CN117263918A - Pyridazine derivative inhibitor, preparation method and application thereof - Google Patents

Pyridazine derivative inhibitor, preparation method and application thereof Download PDF

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CN117263918A
CN117263918A CN202310827414.0A CN202310827414A CN117263918A CN 117263918 A CN117263918 A CN 117263918A CN 202310827414 A CN202310827414 A CN 202310827414A CN 117263918 A CN117263918 A CN 117263918A
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methyl
amino
alkyl
cycloalkyl
hydrogen
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高鹏
曾蜜
谭松良
孙广俊
王少宝
修文华
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

The invention relates to a pyridazine derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (III), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in preparing TYK2 inhibitor medicines.

Description

Pyridazine derivative inhibitor, preparation method and application thereof
The invention relates to a pyridazine derivative inhibitor, a preparation method and application thereof, which are divisional applications of PCT patent application entering China, wherein the application number of the PCT patent application is 202080001485.X, and the international application date is 1 month and 20 days of 2020.
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a pyridazine derivative inhibitor, and a preparation method and application thereof.
Background
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes of JAK1, JAK2, JAK3 and TYK2, each subtype mediates different types of cytokine signal paths, and JAK-1, JAK-2 and TYK-2 are expressed in various tissue cells of a human body, and JAK-3 is mainly expressed in various hematopoietic tissue cells. A common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. When cytokine receptor is combined with ligand thereof, JAKs coupled with receptor is activated, the receptor is further phosphorylated, phosphorylated tyrosine site can be combined with STAT protein containing SH2 structural domain, thereby the STAT is recruited to the receptor and phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred into cell nucleus and activates target gene transcription thereof, and further controls various functions such as growth, activation, differentiation and the like of various cells.
TYK2 is one of the earliest subtypes found in the JAK family, mediates the functions of cytokines such as IFN-alpha, IL-6, IL-10, IL-12, IL-23 and the like, and researches show that TYK2 deletion mutation can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity, inflammation and the like. IL-23 plays a vital role in the development process of psoriasis, and recent researches show that the pathogenesis of the psoriasis is that endogenous unknown antigen-activated antigen presenting cells APC secrete IL-23, IL-23 activates Th17 cells and cytokines such as IL-17 are secreted, keratinocyte differentiation and division are induced, IL-23 is secreted, and inflammation and keratinocyte proliferation are further stimulated to produce psoriasis. TYK2 and JAK2 together mediate the downstream signaling pathway of IL-23, inhibition of JAK2 results in anemia and other blood-related side effects, and thus targeting TYK2 is a good strategy to inhibit IL-23 signaling pathway for the treatment of psoriasis.
Early TYK2 inhibitors such as Tofacitinib and the like belong to JAK non-selective inhibitors, are first oral JAK inhibitors, and have remarkable inhibitory activity on JAK1, 2 and 3 subtypes. Inhibition of the activity of other subtypes such as JAK1, JAK2 and JAK3 increases the efficacy of tofacitinib, but also brings about more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, cholesterol increase, and the like. Since JAK2 activity is associated with erythroid differentiation and lipid metabolism, the above-mentioned partial adverse reactions such as anemia are considered to be associated with insufficient selectivity of Tofacitinib for JAK-2, which is caused by nonselective inhibition of the drug. Currently, TYK2 selective inhibitors are not marketed, and early JAK inhibitors mainly compete for the binding of kinase domains to ATP and thus have a general problem of low selectivity.
The drug is between the good curative effect of JAK nonselective inhibitor and the serious side effect related to various targets, and the development of TYK2 selective inhibitor drug with higher safety for treating inflammatory diseases such as psoriasis has great clinical application potential. BMS International applications WO2015069310A1 and WO2018081488A1 report TYK2 selective inhibitors, and the developed BMS-986165 has good curative effects in the current clinical second phase and enters a clinical study in the third phase, so that the advantages of the TYK2 selective inhibitors are reflected, and the BMS-986165 has great clinical application value.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
r is selected from: from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR aa 、-SR aa 、-C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb ；
R 1 Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-NR aa CR bb ＝NR cc 、-NR aa CR bb ＝CR cc R dd 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa C(O)C(O)R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with a member selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio Substituted with one or more substituents selected from the group consisting of a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
R 2 selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa 、-C(O)R aa 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-NR aa CR bb ＝NR cc 、-NR aa CR bb ＝CR cc R dd 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 3 selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl or alkynyl;
R 4 、R 5 、R 6 and R is 7 Is present or absent and is selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl Cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb ；
Alternatively, R 4 And R is 6 Or R is 6 And R is 7 Linking to form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl group is optionally further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R aa 、R bb 、R cc and R is dd Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
Or, any two adjacent or non-adjacent R aa 、R bb 、R cc And R is dd Linking to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkylThe radicals, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
x is an integer of 0, 1, 2 or 3;
m1 is an integer of 0, 1 or 2; and is also provided with
n1 is an integer of 0, 1, 2, 3, 4 or 5.
The preferable scheme is as follows: r is selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, halogen, amino, mercapto, -OR aa 、-SR aa 、-S(O) m1 R aa or-NR aa R bb Preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, fluoro, chloro, bromo, -OR aa 、-SR aa 、-S(O) m1 R aa or-NR aa R bb More preferably hydrogen, methyl, ethyl, propyl, FCH 2 -、F 2 CH-、F 3 C-、ClCH 2 -、Cl 2 CH-、Cl 3 C-、CH 3 O-、CH 3 CH 2 O-、CH 3 CH 2 CH 2 O-、FCH 2 O-、F 2 CHO-、F 3 CO-, fluorine-, chlorine, -OR aa 、-SR aa 、-S(O) m1 R aa or-NR aa R bb Further preferably CH 3 O-、(CH 3 ) 2 N-、CH 3 S-、F 3 CO-、F 2 HCO-, F-or CH 3 S(O) 2 -；
Wherein R is aa Or R is bb Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl, preferably hydrogen, hydroxy, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD 3 、-CD 2 CD 3 Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH 2 -、F 2 CH-、F 3 C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, epoxypentyl, tetrahydropyrrolyl or piperidinyl; further preferred is hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
R 1 selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl, 3-7 membered heteroaryl, -NR c C(O)R d 、-NR c C(O)NR d R e 、-NR c S(O) m1 R d 、-NR c CR d ＝NR e 、-NR c CR d ＝CR e R f 、-NR c C(O)OR d 、-(CH 2 ) n1 S(O) m1 R c 、-(CH 2 ) n1 NR c C(O)C(O)R g Or- (CH) 2 ) n1 NR c S(O) m1 R d 、-NR c CR d R e R f 、-NR c C(S)R d 、-OC＝ONR c R d or-CR e R f C＝ONR c R d Preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl, 3-6 membered heteroaryl, -NR c C(O)R d 、-NR c C(O)NR d R e 、-NR c S(O) m1 R d 、-NR c CR d ＝NR e 、-NR c CR d ＝CR e R f 、-NR c C(O)OR d 、-(CH 2 ) n1 S(O) m1 R c 、-(CH 2 ) n1 NR c C(O)C(O)R g Or- (CH) 2 ) n1 NR c S(O) m1 R d 、-NR c CR d R e R f 、-NR c C(S)R d 、-OC＝ONR c R d or-CR e R f C＝ONR c R d More preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, -NR c C(O)R d 、-NR c C(O)NR d R e 、-NR c S(O) m1 R d 、-NR c CR d ＝NR e 、-NR c CR d ＝CR e R f 、-NR c C(O)OR d 、-(CH 2 ) n1 S(O) m1 R c 、-(CH 2 ) n1 NR c C(O)C(O)R g Or- (CH) 2 ) n1 NR c S(O) m1 R d 、-NR c CR d R e R f 、-NR c C(S)R d 、-OC＝ONR c R d or-CR e R f C＝ONR c R d Further preferably
R c 、R d 、R e 、R f Or R is g Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-12 Aryl and 3-7 membered heteroaryl, preferably hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluorine, chlorineBromine, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl and 3-to 6-membered heteroaryl groups containing 1 to 3N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD 3 、-CD 2 CD 3 Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH 2 -、F 2 CH-、F 3 C-, cyano-, fluorine-, chlorine-, CH 3 O-、CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Further preferred are hydrogen, methyl, ethyl, -CD 3 、-CD 2 CD 3 Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH 2 -、F 2 CH-、F 3 C-, cyano-, fluorine-, chlorine-, CH 3 O-、CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -/->
Or, any two adjacent or non-adjacent R c 、R d 、R e Or R is f Linking to form a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, aryl and 3-7 membered heteroaryl, preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-12 Aryl and 3-6 membered heteroaryl, more preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl and 3-6 membered heteroaryl containing 1-2N, O or S atoms, more preferably cyclopropyl, cyclobutyl, cyclopentylA cyclohexyl group,
More preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
R 2 Selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl, 3-7 membered heteroaryl, C 1-6 Hydroxyalkyl, -C (O) R hh 、-(CH 2 ) n1 OR ii 、-(CH 2 ) n1 NR hh R ii 、-NR hh C(O)R ii 、-NR hh C(O)NR ii R jj 、-C(O)NR hh R ii 、-NR hh S(O) m1 R ii 、-NR hh CR ii ＝NR jj 、-NR hh CR ii ＝CR jj R kk 、-(CH 2 ) n1 S(O) m1 NR hh R ii 、-(CH 2 ) n1 C(O)R hh 、-NR hh C(O)OR ii 、-(CH 2 ) n1 S(O) m1 R hh Or- (CH) 2 ) n1 NR hh S(O) m1 R ii Wherein said C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 One or more substituents in cycloalkyl; preferably C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl、C 6-10 Aryl, substituted or unsubstituted 3-6 membered heteroaryl, C 1-3 Hydroxyalkyl, -C (O) R hh 、-(CH 2 ) n1 OR ii 、-(CH 2 ) n1 NR hh R ii 、-NR hh C(O)R ii 、-NR hh C(O)NR ii R jj 、-C(O)NR hh R ii 、-NR hh S(O) m1 R ii 、-NR hh CR ii ＝NR jj 、-NR hh CR ii ＝CR jj R kk 、-(CH 2 ) n1 S(O) m1 NR hh R ii 、-(CH 2 ) n1 C(O)R hh 、-NR hh C(O)OR ii 、-(CH 2 ) n1 S(O) m1 R hh Or- (CH) 2 ) n1 NR hh S(O) m1 R ii Wherein said C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, optionally substituted with hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 Alkyl or C 3-5 One or more substituents in cycloalkyl; more preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, C 1-3 Hydroxyalkyl, -C (O) R hh 、-(CH 2 ) n1 OR ii 、-(CH 2 ) n1 NR hh R ii 、-C(O)NR hh R ii 、-(CH 2 ) n1 S(O) m1 NR hh R ii 、-(CH 2 ) n1 C(O)R hh 、-(CH 2 ) n1 S(O) m1 R hh Or- (CH) 2 ) n1 NR hh S(O) m1 R ii Wherein said C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl; further preferred is HOCH 2 -、HOCH 2 CH 2 -、HOCH 2 C(O)-、CH 3 NHC(O)-、D 3 CNHC(O)-、CH 3 NHS(O) 2 -、D 3 CNHS(O) 2 -、
R hh 、R ii 、R jj Or R is kk Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluorine, chlorine, bromine, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD 3 、-CD 2 CD 3 Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH 2 -、F 2 CH-、F 3 C-, cyano-, fluorine-, chlorine-, CH 3 O-、CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl or piperidinyl;
R 3 selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, Propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;
R 4 、R 5 、R 6 and R is 7 Is present or absent, where present is selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, aryl, 3-7 membered heteroaryl, - (CH) 2 ) n1 R ll 、-(CH 2 ) n1 OR ll 、-SR ll 、-(CH 2 ) n1 C(O)R ll 、-C(O)OR ll 、-S(O) m1 R ll 、-NR ll R mm 、-C(O)NR ll R mm 、-NR ll C(O)R mm or-NR ll S(O) m1 R mm Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-12 Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n1 R ll 、-(CH 2 ) n1 OR ll 、-SR ll 、-(CH 2 ) n1 C(O)R ll 、-C(O)OR ll 、-S(O) m1 R ll 、-NR ll R mm 、-C(O)NR ll R mm 、-NR ll C(O)R mm or-NR ll S(O) m1 R mm More preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, amino, mercapto, nitro, hydroxy, cyano, oxo, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3- > containing 1-3N, O or S atoms6 membered heterocyclyl, C 6-10 Aryl, 3-6 membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n1 R ll 、-(CH 2 ) n1 OR ll or-NR ll R mm Further preferred are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, (CH) 3 ) 3 C-、CF 3 CH 2 -, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH 2 ＝CHCH 2 -, a part of ethynyl group,Cyano group, CNCH 2 -、CNCH 2 CH 2 -、CH 3 OCH 2 -、CH 3 OCH 2 CH 2 -、CF 3 C(CH 3 ) 2 -、/>
R ll Or R is mm Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluorine, chlorine, bromine, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl containing 1-3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD 3 、-CD 2 CD 3 Propyl, hydroxymethyl, hydroxyethyl, ethenyl, propenyl, ethynyl, propynyl, FCH 2 -、F 2 CH-、F 3 C-, cyano-, fluoro-, chloro-, cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, epoxypropyl-Epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl, or piperidinyl;
alternatively, R 4 And R is 6 Or R is 6 And R is 7 Linking to form a heterocyclic or heteroaryl group, wherein said heterocyclic or heteroaryl group is optionally substituted with hydrogen, deuterium, halogen, C 1-6 Alkyl or C 3-6 One or more substituents in cycloalkyl; preferably 3-to 6-membered heterocyclyl or 3-to 7-membered heteroaryl, wherein said heterocyclyl or heteroaryl is optionally substituted with hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 Alkyl or C 3-5 One or more substituents in cycloalkyl; more preferably a 3-6 membered heterocyclyl containing 1 to 3N, O or S atoms or a 3-7 membered heteroaryl containing 1 to 3N, O or S atoms, wherein said heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl; further preferred is
Optionally with the proviso that the compound of formula I is not
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (I), and the general formula (I) is further shown in the general formula (II):
wherein the method comprises the steps of
R～R 6 And x is as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (III):
wherein:
R、R 1 、R 3 ～R 6 and x is as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (V):
wherein:
R 9 selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R、R 3 ～R 6 、R aa 、R bb and x is as described in formula (I).
The preferable scheme is as follows: r is R 9 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 Haloalkyl, hydroxy, amino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, amino, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl or 3-6 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb More preferably hydrogen, deuterium, hydroxy substituted C 1-3 Alkyl, C 1-3 Cycloalkyl-substituted C 1-3 Alkyl, hydroxy substituted C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, C 3-6 Cycloalkyl-substituted amino, halogen-substituted C 2-5 Alkenyl, halogen substituted C 2-5 Alkynyl, halogen substituted C 3-6 Cycloalkyl, C 1-3 Alkyl substituted C 3-6 Cycloalkyl, cyano-substituted C 3-6 Cycloalkyl, C 1-3 Alkoxy substituted C 3-6 Cycloalkyl, C 1-3 Haloalkyl extractionSubstituted C 3-6 Cycloalkyl, 3-7 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl or 3-7 membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)R aa or-NR aa R bb More preferably
R aa Or R is bb Independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, halogen, cyano, nitro, C 1-6 Haloalkyl, hydroxy, amino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, amino, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or 3-7 membered heteroaryl containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;
m1 is 0, 1, 2 or 3;
n1 is 0, 1, 2 or 3.
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is further shown in the general formula (VIII):
Wherein:
R 3 ～R 6 and x is as described in formula (I).
Preferably, the method comprises the steps of
R 3 Selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
R 4 selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, optionally substituted with one or more substituents further selected from methyl, ethyl, fluoro or chloro; preferably C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, more preferably C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclic group containing 1 to 3N, O or S atoms, further preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl,
R 5 Or R is 6 Each independently hydrogen or deuterium;
x is 0, 1, 2 or 3.
The present invention also provides a preferred embodiment, each of the general formulae, stereoisomers thereof, or pharmaceutically acceptable salts thereof, as defined in any one of the claims, wherein,
r is selected from hydrogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR aa 、-SR aa or-NR aa R bb ；
R 1 Selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH) 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(＝S)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa C(O)OR bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 NR aa C(O)C(O)R aa 、-NR aa CR bb ＝NR cc or-NR aa CR bb ＝CR cc R dd Wherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano, oxo and C 3-8 One or more substituents in cycloalkyl are substituted;
R 2 selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -C (O) R aa 、-(CH 2 ) n1 OR aa 、-C(O)NR aa R bb or-S (O) m1 NR aa R bb Wherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano and C 3-8 One or more substituents in cycloalkyl are substituted;
R 3 selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 5 selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 4 and R is 6 Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or- (CH) 2 ) n1 R aa The method comprises the steps of carrying out a first treatment on the surface of the Preferably hydrogen, cyclopropyl or
Or R is 4 And R is 6 Linking to form a C 3-8 Cycloalkyl; preferably a cyclopentylalkyl group;
R 7 selected from the group consisting of absent, hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
or R is 6 And R is 7 Linking to form a C 3-8 Cycloalkyl; preferably a cyclopentylalkyl group;
R 9 selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-NR aa R bb or-C (O) NR aa R bb Wherein said C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl and 5-8 membered heteroaryl;
R aa 、R bb 、R cc and R is dd Each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, hydroxy, amino, oxo, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl and 5-8 membered heteroaryl;
alternatively, R cc And R is dd Linking to form a C 3-8 Cycloalkyl, wherein said C 3-8 Cycloalkyl is optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, amino, oxo,Cyano, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 One or more substituents in the hydroxyalkyl group are substituted.
The invention also relates to a technical scheme, and provides a compound shown in a general formula (XI), a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
R 18 selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or- (CH) 2 ) n1 R aa Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or- (CH) 2 ) n1 R aa More preferably hydrogen, methyl, cyclopropyl,
R 19 Selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, hydroxy or cyano, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, amino, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;
R aa selected from hydrogen, deuterium, cyano, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, fluoro, chloro, bromo, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl or C 3-6 Cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl;
n1 is 0, 1 or 2;
r is 0, 1, 2 or 3.
The invention also relates to a technical scheme, a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
reacting the general formula (V-1) with the general formula (V-2) to obtain the general formula (V-3), and further reacting the general formula (V-3) to obtain a compound shown in the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;
wherein:
x is selected from halogen;
R 3 ～R 6 、R 9 and x is as described in formula (V).
The invention also relates to a technical scheme, a method for preparing the compound shown in the general formula (V) or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps,
reacting the general formula (V-4) with the general formula (V-5) to obtain the general formula (V-6), and further reacting the general formula (V-6) with the general formula (V-2) to obtain a compound shown as the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;
Wherein:
x is selected from halogen;
R 3 ～R 6 、R 9 and x is as described in formula (V).
The invention also relates to a technical scheme, a medicinal composition comprising a therapeutically effective dose of the compound of the general formula (I) shown in any one of claims, the compound of the general formula (IX) shown in any one of claims and the compound of the general formula (X) shown in any one of claims, stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also relates to a technical scheme, application of the compound shown in any one of the general formula (I), the compound shown in any one of the general formula (IX) and the compound shown in any one of the general formula (X), stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of TYK2 inhibitor drugs.
The invention also relates to a technical scheme, application of the compound of the general formula (I), the compound of the general formula (IX) and the compound of the general formula (X) and stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of drugs for treating inflammatory diseases and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
The invention further relates to a method for preparing the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof for treating inflammatory diseases.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl.
Also included are spirocycloalkyl groups in which the single spirocycloalkyl group and the heterocycloalkyl group share a spiro atom.
The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably comprises 3 to12 ring atoms, 1 to 4 of which are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having 3 to 20 membered monocyclic rings sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl.
The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. They can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent ringsPreferably a bicyclic or tricyclic, more preferably a 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Drawings
FIG. 1 is a graph showing the PASI score results for various compounds in an imiquimod-induced murine psoriasis model.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
The first step: preparation of 2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
3-bromo-2-methoxyaniline (2.02 g,10 mmol), bis-pinacolatyldiborane (3.05 g,12 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (816.6 mg,1 mmol), potassium acetate (2.45 g,25 mmol), and mixed in dioxane (20 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100deg.C, cooled to room temperature, the reaction solution concentrated under reduced pressure, the residue was taken up with water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0 g, 80%).
1 H NMR(400MHz,CDCl 3 )δ1.36(s,12H),3.83(s,3H),6.92-6.99(m,2H),7.16-7.20(m,2H)；
MS m/z(ESI):250.1[M+H] + .
And a second step of: preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0 g,8 mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61 g,10 mmol), cs 2 CO 3 (7.6 g,20 mmol) tetrakis (triphenylphosphine) palladium (924.5 mg,0.8 mmol) was mixed with 1, 4-dioxane (40 mL) and water (5 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100℃and cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was taken up with water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.14 g, 70%).
1 H NMR(400MHz,CDCl 3 )δ3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H),8.1(s,1H)；
MS m/z(ESI):205.1[M+H] + .
And a third step of: preparation of lithium 4, 6-dichloropyridazine-3-carboxylate
Methyl 4, 6-dichloropyridazine-3-carboxylate (2.07 g,10 mmol), lithium bromide (2.6 g,30 mmol) was dissolved in acetonitrile (20 mL) and water (2 mL), cooled to 0℃and DIPEA (5.2 mL,30 mmol) was added dropwise, the reaction was naturally warmed to room temperature for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2 mL. Times.4), the filter cake was collected and dried to give the title compound lithium 4, 6-dichloropyridazine-3-carboxylate (1.73 g, 87%).
MS m/z(ESI):193.1[M+H] + .
Fourth step: preparation of((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-carbonyl) oxo) zinc
2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.02 g,5.0 mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (1.19 g,6.0 mmol) and zinc acetate (1.1 g,6.0 mmol) were mixed in isopropanol (1 mL) and water (7 mL) and reacted overnight at 65 ℃. The reaction was cooled to room temperature, water (6 mL) was added, stirring was performed for 1H, the reaction solution was filtered, the filter cake was washed with water (6 mL. Times.2) and THF (6 mL), and the filter cake was collected and dried to give the title compound ((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc (1.44 g, 73%).
MS m/z(ESI):361.1[M+H] + .
Fifth step: preparation of((6- (bicyclo [1.1.1] pentane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc
((6-chloro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo) zinc (157 mg,0.4 mmol), bicyclo [1.1.1]Pentane-1-carboxamide (111 mg,1.0 mmol), DBU (61 mg,0.4 mmol), potassium carbonate (110 mg,0.8 mmol), and mixtures thereof in toluene (1.2 mL) and acetonitrile (0.6 mL), palladium acetate (4.5 mg,0.02 mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyl di-tert-butylphosphine (22 mg,0.04 mmol), the reaction was replaced with nitrogen three times and reacted overnight at 75 ℃. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, washed with petroleum ether (6 mL. Times.2), the aqueous phase was then separated, water (2 mL) was added to the aqueous phase, CH 2 Cl 2 (5 mL. Times.3) extraction, combining the organic phases, washing with saturated aqueous NaCl, separating the organic phases, drying over anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure to give the title compound ((6- (bicyclo [ 1.1.1.)]Pentane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-carbonyl) oxo) zinc (122 mg, 65.2%).
MS m/z(ESI):436.2[M+H] + .
Sixth step: 6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
((6- (bicyclo [ 1.1.1)]Pentane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carbonyl) oxo-zinc (94 mg,0.2 mmol), deutero-methylamine hydrochloride (71 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) were mixed in DMF (1 mL), HATU (380 mg,1.0 mmol) was added and reacted overnight at 40 ℃. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was used with CH 2 Cl 2 Separating, washing the organic phase with saturated NaCl aqueous solution, drying with anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure, and column chromatography to obtain the title compound 6- (bicyclo [ 1.1.1)]Pentane-1-carboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Pyridazine-3-carboxamide (41 mg, 45%).
1 H NMR(400MHz,CDCl 3 )δ2.17(s,6H),2.53(s,1H),3.80(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.51(dd,J＝7.9,1.3Hz,1H),7.81(dd,J＝7.9,1.4Hz,1H),8.09-8.14(m,2H),8.21(s,1H),8.39(s,1H),11.03(s,1H)；
MS m/z(ESI):452.2[M+H] + .
Example 2
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- (oxetane-3-carboxamide) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- (oxetane-3-carboxamide) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):442.2[M+H] + .
Example 3
6- (Cyclobutanamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclobutanamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ1.85-2.05(m,2H),2.16-2.27(m,2H),2.45-2.33(m,2H),3.33-3.43(m,1H),3.82(s,3H),4.01(s,3H),7.26-7.33(m,1H),7.55(dd,J＝7.0Hz,1H),7.83(dd,J＝7.8,1.1Hz,1H),8.03-8.15(m,2H),8.29(s,1H),9.18(s,1H),11.06(s,1H)；
MS m/z(ESI):440.2[M+H] + .
Example 4
6- ((1R, 2R) -2-fluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
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6- ((1R, 2R) -2-fluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ1.18-1.28(m,1H),1.88-2.06(m,2H),3.81(s,3H),4.01(s,3H),4.65-4.95(m,1H),7.24-7.30(m,1H),7.53(dd,J＝7.9,1.3Hz,1H),7.81(dd,J＝7.9,1.4Hz,1H),8.02(s,1H),8.11(s,1H),8.27(s,1H),9.82(s,1H),11.07(s,1H)；
MS m/z(ESI):444.2[M+H] + .
Example 5
4- ((2-methoxy-3)(1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Preparation of-6- ((1S, 2R) -2-methylcyclopropane-1-carboxamide) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- ((1S, 2R) -2-methylcyclopropane-1-carboxamide) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):440.2[M+H] + .
Example 6
6- ((3-cyclopropyl-oxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- ((3-cyclopropyl-oxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):454.2[M+H] + .
Example 7
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((3-methyl-oxazol-3-yl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- ((3-methyl-oxabutan-3-yl) amino) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):428.2[M+H] + .
Example 8
6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):480.2[M+H] + .
Example 9
(R) -6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(R) -6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):480.2[M+H] + .
Example 10
(S) -6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(S) -6- ((1-cyclopropyl-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):480.2[M+H] + .
Example 11
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide the procedure described in example 1 was followed.
MS m/z(ESI):454.2[M+H] + .
Example 12
(R) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
(R) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide the procedure described in example 1 was followed.
MS m/z(ESI):454.2[M+H] + .
Example 13
(S) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamide
(S) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Process for the preparation of-6- ((1, 1-trifluoropropan-2-yl) amino) pyridazine-3-carboxamideReference is made to example 1.
MS m/z(ESI):454.2[M+H] + .
Example 14
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- (1-methylcyclopropane-1-carboxamide) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- (1-methylcyclopropane-1-carboxamide) pyridazine-3-carboxamide is described in example 1.
1 H NMR(400MHz,CD 3 OD)δ0.77-0.78(m,2H),1.23-1.25(m,2H),1.48(s,3H),3.73(s,3H),4.01(s,3H),7.32(t,J＝8.0Hz,1H),7.58(dd,J＝8.0,1.2Hz,1H),7.68(dd,J＝8.0,1.2Hz,1H),8.18(s,1H),8.47(s,1H)；
MS m/z(ESI):440.2[M+H] + .
Example 15
6- (1-cyanocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (1-cyanocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ1.20-1.31(m,2H),1.63-1.67(m,2H),3.76(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J＝8.0,1.2Hz,1H),7.80(dd,J＝8.0,1.2Hz,1H),7.96(s,1H),8.11(s,1H),8.16(br s,1H),9.00(br s,1H),10.99(br s,1H)；
MS m/z(ESI):451.2[M+H] + .
Example 16
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- (1- (trifluoromethyl) cyclopropane-1-carboxamide) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- (1- (trifluoromethyl) cyclopropane-1-carboxamide) pyridazine-3-carboxamide is described in example 1.
1 H NMR(400MHz,CD 3 OD)δ1.28-1.38(m,2H),1.40-1.48(m,2H),3.73(s,3H),4.01(s,3H),7.29-7.33(m,1H),7.58(dd,J＝8.0,1.2Hz,1H),7.70(dd,J＝8.0,1.2Hz,1H),8.12(s,1H),8.48(s,1H)；
MS m/z(ESI):494.2[M+H] + .
Example 17
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1-methoxycyclopropane-1-carboxamide) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1-methoxycyclopropane-1-carboxamide) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):456.2[M+H] + .
Example 18
(S) -6- (2, 2-dimethylcyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
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(S) -6- (2, 2-dimethylcyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):454.2[M+H] + .
Example 19
(R) -6- (2, 2-dimethylcyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(R) -6- (2, 2-dimethylcyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):454.2[M+H] + .
Example 20
(R) -6- (2, 2-difluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(R) -6- (2, 2-difluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):462.2[M+H] + .
Example 21
(S) -6- (2, 2-Difluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(S) -6- (2, 2-Difluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):462.2[M+H] + .
Example 22
6- (cyclopropanesulfonylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (cyclopropanesulfonylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CD 3 OD)δ0.80-0.87(m,2H),0.90-0.93(m,2H),2.51-2.55(m,1H),3.65(s,3H),3.92(s,3H),7.08(s,1H),7.21(t,J＝8.20Hz,1H),7.48(dd,J＝8.0,1.2Hz,1H),7.62(dd,J＝8.0,1.2Hz,1H),8.38(s,1H)；
MS m/z(ESI):462.2[M+H] + .
Example 23
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d) 3 ) Carbamoyl) pyridazin-3-yl) morpholine-4-carboxamide
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d) 3 ) Carbamoyl) pyridazin-3-yl) morpholine-4-carboxamide the method of preparation is described in example 1.
MS m/z(ESI):471.2[M+H] + .
Example 24
6-(3-cyclopropylureido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
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6- (3-cyclopropylureido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.64-0.66(m,2H),0.82-0.87(m,2H),2.71-2.73(m,1H),3.79(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J＝8.0,1.2Hz,1H),7.84(dd,J＝8.0,1.2Hz,1H),8.11(s,1H),11.01(br s,1H)；
MS m/z(ESI):441.2[M+H] + .
Example 25
Cyclopropyl (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d) 3 ) Carbamoyl) pyridazin-3-yl) carbamates
Cyclopropyl (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- ((methyl-d) 3 ) Carbamoyl) pyridazin-3-yl) carbamate was prepared according to example 1.
MS m/z(ESI):442.2[M+H] + .
Example 26
6- (2-cyclopropylacetylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (2-cyclopropylacetylamino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino)) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CD 3 OD)δ0.24-0.28(m,2H),0.57-0.61(m,2H),1.12-1.15(m,1H),2.37(d,J＝8.0Hz,2H),3.76(s,3H),4.04(s,3H),7.32(t,J＝8.0Hz,1H),7.64(dd,J＝8.0,1.2Hz,1H),7.70(dd,J＝8.0,1.2Hz,1H),8.20(s,1H),8.50(s,1H)；
MS m/z(ESI):440.2[M+H] + .
Example 27
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):455.2[M+H] + .
Example 28
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetamido-amido) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetamido-amido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):429.2[M+H] + .
Example 29
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamide amino)-N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxycyclopropanecarboxamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):455.2[M+H] + .
Example 30
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetamido-amido) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(Z) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N' -methoxyacetamido-amido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):429.2[M+H] + .
Example 31
(E) -6- (N' -cyanocyclopropylaminoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(E) -6- (N' -cyanocyclopropylaminoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):450.2[M+H] + .
Example 32
(E) -6- (N' -cyanoacetyl)Iminoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
(E) -6- (N' -cyanoacetamido amido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):424.2[M+H] + .
Example 33
(Z) -6- (N' -cyanocyclopropylaminoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(Z) -6- (N' -cyanocyclopropylaminoamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):450.2[M+H] + .
Example 34
(Z) -6- (N' -cyanoacetamido-amido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(Z) -6- (N' -cyanoacetamido-amido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):424.2[M+H] + .
Example 35
6- ((cyclopropylene fluoromethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- ((cyclopropylene fluoromethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):428.2[M+H] + .
Example 36
(Z) -6- ((1-Fluoroprop-1-en-1-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(Z) -6- ((1-Fluoroprop-1-en-1-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):416.2[M+H] + .
Example 37
6- ((1-Cyclopropylene-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- ((1-Cyclopropylene-2, 2-trifluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):478.2[M+H] + .
Example 38
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoro-but-2-en-2-yl) amino) pyridazine-3-carboxamide
(E) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1, 1-trifluoro-but-2-en-2-yl) amino) pyridazine-3-carboxamide the procedure described in example 1 is followed.
MS m/z(ESI):466.2[M+H] + .
Example 39
6- ((1-Cyclopropylene-2, 2-difluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- ((1-Cyclopropylene-2, 2-difluoroethyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):460.2[M+H] + .
Example 40
(E) -6- ((1, 1-difluorobut-2-en-2-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
(E) -6- ((1, 1-difluorobut-2-en-2-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Process for preparing pyridazine-3-carboxamides Reference is made to example 1.
MS m/z(ESI):448.2[M+H] + .
Example 41
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of-6- ((1-methylcyclopropyl) amino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation of 6- ((1-methylcyclopropyl) amino) pyridazine-3-carboxamide the procedure described in example 1 is followed.
MS m/z(ESI):412.2[M+H] + .
Example 42
6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):450.2[M+H] + .
Example 43
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazin-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Preparation method of (E) -6- (5-methyl-4H-1, 2, 4-triazole-3-yl) pyridazine-3-carboxamideThe method is described in example 1.
MS m/z(ESI):424.2[M+H] + .
Example 44
6- (5-cyclopropyl-1H-imidazol-2-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (5-cyclopropyl-1H-imidazol-2-yl) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):449.2[M+H] + .
Example 45
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -6- (5-methyl-1H-imidazol-2-yl) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- (5-methyl-1H-imidazol-2-yl) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):423.2[M+H] + .
Example 46
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -6- (pyridine-2-sulfonylamino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- (pyridine-2-sulfonylamino) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):499.2[M+H] + .
Example 47
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -6- ((1-methyl-1H-pyrazole) -3-sulfonylamino) pyridazine-3-carboxamide
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of 6- ((1-methyl-1H-pyrazole) -3-sulfonylamino) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):502.2[M+H] + .
Example 48
6- (cyclopropylamido) -4- ((2- (dimethylamino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2- (dimethylamino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):439.2[M+H] + .
Example 49
6- (cyclopropylamido) -N- (methyl-d) 3 ) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfanyl) phenyl) amino) pyridazine-3-carboxamide
6- (cyclopropylamido) -N- (methyl-d) 3 ) Preparation of 4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfanyl) phenyl) amino) pyridazine-3-carboxamide the procedure of example 1 was followed.
1 H NMR(400MHz,CDCl 3 )δ0.87-0.92(m,2H),1.09-1.12(m,2H),1.88-1.96(m,1H),2.27(s,3H),3.99(s,3H),7.41-7.49(m,2H),7.57-7.59(m,1H),8.04(s,1H),8.14(s,1H),8.30(s,1H),10.20(s,1H),11.30(s,1H)；
MS m/z(ESI):442.2[M+H] + .
Example 50
6- (cyclopropylamido) -N- (methyl-d) 3 ) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (trifluoromethoxy) phenyl) amino) pyridazine-3-carboxamide
6- (cyclopropylamido) -N- (methyl-d) 3 ) Preparation of 4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (trifluoromethoxy) phenyl) amino) pyridazine-3-carboxamide the procedure described in example 1 was followed.
MS m/z(ESI):480.2[M+H] + .
Example 51
6- (cyclopropylamido) -4- ((2- (difluoromethoxy) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2- (difluoromethoxy) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.85-0.99(m,2H),1.03-1.12(m,2H),1.73-1.81(m,1H),4.00(s,3H),6.63-7.01(m,1H),7.43-7.48(m,1H),7.54-7.58(m,1H),7.92-7.99(m,2H),8.08-8.16(m,2H),9.83(s,1H),11.16(s,1H)；
MS m/z(ESI):462.2[M+H] + .
Example 52
6- (cyclopropylamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl)) Amino) -N- (methyl-d 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.84-0.95(m,2H),1.02-1.11(m,2H),1.67-1.76(m,1H),3.78(s,3H),4.00(s,3H),7.06-7.13(m,1H),7.63-7.67(m,1H),7.91-7.97(m,1H),7.98-8.02(m,1H),8.08-8.12(m,1H),9.77(s,1H),10.80(s,1H)；
MS m/z(ESI):444.2[M+H] + .
Example 53
6- (cyclopropylamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((6-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz，CDCl 3 )δ0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84(m,1H),3.81(s,3H),4.01(s,3H),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H)；
MS m/z(ESI):444.2[M+H] + .
Example 54
6- (Cyclopropanamido) -4- ((4-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (Cyclopropanamido) -4- ((4-fluoro-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):444.2[M+H] + .
Example 55
4- ((6-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
4- ((6-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):451.2[M+H] + .
Example 56
4- ((5-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
4- ((5-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):451.2[M+H] + .
Example 57
4- ((4-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
4- ((4-cyano-2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):451.2[M+H] + .
Example 58
6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
First step preparation of 2-methoxy-3-nitroaniline
Methyl 2-methoxy-3-nitrophenyl ester (5 g,23.7 mmol) was dissolved in methanolic ammonia (100 mL, 7M) at room temperature, ammonia water (28 wt%,50 mL) was added, the mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 mL) and the organic phase was then successively diluted with saturated NaHCO 3 The mixture was washed with an aqueous solution (300 mL. Times.2) and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound 2-methoxy-3-nitroaniline (4.3 g, 92%).
MS m/z(ESI):197.1[M+H] + .
Second step preparation of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
2-methoxy-3-nitroaniline (4.2 g,21.4 mmol) was dissolved in DMF-DMA (28.6 mL), heated to 95℃and reacted for 1 hour, concentrated under reduced pressure to give crude DMF-DMA addition product, which was dissolved in ethanol (20 mL) for use. Under ice bath, ethanol (70 mL), acetic acid (21 mL) and stirring are added into a reaction bottleAfter 5 minutes, hydrazine hydrate (80 wt.%,10.5 mL) was slowly added dropwise and stirring was continued for 15 minutes, then an ethanol solution of the above crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature, and stirring was continued at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300 mL), and the organic phase was successively saturated with NaHCO 3 The aqueous solution (300 mL. Times.2) was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give the title compound 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (4.5 g, 95%).
MS m/z(ESI):221.1[M+H] + .
Third step preparation of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (200 mg,0.91 mmol), copper acetate (198 mg,1.1 mmol), 2' -bipyridine (170 mg,1.1 mmol), sodium carbonate (192 mg,1.8 mmol), and mixed in 1, 2-dichloroethane (5 mL), cyclopropylboronic acid (234 mg,2.72 mmol) was added at room temperature and heated to 85deg.C and stirred overnight. After the reaction solution was cooled to room temperature, a large amount of ethyl acetate was added to dilute. The organic phase was washed with saturated brine several times, then the organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and then separated by column chromatography to give the title compound 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (125 mg, 53%).
1 H NMR(400MHz,CDCl 3 )δ1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79(m,1H),3.94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H)；
MS m/z(ESI):261.1[M+H] + .
Fourth step preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline
Palladium on carbon (30 mg) was added to a methanol (5 mL) solution of 1-cyclopropyl-3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (120 mg,0.46 mmol), and the catalyst was filtered off with celite after 12 hours of reaction under normal temperature and pressure hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title compound 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (102 mg) which was used directly in the next reaction.
MS m/z(ESI):231.1[M+H] + .
Fifth step preparation of zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate
3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyaniline (100 mg,0.4 mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (103.7 mg,0.5 mmol) and zinc acetate (95.6 mg,0.5 mmol) were mixed in isopropanol (0.5 mL) and water (3.5 mL) and heated to 80℃to react overnight. The reaction was cooled to room temperature, water (3 mL) was added, stirring was performed for 1H, the reaction solution was filtered, the filter cake was washed with water (3 mL. Times.2) and THF (2 mL), and the filter cake was collected and dried to give the title compound, zinc 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (130 mg, 78%).
MS m/z(ESI):387.1[M+H] + .
Sixth step preparation of zinc 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate
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6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylic acid zinc (130 mg,0.31 mmol), cyclopropylamide (86 mg,1.0 mmol), DBU (61 mg,0.4 mmol), potassium carbonate (110 mg,0.8 mmol), and mixtures in toluene (1.2 mL) and acetonitrile (0.6 mL), palladium acetate (4.5 mg,0.02 mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyldi-tert-butylphosphine (22 mg,0.04 mmol), the reaction system was replaced with nitrogen three times and heated to The reaction was carried out overnight at 75 ℃. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, washed with petroleum ether (6 mL. Times.2), the aqueous phase was then separated, water (2 mL) was added to the aqueous phase, CH 2 Cl 2 (5 mL. Times.3) extraction, combining the organic phases, washing with saturated aqueous NaCl, separating the organic phases, drying over anhydrous sodium sulfate, and concentrating the organic solvent under reduced pressure afforded the title compound, zinc 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylate (109 mg, 75%).
MS m/z(ESI):436.1[M+H] + .
Seventh step preparation of 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6- (Cyclopropanamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) pyridazine-3-carboxylic acid zinc (90 mg,0.19 mmol), deuterated methylamine hydrochloride (71 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) were mixed in DMF (1 mL), HATU (380 mg,1.0 mmol) was added and reacted overnight at 50 ℃. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was used with CH 2 Cl 2 The organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure followed by column chromatography to give the title compound 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (35 mg, 38%).
1 H NMR(400MHz,CDCl 3 )δ0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26(m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81(s,3H),7.27-7.29(m,1H),7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H)；
MS m/z(ESI):452.2[M+H] + .
Example 59
6- (cyclopropylamido) -4- ((3- (1-isopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((3- (1-isopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 58.
MS m/z(ESI):454.2[M+H] + .
Example 60
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (oxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (oxetan-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 58.
1 H NMR(400MHz,CDCl 3 )δ0.90-0.96(m,2H),1.08-1.13(m,2H),1.74-1.80(m,1H),3.87(s,3H),5.07-5.09(m,2H),5.17-5.21(m,2H),5.57-5.64(m,1H),7.27-7.32(m,1H),7.53-7.56(m,1H),7.84-7.87(m,1H),8.02(s,1H),8.23-8.27(m,2H),9.64(s,1H),11.21(s,1H)；
MS m/z(ESI):468.2[M+H] + .
Example 61
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (2-methoxyethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (2-methoxyethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Process for preparing pyridazine-3-carboxamidesReference is made to example 58.
1 H NMR(400MHz,CDCl 3 )δ0.80-0.95(m,2H),1.05-1.15(m,2H),1.85-1.93(m,1H),3.35(s,3H),3.77-3.86(m,5H),4.36-4.44(m,2H),7.23-7.30(m,1H),7.52(dd,J＝7.6Hz,1H),7.82(dd,J＝7.7Hz,1H),8.02(s,1H),8.17-8.30(m,2H),10.14(s,1H),11.06(s,1H)；
MS m/z(ESI):470.2[M+H] + .
Example 62
4- ((3- (1- (2-cyanoethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
4- ((3- (1- (2-cyanoethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 58.
1 H NMR(400MHz,CDCl 3 )δ0.86-0.94(m,2H),1.07-1.12(m,2H),1.22-1.26(m,2H),1.74-1.80(m,1H),3.08(t,J＝8.0Hz,2H),3.81(s,3H),4.53(t,J＝8.0Hz,2H),7.27-7.31(m,1H),7.53-7.55(m,1H),7.81-7.83(m,1H),8.05(s,1H),8.23(s,1H),8.26(s,1H),9.57(br s,1H),11.11(br s,1H)；
MS m/z(ESI):465.2[M+H] + .
Example 63
6- (cyclopropylamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [1, 2-b)][1,2,4]Triazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.90-0.95(m,2H),1.08-1.12(m,2H),1.68-1.75(m,1H),2.72-2.79(m,2H),2.98-3.05(m,2H),3.80(s,3H),4.21-4.27(m,2H),7.23-7.28(m,1H),7.46-7.49(m,1H),7.81-7.84(m,1H),8.00(s,1H),8.19(s,1H),9.42(s,1H),11.12(s,1H)；
MS m/z(ESI):452.2[M+H] + .
Example 64
6- (cyclopropylamido) -4- ((2-methoxy-3- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2-methoxy-3- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.94-1.02(m,2H),1.07-1.11(m,2H),1.76-1.84(m,1H),3.48(s,3H),3.83(s,3H),7.30-7.42(m,2H),7.57-7.61(m,1H),7.97-8.02(m,2H),8.19(s,1H),9.97(s,1H),11.28(s,1H)；
MS m/z(ESI):426.2[M+H] + .
Example 65
6- (cyclopropylamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((3- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.91-0.97(m,2H),1.08-1.12(m,2H),1.96-2.02(m,2H),1.71-1.76(m,1H),2.76-2.80(m,2H),3.13-3.16(m,2H),3.57(s,3H),4.16-4.19(m,2H),7.41-7.43(m,1H),7.50-7.52(m,1H),7.69-7.71(m,1H),7.79(s,1H),8.09(s,1H),11.84(s,1H)；
MS m/z(ESI):452.2[M+H] + .
Example 66
6- (cyclopropylamido) -4- ((3- (5-fluoro-1-methyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((3- (5-fluoro-1-methyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):444.2[M+H] + .
Example 67
6- (Cyclopropanamido) -5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (Cyclopropanamido) -5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):444.2[M+H] + .
Example 68
6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-methyl-N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-methyl-N- (methyl-d) 3 ) Pyridazine-3-carboxylic acid methyl esterThe preparation of the amide is described in example 1.
MS m/z(ESI):440.2[M+H] + .
Example 69
5-cyano-6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
5-cyano-6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):451.2[M+H] + .
Example 70
N- (6- (1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (6- (1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):432.2[M+H] + .
Example 71
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):433.2[M+H] + .
Example 72
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1H-tetrazol-5-yl) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (1H-tetrazol-5-yl) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):434.2[M+H] + .
Example 73
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-1H-imidazol-2-yl) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-1H-imidazol-2-yl) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):446.2[M+H] + .
Example 74
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (5-methyl-4H-1, 2, 4-triazol-3-yl) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):447.2[M+H] + .
Example 75
N- (6- (5-cyclopropyl-1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (6- (5-cyclopropyl-1H-imidazol-2-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):472.2[M+H] + .
Example 76
N- (6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (6- (5-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):473.2[M+H] + .
Example 77
N 6 -cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N 3 - (methyl-d) 3 ) Pyridazine-3, 6-dicarboxamides
N 6 -cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N 3 - (methyl-d) 3 ) The preparation of pyridazine-3, 6-dicarboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.67-0.72(m,2H).0.86-0.90(m,2H),2.92-2.99(m,1H),3.79(s,3H),4.02(s,3H),7.23-7.27(m,1H),7.43-7.45(m,1H),7.88-7.90(m,2H),8.16(s,1H),8.22(s,1H),8.29(s,1H),11.15(s,1H)；
MS m/z(ESI):426.2[M+H] + .
Example 78
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N- (methyl-d) amino) 3 ) Sulfamoyl) pyridazin-3-yl) cyclopropanecarboxamides
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (N- (methyl-d) amino) 3 ) Sulfamoyl) pyridazin-3-yl) cyclopropanecarboxamide the procedure for the preparation of which is described in example 1.
MS m/z(ESI):462.2[M+H] + .
Example 79
N- (6- (hydroxymethyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (6- (hydroxymethyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):396.2[M+H] + .
Example 80
N- (6- (2-hydroxyacetyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide
The preparation of N- (6- (2-hydroxyacetyl) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazin-3-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):424.2[M+H] + .
Example 81
2- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyrimidine-5-carboxamides
2- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyrimidine-5-carboxamide is described in example 1.
MS m/z(ESI):426.2[M+H] + .
Example 82
3- (cyclopropylamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -1,2, 4-triazine-6-carboxamide
3- (cyclopropylamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The process for the preparation of 1,2, 4-triazine-6-carboxamide is described in example 1.
MS m/z(ESI):427.2[M+H] + .
Example 83
6-methoxy-N 2 - (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N 4 - (5-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine
6-methoxy-N 2 - (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N 4 The preparation of- (5-methyl-1H-pyrazol-3-yl) pyrimidine-2, 4-diamine is described in example 1.
MS m/z(ESI):408.2[M+H] + .
Example 84
2- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrimidine-5-carboxamide
The preparation of 2- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrimidine-5-carboxamide is described in example 1.
1 H NMR(400MHz,DMSO-d 6 )δ0.76-0.95(m,4H),2.09-2.21(m,1H),2.82(d,J＝4.4Hz,3H),3.80(s,3H),3.95(s,3H),7.15(t,J＝8.1Hz,1H),7.49(dd,J＝7.8,1.6Hz,1H),8.55(s,1H),8.67(d,J＝4.7Hz,1H),8.75(s,1H),10.92(s,1H),11.90(s,1H)；
MS m/z(ESI):423.2[M+H] + .
Example 85
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5- (N-methylsulfamoyl) pyridin-2-yl) cyclopropanecarboxamide
The preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5- (N-methylsulfamoyl) pyridin-2-yl) cyclopropanecarboxamide is described in example 1.
MS m/z(ESI):458.2[M+H] + .
Example 86
3- (cyclopropylamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1, 2, 4-triazine-6-carboxamide
The preparation of 3- (cyclopropylamido) -5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1, 2, 4-triazine-6-carboxamide is described in example 1.
MS m/z(ESI):424.2[M+H] + .
Example 87
6- (2-cyclopropyl-2-carbonyl-acetamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamides
6- (2-cyclopropyl-2-carbonyl-acetamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) The preparation of pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):454.2[M+H] + .
Example 88
6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
First step preparation of 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole
5-fluoro-2-methoxybenzamide (3.5 g,20.7 mmol) was dissolved in DMF-DMA (25 mL), heated to 95℃and reacted for 1 hour, concentrated under reduced pressure to give crude DMF-DMA addition product, which was dissolved in ethanol (20 mL) for use. Ethanol (56 mL), acetic acid (17 mL) and, after stirring for 5 minutes, hydrazine hydrate (80 wt.%,8.4 mL) was added dropwise and stirring was continued for 15 minutes under ice bath, then an ethanol solution of the above crude DMF-DMA addition product was added dropwise, slowly warmed to room temperature and stirring was continued at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (300 mL), and saturated NaHCO 3 Washing with aqueous solution (300 mL. Times.2), washing the separated organic phase with saturated saline solution, and washing withThe organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to give the title compound 3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (3.1 g, 77%).
MS m/z(ESI):194.2[M+H] + .
Second step preparation of 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (5-fluoro-2-methoxyphenyl) -1H-1,2, 4-triazole (1.1 g,5.69 mmol) was dissolved in concentrated sulfuric acid (10 mL), nitric acid (68 wt.%,1.05g,11.39 mmol) was added dropwise under ice bath, and stirring was continued under ice bath for 2 hours after the addition was completed. The reaction solution was poured into ice water, ammonia water was slowly added dropwise thereto, the pH was adjusted to about 9, ethyl acetate was extracted, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure to give the title compound 3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole crude product (1.26 g) which was directly used in the next reaction.
MS m/z(ESI):239.2[M+H] + .
Preparation of third step 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole
3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (600 mg,2.52 mmol), copper acetate (688 mg,3.8 mmol), 2' -bipyridine (560 mg,3.8 mmol), sodium carbonate (534 mg,5.0 mmol), were mixed in 1, 2-dichloroethane (5 mL), cyclopropylboronic acid (865 mg,10.0 mmol) was added at room temperature and heated to 85deg.C and stirred overnight. After the reaction solution was cooled to room temperature, a large amount of ethyl acetate was added to dilute. The organic phase was washed with saturated brine several times, then the organic phase was separated and dried over anhydrous sodium sulfate, and after concentrating the organic solvent under reduced pressure, column chromatography was performed to obtain the title compound, 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260 mg, 38%).
1 H NMR(400MHz,CDCl 3 )δ1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73(m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H)；
MS m/z(ESI):279.0[M+H] + .
Fourth step preparation of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline
To a solution of 1-cyclopropyl-3- (5-fluoro-2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (260 mg,0.93 mmol) in methanol (5 mL) was added palladium on carbon (60 mg), and after reacting for 8 hours under a normal temperature and pressure hydrogen atmosphere, the catalyst was filtered off with celite. The filtrate was concentrated under reduced pressure to give the title compound 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230 mg) which was used directly in the next reaction.
MS m/z(ESI):249.2[M+H] + .
Fifth step preparation of 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyaniline (230 mg,0.93 mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (194 mg,0.93 mmol) in tetrahydrofuran (8 mL) at room temperature was added dropwise a solution of LiHMDS (1M, 2.78mL,2.78 mmol) in tetrahydrofuran, and the reaction mixture was stirred at room temperature for 2 hours and then quenched with saturated aqueous ammonium chloride. The reaction solution was diluted with methylene chloride, the organic phase was washed with saturated brine several times, then the organic phase was separated and dried over anhydrous sodium sulfate, and after concentrating the organic solvent under reduced pressure, the column chromatography was carried out to obtain the title compound 6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (290 mg, 74%).
MS m/z(ESI):421.2[M+H] + .
Sixth step preparation of 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (155 mg,0.37 mmol), cyclopropylamide (62 mg,0.74 mmol), cesium carbonate (360 mg,1.1 mmol) were mixed in dioxane (5 mL), tris (dibenzylideneacetone) dipalladium (101 mg,0.11 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (127 mg,0.22 mmol) were added, deoxygenated with nitrogen for 5 minutes, and the reaction was carried out at 145℃for 2 hours. The reaction solution was diluted with methylene chloride, and the organic phase was washed with saturated brine several times, then the organic phase was separated and dried over anhydrous sodium sulfate, and after concentrating the organic solvent under reduced pressure, the column chromatography was carried out to obtain the title compound, 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (116 mg, 67%).
1 H NMR(400MHz,CDCl 3 )δ0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26(m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H),3.80(s,3H),7.22-7.25(m,1H),7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H)；
MS m/z(ESI):470.2[M+H] + .
Example 89
6- (Cyclopropanamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-5-methyl-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):440.2[M+H] + .
Example 90
6- (cyclopropylamido) -4- ((2-fluoro-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazin-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-fluoro-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in reference to example 1.
1 H NMR(400MHz,CDCl 3 )δ0.86-0.93(m,2H),1.06-1.11(m,2H),1.78-1.87(m,1H),4.04(s,3H),7.27-7.33(m,1H),7.46-7.52(m,1H),7.90-7.96(m,1H),8.03(s,1H),8.08-8.15(m,2H),9.99(s,1H),10.95(s,1H)；
MS m/z(ESI):414.2[M+H] + .
Example 91
4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of first step 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00 g,4.54 mmol), DMAP (55.0 mg,0.454 mmol) and DIPEA (1.05 mL,6.36 mmol) in dichloromethane (20 mL) at-20deg.C was slowly added dropwise a solution of SEM-Cl (0.964 mL,5.45 mmol) in dichloromethane (10 mL). After the addition was completed, the temperature was slowly raised to-10℃and stirred at that temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole which was used directly in the next reaction.
MS m/z(ESI):351.2[M+H] + .
Preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g,30.0 mmol) and reduced iron powder (1.67 g,30.0 mmol) were sequentially added, followed by stirring at 50℃for 2 hours, then cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with methylene chloride, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] + .
Preparation of step 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640 mg,2.00 mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417 mg,2.00 mmol) in THF (20 mL) at 0deg.C was added LiHMDS (1M in THF,5.00 mL) dropwise, and the mixture was warmed slowly to room temperature and stirred at room temperature for 2 hours. Saturated brine was added, quenched twice with DCM, the organic phases were combined, dried and the organic solvent concentrated under reduced pressure, and the column chromatographed to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] + .
Preparation of fourth step 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850 mg,1.73 mmol), cyclopropylamide (372 mg,4.38 mmol) and cesium carbonate (2.14 g,6.57 mmol) were mixed in 1,4-dioxane (20 mL), deoxygenated with nitrogen eluting the reaction solution for 5 min and then Pd was added sequentially 2 (dba) 3 (400 mg,0.438 mmol) and Xantphos (506 mg,0.876 mmol). The title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (680 mg, 73%) was isolated by column chromatography after concentration of the organic solvent under nitrogen protection with heating at 130℃for 90 min, cooling to room temperature.
MS m/z(ESI):542.3[M+H] + .
Fifth step preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630 mg,1.16 mmol) in DCM was added TFA (6.0 mL) at 0 ℃ and then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate and then brine, the organic phase dried and concentrated under reduced pressure, and the column chromatographed to give the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270 mg, 57%).
1H NMR(400MHz,CDCl 3 )δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)；
MS m/z(ESI):412.2[M+H] + .
Sixth step preparation of 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide
6- (Cyclopropanamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30 mg,0.073 mmol), allyl bromide (8.7 mg,0.073 mmol) and potassium carbonate (20 mg,0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0deg.C for 2 days. The reaction solution was concentrated under reduced pressure, and the title compound 4- ((3- (1-allyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide (12 mg, 39%) was obtained by column chromatography.
1 H NMR(400MHz,CDCl 3 )δ0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85(m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H),6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H)；
MS m/z(ESI):452.2[M+H] + .
Example 92
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of first step 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00 g,4.54 mmol), DMAP (55.0 mg,0.454 mmol) and DIPEA (1.05 mL,6.36 mmol) in dichloromethane (20 mL) at-20deg.C was slowly added dropwise a solution of SEM-Cl (0.964 mL,5.45 mmol) in dichloromethane (10 mL). After the addition was completed, the temperature was slowly raised to-10℃and stirred at that temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole which was used directly in the next reaction.
MS m/z(ESI):351.2[M+H] + .
Preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g,30.0 mmol) and reduced iron powder (1.67 g,30.0 mmol) were sequentially added, followed by stirring at 50℃for 2 hours, then cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with methylene chloride, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] + .
Preparation of step 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640 mg,2.00 mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417 mg,2.00 mmol) in THF (20 mL) at 0deg.C was added LiHMDS (1M in THF,5.00 mL) dropwise, and the mixture was warmed slowly to room temperature and stirred at room temperature for 2 hours. Saturated brine was added, quenched twice with DCM, the organic phases were combined, dried and the organic solvent concentrated under reduced pressure, and the column chromatographed to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] + .
Preparation of fourth step 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850 mg,1.73 mmol), cyclopropylamide (372 mg,4.38 mmol) and cesium carbonate (2.14 g,6.57 mmol) were mixed in 1,4-dioxane (20 mL), deoxygenated with nitrogen eluting the reaction solution for 5 min and then Pd was added sequentially 2 (dba) 3 (400 mg,0.438 mmol) and Xantphos (506 mg,0.876 mmol). Under the protection of nitrogen, heating and reacting for 90 minutes at the temperature of 130 ℃ by microwaves, cooling to room temperature, concentrating an organic solvent under reduced pressure, and separating by column chromatography to obtain the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole-3-yl) benzeneAmino) -N- (methyl-d 3) pyridazine-3-carboxamide (680 mg, 73%).
MS m/z(ESI):542.3[M+H] + .
Fifth step preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630 mg,1.16 mmol) in DCM (20 mL) was added TFA (6.0 mL) at 0 ℃ and then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate and then brine, the organic phase dried and concentrated under reduced pressure, and the column chromatographed to give the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270 mg, 57%).
1 H NMR(400MHz,CDCl 3 )δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)；
MS m/z(ESI):412.2[M+H] + .
Sixth step preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6- (Cyclopropionylamino) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (30 mg,0.073 mmol), bromopropyne (8.7 mg,0.073 mmol) and potassium carbonate (20 mg,0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0deg.C for 2 days. The reaction solution was concentrated under reduced pressure, and the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (10 mg, 31%) was obtained by column chromatography.
1 H NMR(400MHz,CDCl 3 )δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H)；
MS m/z(ESI):450.2[M+H] + .
Example 93
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was according to example 1.
MS m/z(ESI):494.2[M+H] + .
Example 94
4- ((3- (1- (tert-butyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 4- ((3- (1- (tert-butyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):468.2[M+H] + .
Example 95
6- (cyclopropylamido) -4- ((2-methoxy-3- (1, 1-trifluoro-2-methylpropan-2-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazin-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1, 1-trifluoro-2-methylpropan-2-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):522.2[M+H] + .
Example 96
4- ((3- (1- (bicyclo [1.1.1] pentan-1-yl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 4- ((3- (1- (bicyclo [1.1.1] pentan-1-yl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):478.2[M+H] + .
Example 97
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (thietanyl-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (thietanyl-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in reference to example 1.
MS m/z(ESI):484.2[M+H] + .
Example 98
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (3-methyl-oxazol-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (3-methyl-oxazol-3-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75(m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J＝6.6Hz,2H),5.25(d,J＝6.4Hz,2H),7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H)；
MS m/z(ESI):482.2[M+H] + .
Example 99
6- (Cyclopropylmethylthioamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylmethylthioamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):442.2[M+H] + .
Example 100
6- (cyclopropylamido) -4- ((2- (dimethylphosphino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2- (dimethylphosphino) -3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):472.2[M+H] + .
Example 101
6- (cyclopropylamido) -N- (methyl-d 3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -N- (methyl-d 3) -4- ((3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):474.2[M+H] + .
Example 102
4- ((3- (1- (cyanomethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 4- ((3- (1- (cyanomethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):451.2[M+H] + .
Example 103
4- ((3- (1- (bicyclo [1.1.1] pentan-1-ylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 4- ((3- (1- (bicyclo [1.1.1] pentan-1-ylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6- (cyclopropylamido) -N- (methyl-d 3) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):492.2[M+H] + .
Example 104
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (oxetan-3-ylmethyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 92.
1 H NMR(400MHz,CDCl 3 )δ0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62(m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2H),7.27-7.29(m,1H),7.50-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H)；
MS m/z(ESI):482.2[M+H] + .
Example 105
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- (4-carbonyl-5-azaspiro [2.4] heptane-5-yl) pyridazine-3-carboxamide
The preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- (4-carbonyl-5-azaspiro [2.4] heptane-5-yl) pyridazine-3-carboxamide was described with reference to example 1.
MS m/z(ESI):452.2[M+H] + .
Example 106
6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide the procedure was as described in example 1.
MS m/z(ESI):437.2[M+H] + .
Example 107
(R) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of (R) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):437.2[M+H] + .
Example 108
(S) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of (S) -6- ((cyano (cyclopropyl) methyl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):437.2[M+H] + .
Example 109
6- (1-fluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (1-fluorocyclopropane-1-carboxamide) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ1.38-1.50(m,4H),3.81(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.49(dd,J＝7.9,1.4Hz,1H),7.81(dd,J＝7.9,1.5Hz,1H),8.09-8.22(m,3H),9.09(s,1H),11.00(s,1H)；
MS m/z(ESI):444.2[M+H] + .
Example 110
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- ((3-vinyloxetan-3-yl) amino) pyridazine-3-carboxamide
The preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) -6- ((3-vinyloxetan-3-yl) amino) pyridazine-3-carboxamide is described in example 1.
MS m/z(ESI):440.2[M+H] + .
Example 111
6- ((3-ethynyl oxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- ((3-ethynyloxetan-3-yl) amino) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide the procedure for preparation was as described in example 1.
MS m/z(ESI):438.2[M+H] + .
Example 112
6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of first step 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole
To a solution of 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole (1.00 g,4.54 mmol), DMAP (55.0 mg,0.454 mmol) and DIPEA (1.05 mL,6.36 mmol) in dichloromethane (20 mL) at-20deg.C was slowly added dropwise a solution of SEM-Cl (0.964 mL,5.45 mmol) in dichloromethane (10 mL). After the addition was completed, the temperature was slowly raised to-10℃and stirred at that temperature overnight. The reaction solution was washed with saturated brine, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure after filtration to give crude 3- (2-methoxy-3-nitrophenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole which was used directly in the next reaction.
MS m/z(ESI):351.2[M+H] + .
Preparation of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline
The above crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g,30.0 mmol) and reduced iron powder (1.67 g,30.0 mmol) were sequentially added, followed by stirring at 50℃for 2 hours, then cooling the reaction system, filtering off insoluble matter with celite, concentrating the filtrate, dissolving the residue with methylene chloride, washing with saturated brine, separating the organic phase, drying with a drying agent, filtering, concentrating the organic solvent under reduced pressure, and separating by column chromatography to give the title compound 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] + .
Preparation of step 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) aniline (640 mg,2.00 mmol) and 4, 6-dichloro-N- (methyl-d 3) pyridazine-3-carboxamide (417 mg,2.00 mmol) in THF (20 mL) at 0deg.C was added LiHMDS (1M in THF,5.00 mL) dropwise, and the mixture was warmed slowly to room temperature and stirred at room temperature for 2 hours. Saturated brine was added, quenched twice with DCM, the organic phases were combined, dried and the organic solvent concentrated under reduced pressure, and the column chromatographed to give the title compound 6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] + .
Preparation of fourth step 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
6-chloro-4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (850 mg,1.73 mmol), cyclopropylamide (372 mg,4.38 mmol) and cesium carbonate (2.14 g,6.57 mmol) were mixed in 1,4-dioxane (20 mL), deoxygenated with nitrogen eluting the reaction solution for 5 min and then Pd was added sequentially 2 (dba) 3 (400 mg,0.438 mmol) and Xantphos (506 mg,0.876 mmol). Under the protection of nitrogen, the reaction is carried out for 90 minutes at the temperature of 130 ℃ under the microwave, the reaction is cooled to the room temperature, and after the organic solvent is concentrated under reduced pressure, column chromatography is carried out to obtain the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazole-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazineOxazine-3-carboxamide (680 mg, 73%).
MS m/z(ESI):542.3[M+H] + .
Fifth step preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
To a solution of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (630 mg,1.16 mmol) in DCM was added TFA (6.0 mL) at 0 ℃ and then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate and then brine, the organic phase dried and concentrated under reduced pressure, and the column chromatographed to give the title compound 6- (cyclopropylamido) -4- ((2-methoxy-3- (1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide (270 mg, 57%).
1 H NMR(400MHz,CDCl 3 )δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)；
MS m/z(ESI):412.2[M+H] + .
Example 113
6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxamide is described in example 1.
1 H NMR(400MHz,DMSO)δ0.79-0.86(m,4H),2.04-2.12(m,1H),3.71(s,3H),3.95(s,3H),7.24-7.25(m,1H),7.49-7.52(m,1H),7.63-7.67(m,1H),7.89(s,1H),8.16(s,1H),8.53-8.58(m,2H),11.06(s,1H),11.33(s,1H)；
MS m/z(ESI):409.2[M+H] + .
Example 114
6- (cyclopropylamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylamido) -4- ((5-fluoro-2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide the procedure of example 92 is followed.
1 H NMR(400MHz,DMSO-d 6 )δ0.84-0.87(m,2H),1.23-1.34(m,2H),2.09-2.12(m,1H),3.60(s,1H),3.75(s,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H)；
MS m/z(ESI):468.2[M+H] + .
Example 115
6- (cyclopropylamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((3- (1- (cyclopropylmethyl) -1H-1,2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93(m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10(d,J＝7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H)；
MS m/z(ESI):466.2[M+H] + .
Example 116
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide example 116 was one of the products of the sixth step reaction as described in example 92.
1 H NMR(400MHz,CDCl 3 )δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.39(s,1H),3.48(s,3H),4.94(d,J＝6.4Hz,2H),7.26-7.36(m,1H),7.43(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),8.07(s,1H),8.12(s,1H),9.64(br s,1H),11.07(s,1H)；
MS m/z(ESI):450.2[M+H] + .
Example 117
6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-5-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-5-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.93-1.02(m,4H),1.05-1.11(m,4H),1.75-1.82(m,1H),3.48(s,3H),3.61-3.70(m,1H),7.13-7.17(m,1H),7.29-7.33(m,1H),7.93(s,2H),8.18(s,1H),10.61(s,1H),11.59(s,1H)；
MS m/z(ESI):470.1[M+H] + .
Example 118
6- (cyclopropylamido) -4- ((2-methoxy-3- (4- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (4- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide the procedure was as described in example 92 and example 118 was one of the products of the sixth step reaction.
1 H NMR(400MHz,CDCl 3 )δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),1.71(s,1H),3.81(s,3H),5.71(d,J＝6.4Hz,2H),7.22-7.30(m,1H),7.52(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),8.07(s,1H),8.20(s,1H),8.29(s,1H),9.10(br s,1H),11.07(s,1H)；
MS m/z(ESI):450.2[M+H] + .
Example 119
6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) nicotinamide
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Preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (1- (prop-2-yn-1-yl) -1H-1,2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) nicotinamide the procedure of example 92 is followed.
1 H NMR(400MHz,DMSO-d 6 )δ0.88-0.91(m,2H),1.03-1.09(m,2H),1.55-1.65(m,1H),3.81(s,3H),5.06(s,2H),6.79(s,1H),7.26-7.77(m,2H),8.06-8.37(m,3H),9.01(br s,1H),10.63(br s,1H)；
MS m/z(ESI):449.2[M+H] + .
Example 120
6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide
The preparation of 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide is described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.84-0.89(m,2H),1.03-1.08(m,2H),1.11-1.14(m,2H),1.21-1.25(m,2H),1.51-1.57(m,1H),3.63-3.70(m,1H),3.81(s,3H),6.46(s,1H),7.19-7.24(m,1H),7.51-7.54(m,1H),7.68-7.70(m,1H),8.06(s,1H),8.17(s,1H),8.30(s,1H),8.60(s,1H),10.41(s,1H)；
MS m/z(ESI):451.1[M+H] + .
Example 121
6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide
The preparation of 6- (cyclopropylamido) -4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -5-fluoro-2-methoxyphenyl) amino) -N- (methyl-d 3) nicotinamide is described in example 1.
1 H NMR(400MHz,CDCl 3 )δ0.87-0.94(m,2H),1.06-1.16(m,4H),1.20-1.25(m,2H),1.56-1.66(m,1H),3.65-3.69(m,1H),3.81(s,3H),6.84(s,1H),7.44-7.50(m,1H),8.13-8.17(m,2H),8.47(s,1H),9.12(s,1H),10.77(s,1H)；
MS m/z(ESI):469.2[M+H] + .
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 measurement of the inhibitory Effect of the Compound of the present invention on cellular TYK2 Signal pathway
The purpose of the experiment is as follows: the purpose of this test case is to test compounds for their activity against inhibition of cellular TYK2 signaling pathways.
Experimental instrument:
centrifuge (5702R) was purchased from Eppendorf company,
pipettes were purchased from Eppendorf corporation,
the microplate reader was purchased from BioTek company, usa under the model number synergy h1 full function microplate reader.
The experimental method comprises the following steps: the experiment adopts a U266 cell line expressing TYK2, activates a TYK2 signal path through INF-alpha stimulation, detects the inhibitory activity of a compound on downstream STAT3 phosphorylation of the compound, and obtains half inhibition concentration IC of the compound on the activity of the TYK2 signal path 50 。
The specific experimental operation is as follows:
u266 is paved into 384-hole detection plates for 3-12 mu L, the number of cells in each hole is 100-300K, 2 mu L of compound solution which is diluted in a gradient way is added, and the mixture is incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. Mu. LINF-alpha, INF-alpha final concentration 1000U/mL was added and the mixture was shaken at room temperature for 20min. 2-5. Mu.L (5X) LANCE Ultra Lysis Buffer 2 solution was added and the mixture was shaken at room temperature for 2h. After 2h, 5. Mu.L of LANCE Ultra Eu-labeled Anti-STAT5 (Y694/Y699) Antibody (PerkinElmer) at a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT5 Antibody (PerkinElmer) at a final concentration of 20nM were added and incubated overnight at room temperature. The enzyme-labeled instrument measures 665nm fluorescence signal value of each plate hole, the inhibition rate is calculated through the fluorescence signal value, and the IC of the compound is obtained through curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate ]/(positive control value-negative control value) ×100}. Calculation of IC using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4 parameter nonlinear logic formula 50 Values.
Conclusion of experiment:
the activity test data for inhibition of the TYK2 signaling pathway of the compounds of the present invention in cells obtained by the above protocol are shown in the following table:
numbering of compounds Cell Activity U266 pSTAT3 (nM)
Example 3 4.36
Example 4 4.22
Example 53 2.43
Example 58 1.41
Example 60 6.01
Example 88 0.83
Example 89 4.95
Example 91 0.34
Example 92 0.13
Example 98 0.90
Example 104 1.88
Example 112 4.6
Example 114 2.10
Example 115 3.43
Example 118 1.27
Example 119 4.22
Example 120 1.65
Example 121 3.01
Test example 2 measurement of the inhibitory Effect of the Compound of the present invention on the cell JAK2 Signal pathway
The purpose of the experiment is as follows: the purpose of this test case is to test compounds for their activity against cellular JAK2 signaling pathway inhibition.
Experimental instrument:
centrifuge (5702R) was purchased from Eppendorf company,
pipettes were purchased from Eppendorf corporation,
the microplate reader was purchased from BioTek company, usa under the model number synergy h1 full function microplate reader.
The experimental method comprises the following steps: the present experiment uses TF-1 cell line to activate JAK2 signal pathway by IL6 stimulation, and detects downstream of the compound Inhibitory Activity of STAT3 phosphorylation and half inhibitory concentration IC of Compounds against JAK2 Signal pathway Activity 50 。
The specific experimental operation is as follows:
TF-1 cells are paved into 384-hole detection plates with 3-12 mu L, the number of each hole of cells is 100-300K, 2 mu L of compound solution which is diluted in a gradient way is added, and the cells are incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. Mu.LIL 6 was added and the mixture was shaken at room temperature for 20min at a final IL6 concentration of 30 ng/mL. 2-5. Mu.L (5X) LANCE Ultra Lysis Buffer 2 solution was added and shaken at 4℃for 2h. After 2h, 5. Mu.L of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr 705) Antibody (PerkinElmer) at a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) at a final concentration of 20nM were added and incubated overnight at room temperature. The enzyme-labeled instrument measures 665nm fluorescence signal value of each plate hole, the inhibition rate is calculated through the fluorescence signal value, and the IC of the compound is obtained through curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate]/(positive control value-negative control value) ×100}. Calculation of IC using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4 parameter nonlinear logic formula 50 Values.
Conclusion of experiment:
the activity test data for inhibition of the JAK2 signaling pathway of the compounds of the present invention in cells obtained by the above protocol are shown in the following table:
conclusion of experiment: from the data in the table, the selectivity of the compounds of the examples for JAK2 cell activity compared to TYK2 cell activity is higher.
Test example 3 plasma protein binding Rate test in mice
1. Study purposes:
the purpose of this experiment was to evaluate the protein binding rate of example 58, example 88 and example 92 (5. Mu.M) in mouse plasma using equilibrium dialysis.
2. Compound and experimental materials:
1) Preparing a test compound into a 10mM stock solution by using DMSO, and preserving the stock solution in a refrigerator at the temperature of-20 ℃ for later use;
2) Frozen plasma of the desired species, dialysate (100 mM phosphate buffer (Lot#SLBS7904 and Lot#SLBR3106V), pH 7.4).
3. Experimental instrument
96-well plate (Lot# 07917415), detection membrane device (Lot#SD 2369421), liquid chromatography tandem mass spectrometer (LC-MS/MS) (LC-20 AD, API 4000), centrifuge (Eppendorf 5804R/5424R), vortex meter (IKA VORTEX GENIUS 3), pipette (Eppendorf 10-100. Mu.L (PIP-100-002), eppendorf 100-1000. Mu.L (PIP-1000-002), RAININ 0.5-10. Mu.L (PIP-10-002), water bath (Shanghai Henggaku).
4. Experimental procedure
4.1 preparation of dialysate
1M of K2HPO4 (AR grade) 4.01mL and 1M of KH2PO4 (AR grade) 0.99mL were diluted with ultrapure water to 50mL, and 100mM phosphate buffer (pH=7.4) was prepared as a dialysate.
4.2 preparation of plasma
Thawing the frozen plasma in a water bath at room temperature or 37deg.C, centrifuging at 3500rpm for 5min, and collecting supernatant.
4.3 preparation of reaction termination solution
Acetonitrile (or other suitable solution) containing an internal standard is used as a stop solution, stored in a refrigerator at a temperature of 2-8 ℃, and the specific concentration of the internal standard is reported finally.
4.4 preparing working solution of Compound
Working solution preparation of the compound: stock was diluted with DMSO to a final concentration of 1mM.
4.5 preparation of plasma solutions
4 mu L of compound working solution is added into 796 mu L of blank plasma, the final concentration is 5 mu M, and the mixture is mixed by shaking.
4.6 Balanced dialysis
1) Preparing a balance dialysis device, and placing the detection membrane device into a balance dialysis 96-well plate;
2) Adding 200 μl of the prepared plasma solution into the membrane, n=2;
3) Diluting 4 μl of the plasma solution with 36 μl of blank plasma of the same species for 10 times, adding 160 μl of acetonitrile stop solution containing internal standard, and storing in-20deg.C refrigerator to obtain T0 (Total) sample;
4) Adding 350. Mu.L of dialysis fluid (100 mM phosphate buffer) outside the membrane;
5) Sealing the dialysis plate, and incubating in a water bath at 37deg.C for 6 hr;
6) After dialysis, 4. Mu.L of the sample is taken out from the sample hole in the membrane and diluted 10 times by 36. Mu.L of blank plasma of the same species; taking 40 mu L of dialyzate from the sample hole outside the membrane, and adding 160 mu L of acetonitrile stop solution with an internal standard to obtain a T6 (Total) sample and an F6 (Total) sample;
7) Centrifuging the T0 (Total) and T6 (Total) samples, and taking supernatant;
8) LC-MS analysis.
5. Experimental results
Test example 4, balb/C mouse pharmacokinetic assay
1. Study purposes:
the pharmacokinetic behavior of the compounds example 58, example 88 and example 92 in plasma in mice were studied orally at a dose of 5mg/kg in Balb/C mice as test animals.
2. Test protocol
2.1 test drug:
inventive examples 58, 88 and 92 were self-made.
2.2 test animals:
Balb/C Mouse 18 (6/example), male, shanghai Jieshijie laboratory animal Co., ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.3 administration:
18 Balb/C mice, male; after one night of fasting, the dosages were 5mg/kg, respectively, and the dosing volumes were 10mL/kg.
2.4 sample collection:
Mice were bled with 0.1mL of orbital blood at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, and placed in EDTA-K before and after dosing 2 In a test tube, plasma was separated by centrifugation at 6000rpm at 4℃for 6min and stored at-80 ℃.
2.5 sample treatment:
1) The plasma sample 40uL was precipitated by adding 160uL acetonitrile, and centrifuged at 3500 Xg for 5-20 minutes after mixing.
2) The concentration of the test compound was analyzed by LC/MS/MS by taking 100uL of the supernatant solution after the treatment.
2.6 liquid phase analysis
Liquid phase conditions: shimadzu LC-20AD pump
Mass spectrometry conditions AB Sciex API 4000 Mass spectrometer
Chromatographic column: phenomenex Gemiu 5um C18.times.4.6 mm
Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
Flow rate: 0.8mL/min
Elution time: 0-4.0 minutes, the eluent is as follows:
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 6.1 and the results of the mouse drug substitution experiments are shown in the following table:
compounds of formula (I) t max (h) C max (ng/mL) AUC 0-t (ng/mL*h) AUC 0-∞ (ng/mL*h) t 1/2 (h) MRT 0-∞ (h)
BMS-986165 1.0 696 1987 2038 1.4 2.3
Example 53 0.5 2043 6250 6348 1.3 2.3
Example 58 0.5 3930 13590 14473 1.9 3.0
Example 88 1.0 2190 20991 21001 2.1 5.6
Example 92 1.0 939 2466 2637 2.0 2.8
Example 118 0.5 1927 3391 3719 2.7 2.5
Conclusion of experiment: as can be seen from the data in the table, the drug substitution exposure AUC of the example compounds in mice 0-t (ng/mL h) is superior to reference compound BMS-986165, in particular example 58 and example 88, and drug exposure is far superior to reference compound BMS-986165, preferably 6-fold and more than 10-fold.
Test example 5 determination of the efficacy of the Compounds of the invention in the mode of imiquimod-induced psoriasis in mice
1. The purpose of the experiment is as follows:
the compounds were evaluated for their efficacy in imiquimod-induced murine psoriasis pattern.
2. Experimental main instrument and reagent
2.1 instruments
Instrument and device name Model number Manufacturer' s
Electronic balance SQP SECURA225D-1CN Sartorius
Electronic balance MP5002 type Shunhai Shunfu
2.2 reagents
3. Experimental procedure
3.1 moulding
Day 0 shaves the animal back test site. Day 1 to Day 6 were applied with 62.5mg imiquimod once daily to the animal back test site.
3.2 administration of drugs
Day 1 to Day 7 were dosed separately to each group of animals according to the protocol, and the model experimental design for imiquimod-induced psoriasis in mice is shown in the following table:
3.3 dermatitis skin injury severity index score
Day 1 to Day 7 score redness, scaling and thickening of the back test part of the animal according to 0 to 4 points respectively. 0, no damage; 1, slightly; 2, moderate; 3, obvious; 4, very obvious.
The total score indicates the severity of the injury
4. Test data
4.1 comparison of PASI scores for different compounds in imiquimod-induced mice model of psoriasis the following table:
4.2 PASI scoring results for different compounds in imiquimod-induced murine psoriasis model are shown in fig. 1, where data points represent the mean of the PASI scores in the group, n=8, p <0.001 using One-way ANOVA compared to Vehicle group.
5. Experimental results
From the above results, it can be seen that examples 58, 88 and 92 of this patent are effective in ameliorating psoriasis symptoms in imiquimod-induced mice psoriasis-like models, with very significant differences compared to the veccle group, P <0.001, superior to the reference compound BMS-986165 (P < 0.01).

Claims (14)

1. A compound represented by the general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
wherein:
r is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR aa 、-SR aa 、-C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb ；
R 1 Selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa 、-(CH 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-NR aa CR bb ＝NR cc 、-NR aa CR bb ＝CR cc R dd 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa C(O)C(O)R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 3 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, alkenyl or alkynyl;
R 4 、R 5 、R 6 selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclylAryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb ；
Alternatively, R 4 And R is 6 Linking to form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl group is optionally further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R aa 、R bb 、R cc and R is dd Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
Or, any two adjacent or non-adjacent R aa 、R bb 、R cc And R is dd Linking to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally furtherSubstituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
x is 0, 1, 2 or 3;
m1 is 0, 1 or 2; and is also provided with
n1 is 0, 1, 2, 3, 4 or 5.
2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the formula (III) being further represented by formula (V):
wherein:
R 9 selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb Wherein said alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R、R 3 ～R 6 、R aa 、R bb And x is as claimed in claim 1.
3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, wherein the
R 9 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 Haloalkyl, hydroxy, amino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, amino, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl or 3-6 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-SR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-S(O) m1 R aa 、-NR aa R bb 、-C(O)NR aa R bb 、-NR aa C(O)R bb or-NR aa S(O) m1 R bb More preferably hydrogen, deuterium, hydroxy substituted C 1-3 Alkyl, C 1-3 Cycloalkyl-substituted C 1-3 Alkyl, hydroxy substituted C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, C 3-6 Cycloalkyl-substituted amino, halogen-substituted C 2-5 Alkenyl, halogen substituted C 2-5 Alkynyl, halogen substituted C 3-6 Cycloalkyl, C 1-3 Alkyl substituted C 3-6 Cycloalkyl, cyano-substituted C 3-6 Cycloalkyl, C 1-3 Alkoxy substituted C 3-6 Cycloalkyl, C 1-3 Haloalkyl substituted C 3-6 Cycloalkyl, 3-7 membered heterocyclic groups containing 1-3N, O or S atoms, phenyl, naphthyl or 3-7 membered heteroaryl groups containing 1-3N, O or S atoms, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)R aa or-NR aa R bb More preferably
R aa Or R is bb Independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, halogen, cyano, nitro, C 1-6 Haloalkyl, hydroxy, amino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-12 Aryl or 3-7 membered heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Haloalkyl, hydroxy, amino, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or 3-6 membered heteroaryl containing 1 to 3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluoro, chloro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;
m1 is 0, 1, 2 or 3;
n1 is 0, 1, 2 or 3.
4. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the formula (III) being further represented by formula (VIII):
wherein:
R 3 ～R 6 and x is as claimed in claim 1.
5. The compound of claim 4, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt of a compound of formula (i)
R 3 Selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
R 4 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, optionally substituted with one or more substituents further selected from methyl, ethyl, fluoro or chloro; preferably C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclyl, more preferably C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-5 membered heterocyclic group containing 1 to 3N, O or S atoms, further preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl,
R 5 Or R is 6 Each independently hydrogen or deuterium;
x is 0, 1, 2 or 3.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5,
r is selected from hydrogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR aa 、-SR aa or-NR aa R bb ；
R 1 Selected from 3-8 membered heterocyclic groups5-8 membered heteroaryl, - (CH) 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(＝S)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa C(O)OR bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 NR aa C(O)C(O)R aa 、-NR aa CR bb ＝NR cc or-NR aa CR bb ＝CR cc R dd Wherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano, oxo and C 3-8 One or more substituents in cycloalkyl are substituted;
R 2 selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -C (O) R aa 、-(CH 2 ) n1 OR aa 、-C(O)NR aa R bb or-S (O) m1 NR aa R bb Wherein said 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano and C 3-8 One or more substituents in cycloalkyl are substituted;
R 3 selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 5 selected from hydrogen, halogen, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 4 and R is 6 Each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or- (CH) 2 ) n1 R aa The method comprises the steps of carrying out a first treatment on the surface of the Preferably hydrogen, cyclopropyl orOr R is 4 And R is 6 Link formationC (C) 3-8 Cycloalkyl, preferably cyclopentyl;
R 9 selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 C(O)R aa 、-C(O)OR aa 、-NR aa R bb or-C (O) NR aa R bb Wherein said C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl and 5-8 membered heteroaryl;
R aa 、R bb 、R cc And R is dd Each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, hydroxy, amino, oxo, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl and 5-8 membered heteroaryl;
alternatively, R cc And R is dd Linking to form a C 3-8 Cycloalkyl, wherein said C 3-8 Cycloalkyl is optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, amino, oxygenSubstituents, cyano, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 One or more substituents in the hydroxyalkyl group are substituted.
7. The compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the general formula (III) is selected from the group consisting of:
8. a compound of formula (XI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Wherein:
R 18 selected from hydrogen, deuterium, halogen, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl or- (CH) 2 ) n1 R aa Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or- (CH) 2 ) n1 R aa More preferably hydrogen, methyl, cyclopropyl,
R 19 Selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, amino, hydroxy or cyano, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, fluoro, chloro, bromo, amino, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro, hydroxy or cyano;
R aa selected from hydrogen, deuterium, cyano, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, fluoro, chloro, bromo, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl or C 3-6 Cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl；
n1 is 0, 1 or 2;
r is 0, 1, 2 or 3.
9. The compound of formula (XI), its stereoisomers or a pharmaceutically acceptable salt thereof according to claim 8, selected from the group consisting of:
10. a process for producing a compound represented by the general formula (V) as claimed in claim 2 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
reacting the general formula (V-1) with the general formula (V-2) to obtain the general formula (V-3), and further reacting the general formula (V-3) to obtain a compound shown in the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;
wherein:
x is selected from halogen;
R 3 ～R 6 、R 9 and x is as claimed in claim 2.
11. A process for producing a compound represented by the general formula (V) as claimed in claim 2 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
reacting the general formula (V-4) with the general formula (V-5) to obtain the general formula (V-6), and further reacting the general formula (V-6) with the general formula (V-2) to obtain a compound shown as the general formula (V) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;
wherein:
x is selected from halogen;
R 3 ～R 6 、R 9 and x is as claimed in claim 2.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound as set forth in any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
13. Use of a compound according to any one of claims 1 to 9, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of a TYK2 inhibitor drug.
14. Use of a compound according to any one of claims 1 to 9, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of a medicament for the treatment of inflammatory and autoimmune diseases; wherein the inflammatory and autoimmune disease is selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.
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