CN103509008A - Derivatives of pyrazole-substituted amino-heteroaryl compounds - Google Patents

Derivatives of pyrazole-substituted amino-heteroaryl compounds Download PDF

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CN103509008A
CN103509008A CN201210326710.4A CN201210326710A CN103509008A CN 103509008 A CN103509008 A CN 103509008A CN 201210326710 A CN201210326710 A CN 201210326710A CN 103509008 A CN103509008 A CN 103509008A
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deuterium
compound
hydrogen
cancer
carcinoma
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包米克·潘迪亚
克雷格·E·马斯
艾安·罗伯托·西尔弗曼
罗格·通
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Concert Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • 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

Abstract

The invention relates to pyrazole-substituted amino-heteroaryl compounds of Formula (I) and pharmaceutically acceptable salts thereof. The invention also provides compositions comprising a compound of the invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of anaplastic lymphoma kinase (ALK).

Description

The derivative of amino-heteroaryl compound that pyrazoles replaces
Background technology
Current many medicines run into poor absorption, dispersion, metabolism and/or excretion (ADME) performance, and it has hindered them to use widely or limited their application in specific adaptations disease.Poor ADME performance is also the major cause of drug candidate failure in clinical trial.Although can adopt in some cases preparation technique and prodrug strategy to improve some ADME performance, the often failure when putting forth effort to solve many medicines and drug candidate exist potential ADME problem of these methods.Such problem is to cause the high amount of drug tachymetabolism from removing in body too soon, and not so this medicine will be very effective in treatment disease.The possible terms of settlement that medicine is removed is fast continually or gives high dosage to obtain sufficiently high medicine blood plasma level.Yet this has introduced a large amount of potential treatment problems, if patient is for the poor conformability of dosage regimen, follow higher dosage, it is more violent that side effect becomes, and increased treatment cost.The medicine of tachymetabolism also can make patient be exposed in less desirable toxicity or reactive metabolite.
The other ADME restriction that affects many medicines is the formation of toxicity or biologically metabolite.Therefore, some patients that accept medicine may experience toxicity, or the safe dose that can limit such medicine make patient accept not optimum quantity (suboptimal, activating agent suboptimal).In some cases, changing take medicine interval or compound method and can contribute to reduce clinical adverse, is that compound metabolism is intrinsic but often form so less desirable metabolite.
In the situation that some are selected, by metabolic poison and too fast medication combined giving of removing.Like this proteinase inhibitor class medicine that is used for the treatment of hiv virus (HIV) infection is exactly.FDA advises these medicines and ritonavir, a kind of cytochrome P 450 enzymes 3A4(CYP3A4) inhibitor, combine and give, this enzyme typically the reason of their metabolism (referring to Kempf, D.J.et al.Antimicrobial agents and chemotherapy, 1997,41 (3): 654-60).Yet ritonavir causes untoward reaction, and increased pill burden for the HIV patient that must take different pharmaceutical combination.Similarly, in order to reduce the quick CYP2D6 metabolism of Dextromethorphane Hbr in the false oblongata for the treatment of sick (pseudobulbar) invasion and attack, CYP2D6 inhibitor Quinidine is joined in Dextromethorphane Hbr.Yet Quinidine has unnecessary side effect, greatly limited its application in potential conjoint therapy (referring to Wang, L et al.Clinical Pharmacology and Therapeutics, 1994,56 (6Pt 1): 659-67; With on www.accessdata.fda.gov for the FDA label of Quinidine.
Conventionally, medicine is combined with cytochrome P 450 inhibitors and is used for reducing that medicine removes not is gratifying strategy.The activity that suppresses CYP enzyme can affect metabolism and the removing by the other drug of identical enzymes metabolism.Suppress CYP and can cause that other drug accumulation reaches toxic level in vivo.
A kind of potential attractive strategy for improvement of drug metabolism performance is that deuterium is modified (modification).In this method, people's trial slows down the metabolism of the CYP-mediation of medicine, or by replacing one or more hydrogen atoms with D atom to reduce the formation of less desirable metabolite.Deuterium is a kind of safe, stable, the inactive isotropic substance of hydrogen.Compare with hydrogen, deuterium and carbon form stronger key.Selected in the situation that, the bonding strength of the increase of being given by deuterium can pro affect the ADME performance of medicine, for improved medicine usefulness, security and/or tolerance Production capacity., because the size and shape of deuterium is equal to hydrogen substantially, compare with the original chemical entities that only comprises hydrogen, expection replaces hydrogen with deuterium will not affect biological chemistry usefulness and the selectivity of medicine meanwhile.
In in the past 35 years, the deuterium of having reported the medicine through approval of considerably less per-cent replace on the impact of metabolic rate (referring to, Blake for example, MI et al, J Pharm Sci, 1975,64:367-91; Foster, AB, Adv Drug Res 1985,14:1-40(" Foster "); Kushner, DJet al, Can J Physiol Pharmacol 1999,79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006,9:101-09(" Fisher ")).Result be always change with uncertain.For some compounds, deuterate causes the reduction that internal metabolism is removed.For other compound, metabolism does not change.Other other compounds have proved the metabolite clearance increasing.The variation that deuterium affects aspect also causes expert to query or does not consider that deuterium modification (deuterium modification) is as the feasible medicinal design strategy (referring to the 35th page and the 101st page of Fisher of Foster) that is used for suppressing unfavorable metabolism.
Even, when D atom being incorporated to the known location (position) of metabolite, deuterium is modified (deuterium modification) neither be predictable on the impact of the metabolism performance of medicine.Only have the medicine of being prepared and tested deuterate by reality, people could determine that whether and how the speed of metabolism will be different from the counterpart of non-deuterate.Referring to, for example, Fukuto et al.(J.Med.Chem.1991,34,2871-76).Many medicines have a plurality of positions that can energy metabolism.Needing position (position) and discovery that deuterium replaces to affect the necessary degree of deuterium of metabolism, if had, will be different for every kind of medicine.
Known Crizotinib (Crizotinib) is (also referred to as 3-[1 (R)-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group]-5-[1-(4-piperidyl)-1H-pyrazoles-4-yl] pyridine-2-amine) inhibition hepatocyte growth factor receptor (c-met/HGFR) kinases, and blocking-up Nucleophosmin-anaplastic lymphoma kinase (anaplastic lymphoma kinase, anaplastic lymphoma kinase) Tyrosylprotein kinase (ALK).The Patients with Non-small-cell Lung of certain percentage, carries (EML4-ALK) fusion gene of echinoderms microtubule-associated protein sample 4 Nucleophosmin-anaplastic lymphoma kinases (echinoderm microtubule-associated protein-like4anaplastic lymphoma kinase).EML4-ALK, in the time of in being inserted into normal cell, causes cell to become carcinous.Crizotinib (Crizotinib) is blocked the Tyrosylprotein kinase of the ALK structural domain of this fusion gene.Referring to Sasaki, t et al., The Biology and Treatment of EML4-ALK Non-Small Cell Lung Cancer, Eur.J.Cancer, 2010, July; 46 (10): 1773-80.
Recommend at present approval Crizotinib for nonsmall-cell lung cancer (NSCLC), and carrying out for solid tumor cancer with for lymphadenomatous I/II stage clinical trial.
Will link together to the relevant event of moderate stomach and fatigue with slight with Crizotinib treatment.
Although Crizotinib has useful activity, yet for thering is lasting demand in order to treat the new compound of above-mentioned disease and illness.
Summary of the invention
The present invention relates to amino-heteroaryl compound and its pharmaceutical salts that novel pyrazoles replaces.The present invention also provides the composition that comprises compound of the present invention, and the application of such composition in the method for the treatment of disease and illness, these diseases and illness be treatment valuably by giving Nucleophosmin-anaplastic lymphoma kinase (ALK) and the kinase whose inhibitor of hepatocyte growth factor receptor (c-met/HGFR).
Accompanying drawing explanation:
Figure 1A illustrates the IC for Crizotinib (crizotinib) 50change evaluation graph.
Figure 1B illustrates the IC for compound 212 50change evaluation graph.
Fig. 1 C illustrates the IC for compound 211 50change evaluation graph.
Embodiment
Definition
Term " treatment " means reduction, inhibition, weakening, reduces, stop or development or the progress (example is disease or disorder as described in this article) of stable disease the seriousness palliating a disease or improvement or alleviate the seriousness with one or more symptoms of disease-related.
" disease " means any illness or the disorder of the normal function of infringement or interference cell, tissue or organ.
Should be understood that the source that depends on the chemical material using in synthetic, there are some variations in the abundance of natural isotopic in synthetic compound.Therefore, the preparation of Crizotinib (crizotinib) will comprise the isotropic substance body (isotopologue) of a small amount of deuterate inherently.Although this variation, compares with the degree that the stable isotope of compound of the present invention replaces, the natural concentration of enriching stable hydrogen and carbon isotope is little of unessential.Referring to for example Wada, E et al., Seikagaku, 1994,66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.
In compound of the present invention, any atom not specifying as specific isotope means any stable isotope that represents that atom.When ，Dang somewhere specifies as " H " or " hydrogen " except as otherwise noted, this place is interpreted as the hydrogen of its natural abundance isotopics.In addition except as otherwise noted ，Dang Mou position be appointed as especially " D " or " deuterium ”Shi，Gai position is interpreted as that it be at least incorporated to 45% deuterium for 0.015%(than the deuterium of the abundance of at least 3000 times of the natural abundance height of deuterium).
As used in this article, term " Isotope enrichment factor " means the isotopic isotopic abundance of appointment and the ratio between natural abundance.
In other embodiments, the Isotope enrichment factor of the D atom of each appointment of compound of the present invention is incorporated to 52.5% deuterium at the D atom place of each appointment for 3500(at least), at least 4000(is incorporated to 60% deuterium), at least 4500(is incorporated to 67.5% deuterium), 5000(75% deuterium at least), at least 5500(is incorporated to 82.5% deuterium), at least 6000(is incorporated to 90% deuterium), at least 6333.3(is incorporated to 95% deuterium), at least 6466.7(is incorporated to 97% deuterium), at least 6600(is incorporated to 99% deuterium) or at least 6633.3(be incorporated to 99.5% deuterium).
Term " isotropic substance body (isotopologue) " only refers to and is different from the material of specific compound of the present invention in chemical structure aspect its isotopics.
Term " compound " when referring to compound of the present invention, refers to except can have isotropic substance variation in the constituting atom of molecule, has the elements collection of identical chemical structure.Therefore, those skilled in the art can understand, by the compound of the specific chemical representation that comprises the D atom indicating, also can comprise the isotropic substance body of small amount, and in this structure, isotropic substance body has hydrogen atom in the deuterium position of one or more appointments.In compound of the present invention, the relative quantity of such isotropic substance body will depend on many factors, comprise the isotopic purity for the preparation of the deuteration agents of this compound, and the efficiency that is incorporated to (incorporation of deuterium) for the preparation of the deuterium in each synthesis step of this compound.Yet as given above, all the relative quantity of such isotropic substance bodies is by lower than 49.9% of compound.In other embodiments, all the relative quantity of such isotropic substance bodies by lower than compound 47.5%, lower than 40%, lower than 32.5%, lower than 25%, lower than 17.5%, lower than 10%, lower than 5%, lower than 3%, lower than 1% or lower than 0.5%.
The present invention also provides the salt of compound of the present invention.
Between acid and the basic group (as amido functional group) of this compound or form the salt of compound of the present invention between the acidic-group (as carboxyl functional group) of alkali and this compound.According to other embodiment, the salt of the compound providing is medicinal acid addition salt.
As used in this article, term " medicinal (pharmacy is acceptable; pharmaceutically acceptable) " refers to a kind of component, it is within the scope of reliable medical judgment, be suitable for contacting with people or other mammiferous tissues and there is no unsuitable toxicity, stimulation, anaphylaxis (allergic response) etc., and suitable with rational benefit/risk ratio." pharmaceutical salts (pharmacologically acceptable salts, pharmaceutically acceptable salt) " means any nontoxic salt, and when giving acceptor, it can be directly or compound of the present invention is provided indirectly." medicinal counterion (the acceptable counterion of pharmacy, pharmaceutically acceptable counterion) " is the ion part of salt, and when discharging from give the salt of acceptor, it is nontoxic.
The acid that is used to form the common employing of pharmaceutical salts comprises: mineral acid, as disulfides other than hydrogen, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid, and organic acid, as tosic acid, Whitfield's ointment, tartrate, liquor epinephrinae bitartratis ophthalmicus (bitartaric acid), xitix, toxilic acid, Phenylsulfonic acid (besylic acid), fumaric acid (fumaric acid), glyconic acid, glucuronic acid, formic acid, L-glutamic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, lactic acid, oxalic acid (oxalic acid), p-bromo-benzene sulfonic acid, carbonic acid, succsinic acid, citric acid, phenylformic acid and acetic acid, and relevant inorganic and organic acid.Such pharmaceutical salts thereby comprise: vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, mono phosphoric acid ester hydrogen salt (monohydrogenphosphate), dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate (decanoate), octylate, acrylate, formate, isobutyrate, ten carbonate (caprate), enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate (fumarate), maleate, butine-Isosorbide-5-Nitrae-diacid salt (butyne-1,4-dioate), hexin-l, 6-diacid salt (hexyne-l, 6-dioate), benzoate, chloro-benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, PB, Citrate trianion, lactic acid salt, beta-Hydroxybutyrate, oxyacetate, maleate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate and other salt.In one embodiment, medicinal acid addition salt comprises those that form with all example hydrochloric acids and hydrobromic mineral acid, and uses especially the organic acid such as toxilic acid forms those.
Except as otherwise noted, do not specifying in stereochemical situation, when the compound of the compound of naming or describe (drafting) to disclose by structure and this disclosure has one or more chiral centre, by all possible steric isomer of understanding it and representing this compound.
As used in this article, term " experimenter (subject) ", comprises people or inhuman animal, for example, as mouse, rat, guinea pig (guinea pig), dog, cat, horse, ox, pig, monkey (macaque), chimpanzee or baboon.In one embodiment, experimenter is inhuman animal.In other embodiment, experimenter is people.
Compound of the present invention (for example compound of Formula I) can comprise unsymmetrical carbon, for example, as deuterium, replaces or contrary result.So, the mixture that compound of the present invention can be used as independent enantiomer (enantiomorph) or two kinds of enantiomers exists.Correspondingly, compound of the present invention can be used as the mixture (scalemic mixture) of racemic mixture or part racemization, or as the basic not independent steric isomer separately of not possible steric isomer in addition.As used in this article, term " does not substantially have other steric isomers " and means other steric isomers lower than 25%, preferably lower than other steric isomers of 10%, other steric isomers more preferably less than 5%, and most preferably lower than other steric isomers of 2%.For given compound, acquisition known in the art or the method for synthesizing independent steric isomer, and it can be applied as the practice of final compound or initial feed or intermediate.
Except as otherwise noted, do not specifying in stereochemical situation, when naming or describing the compound of disclosure and the compound of this disclosure by structure and there is one or more chiral centre, should understand all possible steric isomer that represents this compound.
As used in this article, term " stable compound " refers to has the stability that enough makes its production, and the integrity that makes compound maintains time enough section, and to be useful on the compound of the object of describing in detail herein, (this object is for being for example mixed with therapeutic product, for the production of the intermediate of therapeutic compound, separable or storable midbody compound, disease or illness that treatment responds to therapeutical agent).
Both refer to deuterium " D " and " d "." steric isomer " refers to enantiomorph and diastereomer." Tert " and " t-" refers to uncle separately." US " refers to the United States of America.
" with deuterium, replace " to refer to one or more hydrogen atoms are replaced to (replacement) with the D atom of respective numbers.
Run through whole specification sheets, variable can refer to general (such as " each R ") or can refer to specific (such as R1, R2, R3 etc.).Except as otherwise noted, when variable refers to that general time, it means all embodiments that comprise that particular variables.
Therapeutic compound
The invention provides the compound or pharmaceutically acceptable salt thereof of Formula I:
Figure BDA00002102779200071
Wherein:
R 1and R 2be selected from independently of one another Cl, CH 3and CD 3;
R 3cH 3or CD 3;
X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5be selected from independently of one another hydrogen and deuterium;
Y 1hydrogen or deuterium; And
Y 2hydrogen or deuterium;
Condition is to work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5in each be hydrogen, and Y 1and Y 2in each while being hydrogen, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5in each be hydrogen, and Y 1while being hydrogen, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, and Y 1and Y 2in each while being Cl, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, Y 1hydrogen, and X 5while being deuterium, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, Y 1hydrogen, Y 2while being deuterium, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2in each be Cl, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, Y 1hydrogen, and X 5and Y 2each is naturally during deuterium, R 3cD 3.
In an embodiment of the compound of Formula I, work as R 1and R 2be selected from independently of one another Cl and CH 3, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5in each be hydrogen, and Y 1and Y 2in each while being hydrogen, R 3cD 3.
In an embodiment of the compound of Formula I, X 1aand X 1bidentical, X 2aand X 2bidentical, X 3aand X 3bidentical, and X 4aand X 4bidentical.In aspect the Yi Ge of this embodiment, R 1and R 2independently selected from Cl and CD 3.In aspect this embodiment is further, R 1and R 2identical and each Cl naturally.This embodiment in addition further aspect in, R 1and R 2identical and each CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2aand X 2bidentical, X 3a, X 3b, X 4aand X 4bidentical, and R 1and R 2independently selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen; And X 3a, X 3b, X 4aand X 4bin each be deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each is deuterium; And X 3a, X 3b, X 4aand X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.Aspect the Yi Ge of this embodiment, R 1and R 2identical and each Cl naturally.In aspect the Yi Ge of this embodiment, R 1and R 2identical and each CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, R 1and R 2be identical and be selected from Cl and CD 3, R 3cH 3.In one aspect, R 1and R 2each is chlorine naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, R 1and R 2be identical and be selected from Cl and CD 3, R 3cD 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each is deuterium, R 1and R 2be identical and be selected from Cl and CD 3, R 3cH 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium; R 1and R 2be identical and be selected from Cl and CD 3, R 3cD 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2aand X 2bin each be deuterium, X 3a, X 3b, X 4aand X 4bin each be hydrogen, R 1and R 2be identical and be selected from Cl and CD 3, and R 3cH 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2aand X 2bin each be deuterium, X 3a, X 3b, X 4aand X 4bin each be hydrogen, R 1and R 2be identical and be selected from Cl and CD 3, and R 3cD 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2aand X 2bin each be hydrogen, X 3a, X 3b, X 4aand X 4bin each be deuterium, R 1and R 2be identical and be selected from Cl and CD 3, and R 3cH 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 1a, X 1b, X 2aand X 2bin each be hydrogen, X 3a, X 3b, X 4aand X 4bin each be deuterium, R 1and R 2be identical and be selected from Cl and CD 3, and R 3cD 3.In one aspect, R 1and R 2each is Cl naturally.In one aspect, R 1and R 2each is CD naturally 3.
In an embodiment of the compound of Formula I, X 5hydrogen, Y 1hydrogen, Y 2hydrogen, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in the other embodiment aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5hydrogen, Y 1deuterium, Y 2hydrogen, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In the embodiment of the compound of Formula I, X 5hydrogen, Y 1hydrogen, Y 2deuterium, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5hydrogen, Y 1deuterium, Y 2deuterium, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5deuterium, Y 1hydrogen, Y 2hydrogen, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5deuterium, Y 1deuterium, Y 2hydrogen, R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5deuterium, Y 1hydrogen, Y 2deuterium, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In an embodiment of the compound of Formula I, X 5deuterium, Y 1deuterium, Y 2deuterium, and R 1and R 2be identical and be selected from Cl and CD 3.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen.In one aspect, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be hydrogen, and X 3a, X 3b, X 4aand X 4bin each be deuterium.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.In one aspect, X 1a, X 1b, X 2aand X 2bin each be deuterium, and X 3a, X 3b, X 4aand X 4bin each be hydrogen.R in the embodiment aspect this 3cH 3.R in embodiment other aspect this 3cD 3.Y in the embodiment aspect this 2hydrogen.Y in embodiment other aspect this 2it is deuterium.
In the embodiment of any aforementioned embodiments, compound is the compound as Formula I defined above, is not wherein appointed as any atom of deuterium with its natural isotopic abundance.
In one embodiment, compound is selected from any one or its pharmaceutical salts in the compound (Cmpd) providing in (below) table 1:
The compound of table 1, Formula I
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
In one embodiment, compound is selected from any one or its pharmaceutical salts in the compound (Cmpd) providing in (below) table 2:
The compound of table 2, Formula I
Figure BDA00002102779200142
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
In one embodiment, compound is selected from any one or its pharmaceutical salts in the compound (Cmpd) providing in (below) table 3:
The compound of table 3, Formula I
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
By reference to the exemplary synthetic and embodiment disclosing in this article, the synthetic chemistry personnel of common skill can easily realize the compou nd synthesis of Formula I.Disclosed those the correlated process being similar to for the preparation of the compound of Formula I and its intermediate, for example, at Cui, J., WO2006/021881, Cui, J.WO 2006/021884, Lui, J.WO 2010/108103, O'Donnell, C.J.; J.Med.Chem.2010,53,1222-1237, and Shimizu, H.Tetrahedron Lett.2006, in 47,5927-5931.
Utilize corresponding deuterate and alternatively, other comprise isotopic reagent and/or intermediate to synthesize the compound of describing in this article (drafting), or use known in the artly for introduce the standard synthetic schemes of isotope atom to chemical structure, can carry out such method.
Exemplary synthetic
The method that facilitates for the synthesis of the compound of Formula I has been described in scheme 1.
scheme 1a: the synthetic route (R of the compound of Formula I 1 and R 2 =Cl)
Figure BDA00002102779200161
Formula I (R 1=R 2=Cl)
scheme 1b: the synthetic route (R of the compound of Formula I 1 and R 2 =CD 3 )
Figure BDA00002102779200162
Figure BDA00002102779200171
Formula I (R 1=R 2=CD 3)
By the conventional multistep organic synthesis of implementing of those skilled in the art and according to scheme Ia above and the description of Ib, can obtain the new chemical entity corresponding to Formula I.First deuterium chloride in water-d2 can make 2 ', 6 '-bis-chloro-3 '-fluoro acetophenone 10a that are purchased stand hydrogen-deuterium exchange so that entity to be provided, wherein R under existing 3=CD 3.
Alternatively, can make 10a stand with Pu, Suzuki-palace (Suzuki-Miyaura) cross-coupling of three deuterated methyl-boron-dihydroxides (being purchased) so that ketone 10b, wherein R to be provided 1=R 2=CD 3.After with hydroborate or boron heavy hydride (borodeuteride) carbonyl reduction ketone 10a or 10b, with diacetyl oxide by the racemize phenylcarbinol acetylize obtaining.Can split with the enzyme that Pig Liver Esterase (PLE) realize enantiomorph (corresponding isomer) mixture, to provide enantiomeric excess (ee) higher than 97.5% chiral alcohol 11a or 11b.
With di-isopropyl azido-dicarboxylic acid (diisopropyl azidodicarboxylate) (DIAD) and triphenylphosphine can realize secondary alcohol and 2-nitropyridine-3-alcohol (12, Y wherein 1=H or D) light prolong upset (Mitsunobu inversion), so that diaryl ether 13a or 13b to be provided.Liang Ge functional group exchanges (comprising the reduction of nitro and the introducing of the 5-position on pyridine iodine), and afterwards, the skeleton being connected with heterocycle 15 is ready to.
Under alkaline two-phase condition, can the boron-pinacol ester of suitable deuterate (boron-pinacolate) 15 be connected with aryl iodide 13a or 13b via the cross-coupling of palladium catalysis.With concentrated hydrochloric acid, remove the active pharmaceutical ingredient as free alkali that t-butyl carbamate (BOC) protecting group obtains expectation.It can be necessary preparing suitable pharmaceutical grade salt (multiple salt), and can use standing procedure to complete.
scheme 2: the synthetic route of intermediate 15
Figure BDA00002102779200181
In patent publications WO 2010/108103, disclosed the functionalization piperidines of preparation such as 16a, 16b and for the precursor of 16c and 16d, it comprises high-caliber isotopic abundance before.By using respectively NaBD 4or NaBH 4reduction, can prepare intermediate 16c and 16d by ketone precursor.
Figure BDA00002102779200182
Under negatively charged ion condition, secondary alcohol is converted into corresponding methanesulfonates the iodo-1-H-pyrazoles of 3-is partly assembled by direct replacement.Under palladium catalysis, 18 iodo part exquisiteness is changed into boron pinacol ester (boron pinacolate) to provide 15, be that the reduction by dioxa boron heterocycle pentane (dioxoboralane) realizes.
As disclosed, also can prepare the embodiment (scheme 2) of 16 or 17 suitable deuterates in following scheme 2b-2d:
The preparation of scheme 2b:16b and 17b:
Figure BDA00002102779200191
As shown in scheme 2b, use alkali and CDCl such as 22 3process 21 to provide 23.Use NaBH 4reduction C=O group provides 16b.With methylsulfonyl chloride (mesyl chloride), 16b is converted into 17b.Similarly, by use NaBD in C=O reduction step 4replace NaBH 4can prepare 16f and 17f(is as follows):
Figure BDA00002102779200192
The preparation of scheme 2c:16d and 17d:
Figure BDA00002102779200193
As shown in scheme 2c, with allyl trimethyl silane and benzylamine, process 24 to provide 25, as at JLCR, described in 2007,50,131-137.With Pd/C and formic acid, process (Boc) that uses as describe after 25 in identical JLCR article 2o protection, provides 16d, processes 16d provide 17d with methylsulfonyl chloride.
The preparation of scheme 2d:16g and 17g:
As shown in scheme 2d, Dai Si-Martin (Dess-Martin) oxidation 16d(is referring to scheme 2c) provide 26, it is with 22 and CDCl 3processing is to provide 27.Use NaBH 4reduction C=O group provides 16g, processes 16g provide 17g with methylsulfonyl chloride.Similarly, can be by use NaBD in C=O reduction step 4replace NaBH 4preparation 16h and 17h(are as follows):
Figure BDA00002102779200202
scheme 3a: the synthetic route of intermediate 12b
scheme 3b: the interchangeable synthetic route of intermediate 12b
Figure BDA00002102779200211
As by O'Donnell(J.Med.Chem.2010,53,1222-1237) report, by preparing the isotropic substance body such as 2-nitropyridine-3-alcohol of 12b, wherein Y for the regioselectivity bromination of 2-nitropyridine-3-alcohol 12a 1=D.After halogen metal displacement, with the suitable isotopic electrophile low temperature cancellation that comprises, then in correct position, insert the isotropic substance of expectation.Alternatively, under alkaline condition, in deuterium exchange thing (deuterium exchange body, deuterium exchange) and water-d2, introduce hydrogen general directly by 12a acquisition 12b.
Concrete grammar as implied above and compound are not used for being construed as limiting.Chemical structure in scheme has herein been described the variable of definition thus, and whether it is equivalent to the definition of the chemical group (partly, atom etc.) of corresponding position in the chemical formula of compound herein, no matter (be R with identical name variable 1, R 2, R 3deng) identification.Chemical group in compound structure to the suitability of synthetic other compound in those of ordinary skills' knowledge.
The other method of the synthetic precursor of the compound of synthetic chemistry formula I and they, is included within the scope of chemical personnel's the ways and means of those ，Shi this area common skills in the route clearly not illustrating in scheme herein.Synthetic chemistry conversion and protecting group method (protect and go and protect) useful in synthetic applicable compound are known in this area, and be included in, LarockR for example, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al., Protective Groups in Organic Synthesis, 3 rded., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); And Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) with and version subsequently in.
The substituting group of this invention expection and the combination of variable are only to cause those that stable compound forms.
Composition
The present invention also provides pharmaceutical composition, and it comprises the compound (for example comprising any chemical formula herein) of the Formula I of significant quantity or the pharmaceutical salts of described compound; And pharmaceutical carrier.In the compatible meaning of other compositions with preparation (preparation), carrier (variety carrier) is " available (acceptable, acceptable) ", and the in the situation that of pharmaceutical carrier, the amount of using in medicine is harmless to its acceptor.
In some embodiments, the invention provides a kind of apyrogenic pharmaceutical composition, it comprises the compound (being for example included in any chemical formula herein) of the Formula I of significant quantity or the pharmaceutical salts of compound or tautomer; And pharmaceutical carrier.
Can be for the pharmaceutical carrier of pharmaceutical composition of the present invention, adjuvant and vehicle (vehicles) comprise, but be not limited to, ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein (as human serum protein), buffer substance (as phosphoric acid salt), glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen are (as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt), silica gel, Magnesium Trisilicate, Polyvinylpyrolidone (PVP), based on cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene-block polymer, polyoxyethylene glycol and lanolin.
If need, can improve solubleness and the bioavailability of compound of the present invention in pharmaceutical composition by methods known in the art.A kind of method is included in use lipid vehicle in preparation (preparation).Referring to " Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences); " David J.Hauss, ed.Informa Healthcare, 2007; " Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery:Basic Principles and Biological Examples; " Kishor M.Wasan, ed.Wiley-Interscience, 2006.
The method of known raising bioavailability is to use the amorphous form of compound of the present invention in addition, alternatively with poloxamer (as LUTROL tMand PLURONIC tM(BASFCorporation)) or together with the segmented copolymer of oxyethane and propylene oxide prepare.Referring to United States Patent (USP) 7,014,866; And United States Patent (USP) publication 20060094744 and 20060079502.
Pharmaceutical composition of the present invention comprises those that are suitable for per os (oral), rectum, nose, part (comprising Jia He hypogloeeis), sheath or enteron aisle outer (comprising subcutaneous, intramuscular, intravenously and intracutaneous) administration.In specific embodiment, transdermal gives the compound (for example using transdermal patch or Iontophoretic technology) of chemical formula herein.Other preparations can be easily exist with the form of unit dosage, for example tablet, sustained release capsule and in liposome, and can prepare by the known any method of pharmaceutical field.Referring to, for example, Remington:The Science and Practice of Pharmacy, Lippincott Williams& Wilkins, Baltimore, MD (20th ed.2000).
Such preparation method comprises and introduces the one-tenth relevant to the molecule that will give step by step, and this composition is as formed the carrier of one or more auxiliary agents (ancillary component, accessory ingredient).Conventionally, said composition is by equably and closely introducing and the solid carrier of liquid vehicle, liposome or finely-divided or the activeconstituents that both are relevant, then, if desired, forms product.
In specific embodiment, compound is that per os (oral) gives.Be applicable to the oral composition of the present invention giving and can be used as discrete unit existence, as the capsule of the activeconstituents of each self-contained predetermined amount, sachet or tablet; Pulvis or granule; Solution or suspension in liquid, aqueous or water-free liquid; Oil-in-water liquid emulsion; Water-in-oil liquid emulsion; Pack in liposome; Or as inject fast agent (bolus, bolus), etc.It is useful that soft gelatin capsule comprises such suspension that can advantageously improve compound uptake rate.
In the situation that the tablet orally using, conventional carrier comprises lactose and W-Gum.Also typically add lubricant (as Magnesium Stearate).For the oral administration of capsule form, useful thinner comprises lactose and dried corn starch.When oral, while giving aq suspension (suspension), activeconstituents is combined with emulsifying agent and suspending agent.If need, can add some sweeting agent and/or seasonings (correctives) and/or tinting material.
Be applicable to the oral composition giving and comprise lozenge, it is included in (activity) composition in the substrate (basis) (being generally sucrose and gum arabic or tragacanth gum) of seasoning; And pastille, it is included in the activeconstituents in inert substrate (basis) (as gelatin and glycerine or sucrose and gum arabic).
The composition that is applicable to enteron aisle external administration comprises moisture and anhydrous aseptic injectable solution, and it can comprise antioxidant, damping fluid, fungistat and solute, and it provides with the blood of stand-by acceptor etc. and ooze to preparation (preparation); And moisture and anhydrous sterile suspensions, it can comprise suspending agent and thickening material.For example, preparation for example may reside in, in unitary dose or multi-dose container (ampoule and the bottle of sealing), and can under lyophilize (freeze-drying) condition, store, and only need to before using, immediately add aseptic liquid vehicle, for example water for injection.(instant, extemporaneous) injection solution and suspension can be prepared by sterile powder, granule and tablet temporarily.
For example, such injection solution can be sterile injectable aq suspension or the form that contains oil suspension.This suspension can be according to technology known in the art, uses suitable dispersion agent or wetting agent (for example, as,, tween 80) and suspending agent preparation.For example, sterile injectable preparation can be also thinner available outside nontoxic enteron aisle or solution or the wetting agent of the sterile injectable in solvent, for example solution in 1,3 butylene glycol.In available carrier and solvent, can adopt is N.F,USP MANNITOL, water, Ringer's solution and isotonic sodium chlorrde solution.In addition, usually adopt aseptic fixedly oil as solvent or suspension medium.For this reason, can adopt any gentleness (non-irritating, bland) fixing oil, comprises synthetic direactive glyceride or triglyceride.Lipid acid (as oleic acid) and its glyceride derivative are useful in the preparation of injectable agent, as natural medicinal oil (as sweet oil or Viscotrol C), particularly with its polyoxyethylene form.These oil solutions or suspension also can comprise long-chain alcohol thinner or dispersion agent.
Composite medicine of the present invention can give for the suppository form of rectal administration.Can be by compound of the present invention is mixed to prepare these compositions with suitable nonirritant excipient, this vehicle is at room temperature solid and be liquid under rectal temperature, thereby can fusing in rectum to discharge active ingredient.Such material includes, but are not limited to, theobroma oil, beeswax and polyoxyethylene glycol.
Can give pharmaceutical composition of the present invention by nose aerosol or inhalation.According to field of pharmaceutical preparations known technology, prepare such composition, and can be prepared into the solution in salt solution, adopt phenylcarbinol or other suitable sanitass, absorption enhancer to improve bioavailability, fluorocarbon and/or other solubilizing agent known in the art or dispersion agent.Referring to, for example Rabinowitz JD and Zaffaroni AC, United States Patent (USP) 6,803,031, assigns in Alexza Molecular Delivery Corporation.
When the treatment of expectation comprises that can hold accessible region or organ by topical application time, the part of pharmaceutical composition of the present invention is useful especially.For the topical application to skin typically, this pharmaceutical composition should be mixed with and comprise the suitable ointment that suspends or be dissolved in the active ingredient in carrier.For the local carrier that gives compound of the present invention, include, but are not limited to mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, pharmaceutical composition can be mixed with and comprise suitable lotion or the emulsifiable paste (creme) that suspends or be dissolved in the active compound in carrier.Suitable carrier includes, but are not limited to, mineral oil, the smooth monostearate of sorb, polysorbate60, hexadecyl ester type waxes (cetyl esters wax), cetostearyl alcohol (16 Stearyl alcohol), 2-octyl dodecanol, phenylcarbinol and water.Pharmaceutical composition of the present invention also can be applied to low level enteron aisle partly by rectal suppository formulation or with suitable enema formulation.Also comprise in the present invention topical transdermal patch and iontophoretic delivery.
The application of theme (target) curative can be local, to give at the position of paying close attention to.Can use various technology to provide theme (target) composition for the position paying close attention to, as injection, use conduit, trochar, projectile (bullet, projectile), general stream Buddhist nun's gram gel (pluronic gel), support, continue drug release polymkeric substance or provide from other equipment of inside contact (internal access).
Therefore, according to another embodiment, compound of the present invention can be incorporated in composition, for applying implantable medical supply, as prosthese, artificial valve, vascular graft, support or conduit.The general preparation of suitable coating and the implantable devices through applying is known in the art, and in United States Patent (USP) 6,099,562; 5,886,026; With 5,304, illustration in addition in 121.Coating is the polymeric material of biocompatibility typically, as aquogel polymer, poly-methyl sily oxide, pla-pcl, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, with and composition thereof.Coating can be alternatively further by following suitable top coat (external coating (EC), topcoat) covers: fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination, to give the characteristic of composition controlled release.Those terms, will be included in the definition of pharmaceutical carrier, adjuvant or vehicle (vehicle) for the coating of invasive device as used in this article.
According to other embodiment, the invention provides a kind of method that applies implantable medical supply, it comprises the step that described equipment is contacted with the coating composition of hereinafter describing.Before the coating of equipment will occur in and implant in mammalian body, this will be apparent for those skilled in the art.
According to other embodiment, the invention provides the method for the implantable drug release device of dipping, it comprises the step that described drug release device is contacted with compound of the present invention or composition.Implantable drug release device includes, but are not limited to, and biodegradable polymer capsule or connector (bullet, bullets), nondegradable diffustivity polymer capsule and biodegradable polymkeric substance disk (wafer).
According to other embodiment, the invention provides the implantable medical supply applying with compound or the composition that comprises compound of the present invention, making described compound is therapeutic activity.
According to other embodiment, the invention provides the implantable drug release device with compound or the composition dipping that comprises compound of the present invention or the composition that holds this compound or comprise compound of the present invention, make described compound discharge and be therapeutic activity from described equipment.
When owing to removing from experimenter, organ or tissue is in come-at-able situation, such organ or tissue can be immersed in the medium that comprises the present composition, composition of the present invention can spread upon on organ, or can with other easily mode apply (application) composition of the present invention.
In other embodiment, composition of the present invention further comprises the combination of a kind of the second therapeutical agent or multiple the second therapeutical agent.One or more second therapeutical agents can be selected from when giving together with having the compound (as Crizotinib) of same function mechanism, and known have or any compound or the therapeutical agent of its proof advantageous property.Such medicament is included in the coupling with Crizotinib, to show it is useful those, those that include but not limited to describe in the ， U.S. 2011003805 and CN101836991.
Preferably, one or more second therapeutical agents are useful medicaments in treatment or preventing cancer, be more specifically prostate cancer, osteosarcoma, lung cancer (particularly nonsmall-cell lung cancer), mammary cancer, carcinoma of endometrium, glioblastoma multiforme, colorectal carcinoma, ovarian cancer, carcinoma of the pancreas, kidney, carcinoma of small intestine, esophagus cancer or cancer of the stomach.
In one embodiment, the second therapeutical agent is selected from kinase inhibitor.In aspect the Yi Ge of this embodiment, kinase inhibitor is selected from Tarceva (erlotinib), Xarelto (sorafenib), as in U.S. Patent Application No. 11/957, 442 and U.S. Patent Application No. 12/413, the deuterate form of the Tarceva disclosing in 510, at PCT number of patent application PCT/US2009/053595, the deuterate form of the Xarelto disclosing in PF-00299804 and N-{2-[4-(the chloro-4-[3-of 3-(trichloromethyl) phenoxy group] and phenyl } amino)-5H-pyrrolo-[3, 2-d] pyridine-5-yl] ethyl }-3-hydroxy-3-methyl butyramide (referring to United States Patent (USP) publication 2011/0003805).One, more specifically in embodiment, the deuterate form of Tarceva is compd A,
Figure BDA00002102779200261
at another, more specifically in embodiment, the deuterate form of Tarceva is compd B, at one, more specifically in embodiment, the deuterate form of Xarelto is Compound C,
Figure BDA00002102779200271
in one aspect, kinase inhibitor is Tarceva or Xarelto.In one aspect, kinase inhibitor is a kind of deuterate form (as disclosed in above-cited patent application) of Tarceva or a kind of deuterate form (as disclosed in above-cited patent application) of Xarelto.
In one embodiment, composition of the present invention comprises the combination of compound and two kinds of second therapeutical agents that are selected from kinase inhibitor of Formula I.In aspect the Yi Ge of this embodiment, this combination be with Tarceva or as in U.S. Patent Application No. 11/957,442 and U.S. Patent Application No. 12/413, the deuterate form of the Tarceva disclosing in 510, and Xarelto or as the deuterate form of the Xarelto that discloses in PCT number of patent application PCT/US2009/053595 together.This embodiment more specifically aspect in, this combination is together with Tarceva or compd A and Xarelto or Compound C.This embodiment another more specifically aspect in, this combination is together with Tarceva or compd B and Xarelto or Compound C.In aspect the Yi Ge of this embodiment, this combination is Tarceva and Xarelto.In aspect the Yi Ge of this embodiment, this combination is the deuterate form of Tarceva and the deuterate form of Xarelto.In aspect the Yi Ge of this embodiment, this combination is deuterate form and the Xarelto of Tarceva.In aspect the Yi Ge of this embodiment, this combination is the deuterate form of Tarceva and Xarelto.
In other embodiment, the invention provides compound of the present invention and one or more independent formulation of above-mentioned the second therapeutical agent arbitrarily, wherein this compound and the second therapeutical agent are relative to each other.As used in this article, term " (associated with one other) is relative to each other " means that independent formulation is packaged together, otherwise be attached to each other, go up, make easily to understand that independent formulation is used for selling together or gives (being less than each other in 24 hours, (giving) continuously or side by side).
In pharmaceutical composition of the present invention, compound of the present invention exists with significant quantity.As used in this article, term " significant quantity " refers to when the dosage regimen with suitable gives, and is enough to therapeutic goal disorder.
At Freireich et al., Cancer Chemother.Rep, has described the mutual relationship (the milligram number based on every square metre of surface) for animal and human's dosage in 1966,50:219.Body surface area can be determined approx by experimenter's height and weight.Referring to, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.
In one embodiment, the significant quantity of the compounds of this invention can be in the scope of each treatment 25mg to 500mg.Treat and typically give 1 to 2 every day.One, more specifically in embodiment, significant quantity can be in following quantity or scope:
300mg, preferred oral gives twice of every day;
250mg, preferred oral gives twice of every day;
200mg, preferred oral gives twice of every day or once a day;
100mg, preferred oral gives once a day;
50mg, preferred oral gives once a day;
From 200 to 300mg, preferred oral gives twice of every day; Or
50-200mg, preferred oral gives once a day.
Just as understood by a person skilled in the art, significant quantity also will depend on the disease for the treatment of, the use of the seriousness of disease, route of administration, experimenter's sex, age and general health situation, vehicle, combine the possibility of use and treatment doctor's judgement and change with other treatment punishment (as the use of other medicaments).For example,, for selecting the guidance of significant quantity to determine by reference to the prescription information for Crizotinib.
For the pharmaceutical composition that comprises the second therapeutical agent, dosage approximately 20% to 100% between of the significant quantity of the second therapeutical agent for conventionally adopting in only using single treatment plan of this medicament.Preferably, significant quantity is common single therapeutic dose approximately between 70% to 100%.Common single therapeutic dose of these the second therapeutical agents is known in this area.Referring to, Wells et al. for example, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000).Each in these reference is integrated with herein by quoting its integral body.
Can expect that some meetings and compound of the present invention in above-cited the second therapeutical agent act synergistically.When this synergy occurs, allow the effective dose of the compound of the second therapeutical agent and/or this invention to reduce from the amount needing single current system method.This has following advantage: the second therapeutical agent or both toxic side effect of compound of the present invention are minimized, the collaborative improvement of usefulness, the improved easiness that gives or use, and/or the total expenses of minimizing compound formulation or preparation.
Methods for the treatment of
In another embodiment, the invention provides a kind of Nucleophosmin-anaplastic lymphoma kinase (ALK) in cell and method of the kinase whose activity of stem cell factor acceptor (c-met/HGFR) of regulating, it comprises makes cell contact with the compound or pharmaceutically acceptable salt thereof of one or more Formula I herein.
According to other embodiment, the invention provides a kind of method for the treatment of disease, this disease by suppressing for example Crizotinib of ALK and c-met/HGFR(in its experimenter of needs) and advantageously treatment, it comprises and gives the compound of the present invention of experimenter's significant quantity or the step of composition.In one embodiment, experimenter is the patient who needs such treatment.Such disease is well known in the art, and is disclosed in, but is not limited to disclosed application WO 2006/021884.Such disease includes, but are not limited to, cancer, particularly lung cancer, nonsmall-cell lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head and neck cancer, cutaneous melanoma or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the anal region, cancer of the stomach (stomach cancer), colorectal carcinoma, colorectal carcinoma, stomach cancer (gastric cancer), mammary cancer, carcinoma of endometrium, uterine tube tumour, cervical cancer, vaginal tumor, vaginal orifice tumour, Hodgkin's disease, esophagus cancer, carcinoma of small intestine, endocrine system cancer, thyroid carcinoma (cancer of the thyroid gland), parathyroid carcinoma, adrenal carcinoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, lymphoma, soft tissue sarcoma, bladder cancer, kidney or carcinoma of ureter (cancer of the kidney or ureter), renal cell carcinoma, kidney pelvic tumor, the tumour of central nervous system (CNS) (vegetation, neoplasms), primary CNS lymphoma, Vertebral Neoplasms: (spinal axis tumors), glioblastoma multiforme, brain stem neurospongioma (brain stem glioma), neuroblastoma, pituitary adenoma, solid tumor, or the combination of one or more aforementioned cancers.Such disease also comprises abnormal Growth of Cells obstacle, and wherein disease is benign proliferative diseases, includes but not limited to psoriatic, benign prostatic hyperplasia and restenosis.
According to other embodiment, the invention provides the method for Growth of Cells abnormal in treatment Mammals.
In a special embodiment, method of the present invention is for being selected from disease or the illness of lymphoma, neuroblastoma, solid tumor and nonsmall-cell lung cancer in its experimenter treatment of needs.
Determine and need the experimenter of such treatment to be judged by experimenter or health care professional, and can be subjective (for example suggestion) or objective (for example by test or diagnostic method, measuring).
In other embodiment, any above methods for the treatment of comprises combines the further step that needs one or more the second therapeutical agents of its experimenter.The selection of the second therapeutical agent can by known for give useful any the second therapeutical agent combining of Crizotinib and make.The selection of the second therapeutical agent also depends on specified disease or the illness that will treat.The example of the second therapeutical agent adopting is in the method for the invention those that provide hereinbefore, and it is for combining the composition that comprises compound of the present invention and the second therapeutical agent.
Especially, conjoint therapy of the present invention comprises combines to its experimenter of needs the compound or pharmaceutically acceptable salt thereof that gives Formula I, and second therapeutical agent, be used for the treatment of following illness and (be included in following indication: specific the second therapeutical agent (PF-00299804) indicating in nonsmall-cell lung cancer bracket below).
As used in this article, term " is combined and is given (co-administered) " and means that the second therapeutical agent can give as a part (as composition of the present invention comprises compound of the present invention as above and the second therapeutical agent) for single formulation or as the multi-form that separates together with compound of the present invention.Alternatively, other medicament can be before compound of the present invention, simultaneously or give afterwards.In the treatment of such conjoint therapy, by traditional method, give compound of the present invention and a kind of (multiple) second therapeutical agent.Give experimenter composition of the present invention, comprise compound of the present invention and the second therapeutical agent, the other time during therapeutic process of being not precluded within gives separately therapeutical agent that described experimenter is identical, any other the second therapeutical agent or any compound of the present invention.
The significant quantity of these the second therapeutical agents is known for those skilled in the art, and the patent that can quote in this article and disclosed patent application and at Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, finds the guide for dosage in Calif. (2000) and other medical books.Yet, determine that the best significant quantity scope of the second therapeutical agent is also completely in technician's ken (purview).
In an embodiment of invention, wherein give experimenter the second therapeutical agent, the significant quantity of compound of the present invention is lower than its significant quantity that ought not give in the situation of the second therapeutical agent.In other embodiment, the significant quantity of the second therapeutical agent is lower than its significant quantity that ought not give in the situation of compound of the present invention.By this way, can make the less desirable side effect relevant to the high dosage of any medicament minimize.Other potential advantages (including but not limited to the medicine cost of improved dosage regimen and/or reduction) will be obvious to those skilled in the art.
In a further aspect, the invention provides the application in drug manufacture together with the compound of independent Formula I or the second therapeutical agent above-mentioned with one or more, as single composition or as the formulation of separating, the disease, disorder or the illness that are used for the treatment of or prevent to provide above in experimenter.The other aspect of the present invention is compound or its pharmaceutical salts of Formula I, the application in its disease, disorder or the illness of describing in this article in treatment or prevention experimenter.
Embodiment
Embodiment 1, compound 212:
Figure BDA00002102779200311
By diaryl bromide 34a(69mg, 0.182mmol) in water-soluble and acetonitrile (1.3mL) (0.455mL) and add 15c(83.0mg, 0.218mmol), K 2cO 3(63.0mg, 0.165mmol) and four (triphenylphosphine) closes palladium (0) (63mg, 0.055mmol).The solution obtaining is stirred 15 hours under 80 ° of C, at this moment between after LCMS show the product be converted into hope completely.Under reduced pressure reaction is concentrated and on ISCO Combiflash purification system, directly carry out silica gel chromatography (chromatography), 0-10% ethanol/methylene gradient.Thereby the flow point containing wishing product is merged and the concentrated water white oil (75mg, 0.141mmol, 77%) that provides.
The oil obtaining is dissolved in the hydrochloric acid soln in Virahol to (4M, 0.1mL) and stirs 2h, at this moment between after LCMS show the product that is converted into hope completely.To react with ethyl acetate and water dilution.Be separated, and water is extracted with ethyl acetate.By aqueous hydrochloric acid for organic phase (1M) washing merging.The water layer merging is then alkalized with aqueous sodium hydroxide solution (3N).Then the product of hope is extracted with ethyl acetate to (3x).By organic phase dried over sodium sulfate, filter and concentrate to provide water white oil, it is dissolved in benzene/methyl alcohol solvent pairs centering.With dry ice/acetone batch solution is cooled to-78C, and the solid obtaining is carried out to freeze-drying, its output is as the compound 212(39mg of white powder, 0.086mmol, productive rate 61%).
(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(1-(2,2,6,6-, tetra-deuterium piperidin-4-yls)-1H-pyrazoles-4-yl) piperidines-2-amine 212. 1H?NMR(400MHz,CDCl 3)δ：7.74(br?s,1H),7.56(d,J＝4Hz,1H),7.49(s,1H),7.31(dd,J=8,4Hz,1H),7.04(m,1H),6.86(br?s,1H),6.07(q,1H),4.79(br?s,2H),4.21(m,1H),2.15(m,2H),1.90(m,2H),1.86(d,J=12Hz,3H)，MS（ESI）454.2[(M+H) +]。
Embodiment 2, compound 211:
Figure BDA00002102779200321
Utilize with the similar process disclosing in above embodiment 1 and prepare compound 211.
(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group)-5-(1-(3,3,5,5-, tetra-deuterium piperidin-4-yls)-1H-pyrazoles-4-yl) pyridine-2-amine 211 obtains (41mg, 0.087mmol) as white powder. 1H?NMR(400MHz,CDCl 3)δ：7.74(br?s,1H),7.56(d,J＝4Hz,1H),7.49(s,1H),7.31(dd,J=8,4Hz,1H),7.04(m,1H),6.86(br?s,1H),6.07(q,1H),4.79(br?s,2H),4.21(m,1H),3.21(d,J=12Hz,2H),2.73(d,J=12Hz,2H),1.86(d,J=6.7Hz,3H)，MS(ESI)454.2[(M+H) +]。
Embodiment 3, compound 215:
Figure BDA00002102779200331
Utilize with the similar process disclosing in above embodiment 1 and prepare compound 215.
(R) (1-(2,2,6 for-5-, 6-tetra-deuterium piperidin-4-yls)-1H-pyrazoles-4-yl)-3-(2,2,2-, tri-deuteriums-1-(2, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group) pyridine-2-amine 215 obtains (11mg, 0.024mmol) as pale powder. 1H?NMR(400MHz,CDCl 3)δ：7.74(br?s,1H),7.56(d,J＝4Hz,1H),7.49(s,1H),7.31(dd,J=8,4Hz,1H),7.04(m,1H),6.86(br?s,1H),6.07(s,1H),4.79(br?s,2H),4.21(m,1H),2.15(m,2H),1.90(m,2H)，MS(ESI)458.4[(M+H) +]。
Embodiment 4, compound 214:
Figure BDA00002102779200332
Utilize with the similar process disclosing in above embodiment 1 and prepare compound 214.Reaction product, without being further purified, is carried out 1h NMR(discloses as follows) its prompting 214 is main ingredients in mixture.
(R)-5-(1-(3,3,5,5-, tetra-deuterium piperidin-4-yls)-1H-pyrazoles-4-yl)-3-(2,2,2-, tri-deuteriums-1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine 214. 1H?NMR(400MHz,CDCl 3)δ：7.74(br?s,1H),7.56(d,J＝4Hz,1H),7.49(s,1H),7.31(dd,J=8,4Hz,1H),7.04(m,1H),6.86(br?s,1H),6.07(q,1H),4.79(br?s,2H),4.21(m,1H),3.21(d,J=12Hz,2H),2.73(d,J=12Hz,2H)。MS(ESI)458.4[(M+H) +]。Exemplary diaryl bromide (as the 34a adopting in embodiment 1), its can the preparation for the following compound disclosing herein in.
Figure BDA00002102779200341
Diaryl bromide 34a-d's is synthetic
The preparation of embodiment 5,34d:
Figure BDA00002102779200342
The preparation of intermediate 10c
Figure BDA00002102779200343
By the 1-being purchased (the chloro-3-fluorophenyl of 2,6-bis-) ethyl ketone 10a(3.4g, 16.4mmol) use in D 2o(10mL) salt of wormwood in (250mg) carries out H-D exchange under refluxing.By 1h NMR analyzes deuterium enriched (deuterium enrichment) and reaches 85%.Reaction neutralizes with aqueous hydrochloric acid, and is extracted with ethyl acetate product.By the organic phase dried over sodium sulfate of merging.Raw material is passed through at CDCl 3(16mL) 1,5 in, 7-tri-azabicyclos [4.4.0] last of the ten Heavenly stems-5-alkene (0.2g) carry out further H-D exchange.Solution is stirred and spent the night under envrionment temperature and pressure.After 12h, 1h NMR shows deuterium enriched abundant (>99%).Reaction is diluted with methylene dichloride and is used aqueous hydrochloric acid (1M) and salt water washing.By organic phase dried over sodium sulfate, filter and concentrate to provide as 2,2 of water white oil, 2-tri-deuteriums-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethyl ketone (10c) (2.84g, productive rate 82%).Without any being further purified, this material is sent into enzymatic reaction.
The preparation of intermediate 11d
Figure BDA00002102779200351
2,2,2-, tri-deuteriums-1-(the chloro-3-fluorophenyl of 2,6-bis-) ethyl ketone (10a, 1.29g) is dissolved in to the 30% trolamine aqueous solution (pH 7) and d 1in-Virahol (5g).Disposable ketoreductase (KRED-P1-H08,50mg) and the NADP of adding +(50mg).Reaction is stirred thinking that outlet by pin is bonded under the barotropic flow thigh of nitrogen of oily bubbler.Become the transformation efficiency of wishing product quantitative by LCMS, and at 3d(3 days) after add other enzyme (50mg), NADP +(50mg) and d 1-Virahol (5g).Make reaction carry out other 4d(4 days), at this moment between after, LCMS shows the product that is converted into hope completely.Heptane (20mL) dilution for reaction, and be heated to the lasting 1h of 40 ° of C.The suspension obtaining is diluted with ethyl acetate and water and filter by short celite pad.The two-phase mixture obtaining is separated, and water is returned and is extracted with ethyl acetate.The organic phase of merging is used to sodium bicarbonate aqueous solution, ammonium chloride and water washing in succession.Organic layer dried over sodium sulfate, filters and concentrates to provide the 1-deuterium-1-(the chloro-3-fluorophenyl of 2,6-bis-)-2,2 as water white oil, 2-tri-deuterium ethanol 11d(1.1g, and productive rate 86%, > 99% isotopic enrichment).Without any being further purified, this material is sent into enzymatic reaction.
The preparation of intermediate 13d
Figure BDA00002102779200352
Prepare at ambient temperature 1-deuterium-1-(2, the chloro-3-fluorophenyl of 6-bis-)-2,2,2-tri-deuterium ethanol (1.00g, 4.76mmol), 3-hydroxyl amino pyridine (733mg, 5.23mmol) and the tetrahydrofuran solution of triphenylphosphine (1.87g, 7.14mmol) (43mL), and be cooled to 0 ° of C with ice bath.Then by syringe, add Diisopropyl azodicarboxylate (1.0mL).Make reaction in 12h, be warming up to envrionment temperature, carve at this moment, with LCMS, determine that chiral alcohol is to the transformation efficiency of diaryl ether.Concentration response directly carry out silica gel chromatography (chromatography), 0-30% ethyl acetate/heptane gradient on ISCO Combiflash purification system under reduced pressure.Thereby the flow point of the diaryl ether containing wishing is merged and concentrated and provide (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-)-1,2,2, the 2-tetra-deuterium oxyethyl group nitropyridines (13d) (0.89g, 56%) as white solid.
The preparation of intermediate 34d
Figure BDA00002102779200361
By (R)-3-, (1-(the chloro-3-fluorophenyl of 2,6-bis-)-1,2,2,2-tetra-deuterium oxyethyl group nitropyridines (13d) (0.889mg, 2.66mmol) are dissolved in the solution (133mL 1:1.15) of ethanol and acetic acid.With the disposable iron powder (1.49g) that adds of solid.Suspension is heated to gentle reflux and continues 1h, now LCMS thinks and is converted into aminopyridine completely.To react cooling, with Anaesthetie Ether dilution, also carefully be used in the wet chemical neutralization in ice.Then with sodium hydroxide, two phase liquid is become to alkaline pH, now by product Anaesthetie Ether. extraction.By the organic phase dried over sodium sulfate merging, filter and concentrate to provide (R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-)-1,2,2, the 2-tetra-deuterium oxyethyl groups) pyridine-2-amine (1.0g) as pale solid.Without being further purified, this material is sent into next step reaction.
(R)-3-(1-(the chloro-3-fluorophenyl of 2,6-bis-)-1,2,2,2-tetra-deuterium oxyethyl groups) pyridine-2-amine (2.66mmol) is dissolved in methylene dichloride (10mL) and with ice bath and is cooled to 0 ° of C.By syringe, be added in N-bromine succinimide (2.66mmol) solution in acetonitrile (1mL).After 1h, LCMS shows to be converted into completely the bromide of hope.Concentration response directly carry out silica gel chromatography (chromatography), 0-100% ethyl acetate/heptane gradient on ISCO Combiflash purification system under reduced pressure.Thereby the flow point of the bromide containing wishing is merged and concentrated and provide the bromo-3-of (R)-5-(1-deuterium-1-(2 as brown solid, the chloro-3-fluorophenyl of 6-bis-)-2,2,2-, tri-deuterium oxyethyl groups) pyridine-2-amine (34d) (820mg, 2.12mmol).
The preparation of embodiment 6,34a:
Figure BDA00002102779200371
According to by de Koning, P.D.et al.Org.Res.Process Dev.2011, the process preparation bromo-3-of (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group) pyridine-2-amine (34a that 15,1018-1026 describes.
The preparation of embodiment 7,34b:
Figure BDA00002102779200372
Can utilize with disclose for the synthesis of diaryl bromide 34d(embodiment 5) the similar process preparation bromo-3-of (R)-5-(1-deuterium-1-(the chloro-3-fluorophenyl of 2,6-bis-)-oxyethyl group) pyridine-2-amine (34b).Therefore, embodiment 5 is by providing the 1-being purchased (the chloro-3-fluorophenyl of 2,6-bis-) ethyl ketone 10a the H-D exchange of H in the methyl group that there is no previous 10a to enzymatic reaction and changing.
The preparation of embodiment 8,34c:
Figure BDA00002102779200373
Utilize with disclose for the synthesis of diaryl bromide 34d(embodiment 5) the similar process preparation bromo-3-of (R)-5-(1-(the chloro-3-fluorophenyl of 2,6-bis-)-2,2,2-tri-deuterium oxyethyl groups) pyridine-2-amine (34c).Therefore, embodiment 5 passes through in the reduction of 10c d 1-Virahol is replaced with Virahol to finally using good productive rate and is provided 34c as single stereoisomers.
The preparation of embodiment 9,16b-16h:
The exemplary deuterate 4-Boc-piperidines-1-alcohols 16b-16h as useful in 15b-h for the preparation of piperidines-pyrazoles dioxa boron Polymorphs alkanes (piperidine-pyrazole boroxalanes) can be prepared as shown in following scheme 4.
Scheme 4: the preparation of compound 16b-16h:
Figure BDA00002102779200381
23 preparation:
By 3,3,5,5-, tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester (23): 1-Boc-4-piperidone (10g, 50.2mmol) is dissolved in CDCl 3(100mL) in.Disposable 1,5,7-, tri-azabicyclos [4.4.0] last of the ten Heavenly stems-5-alkene (0.5g) that add, and solution is stirred and spent the night under envrionment temperature and pressure.By 1h NMR analyzes α proton resonance deuterium enriched and that ought be assigned to carbonyl by inciting somebody to action 1h NMR thinks and reacts completely in the time of no longer can detecting.By aqueous hydrochloric acid (1M) neutralization reaction and be extracted with ethyl acetate product.By the organic phase dried over sodium sulfate merging, filter and concentrate to provide as 3,3,5 of water white oil, 5-tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 23(8.72g, 43.0mmol, productive rate 86%,>99%D 4), 1h NMR (400MHz, CDCl 3) δ: 3.71 (s, 4H), 1.47 (s, 9H).
The preparation of 16b:
Figure BDA00002102779200391
By 3,3,5,5-, tetra-deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16b:3,3,5,5-, tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 23(1.1g, 5.41mmol) be dissolved in methyl alcohol (10mL) and with ice bath and be cooled to 0 ° of C.Disposablely add sodium borohydride (0.2g), and solution is stirred to 12h under envrionment temperature and pressure.Reaction neutralizes with saturated aqueous ammonium chloride, makes volatile matter concentrated, then with ethyl acetate and water reallocation.Product is extracted with ethyl acetate.By the organic phase dried over sodium sulfate merging, filter and concentrate to provide as 3,3,5 of water white oil, 5-tetra-deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16b(0.955g, 4.65mmol, productive rate 86%,>99%D 4). 1H?NMR(400MHz,CDCl 3)δ：3.84-3.81(br?s,3H),2.99(d,J=4Hz,2H),1.47(s,9H)；MS(ESI)206.2[(M+H) +]。
The preparation of 16f:
Figure BDA00002102779200392
By 3,3,4,5,5-, five deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16f:3,3,5,5-, tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 23(2.0g, 9.84mmol) be dissolved in methyl alcohol (16mL), and be cooled to 0 ° of C with ice bath.Disposablely add sodium borohydride (0.4g), and solution is stirred to 12h under envrionment temperature and pressure.Reaction neutralizes with saturated aqueous ammonium chloride, makes volatile matter concentrated, then water and ethyl acetate reallocation.Product is extracted with ethyl acetate.By the organic phase dried over sodium sulfate merging, filter and concentrate to provide as 3,3,4,5 of water white oil, 5-five deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16f(1.75g, 8.53mmol, productive rate 87%,>99%D 5). 1H?NMR(400MHz,CDCl 3)δ：3.84(d,J=16Hz,2H),3.00(d,J=16Hz,2H),1.47(s,9H)；MS(ESI)207.2[(M+H) +]。
The preparation of 16d:
Figure BDA00002102779200401
As by Hesk, D.et al.J.Label Compd Radiopharm.2007; The process that 50:131-137 describes is prepared 2,2,6,6-, tetra-deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16d.
26 preparation:
Figure BDA00002102779200402
2,2,6,6-, tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 26: in methylene dichloride (41mL), prepare sodium bicarbonate (4.0g),
Figure BDA00002102779200403
molecular sieve (4.0g) and 16d(1.66g, 8.1mmol) suspension.Follow the high iodine alkane of the disposable Dai Si of adding-Martin (Dess-Martin periodinane) (3.82g, 8.9mmol).Be that 12h is carried out in reaction, by TLC, confirm to react completely afterwards.Add Sulfothiorine (4g), and realize the exchange of solvent (solvent swap) with heptane by condistillation.The slurry that obtains filters by short celite pad, its with 30% ethyl acetate/heptane solvent to washing.Then filtrate is used in succession to 10% sodium sulfate, saturated sodium thiosulfate solution, sodium bicarbonate and salt water washing.The organic phase of distribution is washed with sodium sulfate, filter and concentrate to provide as 2,2,6 of white powder, 6-tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 26(8.1mmol, productive rate 99%,>99%D 4). 1H?NMR(400MHz,CDCl 3)δ：2.43(s,4H),1.47(s,9H)。? 1in H NMR, can't detect remaining high iodine alkane resonance.Think that this material is enough pure for sending into next step.
27 preparation:
Figure BDA00002102779200404
2,2,3,3,5,5,6,6-octa deuterium-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 27: as the process of describing for 3,3,5,5-, tetra-deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 23, by being used in CDCl 3(40mL) the ketone 26(8.1mmol in) and the direct H-D of TBD catalyzer (0.2g) exchange realize deuterium enriched.As water white oil, obtain 2,2,3,3,5,5,6,6-, eight deuteriums-4-oxo-piperidine-1-carboxylic acid tertiary butyl ester 27(1.54g, 7.44mmol, productive rate 92%,>99%D 8). 1H?NMR(400MHz,CDCl 3)δ：1.47(s,9H)。
The preparation of 16g:
Figure BDA00002102779200411
As the process of describing for alcohol 16b, by ketone 27(0.55g, 2.68mmol) prepare 2,2 with the reacting of sodium borohydride (0.1g) in methyl alcohol, 3,3,5,5,6,6-eight deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16g using provide the 16g(0.35g as water white oil, 1.65mmol, productive rate 62%). 1HNMR(400MHz,CDCl 3)δ：3.81(br?s,1H),1.47(s,9H)。
The preparation of 16h:
As the process of describing for alcohol 16b, by ketone 27(0.55g, 2.68mmol) prepare 2 with boron deuterate sodium (sodium borodeuteride) in methyl alcohol reacting (0.12g), 2,4,3,3,5,5,6,6-, nine deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16h is usingd and is provided the 16h(0.39g as water white oil, 1.84mmol, productive rate 66%). 1H?NMR(400MHz,CDCl 3)δ：1.47(s,9H)。
The preparation of 16c:
Figure BDA00002102779200413
As the process that the preparation for alcohol 16b is described, by ketone 26 and boron deuterate sodium, prepare 2,2,4,6,6-, five deuteriums-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16c.
The preparation of 16e:
Figure BDA00002102779200421
As the process that the preparation for alcohol 16f is described, by the ketone 21 and the boron deuterate sodium that are purchased, prepare 4-deuterium-4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester 16e.
Can disclose as follows for exemplary pyridine-pyrazoles dioxa boron Polymorphs alkanes of the preparation of compound herein:
Figure BDA00002102779200422
The preparation of embodiment 10,15c:
The preparation of scheme 5:15c:
Figure BDA00002102779200431
The preparation of intermediate 17c:
Figure BDA00002102779200432
2,2,6,6-, tetra-deuteriums-4-((methyl sulphonyl) oxygen base) piperidines-1-carboxylic acid tertiary butyl ester 17c: by alcohol 16c(0.78g, 3.81mmol) and N-methylmorpholine (0.46mL) be dissolved in methylene dichloride (10mL), then with ice bath, be cooled to 0 ° of C.Then by the disposable methylsulfonyl chloride (0.3mL) that adds of syringe.After 10 minutes, ice bath removed and reaction is warming up to the lasting 2h of envrionment temperature, now by TLC, thinking and react completely.Reaction is diluted with methylene dichloride and is used aqueous hydrochloric acid (1M) quencher (termination).Be separated, then by aqueous hydrochloric acid, salt solution and water washing for organic phase.By the organic phase dried over sodium sulfate merging, filter and concentrate to provide pale solid (3.81mmol, productive rate > 95%).2,2,6,6-, tetra-deuteriums-4-((methyl sulphonyl) oxygen base) piperidines-1-carboxylic acid tertiary butyl ester 17c: 1h NMR (400MHz, CDCl 3) δ: 4.89 (m, 1H), 3.04 (s, 3H), 1.95 (dd, J=12,4Hz, 2H), 1.80 (dd, J=16,8Hz, 2H), 1.46 (s, 9H).
The preparation of intermediate 18c:
Figure BDA00002102779200433
2,2,6,6-, tetra-deuteriums-4-(the iodo-1H-pyrazol-1-yl of 4-) piperidines-1-carboxylic acid tertiary butyl ester 18c: add cesium carbonate (1.63g) in the solution of the iodo-pyrazoles of the 4-in N-Methyl pyrrolidone (NMP, 3.5mL) (0.81g, 4.17mmol).Solution is heated to 80C, now the disposable methanesulfonates 17c(3.81mmol that adds) nmp solution, and will react and stir 12h, now by LCMS, think and react completely.To react cooling, under reduced pressure concentrated and on ISCO Combiflash purification system, directly carry out silica gel chromatography (chromatography), 0-40% acetone/heptane gradient.Thereby the flow point containing wishing product is merged and the concentrated water white oil (0.45g, 1.19mmol, 32%) that provides.2,2,6,6-, tetra-deuteriums-4-(the iodo-1H-pyrazol-1-yl of 4-) piperidines-1-carboxylic acid tertiary butyl ester 18c: 1h NMR (400MHz, CDCl 3) δ: 7.53 (s, 1H), 7.46 (s, 1H), 4.29 (m, 1H), 2.09 (dd, J=12,4Hz, 2H), 1.85 (m, 2H), 1.46 (s, 9H).
The preparation of 15c:
Figure BDA00002102779200441
2,2,6, (4-(4,4,5 for 6-tetra-deuteriums-4-, 5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tertiary butyl ester 15c: by pyrazoles iodide (Pyrazole iodide) 18c(0.45g, 1.2mmol) be dissolved in tetrahydrofuran (THF) (5mL) and be cooled to 0 ° of C.Then dropwise add in 2-methyl-THF(0.74mL, 2.4M) in isopropylmagnesium chloride solution.After 15 minutes, by syringe, add 2-methoxyl group-4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane (0.41mL).Within 12h, make reaction be warming up to envrionment temperature, now by LCMS, think and react completely.Saturated ammonium chloride quencher (termination) for reaction, and under reduced pressure remove volatile matter.Then reaction is distributed between ethyl acetate and water.Organic phase is used saturated ammonium chloride and salt water washing in succession.The organic phase dried over sodium sulfate merging, filters, concentrated and on ISCO Combiflash purification system, pass through silica gel chromatography (chromatography) purifying, 0-50% ethyl acetate/heptane gradient.Thereby the flow point of the bromide containing wishing is merged and the concentrated water white oil (0.34g, 0.89mmol, 75%) that provides.2,2,6,6-, tetra-deuteriums-4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazol-1-yl) piperidines-1-carboxylic acid tertiary butyl ester 15c: 1h NMR (400MHz, CDCl 3) δ: 7.86 (s, 1H), 7.77 (s, 1H), 4.29 (m, 1H), 2.09 (m, 2H), 2.1 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12H).
Piperidines-pyrazoles dioxa boron Polymorphs alkanes, as 15a, 15b and 15d-h can be prepared as the 4-hydroxy piperidine by corresponding of describing for compound 15c in above embodiment 10.For example, compound 15a can be as being prepared by the 4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester (CAS 109384-19-2) being purchased of describing in embodiment 10.Compound 15b can be as being prepared by compound 16e of describing in embodiment 10.Compound 15d can be as being prepared by compound 16d of describing in embodiment 10.Compound 15e can be as being prepared by compound 16c of describing in embodiment 10.Compound 15f can be as being prepared by compound 16f of describing in embodiment 10.Compound 15g can be as being prepared by compound 16g of describing in embodiment 10.Compound 15h can be as being prepared by compound 16h of describing in embodiment 10.
Biological test:
Embodiment 11, metabolic stability assessment:
Microsome test: from Xenotech, LLC(Lenexa, KS) obtain people's hepatomicrosome (20mg/mL).From Sigma-Aldrich, buy reduction form (NADPH), the magnesium chloride (MaCl of β-Triphosphopyridine nucleotide, reduced 2) and dimethyl sulfoxide (DMSO) (DMSO).
The mensuration of metabolic stability: the stock solution of preparing 7.5mM test compounds in DMSO.7.5mM stock solution is diluted in acetonitrile (ACN) to 12.5-50 μ M.By 20mg/mL people's hepatomicrosome, at 0.1M potassium phosphate buffer, (pH 7.4, the MgCl that contains 3mM 2) in be diluted to 0.625mg/mL.In triplicate, in the hole of 96-hole depth hole polypropylene board, add diluted microsome.The aliquots containig of 10 μ L of 12.5-50 μ M test compounds is joined in microsome, and by mixture preheating 10 minutes.By adding the NADPH solution initiation reaction of preheating.End reaction volume is 0.5mL, and at 0.1M potassium phosphate buffer (pH7.4, the MgCl of 3mM 2) in contain 0.5mg/mL people's hepatomicrosome, 0.25-1.0 μ M test compounds and 2mM NADPH.Incubation reaction mixture under 37 ° of C, in 0,5,10,20 and 30 minute shifts out 50 μ L aliquots containigs and joins the shallow bore hole 96-orifice plate that contains the ice-cold ACN of target in 50 μ L with stopped reaction.Orifice plate is stored to 20 minutes under 4 ° of C, after this, centrifugal so that precipitation protein particulate (pellet) before the water of 100 μ L is joined in the hole of orifice plate.Supernatant liquor is transferred in other 96-orifice plate, and uses Applied Bio-systems API 4000 mass spectrographs to analyze remaining maternal quantity by LC-MS/MS.For counterpart and the positive control of the non-deuterate of the compound of Formula I, CYP1A (1 μ M) carries out identical process.Test is carried out three times.
Data analysis: calculate the external t for test compounds with respect to the slope of the linear regression of the relation of incubation time by % parent residue (ln) 1/2.
External t 1/2=0.693/k
K=-[% parent residue (ln) is with respect to the slope of the linear regression of incubation time]
Use Microsoft Excel Software to carry out data analysis.
Embodiment 12, for assessment of IC 50change the method for (Shift):
By people's hepatomicrosome (0.25mg/mL) with 100,50,25,12.5,6.25,3.125,1.563,0.781,0.391,0.195,0.098 and the Crizotinib (Crizotinib) of 0mM under 2mM NADPH exists, preincubate 0 and 30min in shallow 96-orifice plate.In order to measure remaining CYP3A4 enzymic activity after preincubate, by the aliquots containig of reaction mixture, in independent shallow 96-orifice plate, at 0.1M potassium phosphate buffer, (pH 7.4, containing 3mM MgCl 2) middle dilution for 1:10.Add testosterone (testosterone) (final concentration 50mM), and by adding 2mM NADPH initiation reaction.These reactions are composed and educated other 10min, and by adding with interior target acetonitrile termination reaction.Orifice plate is centrifugal with so that the protein particulate (pellet) of precipitation, and for the 6 β-OH-testosterone forming, analyze supernatant liquor by LC-MS/MS.
Same test operation is other twice, replaces Crizotinib (crizotinib): the test compounds in twice operation is respectively compound 212 and compound 211 by different representative compounds at every turn.
IC described above 50change assessment (the Assessment ofIC of test 50shift assays) result for the azoles base of a fruit (crizotinib), compound 212 and compound 211 in three kinds of test compounds-Ke each respectively shown in Figure 1A, 1B and 1C.As seen in the drawings, gram in the azoles base of a fruit exist under for the IC of the metabolism of the testosterone by CYP3A4 50change (IC 50shift) be 7.5-doubly (from 11.2 to 1.5 μ M).In contrast, under compound 212 and compound 211 exists for the IC of the metabolism of the testosterone by CYP3A4 50change (IC 50shift) be only respectively 3.0-doubly (from 9.8 to 3.3 μ M) and 3.3-times (from 13.7 to 4.1 μ M).Therefore, under compound 212 and compound 211 exists, being changed significantly of the metabolism of the testosterone by CYP3A4 be less than gram in the variation of the azoles base of a fruit under existing.
In the situation that not further describing, think that those of ordinary skills can utilize above-mentioned explanation and exemplary embodiment, prepare and use compound of the present invention and implement claimed method.Be to be understood that aforementioned discussion and embodiment only provide the detailed description of some preferred implementation.Those of ordinary skills will understand that can make various changes does not deviate from the spirit and scope of the present invention with distortion of equal value.

Claims (31)

1. the compound or pharmaceutically acceptable salt thereof of a Formula I:
Figure FDA00002102779100011
Wherein:
R 1and R 2be selected from independently of one another Cl, CH 3and CD 3;
R 3cH 3or CD 3;
X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5be selected from independently of one another hydrogen and deuterium;
Y 1hydrogen or deuterium; And
Y 2hydrogen or deuterium;
Condition is to work as R 1and R 2be selected from independently of one another Cl and CH 3, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, X 4b, and X 5in each be hydrogen, and Y 1and Y 2in each while being hydrogen, R 3cD 3.
2. compound according to claim 1, wherein, X 1aand X 1bidentical; X 2aand X 2bidentical; X 3aand X 3bidentical; X 4aand X 4bidentical; And R 1and R 2independently selected from Cl and CD 3.
3. compound according to claim 2, wherein, X 1a, X 1b, X 2aand X 2bidentical; And X 3a, X 3b, X 4aand X 4bidentical.
4. compound according to claim 3, wherein, R 1and R 2identical.
5. compound according to claim 4, wherein, each X 1, each X 2, each X 3and each X 4hydrogen.
6. compound according to claim 4, wherein, each X 1, each X 2, each X 3and each X 4it is deuterium.
7. compound according to claim 4, wherein, each X 1with each X 2hydrogen; And each X 3with each X 4it is deuterium.
8. compound according to claim 4, wherein, each X 1with each X 2it is deuterium; And each X 3with each X 4hydrogen.
9. according to the compound described in any one in claim 5-8, wherein X 5hydrogen, Y 1hydrogen, and Y 2hydrogen.
10. according to the compound described in any one in claim 5-8, wherein X 5hydrogen, Y 1deuterium, and Y 2hydrogen.
11. according to the compound described in any one in claim 5-8, wherein X 5hydrogen, Y 1hydrogen, and Y 2it is deuterium.
12. according to the compound described in any one in claim 5-8, wherein X 5hydrogen, Y 1deuterium, and Y 2it is deuterium.
13. according to the compound described in any one in claim 5-8, wherein X 5deuterium, Y 1hydrogen, and Y 2hydrogen.
14. according to the compound described in any one in claim 5-8, wherein X 5deuterium, Y 1deuterium, and Y 2hydrogen.
15. according to the compound described in any one in claim 5-8, wherein X 5deuterium, Y 1hydrogen, and Y 2it is deuterium.
16. according to the compound described in any one in claim 5-8, wherein X 5deuterium, Y 1deuterium, and Y 2it is deuterium.
17. according to the compound described in any one in aforementioned claim, wherein, and R 3cH 3.
18. according to the compound described in any one in aforementioned claim, wherein R 3cD 3.
19. according to the compound described in any one in claim 1,2,3,4,5,9,13,15 and 18, wherein, and R 1and R 2each is Cl naturally, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, Y 1hydrogen, and X 5deuterium, R 3cD 3.
20. according to the compound described in any one in claim 1,2,3,4,5,9,11,15 and 18, wherein, and R 1and R 2each is Cl naturally, X 1a, X 1b, X 2a, X 2b, X 3a, X 3b, X 4a, and X 4bin each be hydrogen, Y 1hydrogen, and Y 2deuterium, R 3cD3.
21. compounds according to claim 4, are selected from any or its pharmaceutical salts in the compound in following table:
Figure FDA00002102779100031
Figure FDA00002102779100041
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
22. compounds according to claim 4, are selected from any or its pharmaceutical salts in the compound in following table:
Figure FDA00002102779100042
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
23. compounds according to claim 4, are selected from any or its pharmaceutical salts in the compound in following table:
Figure FDA00002102779100043
Figure FDA00002102779100051
Wherein, any atom of not being appointed as deuterium is with its natural isotopic abundance.
24. according to the compound described in any one in claim 1-23, wherein, is not appointed as any atom of deuterium with its natural isotopic abundance.
25. 1 kinds of apyrogenic pharmaceutical compositions, comprise compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier described in claim 1 or 24.
26. compositions according to claim 25, further comprise the second therapeutical agent that is selected from kinase inhibitor.
27. compositions according to claim 26, wherein, described kinase inhibitor is selected from Tarceva, Xarelto, the Xarelto of deuterate, the PF-00299804 and 454283 of Tarceva, deuterate.
28. compositions according to claim 25, further comprise the combination that is selected from two kind of second therapeutical agent in the Tarceva of Tarceva or deuterate and the Xarelto of Xarelto or deuterate.
Treat in experimenter for 29. 1 kinds and be selected from following disease or the method for illness, comprise the composition described in the described experimenter's claim 25 that needs it, described disease or illness are selected from: cancer, especially lung cancer, nonsmall-cell lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head and neck cancer, cutaneous melanoma or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the anal region, cancer of the stomach, colorectal carcinoma, colorectal carcinoma, stomach cancer, mammary cancer, carcinoma of endometrium, uterine tube tumour, cervical cancer, vaginal tumor, vaginal orifice tumour, Hodgkin's disease, esophagus cancer, carcinoma of small intestine, endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, adrenal carcinoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, lymphoma, soft tissue sarcoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, kidney pelvic tumor, the tumour of central nervous system (CNS), primary CNS lymphoma, Vertebral Neoplasms:, glioblastoma multiforme, brain stem glioma, neuroblastoma, pituitary adenoma, the combination of solid tumor or one or more aforementioned cancers, benign proliferative diseases, comprises, but is not restricted to, psoriatic, benign prostatic hyperplasia and restenosis.
30. methods according to claim 28, wherein, described disease or illness are selected from nonsmall-cell lung cancer (NSCLC), noumenal tumour cancer, neuroblastoma and lymphoma.
31. methods according to claim 29, wherein, described disease or illness are nonsmall-cell lung cancer (NSCLC).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304552A (en) * 2012-03-09 2013-09-18 广东东阳光药业有限公司 Substituted pyridine compound as well as application method and usage thereof
CN104650049A (en) * 2013-08-28 2015-05-27 广东东阳光药业有限公司 Substitutive pyridine compound and application method and application thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6887430B2 (en) * 2015-11-27 2021-06-16 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. Deuterated Brigatinib derivatives, pharmaceutical compositions containing such derivatives, and their use.
EP3415518B1 (en) * 2016-03-03 2020-07-08 Shenzhen TargetRx, Inc. Macrocycle and composition comprising thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101023064A (en) * 2004-08-26 2007-08-22 辉瑞大药厂 Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
CN101967140A (en) * 2010-09-14 2011-02-09 郑州泰基鸿诺药物科技有限公司 Deuterated crizotinib as well as derivant, preparation method and application thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1959955T3 (en) * 2005-12-05 2011-02-07 Pfizer Prod Inc Method of Treating Abnormal Cell Growth

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101023064A (en) * 2004-08-26 2007-08-22 辉瑞大药厂 Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
CN101967140A (en) * 2010-09-14 2011-02-09 郑州泰基鸿诺药物科技有限公司 Deuterated crizotinib as well as derivant, preparation method and application thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304552A (en) * 2012-03-09 2013-09-18 广东东阳光药业有限公司 Substituted pyridine compound as well as application method and usage thereof
CN103304552B (en) * 2012-03-09 2016-12-28 广东东阳光药业有限公司 Substituted pyridine compounds and using method thereof and purposes
CN104650049A (en) * 2013-08-28 2015-05-27 广东东阳光药业有限公司 Substitutive pyridine compound and application method and application thereof

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