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CN107226805A - Aromatic amides analog derivative, its preparation method and its in application pharmaceutically - Google Patents

Aromatic amides analog derivative, its preparation method and its in application pharmaceutically Download PDF

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Publication number
CN107226805A
CN107226805A CN201610181525.9A CN201610181525A CN107226805A CN 107226805 A CN107226805 A CN 107226805A CN 201610181525 A CN201610181525 A CN 201610181525A CN 107226805 A CN107226805 A CN 107226805A
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alkyl
compound
heteroaryl
independently selected
aryl
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Inventor
陈向阳
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Beijing Tiancheng Pharmaceutical Technology Co Ltd
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Beijing Tiancheng Pharmaceutical Technology Co Ltd
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Priority to CN201610181525.9A priority Critical patent/CN107226805A/en
Priority to PCT/CN2017/075207 priority patent/WO2017162007A1/en
Publication of CN107226805A publication Critical patent/CN107226805A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The present invention relates to aromatic amides analog derivative, its preparation method and its in application pharmaceutically.Pharmaceutical composition specifically, the present invention relates to the new derivative shown in a kind of logical formula (I) and its pharmaceutically useful salt or containing it, and preparation method thereof.Pharmaceutical composition the invention further relates to the derivative and its pharmaceutically useful salt or containing it is preparing therapeutic agent, particularly Bruton tyrosine kinase inhibitors, and is preparing treatment and/or pre- preventing tumor and the purposes in the medicine of the immune disease such as related.Each substituent of its formula of (I) is identical with the definition in specification.

Description

Aromatic amides analog derivative, its preparation method and its in application pharmaceutically
Technical field
A kind of drug regimen the present invention relates to new aromatic amides analog derivative and its pharmaceutically useful salt or containing it Thing, and preparation method thereof.Pharmaceutical composition the invention further relates to the analog derivative and its pharmaceutically useful salt or containing it exists Prepare therapeutic agent, Bruton tyrosine kinase inhibitors, and in the medicine for preparing the diseases such as treatment and/or pre- preventing tumor and inflammation In purposes.
Background technology
Bruton EGFR-TKs (BTK) are a kind of enzymes of important mediated cell signal transduction, are present in thick liquid cell, bag Include in B cell.B cell is activated by B-cell receptor (BCR), and BTK has risen certainly in the signal path that BCR is mediated Qualitatively act on.After BCR in B cell is activated, cause BTK activation, causing phospholipase C (PLC) concentration in downstream increases, And activate IP3 and DAG signal paths.This signal path can promote propagation, adhesion and the survival of cell, in B cell lymph Played an important role in the evolution of knurl.
Presence of the BTK mutant in crowd, which demonstrates BTK, can turn into drug target.Sex-linked agammaglobulinemia (XLA) it is a kind of rare genetic disease, in the male for being present in 1/250,000.In this disease, BTK function is pressed down System, so as to result in generation or the anacmesis of B cell.Male with XLA diseases, in vivo substantially without B cell, circulation is anti- Body is also seldom, serious or even fatal infection easily occurs.As can be seen here, BTK is played extremely in the growth and differentiation of B cell Important effect.
BTK inhibitor can suppress the propagation of B lymphoma cells by suppressing BTK activity, destruction oncocyte it is viscous It is attached, promote the apoptosis of oncocyte, Btk is turned into compelling drug target in the relevant cancer of B cell, it is especially thin to B Born of the same parents' lymthoma and leukaemia, such as NHL (non-Hodgkin ' s lymphoma, NHL), chronic lymphocytic Leukaemia (chronic lymphocytic leukemia, CLL) and anti-recurrence or intractable lymphoma mantle cell (mantle cell lymphoma, MCL) etc..Unique medicine with BTK specificity suppression is in the market Pharmacyclics/JNJ Ibrutinib.Ibrutinib is a kind of non-reversible small molecule BTK inhibitor, to treatment MCL, CLL, WM have obviously curative effect, and safety.Other clinics that enter also have for the BTK inhibitor of cell lymphoma The BGB- of ONO-4059, Beigene company of ACP-196, ONO company of CC-292, Acerta company of Celgene companies 3111 etc..
BTK inhibitor can also suppress B cell autoantibody and cell except that can resist B cell lymphoma and leukaemia The generation of the factor.In autoimmune disease, B cell presents autoantigen, promotes T cell activation secretion to cause inflammatory factor to make Into tissue damage, while activation B cell produces lot of antibodies again, autoimmune response is triggered.T and B cell interact to be formed Positive feedback adjusts chain, causes autoimmune response out of control, aggravates Histopathological lesions.Modulability B is there is in studies have shown that body Cell, can pass through secreting leukocytes mesonium 10 (IL-10) or transforminggrowthfactor-β1 (TGF-β 1) and other mechanism, negative regulation Immune response, suppresses immune-mediated inflammatory reaction.So, B cell can be used as autoimmune disease, such as rheumatoid Arthritis (rheumatoid arthritis, RA), systemic loupus erythematosus (systemic lupus erythematosus, SLE), the drug target anaphylactia (such as esophagitis, eosoniphilic esophagitis).On Vehicles Collected from Market also Not used for the BTK specific inhibitors of immunity disease, but there are several CC- for being in clinical stage, such as Celgene companies 292nd, ACP-196, Hanmi of Acerta companies HM-71224, Principia PRN-1008, Merck Serono M- A 2951 and Pharmacyclics compound.
The market of global NHL will rise to 4,700,000,000 dollars of (years of 2017 from 3,300,000,000 in 2007 dollars Increase by 3.7%).As the biological agent based on B cell antibody,Will be from the sales volume of NHL therapy fields 2,800,000,000 dollars in 2007 rise to 3,200,000,000 dollars in 2017.But as a kind of biological agent,With Lymphostat B, have deficiency in terms of a wide range of B cell removing, also without suitable oral consumption.For autoimmunity Property disease, the potential market of such as resisting rheumatoid disease class oral drugs is bigger.Anti-tumor necrosis factor (TNF) medicine is now based on, Market is 5,000,000,000 dollars, but is currently based on anti-TNF medicine, for exampleWithIt is that specificity is directed to T cell , all using hypodermic mode.For the market of rheumatoid arthritis treatment, it will increase about from 2009 to 2017 Twice, reach 13,400,000,000 dollars.For other diseases treatment, the potential market of such as lupus erythematosus is also very big.Therefore BTK suppressions Preparation has very wide prospect.
Due to important function of the BTK played in multiple signal paths, the exploitation of BTK inhibitor has attracted numerous biological systems The concern of medicine company, has been disclosed the patent application of a series of BTK inhibitor at present, including WO2007087068, WO2010126960、WO2011019780、WO2011090760、WO2012135801、WO2012158764、 WO2013060098、WO2013081016、WO2013010869、WO2013113097、CN103113375、WO2014068527、 WO2014125410, WO2014173289, WO2013118986, WO2015017502 and WO2015048689 etc., but still need The new compound with more preferable drug effect of exploitation.By being continually striving to, change of the present invention design with the structure shown in logical formula (I) Compound, and find that the compound with this class formation shows excellent effect and effect.
The content of the invention
It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its dynamic isomer, mesomer, outer Raceme, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt：
Wherein：
Ring A and B1Aryl or heteroaryl are each independently selected from, wherein the aryl or heteroaryl are optionally by one or many Individual G1Replaced；
B2Independently selected from H, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl, wherein the ring group, heterocyclic radical, virtue Base or heteroaryl are optionally by one or more G2Replaced；
L1Independently selected from-C0-2Alkyl-,-CR2R3-、-C1-2Alkyl (R1)(OH)-、-C(O)-、-CR1R2O-、- OCR1R2-、-SCR1R2-、-CR1R2S-、-NR1-、-NR1C(O)-、-C(O)NR1-、-NR1CONR2-、-CF2-、-O-、-S-、-S (O)m-、-NR1S(O)m- or-S (O)mNR1-；
L2Independently selected from-C0-4Alkyl-,-C (O)-,-O- ,-NR3-、-NR3C (O)-or-NR3S(O)m-；
X is independently selected from C0-4Alkyl, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl, wherein the alkyl, ring Base, heterocyclic radical, aryl or heteroaryl are optionally by one or more G3Replaced；
Y independently selected from-C (O)-,-NR4C(O)-、-S(O)m- or-NR4S(O)m-；
R is independently selected from H, D, alkyl, ring group, heterocyclic radical, aryl or heteroaryl, wherein the alkyl, ring group, heterocycle Base, aryl or heteroaryl are optionally by one or more G4Replaced；
R1、R2、R3And R4It is each independently selected from H, D, C1-8Alkyl, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl Base, wherein the alkyl, ring group, heterocyclic radical, aryl or heteroaryl are optionally by one or more G5Replaced；
G1、G2、G3、G4And G5Be each independently selected from H, D, halogen, cyano group, alkyl, alkenyl, alkynyl, ring group, heterocyclic radical, Aryl, heteroaryl ,-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C (O)NR6R7、-S(O)mR5Or-NR5S(O)mR6, wherein the alkyl, alkenyl, alkynyl, ring group, heterocyclic radical, aryl or heteroaryl Optionally D, halogen, cyano group, C are selected from by one or more1-8Alkyl, C3-8Cycloalkyl, 3-8 circle heterocycles base ,-OR7、-OC(O) NR7R8、-C(O)OR7、-C(O)NR7R8、-C(O)R7、-NR7R8、-NR7C(O)R8、-NR7C(O)NR8R9、-S(O)mR7、-NR7S (O)mR8Substituent replaced；
R5、R6、R7、R8And R9It is each independently selected from H, C1-6Alkyl, C1-6Miscellaneous alkyl, C3-8Ring group, 3-8 unit monocycle heterocycles Base, bicyclic heteroaryl or monocyclic aryl；And
M is 1 or 2.
In one embodiment of the invention, the compound shown in a kind of logical formula (I) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, it is logical formula (II) Described compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its mixture Form and its pharmaceutically useful salt：
Wherein：
Ring B is
Z1And Z2It is each independently selected from CH or N；
Z3For O or S；
B1、B2、L1、L2, X, Y and R definition as described in the appended claim 1.
In another embodiment of the present invention, shown in a kind of logical formula (I) compound or its dynamic isomer, interior disappear Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt are revolved, it is formula (III) compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer described in, its Form of mixtures and its pharmaceutically useful salt：
Wherein：
B1And B2For phenyl ring or six-membered Hetero-aromatic；
Ring B, L2、X、Y、R、G1And G2Definition as described in claim 1-2.
In another embodiment of the present invention, shown in a kind of logical formula (I) compound or its dynamic isomer, interior disappear Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt are revolved, it is formula (IV) compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer described in, it mixes Solvate form and its pharmaceutically useful salt：
Wherein：
P1And P2It is each independently selected from C (Ra) or N；
RaFor H or alkyl；
N and o are each independently selected from 0,1 or 2；
Ring B, B1、B2、L2, Y and R definition as described in claim 1-3.
In another embodiment of the present invention, shown in a kind of logical formula (I) compound or its dynamic isomer, interior disappear Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt are revolved, wherein wherein R is only On the spot it is selected from H, D, alkyl or miscellaneous alkyl.
The typical compound of the present invention is included, but is not limited to：
Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its mixture shape Formula and its pharmaceutically useful salt.
The invention further relates to a kind of pharmaceutical composition, it contains the compound shown in the logical formula (I) of therapeutically effective amount Or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its can Medicinal salt and pharmaceutically acceptable carrier, diluent and excipient.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, or the pharmaceutical composition comprising it exist Prepare the purposes in Bruton tyrosine kinase inhibitors.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, or the pharmaceutical composition comprising it exist Prepare the purposes in the medicines of disease such as treatment and/or pre- preventing tumor and inflammation.
The invention further relates to a kind of method of the diseases such as treatment and/or pre- preventing tumor and inflammation, this method, which includes giving, to be needed Compound or its dynamic isomer, mesomer, racemic modification shown in the logical formula (I) for the bacterium to be treated, Enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, or the pharmaceutical composition comprising it.
Another aspect of the present invention is related to the logical formula (I) of the medicine as diseases such as treatment and/or pre- preventing tumor and inflammation Shown compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its mixture Form and its pharmaceutically useful salt.
Embodiment
Unless stated to the contrary, it is otherwise following that there are following implications with term in the specification and in the claims.
Representation " C used hereinx-y" represent carbon number scope, wherein x and y are integer, for example C3-8Ring group represents the ring group with 3-8 carbon atom ,-C0-2Alkyl represents the alkyl with 0-2 carbon atom, wherein-C0Alkane Base refers to chemical single bond.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom, for example, can be 1 to 18 carbon atom, 1 to 12 carbon atom, 1 to 8 carbon atom, the straight chain and branch of 1 to 6 carbon atom or 1 to 4 carbon atom Chain group.Herein " alkyl " can be monovalence, divalence or trivalent radical.Non-limiting example includes methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl Propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls and its various branched chain isomers etc..Non-limiting example also include methylene, methine, ethylidene, Ethylidine, propylidene, propylidyne, butylidene, butylidyne and its various branched chain isomers.Alkyl can be optionally substituted or not Substitution.
" ring group " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 12 annular atoms, example It such as can be 3 to 12,3 to 10 or 3 to 6 annular atoms, or can be 3,4,5,6 yuan of rings.Monocyclic ring group it is unrestricted Property embodiment comprising cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, Cycloheptatriene base, cyclooctyl etc..Ring group can be optionally substituted or unsubstituted.
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, For example can be 3 to 16,3 to 12,3 to 10,3 to 6 or 5 to 6 annular atoms, the choosing of wherein one or more annular atoms From nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include-O-O- ,-O-S- or-S-S- loop section, its Remaining annular atom is carbon.Preferably include 3 to 12 annular atoms, wherein 1~4 is hetero atom, more preferably heterocycloalkyl ring comprising 3 to 10 annular atoms, most preferably 5 yuan of rings or 6 yuan of rings, wherein 1~4 is hetero atom, more preferably 1~3 is hetero atom, most preferably 1 ~2 are hetero atoms.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, sulphur For morpholinyl, homopiperazine base and azetidinyl etc..Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.
" spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein One or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.These One or more double bonds can be contained, but neither one ring has the pi-electron system gripped altogether completely.It is preferably 6 to 14 yuan, more excellent Elect 7 to 10 yuan as.Spiro cycloalkyl group is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring Or many spiro heterocyclic radicals, it is preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting example of spiro cycloalkyl group is included
" condensed hetero ring base " refers to each ring in 5 to 20 yuan, system and shared a pair of the atoms adjoined of other rings in system Polycyclic heterocyclic group, one or more rings can contain one or more double bonds, but neither one ring has the π that grips altogether completely Electronic system, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining ring Atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring can be divided into according to the number of composition ring Or polycyclic fused heterocycloalkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases.Condensed hetero ring The non-limiting example of base is included
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocyclic radical, and non-limiting example is included：
Deng.
Heterocyclic radical can be optionally substituted or unsubstituted.
" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, tool There are polycyclic (i.e. its ring for carrying phase adjacency pair carbon atom) group, such as preferably 6 to 10 yuan, phenyl of the pi-electron system gripped altogether And naphthyl, most preferably phenyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein with parent knot The ring that structure links together is aryl rings, and non-limiting example is included：
Aryl can be substituted or unsubstituted.
" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom include Oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.More preferably heteroaryl is 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrroles Base, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl Deng the heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure For heteroaryl ring, non-limiting example is included：
Heteroaryl can be optionally substituted or unsubstituted.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" cyano group " refers to-CN.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes The event or environment generation or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can be with But necessarily exist, the explanation includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent of respective number.Self-evident, substituent is only in their possible chemical position, this Art personnel can determine that (by experiment or theoretical) may or impossible take in the case where not paying excessive make great efforts Generation.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
Embodiment
The preparation of compound or its pharmaceutically useful salt described in the logical formula (I) of the present invention, can be by described in following examples Illustrative methods and those skilled in the art used in the operation of related open source literature complete, but these embodiments not limit The scope of the present invention.
The structure of compound is determined by nuclear magnetic resonance (NMR) or mass spectrum (MS).NMR measure is to use Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic resonance spectrometers, measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chlorine Imitative (CDCl3), deuterated methanol (CD3OD), tetramethylsilane (TMS) is inside designated as, chemical shift is with 10-6(ppm) as unit Provide.
MS measure is with Agilent SQD (ESI) mass spectrograph (manufacturer：Agilent, model：Or Shimadzu 6110) SQD (ESI) mass spectrograph (manufacturer：Shimadzu, model：2020).
HPLC measure using Agilent 1200DAD high pressure liquid chromatographs (Sunfirc C18,150 × 4.6mm, 5 μm, Chromatographic column) and Waters 2695-2996 high pressure liquid chromatographs (150 × 4.6mm of Gimini C18,5 μm of chromatographic columns).
Tlc silica gel plate uses Qingdao Haiyang GF254 silica gel plates, and the silica gel plate that thin-layered chromatography (TLC) is used is used Specification be 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm silica gel plates.
Column chromatography is carrier typically using the mesh silica gel of Qingdao Haiyang 200~300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or can purchase certainly ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), Beijing coupling chemistry Pin Deng companies.
In embodiment unless otherwise specified, reaction is carried out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Beijing Jia Wei Kechuangs Science and Technology Ltd. GCD-500G high-purity hydrogen generators and BLT- Pressure hydrogenation instrument in 2000.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses CEM Discover-SP type microwave reactors.
In embodiment unless otherwise specified, the temperature of reaction is room temperature, and temperature range is 20 DEG C -30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), the system of solvent used in reaction There is A：Dichloromethane and methanol system；B：Petroleum ether and ethyl acetate system, the volume ratio of solvent according to the polarity of compound not It is adjusted together.
The system of the eluant, eluent for the column chromatography that purifying compound is used and the system of the solvent of thin-layered chromatography include A： Dichloromethane and methanol system；B：Petroleum ether and ethyl acetate system, the volume ratio of solvent is according to the polarity difference of compound It is adjusted, a small amount of triethylamine and acid or alkaline reagent etc. can also be added and be adjusted.
Synthetic method：
Compound can be obtained according to following classical acid amides coupled reaction, and amine precursor can be according to patent WO2015048662's Synthetic method is obtained.
Embodiment 1
6- (1- (butyl- 2- alkynes acyl) piperidin-4-yl) -2- (4- Phenoxyphenyls) niacinamide
The first step
2,6- dichloro niacinamides
By compound 2,6- dichloro 3-cyanopyridine 1a (1.73g, 10mmol), the concentrated sulfuric acid (10mL) and water (2mL) are mixed, plus Heat is stirred 1 hour to 90 DEG C.Room temperature is cooled to, reactant mixture is poured onto in ice-water bath, pH value is adjusted to 8 with ammoniacal liquor.Cross Filter, filter cake is washed with water, and target product 2,6- dichloro niacinamides 1b (1.4g, solid), yield are obtained after drying：73%.
MS m/z(ESI)：191[M+1]
Second step
The chloro- 2- of 6- (4- Phenoxyphenyls) niacinamide
By compound 2,6- dichloro niacinamide 1b (0.678g, 3.5mmol), (4- Phenoxyphenyls) boric acid (0.835g, 3.9mmol), cesium carbonate (0.977g, 7.1mmol), three (dibenzalacetone) two palladium (0.324g, 0.35mmol), water (4mL) With Isosorbide-5-Nitrae-dioxane (15mL) mixing, deoxygenation is heated to reflux 16 hours under argon gas protection.Room temperature is cooled to, precipitation is depressurized, it is residual Excess purified with silica gel column chromatography (petrol ether/ethyl acetate=1/1) obtain the chloro- 2- of target product 6- (4- Phenoxyphenyls) Buddhist nun Gram acid amides 1c (0.611g, solid), yield：53%.
MS m/z(ESI)：325[M+1]
3rd step
5- carbamyls -6- (4- Phenoxyphenyls) -5 ', 6 '-dihydro-[2,4 '-bipyridyl] -1 ' tertiary fourth of (2 ' H)-carboxylic acid Ester
By the chloro- 2- of compound 6- (4- Phenoxyphenyls) niacinamide 1c (0.162g, 0.50mmol), (1- (tert-butoxies Carbonyl) -1,2,3,6- tetrahydropyridine -4- bases) boric acid (0.232g, 0.75mmol), tetrakis triphenylphosphine palladium (0.115g, 0.1mmol), after potassium carbonate (0.207g, 1.5mmol), glycol dimethyl ether (10mL) and water (2mL) mixing, 90 DEG C are heated to, Stirring 5 hours.Room temperature is cooled to, precipitation is depressurized, residue is purified (methylene chloride/methanol=700/1) with silica gel column chromatography, obtained To target product 5- carbamyls -6- (4- Phenoxyphenyls) -5 ', 6 '-dihydro-[2,4 '-bipyridyl] -1 ' (2 ' H)-carboxylic acid uncle Butyl ester 1d (0.21g, solid), yield：89%.
MS m/z(ESI)：472[M+1]
4th step
4- (5- carbamyls -6- (4- Phenoxyphenyls) pyridine -2- bases) piperidines -1- carboxylic acid tert-butyl esters
By compound 5- carbamyls -6- (4- Phenoxyphenyls) -5 ', 6 '-dihydro-[2,4 '-bipyridyl] -1 ' (2 ' H) - Room under carboxylic acid tert-butyl ester 1d (0.21g, 0.45mmol), palladium charcoal (10mg) and ethyl acetate (10mL) mixing, deoxygenation, hydrogen atmosphere Temperature stirring 16 hours.Precipitation is depressurized, residue is purified (methylene chloride/methanol=70/1) with silica gel column chromatography, obtain target production Thing 4- (5- carbamyls -6- (4- Phenoxyphenyls) pyridine -2- bases) piperidines -1- carboxylic acid tert-butyl esters 1e (0.20g, solid), production Rate：94%.
MS m/z(ESI)：474[M+1]
5th step
2- (4- Phenoxyphenyls) -6- (piperidin-4-yl) niacinamide
By compound 4- (5- carbamyls -6- (4- Phenoxyphenyls) pyridine -2- bases) piperidines -1- carboxylic acid tert-butyl esters 1e (0.215g, 0.45mmol), trifluoroacetic acid (2mL) and dichloromethane (5mL) mixing, stir at room temperature it is 1 small, when.Depressurize precipitation, Residue is dissolved in dichloromethane, is washed with saturated sodium bicarbonate solution.Organic phase anhydrous sodium sulfate drying, is filtered to remove dry Drying prescription, depressurizes precipitation, and residue is purified (methylene chloride/methanol=70/1 to 5/1) with silica gel column chromatography, obtains target product 2- (4- Phenoxyphenyls) -6- (piperidin-4-yl) niacinamides 1f (0.12g, solid), yield：71%.
MS m/z(ESI)：374[M+1]
6th step
6- (1- (butyl- 2- alkynes acyl) piperidin-4-yl) -2- (4- Phenoxyphenyls) niacinamide
By compound 2- (4- Phenoxyphenyls) -6- (piperidin-4-yl) niacinamide 1f (100mg, 0.27mmol), butyl- 2- acetylenic acids (34mg, 0.405mmol), 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (114mg, 0.3mmol), triethylamine (55mg, 0.54mmol) and DMF (10mL) mixing, are stirred at normal temperatures Mix 3 hours.Precipitation is depressurized, residue is purified (methylene chloride/methanol=50/1) with silica gel column chromatography, obtains target product 6- (1- (butyl- 2- alkynes acyl) piperidin-4-yl) -2- (4- Phenoxyphenyls) niacinamide 1 (54mg, solid), yield：46%.
MS m/z(ESI)：440[M+1]
1H NMR (400MHz, CD3OD) δ 7.87 (d, J=7.9Hz, 1H), 7.79-7.67 (m, 2H), 7.45-7.29 (m, 3H), 7.17 (t, J=7.4Hz, 1H), 7.12-7.00 (m, 4H), 4.59 (dd, J=18.1,15.6Hz, 2H), 3.38 (d, J= 2.8Hz, 1H), 3.13 (tt, J=11.8,3.6Hz, 1H), 2.91 (td, J=12.9,3.0Hz, 1H), 2.14-1.97 (m, 5H), 1.82 (m, 2H).
Embodiment 2
2- (4- Phenoxyphenyls) -6- (1- propioloyls piperidin-4-yl) niacinamide
Replace butyl- 2- acetylenic acids with propiolic acid with reference to the operating procedure synthetic example 2 of embodiment 1, but in the 6th step.
MS m/z(ESI)：426[M+1]
1H NMR (400MHz, CDCl3) δ 8.08 (d, J=7.9Hz, 1H), 7.70 (d, J=8.6Hz, 2H), 7.40 (t, J =7.9Hz, 2H), 7.28-7.16 (m, 2H), 7.10 (d, J=8.3Hz, 4H), 5.54 (d, J=61.1Hz, 2H), 4.73 (d, J =13.3Hz, 1H), 4.56 (d, J=13.7Hz, 1H), 3.31 (t, J=11.7Hz, 1H), 3.18 (d, J=19.3Hz, 2H), 2.86 (td, J=13.0,2.7Hz, 1H), 2.11 (dd, J=23.9,13.5Hz, 2H), 2.00-1.74 (m, 2H).
Embodiment 3
6- (1- (butyl- 2- alkynes acyl) pyrrolidin-3-yl) -2- (4- Phenoxyphenyls) niacinamide
With reference to the operating procedure synthetic example 3 of embodiment 1, but tert-butyl 3- (4,4,5,5- tetramethyls are used in the third step Base -1,3, the ring -2- bases of 2- bis- Evil boron penta) substitution of -2,5- dihydro -1H- pyrroles -1- carboxylates (1- (tert-butoxycarbonyl) -1,2, 3,6- tetrahydropyridine -4- bases) boric acid.
MS m/z(ESI)：426[M+1]
1H NMR (400MHz, CDCl3) δ 8.05 (t, J=7.9Hz, 1H), 7.71 (dd, J=8.5,5.6Hz, 2H), 7.44-7.34 (m, 2H), 7.27-7.15 (m, 2H), 7.13-6.99 (m, 5H), 5.77-5.43 (m, 2H), 4.16 (dd, J= 10.8,7.5Hz, 0.5H), 4.03-3.92 (m, 2H), 3.76 (ddd, J=26.2,15.4,7.6Hz, 3H), 3.56 (dt, J= 12.4,8.0Hz, 0.5H), 2.46-2.29 (m, 2H), 2.01 (d, J=13.1Hz, 3H), 1.49 (dd, J=16.2,9.7Hz, 1H)。
Embodiment 4
6- (4- (butyl- 2- alkynes acyl) piperazine -1- bases) -2- (4- Phenoxyphenyls) niacinamide
The first step
4- (the chloro- 5- cyanopyridines -2- bases of 6-) piperazine -1- carboxylic acid tert-butyl esters
By compound 2,6- dichloro 3-cyanopyridine 1a (0.519g, 3.0mmol), piperazine -1- carboxylic acid tert-butyl esters (0.558g, 3.0mmol), potassium carbonate (0.636g, 6.0mmol) and ethanol (30mL) mixing, are heated to 80 DEG C, return stirring 3 hours.Cooling To room temperature, depressurize precipitation, residue purified with silica gel column chromatography (petrol ether/ethyl acetate=20/1 to 1/1) obtain target production Thing 4- (the chloro- 5- cyanopyridines -2- bases of 6-) piperazine -1- carboxylic acid tert-butyl esters 4a (0.59g, solid), yield：60%.
MS m/z(ESI)：323[M+1]
Second step
The chloro- 6- of 2- (piperazine -1- bases) niacinamide
It is original using 4- (the chloro- 5- cyanopyridines -2- bases of 6-) piperazine -1- carboxylic acid tert-butyl esters 4a (0.60g, 1.86mmol) Material, with reference to the synthetic method synthesis of 1b in embodiment 1, obtains the chloro- 6- of title product 2- (piperazine -1- bases) niacinamide 4b (0.42g, solid), yield：94%.
MS m/z(ESI)：241[M+1]
3rd step
2- (4- Phenoxyphenyls) -6- (piperazine -1- bases) niacinamide
It is raw material using the chloro- 6- of 2- (piperazine -1- bases) niacinamide 4b (0.29g, 1.2mmol), with reference to 1c in embodiment 1 Synthetic method synthesis, obtain title product 2- (4- Phenoxyphenyls) -6- (piperazine -1- bases) niacinamide 4c (0.26g, Gu Body), yield：58%.
MS m/z(ESI)：375[M+1]
4th step
6- (4- (butyl- 2- alkynes acyl) piperazine -1- bases) -2- (4- Phenoxyphenyls) niacinamide
It is raw material, ginseng using 2- (4- Phenoxyphenyls) -6- (piperazine -1- bases) niacinamide 4c (80mg, 0.21mmol) According in embodiment 11 synthetic method synthesis, title product 6- (4- (butyl- 2- alkynes acyl) piperazine -1- bases) -2- (4- phenoxy groups are obtained Phenyl) niacinamide 4 (28mg, solid), yield：30%.
MS m/z(ESI)：441[M+1]
1H NMR (400MHz, CD3OD) δ 7.78 (d, J=8.7Hz, 1H), 7.73-7.61 (m, 2H), 7.46-7.33 (m, 2H), 7.16 (t, J=7.4Hz, 1H), 7.13-6.97 (m, 4H), 6.83 (d, J=8.7Hz, 1H), 3.92 (dd, J=6.4, 3.9Hz, 2H), 3.79 (dd, J=6.3,4.0Hz, 2H), 3.73 (s, 1H), 2.08 (s, 3H).
Embodiment 5
6- (1- (butyl- 2- alkynes acyl) pyrrolidin-3-yl) -2- (4- Phenoxyphenyls) niacinamide
With reference to the operating procedure synthetic example 5 of embodiment 4, but tert-butyl pyrrolidin-3-yl amino is used in the first step Formic acid esters substituted-piperazinyl -1- carboxylic acid tert-butyl esters.
MS m/z(ESI)：441[M+1]
1H NMR (400MHz, CD3OD) δ 7.70 (ddd, J=11.7,9.5,5.7Hz, 3H), 7.45-7.30 (m, 2H), 7.15 (t, J=7.4Hz, 1H), 7.03 (ddd, J=9.5,6.7,1.9Hz, 4H), 6.47 (d, J=8.7Hz, 1H), 4.57- 4.44 (m, 1H), 3.82 (dd, J=11.1,6.3Hz, 1H), 3.65 (ddd, J=20.2,12.1,4.4Hz, 2H), 3.48 (dd, J=11.1,4.4Hz, 1H), 2.31 (dd, J=13.4,6.2Hz, 1H), 2.13-2.01 (m, 1H), 1.97 (s, 3H).
Embodiment 6
6- ((1- (butyl- 2- alkynes acyl) pyrrolidin-3-yl) amino) -2- (4- Phenoxyphenyls) niacinamide
With reference to the operating procedure synthetic example 6 of embodiment 4, but tert-butyl 3- amino-pyrrolidines -1- is used in the first step Carboxylate substituted-piperazinyl -1- carboxylic acid tert-butyl esters.
MS m/z(ESI)：441[M+1]
1H NMR (400MHz, CD3OD) δ 7.71-7.58 (m, 3H), 7.39 (t, J=7.7Hz, 2H), 7.16 (dd, J= 7.4,6.5Hz, 1H), 7.10-6.96 (m, 4H), 6.52 (dd, J=8.6,5.3Hz, 1H), 4.61 (dd, J=6.8,3.3Hz, 1H), 4.07 (dd, J=11.3,5.9Hz, 1H), 3.93-3.72 (m, 2H), 3.70-3.37 (m, 2H), 2.39-2.24 (m, 1H), 2.11-1.94 (m, 4H).
Embodiment 7
1- (1- (butyl- 2- alkynes acyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrazole-4-carboxamides
The first step
Tert-butyl 3- ((methylsulfonyl) oxo) pyrrolidines -1- carboxylates
By compound tert-butyl 3- hydroxyl pyrrolidine -1- carboxylates 7a (561mg, 3.0mmol), methylsufonyl chloride (410mg, 3.6mmol), triethylamine (606mg, 6.0mmol) and dichloromethane (50mL) mixing, are stirred 4 hours at room temperature.This Mixture is washed with saturated ammonium chloride solution (20mL) and saturated aqueous common salt (20mL × 2) successively with after 50mL dchloromethanes Wash.By organic phase anhydrous sodium sulfate drying, drier is filtered to remove, decompression precipitation obtains target product tert-butyl 3- ((first Sulphonyl) oxo) pyrrolidines -1- carboxylates 7b (790mg), yield：99%.Product is not purified to be directly used in next step reaction.
MS m/z(ESI)：266[M+1]
Second step
3- carbonyls -3- (4- Phenoxyphenyls) ethyl propionate
By mixture diethyl carbonate (8.8g, 75mmol), sodium hydride (60%, 3.0g, 75mmol) and toluene (50mL) 90 DEG C are heated to, the toluene (50mL) for then adding compound 1- (4- Phenoxyphenyls) ethyl ketone 7c (6.36g, 30mmol) is molten Liquid, by above-mentioned reactant mixture return stirring 50 minutes.Room temperature is cooled to, 50mL water is added, toluene is removed under reduced pressure, residue is used 100mL water dilutes, and is extracted with dichloromethane (100mL × 3).Anhydrous sodium sulfate drying is used after organic phase is merged, is filtered to remove Drier, depressurizes precipitation, and residue is purified (petrol ether/ethyl acetate=50/1) with silica gel column chromatography, obtains target product 3- Carbonyl -3- (4- Phenoxyphenyls) ethyl propionate 7d (5.54g), yield：65%.
MS m/z(ESI)：285[M+1]
3rd step
3- ethyoxyls -2- (4- phenoxy groups benzoyl) ethyl acrylate
By compound 3- carbonyls -3- (4- Phenoxyphenyls) ethyl propionate 7d (5.54g, 19.5mmol), primitive nail triethylenetetraminehexaacetic acid After ester (11mL, 66mmol) and acetic anhydride (28mL) mixing, 120 DEG C are heated to, is stirred 4 hours.Depressurize precipitation, residue silicon Gel column chromatography eluting (petrol ether/ethyl acetate=50/1), obtains target product 3- ethyoxyls -2- (4- phenoxy groups benzoyl) third Olefin(e) acid ethyl ester 7e (2.6g), yield：25%.
MS m/z(ESI)：341[M+1]
4th step
3- (4- Phenoxyphenyls) -1H- pyrazoles -4- carboxylic acid, ethyl esters
By compound 3- ethyoxyls -2- (4- phenoxy groups benzoyl) ethyl acrylate 7e (2.6g, 7.6mmol), hydrazine hydrate After the mixing of (0.39g, 7.6mmol) and ethanol (50mL), 85 DEG C are heated to, is stirred 21 hours.Room temperature is cooled to, precipitation is depressurized, Residue is purified (petrol ether/ethyl acetate=5/1) with silica gel column chromatography, obtains target product 3- (4- Phenoxyphenyls) -1H- Pyrazoles -4- carboxylic acid, ethyl esters 7f (2.0g), yield：85%.
MS m/z(ESI)：309[M+1]
5th step
Ethyl 1- (1- (t-butoxy carbonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrazoles -4- carboxylic acids Ester
By compound 3- (4- Phenoxyphenyls) -1H- pyrazoles -4- carboxylic acid, ethyl esters 7f (308mg, 1.0mmol), 3- ((first sulphurs Acyl) oxo) tert-butyl 3- ((methylsulfonyl) oxo) pyrrolidines -1- carboxylates 7b (477mg, 1.8mmol), cesium carbonate (650mg, 2.0mmol) mixed with anhydrous DMF (20mL), be heated to 100 DEG C, stirred 16 hours.Room temperature is cooled to, is subtracted Pressure-off is molten, and residue adds saturated sodium bicarbonate (30mL), is extracted with dichloromethane (50mL × 3).With anhydrous after organic phase merging Sodium sulphate is dried, and is filtered to remove drier, depressurizes precipitation, residue purified with silica gel column chromatography (petrol ether/ethyl acetate= 10/1) target product ethyl 1- (1- (t-butoxy carbonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrroles, are obtained Azoles -4- carboxylates 7g (334mg), yield：70%.
MS m/z(ESI)：478[M+1]
6th step
1- (1- (t-butoxy carbonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrazoles -4- carboxylic acids
By mixture ethyl 1- (1- (t-butoxy carbonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrroles Azoles -4- carboxylates 7g (334mg, 0.7mmol), lithium hydroxide aqueous solution (1N, 7mL, 7.0mmol) and ethanol (20mL) are heated to 75 DEG C, stir 1 hour.Room temperature is cooled to, precipitation is depressurized, residue is diluted with 5mL water, it is 6 that pH is acidified to 2N hydrochloric acid.Cross Target product 1- (1- (t-butoxy carbonyl) pyrrolidines -3- are dried to obtain under filter, obtained solid 15mL water washings, vacuum Base) -3- (4- Phenoxyphenyls) -1H- pyrazoles -4- carboxylic acids 7h (230mg, solid), yield：73%.
MS m/z(ESI)：450[M+1]
7th step
Tert-butyl 3- (4- carbamyls -3- (4- Phenoxyphenyls) -1H- pyrazol-1-yls) pyrrolidines -1- carboxylates
With ammonia to compound 1- (1- (t-butoxy carbonyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrroles Azoles -4- carboxylic acids 7h (230mg, 0.51mmol), 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester Bubbling 30 minutes in the mixture of (232mg, 0.61mmol) and anhydrous DMF (10mL), obtained reaction is mixed Compound continues stirring 30 minutes at room temperature.Diluted with 30mL ethyl acetate, successively with water (20mL × 2) and saturated aqueous common salt (20mL × 2) are washed.Organic phase anhydrous sodium sulfate drying, is filtered to remove drier, depressurizes precipitation, residue silica gel column layer Analysis purifying (methylene chloride/methanol=50/1), obtains target product tert-butyl 3- (4- carbamyls -3- (4- phenoxy group benzene Base) -1H- pyrazol-1-yls) pyrrolidines -1- carboxylates 7i (190mg, grease), yield：83%.
MS m/z(ESI)：449[M+1]
8th step
3- (4- Phenoxyphenyls) -1- (pyrrolidin-3-yl) -1H- pyrazole-4-carboxamides
By compound tert-butyl 3- (4- carbamyls -3- (4- Phenoxyphenyls) -1H- pyrazol-1-yls) pyrrolidines -1- After carboxylate 7i (190mg, 0.42mmol), the ethanol solution (4N, 1mL, 4.0mmol) of hydrochloric acid and dichloromethane (2mL) mixing, Stir 16 hours at room temperature.Precipitation is depressurized, target product 3- (4- Phenoxyphenyls) -1- (pyrrolidin-3-yl) -1H- pyrroles are obtained Azoles -4- formamides 7j (120mg, grease).
MS m/z(ESI)：349[M+1]
9th step
1- (1- (butyl- 2- alkynes acyl) pyrrolidin-3-yl) -3- (4- Phenoxyphenyls) -1H- pyrazole-4-carboxamides
Using 3- (4- Phenoxyphenyls) -1- (pyrrolidin-3-yl) -1H- pyrazole-4-carboxamides 7j (120mg, It is 0.34mmol) raw material, with reference in embodiment 11 synthetic method synthesis, obtains title product 1- (1- (butyl- 2- alkynes acyl) pyrroles Alkane -3- bases) -3- (4- Phenoxyphenyls) -1H- pyrazole-4-carboxamides 7 (30mg, solid), yield：21%.
MS m/z(ESI)：415[M+1]
1H NMR (400MHz, CD3OD) δ 8.18 (d, J=7.0Hz, 1H), 7.71 (dd, J=8.7,1.9Hz, 2H), 7.39 (t, J=7.9Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 7.04 (dd, J=13.9,8.3Hz, 4H), 5.10 (d, J= 2.9Hz, 1H), 4.22-4.12 (m, 1H), 4.06-3.86 (m, 2H), 3.83-3.62 (m, 1H), 2.60-2.44 (m, 2H), 2.05 (d, J=12.0Hz, 3H).
Embodiment 8
1- ((1- (butyl- 2- alkynes acyl) piperidin-4-yl) methyl) -3- (4- Phenoxyphenyls) -1H- pyrazole-4-carboxamides
With reference to embodiment 7 operating procedure synthetic example 8, but in the first step with tert-butyl 4- (methylol) piperidines- 1- carboxylates replace tert-butyl 3- hydroxyl pyrrolidine -1- carboxylates.
MS m/z(ESI)：443[M+1]
1H NMR (400MHz, CD3OD) δ 8.10 (s, 1H), 7.72-7.64 (m, 2H), 7.45-7.34 (m, 2H), 7.16 (t, J=7.4Hz, 1H), 7.10-6.98 (m, 4H), 4.46 (dd, J=12.7,8.8Hz, 2H), 4.12 (d, J=7.2Hz, 2H), 3.17 (d, J=2.5Hz, 1H), 2.74 (d, J=2.9Hz, 1H), 2.35-2.19 (m, 1H), 2.04 (s, 3H), 1.71 (d, J=15.5Hz, 2H), 1.31 (s, 2H).
Embodiment 9
1- (1- (butyl- 2- alkynes acyl) azetidine -3- bases) -3- (4- Phenoxyphenyls) -1H- pyrazole-4-carboxamides
With reference to the operating procedure synthetic example 9 of embodiment 7, but tert-butyl 3- hydroxyazetidiniums -1- is used in the first step Carboxylate replaces tert-butyl 3- hydroxyl pyrrolidine -1- carboxylates.
MS m/z(ESI)：401[M+1]
1H NMR (400MHz, MeOD) δ 8.21 (s, 1H), 7.75 (d, J=8.7Hz, 2H), 7.44-7.33 (m, 2H), 7.16 (t, J=7.4Hz, 1H), 7.11-6.93 (m, 4H), 5.33 (s, 1H), 4.69 (dd, J=20.5,6.8Hz, 2H), 4.47 (dd, J=27.8,6.7Hz, 2H), 2.05 (s, 3H).
BTK activity suppression test
Shadow of the compound to Bruton EGFR-TKs (BTK) activity of the present invention is assessed using vitro kinase test experience Ring
Experimental method is summarized as follows：
Use the ADP-Glo of Promega companiesTMKinase assay kit, the ADP produced by by detecting in kinase reaction Level determines BTK external activity.In kinase assay experiment, kinases consumes ATP by substrate phosphorylation, while producing into ADP. ADP-Glo reagents will terminate kinase reaction and consume remaining ATP completely, be eventually adding kinase assay reagent, ADP is turned Turn to new ATP.Luciferase in detection reagent is in ATP and O2Participate in it is lower can produces chemiluminescence, generation oxidized form it is glimmering Light element, AMP and light quantum is produced, so that chemical signal is switched into optical signal (Luminecence).The intensity of optical signal is with swashing ADP yields are proportionate in enzyme reaction, so as to quantitative detection kinase b TK activity.
All test experiences are carried out in 23 DEG C of constant temperature, use the white 384 hole detection plates of Corning 3674, kinase b TK (total length His-Tag) by intra-company's expression and purification, kinase substrate be polypeptide (4: 1Glu, Tyr) (being purchased from SignalChem) and ATP (Sigma), optical signal is read using ELIASA EnVision (Perkin Elmer).Detect that buffer solution includes 40mM Tris-HC(pH 7.5)、10mM MgCl2(Sigma)、2mM MnCl2(Sigma), 0.05mM DTT (Sigma) and 0.01% BSA(Sigma)；Kinase b TK is used into the kinase reaction solution that detection buffer is 1.6ng/uL concentration；Substrate reactions are molten Liquid includes 0.2mg/mL peptide substrates and 50 μm of ATP.
Compound IC50Calculated by 10 concentration points by below equation.First by compound in 100%DMSO dissolved dilution To 1mM, it is 0.05 μm that 3 times be serially diluted to least concentration is then carried out with DMSO, and each concentration point reuses detection buffering Liquid dilutes 40 times.The compound solution and 2uL kinase reaction solution of 1uL series concentrations are first added into 384 hole detection plates, is mixed Room temperature lucifuge is incubated 30 minutes after uniform；2uL substrate reactions solution is subsequently added, reaction cumulative volume is 5uL, by reactant mixture Reacted 60 minutes in room temperature lucifuge；It is subsequently added with reacting isometric 5uLADP-GloTMReagent terminating reaction, after being well mixed Room temperature is placed 40 minutes；10uL kinase assay reagents are eventually adding, then room temperature avoid light place 30 minutes is read on Envision Access value.
Suppress percentage to calculate based on below equation：
Suppress %=[1- (RLUCompound-RLUmin)/(RLUmax-RLUmin)]X100
Wherein RLUCompoundTo give the cold light reading under compound concentration, RLUminIt is cold in the case of kinases to be added without Photoreading, RLUmaxTo be added without the cold light reading in the case of compound.By using XLfit programs in Excel come calculating The IC of compound50。
Compound number IC50(nM) Compound number IC50(nM)
1. A 2. A
3. C 4. A
5. A 6. A
7. A 8. C
9. A
A ＜ 100nM；B=100 to 500nM；C ＞ 500nM
Conclusion：The compound of the present invention has obvious depression effect to the activity of Bruton EGFR-TKs (BTK).

Claims (9)

1. it is compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in a kind of logical formula (I), non-right Reflect isomers, its form of mixtures and its pharmaceutically useful salt：
Wherein：
Ring A and B1Aryl or heteroaryl are each independently selected from, wherein the aryl or heteroaryl are optionally by one or more G1Institute Substitution；
B2Independently selected from H, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl, wherein the ring group, heterocyclic radical, aryl or Heteroaryl is optionally by one or more G2Replaced；
L1Independently selected from-C0-2Alkyl-,-CR1R2-、-C1-2Alkyl (R1)(OH)-、-C(O)-、-CR1R2O-、-OCR1R2-、- SCR1R2-、-CR1R2S-、-NR1-、-NR1C(O)-、-C(O)NR1-、-NR1CONR2-、-CF2-、-O-、-S-、-S(O)m-、-NR1S (O)m- or-S (O)mNR1-；
L2Independently selected from-C0-4Alkyl-,-C (O)-,-O- ,-NR3-、-NR3C (O)-or-NR3S(O)m-；
X is independently selected from C0-4Alkyl, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl, wherein the alkyl, ring group, miscellaneous Ring group, aryl or heteroaryl are optionally by one or more G3Replaced；
Y independently selected from-C (O)-,-NR4C(O)-、-S(O)m- or-NR4S(O)m-；
R is independently selected from H, D, alkyl, ring group, heterocyclic radical, aryl or heteroaryl, wherein the alkyl, ring group, heterocyclic radical, virtue Base or heteroaryl are optionally by one or more G4Replaced；
R1、R2、R3And R4It is each independently selected from H, D, C1-8Alkyl, C3-8Ring group, 3-8 circle heterocycles base, aryl or heteroaryl, wherein The alkyl, ring group, heterocyclic radical, aryl or heteroaryl are optionally by one or more G5Replaced；
G1、G2、G3、G4And G5Be each independently selected from H, D, halogen, cyano group, alkyl, alkenyl, alkynyl, ring group, heterocyclic radical, aryl, Heteroaryl ,-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C(O) NR6R7、-S(O)mR5Or-NR5S(O)mR6, wherein the alkyl, alkenyl, alkynyl, ring group, heterocyclic radical, aryl or heteroaryl are optional D, halogen, cyano group, C are selected from by one or more1-8Alkyl, C3-8Ring group, 3-8 circle heterocycles base ,-OR7、-OC(O)NR7R8、-C(O) OR7、-C(O)NR7R8、-C(O)R7、-NR7R8、-NR7C(O)R8、-NR7C(O)NR8R9、-S(O)mR7、-NR7S(O)mR8Substitution Base is replaced；
R5、R6、R7、R8And R9It is each independently selected from H, C1-6Alkyl, C1-6Miscellaneous alkyl, C3-8Ring group, 3-8 unit monocycles heterocyclic radical, list Ring heteroaryl or monocyclic aryl；And
M is 1 or 2.
2. compound or its dynamic isomer, mesomer shown in a kind of logical formula (I) according to claim 1, disappear outside Body, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt are revolved, it is the change described in logical formula (II) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its form of mixtures and Its pharmaceutically useful salt：
Wherein：
Ring B is
Z1And Z2It is each independently selected from CH or N；
Z3For O or S；
B1、B2、L1、L2, X, Y and R definition as described in the appended claim 1.
3. compound shown in logical formula (I) or its dynamic isomer, meso according to claim 1-2 any one Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, it is logical formula (III) Described compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its mixture Form and its pharmaceutically useful salt：
Wherein：
B1And B2For phenyl ring or six-membered Hetero-aromatic；
Ring B, L2、X、Y、R、G1And G2Definition as described in claim 1-2.
4. compound shown in logical formula (I) or its dynamic isomer, meso according to claim 1-3 any one Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, it is logical formula (IV) Described compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, its mixture Form and its pharmaceutically useful salt：
Wherein：
P1And P2It is each independently selected from C (Ra) or N；
RaFor H or alkyl；
N and o are each independently selected from 0,1 or 2；
Ring B, B1、B2、L2, Y and R definition as described in claim 1-3.
5. compound shown in logical formula (I) or its dynamic isomer, meso according to claim 1-4 any one Body, racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, wherein R are independently selected From H, D, alkyl or miscellaneous alkyl.
6. compound or its dynamic isomer, mesomer, racemic modification shown in logical formula (I) according to claim 1, Enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, the wherein compound are：
7. a kind of pharmaceutical composition, described pharmaceutical composition contain therapeutically effective amount according to claim 1 any one Logical formula (I) shown in compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereo-isomerism Body, its form of mixtures and its pharmaceutically useful salt and pharmaceutically acceptable carrier, diluent and excipient.
8. compound shown in logical formula (I) or its dynamic isomer, mesomer according to claim 1 any one, Racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, or according to claim 7 Purposes of the described pharmaceutical composition in Bruton EGFR-TKs (BTK) inhibitor is prepared.
9. compound shown in logical formula (I) or its dynamic isomer, mesomer according to claim 1 any one, Racemic modification, enantiomter, diastereoisomer, its form of mixtures and its pharmaceutically useful salt, or according to claim 8 Purposes of the described pharmaceutical composition in the medicine for preparing the diseases such as treatment and/or pre- preventing tumor and inflammation.
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