cyclic amine ALK kinase inhibitor for treating cancer - Google Patents

Three-level cyclic amine ALK kinase inhibitor for treating cancer Download PDF

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CN104059054B
CN104059054B CN201310087381.7A CN201310087381A CN104059054B CN 104059054 B CN104059054 B CN 104059054B CN 201310087381 A CN201310087381 A CN 201310087381A CN 104059054 B CN104059054 B CN 104059054B
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amino
chloro
phenyl
ethyoxyl
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CN104059054A (en
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何伟
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ZHEJIANG DAOMING PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The present invention provides certain new substituted cyclic amine compounds or salt.This kind of compound or salt are the inhibitor of anaplastic lymphoma kinase (ALK).The invention further relates to contain pharmaceutical preparation of these compounds as active constituent.The invention also includes use these compounds and their preparation to treat and inhibit including non-small cell lung cancer (NSCLC), neuroblastoma, with primary cutaneous type (ALCL), liver cancer and other methods that diseases caused is increased by ALK activity level.

Description

Three-level cyclic amine ALK kinase inhibitor for treating cancer
The technical field of invention
The present invention relates to a series of new substituted cyclic amine compounds and preparation method thereof, have contained the same as The pharmaceutical composition for imitating composition and its application in the diseases such as treatment tumour.
Background of invention
Anaplastic lymphoma kinase (ALK) is the member of Insulin Receptor Family.In the mankind, it is one kind by ALK base Because of a kind of kinases of coding.As a kind of receptor tyrosine kinase, it is by an extracellular domain, transmembrane region and junket ammonia intracellular Acid kinase domain composition.ALK plays an important role in the development of brain and central nervous system.However, function of the ALK in adult It can be unclear.
In human body, abnormal ALK signal transduction is related with the morbidity of kinds cancer.These abnormal ALK signal activity It is caused by resetting (including transposition, amplification amplification and mutation) and the overexpression of ALK kinases by ALK gene.ALK activity is abnormal most Early in discovery in primary cutaneous type (ALCL).In addition, ALK gene is rearranged in Inflammatory myofibroblastic tumor, mind Through being found in blastoma and non-small cell lung cancer.
ALK gene transposition will lead to activating without control property for the unrelated ALK kinases of coactivation ligand.The nothing of this ALK kinases The activation of control property and its caused downstream signal will lead to cell Proliferation, and survival and cell cycle are without control state.It has been demonstrated EML4-ALK transposition in non-small cell lung cancer results in the activation of ERK and STAT3 signal transduction pathway, so as to cause cell Proliferation.In the mouse model of EML4-ALK positive lung cancer, result of study show ALK inhibitor can cause by ERK-BIM and The cancer cell-apoptosis that the signal transduction of STATE3 blocks as inducement.
Primary cutaneous type (ALCL) is a kind of not previously known lympha tumour found for the first time in 1985. ALCL has been demonstrated mainly to be related to the transposition (NPM-ALK of ALK by two：60%-80%；TPM3-ALK：12-18%) draw Hair.It is demonstrated experimentally that the carcinogenic effect of NPM-ALK transposition is the activated channel by STAT3.On ALCL mouse model, It proves, the ALK inhibitor with biocompatibility has antitumous effect.
Neuroblastoma is second most common children malignant tumors.It has been found that in all neuroblastomas In, 8% patient has the activation point mutation of ALK kinases.Moreover, these activation point mutation ratio uniforms be distributed in it is different Clinical stage.However, the most common somatic mutation F1174L, is associated with the amplification of MYCN proto-oncogene.Both eggs The state of an illness that white functional group is combined into the cancer of the cause of disease can be more serious than the cancer individually caused by MYCN gene magnification, this be by Caused by the developing synergistic effect of neuroblastoma.F1174L activation point mutation has more most common than second in vivo Activating mutations, R1275Q, more effective activity of conversion, this also ALK positive tumor to unique ALK inhibitor in the market, gram In azoles base of a fruit Buddhist nun, the reason of generating congenital and acquired drug resistance.In the preclinical models of neuroblastoma, ALK inhibits Agent, including Crizotinib are proved to be effective.
Crizotinib (Xalkori, Pfizer) is the inhibition of anaplastic lymphoma kinase (ALK) and ROS1 kinases Agent.In 2011, in the U.S. and some other country, it was approved for the non-small cell lung cancer of the treatment ALK positive (NSCLC).Now, it is being carried out in primary cutaneous type, neuroblastoma and other advanced malignances The clinical laboratory evaluations of safety and validity in adult and children.Although Crizotinib is to the non-small thin of the ALK positive The outstanding curative effect of born of the same parents' lung cancer.It also has many side effects, including serious dizziness, faints, rapid heart beat or impact；Visual problems, Such as eye-blurred, the photosensitized reaction of eyes, or see scintillation light or " winged mosquito "；Pectoralgia, dry cough cough or have mucus, stridulates, exhale Rapid feeling is inhaled, is easy to dampen, uncommon bleeding (nose, oral cavity, vagina or rectum), the Accurate Points of purple or red, hair It burns, shiver with cold, Muscular stiffness, cold symptoms, oral cavity and throat ulcer, or nausea, upper abdomen pain, itch, loss of appetite urinate color It is deep, clay color of defecating, jaundice (skin or eyes jaundice) etc..Comparing light side effect further includes：Slight dizzy, tired sense Feel, nausea is vomitted, stomachache, loss of appetite, diarrhea, constipation, slight fash or itch；The symptom of flu is such as had a stuffy nose, sneezing, Sore-throat, numb or hand or swollen feet etc..
In these side effects, Crizotinib especially allows people to worry the side effect of eyes and vision, because it is in eye High concentration and ALK the kinases high expression in nervous system in eyeball.
The examination report of Food and Drug Administration points out, " in the clinical test of Crizotinib, 159 patients (62%) there is vision disorder, including dysopia, eye-blurred, photopsia, vitreum floating material, photophobia, diplopia ". Examination report also indicates that " in human clinical trial, high concentration and long half-lift of the Crizotinib in patient's eye may Be cause it to the toxicity of eyes and reason visually impaired ".Concentration of the Crizotinib in eyes is very high, estimation elimination Half-life period (t1/2) be 576 hours, hence it is evident that be longer than its half-life period (42 hours) in blood.Its Cmax ratio is 8.9: 1 (eye: blood) and AUC ratio are 278: 1 (eyes: blood).So invention new A LK compound of low concentration in eyes is Very desirable.
Detailed description of the invention：
Fig. 1：Compound 18 is to tumor inhibition effect：Gross tumor volume and connect tumor number of days
Fig. 2：Compound 18 is at 4 hours and 8 hours in tumour, and blood, the distribution of brain and eye is left wherein respectively in comparison column Side is 4 hours, and right side is 8 hours
The content of invention
The method of the present invention for treating or inhibiting cancer includes, but is not limited to non-small cell lung cancer (NSCLC), Primary cutaneous type (ALCL), liver cancer (HCC) and neuroblastoma, including to the patient apply effective dose by Logical formula (I) or the compound or their pharmaceutically acceptable salt of (II) expression.
In formula, Ar is further defined as formula (III)：
In formula, A1, A2, A3, A4 and A5 are C or N.When for N, unsubstituted is connected thereon.
Ar is optimal to be selected from following formula：
M1 is a saturated or unsaturated C1-C8 carbochain, aromatic ring or heterocycle.The carbon of these carbochains, aromatic ring and heterocycle Or the hydrogen atom on nitrogen-atoms can be optionally by alkyl, naphthenic base, alkoxy, cycloalkyloxy, amino, CN, acylamino-, halogen is taken Generation.
Wherein, M1 can form the saturated or unsaturated aromatic ring of 3-8 or heterocycle with Q or R6.
M2 and M3 is further defined as formula (IV) or (V)：
Preferably, M2 and M3 is ethylene chain.
Wherein, Q is CO and SO2.
Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and Y can independently indicate hydrogen, Deuterium, amino, halogen, hydroxyl, carboxyl, nitro, cyano, (C2-C6) alkenyl, (C2-C6) alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C10) naphthenic base, alkyl therein, alkoxy or naphthenic base can be optionally by under Replaced column group：Hydrogen, deuterium, halogen, amino, hydroxyl, carboxyl, nitro, cyano, (C1-C6) alkyl, (C1-C6) alkoxy.
Wherein the substituent group on these naphthenic base or heterocycle can optionally from：Hydrogen, deuterium, halogen, amino, hydroxyl, carboxyl, nitre Base, cyano, (C2-C6) alkenyl, (C2-C6) alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (substituted C1-C6) Alkoxy, (C3-C10) naphthenic base, wherein alkyl, alkoxy or naphthenic base can be optionally by hydrogen, deuterium, halogen, amino, hydroxyl, nitre Base, cyano, (C1-C6) alkyl, replaced (C1-C6) alkoxy.
Wherein, R6 can also be aromatic ring or heterocycle.
Wherein, R6 can also form the saturated or unsaturated aromatic ring of 3-8 and heterocycle with Q or M1.
The carbon of these aromatic rings or heterocycle or hydrogen atom on nitrogen-atoms can be optionally by alkyl, naphthenic base, alkoxy, cycloalkanes oxygen Base, amino, CN, acylamino-, replaced halogen.
Wherein, the preferred methyl of R8.
Preferentially, R7 is hydrogen atom, and M2, M2, N and CH are formed together piperidine ring and constitute (VI) or (VII)：
Wherein：For pyrazolyl.
Wherein：Preferably
Wherein：More preferablyTo constitute (VIII) or (IX)：
Most preferably, the Q in (VIII) and (XI) formula is carbonyl, and M1 forms (X) and (XI) for methylene or blank：
Wherein：Ar, R6, R8 and Y defined as defined above
Wherein：R6 be preferably methylamino orBase
Wherein：R8 is preferably methyl
Wherein：Y is preferably amino
In the present invention, " alkyl ", " alkenyl " and " alkynyl ", unless otherwise indicated, be one to six carbon atom straight chain or The alkenyl and alkynyl of the alkyl of branch or two to six carbon atom straight chains or branch, for example, methyl, ethyl, propyl, butyl, Amyl or hexyl, vinyl, acrylic, cyclobutenyl, pentenyl or hexenyl and their isomers.
Term " hydroxyl " refers to the group with structural formula-OH.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine or iodine base.
Term " naphthenic base " refers to mono- or polycyclic carbocyclic ring, wherein containing 3 to 10 carbon atom numbers in each ring, and Any ring therein may include one or more double bonds or three key.Example includes group such as cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, cycloalkenyl and suberyl.Term " naphthenic base " additionally includes spiral ring system, has one on cycloalkyl ring therein Common carboatomic ring atom.
Term " Heterocyclylalkyl " is five yuan to hexa-atomic non-aromatic saturated heterocyclic, which can have selected from nitrogen original The identical or different hetero atom of one or more of son, oxygen atom and sulphur atom (it can be oxidized).Heterocyclylalkyl can portion
Be divided into it is unsaturated, or can be condensed with phenyl ring.But not including aza-bridged-ring hydro carbons.The heterocycle Alkyl may include (for example) aziridinyl, azelidinyl, pyrrolidinyl, piperidyl, homopiperidinyl, morpholinyl, thio Quinoline base, piperazinyl, tetrahydrofuran base, tetrahydro-thienyl, dihydro-oxazole base, THP trtrahydropyranyl, tetrahydro thiapyran base, indoline Base, tetrahydric quinoline group, Tetrahydroisoquinoli- beautiful jade base and benzoxazinyl, preferably dihydro-oxazole Ji, oxadiazolyl, Oxadiazolanyl and furyl.
The non-aromatic cyclammonium that term " ring type amidogen " is 3 yuan to 8 yuan in the group defined by " Heterocyclylalkyl ", has At least one nitrogen-atoms, and can have one or more phases in nitrogen-atoms, oxygen atom and sulphur atom (it can be oxidized) Same or different hetero atom, wherein at least one nitrogen-atoms bonding.But aza-bridged-ring hydro carbons is not included." ring type amidogen " May include (for example) '-aziridino, nitrogen fourth piperidinyl, pyrrolidinyl, piperidyl, homopiperidinyl, morpholino, thiomorpholine generation and Piperazinyl.
Term " aryl " is aryl radical, and it may include phenyl, naphthalene and indenyl, and preferably carbon atom number is 6- 10 aryl, more preferably phenyl.
Term " heteroaryl " be monovalence five yuan or six-membered aromatic heterocycle, have selected from nitrogen-atoms, oxygen atom and The identical or different hetero atom of one or more of sulphur atom, and can be condensed with phenyl ring." heteroaryl " may include (for example) Pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, pyrrole radicals, batch oxazolyl, imidazole radicals, oxazolyl, thiazolyl, thienyl, furyl, Oxadiazolyl, thiadiazolyl group, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indyl, indazolyl, quinoxaline Base and quinazolyl, preferably pyridazinyl, batch piperidinyl, batch piperazine base, thiazolyl, pyrazolyl and Liu Dai oxazolyl.
Term " bridged ring base " expression " bridged cyclic hydrocarbon group " and " aza-bridged-ring alkyl "
Term " bridged cyclic hydrocarbon group " is saturated or unsaturated bicyclic or polycyclic bridging alkyl, these alkyl tool there are two or three A carbon atom number is the cycloalkyl ring of 3-10.The naphthenic base of non-bridging is not included.It is especially preferably bicyclic or polycyclic Carbon atom number is the bridging alkyl of 4-16.The bridged cyclic hydrocarbon group may include (for example) bicyclic [2.1.1] hexyl, bicyclic [2.2.1] Heptyl, bicyclic [2.2.2] octyl, bicyclic [4.3.1] decyl, bicyclic [3.3.1] nonyl, bornyl, borneol alkenyl, norborneol Bicyclic [3.1.1] heptyl of base, norbornene, 6,6- dimethyl, three cyclobutyl and adamantyl, preferably adamantyl or Bicyclic [2.2.1] heptyl.
Term " nitro " refers to the group with-NO2.
Term " amino " refers to the group with structure-NH2.Amino can have with one, two or three groups, such as alkane Base, alkenyl, alkynyl, aryl and analog.
Term " cyano " refers to the group with structural formula-CN.
Term " alkoxy " refers to the same oxygen atom connection of the group containing alkyl, such as the part-structure of methoxy group. Other parts of the oxygen atoms bond of the alkoxy of alkoxy portion to molecule.The example of such group includes methoxyl group, second Oxygroup, propoxyl group, iso- propoxyl group, butoxy and tert-butoxy.
Term " acyl group " indicate C (=O)-low alkyl group ,-C (=O)-naphthenic base ,-C (=O)-Heterocyclylalkyl ,-c (= O)-aryl ,-c (=o)-heteroaryl, carbamoyl, elementary alkyl amido methanoyl ,-c (=o)-c (=O)-NH- lower alkyl Base, cycloalkylcarbamoyl, heterocyclalkylamino formoxyl, aryl-amino-carbonyl and heteroarylcarbamoyl.Art The meaning of language " low alkyl group ", " naphthenic base ", " Heterocyclylalkyl ", " aryl " and " heteroaryl " is as described above.
Term " carboxyl " refers to carboxylic group ,-CO2H or its salt.
When used in combination, for example, " alkaryl " or " aralkyl, " each clause listed above have it is indicated above Meaning.
Term " pharmaceutically acceptable salt " refer to by acid or alkali in the form of existing for salt, untethered example be (a) Acid addition salts, inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.), the salt of organic acid, organic acids such as vinegar Acid, oxalic acid (oxalicacid), tartaric acid (tartaric acid), succinic acid (succinic acid), malic acid (malic Acid), ascorbic acid, benzoic acid (benzoic acid), tannic acid (tannic acid), flutter acid (pamoic acid), seaweed Acid (alginic acid) and poly- Vetsin (poly glutamicacid) etc.；(b) base addition salts (base addition Salts), it is formed with metal cation, such as zinc, calcium, sodium, potassium.
Synthetic method
The present invention is illustrated by embodiment and compound disclosed herein.It is selected from particular compound of the invention The following group is disclosed in embodiment compound and their pharmaceutically acceptable salt and their individual diastereomer Compound or salt.
Following reaction scheme elaborates the preparation path of the compounds of this invention.
Unless otherwise indicated, in following reaction scheme and discussion, Ar, M1, M2, M3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, Q, X1, X2, X3, X4and X5, which are as defined above, to be stated.
Reaction equation scheme 1
In the presence of base, such as triethylamine, and in solvent appropriate, such as methylene chloride, boc-protected starting material A1 Intermediate B 1 can be generated under the reaction of methanesulfonic acid chlorine.In alkali appropriate, in the presence of triethylamine, and appropriate molten Agent, in DMF, the methylsulfonyl group in intermediate B 1 can be replaced by a nucleopilic reagent C1 appropriate and be generated to provide Intermediate D1.In solvent appropriate, such as THF, intermediate D1 can be with pinacol diborane in catalyst appropriate (such as palladium acetate) The F1 for being reacted to obtain intermediate E intermediate E and aryl halide under effect is connected under suitable condition and catalyst Suzuki reaction is carried out, intermediate G1 is formed.In acid condition, the Boc group that can remove G1, obtains amine compounds H.Amine Compound H can be reacted with electrophilic reagent H1 or H2 respectively, obtain product (I) or (II).
Reaction equation scheme 2
In solvent appropriate such as (THF), in the presence of highly basic (such as LHMDS), boc-protected cyclic ketones A2 can be with examination Agent PhNTf2 reaction generates intermediate B 2.In suitable solvent (such as DMF), in catalyst appropriate (such as palladium (triphenylphosphine) 4) under acting on, the TFO group of intermediate B 2 and heterocyclic boronic acids ester C2 can occur Suzuki cross-coupling reaction and obtain intermediate D2.? In solvent appropriate such as (THF), under catalyst appropriate (such as palladium carbon) effect, it is hydrogenated to obtain intermediate E 2.Appropriate Under the conditions of, intermediate E 2 and aryl halide can carry out cross-coupling reaction under catalyst (such as CuI) effect and form centre Body G2.In acid condition, the Boc group that can remove G2, obtains amine compounds H.Amine compounds H can respectively with electrophilic Reagent H1 or H2 reaction, obtain product (I) or (II).
Reaction equation scheme 3
Compound A-13 carries out nitration reaction and obtains intermediate B 3 in the presence of the concentrated sulfuric acid and concentrated nitric acid.Suitable molten In agent (such as DMF), under catalyst appropriate (such as palladium (triphenylphosphine) 4) effect, intermediate B 3 and intermediate E can occur Suzuki cross-coupling reaction obtains the Boc group on intermediate C3. intermediate C3, can remove and obtain in acid condition Cyclic amine intermediate D3.Intermediate D3 can generate intermediate E 3 with an electrophilic reagent YCl or YBr appropriate.In reagent Under triphenylphosphine and DEAD effect, intermediate E 3 and alcohol F3 can occur Mistunobu and react to obtain aryl oxide intermediate G3.Intermediate The nitryl group of F3 can obtain product H3 under appropriate reagent (such as Fe and ammonium chloride) effect.When the suitable group of Y group When, H3 is (I) or (II).
ALK inhibitor activity measurement method：
Addition ALK (2 nanomole) in polypropylene board, the peptide substrates of biotin labeling, the ATP (34uM) of Km concentration and examination Test compound (1 mM) kinase reaction buffer (mother's HEPES250 liquid (pH7.0), sodium azide in BSA0.05%, 0.1%, 0.5 millimeter of vanadic acid) it incubates 1 hour together.
After reaction, by containing EDTA, antibody conjugate and Strephavdin-XL665, the HTRF of cryptate europium Detection buffer (HEPES (pH value 7.0) of 50mM, additive, the aqueous solution of the 1xDTT Sigma #D0632 of 100mM concentration, Magnesium chloride (Sigma #M1028,1M), manganese chloride (Sigma #M1787,1M) stop.After being incubated for one hour, analyzed.
The plate is analyzed with the Envision of Perkin Elmer company by TR-FRET mode.A high proportion of 665/620 Indicate no kinase inhibition reaction, and the 665/620 of low ratio indicates complete kinase inhibition reaction.The enzymatic activity of enzyme by relative to The measured value of standard sample calculates, and is expressed as IC50.
The IC50 value for measuring the compound of the embodiment of the present invention by above method is as shown in the table：
The activity data table of compound of embodiment of the present invention inhibition ALK enzyme
The present invention provides by logical formula (I) to (XI) described compound and their enantiomer and diastereomer or its can Medicinal salt.
The present invention provides preparations by leading to formula (I) to (XI) described compound and their enantiomer and diastereomer Method.
The present invention provides a kind of methods for treating and inhibit cancer and other diseases.Verified, of the invention change It is inhibited to ALK activity to close object, the present invention provides by logical formula (I) to (XI) described compound for treating and/or Prevent the active constituent in the medicament of following disease, the disease is the disease caused by unfavorable cytokine signaling conduction Disease, these diseases include, but are not limited to non-small cell lung cancer (NSCLC), liver cancer, primary cutaneous type (ALCL), mind Through blastoma and other diseases for inhibiting ALK kinase activity to benefit patient.The method includes to the patient needed Effective dose such as the compound in claim 1-7.
Other inhibit ALK kinase activities include but is not limited to the disease that patient benefits：Brain tumor, bladder cancer, gastric cancer, ovum Nest cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, kidney, cancer of the esophagus, precedent gland cancer, first Shape gland cancer, osteocarcinoma, cutaneum carcinoma, colon cancer, female reproductive tract tumor, lymthoma, Huppert's disease and carcinoma of testis etc..
More specifically, the present invention provides one kind for treating and inhibit non-small cell UNG lung cancer (NSCLC) method.
More specifically, the present invention provides one kind for treating and inhibit liver cancer method.
More specifically, the present invention provides one kind for treating and inhibit asian patients liver cancer method.
More specifically, the present invention provides one kind for treating and inhibit primary cutaneous type (ALCL) method.
More specifically, the present invention provides one kind for treating and inhibit neuroblastoma method.
The pharmaceutical preparation of the compound of the present invention (ALK inhibitor) can be used alone according to the pharmacy practice of standard Or it is used with one or more other drug combinations, the pharmaceutical preparation of the ALK inhibitor and the other medicament Administration route can be identical or different, and administration time can be identical or different.The other medicament includes (but unlimited In) amide (CTX), ifosfamide (IFO), adriamycin (ADM), vincristine (VCR), vinblastine (VBL), etoposide (VP16), brave and fierce (Vumon), carboplatin (CBP) and methotrexate (MTX) (MTX) cyclosporin A, tacrolimus, sirolimus, Yi Weimo Department, imuran, cloth quinoline that, leflunomide, sphingosine-1-phosphate receptor agonist (such as fingomode, KRP-203 etc.), LEA-29Y, the antibody (such as daclizumab etc.) of anti-IL-2 receptor, anti-(3) 3 antibody (such as 0KT3 etc.), anti-T cell are immune Globulin (such as AtGam etc.), aspirin, (3) 28-B7 blocker molecule (such as Belatacept, Abatacept etc.), CD40_0) 154 blocker molecules (such as anti-CD 40 antibodies etc.), inhibitors of protein kinase C (such as AEB-071 etc.), paracetamol, Brufen, naproxen, piroxicam and anti-inflammatory steroid class (such as prednisolone or dexamethasone).
Carrier, excipient and other additives commonly used in pharmaceutical preparation can be used, to prepare containing one or two Or a variety of formulas (the I)-pharmaceutical composition of (XI) compound represented or its officinal salt as active constituent.
The dosage form of the oral administration of tablet, pill, capsule, granule, powder, liquid preparation etc. can be used, or use The para-oral dosage form of intravenous injection or intramuscular injection, suppository, transdermal agent, intranasal agent, inhalant etc. is given to carry out treatment Medicine.Symptom, age, gender of each patient to be treated etc. is considered as suitably to determine the dosage of compound.Usually come It says, in the case where oral administration, the compound dosage of adult patient daily is 0.001mg/kg to 100mg/kg or so, And the dosage is once taken or is divided intoIt is secondary to take.In the case where being needed according to symptom using intravenously administrable, usually come Say, adult patient according to each 0.0001mg/kg to 10mg/kg dosage range, once a day to multiple dosing.In addition, In the case where being administered using inhalant, usually, adult patient according to each 0.0001mg/kg to 1mg/kg dosage model It encloses, once a day to multiple dosing.
It in the present invention, can be using dosage forms such as tablet, powder, granules for the solid composite of oral administration.? In this solid composite, by one or more kinds of active material and at least one inert excipient (such as lactose, sweet dew Sugar alcohol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminium-magnesium silicate etc.) mixing.According to Conventional method can also contain inert additwe in composition, as (such as carboxymethyl forms sediment for lubricant (such as magnesium stearate), disintegrating agent Powder sodium) and dissolution aids.As needed, tablet or pill can also be wrapped by sugar-coat or gastric solubility or enteric coatings agent It covers.
Liquid composition for oral administration include pharmaceutical emulsion agent, pharmaceutical solutions, suspension, syrup or Elixir etc., and contain usually workable inert diluent (such as purified water, ethyl alcohol).It, should in addition to the inert diluent In composition can also containing such as auxiliary agent of solubilizer, wetting agent, suspending agent etc and sweetener, corrigent, aromatic, Preservative.
It include sterile aqueous or non-aqueous solution preparation, suspension, emulsion for para-oral injection.For The diluent of aqueous solution may for instance comprise distilled water for injection and physiological saline.Diluent for non-aqueous solution can It (for example) include propylene glycol, polyethylene glycol, vegetable oil (such as olive oil), alcohols (such as ethyl alcohol) and polysorbate80.It is such Such as isotonic agent, preservative, wetting agent, emulsifier, dispersing agent, stabilizer, dissolution aids etc can also be contained in composition Additive.The method that can be filtered using the filter by the way that bacterium can be retained, add fungicide or carry out light radiation To sterilize to the composition.In addition it is also possible to these compositions be made to sterile solid composite, before using again It makes it dissolve or is suspended and used with sterile water or sterile solvent for injection.
The transmucosal agent of such as inhalant and intranasal agent etc can be used with solid, liquid or semisolid state, And these transmucosal agent can be prepared according to known method.For example, can according to need and add excipient (such as Newborn sugar and starch), pH adjusting agent, the neat IJ of anti-corrosion, surfactant, the neat IJ of lubrication, stabilizer and thickener etc..It can be with when administration Device is used using suitably sucking or blowing.It is, for example, possible to use device or sprayer well known to metering drug administration device etc., Compound is administered either individually or as the mix powder after formula.In addition it is also possible to by compound and pharmaceutical load After body combination, it is administered as solution or suspension.Dry powder inhaler etc. can be used for single-dose or multiple dosing, and Dried powder or the capsule containing powder can be used.Alternatively, it is also possible to using the forms such as pressurised aerosol is spraying, by using Propellant (for example, the gas appropriate such as chlorofluoro-alkane, hydrofluoroalkane or carbon dioxide) appropriate is administered.
Embodiment 1
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] acetic acid
Step A：
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] methyl acetate
Operating procedure：
By compounds methyl 2- monoxone (11 milligrams, 0.12 mM, 1.2 equivalents), and potassium carbonate (0.5 mM, 5 A equivalent) and sodium iodide (2 milligrams) be added to compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperazine Piperidinyl) pyrazoles -4- base] pyridine -2- amine (45 milligrams, 0.1 mM, 1 equivalent) 2 milliliters of ethanol solution in, heat back It is quenched with water after flowing 2 hours, it is rear that water layer and methylene chloride is added, it is layered, water layer is extracted with dichloromethane three times again, organic phase After merging, drying is spin-dried for, and product directly applies to (40 milligrams, yield 77%) in next step
Step B：
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] pyrazoles -1- Base] -1- piperidyl] acetic acid
Operating procedure：
Sodium hydroxide (30 milligrams, 0.76 mM, 10 equivalents) and 0.5 milliliter of water are added to compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] pyrazol-1-yl] -1- piperidyl] acetic acid It in methyl esters in ethyl alcohol (1.5 milliliters) solution of (40 milligrams, 0.076 mM, 1 equivalent), is then stirred overnight at room temperature, reacts Liquid with HPLC purifies (mobile phase after being neutralized again with hydrochloric acid solution：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 36% to 66% (volume ratio)) obtain target compound (16 milligrams, yield, 42%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=508.0 [M+H]+Total runing time is 2.925 points Clock
1H NMR (400MHz, DMSO-d6) δ 8.63 (br.s., 1H), 8.21-7.97 (m, 2H), 7.89 (d, J=1.3Hz, 1H), 7.72 (s, 1H), 7.63 (dd, J=4.9,8.9Hz, 1H), 7.53-7.41 (m, 1H), 7.17 (s, 1H), 6.30 (q, J= 6.5Hz, 1H), 5.15 (d, J=6.0Hz, 1H), 4.49 (br.s., 1H), 4.18 (s, 2H), 3.78-3.59 (m, 1H), 3.16 (s, 1H), 3.06 (s, 1H), 2.42-2.18 (m, 4H), 1.95-1.79 (m, 3H)
Embodiment 2
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] acetamide
Operating procedure：
By 2- chloroacetamide (132 milligrams, 1.44 mMs, 1.2 equivalents), potassium carbonate (4.8 mMs, 4 equivalents) and Sodium iodide (12 milligrams) is added to compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- pyridyl group) pyrrole Azoles -4- base] piperidyl -2- amine (0.54 milligram, 1.2 mMs, 1 equivalent) 15 milliliters of ethanol solution in, be heated to reflux 2 It is quenched with water after hour, it is rear that water layer and methylene chloride is added, it is layered, water layer is extracted with dichloromethane three times again, and organic phase merges Afterwards, drying is spin-dried for, and crude product chromatograph purifies (instrument：SHIMADZU LC-8A, chromatographic column：Synergi-10 μm, 250 × 50mmI.D. mobile phase：A is that water (containing 1 ‰ TFA, v/v) and B is acetonitrile, concentration gradient：B30-80%. flow velocity：80mL/ points Clock) with HPLC refined solution with sodium bicarbonate adjust pH value be 7-8 after water layer be extracted with dichloromethane three times, organic layer merge after With saturated salt solution backwash, drying obtains target compound (320 milligrams, yield 53%) after being spin-dried for.
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.00 minutes；M/z=507.2 [M+H]+Total runing time is 2.56 points Clock1H NMR (400MHz, CDCl3) δ 1.80 (d, 3H), 2.10 (m, 4H), 2.40 (t, 2H), 3.00-3.10 (m, 4H), 4.10 (m, 1H), 4.75 (s, 2H), 5.60 (br, 1H), 6.05 (q, 1H), 6.85 (s, 1H), 7.19 (t, 2H), 7.25 (m, 1H), 7.48 (s, 1H), 7.55 (s, 1H), 7.70 (s, 1H)
Embodiment 3
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1
Piperidyl]-N- methyl acetamide
Operating procedure：
By compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] methyl acetate (0.8 gram, 1.53 mMs, 1.0 equivalents) is dissolved in the tetrahydrofuran solution of methylamine. Then solvent is spin-dried for after 80 degree of microwave 45 total runing times of reaction are.Purified to obtain target compound (instrument with HPLC： SHIMADZU LC-8A, chromatographic column：Synergi-10 μm, 250 × 50mmI.D. mobile phase：A for water (Add1 ‰ TFA, v/v) And B for CAN, concentration gradient：B30-80%. flow velocity：80mL/ minutes) HPLC refined solution sodium bicarbonate adjusting PH After value is 7-8, water layer is extracted with dichloromethane three times, and organic layer uses saturated salt solution backwash after merging, and drying is spin-dried for obtaining mesh It marks compound (582.4 milligrams).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=521.1 [M+H]+Total runing time is 3.006 points Clock
1H NMR (400MHz, DMSO-d6) δ 10.57 (br.s., 1H), 8.90 (d, J=4.5Hz, 1H), 8.42 (br.s., 1H), 8.17-7.97 (m, 3H), 7.91 (s, 1H), 7.71 (s, 1H), 7.62 (dd, J=5.0,9.0Hz, 1H), 7.49 (t, J=8.7Hz, 1H), 7.22-7.11 (m, 1H), 6.29 (q, J=6.7Hz, 1H), 5.01-4.18 (m, 6H), 3.98 (br.s., 2H), 3.61 (d, J=11.5Hz, 2H), 3.16 (s, 1H), 2.67 (d, J=4.5Hz, 3H), 2.43-2.15 (m, 4H), 2.08 (s, 1H), 1.86 (d, J=6.5Hz, 3H)
Embodiment 4
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N, N- dimethyl-acetamide
Operating procedure：
By compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] Pyrazoles
- 1- base] -1- piperidyl] acetic acid (20 milligrams, 0.04 mM, 1 equivalent), dimethylamine hydrochloride (3.5 milligrams, 0.044 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (22 millis Gram, 0.06 mM, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue slowly to add Enter N, N '-diisopropylethylamine (51 milligrams, 0.4 mM, 10 equivalents).Reaction continues stirring 3 hours at room temperature.Reaction knot Shu Hou dilutes reaction solution with methylene chloride, and organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then use sodium sulphate It is spin-dried for after drying, obtains crude product using efficient liquid phase (instrument：LC8A&Gilson215 fraction collector, chromatographic column：Ge minutes I200*25mm*5um, mobile phase A：BASE water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes, concentration gradient：38-68%B, 0- 12 minutes) isolated target compound (8 milligrams, yield 40%)
HPLC (method：UFLC)：RT=6.00 minutes；Total runing time is 2.84 minutes
Spectroscopic data：
1H NMR (400MHz, DMSO-d6) δ 8.00-7.91 (m, 1H), 7.75 (d, J=1.8Hz, 1H), 7.58 (dd, J= 4.9,8.9Hz, 1H), 7.53 (s, 1H), 7.48-7.39 (m, 1H), 6.90 (d, J=1.8Hz, 1H), 6.09 (q, J=6.6Hz, 1H), 5.65 (s, 2H), 4.17-3.98 (m, 1H), 3.18 (s, 2H), 3.04 (s, 3H), 2.96-2.85 (m, 2H), 2.82 (s, 3H), 2.32-2.17 (m, 2H), 2.02-1.86 (m, 4H), 1.80 (d, J=6.8Hz, 3H)
Embodiment 5
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -1- morpholinyl-ethyl ketone
Operating procedure：
By compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] Pyrazoles
- 1- base] -1- piperidyl] acetic acid (20 milligrams, 0.04 mM, 1 equivalent), morpholine (3.8 milligrams, 0.044 mmoles You, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (22 milligrams, 0.06 milli Mole, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-two Wopropyl ethyl amine (51 milligrams, 0.4 mM, 10 equivalents).Reaction continues stirring 3 hours at room temperature.It after reaction, will be anti- Liquid is answered to be diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry back spin with sodium sulphate It is dry, crude product, which is obtained, using efficient liquid phase separates (instrument：LC8A&Gilson215 fraction collector, chromatographic column：Ge minutes i200* 25mm*5um, mobile phase A：BASE water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：38-68%B, 0-12 points Clock) obtain target compound (10 milligrams, yield 40%)
Spectroscopic data：
HPLC (method：UFLC)：RT=7.00 minutes；Total runing time is 2.80 minutes
1H NMR (400MHz, DMSO-d6) δ 7.96 (s, 1H), 7.76 (d, J=1.8Hz, 1H), 7.62-7.50 (m, 2H), 7.48-7.40 (m, 1H), 6.90 (d, J=1.5Hz, 1H), 6.09 (q, J=6.7Hz, 1H), 5.65 (s, 2H), 4.16-4.04 (m, 1H), 3.67-3.51 (m, 6H), 3.49-3.42 (m, 3H), 3.20 (s, 2H), 2.91 (d, J=11.5Hz, 2H), 2.28- 2.12 (m, 2H), 2.05-1.84 (m, 4H), 1.81 (d, J=6.8Hz, 3H).
Embodiment 6
[4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- Piperidyl]-(5- methylisoxazole base -4- base) ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- pyridyl group) pyrazoles -4- base] piperazine Piperidinyl -2- amine (300 milligrams, 0.666 mM, 1 equivalent), and compound 5- methylisoxazole -4- carboxylic acid (0.093 gram, 0.733 MM, 1.2 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (0.38 gram, 0.999 mM, 1.5 equivalent) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (0.516 gram, 3.996 mMs, 4 equivalent).Reaction continues stirring 12 hours at room temperature.Reaction After reaction solution is spin-dried for, obtained 2 crude product of target compound be used for use HPLC purification (instrument：SHIMADZU LC- 8A, chromatographic column：Synergi-10 μm, 250 × 50mmI.D. mobile phase：A for water (Add1 ‰ TFA, v/v) and B for CAN, concentration gradient：B30-80%. flow velocity：80mL/ minutes) with HPLC refined solution with sodium bicarbonate adjust pH value be 7-8 after water Layer is extracted with dichloromethane three times, and organic layer uses saturated salt solution backwash after merging, and drying is spin-dried for obtaining target compound (130 Milligram, yield：37.6%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.00 minutes；M/z=559.1 [M+H]+Total runing time is 3.749 Minute
1H NMR (400MHz, METHANOL-d4) δ 8.52 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.63 (d, J= 1.5Hz, 1H), 7.53 (dd, J=5.0,9.0Hz, 1H), 7.32 (t, J=8.7Hz, 1H), 7.19 (d, J=1.5Hz, 1H), 6.38 (q, J=6.8Hz, 1H), 4.55 (tt, J=4.0,11.3Hz, 1H), 2.56 (s, 3H), 2.20 (d, J=11.5Hz, 2H), 2.10-2.00 (m, 2H), 1.97 (d, J=6.5Hz, 3H)
Embodiment 7
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] Piperidines -1- carbonyl] -3- oxo-butanenitrile
Operating procedure：
Sodium methoxide (12 milligrams, 0.214 mM, 1.5 equivalents) is dissolved in 2 ml methanols, being then slowly added drop-wise to Close object [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl]
- 1- piperidyl]-(5- methylisoxazole base -4- base) ketone (0.08 gram, 0.143 mM, 1.0 equivalents) 5 milli It rises in tetrahydrofuran solution.3 hours are stirred in reaction at normal temperature.Reaction solution is dissolved in water after being spin-dried for, with the hydrochloric acid of 1 mol/L It adjusts and purifies (instrument with HPLC after PH to 3-4：LC8A&Gilson215 fraction collector chromatographic column：Ge minutes i200* 25mm*5um, mobile phase A：HCl/water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：17-27%B, 0-12 minutes) After obtain target compound (54.7 milligrams, yield 68.3%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.00 minutes；M/z=559.1 [M+H]+Total runing time is 4.091 Minute1H NMR (400MHz, METHANOL-d4) δ 7.92-7.79 (m, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.47 (dd, J=4.6,8.9Hz, 1H), 7.24 (t, J=8.5Hz, 1H), 6.98 (s, 1H), 6.21 (q, J=6.5Hz, 1H), 4.60-4.40 (m, 3H), 3.17 (t, J=12.3Hz, 2H), 2.29 (s, 3H), 2.23-2.11 (m, 3H), 2.10-1.95 (m, 3H), 1.89 (d, J=6.8Hz, 3H).
Embodiment 8
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 4- piperidyl] acetonitrile
Step A：
4- (cyanomethylene) piperidines -1- t-butyl formate
Operating procedure：
To ice bath is cooling and nitrogen protection containing sodium hydride (0.264 gram, 0.011 mole, 1.1 equivalents, in mineral oil 60% content) (64 milliliters) dropwise addition compound 2- diethoxy phosphinylidyne acetonitriles of anhydrous tetrahydrofuran solution, (2.04 grams, 0.0115 mole, 1.15 equivalents) 45 total runing times are stirred under 20 degree is to be cooled back to 0 degree of dropwise addition again for this mixed liquor Close the tetrahydrofuran solution (15 milliliters) of object 4- oxo-piperidine -1- t-butyl formate (1.99 grams, 0.0115 mole, 1 equivalent).This Mixture is stirred at room temperature overnight.Saline solution (40 milliliters) are added under 0 degree and have with (50 milliliter * 3) extraction of ethyl acetate Machine layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtained target compound (2.27 grams, yield 100%)
Step B：
4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -4- Cyanogen methyl -- 4- piperidyl] -1- the tert-butyl ester
Operating procedure：
At room temperature to dissolved with compound 4- (cyanomethylene) piperidines -1- t-butyl formate (20 milligrams, 0.8 mM, 1 equivalent) acetonitrile (5 milliliters) in be added compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1H- pyrazoles -4- Base] pyridine -2- amine, (36 milligrams, 0.1 mM, 1 equivalent) and 1.8- diazabicylo [5.4.0] hendecane -7- alkene (30 millis Gram, 0.2 mole, 2.0 equivalents).This mixed liquor is stirred at room temperature 10 hours.Ethyl acetate is added after being spin-dried in reaction solution decompression (20 milliliters) and successively with dry with anhydrous sodium sulfate after saturated sodium bicarbonate and brine It.Organic phase decompression is spin-dried for system Standby chromatography sheet (petroleum ether: ethyl acetate=1: 1) purify target compound (30 milligrams, yield：51.7%)
Step C：
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl]
- 4- piperidyl] acetonitrile
Operating procedure：
To being cooled with an ice bath dissolved with compound 4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethoxy Base] -3- pyridyl group] pyrazol-1-yl] -4- cyanogen methyl -- 4- piperidyl] -1- the tert-butyl ester (30 milligrams, 0.05 mM, 1 equivalent) Methylene chloride (20 milliliters) solution in be added after hydrochloric acid dioxane (0.5 milliliter, 4 moles every liter) adds, this mixed liquor exists A hour is stirred at room temperature.The crude product that reaction solution is concentrated to get separates (flowing using high performance liquid chromatography on C18 reversed-phase column Phase：Acetonitrile/water/0.5%HCl, gradient elution 5% to 35% (volume ratio) are removed under reduced pressure to be lyophilized after volatile component and are obtained Hydrochloride (5.8 milligrams, yield 23.3%) of target compound
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.67 minutes；M/z=507.1 [M+H]+total runing time is 7.0 points Clock
1H NMR (400MHz, methanol-d4, ppm) and δ 8.35 (s, 1H) 7.79 (s, 1H) 7.72 (s, 1H) 7.51 (dd, J =9.03,4.77Hz, 1H) 7.25-7.33 (m, 1H) 7.18-7.24 (m, 1H) 6.38 (q, J=6.53Hz, 1H) 3.45 (d, J= 14.31Hz, 2H) 3.12 (s, 2H) 2.97 (d, J=10.04Hz, 5H) 2.29-2.41 (m, 2H) 1.96 (d, J=6.53Hz, 3H)。
Embodiment 9
2- [3- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] Azetidine -3- base] acetonitrile
Step A：
3- (cyanomethylene) azetidine -1- t-butyl formate
Operating procedure：
To ice bath is cooling and nitrogen protection containing sodium hydride (0.514 gram, 0.0128 mole, 1.1 equivalents, in mineral oil 60% content) (64 milliliters) dropwise addition compound 2- diethoxy phosphinylidyne acetonitriles of anhydrous tetrahydro furan (2.38 grams, 0.0134 rubs You, 1.15 equivalents) this mixed liquor stirs under 20 degree and is cooled back within 45 minutes zero degree compound 3- oxo aza ring is added dropwise again The tetrahydrofuran solution (15 milliliters) of butane -1- t-butyl formate (2 grams, 0.0117 mole, 1 equivalent).This mixture is in room temperature Under be stirred overnight.Saline solution (40 milliliters) are added under zero degree and with (50 milliliter * 3) extraction organic layer carbonic acid of ethyl acetate Hydrogen sodium solution and each backwash of saline solution are primary, then with sodium sulphate it is dry after be spin-dried for, obtained target compound (2.27 grams, yield 100%).
Step B：
2- [3- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 3- cyanogen methyl azetidine -3- base] -1- the tert-butyl ester
Operating procedure：
At room temperature to dissolved with compound 3- (cyanomethylene) azetidine -1- t-butyl formate (11 milligrams, 0.06 MM, 1 equivalent) acetonitrile (5 milliliters) solution in be added compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- (1H- pyrazoles -4- base) pyridine -2- amine (22 milligrams, 0.06 mM, 1 equivalent) and 1.8- diazabicylo [5.4.0] 11 Alkane -7- alkene (18 milligrams, 0.12 mole, 2.0 equivalents).This mixed liquor is stirred at room temperature 10 hours.After reaction solution decompression is spin-dried for Ethyl acetate (20 milliliters) are added and successively with dry with anhydrous sodium sulfate after saturated sodium bicarbonate and brine It.Organic phase Decompression is spin-dried for, with preparative chromatography thin plate (petroleum ether: ethyl acetate=1: 1) purify target compound (28 milligrams, yield： 84.8%)
Step C：
2- [3- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] Azetidine -3- base] acetonitrile
Operating procedure：
To being cooled with an ice bath dissolved with compound 2- [3- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethoxy Base] -3- pyridyl group] pyrazol-1-yl] -3- cyanogen methyl azetidine -3- base] -1- the tert-butyl ester (40 milligrams, 0.07 mM, 1 Equivalent) methylene chloride (20 milliliters) solution in be added after hydrochloric acid dioxane (0.5 milliliter, 4 moles every liter) adds, this is mixed It closes liquid and a hour is stirred at room temperature.The crude product that reaction solution is concentrated to get is divided on C18 reversed-phase column using high performance liquid chromatography From (mobile phase：Acetonitrile/water/weak base, gradient elution 40% to 60% (volume ratio)), it is lyophilized after removing volatile component under reduced pressure Obtain hydrochloride (9.5 milligrams, yield 30%) of target compound
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.578 minutes；M/z=461.2 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (d, J=6.02Hz, 2H), 7.31 (dd, J=8.66, 4.64Hz, 1H), 7.06 (t, J=8.41Hz, 1H), 6.88 (s, 1H), 6.08 (d, J=6.53Hz, 1H), 4.92 (br.s., 2H), 4.22 (br.s., 1H), 3.85 (s, 1H), 3.29-3.35 (m, 2H), 1.87 (br.s., 3H)
Embodiment 10
3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridyl group -2- amine
Step A：
4- (1H- pyrazoles -4- base) -3,6- dihydro -2H- pyridine -1- t-butyl formate
Operating procedure：
Under nitrogen protection, to dissolved with compound 4- (trimethyl fluoride sulfonyl oxygroup) -3,6- dihydro -2H- pyridine -1- formic acid The tert-butyl ester (1 gram, 3.0 mMs, 1 equivalent) and compound 4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- Base) -1H- pyrazoles (756 milligrams, 3.9 mMs, 1.3 equivalents) saturation sodium bicarbonate aqueous solution (5 milliliters) and acetonitrile (5 milli Rise) mixed solution in 1,1 '-bis- (diphenylphosphine) ferrocene palladium chloride (122 milligrams, 0.15 mM, 5% equivalent) are added After adding, mixture reacts 30 total runing times in microwave under 110 degree be that this reaction solution of is cooled to room temperature and pours into 20 millis It rises in water and the organic phase for extracting merging with (30 milliliter * 2) of ethyl acetate is primary with saline solution backwash then dry with sodium sulphate After be spin-dried for after obtain crude Compound.This crude Compound (petroleum ether: ethyl acetate=1: 1) obtains target with flash column Compound (400 milligrams, 53.5%)
Step B：
4- (1H- pyrazoles -4- base) piperidines -1- t-butyl formate
Operating procedure：
To dissolved with compound 4- (1H- pyrazoles -4- base) -3,6- dihydro -2H- pyridine -1- t-butyl formate (200 milligrams, 0.8 mM, 1.0 equivalent) ethyl alcohol (30 milliliters) solution in this mixed liquor of palladium carbon (100 milligrams) is added in 15psi hydrogen 16 hour reaction solution filtering decompressions are stirred at 40 degree under environment to be spin-dried for obtaining target compound (180 milligrams, yield 90%).
Step C：
4- [1- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -4- base] piperazine Pyridine -1- tertiary butyl ester
Operating procedure：
To containing compound 4- (1H- pyrazoles -4- base) piperidines -1- t-butyl formate, (100 milligrams, 0.4 mM, 1 works as Amount), compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] iodo- pyridine -2- amine of -5- (182 milligrams, 0.48 mM, 1.2 equivalents), cuprous iodide (76 milligrams, 0.4 mM, 1 equivalent), potassium carbonate (116 milligrams, 0.86 mM, 2.1 equivalents) Toluene (20 milliliters) solution in trans--Dimethylcyclohexyl -1,2- diamines (56 milligrams, 0.4 mM, 1.0 equivalents) is added This mixed liquor stirs 48 hours under 110 degree in vexed tank and waits for that reaction solution cooled and filtered filtrate is poured into water (10 milliliters) use The organic phase that (20 milliliter * 2) of ethyl acetate extraction merges is primary with saline solution backwash, then obtains after being spin-dried for after being dried with sodium sulphate To target compound (130 milligrams, 59%).
Step D：
3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridyl group -2- amine
Operating procedure：
To being cooled with an ice bath dissolved with compound 4- [1- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethoxy Base] -3- pyridyl group] pyrazoles -4- base] and piperidines -1- tertiary butyl ester (130 milligrams, 0.236 mM) methylene chloride (20 milliliters) After addition hydrochloric acid dioxane (1.5 milliliters, 4 moles every liter) is added in solution, this mixed liquor is stirred at room temperature one small When.The crude product that reaction solution is concentrated to get separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% HCl, gradient elution 8% to 38% (volume ratio)), freeze-drying obtains the hydrochloric acid of target compound after removing volatile component under reduced pressure Salt (72.7 milligrams, yield 68.5%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.74 minutes；M/z=450.3 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, D2O) δ 7.68 (s, 1H), 7.60 (s, 1H), 7.57 (d, J=1.76Hz, 1H), 7.31 (dd, J=9.03,5.02Hz, 1H), 7.14 (d, J=2.01Hz, 1H), 7.07 (t, J=8.78Hz, 1H), 6.18 (q, J= 6.53Hz, 1H), 3.39 (d, J=13.05Hz, 2H), 3.04 (td, J=12.74,2.64Hz, 2H), 2.85 (tt, J= 11.54,3.64Hz, 1H), 2.10 (d, J=12.05Hz, 2H), 1.78 (d, J=6.78Hz, 3H), 1.63-1.75 (m, 2H).
Embodiment 11 and embodiment 12
3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridine Base -2- amine
3- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridine Base -2- amine
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyrrole (32 milligrams, 0.071 mM) the progress isolated target compound 3- of chirality SFC [(1R) -1- (2,6- bis- of piperidinyl -2- amine Chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] (11,10 milligrams of embodiment) and 3- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridyl group -2- amine (12,9 milli of embodiment Gram).
The spectroscopic data of embodiment 11：
LC/MS (method：UFLC)：M/z=450.3 [M+H]+
The spectroscopic data of embodiment 12：
LC/MS (method：UFLC)：M/z=450.3 [M+H]+
Embodiment 13
3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (1- methyl sulphonyl -4- piperidyl) pyrazoles -4- Base] pyridyl group -2- amine
Operating procedure：
Compound mesyl chloride (3 milligrams, 0.026 mM, 1.2 equivalents) is added to compound 3- [1- (2,6- bis- Chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- amine (10 milligrams, 0.022 mM, 1.0 equivalents) and diisopropylethylamine (5.67 milligrams, 0.044 mM, 2.0 equivalents) 1 milliliter of methylene chloride solution In, reaction, which was stirred at room temperature after 1 hour, to be spin-dried for column purification and (petrol ether/ethyl acetate=1: 1) obtains target compound (2.5 milligrams).Spectroscopic data：
LC/MS (method：UFLC)：RT=2.00 minutes；M/z=528.0 [M+H]+Total runing time is 1.135 points Clock
1H NMR (400MHz, MeOD-d6)：δ 8.00 (s, 1H), 7.60 (s, 1H), 7.65 (s, 1H), 7.40 (t, 1H), 7.20 (s, 1H), 6.45 (q, 1H), 4.40 (m, 1H), 3.87 (dd, 2H), 3.00 (t, 2H), 2.90 (s, 3H), 2.20 (m, 2H), 2.05-2.10 (m, 2H), 2.00-2.30 (m, 4H), 1.95 (d, 3H)
Embodiment 14
3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (1- ethenesulfonyl -4- piperidyl) pyrazoles -4- Base] pyridyl group -2- amine
Operating procedure：
By 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- amine (23 milligrams, 0.05 mM, 1 equivalent), N, N '-diisopropylethylamine (14 milligrams, 0.11 mM, 2.2 equivalents) and 4- bis- Methylamino pyridine (catalytic amount) is dissolved in 5 milliliters of methylene chloride.Then by (11 millis of compound 1 under stirring, ice bath and nitrogen protection Gram, 0.122 mM, 1.1 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 15 hours at room temperature.After reaction, Reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate After be spin-dried for, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% hydrochloric acid, Gradient elution 25% to 55% (volume ratio)), freeze-drying obtains target compound hydrochloride (7 after removing volatile component under reduced pressure Milligram, yield 26%) spectroscopic data：
LC/MS (method：UFLC)：RT=3.87 minutes；M/z=540.1 [M+H]+Total runing time is 7.00 points Clock
Embodiment 15
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl]
- 1- piperidyl] propyl- 2- alkene -1- ketone
Operating procedure：
By 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- Amine, (50 milligrams, 0.11 mM, 1 equivalent), N, N '-diisopropylethylamine (28.7 milligrams, 0.22 mM, 2 equivalents) are dissolved in 1 milliliter of methylene chloride.Then by compound propyl- 2- enoyl- chlorine under stirring, ice bath and nitrogen protection, (11 milligrams, 0.122 in the least Mole, 1.1 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.After reaction, reaction solution is used Methylene chloride dilution, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain Crude product (mobile phase is separated on C18 reversed-phase column using high performance liquid chromatography：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 36% to 66% (volume ratio)), it removes freeze-drying after volatile component under reduced pressure and obtains target compound (6 milligrams, yield is 10.7%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.66 minutes；M/z=503.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 0.90 (br.s., 1H), 1.29 (br.s., 2H), 1.87 (d, J= 6.78Hz, 3H), 1.90-2.04 (m, 2H), 2.15 (br.s., 2H), 2.86-2.98 (m, 1H), 4.25 (d, J=12.05Hz, 1H), 4.46 (t, J=11.29Hz, 1H), 4.54-4.75 (m, 2H), 5.76 (dd, J=10.79,1.76Hz, 1H), 6.13- 6.26 (m, 2H), 6.82 (dd, J=16.81,10.79Hz, 1H), 6.93 (s, 1H), 7.23 (t, J=8.53Hz, 1H), 7.45 (dd, J=8.78,4.77Hz, 1H), 7.55 (s, 1H), 7.64-7.70 (m, 1H), 7.80-7.88 (m, 1H)
Embodiment 16
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl]
- 1- piperidyl] -2- hydroxy-ethanone
Operating procedure：
By 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- Amine, (20.1 milligrams, 0.04 mM, 1.0 equivalent), 2- hydroxyacetic acid (28.5 milligrams, 0.38 mM, 8.5 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (53.5 milligrams, 0.14 mM, 3.1 equivalents) It is dissolved in 10 milliliters of methylene chloride.Then by n,N-diisopropylethylamine, (74 milligrams, 0.57 in the least under stirring, ice bath and nitrogen protection Mole, 12.8 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.After reaction, reaction solution is used Methylene chloride dilution, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain Crude product (pillar is separated on C18 reversed-phase column using high performance liquid chromatography：Synergi-150*30mm*5u, mobile phase：A is salt Aqueous acid B is acetonitrile, gradient：With the percentage containing B, 17-47%. flow velocity：30mL/ minutes, detector：UV Detector220nm), freeze-drying after volatile component is removed under reduced pressure to obtain target compound (9.3 milligrams, yield is 40.9%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.240 minutes；M/z=508.2 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, DMSO-d6)：δ 8.06 (s, 1H), 7.78 (s, 1H), 7.64-7.55 (m, 2H), 7.51- 7.41 (m, 1H), 7.35-7.11 (m, 1H), 7.04 (s, 1H), 6.19 (q, J=6.2Hz, 1H), 4.50-4.37 (m, 2H), 4.20-4.06 (m, 2H), 3.80 (d, J=12.5Hz, 1H), 3.15 (t, J=12.4Hz, 1H), 2.83 (t, J=11.9Hz, 1H), 2.05 (d, J=11.0Hz, 2H), 1.92-1.70 (m, 5H), 1.24 (s, 1H).
Embodiment 17
2- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] ethyl ketone
Step A：
N- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxoethyl] t-butylcarbamate
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (80 milligrams, 0.178 mM, 1 equivalent), 2- (t-butoxycarbonyl amino) acetic acid, (34.2 milligrams, 0.196 mmoles You, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (101 milligrams, 0.267 MM, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (115 milligrams, 0.89 mM, 5 equivalents).Reaction continues stirring 1 hour at room temperature.After reaction will Reaction solution is spin-dried for, and is placed in hydrochloric acid/dioxane (5 milliliters) and is stirred at room temperature 3 hours.After reaction, reaction solution is spin-dried for To crude product (mobile phase is separated on C18 reversed-phase column using high performance liquid chromatography：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient are washed De- 36% to 66% (volume ratio)), remove under reduced pressure freeze-drying after volatile component obtain target compound (10.1 milligrams, total yield Rate is 11.2%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.74 minutes；M/z=506.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.28 (s, 1H), 1.87-2.10 (m, 5H), 2.10-2.22 (m, 2H), 2.89-3.02 (m, 1H), 3.82-4.13 (m, 3H), 4.44-4.54 (m, 1H), 4.61 (d, J=12.30Hz, 1H), 6.36 (q, J=6.61Hz, 1H), 7.16 (s, 1H), 7.29 (t, J=8.66Hz, 1H), 7.43-7.55 (m, 1H), 7.59- 7.70 (m, 2H), 8.00 (s, 1H)
Embodiment 18
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl acetamide
Operating procedure：
By 440 milligrams of compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl]-N- methyl acetamide (see embodiment 3), the 2- [4- obtained with SFC chiral separation [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- piperidines Base]-N- methyl acetamide (137.7 milligrams, yield 62.5%, embodiment 18)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=521.2 [M+H]+Total runing time is 2.763 points Clock
1H NMR (400MHz, DMSO)：δ 7.95 (s, 1H), 7.70-7.80 (m, 2H), 7.55 (m, 2H), 7.545 (m, 1H), 7.49-7.50 (m, 1H), 6.90 (s, 1H), 6.10 (q, 1H), 5.65 (s, 2H), 4.15 (m, 1H), 2.80-3.10 (m, 4H), 2.60 (m, 3H), 2.30 (m, 2H), 2.00-2.10 (m, 4H), 1.75 (d, 3H)
Embodiment 19
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- ethyl-acetamide
Operating procedure：
By compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] Pyrazol-1-yl] -1- piperidyl] acetic acid (37 milligrams, 0.073 mM, 1 equivalent), ethylamine hydrochloride (7 milligrams, 0.087 mmoles You, 1.2 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (41 milligrams, 0.109 MM, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (47 milligrams, 0.364 mM, 5 equivalents).Reaction continues stirring 2 hours at room temperature.After reaction, Reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate After be spin-dried for, obtain crude product using being purified to obtain target compound (3.3 milligrams, yield 8.6%) with HPLC
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.81 minutes；M/z=534.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.19 (t, J=7.28Hz, 4H) 1.30 (s, 2H) 1.97 (d, J= 6.53Hz, 4H) 2.39 (br.s., 5H) 3.52-3.63 (m, 2H) 3.79 (d, J=11.04Hz, 2H) 3.94-4.06 (m, 3H) 4.64 (d, J=19.32Hz, 1H) 6.38 (d, J=6.78Hz, 1H) 7.18 (s, 1H) 7.31 (t, J=8.53Hz, 1H) 7.49- 7.56 (m, 1H) 7.64 (s, 1H) 7.71 (s, 1H) 7.98 (s, 1H).
Embodiment 20
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- (2- hydroxyethyl) acetamide
Operating procedure：
By compound 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] Pyrazol-1-yl] -1- piperidyl] acetic acid (37 milligrams, 0.073 mM, 1 equivalent), 2- ethylaminoethanol, (5 milligrams, 0.088 milli Mole, 1.2 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (41 milligrams, 0.11 MM, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (47 milligrams, 0.367 mM, 5 equivalents).Reaction continues stirring 2 hours at room temperature.After reaction, Reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate After be spin-dried for, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% bicarbonate Ammonia, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target compound (14 millis after removing volatile component under reduced pressure Gram, yield 35%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.62 minutes；M/z=550.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.95 (d, J=6.53Hz, 3H), 2.28-2.54 (m, 3H), 2.70 (s, 1H), 2.86 (s, 1H), 3.00 (s, 1H), 3.33-3.45 (m, 4H), 3.50-3.69 (m, 3H), 3.79 (d, J= 12.05Hz, 1H), 3.97-4.12 (m, 2H), 4.63 (br.s., 1H), 6.37 (q, J=6.27Hz, 1H), 7.17 (s, 1H) 7.30 (t, J=8.53Hz, 1H), 7.51 (dd, J=8.78,4.77Hz, 1H), 7.62-7.72 (m, 2H), 7.96-8.15 (m, 1H).
Embodiment 21
2- [4- [4- [6- amino -5- [(- 1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-N- isopropyl-acetamide
Operating procedure：
By 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] pyrazoles -1- Base] -1- piperidyl] acetic acid (40 milligrams, 0.073 mM, 1 equivalent), (9 milligrams, 0.147 mM, 2 work as propane -2- amine Amount) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (42 milligrams, 0.11 mM, 1.5 Equivalent) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropyl second Amine (47 milligrams, 0.364 mM, 5 equivalents) is added dropwise.It obtains reaction solution and continues stirring 1 hour at room temperature.Reaction terminates Afterwards, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate It is spin-dried for after dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% salt Acid, gradient elution 36% to 66% (volume ratio), freeze-drying obtains target compound (31 millis after removing volatile component under reduced pressure Gram, yield 72.6%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.81 minutes；M/z=549.3 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.21 (d, J=6.53Hz, 9H), 1.97 (d, J=6.02Hz, 4H) 2.40 (br.s., 6H), 3.37 (s, 3H), 3.51-3.66 (m, 1H), 3.78 (br.s., 2H), 3.92-4.12 (m, 4H), 4.65 (br.s., 1H), 6.38 (d, J=6.27Hz, 1H), 7.19 (s, 1H), 7.31 (t, J=8.41Hz, 1H) 7.53 (br.s., 1H), 7.62-7.73 (m, 3H), 8.04 (br.s., 1H).
Embodiment 22
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N, 2- dimethvl-propionamide
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine, (41 milligrams, 0.09 mM, 1 equivalent), the bromo- N of 2-, 2- dimethvl-propionamide (0.019 milligram, 0.11 mmoles You, 1.2 equivalents), sodium hydroxide (2.5 milliliters, 50% aqueous solution) and tetrabutylammonium iodide (0.029 milligram, 0.12 mM, 1.3 equivalents) it is dissolved in 2.5 milliliters of methylene chloride.Then reaction solution is vigorously mixed at room temperature for reaction 20 hours.Reaction was completed Afterwards, reaction is layered, extraction is three times with methylene chloride (10% methanol is added) for water layer.Merge organic layer saline solution backwash one It is secondary, then be spin-dried for after being dried with sodium sulphate, obtained crude product separates (pillar using high performance liquid chromatography on RP18 reversed-phase column： Synergi-150*30mm*5u, mobile phase：A is 0.05%HCl aqueous solution, B is acetonitrile, gradient：With the percentage containing B Meter, 6-36%, flow velocity：30mL/ minutes, detector：UV Detector220nm), it is remaining after removing volatile component under reduced pressure Water phase is extracted with dichloromethane, then obtains target compound (10 milligrams, yield 20%) with freeze-drying after sodium sulphate drying
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.847 minutes；M/z=275.1 [M/2+H]+Total runing time be for 7.00 minute1H NMR (400MHz, METHANOL-d4) δ 8.05 (br.s., 1H), 7.76-7.60 (m, 2H), 7.54 (br.s., 1H), 7.32 (t, J=8.0Hz, 1H), 7.19 (s, 1H), 6.39 (d, J=6.0Hz, 1H), 4.66 (br.s., 1H), 3.58 (br.s., 2H), 2.99-2.77 (m, 5H), 2.63-2.33 (m, 4H), 1.97 (d, J=5.8Hz, 3H), 1.78-1.56 (m, 6H), 1.45-1.22 (m, 1H)
Embodiment 23
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N, 2- dimethvl-propionamide
Operating procedure：
By 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base]
- 1- piperidyl]-N, 2- dimethvl-propionamide (23,49 milligrams of embodiment, 0.041 mM, 1 equivalent) uses SFC Chiral separation, the component after separation are spin-dried for obtaining compound 2- that [[[[(2,6- bis- chloro- 3- are fluoro- by (1R) -1- by 6- amino -5- by 4- by 4- Phenyl) ethyoxyl] -3- pyridine
Base] pyrazol-1-yl] -1- piperidyl]-N, 2- dimethvl-propionamide (5.1 milligrams)
The spectroscopic data of embodiment 25：
LC/MS (method：UFLC)：RT=2.810 minutes；M/z=275.1 [M/2+H]+Total runing time is 7.00 Minute
Embodiment 24
3- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] -1,1,1- trifluoro -propyl- 2- ketone
Operating procedure：
Target compound is according to the method for embodiment 2 by 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- pyridyl group) pyrazoles -4- base] piperidyl -2- amine be raw material preparation.Then target compound is obtained with SFC chiral separation
Spectroscopic data：
LC/MS (method：UFLC)：M/z=560 [M+H]+.
Embodiment 25
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- (2- chloroethyl) acetamide
Operating procedure：
By 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] acetic acid (40 milligrams, 0.073 mM, 1 equivalent), 2-chloroethyl amine hydrochloride (17 milligrams, 0.147 mmoles You, 2 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (42 milligrams, 0.11 mmoles You, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-two is different Propylethylamine (47 milligrams, 0.368 mM, 5 equivalents) is added dropwise.It obtains reaction solution and continues stirring 1 hour at room temperature.Instead After answering, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then use sulphur It is spin-dried for after sour sodium is dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/ 0.5% hydrochloric acid, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target chemical combination after removing volatile component under reduced pressure Object (17 milligrams, yield 40.9%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.92 minutes；M/z=569.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.29 (br.s., 2H), 1.95 (d, J=4.77Hz, 1H), 2.26- 2.49 (m, 1H), 3.50-3.77 (m, 3H), 3.73-3.84 (m, 1H), 4.03 (s, 1H), 6.37 (br.s., 2H), 7.17 (s, 1H), 7.31 (d, J=6.78Hz, 1H), 7.52 (br.s., 1H), 7.61 (s, 1H), 7.70 (br.s., 1H), 7.96 (s, 1H)
Embodiment 26
2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- cyclopropyl-acetamide
Operating procedure：
By 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] pyrazoles -1- Base] -1- piperidyl] acetic acid (40 milligrams, 0.073 mM, 1 equivalent), cyclopropylamine (8 milligrams, 0.147 mM, 2 equivalent) And N, N, N ', (42 milligrams, 0.11 mM, 1.5 work as N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea Amount) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (47 milligrams, 0.368 mM, 5 equivalents) are added dropwise.It obtains reaction solution and continues stirring 1 hour at room temperature.Reaction terminates Afterwards, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate It is spin-dried for after dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% salt Acid, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target compound (12.5 after removing volatile component under reduced pressure Milligram, yield 29.3%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.84 minutes；M/z=547.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 0.50-0.62 (m, 2H), 0.71-0.83 (m, 2H), 0.90 (d, J= 12.30Hz, 1H), 1.24-1.44 (m, 1H), 1.86-2.02 (m, 3H), 2.29-2.52 (m, 4H), 2.70-2.82 (m, 1H), 3.47-3.62 (m, 1H), 3.79 (d, J=11.04Hz, 2H), 3.87-4.05 (m, 2H), 4.61 (br.s., 1H), 6.38 (q, J =6.78Hz, 1H), 7.19 (s, 1H), 7.31 (t, J=8.66Hz, 1H), 7.54 (dd, J=8.91,4.89Hz, 1H), 7.64 (s, 1H), 7.71 (s, 1H), 7.93-8.07 (m, 1H)
Embodiment 27
(E) -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] but-2-ene -1- ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine, (55 milligrams, 0.123 mM, 1 equivalent), (E)-but-2-ene acid, (11 milligrams, 0.136 mM, 1.1 equivalents) And N, N, N ', (70 milligrams, 0.185 mM, 1.5 work as N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea Amount) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (80 milligrams, 0.617 mM, 5 equivalents).Reaction continues stirring 2 hours at room temperature.After reaction, by reaction solution with two Chloromethanes dilution, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain Crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 36% to 66% (volume ratio) removes freeze-drying after volatile component under reduced pressure and obtains target compound (7.6 milligrams, yield is 12%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.65 minutes；M/z=517.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.77-2.00 (m, 8H), 2.13 (br.s., 2H), 2.88 (t, J= 12.17Hz, 1H), 3.17-3.28 (m, 1H), 4.25 (d, J=13.80Hz, 1H), 4.43 (tt, J=11.48,4.08Hz, 1H), 4.53-4.82 (m, 2H), 6.16 (q, J=6.78Hz, 1H), 6.50 (dd, J=14.93,1.63Hz, 1H), 6.74- 6.87 (m, 1H), 6.92 (d, J=1.51Hz, 1H), 7.21 (t, J=8.53Hz, 1H), 7.43 (dd, J=9.03,4.77Hz, 1H), 7.54 (s, 1H), 7.66 (d, J=1.26Hz, 1H), 7.81 (s, 1H)
Embodiment 28
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -3- methyl-but-2-ene -1- ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (64 milligrams, 0.144 mM, 1 equivalent), (15.8 milligrams, 0.158 mM, 1.1 work as but-2-ene acid 3- methyl - Amount) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (82 milligrams, 0.216 mM, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropyl Ethamine (92 milligrams, 0.72 mM, 5 equivalents).Reaction continues stirring 2 hours at room temperature.After reaction, reaction solution is used Methylene chloride dilution, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain Crude product (mobile phase is separated on C18 reversed-phase column using high performance liquid chromatography：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 36% to 66% (volume ratio)), it removes freeze-drying after volatile component under reduced pressure and obtains target compound (27 milligrams, yield is 35.3%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.79 minutes；M/z=531.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.38 (t, J=6.02Hz, 1H), 1.83-2.00 (m, 11H), 2.09- 2.22 (m, 2H), 2.83-2.97 (m, 1H), 3.21-3.28 (m, 1H), 3.60 (s, 1H), 4.06-4.20 (m, 1H), 4.42- 4.54 (m, 1H), 4.58-4.70 (m, 1H), 5.92 (s, 1H), 6.36 (d, J=6.53Hz, 1H), 7.16 (s, 1H), 7.29 (t, J=8.53Hz, 1H), 7.46-7.54 (m, 1H), 7.65 (s, 2H) 7.89-8.09 (m, 1H)
Embodiment 29
(E) -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -4- (dimethylamino) but-2-ene -1- ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine, (40 milligrams, 0.09 mM, 1 equivalent), (E) -4- (dimethylamino) but-2-ene acid (12.6 milligrams, 0.10 milli Mole, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (51.3 milligrams, 0.135 mM, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (116.1 milligrams, 0.9 mM, 10 equivalents).Reaction continues stirring 3 hours at room temperature.Reaction After, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then use sulfuric acid It is spin-dried for after sodium is dry, obtains crude product using efficient liquid phase and separate (instrument：LC8A&Gilson215 fraction collector chromatographic column：Ge Minute i200*25mm*5um, mobile phase A：BASE water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：38-68% B, 0-12 minutes) obtain target compound (17.4 milligrams, yield：34.8%).
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=561.4 [M+H]+Total runing time is 2.966 points Clock
Spectroscopic data：
1H NMR (400MHz, MeOD)：δ 8.00-8.20 (m, 1H), 7.00-7.70 (m, 5H), 6.30-6.80 (m, 2H), 4.00-4.80 (m, 3H), 3.40 (m, 1H), 2.60-3.00 (m, 7H), 1.80-2.30 (m, 6H)
Embodiment 30 and embodiment 31
(E) -1- [4- [4- [6- amino -5- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] -4- (dimethylamino) but-2-ene -1- ketone
(E) -1- [4- [4- [6- amino -5- [(1R) -1- (2,-two chloro- 3- fluoro-phenyls) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] -4- (dimethylamino) but-2-ene -1- ketone
Operating procedure：
By compound (E) -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl]
- 1- piperidyl] (16.1 milligrams, 0.028 mM) progress SFC of -4- (dimethylamino)-but-2-ene -1- ketone points From obtaining target compound (E) -1- [4- [4- [6- amino -5- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl]
- 1- piperidyl] -4- (dimethylamino) but-2-ene -1- ketone (3 milligrams) and (E) -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- piperidyl] -4- (dimethylamino Base) but-2-ene -1- ketone (4 milligrams).
The spectroscopic data of embodiment 30：
LC/MS (method：UFLC)：M/z=561 [M+H]+.
The spectroscopic data of embodiment 31：
LC/MS (method：UFLC)：M/z=561 [M+H]+
Embodiment 32
3- [(2,6- dichlorophenyl) methoxyl group] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridyl group -2- amine
Step A：
3- [(2,6- dichlorophenyl) methoxyl group] -2- nitro-pyridine
Operating procedure：
By substrate 2- nitropyridine -3- alcohol (437.5 milligrams, 3.125 mMs, 1.1 equivalents) and triphenylphosphine (1.116 Gram, 4.216 mMs, 1.5 equivalents) being added to substrate (2,6- dichlorophenyl) methanol, (500 milligrams, 2.842 mMs, 1 works as Amount) 8 milliliters of tetrahydrofuran solution in, under zero degrees celsius, the DIAD (746 that is dissolved in 1mL tetrahydrofuran solution is added dropwise Milligram, 3.693 mMs, 1.3 equivalents).25 degrees Celsius of room temperature are stirred overnight.It is spin-dried for, water and methylene chloride layering is added.
Water phase is extracted with dichloromethane three times, and organic phase merging is dried, filtered, is spin-dried for, and crosses column and obtains target compound (1.2g).Spectroscopic data：
LC/MS (method：UFLC)：RT=0.773 minutes；M/z=298.8 [M+H]+Total runing time is 1.5 points Clock
Step B：
3- [(2,6- dichlorophenyl) methoxyl group] pyridine -2- amine
Operating procedure：
By substrate 3- [(2,6- dichlorophenyl) methoxyl group] -2- nitro-pyridine (500 milligrams, 1.678 mMs, 1 equivalent) The mixture of acetic acid (4 milliliters) and ethyl alcohol (4 milliliters) is dissolved in reduced iron powder (939 milligrams, 16.779 mMs, 10 equivalents) In system, heating stirring flows back 1 hour.It is cooled to room temperature, is filtered by diatomite, filter cake methylene chloride and washing, layering have Machine is mutually washed with saturated common salt, is dried, filtered, and is spin-dried for obtaining target compound (430 milligrams).
Spectroscopic data：
LC/MS (method：UFLC)：RT=0.730 minutes；M/z=268.8 [M+H]+Total runing time is 1.5 points Clock
Step C：
The bromo- 3- of 5- [(2,6- dichlorophenyl) methoxyl group] pyridine -2- amine
Operating procedure：
By compound 3- [(2,6- dichlorophenyl) methoxyl group] pyridine -2- amine (430 milligrams, 1.604 mMs, 1 equivalent) It is dissolved in acetonitrile (5 milliliters), NBS (225 milligrams, 1.925 mMs, 1.15 equivalents) is added portionwise under 0 degree Celsius.It is added After, it is stirred 1 hour under 0 degree Celsius.It is spin-dried for, is poured into water, be extracted with dichloromethane three times.Organic phase dries, filters, rotation It is dry, it crosses column and obtains target compound (230 milligrams).
Spectroscopic data：
LC/MS (method：UFLC)：RT=0.748 minutes；M/z=348.7 [M+H]+Total runing time is 1.5 points Clock
Step D：
4- [4- [[6- amino -5- [(2,6- dichlorophenyl) methoxyl group] -3- pyridyl pyrazoles -1- base] piperidines -1- formic acid The tert-butyl ester
Operating procedure：
By the bromo- 3- of compound 5- [(2,6- dichlorophenyl) methoxyl group] pyridine -2- amine, (50 milligrams, 0.145 mM, 1 works as Amount), compound 4- [4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) pyrazol-1-yl] piperidines -1- first Tert-butyl acrylate (81.7 milligrams, 0.217 mM, 1.5 equivalents) and (31 milligrams, 0.289 mM, 2 equivalents) of sodium carbonate dissolutions Tetra-triphenylphosphine palladium is added in the mixed system of dioxane (2.5 milliliters) and water (2.5 milliliters) and under nitrogen protection It is stirred under 26 degrees Celsius of room temperature of (8.3 milligrams, 0.007 mM, 0.05 equivalent).It is warming up under 80 degrees Celsius and flows back 6 hours.It cries Mixed system is poured into ice water and is extracted with dichloromethane three times, is merged organic phase saturated common salt water washing, is dried, filtered, It is spin-dried for, the isolated target compound of TLC (40 milligrams).
Spectroscopic data：
LC/MS (method：UFLC)：RT=0.753 minutes；M/z=518.1 [M+H]+Total runing time is 1.5 points Clock
Step E：
3- [(2,6- dichlorophenyl) methoxyl group] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridyl group -2- amine
Operating procedure：
By compound 4- [4- [[6- amino -5- [(2,6- dichlorophenyl) methoxyl group] -3- pyridyl pyrazoles -1- base] piperazine Pyridine -1- t-butyl formate (40 milligrams, 0.077 mM) is dissolved in hydrochloric ethyl acetate (4mL), is stirred at room temperature 1 hour. It is spin-dried for obtaining target compound (17 milligrams).
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.363 minutes；M/z=418.1 [M+H]+Total runing time is 7 minutes
Embodiment 33
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] ethyl acetate
Operating procedure：
By compounds methyl 2- monoxone (58 milligrams, 0.53 mM, 1.2 equivalents), and potassium carbonate (0.49 gram, 3.55 MM, 8 equivalents) and sodium iodide (8 milligrams) be added to compound 1,3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethoxy Base] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- amine (200 milligrams, 0.44 mM, 1 equivalent) 2 milliliters of ethyl alcohol In solution, it is quenched with water after being heated to reflux 2 hours, it is rear that water layer and methylene chloride is added, it is layered, water layer is extracted with methylene chloride again It takes three times, after organic phase merges, drying is spin-dried for, and crude product crosses column purification, and (petrol ether/ethyl acetate=4: 1) drying obtains after being spin-dried for To target compound (6.6 milligrams).
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=536.3 [M+H]+Total runing time is 1.798 points Clock
Embodiment 34
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N, N- dimethyl-acetamide
Operating procedure：
By 2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group base] pyrazoles -1- Base] -1- piperidyl] acetic acid (400 milligrams, 0.73 mM, 1 equivalent), compound 1, dimethylamine (295 milligrams, 1.47 mmoles You, 2 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (415 milligrams, 1.1 millis Mole, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-two Wopropyl ethyl amine (380 milligrams, 2.94 mMs, 5 equivalents) is added dropwise.It obtains reaction solution and continues stirring 1 hour at room temperature. After reaction, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then use It is spin-dried for after sodium sulphate is dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/ 0.5% hydrochloric acid, gradient elution 36% to 66% (volume ratio), freeze-drying obtains target compound after removing volatile component under reduced pressure (60 milligrams, yield 15.4%)
LC/MS (method：UFLC)：RT=2.75 minutes；M/z=535.3 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.97 (d, J=6.53Hz, 4H), 2.30-2.60 (m, 5H) 2.96- 3.11 (m, 7H), 3.35-3.49 (m, 2H), 3.61 (d, J=8.78Hz, 1H), 3.84 (d, J=11.54Hz, 2H), 4.26- 4.46 (m, 2H), 4.69 (br.s., 1H), 6.39 (q, J=6.36Hz, 1H), 7.20 (s, 1H), 7.27-7.40 (m, 1H), 7.44-7.58 (m, 1H), 7.72 (d, J=9.54Hz, 2H) 8.02-8.28 (m, 1H)
Embodiment 35
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -2- (dimethylamino) ethyl ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate, (60 milligrams, 0.123 mM, 1 equivalent), 2- (dimethylamino) acetic acid, (15 milligrams, 0.147 mmoles You, 1.2 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (70 milligrams, 0.184 MM, 1.5 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (79 milligrams, 0.615 mM, 5 equivalent).Reaction continues stirring 12 hours at room temperature.After reaction Reaction solution is spin-dried for, obtained target compound crude product, purifies (instrument with HPLC：SHIMADZU LC-8A, chromatographic column： Synergi-10 μm,
250 × 50mmI.D. mobile phase：A for water (Add1 ‰ TFA, v/v) and B for CAN, concentration gradient：B30- 80%. flow velocitys：80mL/ minutes) with HPLC refined solution with sodium bicarbonate adjust pH value be 7-8 after water layer be extracted with dichloromethane Three times, saturated salt solution backwash is used after organic layer merges, it is dry to be spin-dried for obtaining target compound (41.6 milligrams, yield is 63%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=535.3 [M+H]+Total runing time is 2.820 points Clock
1H NMR (400MHz, DMSO-d6) δ 7.95 (s, 1H), 7.75 (d, J=1.8Hz, 1H), 7.61-7.50 (m, 2H), 7.48-7.35 (m, 1H), 6.89 (d, J=1.5Hz, 1H), 6.08 (q, J=6.6Hz, 1H), 5.65 (s, 2H), 4.49-4.31 (m, 2H), 4.13 (d, J=13.6Hz, 1H), 3.23-2.99 (m, 3H), 2.74 (t, J=11.5Hz, 1H), 2.20 (s, 6H), 2.02 (br.s., 2H), 1.91-1.81 (m, 1H), 1.79 (d, J=6.8Hz, 3H), 1.76-1.65 (m, 1H), 1.22 (s, 1H).
Embodiment 36
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -2- (methylamino) ethyl ketone
Step A：
N- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxygen-ethyl]-N- methyl carbamic acid the tert-butyl ester
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate, (60 milligrams, 0.123 mM, 1 equivalent), 2- [tert-butoxycarbonyl (methyl) amino] acetic acid, (27 Milligram, 0.147 mM, 1.2 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid Urea (70 milligrams, 0.184 mM, 1.5 equivalent) is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (79 milligrams, 0.615 mM, 5 equivalent).Reaction continues stirring 12 at room temperature Hour.Reaction solution is spin-dried for after reaction, obtained target compound crude product HPLC purifying (instrument：SHIMADZU LC- 8A, chromatographic column：Synergi-10 μm, 250 × 50mmI.D. mobile phase：A for water (Add1 ‰ TFA, v/v) and B for CAN, concentration gradient：B30-80%. flow velocity：80mL/ minutes) .HPLC refined solution with sodium bicarbonate adjust pH value be 7-8 after water layer It is extracted with dichloromethane three times, organic layer uses saturated salt solution backwash after merging, dry to be spin-dried for obtaining target compound (50 millis Gram, yield 65.7%).
Step B：
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -2- (methylamino) ethyl ketone
Operating procedure：
By compound N-[2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] Pyrazol-1-yl] -1- piperidyl] -2- oxygen-ethyl]-N- methyl carbamic acid the tert-butyl ester (50 milligrams, 0.08 mM, 1 equivalent) It is dissolved in 2 ml methanols, hydrochloric acid/dioxane (2 milliliters) is slowly added dropwise into the solution under -30 degree and stirs at such a temperature It mixes 3 hours.After reaction, reaction solution is spin-dried for obtaining target compound (30 milligrams, yield 71%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=521.3 [M+H]+Total runing time is 2.761 points Clock
1H NMR (400MHz, DEUTERIUM OXIDE) δ 1.66-1.75 (m, 3H), 1.76-1.91 (m, 2H), 2.07 (t, J=16.19Hz, 2H), 2.67-2.76 (m, 4H), 2.82-2.92 (m, 1H), 3.23 (t, J=12.05Hz, 1H), 3.51- 3.57 (m, 1H), 3.59-3.64 (m, 1H), 3.66-3.77 (m, 2H), 3.98-4.17 (m, 3H), 4.33-4.45 (m, 2H), 6.04 (q, J=6.69Hz, 1H), 6.87 (s, 1H), 7.02 (t, J=8.66Hz, 1H), 7.28 (dd, J=8.91,4.89Hz, 1H), 7.39 (d, J=1.51Hz, 1H), 7.49 (s, 1H), 7.73 (s, 1H)
Embodiment 37
N- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl] acetamide
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine, (40 milligrams, 0.09 mM, 1 equivalent), 2- acetylaminoacetic acid (11.7 milligrams, 0.10 mM, 1.1 equivalents) And N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (51.3 milligrams, 0.135 mM, 1.5 Equivalent) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropyl second Amine (116.1 milligrams, 0.9 mM, 10 equivalents).Reaction continues stirring 3 hours at room temperature.After reaction, by reaction solution It is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain (instrument is separated using efficient liquid phase to crude product：LC8A&Gilson215 fraction collector, chromatographic column：Ge minutes i200*25mm* 5um, mobile phase A：Water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：38-68%B, 0-12 minutes) obtain target Compound (14.7 milligrams, yield 30.6%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=549.3 [M+H]+Total runing time is 3.297 points Clock
1H NMR (400MHz, MeOD)：δ 8.05 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.50 (m, 1H), 7.30 (t, 3H), 7.20 (s, 1H), 6.4 (m, 1H), 4.00-4.60 (m, 4H), 2.80 (m, 1H), 2.10-2.00 (m, 2H), 2.05 (s, 3H), 1.90 (d, 3H)
Embodiment 38 and embodiment 39
N- [2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] -2- oxo-ethyl] acetamide
N- [2- [4- [4- [6- amino -5- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] -2- oxo-ethyl] acetamide
Operating procedure：
By compound N-[2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] Pyrazol-1-yl]
- 1- piperidyl] -2- oxo-ethyl] (13.4 milligrams, 0.024 mM) progress chirality SFC of acetamide separate To target compound N- [2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base]
Pyrazol-1-yl] -1- piperidyl] -2- oxo-ethyl] acetamide (2 milligrams) and N- [2- [4- [4- [6- amino -5- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- piperidyl] -2- oxo-second Base] acetamide (3 milligrams).
The spectroscopic data of embodiment 38：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=549.4 [M+H]+Total runing time is 3.297 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.03 (s, 1H), 7.74-7.60 (m, 2H), 7.53 (dd, J=4.8, 8.8Hz, 1H), 7.31 (t, J=8.7Hz, 1H), 7.19 (s, 1H), 6.38 (q, J=6.3Hz, 1H), 4.69-4.46 (m, 2H), 4.24-3.98 (m, 3H), 3.03 (s, 1H), 2.98-2.84 (m, 1H), 2.23-2.13 (m, 2H), 2.08 (s, 3H), 1.97 (d, J=6.5Hz, 3H)
The spectroscopic data of embodiment 39：
LC/MS (method：UFLC)：RT=3.707 minutes；M/z=549.4 [M+H]+Total runing time is 7.00 points Clock
Embodiment 40
3- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] propyl- 1- ketone
Step A：
N- [3- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -3- oxygen-propyl] carbamate
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (60 milligrams, 0.123 mM, 1 equivalent), compound 3- (t-butoxycarbonyl amino) propionic acid (23 milligrams, 0.147 mM, 1.2 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (70 Milligram, 0.184 mM, 1.5 equivalent) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to delay It is slow that N, N '-diisopropylethylamine (79 milligrams, 0.615 mM, 5 equivalents) is added.Reaction continues stirring 12 hours at room temperature. Reaction solution is spin-dried for after reaction, obtained target compound crude product is used to be purified with HPLC (instrument：SHIMADZU LC- 8A, chromatographic column：Synergi-10 μm, 250 × 50mmI.D. mobile phase：A is that water (adding 1 ‰ TFA, v/v) and B is acetonitrile, dense Spend gradient：B30-80%. flow velocity：80mL/ minutes) (50 milligrams, yield 65%).
Step B：
3- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] propyl- 1- ketone
Operating procedure：
By compound N-[3- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] Pyrazol-1-yl] -1- piperidyl] -3- oxygen-propyl] carbamate (50 milligrams, 0.08 mM, 1 equivalent) is placed in It is stirred at room temperature 3 hours in hydrochloric acid/dioxane (2 milliliters).After reaction, reaction solution is spin-dried for obtaining crude product.It is pure with HPLC Change (instrument：LC8A&Gilson215 fraction collector chromatographic column：Ge minutes i200*25mm*5um, mobile phase A：Water, mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：17-27%B, 0-12 minutes) obtain target compound (5.2 milligrams, yield 12.4%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.00 minutes；M/z=521.1 [M+H]+Total runing time is 0.626 point Clock
1H NMR (400MHz, D2O) δ 1.80 (m, 5H), 2.10-2.30 (m, 2H), 2.80 (m, 3H), 3.30 (m, 3H), 3.60-4.10 (m, 7H), 6.4 (m, 1H), 7.05 (s, 1H), 7.15 (m, 1H), 7.40 (m, 1H) 7.50 (s, 1H), 7.70 (s, 1H), 7.80 (s, 1H)
Embodiment 41
4- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] butyl- 1- ketone
Step A：
N- [4- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -4- oxo butyl] carbamate
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (50 milligrams, 0.103 mM, 1 equivalent), compound 3- (t-butoxycarbonyl amino) propionic acid (23 milligrams, 0.133 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (60 Milligram, 0.155 mM, 1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to delay It is slow that N, N '-diisopropylethylamine (100 milligrams, 1.03 mMs, 10 equivalents) is added.It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, obtained target compound is directly used in next step.
Step B：
4- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group]
Pyrazol-1-yl] -1- piperidyl] butyl- 1- ketone
Operating procedure：
By compound N-[4- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group]
Pyrazol-1-yl] -1- piperidyl] -4- oxo butyl] carbamate, it is placed in hydrochloric acid/dioxane (10 Milliliter) in be stirred at room temperature 3 hours.After reaction, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A& Gilson215 fraction collector chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Second Nitrile, flow velocity：30mL/ minutes concentration gradients：13-23%B, 0-11 minutes) after obtain target compound (5.9 milligrams, yield be 9%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=535.4 [M+H]+Total runing time is 1.636 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.16-7.99 (m, 1H), 7.67 (s, 2H), 7.52 (br.s., 1H), 7.31 (t, J=7.8Hz, 1H), 7.19 (br.s., 1H), 6.38 (d, J=5.3Hz, 1H), 4.66 (d, J=11.3Hz, 1H), 4.54 (br.s., 1H), 4.12 (d, J=9.8Hz, 1H), 3.04 (br.s., 2H), 2.88 (d, J=11.5Hz, 1H), 2.66 (br.s., 2H), 2.15 (d, J=10.8Hz, 2H), 2.04-1.85 (m, 7H)
Embodiment 42
[4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- Piperidyl]-(4- piperidyl) ketone
Step A：
4- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl-carbonyl] piperidines -1- t-butyl formate
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (50 milligrams, 0.103 mM, 1 equivalent), 1- tert-butoxycarbonylpiperidine -4- carboxylic acid (26 milligrams, 0.113 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (60 millis Gram, 0.155 mM, 1.5 equivalents) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue slow N, N '-diisopropylethylamine (100 milligrams, 1.03 mMs, 10 equivalents) is added.Reaction continues stirring 12 hours at room temperature. Reaction solution is spin-dried for after reaction, obtained target compound is directly used in next step.
Step B：
[4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- Piperidyl]-(4- piperidyl) ketone
Operating procedure：
By compound 4- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base]
- 1- piperidyl-carbonyl] piperidines -1- t-butyl formate is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 Hour.After reaction, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector Chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration Gradient：13-23%B, 0-11 minutes) after obtain target compound (3.6 milligrams, yield 6%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=561.3 [M+H]+Total runing time is 1.789 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.04 (d, J=5.5Hz, 1H), 7.67 (br.s., 2H), 7.53 (dd, J=4.6,8.7Hz, 1H), 7.32 (t, J=8.5Hz, 1H), 7.18 (s, 1H), 6.38 (d, J=6.5Hz, 1H), 4.73-4.46 (m, 2H), 4.26 (d, J=12.0Hz, 1H), 3.55-3.36 (m, 2H), 3.15 (br.s., 1H), 3.03-2.82 (m, 1H), 2.20 (d, J=18.3Hz, 2H), 2.09-1.85 (m, 7H), 1.52 (dd, J=6.8,17.3Hz, 1H)
Embodiment 43
3- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] -3- methyl-butyl- 1- ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (50 milligrams, 0.103 mM 1,1 equivalent), 3- (t-butoxycarbonyl amino) -3 Methylbutanoic acid (26 millis Gram, 0.113 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (60 milligrams, 0.155 mM, 1.5 equivalents) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue It is slowly added to N, N '-diisopropylethylamine (100 milligrams 1.03 mMs, 10 equivalents).It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 13-23%B, 0-11 minutes) obtain target compound (14.9 milligrams, yield 25%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=549.4 [M+H]+Total runing time is 1.801 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.00 (s, 1H), 7.64 (d, J=5.8Hz, 2H), 7.51 (dd, J= 4.8,9.0Hz, 1H), 7.29 (t, J=8.5Hz, 1H), 7.16 (s, 1H), 6.36 (q, J=6.3Hz, 1H), 4.69 (d, J= 13.3Hz, 1H), 4.51 (t, J=11.2Hz, 1H), 4.11 (d, J=13.8Hz, 1H), 2.94-2.67 (m, 3H), 2.22- 2.08 (m, 2H), 2.05-1.98 (m, 1H), 1.97-1.90 (m, 4H), 1.44 (d, J=6.3Hz, 6H)
Embodiment 44
[4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- Piperidyl]-(azetidine -3- base) ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (50 milligrams, 0.103 mM, 1 equivalent), 1- tert-butoxycarbonyl azetidine -3- carboxylic acid (23 millis Gram, 0.133 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (60 milligrams, 0.155 mM, 1.5 equivalents) are dissolved in 10 milliliter of 1 methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (100 milligrams, 1.03 mMs, 10 equivalent).Reaction continues to stir at room temperature 12 hours.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction knot Reaction solution is spin-dried for obtaining crude product by Shu Hou.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 17-27%B, 0-12 minutes) after obtain target compound (12.6 milligrams, yield 19%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=533.3 [M+H]+Total runing time is 1.646 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.03 (s, 1H), 7.71-7.61 (m, 2H), 7.53 (dd, J=4.8, 8.8Hz, 1H), 7.32 (t, J=8.7Hz, 1H), 7.18 (s, 1H), 6.46-6.31 (m, 1H), 4.64 (d, J=12.5Hz, 1H), 4.53 (br.s., 1H), 4.42-4.25 (m, 4H), 4.16 (q, J=8.3Hz, 1H), 3.79 (d, J=13.1Hz, 1H), 2.96 (t, J=12.0Hz, 1H), 2.15 (br.s., 2H), 2.03-1.86 (m, 5H).
Embodiment 45
(1- Aminocyclobutyl)-[4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl] -1- piperidyl] ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine hydrochlorate (50 milligrams, 0.103 mM, 1 equivalent), compound 1- (t-butoxycarbonyl amino) cyclobutane-carboxylic acid (25 Milligram, 0.113 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (60 milligrams, 0.155 mM, 1.5 equivalent) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (100 milligrams, 1.03 mM of 10 equivalent).Reaction continues stirring 12 at room temperature Hour.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 17-27%B, 0-12 minutes) after obtain target compound (11.4 milligrams, yield 17%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=547.4 [M+H]+Total runing time is 1.778 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.03 (br.s., 1H), 7.70-7.59 (m, 2H), 7.51 (dd, J= 4.6,8.7Hz, 1H), 7.29 (t, J=8.5Hz, 1H), 7.17 (s, 1H), 6.36 (d, J=6.5Hz, 1H), 2.97-2.86 (m, 1H), 2.51-2.30 (m, 2H), 2.21 (d, J=11.0Hz, 2H), 2.07 (br.s., 2H), 1.95 (d, J=6.0Hz, 3H).
Embodiment 46
1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl] -2- methyl -2- (methylamino) propyl- 1- ketone
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine, (50 milligrams, 0.111 mM, 1 equivalent), 2- [benzyloxycarbonyl group (methyl) amino] -2 Methylpropionic acid (29 milligrams, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 millis Gram, 0.166 mM 1,1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to delay It is slow that N, N '-diisopropylethylamine (72 milligrams, 0.555 mM 1,5 equivalents) is added.It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is dissolved in methanol (10 milliliters), middle addition palladium dydroxide (0.2g) is stirred at room temperature.It sets After ventilating, reaction stirring 3 hours under hydrogen atmosphere are placed reaction liquid into.After reaction, reaction solution filtered, be spin-dried for obtaining Crude product purifies (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13-23%B, 0-11 minutes) obtain target Compound (10.2 milligrams, yield 15%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=549.4 [M+H]+Total runing time is 1.757 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.02 (s, 1H), 7.70-7.60 (m, 2H), 7.53 (dd, J=4.8, 9.0Hz, 1H), 7.31 (t, J=8.5Hz, 1H), 7.19 (d, J=1.3Hz, 1H), 6.38 (q, J=6.6Hz, 1H), 4.57 (t, J=11.3Hz, 1H), 2.71 (s, 3H), 2.20 (d, J=10.5Hz, 2H), 2.07-1.91 (m, 5H), 1.73 (s, 6H).
Embodiment 47
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(3R)-nafoxidine -3- base] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (3R) -1- butyloxycarbonyl pyrrolidine -3- carboxylic acid (27 millis Gram, 0.122 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 mM, 1.5 equivalent) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalents).Reaction continues stirring 12 at room temperature Hour.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product, purifies (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 13-23%B, 0-11 minutes) obtain target compound (33.3mg, yield 50%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=547.3 [M+H]+Total runing time is 1.573 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.97 (d, J=6.27Hz, 4H), 2.03-2.30 (m, 4H), 2.43 (br.s., 1H), 2.93 (t, J=11.80Hz, 1H), 3.36-3.50 (m, 4H), 3.60-3.86 (m, 2H), 4.21 (d, J= 12.05Hz, 1H), 4.48-4.73 (m, 2H), 6.38 (d, J=6.27Hz, 1H), 7.18 (s, 1H), 7.32 (t, J=8.53Hz, 1H), 7.53 (dd, J=8.53,4.52Hz, 1H), 7.68 (br.s., 2H), 8.05 (br.s., 1H).
Embodiment 48
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(3S)-nafoxidine -3- base] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (3S) -1- butyloxycarbonyl pyrrolidine -3- carboxylic acid (27 millis Gram, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 mM, 1.5 equivalents) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue It is slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalent).It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product, purifies (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：
13-23%B, 0-11 minutes) obtain target compound (21.6 milligrams, yield 32%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=548.4 [M+H]+Total runing time is 1.641 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.87-2.01 (m, 4H), 2.02-2.28 (m, 4H), 2.42 (dt, J =13.43,7.97Hz, 1H), 2.93 (t, J=13.05Hz, 1H), 3.35-3.48 (m, 4H), 3.60-3.85 (m, 2H), 4.21 (d, J=13.30Hz, 1H), 4.47-4.60 (m, 1H), 4.65 (d, J=13.30Hz, 1H), 6.38 (d, J=6.78Hz, 1H), 7.18 (d, J=1.25Hz, 1H), 7.32 (t, J=8.53Hz, 1H), 7.53 (dd, J=9.03,4.77Hz, 1H), 7.64- (7.71 m, 2H), 8.03 (d, J=4.02Hz, 1H)
Embodiment 49
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(3S)-morpholine -3- base] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (3S) -4- methyl morpholine -3- carboxylic acid (29 milligrams, 0.122 milli Mole, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 mM, 1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue slowly to add Enter N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalent).Reaction continues stirring 12 hours at room temperature.Instead Reaction solution is spin-dried for after answering, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.It after reaction, will be anti- Liquid is answered to be spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Synergi150* 30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13-23%B, 0-11 Minute) obtain target compound (28.1mg, yield 42%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=563.3 [M+H]+Total runing time is 1.584 points Clock
1H NMR (400MHz, Methanol-d4) δ 1.90 (m, 4H), 2.10-2.40 (m, 3H), 3.00 (m, 1H), 3.40 (br, 3H), 3.60-3.80 (m, 2H), 4.10 (m, 2H), 4.25 (m, 1H), 4.50-4.70 (m, 3H), 6.40 (m, 1H), 7.19 (s, 1H), 7.30 (m, 1H), 7.50 (m, 1H), 7.65 (m, 2H), 8.05 (s, 1H)
Embodiment 50
2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl] -1- piperidyl] -3,3,3- trifluoros -propyl- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (10 milligrams, 0.0222 mM, 1 equivalent), compound 2- amino -3,3,3- trifluoroacetic acid, (3.5 milligrams, 0.0244 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (12.6 milligrams, 0.033 mM, 1.5 equivalent) are dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (14.3 milligrams, 0.111 mM, 5 equivalent).Reaction continues to stir at room temperature 2 hours.After reaction, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash one of saline solution It is secondary, then with sodium sulphate it is dry after be spin-dried for, obtained crude product, which is used, purifies (instrument with HPLC：LC8A&Gilson215 fraction collection Device chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes dense Spend gradient：13-23%B, 0-11 minutes) obtain target compound (8 milligrams, yield 61%)
Spectroscopic data：
LC/MS (method：UFLC)：M/z=575 [M+H]+.
Embodiment 51
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(3S) -3- piperidyl] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (300 milligrams, 0.666 mM, 1 equivalent), (3S) -1- tert-butoxycarbonylpiperidine -3- carboxylic acid, (168 millis Gram, 0.733 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (384 milligrams, 0.999 mM, 1.5 equivalents) are dissolved in 30 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, after It is continuous to be slowly added to N, N '-diisopropylethylamine (430 milligrams, 3.33 mMs, 5 equivalent).Reaction continues stirring 12 at room temperature Hour.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (30 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 13-23%B, 0-11 minutes) obtain target compound (213 milligrams, yield 53%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=561.3 [M+H]+Total runing time is 1.773 points Clock
1HNMR (400MHz, METHANOL-d4) δ 1.97 (d, J=6.27Hz, 4H) 2.18 (d, J=16.81Hz, 1H) 2.90-3.09 (m, 1H) 3.36-3.50 (m, 3H) 3.57-3.73 (m, 1H) 3.75-3.87 (m, 1H) 4.07 (d, J= 12.30Hz, 2H) 4.27 (d, J=10.29Hz, 1H) 4.50-4.80 (m, 3H) 6.38 (q, J=6.19Hz, 1H) 7.19 (s, 1H) 7.31 (t, J=8.53Hz, 1H) 7.49-7.57 (m, 1H) 7.66 (d, J=4.02Hz, 2H) 8.05 (br.s., 1H).
Embodiment 52
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(3R) -3- piperidyl] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (3R) -1- t-butoxy carbonyl piperidines -3- carboxylic acid, (28 millis Gram, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 mM, 1.5 equivalents) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue It is slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalents).It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product, purifies (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Ge minutes I200*25mm*5um, mobile phase A：HCl/water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：17-27%B, 0-12 Minute) obtain target compound (14.7 milligrams, yield 22%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=561.3 [M+H]+Total runing time is 1.779 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.75-2.09 (m, 9H), 2.10-2.28 (m, 2H), 2.84-2.95 (m, 1H), 3.19 (br.s., 2H), 3.33-3.44 (m, 2H), 4.11 (d, J=12.55Hz, 1H), 4.53 (br.s., 1H), 4.65 (d, J=10.79Hz, 1H), 6.36 (d, J=6.27Hz, 1H), 7.16 (s, 1H), 7.29 (s, 1H), 7.51 (d, J= 3.76Hz, 1H), 7.65 (s, 2H), 8.02 (br.s., 1H)
Embodiment 53
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base]-1- piperidyl]-[(2R)-morpholine -2-yl] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (2R) -4- tert-butyl
Butoxycarbonylmorpholine-2- carboxylic acid (29 milligrams, 0.122 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7-
Azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 mM, 1.5 equivalent) is dissolved in 10 milliliter two Chloromethanes.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, (72 milligrams, 0.555 in the least for N '-diisopropylethylamine Mole, 5 equivalent).Reaction continues stirring 12 hours at room temperature.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxy It is stirred at room temperature 3 hours in six rings (10 milliliters).After reaction, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC： LC8A&Gilson215 fraction collector chromatographic column：Ge minutes i200*25mm*5um, mobile phase A：HCl/water, Mobile phase B：Second Nitrile, flow velocity：30mL/ minutes concentration gradients：17-27%B, 0-12 minutes) obtaining target compound, (13 milligrams, yield is 20%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=563.3 [M+H]+Total runing time is 1.687 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.80-2.30 (m, 7H), 2.90 (m, 1H), 3.20-3.50 (m, 3H), 4.05 (m, 2H), 4.20 (m, 1H), 4.60 (m, 2H), 6.40 (m, 1H), 7.15 (s, 1H), 7.25 (m, 1H) 7.50 (s, 1H), 7.60 (s, 2H), 8.02 (br, 1H).
Embodiment 54
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base]-1- piperidyl]-[(2S)-morpholine -2-yl] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine-2- amine (50 milligrams, 0.111 mM, 1 equivalent), (2S)-4- tert-butoxycarbonyl morpholine -2-carboxylic acid (29 milligrams, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 millis Gram, 0.166 mM, 1.5 equivalents) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue slow N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalents) is added.Reaction continues stirring 12 hours at room temperature.Instead Reaction solution is spin-dried for after answering, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.It after reaction, will be anti- Liquid is answered to be spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Ge minutes i200* 25mm*5um, mobile phase A：HCl/water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：17-27%B, 0-12 minutes) Obtain target compound (4 milligrams, yield 6%)
Spectroscopic data：
1H NMR (400MHz, Methanol-d4) δ 1.80-2.20 (m, 6H), 2.90 (m, 1H), 3.00-3.50 (m, 4H), 4.00 (m, 2H), 4.15 (m, 1H), 4.50-4.80 (m, 3H), 6.40 (m, 1H), 7.08 (s, 1H), 7.40 (m, 1H) 7.50 (m, 1H), 7.60 (m, 2H), 7.90 (s, 1H)
Embodiment 55
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-[(2R)-nafoxidine -2- base] ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (3S) -1- tertbutyloxycarbonyl pyrrolidines -3- carboxylic acid (27 milligrams, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 millis Gram, 0.166 mM, 1.5 equivalents) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue slow N, N '-diisopropylethylamine (72 milligrams 0.555 mM, 5 equivalents) is added.Reaction continues stirring 12 hours at room temperature.Instead Reaction solution is spin-dried for after answering, is placed in HCl/ dioxane (10 milliliters) and is stirred at room temperature 3 hours.It after reaction, will be anti- Liquid is answered to be spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Synergi150* 30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13-23%B, 0-11 Minute) obtain target compound (11.8 milligrams, yield 18%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=547.3 [M+H]+Total runing time is 1.538 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.05 (d, J=4.0Hz, 1H), 7.68 (d, J=3.0Hz, 2H), 7.53 (dd, J=4.6,7.4Hz, 1H), 7.32 (t, J=8.5Hz, 1H), 7.19 (s, 1H), 6.38 (d, J=6.8Hz, 1H), 4.84-4.71 (m, 2H), 4.68-4.48 (m, 2H), 4.11-3.96 (m, 1H), 3.50-3.36 (m, 3H), 3.02 (q, J= 12.3Hz, 1H), 2.56 (d, J=12.5Hz, 1H), 2.29-2.09 (m, 4H), 2.08-2.00 (m, 2H), 1.97 (d, J= 6.3Hz, 4H)
Embodiment 56
[4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-(2- piperidyl) ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), 1- Benzyloxycarbonylpiperidin -2- carboxylic acid (33 milligrams, 0.122 mmoles You, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.166 MM, 1.5 equivalents) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (72 milligrams, 0.555 mM 1,5 equivalents).Reaction continues stirring 12 hours at room temperature.After reaction Reaction solution is spin-dried for, is dissolved in methanol, middle addition palladium dydroxide (0.2g) is stirred at room temperature.After displaced air, place reaction liquid into Reaction stirring 3 hours under hydrogen atmosphere.After reaction, by reaction solution filtering, be spin-dried for obtaining crude product, purify (instrument with HPLC： LC8A&Gilson215 fraction collector chromatographic column：Synergi Synergi150*30mm*5u, mobile phase A：0.05%HCl Water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13-23%B, 0-11 minutes) obtain target compound (1 milli Gram, yield 1.4%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=561.3 [M+H]+Total runing time is 1.884 points Clock
Embodiment 57
(2S) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -6- (dimethylamino) hex- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (500 milligrams, 1.11 mMs, 1 equivalent), (2S) -6- (dimethylamino) -2- (9H- fluorenes -9- base methoxy Carbonylamino) caproic acid (530 milligrams, 1.22 mMs, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo three Azoles -1- base) hexafluorophosphoric acid urea (640m g, 1.66 mMs, 1.5 equivalent) is dissolved in 50 milliliters of methylene chloride.Then stirring, ice Under bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (720 milligrams, 5.55 mMs, 5 equivalent).Reaction Continue stirring 12 hours at room temperature.Reaction solution is spin-dried for after reaction,
It is dissolved in methanol (50 milliliters), middle addition palladium dydroxide (0.1g) is stirred at room temperature.After displaced air, reaction solution is set Reaction stirring 3 hours under hydrogen atmosphere.After reaction, reaction solution filtered, be spin-dried for obtaining crude product, efficient liquid phase separation (instrument：LC8A&Gilson215 fraction collector chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：1-30%B, 0-8 minutes) be spin-dried for after obtain target compound (379 Milligram, yield 50%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=606.4 [M+H]+Total runing time is 1.291 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.53 (br.s., 2H), 1.72-1.86 (m, 2H), 1.89-1.99 (m, 6H), 2.08-2.28 (m, 3H), 2.90 (s, 7H), 2.98 (d, J=17.57Hz, 1H), 3.12-3.22 (m, 2H), 3.25 (br.s., 1H), 3.42 (d, J=13.05Hz, 1H), 4.07 (br.s., 1H), 4.49-4.69 (m, 3H), 6.33-6.41 (m, 1H), 7.17 (s, 1H), 7.30 (t, J=8.66Hz, 1H), 7.51 (dd, J=9.03,4.77Hz, 1H), 7.62-7.68 (m, 2H), 7.99-8.10 (m, 1H)
Embodiment 58
(2S) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -3- (1H- imidazol-4 yl) propyl- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), 2S) -2- (tertbutyloxycarbonylamino) -3- (1H- imidazoles -5- Base) propionic acid (32 milligrams, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) Hexafluorophosphoric acid urea (64 milligrams 0.166 mM, 1.5 equivalents) is dissolved in 10 milliliters of methylene chloride.Then stirring, ice bath and nitrogen are protected Under shield, continue to be slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalent).Reaction at room temperature after Continuous stirring 12 hours.Reaction solution is spin-dried for after reaction, is placed in HCl/ dioxane (10 milliliters) and is stirred at room temperature 3 hours. After reaction, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatography Column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration ladders Degree：1-30%B, 0-8 minutes) obtain target compound (6.9 milligrams, yield 9%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=588.4 [M+H]+Total runing time is 1.221 points Clock
1HNMR (400MHz, METHANOL-d4) δ 1.17-1.41 (m, 1H), 1.95 (d, J=6.53Hz, 3H), 2.91- 3.07 (m, 1H), 3.37 (d, J=1.76Hz, 1H), 3.50-3.64 (m, 2H), 3.65-3.71 (m, 1H), 4.17 (d, J= 12.80Hz, 1H), 4.50-4.81 (m, 2H), 6.37 (q, J=6.61Hz, 1H), 7.17 (s, 1H), 7.30 (t, J=8.53Hz, 1H), 7.48-7.59 (m, 2H), 7.62-7.67 (m, 2H), 8.02 (s, 1H), 8.95-9.00 (m, 1H)
Embodiment 59
(2R) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -3- methyl-butyl- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (2R) -2- (tertbutyloxycarbonylamino) -3- metliyl-butyric acid (27 milligrams, 0.122 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluoro phosphorus Sour urea (64 milligrams, 0.166 mM, 1.5 equivalent) is dissolved in 10 milliliters of methylene chloride.Then stirring, ice bath and nitrogen protection Under, continue to be slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalents).Reaction continues to stir at room temperature It mixes 12 hours.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction After, reaction solution is spin-dried for obtain crude product.Crude product efficient liquid phase is separated into (instrument again：LC8A&Gilson215 fraction collection Device chromatographic column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes dense Spend gradient：16-26%B, 0-8 minutes) be spin-dried for after obtain target compound (28.1 milligrams, yield 37%) spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=550.4 [M+H]+Total runing time is 1.800 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.03-1.21 (m, 6H), 1.97 (d, J=6.27Hz, 4H), 2.04- 2.13 (m, 1H), 2.14-2.32 (m, 3H), 2.91-3.09 (m, 1H), 4.06-4.20 (m, 1H), 4.36-4.47 (m, 1H), 4.51-4.75 (m, 2H), 6.33-6.42 (m, 1H), 7.19 (s, 1H), 7.32 (t, J=8.53Hz, 1H) 7.52 (d, J= 4.52Hz, 1H), 7.63-7.71 (m, 2H), 8.05 (br.s., 1H)
Embodiment 60
(2R) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] propyl- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine, (50 milligrams, 0.111 mM, 1 equivalent), (2R) -2- (t-butoxycarbonyl amino) propionic acid, (24 milligrams, 0.122 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 Milligram, 0.166 mM, 1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to delay It is slow that N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalent) is added.It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane and is stirred at room temperature 3 hours.After reaction, it will react Liquid is spin-dried for obtaining crude product.Crude product HPLC is purified into (instrument again：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.05%HCl water flowing phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13- 23%B, 0-11 minutes) obtain target compound (12 milligrams, yield 18%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=521.3 [M+H]+Total runing time is 1.594 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.52 (dd, J=17.07,7.03Hz, 3H), 1.92-2.11 (m, 5H), 2.13-2.30 (m, 2H), 2.91-3.05 (m, 1H), 4.04 (d, J=13.55Hz, 1H), 4.44-4.69 (m, 3H), 6.38 (q, J=6.53Hz, 1H), 7.18 (d, J=1.25Hz, 1H), 7.31 (t, J=8.53Hz, 1H), 7.53 (dd, J= 9.03,4.77Hz, 1H), 7.66 (d, J=5.77Hz, 2H), 8.02 (s, 1H).
Embodiment 61
(2S) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] propyl- 1- ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), (2S) -2- (t-butoxycarbonyl amino) propionic acid (24 milligrams, 0.122 mM, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 Milligram, 0.166 mM, 1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue It is slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.555 mM, 5 equivalent).It is small that reaction continues stirring 12 at room temperature When.Reaction solution is spin-dried for after reaction, is placed in hydrochloric acid/dioxane (10 milliliters) and is stirred at room temperature 3 hours.Reaction terminates Afterwards, reaction solution is spin-dried for obtaining crude product.Purify (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column： Synergi150*30mm*5u, mobile phase A：0.075%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients： 13-23%B, 0-11 minutes) obtain target compound (13.1 milligrams, yield 19%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=521.3 [M+H]+Total runing time is 1.645 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.08-7.98 (m, 1H), 7.67 (d, J=4.3Hz, 2H), 7.53 (dd, J=4.8,8.5Hz, 1H), 7.32 (t, J=8.7Hz, 1H), 7.19 (s, 1H), 6.38 (d, J=6.5Hz, 1H), 4.70- 4.46 (m, 3H), 4.05 (d, J=16.1Hz, 1H), 3.67-3.57 (m, 1H), 3.46-3.37 (m, 1H), 3.08-2.83 (m, 1H), 2.72 (s, 1H), 2.19 (br.s., 2H), 2.04-1.91 (m, 4H), 1.52 (dd, J=6.4,18.2Hz, 4H)
Embodiment 62
(4S) -4- amino -5- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -5- oxo-pentanamide
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (20 milligrams, 0.044 mM, 1 equivalent), (2S) -5- amino -2- (t-butoxycarbonyl amino) -5- oxo Valeric acid (12 milligrams, 0.049 mM, 1.1 equivalents), 1- hydroxy benzo triazole (7 milligrams, 0.049 mM, 1.1 equivalents) And N, N '-dicyclohexylcarbodiimide (13 milligrams, 0.05 mM, 1.1 equivalents) are dissolved in 5 milliliters of tetrahydrofurans.Then it stirs Under nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (26 milligrams, 0.2 mM, 5 equivalents).Reaction is in room temperature Under continue stirring 3 hours.After reaction, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and salt Each backwash of water is primary, then is spin-dried for after being dried with sodium sulphate, is placed in hydrochloric acid l/ ethyl acetate (5 milliliters) and is stirred at room temperature 3 hours.Instead After answering, reaction solution is spin-dried for obtain compound (4 milligrams, yield 47%)
Spectroscopic data：
LC/MS (method：UFLC)：M/z=578 [M+H]+.
Embodiment 63
2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.11 mM, 1 equivalent), 2- (t-butoxycarbonyl amino) -2- (3- pyridyl group) acetic acid (31 Milligram, 0.12 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (64 milligrams, 0.17 mM, 1.5 equivalent) are dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue It is slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.56 mM, 5 equivalent).It is small that reaction continues stirring 3 at room temperature When.After reaction, reaction solution being diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, It is spin-dried for after being dried again with sodium sulphate, obtained crude product 30 total runing times of stirring in hydrochloric acid/dioxane (4N) are back spin The dry crude product that obtains is using efficient liquid phase separation (instrument：LC8A&Gilson215 fraction collector chromatographic column：Synergi150* 30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：13-35%B, 0-6 Minute) after be spin-dried for obtaining target compound (25 milligrams, yield 52%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=584.1 [M+H]+Total runing time is 1.695 points Clock
1H NMR (400MHz, METHANOL-d4) δ 9.23 (d, J=16.1Hz, 1H), 9.06 (d, J=5.5Hz, 1H), 8.82 (dd, J=8.7,17.9Hz, 1H), 8.34-8.19 (m, 1H), 8.02 (s, 1H), 7.94 (d, J=2.3Hz, 1H), 7.71-7.56 (m, 2H), 7.50 (dt, J=5.0,9.3Hz, 1H), 7.35-7.23 (m, 1H), 7.18-7.06 (m, 1H), 6.40-6.27 (m, 1H), 6.14-6.00 (m, 1H), 4.75-4.59 (m, 1H), 4.56-4.41 (m, 1H), 4.06-3.83 (m, 1H), 3.41 (t, J=11.8Hz, 1H), 3.16-2.86 (m, 2H), 2.23-1.99 (m, 3H), 1.98-1.82 (m, 4H), 1.44-1.33 (m, 1H), 1.21 (d, J=11.8Hz, 1H)
Embodiment 64 and 65
(2R) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone
(2S) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- Pyridyl group] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone
Operating procedure：
By compound 2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] - 3- pyridyl group] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone (24 milligrams, 0.041 mM, implemented by 1 equivalent Example 63) carry out chirality SFC isolated target compound (2R) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- Two chloro- 3- fluoro-phenyls) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone (3.6 millis Gram) and (2S) -2- amino -1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone (5.8 milligrams).
The spectroscopic data of embodiment 64：
LC/MS (method：UFLC)：M/z=584.1 [M+H]+
The spectroscopic data of embodiment 65：
LC/MS (method：UFLC)：M/z=584.1 [M+H]+
Embodiment 66
1- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl] -3- methyl-urea
Operating procedure：
By 2- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base]
- 1- piperidyl] ethyl ketone (80 milligrams, 0.157 mM, 1 equivalent, embodiment 17), N- methyl amido formyl chloride (29 Milligram, 0.315 mM, 2 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then by compound 1 under stirring, ice bath and nitrogen protection (29 milligrams, 0.315 mM, 2 equivalents) are added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.Reaction terminates Afterwards, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate It is spin-dried for after dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% carbonic acid Hydrogen ammonia, gradient elution 36% to 66% (volume ratio), freeze-drying obtains target compound (33.5 after removing volatile component under reduced pressure Milligram, yield 33.5%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.368 minutes；M/z=563.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.87 (d, J=6.53Hz, 4H), 1.92-2.04 (m, 2H), 2.08- 2.20 (m, 2H), 2.66-2.74 (m, 3H), 2.81-2.93 (m, 1H), 3.22-3.28 (m, 1H), 3.96-4.11 (m, 3H), 4.40-4.48 (m, 1H), 4.61 (br.s., 1H), 6.18 (q, J=6.69Hz, 1H), 6.93 (d, J=1.51Hz, 1H), 7.23 (t, J=8.66Hz, 1H), 7.46 (dd, J=9.03,4.77Hz, 1H), 7.55 (s, 1H), 7.67 (d, J=1.51Hz, 1H), 7.84 (s, 1H)
Embodiment 67
1- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl] -3- ethyl-urea
Operating procedure：
By 2- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] ethyl ketone (117 milligrams, 0.22 mM, 1 equivalent), N, N '-diisopropylethylamine (110 milligrams, 0.86 mM, 4 equivalents) it is dissolved in 3 milliliters of methylene chloride.Then ethyl isocyanate (16 millis under stirring, ice bath and nitrogen protection Gram, 0.23 mM, 1.1 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.After reaction, will Reaction solution is diluted with methylene chloride, and organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then with after sodium sulphate drying It is spin-dried for, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% bicarbonate Ammonia, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target compound (4 millis after removing volatile component under reduced pressure Gram, yield 3.3%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.423 minutes；M/z=577.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.14 (t, J=7.28Hz, 3H), 1.88-2.00 (m, 4H), 2.11- 2.24 (m, 2H), 2.84-2.99 (m, 1H), 3.13-3.24 (m, 2H), 3.62 (s, 1H), 3.98-4.08 (m, 2H), 4.09- 4.18 (m, 1H), 4.45-4.55 (m, 1H), 4.62 (d, J=12.05Hz, 1H), 6.38 (q, J=6.69Hz, 1H), 7.19 (d, J=1.25Hz, 1H), 7.32 (t, J=8.53Hz, 1H), 7.53 (dd, J=9.03,4.77Hz, 1H), 7.63 (d, J= 1.51Hz, 1H), 7.64-7.69 (m, 1H), 7.96-8.01 (m, 1H)
Embodiment 68
N- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl] albendazole
Operating procedure：
By 2- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] ethyl ketone, (80 milligrams, 0.158 mM, 1 equivalent), N, N '-diisopropylethylamine (40 milligrams, 0.316 mM, 2 equivalents) it is dissolved in 3 milliliters of methylene chloride.Then by methylchloroformate (300 under stirring, ice bath and nitrogen protection Milligram, 0.32 mM, 2 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.After reaction, will Reaction solution is diluted with methylene chloride, and organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then with after sodium sulphate drying It is spin-dried for, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% bicarbonate Ammonia, gradient elution 36% to 66% (volume ratio), freeze-drying obtains target compound (7.2 millis after removing volatile component under reduced pressure Gram, yield 90%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.456 minutes；M/z=564.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 0.84-1.08 (m, 2H), 1.30 (s, 1H), 1.43-1.63 (m, 2H), 1.73-1.88 (m, 1H), 1.88-2.06 (m, 5H), 2.10-2.25 (m, 2H), 2.82-2.98 (m, 1H), 3.69 (s, 3H), 3.96-4.14 (m, 3H), 4.46-4.56 (m, 1H), 4.62 (d, J=14.56Hz, 1H), 6.38 (q, J=6.78Hz, 1H), 7.19 (d, J=1.51Hz, 1H), 7.32 (t, J=8.66Hz, 1H), 7.54 (dd, J=9.03,4.77Hz, 1H), 7.63 (d, J =1.51Hz, 1H), 7.66 (s, 1H), 7.98 (s, 1H)
Embodiment 69
N- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl] Methanesulfonamide
Operating procedure：
By 2- amino -1- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -1- base] -1- piperidyl] ethyl ketone, (5 milligrams, 0.1 mM, 1 equivalent), N, N '-diisopropylethylamine (25 milligrams, 0.2 milli Mole, 2 equivalents) it is dissolved in 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection by mesyl chloride (20 milligrams, 0.11 MM, 1.1 equivalents) it is added dropwise.It obtains reaction solution and continues stirring 10 minutes at room temperature.After reaction, by reaction solution It is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, obtain To crude product (mobile phase is separated on C18 reversed-phase column using high performance liquid chromatography：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient are washed De- 36% to 66% (volume ratio) removes freeze-drying after volatile component under reduced pressure and obtains target compound (5 milligrams, yield is 8.7%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.373 minutes；M/z=584.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.90-1.99 (m, 4H), 2.08-2.22 (m, 2H), 2.97-3.02 (m, 3H), 3.96-4.04 (m, 1H), 4.08 (d, J=13.55Hz, 2H), 6.26-6.45 (m, 1H), 7.08-7.18 (m, 1H), 7.29 (s, 1H), 7.51 (dd, J=9.03,4.77Hz, 1H), 7.57-7.67 (m, 2H), 7.89-8.03 (m, 1H)
Embodiment 70
1- [2- [4- [4- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl] -2- oxo-ethyl-urea
Operating procedure：
By compound 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (23 milligrams, 0.05 mM, 1 equivalent), 2- hydantoic acid (7 milligrams, 0.06 mM, 1.2 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (29 milligrams, 0.075 mM, 1.5 equivalents) are molten In 2 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (33 millis Gram, 0.25 mM, 5 equivalents).Reaction continues stirring 2 hours at room temperature.After reaction, by reaction solution methylene chloride Dilution, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then are spin-dried for after being dried with sodium sulphate, and obtained crude product is adopted (mobile phase is separated on C18 reversed-phase column with high performance liquid chromatography：Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 36% to 66% (volume ratio), freeze-drying obtains target compound (7 milligrams, yield 25%) after removing volatile component under reduced pressure
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.166 minutes；M/z=549.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.14-1.45 (m, 1H), 1.85-2.08 (m, 5H), 2.15 (d, J= 14.05Hz, 2H), 2.67 (br.s., 1H), 2.81-3.03 (m, 1H), 4.04-4.29 (m, 2H), 4.39-4.70 (m, 2H), 6.26-6.44 (m, 1H), 7.12-7.20 (m, 1H), 7.25-7.33 (m, 1H), 7.51 (dd, J=8.78,4.52Hz, 1H), 7.59-7.69 (m, 2H), 7.89-8.06 (m, 1H)
Embodiment 71
1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] -2- (3- pyridyl group) ethyl ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (100 milligrams, 0.222 mM, 1.0 equivalents), 2- (3- pyridyl group) acetic acid, (42 milligrams, 0.245 mmoles You, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (126 milligrams, 0.334 MM, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '- Diisopropylethylamine (0.143 milligram, 1.11 mMs, 5 equivalents).Reaction continues stirring 2 hours at room temperature.Reaction terminates Afterwards, reaction solution is diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry with sodium sulphate It is spin-dried for after dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% carbonic acid Hydrogen ammonia, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target compound after removing volatile component under reduced pressure (23.3 milligrams, yield 18.5%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.127 minutes；M/z=568.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.83-1.98 (m, 5H), 2.12 (d, J=3.26Hz, 2H), 2.87 (t, J=11.67Hz, 1H), 3.33-3.40 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=13.80Hz, 1H), 4.43 (tt, J =11.42,4.02Hz, 1H), 4.59-4.69 (m, 1H), 6.16 (q, J=6.69Hz, 1H), 6.92 (d, J=1.51Hz, 1H), 7.22 (t, J=8.66Hz, 1H), 7.38-7.47 (m, 2H), 7.55 (s, 1H), 7.66 (d, J=1.51Hz, 1H), 7.72- 7.79 (m, 1H), 7.79-7.84 (m, 1H), 8.35-8.60 (m, 2H)
Embodiment 72
1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] -2- (4- pyridyl group) ethyl ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (100 milligrams, 0.227 mM, 1 equivalent), 2- (4- pyridyl group) acetic acid (42 milligrams, 0.245 mM, 1.1 equivalents) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (126 milligrams, 0.334 milli Mole, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-two Wopropyl ethyl amine (143 milligrams, 1.1 mMs, 1 equivalent).Reaction continues stirring 3 hours at room temperature.It after reaction, will be anti- Liquid is answered to be diluted with methylene chloride, organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then dry back spin with sodium sulphate Dry, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% ammonium hydrogencarbonate, Gradient elution 36% to 66% (volume ratio) removes freeze-drying after volatile component under reduced pressure and obtains target compound (72 milligrams, produce Rate is 57%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.977 minutes；M/z=568.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.87 (d, J=6.53Hz, 3H), 1.89-1.99 (m, 2H), 2.12 (d, J=11.80Hz, 2H), 2.81-2.94 (m, 1H), 3.24-3.35 (m, 2H), 3.88-3.92 (m, 1H), 4.13 (d, J= 14.05Hz, 1H), 4.42 (tt, J=11.36,3.95Hz, 1H), 4.67 (d, J=13.05Hz, 1H), 6.16 (q, J= 6.53Hz, 1H), 6.92 (d, J=1.25Hz, 1H), 7.21 (t, J=8.53Hz, 1H), 7.38 (d, J=6.02Hz, 2H), 7.43 (dd, J=8.91,4.89Hz, 1H), 7.52-7.60 (m, 2H), 7.61-7.71 (m, 2H), 7.81 (s, 1H), 8.50 (d, J=5.52Hz, 2H)
Embodiment 73
1- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] -2- (2- pyridyl group) ethyl ketone
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (100 milligrams, 0.227 mM, 1.1 equivalents), 2- (2- pyridyl group) acetic acid (42 milligrams, 0.245 mmoles You, 1.1 equivalent) and N, N, N ', N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (126 milligrams, 0.334 mM, 1.5 equivalents) it is dissolved in 5 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (143 milligrams, 1.11 mMs, 5 equivalents).Reaction continues stirring 3 hours at room temperature.Reaction knot Shu Hou dilutes reaction solution with methylene chloride, and organic layer sodium bicarbonate solution and each backwash of saline solution are primary, then use sodium sulphate It is spin-dried for after drying, obtained crude product separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% carbon Sour hydrogen ammonia, gradient elution 36% to 66% (volume ratio)), freeze-drying obtains target compound after removing volatile component under reduced pressure (109 milligrams, yield 86.5%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.101 minutes；M/z=568.1 [M+H]+total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.82-1.92 (m, 4H), 1.92-2.00 (m, 1H), 2.06-2.18 (m, 2H), 2.84-2.95 (m, 1H), 3.26-3.35 (m, 4H), 3.97-4.07 (m, 1H), 4.24 (d, J=13.80Hz, 1H), 4.43 (tt, J=11.29,4.02Hz, 1H), 4.67 (d, J=13.30Hz, 1H), 6.18 (q, J=6.53Hz, 1H), 6.94 (d, J=1.76Hz, 1H), 7.24 (t, J=8.66Hz, 1H), 7.32 (dd, J=7.28,5.27Hz, 1H) 7.38-7.48 (m, 2H), 7.56 (s, 1H), 7.68 (d, J=1.76Hz, 1H), 7.78-7.86 (m, 2H), 8.47-8.54 (m, 1H)
Embodiment 74
3- [1- (2,6- dichlorophenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridyl group -2- amine
Operating procedure：
This compound is prepared by previously described method.
Spectroscopic data：
LC/MS (method：UFLC)：M/z=432 [M+H]+
Embodiment 75
2- [4- [4- [6- amino -5- [1- (2,6- dichlorophenyl) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] -1- piperidines Base]-N- methyl acetamide
Operating procedure：
This compound is prepared by previously described method.
Spectroscopic data：
LC/MS (method：UFLC)：M/z=503 [M+H]+
Embodiment 76
2- [4- [4- [6- amino -5- [1- (the chloro- 6- methoxyl group-phenyl of 2-) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- methyl acetamide
Step A：
The chloro- 3- methoxyl group-benzene of 2- (1- bromoethyl) -1-
Operating procedure：
To ice bath it is cooling dissolved with compound 1- (the chloro- 6- methoxyphenyl of 2-) ethyl alcohol (93 milligrams, 0.5 mM, 1.0 Equivalent) and anhydrous methylene chloride (5 milliliters) solution of 4-dimethylaminopyridine (6 milligrams, 0.05 mM, 0.1 equivalent) in drip This mixture of phosphorus tribromide (148 milligrams, 0.55 mM, 1.1 equivalents) is added to be stirred at room temperature 2 hours.It is added under zero degree Water (1 milliliter) and with (10 milliliter * 3) extraction organic layer of methylene chloride with sodium sulphate it is dry after be spin-dried for, obtained crude product chemical combination Object.This crude Compound with thin layer chromatography prepare plate (petroleum ether: ethyl acetate=5: 1) obtain target compound (70 milli Gram, 50%).
Step B：
2- [4- [4- [6- amino -5- [1- (the chloro- 6- methoxyl group-phenyl of 2-) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- methyl acetamide
Operating procedure：
To ice bath is cooling and nitrogen protection contains compound 2- [4- [4- (6- amino -5- hydroxyl -3- pyridyl group) pyrazoles - 1- yl] -1- piperidyl]-N- methyl acetamide (93 milligrams, 0.28 mM, 1.0 equivalents) anhydrous N, N '-dimethyl formyl This mixed liquor of amine (3 milliliters) addition sodium hydrides (13 milligrams, 0.34 mM, 1.2 equivalents, in the content of mineral oil 60%) is 0 After 30 total runing times of the lower stirring of degree are, then be added dropwise the chloro- 3- methoxyl group-benzene of compound 2- (1- bromoethyl) -1- (70 milligrams, 0.28 mM, 1.0 equivalents) N, N '-dimethyl formamide (3 milliliters).This mixture is stirred at room temperature overnight.At 0 degree It is lower that saline solution (5 milliliters) are added and extract the organic layer sodium bicarbonate solution and food that merges with (10 milliliter * 3) of ethyl acetate Each backwash of salt water is primary, then the crude product being spin-dried for after dry with sodium sulphate, this crude product, which is used, is purified with HPLC using efficient liquid Phase chromatography separates (mobile phase on C18 reversed-phase column：Acetonitrile/water/0.5% the ammonium hydrogen carbonate, (volume of gradient elution 25% to 55% Than), obtain target compound (10 milligrams, yield 7%).
Spectroscopic data：
LC/MS (method：UFLC)：RT ,=1.79 minutes；M/z=499.2 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 7.85 (s, 1H), 7.53-7.67 (m, 2H), 7.18-7.31 (m, 1H), 7.11 (d, J=1.76Hz, 1H), 7.01 (dd, J=8.16,1.38Hz, 2H), 6.18 (q, J=6.36Hz, 1H), 4.13- 4.34 (m, 1H), 3.94 (s, 3H), 3.17 (s, 2H), 3.07 (d, J=11.54Hz, 2H), 2.82 (s, 3H) 2.39-2.56 (m, 2H), 2.01-2.31 (m, 4H), 1.85 (d, J=6.78Hz, 3H), 1.32 (br.s., 3H).
Embodiment 77
2- [4- [4- [6- amino -5- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- methyl acetamide
Step A：
3,5- bis- chloro- 4- [1- [(2- nitro -3- pyridyl group) oxygen] ethyl] pyridines
Operating procedure：
Past compound 1- (3,5- bis- chloro- 4- pyridyl group) ethyl alcohol (180 milligrams, 0.94 mM, 1 equivalent) under zero degree, (357 milligrams, 1.12 mMs, 1.5 work as 2- nitropyridine -3- alcohol (131 milligrams, 0.94 mM, 1 equivalent) and triphenylphosphine Amount) 10 milliliters of addition diisopropyl azodiformates of anhydrous tetrahydro furan (227 milligrams, 1.12 mMs, 1.5 equivalents) it is anti- Is spin-dried for after answering liquid that 12 hours are stirred at room temperature water (20 milliliters) are then added into reaction solution and (3* is extracted with ethyl acetate 20 milliliters) organic layer dries, filters after being spin-dried for sodium sulphate after merging and with thin layer chromatography prepares plate (petroleum ether: acetic acid second Ester=2: 1) purifying obtains target compound (180 milligrams, yield 61%)
Step B：
3- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] pyridine -2- amine
Operating procedure：
By compound 3, and the chloro- 4- of 5- bis- [1- [(2- nitro -3- pyridyl group) oxygen] ethyl] pyridine (180 milligrams, 0.57 mmoles You, 1 equivalent), 4.2 grams of iron powder (160 milligrams, 2.87 mMs, 5 equivalents) and ammonium chloride (45.5 milligrams, 0.86 mM, 1.5 Equivalent) it is dissolved in 5 milliliters of ethyl alcohol and 1 milliliter of ethyl alcohol reaction solution diatomite after 6 hours that flows back filters and (10 in the least with methanol Rise) it washs that water (10 milliliters) are added after filtrate decompression is concentrated and are extracted with ethyl acetate after (3*20 milliliters) organic layer merges and uses Sodium sulphate dries, filters be spin-dried for after with thin layer chromatography prepare plate (petroleum ether: ethyl acetate=1: 1) purifying obtain targeted Close object (100 milligrams, yield 61.8%)
Step C：
The bromo- 3- of 5- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] pyridine -2- amine
Operating procedure：
In zero degree, toward compound 3- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] pyridine -2- amine, (100 milligrams, 0.35 in the least Mole, 1 equivalent) acetonitrile (20 milliliters) solution in be added portionwise N- bromo-succinimide (75 milligrams, 0.42 mM, 1.2 Equivalent) it reacts after and stirs hour addition saturated sodium bicarbonate aqueous solution (5 milliliters) under 0 degree and extracted with ethyl acetate Take (3*20 milliliters) organic layer merge after dried, filtered with sodium sulphate be spin-dried for after with thin layer chromatography prepare plate (petroleum ether: Ethyl acetate=1: 1) purifying obtains target compound (86 milligrams, yield 93%)
Step D：
3- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyridine -2- amine behaviour Make step：
Under nitrogen protection, to dissolved with the bromo- 3- of compound 5- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] pyridine -2- Amine (86 milligrams, 0.24 mM, 1 equivalent) and compound 4- [4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes - 2- yl) pyrazol-1-yl] piperidines -1- t-butyl formate (134 milligrams, 0.35 mM, 1.5 equivalents) saturation sodium bicarbonate 1,1 '-bis- (diphenylphosphine) ferrocene palladium chloride (17 millis are added in the mixed solution of aqueous solution (5 milliliters) and acetonitrile (5 milliliters) Gram, 0.024 mM, 10% equivalent).After adding, mixture in microwave under 100 degree react 30 total runing times be this Reaction solution is cooled to room temperature and pours into 20 milliliters of water and extract the organic phase salt that merges with (30 milliliter * 2) of ethyl acetate Water backwash is primary, then obtains crude Compound after being spin-dried for after being dried with sodium sulphate.This crude Compound flash column (petroleum Ether: it ethyl acetate=1: 1), is then dissolved in methylene chloride (10 milliliter) solution and is added hydrochloric acid methanol (0.3 milliliter, 4 mole Every liter).Reaction is in 0 degree of 3 hour of stirring.Directly it is spin-dried for obtaining target compound (35 milligrams)
Step E：
2- [4- [4- [6- amino -5- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] -3- pyridyl group] pyrazol-1-yl] - 1- piperidyl]-N- methyl acetamide
Operating procedure：
By compound 3- [1- (3,5- bis- chloro- 4- pyridyl group) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (35 milligrams, 0.066 mM), the bromo- N- methyl acetamide of 2- (13 milligrams, 0.087 mM), sodium iodide (1 milli Gram, 0.0067 mM) and potassium carbonate (73 milligrams, 0.54 mM) be dissolved in after ethyl alcohol (3 milliliters) under 80 degree react 12 Hour.It is then cooled to room temperature, reaction solution is diluted with saturated salt solution (10ml), and is extracted with (10 milliliter * 2) of ethyl acetate The organic phase for taking to merge is primary with saline solution backwash, then obtains crude Compound after being spin-dried for after being dried with sodium sulphate.It is obtained Crude product uses to be purified with HPLC separates (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% ammonium hydroxide, Gradient elution 25% to 55% (volume ratio), obtaining target compound, (13 milligrams, 39%) two step yields are.Spectroscopic data：
LC/MS (method：UFLC)：RT=2.41 minutes；M/z=504.1 [M+H]+total runing time is 7.0 minutes
1H NMR (400MHz, METHANOL-d4) δ 8.56 (s, 2H), 7.85 (s, 1H), 7.71 (d, J=1.76Hz, 1H), 7.59 (s, 1H), 6.94 (d, J=1.51Hz, 1H), 6.19 (q, J=6.78Hz, 1H), 4.13-4.24 (m, 1H), 3.08 (s, 2H), 2.99 (d, J=11.80Hz, 2H), 2.82 (s, 3H), 2.32-2.42 (m, 2H), 2.04-2.23 (m, 4H), 1.89 (d, J =6.53Hz, 3H).
Embodiment 78
2- [4- [4- [6- amino -5- [1- [the chloro- 6- of 2- (cyclopropyl oxygroup) phenyl] ethyoxyl] -3- pyridyl group] pyrazoles -1- Base]
- 1- piperidyl]-N- methyl acetamide
Step A：
2- (1- bromoethyl) -1- chloro- 3- (cyclo propyl methoxy) benzene
Operating procedure：
To ice bath it is cooling dissolved with compound 1- [2- chloro- 6- (cyclo propyl methoxy) phenyl] ethyl alcohol (113 milligrams, 0.5 milli Mole, 1.0 equivalents) and 4-dimethylaminopyridine (6 milligrams, 0.05 mM, 0.1 equivalent) anhydrous methylene chloride (5 milliliters) This mixture of phosphorus tribromide (148 milligrams, 0.55 mM, 1.1 equivalents) is added dropwise in solution to be stirred at room temperature 2 hours.Zero Degree is lower to be added water (1 milliliter) and with (10 milliliter * 3) extraction organic layer of methylene chloride with being spin-dried for after sodium sulphate drying, obtains Crude Compound.This crude Compound with thin layer chromatography prepare plate (petroleum ether: ethyl acetate=5: 1) purifying obtain target Compound (80 milligrams, 56%).
Step B：
2- [4- [4- [6- amino -5- [1- [the chloro- 6- of 2- (cyclopropyl oxygroup) phenyl] ethyoxyl] -3- pyridyl group] pyrazoles -1- Base]
- 1- piperidyl]-N- methyl acetamide
Operating procedure：
To ice bath is cooling and nitrogen protection contains compound 2- [4- [4- (6- amino -5- hydroxyl -3- pyridyl group) pyrazoles - 1- yl] -1- piperidyl]-N- methyl acetamide (91 milligrams, 0.28 mM, 1.0 equivalents) anhydrous N, N '-dimethyl formyl This mixed liquor of amine (3 milliliters) addition sodium hydrides (13 milligrams, 0.34 mM, 1.2 equivalents, in the content of mineral oil 60%) exists After being stirred 30 minutes under zero degree, then be added dropwise compound 2- (1- bromoethyl) -1- chloro- 3- (cyclo propyl methoxy) benzene (70 milligrams, 0.28 mM, 1.0 equivalents) N, N '-dimethyl formamide (3 milliliters).This mixture is stirred at room temperature overnight.At 0 degree It is lower that saline solution (5 milliliters) are added and extract the organic layer sodium bicarbonate solution and food that merges with (10 milliliter * 3) of ethyl acetate Each backwash of salt water is primary, then the crude product being spin-dried for after dry with sodium sulphate, this crude product, which is used, is purified with HPLC using efficient liquid Phase chromatography separates (mobile phase on C18 reversed-phase column：Acetonitrile/water/0.5% the ammonium hydrogen carbonate, (volume of gradient elution 25% to 55% Than), obtain target compound (25 milligrams, yield 16.8%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.40 minutes；M/z=539.2 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 7.82 (s, 1H), 7.63 (d, J=1.51Hz, 1H), 7.55 (s, 1H), 7.17-7.26 (m, 1H), 7.10 (d, J=1.51Hz, 1H), 6.97 (dd, J=11.29,8.28Hz, 2H), 6.18 (q, J= 6.61Hz, 1H), 5.51 (s, 1H), 4.13-4.25 (m, 1H), 3.87-4.02 (m, 2H), 3.08 (s, 2H), 3.00 (d, J= 11.80Hz, 2H), 2.82 (s, 3H), 2.33-2.43 (m, 2H), 2.04-2.23 (m, 4H), 1.87 (d, J=6.53Hz, 3H), 1.30-1.44 (m, 1H), 0.63-0.73 (m, 2H), 0.36-0.46 (m, 2H)
Embodiment 79
2- [4- [4- [6- amino -5- [1- (2,6- dichlorophenyl) -2,2,2- trifluoro-ethoxies] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl acetamide
Step A：
[1- (2,6- dichlorophenyl) -2,2,2- trifluoro ethyls] triflate
Operating procedure：
Under nitrogen protection under zero degree, sodium hydride (33 milligrams, 816 micro- mMs) is slowly added to compound 1- (2,6- dichlorophenyl) -2, in the tetrahydrofuran (8 milliliters) of 2,2- trifluoroethanols (100 milligrams, 408 micro- mMs) and in room Temperature 1 hour of stirring, then (138 milligrams, 816 micro- mMs) of paratoluensulfonyl chloride are added, reaction continues to stir at room temperature It reacts and is diluted with water after mixing overnight, water layer is extracted with dichloromethane, and organic layer separates, and drying is directly used in next step after being spin-dried for.
Step B：
2- [4- [4- [6- amino -5- [1- (2,6- dichlorophenyl) -2,2,2- trifluoro-ethoxies] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl acetamide
Operating procedure：
By compound 2- [4- [4- (6- amino -5- hydroxyl -3- pyridyl group) pyrazol-1-yl] -1- piperidyl]-N- methyl - Acetamide (50 milligrams, 151 micro- mMs) and cesium carbonate (60 milligrams, 184 mMs) are added to compound [1- (2,6- dichloros Phenyl) -2,2,2- trifluoro ethyls] triflate (57 milligrams, 151 micro- mMs) n,N-Dimethylformamide (20 milli Rise) solution in, reaction is reacted 12 hours at 25 degrees c, and rear reaction is diluted with water and is extracted with ethyl acetate three times, is had Machine layer is spin-dried for after separating with sodium sulphate drying.Crude product HPLC purifies (instrument：LC8A&Gilson215 fraction collector chromatography Column：Synergi150*30mm*5u, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration ladders Degree：13-23%B, 0-11 minutes) after obtain 6.7 milligrams of target compounds.
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.77 minutes；M/z=557.2 [M+H]+total runing time is 6.00 points Clock
Embodiment 80
4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl-butyramide
Step A：
4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-ethyl butyrate
Operating procedure：
By 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (150 milligrams, 0.33 mM, 1 equivalent), 4- bromobutyrate (77 milligrams, 0.4 mM, 1.2 equivalents), three second Amine (67 milligrams, 0.66 mM, 2 equivalents) is dissolved in n,N-Dimethylformamide (2 milliliters) and reacting 4 hours for 80 DEG C.Finish, water It in (10 milliliters) addition reaction solutions, is extracted through ethyl acetate (10 milliliters × 3), merges organic phase, evaporating solvent under reduced pressure obtains mesh It marks compound (90 milligrams, yield 47.8%).
Step B：
4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-butyric acid
Operating procedure：
By compound 4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridine Base] pyrazol-1-yl]
- 1- piperidyl]-ethyl butyrate (90 milligrams, 0.16 mM, 1 equivalent) is dissolved in methanol (0.2 milliliter), it is added 2 (4 milliliters) of sodium hydrate aqueous solution of mol/L stir 1 hour, and then (0.5 milliliter) adjusting pH value of enriching hydrochloric acid is 2.Decompression Solvent is evaporated off and obtains target compound.
Step C：
4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl-butyramide
Operating procedure：
Under ice-water bath, 2 mol/L methylamine tetrahydrofuran solutions (0.3 milliliter, 0.6 mM, 4 equivalents) are slowly dripped Solubilization has N, N, N ', and N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (85 milligrams, 0.0.224 mmoles You, 1.5 equivalent), compound 4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyrrole Piperidinyl] pyrazol-1-yl] -1- piperidyl]-butyric acid (80 milligrams, 0.15 mM, 1 equivalent), drop is complete, continues to stir at room temperature 2 hours, reaction solution separated (mobile phase using high performance liquid chromatography on C18 reversed-phase column：Acetonitrile/water/0.5% ammonium hydrogen carbonate, ladder 43% to 53% (volume ratio) of degree elution), remove under reduced pressure freeze-drying after volatile component obtain target compound (13 milligrams, always Yield is 15.8%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=2.957 minutes；M/z=549.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.09 (s, 1H), 7.87-7.81 (m, 1H), 7.69 (d, J=1.8Hz, 1H), 7.57 (s, 1H), 7.48 (dd, J=4.8,9.0Hz, 1H), 7.26 (t, J=8.7Hz, 1H), 6.95 (d, J=1.5Hz, 1H), 6.20 (q, J=6.8Hz, 1H), 4.65 (br.s., 2H), 4.30-4.18 (m, 1H), 3.19 (d, J=12.5Hz, 2H), 2.75 (s, 3H), 2.56 (t, J=7.5Hz, 2H), 2.45-2.33 (m, 2H), 2.28 (t, J=7.3Hz, 2H), 2.20-2.06 (m, 4H), 1.96-1.80 (m, 5H)
Embodiment 81
5- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl-pentanamide
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.11 mM, 1.0 equivalents), the bromo- N- methylpentanamide of 5- (32 milligrams, 0.12 mM, 1.1 equivalents) and potassium carbonate (122 milligrams, 0.88 mM, 8 equivalent) be dissolved in 10 milliliters of ethyl alcohol.Then it stirs, in nitrogen protection Under, continuously add sodium iodide (1.5 milligrams 0.01 mM, 0.1 equivalent).Reaction continues stirring 12 hours in the case where being heated to reflux. After reaction, crude Compound is obtained after solvent being spin-dried for.This obtained crude product, which is used, is purified with HPLC using efficient liquid phase Chromatography separates (mobile phase on C18 reversed-phase column：Acetonitrile/alkaline water, gradient elution 43% to 73% (volume ratio)), obtain target Compound (4 milligrams, yield 6%).
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=563.2 [M+H]+Total runing time is 1.892 points Clock
Embodiment 82
4- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl -4- oxo-butyramide
Operating procedure：
By compound 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- Base] pyridine -2- amine (50 milligrams, 0.111 mM, 1 equivalent), 4- (methylamino) -4- oxo-butynic acid (16 milligrams, 0.12 MM, 1.1 equivalent) and N, N, N, N '-tetramethyl-O- (7- azepine benzo triazol-1-yl) hexafluorophosphoric acid urea (63 milligrams, 0.16 mM, 1.5 equivalent) it is dissolved in 10 milliliters of methylene chloride.Then under stirring, ice bath and nitrogen protection, continue to be slowly added to N, N '-diisopropylethylamine (72 milligrams, 0.55 mM of 5 equivalent).Reaction continues stirring 12 hours at room temperature.Reaction terminates Reaction solution is spin-dried for afterwards to obtain crude product, purifies (instrument with HPLC：LC8A&Gilson215 fraction collector chromatographic column：Ge minutes I150*30mm*4um, mobile phase A：0.05%HCl water, Mobile phase B：Acetonitrile, flow velocity：30mL/ minutes concentration gradients：15-40% B, 0-8 minutes) obtain target compound (47 milligrams, yield 74%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=7.00 minutes；M/z=563.1 [M+H]+Total runing time is 2.321 points Clock
1H NMR (400MHz, METHANOL-d4) δ 8.05 (s, 1H), 7.71 (s, 1H), 7.66 (d, J=1.5Hz, 1H), 7.53 (dd, J=4.9,8.9Hz, 1H), 7.32 (t, J=8.5Hz, 1H), 7.19 (d, J=1.5Hz, 1H), 6.39 (q, J= 6.7Hz, 1H), 4.64 (d, J=11.0Hz, 1H), 4.58-4.47 (m, 1H), 4.17 (d, J=13.6Hz, 1H), 3.00-2.76 (m, 7H), 2.72-2.57 (m, 2H), 2.39-2.01 (m, 4H), 1.99-1.85 (m, 4H).
Embodiment 83
2- [4- [4- [6- amino -5- [(1R) -1- (2,-two chloro- 3- fluoro-phenyls) ethyoxyl] -3- pyridyl group] pyrazoles -1- Base] -1- piperidyl]-N- methyl-ethane sulphonamide
Step A：
N- methylethesulfonamides
Operating procedure：
Under ice bath, 4- chloroethene alkanesulphonyl chlorides (200 milligrams, 1.23 mMs, 1 equivalent) are slowly dropped to 2 mol/Ls (249 milligrams, 2.46 mMs, 2 work as methylamine tetrahydrofuran solution (0.68 milliliter, 1.36 mMs, 1.1 equivalents) and triethylamine Amount) dichloromethane solution (2 milliliters) in, drop finish, be maintained under ice bath and stir 2 hours, water (10 milliliters) and methylene chloride (10 Milliliter) it is added in reaction flask, water phase is extracted through methylene chloride (10 milliliters × 3), merges organic phase, and evaporating solvent under reduced pressure obtains mesh It marks compound (79 milligrams, yield 53%).
Step B：
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl-ethane sulphonamide
Operating procedure：
It will be dissolved with 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] Pyridine -2- amine (70 milligrams, 0.156 mM, 1 equivalent), and compound N-methy ethenesulfonamide (37.7 milligrams, 0.312 milli Mole, 2 equivalent) methanol (0.5 milliliter) solution stir at room temperature 24 hours, reaction solution using high performance liquid chromatography it is anti-in C18 (mobile phase is separated on phase column：Acetonitrile/water/0.5% ammonium hydrogen carbonate, gradient elution 42% to 52% (volume ratio) remove under reduced pressure easily Freeze-drying obtains target compound (22 milligrams, yield 25%) after the component of volatilization
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.043 minutes；M/z=571.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, METHANOL-d4) δ 1.87 (d, J=6.53Hz, 3H), 1.99-2.16 (m, 4H), 2.21- 2.35 (m, 2H), 2.74 (s, 3H), 2.85 (t, J=7.28Hz, 2H), 3.08 (d, J=11.54Hz, 2H), 3.27 (d, J= 7.53Hz
2H), 3.35 (s, 1H), 4.09-4.22 (m, 1H), 5.49 (s, 8H), 6.17 (q, J=6.78Hz, 1H), 6.92 (s, 1H), 7.23 (t, J=8.53Hz, 1H), 7.45 (dd, J=8.66,4.89Hz, 1H), 7.55 (s, 1H), 7.67 (s, 1H), 7.81 (s, 1H)
Embodiment 84
3- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl]-N- methyl-propan -1- sulfonamide
Operating procedure：
This compound is prepared by previously described method.
Spectroscopic data：
LC/MS (method：UFLC)：M/z=585 [M+H]+
Embodiment 85
2- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] ethane sulphonamide
Operating procedure：
This compound is prepared by previously described method.
Spectroscopic data：
LC/MS (method：UFLC)：M/z=557 [M+H]+
Embodiment 86
3- [4- [4- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 1- yl] -1- piperidyl] the amyl- 2- alkene -1- ketone of ring
Operating procedure：
By 3- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [1- (4- piperidyl) pyrazoles -4- base] pyrrole Pyridine -2- amine (100 milligrams, 0.222 mM, 1 equivalent), 1,3- cyclopentanedione (23.7 milligrams, 0.267 mM, 1.2 equivalents) And p-methyl benzenesulfonic acid (3.8 milligrams, 0.022 mM, 0.1 equivalent) in 0.5 milliliter reflux in toluene 14 hours.It is true through LCMS It is fixed to remove toluene under reduced pressure after reaction and obtain residue, (flowing is separated on the reversed-phase column of C18 using high performance liquid chromatography Phase：Acetonitrile/water/0.5% ammonium hydrogencarbonate after gradient elution 40% to 50% (volume ratio) removes volatile component under reduced pressure, is frozen It is dry to obtain target compound (22 milligrams, yield 18.8%)
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.695 minutes；M/z=530.1 [M+H]+Total runing time is 7.00 points Clock
1H NMR (400MHz, CHLOROFORM-d) δ 0.81-0.94 (m, 1H), 1.25 (br.s., 1H), 1.72 (br.s., 3H), 1.86 (d, J=6.78Hz, 3H), 2.09 (d, J=10.04Hz, 2H), 2.25 (d, J=11.80Hz, 2H), 2.41-2.53 (m, 2H), 2.61-2.74 (m, 2H), 3.21 (t, J=12.55Hz, 2H), 3.49 (s, 2H), 3.88 (br.s., 2H) 4.38 (t, J=11.17Hz, 1H), 4.85 (br.s., 2H), 5.15 (s, 1H), 6.07 (q, J=6.44Hz, 1H), 6.87 (s, 1H), 7.01-7.12 (m, 1H), 7.30 (dd, J=8.78,4.77Hz, 1H), 7.50 (s, 1H), 7.57 (s, 1H), 7.74 (s, 1H)
Embodiment 87
2- [4- [1- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles - 4- yl] -1- piperidyl]-N- methyl acetamide
Step A：
2- [4- [1- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -4- base] - 1- piperidyl]-N- methyl acetamide
Operating procedure：
By 3- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -5- [4- (4- piperidyl) pyrazol-1-yl] pyridyl group -2- Amine (30 milligrams, 0.067 mM, embodiment 10), the bromo- N- methyl acetamide of 2- (13 milligrams, 0.087 mM), sodium iodide (1 milligram, 0.0067 mM) and potassium carbonate (73 milligrams, 0.54 mM) react under 80 degree after being dissolved in ethyl alcohol (3 milliliters) 12 hours.It is then cooled to room temperature, reaction solution is diluted with saturated salt solution (10ml), and with ethyl acetate (10 milliliter * 2) It is primary with saline solution backwash to extract the organic phase that merges, then obtain crude Compound after being spin-dried for after being dried with sodium sulphate.This is obtained Crude product use with HPLC purify use high performance liquid chromatography (mobile phase is separated on C18 reversed-phase column：Acetonitrile/water/0.5% ammonia Water, gradient elution 25% to 55% (volume ratio) obtain target compound (30 milligrams, yield 86%).
Step B：
Operating procedure：
By compound 2- [4- [1- [6- amino -5- [1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrrole Azoles -4- base] -1- piperidyl] (30 milligrams, 0.056 mM) of-N- methyl acetamide with SFC hand-type split (Chiralpak AD-350*4.6mmI.D., 3um mobile phase：Ethyl alcohol (0.05%DEA) CO2 gradient 5%to40% flow velocity：4mL/ minutes) concentration Obtain target compound 2- [4- [1- [6- amino -5- [(1R) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] Pyrazoles -4- base] -1- piperidyl]-N- methyl acetamide (10 milligrams, 33%) and 2- [4- [1- [6- amino -5- [(1S) -1- (2,6- bis- chloro- 3- fluoro-phenyl) ethyoxyl] -3- pyridyl group] pyrazoles -4- base] -1- piperidyl]-N- methyl acetamide (11 millis Gram, 34%) two step yields are.
Spectroscopic data：
LC/MS (method：UFLC)：RT=3.27 minutes；M/z=521.2 [M+H]+total runing time is 7.00 points Clock, 100%ee.
1H NMR (400MHz, METHANOL-d4) δ 7.69-7.79 (m, 2H), 7.54 (s, 1H), 7.44 (dd, J=9.03, 5.02Hz, 1H), 7.23 (t, J=8.53Hz, 1H), 7.13 (s, 1H), 6.14-6.24 (m, 1H), 4.93-5.00 (m, 2H), 3.33-3.47 (m, 1H), 3.03 (s, 2H), 2.92 (d, J=11.29Hz, 2H), 2.78 (s, 3H), 2.51-2.58 (m, 1H), 2.22-2.33 (m, 2H), 1.88-1.96 (m, 5H), 1.68-1.81 (m, 2H)
Table 1：The compound of ALK inhibitor
Embodiment 88：Animal experiment method and activity data
Pharmacokinetics test in male SD rat 24 hours is divided into vein and takes orally two groups, and every group 3 dynamic It is before being administered, 0.0833,0.167,0.5,1,2,4,8,24 hour after administration that object vein group, which takes blood time point,；Oral group takes blood Time point is before being administered, 0.167,0.5,1,2,4,8,24 hour after administration.After blood sampling, given birth to using HPLC-MS/MS Object analysis, the calculated pharmacokinetic parameter of blood concentration of report compound are the average removing of vein group animal Rate (Clp), average apparent distribution volume (Vdss), distribution area (AUC) under 0-24h curve, when 0-24 hours Mean Residences Between (MRT), half-life period T1/2；The average maximum drug concentration (Cmax) of group animal upon administration is taken orally, is distributed under 0-24h curve Area (AUC), 0-24 hours mean residence times (MRT)；The mean relative bioavailability of this test.
Pharmacokinetics test in beasle dog 24 hours is divided into vein and takes orally two groups, and every group of 3 animal are quiet It is before being administered, 0.033,0.083,0.25,0.5,1,3,6,9,24 hour after administration that arteries and veins group, which takes blood time point,；Oral group when taking blood Between point for administration before, 0.083 after administration, 0.25,0.5,1,3,6,9,24 hour.After blood sampling, using HPLC-MS/MS into Row bioanalysis, the calculated pharmacokinetic parameter of blood concentration of report compound are being averaged for vein group animal Clearance rate (Clp), average apparent distribution volume (Vdss), distribution area (AUC) under 0-24h curve, 0-24 hours average stagnant Stay time (MRT), half-life period T1/2；It takes orally and organizes the average maximum drug concentration (Cmax) of animal upon administration, under 0-24h curve Distribution area (AUC), 0-24 hours mean residence times (MRT)；The mean relative bioavailability of this test.
The inhibiting effect that compound 18 increases tumour in experimental animal body：(18g is left when experiment starts for SCID mouse or nude mice It is right) by software divide multiple groups at random, it is close to reach group mesosome weight-average value, and within the allowable range by deviation control, it is injected ALK Cell strain (for example, lymthoma KARPAS299, lung cancer NCI-H441) tumor formation of driving.Oral administration, once a day, totally 7 or 14 It.Record weight, gross tumor volume.Tumour, blood, brain and eyes sampling carry out compound analysis detection by LC-MS/MS.Knot Fruit shows as depicted in figs. 1 and 2.It can be seen that compound 18 with good tumor inhibition effect and eyes from Fig. 1 and Fig. 2 The sudden and violent brightness of middle compound is relatively low.

Claims (9)

1. the compound as expressed by having structure formula (X), their enantiomer and diastereomer or its pharmaceutical salt：
Wherein：R6For
Wherein：R8For methyl；
Wherein：Y is amino；
Wherein：Ar is the phenyl replaced, and wherein substituent group is each independently hydrogen, deuterium, amino, halogen, hydroxyl, carboxylic on phenyl Base, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, alkyl or alkoxy therein It can be optionally replaced following groups：Hydrogen, deuterium, halogen, amino, hydroxyl, carboxyl, nitro, cyano, (C1-C6) alkyl, (C1- C6) alkoxy.
2. the compound as expressed by following structural (XI), their enantiomer and diastereomer or its pharmaceutical salt：
Wherein：R6For
Wherein：R8For methyl；
Wherein：Y is amino；
Wherein：Ar is the phenyl replaced, and wherein substituent group is each independently hydrogen, deuterium, amino, halogen, hydroxyl, carboxylic on phenyl Base, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, alkyl or alkoxy therein It can be optionally replaced following groups：Hydrogen, deuterium, halogen, amino, hydroxyl, carboxyl, nitro, cyano, (C1-C6) alkyl, (C1- C6) alkoxy.
3. the compound indicated by following structural, their enantiomer and diastereomer or its pharmaceutical salt
4. a kind of pharmaceutical composition, it includes the compound in a kind of inert carrier and claim 1-3.
5. a kind of drug, it includes compound described in any one of a kind of inert carrier and claim 1-3 or it can medicine The salt used is as active constituent.
6. purposes of the compound of claim 1-3 in the drug of preparation treating cancer or other diseases, wherein the cancer Or other diseases are non-small cell UNG lung cancer (NSCLC), primary cutaneous type (ALCL), neuroblastoma.
7. purposes as claimed in claim 6, wherein the cancer is non-small cell lung cancer (NSCLC).
8. method as claimed in claim 6, wherein the cancer is primary cutaneous type (ALCL).
9. method as claimed in claim 6, wherein the cancer is neuroblastoma.
CN201310087381.7A 2013-03-19 2013-03-19 Three-level cyclic amine ALK kinase inhibitor for treating cancer Expired - Fee Related CN104059054B (en)

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