CN111484480A - Polycyclic derivative inhibitor, preparation method and application thereof - Google Patents

Polycyclic derivative inhibitor, preparation method and application thereof Download PDF

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CN111484480A
CN111484480A CN202010070932.9A CN202010070932A CN111484480A CN 111484480 A CN111484480 A CN 111484480A CN 202010070932 A CN202010070932 A CN 202010070932A CN 111484480 A CN111484480 A CN 111484480A
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amino
cycloalkyl
aryl
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CN111484480B (en
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高鹏
曾蜜
王少宝
修文华
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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Abstract

The invention relates to a polycyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula, a preparation method thereof, a pharmaceutical composition containing the compound, and a method for mediating signal transduction and activation of various cytokines by using the compound as an intracellular non-receptor tyrosine kinase; especially plays a key role in the biological processes of immune regulation, immune cell proliferation and the like, and is closely related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel diseases (ulcerative colitis, Crohn's disease) and the likeIn the following general formula (I), the substituents are as defined in the specification.

Description

Polycyclic derivative inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a polycyclic derivative inhibitor, and a preparation method and application thereof.
Background
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the 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 pathways, JAK-1, JAK-2 and TYK-2 are expressed in each tissue cell of a human body, and JAK-3 is mainly expressed in each hematopoietic tissue cell. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cell factor receptor is combined with a ligand thereof, JAKs coupled with the receptor are activated, so that the receptor is phosphorylated, a phosphorylated tyrosine site can be combined with STAT protein containing an SH2 structural domain, STAT is recruited to the receptor and is phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred to a cell nucleus and activates target gene transcription of the cell nucleus, so that multiple functions of growth, activation, differentiation and the like of multiple cells are regulated.
TYK2 is a subtype discovered in the JAK family at the earliest, mediates the functions of cytokines such as IFN- α, I L-6, I L0-10, I L1-12 and I L-23, and research shows that deletion mutation of TYK2 can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity and inflammation, I L-23 plays a crucial role in the occurrence and development processes of psoriasis, and recent research shows that the pathogenesis of psoriasis is that endogenous antigen activating antigen presenting cells APC secrete I L-23, I L-23 activate Th17 cells and secrete cytokines such as I L-17, the differentiation and division of keratinocytes and the secretion of I L-23 are induced, further inflammation and proliferation of keratinocytes are stimulated to generate psoriasis.TYK 2 and JAK2 jointly mediate downstream signal channels of I L-23, and inhibition of JAK2 can cause anemia and other blood-related side effects, so that TYK2 is a good target for inhibiting signal channels of I L-23.
Early TYK2 inhibitors such as Tofacitinib belong to JAK non-selective inhibitors, are the first oral JAK inhibitors, and have obvious inhibitory activity on JAK1, 2 and 3 subtypes. The activity inhibition of other subtypes such as JAK1, JAK2 and JAK3 increases the curative effect of tofacitinib, but also brings more serious side effects, and adverse reactions comprise infection, tuberculosis, tumor, anemia, liver injury, cholesterol increase and the like. Because the activity of JAK2 is related to erythroid cell differentiation and lipid metabolism processes, part of adverse reactions such as anemia are considered to be possibly related to insufficient selectivity of Tofacitinib on JAK-2, and are caused by non-selective inhibition of the medicine. At present, no TYK2 selective inhibitor is on the market, and the early JAK inhibitor mainly plays a role by competing the binding of a kinase domain and ATP, so that the problem of low selectivity generally exists.
The compound is intermediate between the good curative effect of the JAK non-selective inhibitor and the relevant serious side effect of various targets, and the development of a TYK2 selective inhibitor medicament with higher safety has huge clinical application potential for treating inflammatory diseases such as psoriasis and the like. BMS international applications WO2015069310A1 and WO2018081488A1 report TYK2 selective inhibitors, and developed BMS-986165 achieves good curative effect in the second clinical stage at present and enters the third clinical stage, so that the advantages of the TYK2 selective inhibitors are reflected, and the TYK2 selective inhibitors have great clinical application values.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure BDA0002377299080000021
wherein:
l is a bond or NRaa；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R2selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group or a cycloalkyl group;
Raa、Rbband RccThe same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, 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; and is
x is an integer of 0, 1,2, 3 or 4.
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (II), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002377299080000031
wherein:
ring a is selected from monocyclic aryl, monocyclic heteroaryl, or a bicyclic ring which is aryloaryl, heteroaryloaryl, aryloaterocyclyl, heterocycloaryl, heterocycloateroaryl, and heteroaryloaryl;
R3one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, mercapto group, nitro group, hydroxyl group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; and is
y is an integer of 0, 1,2, 3 or 4.
The invention also provides a preferable scheme, the compound shown in the general formula (I) and the general formula (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, and the preferable scheme is characterized in that:
ring a is selected from the following groups:
Figure BDA0002377299080000032
the present invention also provides a preferable embodiment, a compound represented by the general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002377299080000041
wherein:
q is a bond or NRaa；
Ring B is selected from the group consisting of a bicyclic ring, said bicyclic ring being an aryloaryl, aryloateroaryl, heteroaryloateroaryl, aryloateroheterocyclyl, heterocycloaryl, heterocycloateroaryl, and heteroaryloaryl;
R4selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, alkyl halideOptionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Raa、Rbband RccThe same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl groupWherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, 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;
q is an integer of 0, 1,2, 3 or 4; and is
z is an integer of 0, 1,2, 3 or 4.
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in a general formula (IV), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002377299080000051
wherein:
R6selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group or a cycloalkyl group;
R7selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is an integer of 0, 1,2, 3 or 4;
ring B, R4、q、Raa、RbbAnd RccAs described in general formula (III).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof is a compound shown in the general formula (V), the stereoisomer or the pharmaceutically acceptable salt thereof:
Figure BDA0002377299080000061
wherein:
R8selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R9selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
r is an integer of 0, 1,2, 3 or 4;
ring B, R4、q、Raa、RbbAnd RccAs described in general formula (III).
The present invention also provides a preferable embodiment, a compound represented by the general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002377299080000062
wherein:
ring C is selected from bicyclic;
R10selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R11selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, 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, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thioxo, and heteroarylNitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R12selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group or a cycloalkyl group;
Raa、Rbband RccThe same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, 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;
s is an integer of 0, 1,2, 3 or 4; and is
t is an integer of 0, 1,2, 3 or 4.
The invention also provides a preferable scheme, the compound shown in the general formula (III) and the general formula (IV), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, and the preferable scheme is characterized in that:
ring B is selected from the following groups:
Figure BDA0002377299080000071
Figure BDA0002377299080000081
the invention also provides a preferable scheme, the compound shown in the general formula (VI), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is characterized in that:
ring B is selected from the following groups:
Figure BDA0002377299080000082
the present invention also provides a preferred embodiment, wherein the general formula (III) is further represented by the general formula (VII):
Figure BDA0002377299080000083
wherein:
ring D is selected from phenyl, 5-6 membered heterocyclic group containing 1-2N or O atoms or 5-6 membered heteroaryl group containing 1-2N or O atoms;
preference is given to
Figure BDA0002377299080000091
M1、M2、M3、M4And M5Each independently selected from O, N, C (O), CR13、CR13R14Or NR15，
R13And R14Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl radicalsOr 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
R15selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
more preferably
Figure BDA0002377299080000101
R16Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)ORa、-(CH2)n2C(O)NRaRb、-(CH2)n2S(O)m2RaOr- (CH)2)n2NRaS(O)m2Rb(ii) a Preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)NRaRbOr- (CH)2)n2S(O)m2Ra(ii) a More preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl, 5-10 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)NRaRbOr- (CH)2)n2S(O)m2Ra(ii) a Further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl, naphthyl or-NHCH3；
RaAnd RbEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, 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;
m is an integer of 0 to 3;
m2 is an integer of 0-2; and is
n2 is an integer from 0 to 3.
The present invention also provides a preferred embodiment, wherein the general formula (III) is further represented by the general formula (VIII):
Figure BDA0002377299080000111
wherein:
ring E is selected from a 5-6 membered heterocyclic group containing 1-2N or O atoms;
preference is given to
Figure BDA0002377299080000112
M6And M7Each independently selected from N or CR17，
R17Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxygenA substituent, thio group, methyl group, ethyl group, propyl group, vinyl group, propenyl group, allyl group, ethynyl group, propynyl group, propargyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, fluoromethyl group, fluoroethyl group, fluoropropyl group, chloromethyl group, chloroethyl group, chloropropyl group, bromomethyl group, bromoethyl group, bromopropyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoromethoxy group, chloroethoxy group, chloropropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, glycidyl group, epoxybutyl group, epoxypentyl group, epoxyhexyl group, epoxyheptyl group, aziridinyl group, azetidinyl group, azacyclohexyl group, azepinyl group, thienyl group, pyrrolyl group, pyridyl group, pyranyl group, piperazinyl group, phenyl group or naphthyl group;
more preferably
Figure BDA0002377299080000121
R18Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Alkyl halidesOxy radical, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl; and is
n is an integer of 0 to 3.
The present invention also provides a preferable embodiment, a method for preparing the compound represented by the general formula (VII) or the stereoisomer and the pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
Figure BDA0002377299080000122
reacting the general formula (VII-1) with the general formula (VII-2) to obtain a compound shown as the general formula (VII) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
X1selected from halogens.
The present invention also provides a preferable embodiment, a method for preparing the compound represented by the general formula (VIII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
Figure BDA0002377299080000131
the general formula (VII-1) reacts with the general formula (VIII-1) to obtain a general formula (VIII-2), and the general formula (VIII-2) further reacts to obtain a compound shown as the general formula (VIII) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
X2selected from halogens;
X3selected from halogens.
The invention also relates to a technical scheme, a pharmaceutical composition, which comprises a therapeutically effective dose of any one of the compounds shown in the general formulas (I) to (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also relates to a technical scheme, and the compounds shown in the general formulas (I) to (IV), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the application of the pharmaceutical composition in the preparation of TYK2 inhibitor drugs.
The invention also relates to a technical scheme, and the compounds shown in the general formulas (I) to (IV) and stereoisomers or pharmaceutically acceptable salts thereof, or the application of the pharmaceutical composition in preparing medicines for treating inflammatory diseases and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
The invention further relates to a method for preparing compounds shown in general formulas (I) to (IV), stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for treating inflammatory diseases.
The invention also relates to a method for treating, preventing and/or treating autoimmune diseases, which comprises the step of administering a therapeutically effective dose of the compounds shown in the general formulas (I) to (IV) or the stereoisomers or the pharmaceutically acceptable salts thereof or the pharmaceutical composition thereof to a patient.
The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with TYK2 kinase dysfunction.
The present invention also relates to a method of treating a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the methods relate to the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and cardiac disease.
In some embodiments, the present methods relate to the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and crohn's disease).
The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention provides a method of treating an inflammatory disorder, including an autoimmune disease, in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
Detailed description of the invention
Unless stated to the contrary, 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 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 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-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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "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, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group 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 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0002377299080000151
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure BDA0002377299080000152
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with 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 completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0002377299080000153
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0002377299080000161
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, 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, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms 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) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 3 to 20 membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably a 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0002377299080000171
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 other rings in the system, one or more rings 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 is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-to 5-membered, 4-to 5-membered or 5-to 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0002377299080000172
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 have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0002377299080000181
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0002377299080000182
and the like.
The heterocyclyl group 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, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share 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, non-limiting examples of which include:
Figure BDA0002377299080000183
the aryl group may be 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, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 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 joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0002377299080000191
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, hydroxyl, 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, cyclopentyloxy, cyclohexyloxy. 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, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein 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, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"L iHMDS" refers to lithium bistrimethylsilyl amide.
"Me L i" refers to methyllithium.
"n-Bu L i" refers to n-butyllithium.
“NaBH(OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "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" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"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" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, 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 the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (L C-MS). NMR chemical shifts () are given in parts per million (ppm). NMR is measured using a Bruker AVANCE-400 nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d) as the solvent6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
Determination of LC-MS L C-MS by Agilent 1200Infinity Series Mass spectrometer HP L C was determined using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 ×.6mm column) and Waters 2695-.
The thin-layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, T L C adopts the specification of 0.15 mm-0.20 mm, the thin-layer chromatography separation and purification product adopts the specification of 0.4 mm-0.5 mm, and the column chromatography generally adopts the tobacco yellow sea silica gel 200-300 meshes 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 present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
6- (Cyclopropanecarbonyl)Amine) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000221
The first step is as follows: preparation of 4-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine
Figure BDA0002377299080000222
5-bromo-4-methoxypyridin-3-amine (2.02g,10mmol), bis-pinacolylboron (3.05g,12mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (816.6mg,1mmol), potassium acetate (2.45g,25mmol) were mixed in dioxane (20m L), the reaction system was replaced with nitrogen three times, reacted at 100 ℃ overnight, cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 4-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine (2.1g, 85%).
MS m/z(ESI):251.1[M+H]+.
The second step is that: preparation of 4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine
Figure BDA0002377299080000223
4-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine (2.0g,8mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61g,10mmol), Cs2CO3(7.6g,20mmol) and tetrakis (triphenylphosphine) palladium (925mg,0.8mmol) were mixed in 1, 4-dioxane (40m L) and water (5m L), the reaction system was replaced with nitrogen three times, the mixture was reacted at 100 ℃ overnight, the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2Separating, separatingThe organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine (1.0g, 61%).
MS m/z(ESI):206.1[M+H]+.
The third step: preparation of lithium 4, 6-dichloropyridazine-3-carboxylate
Figure BDA0002377299080000231
Methyl 4, 6-dichloropyridazine-3-carboxylate (2.07g,10mmol), lithium bromide (2.6g,30mmol) were dissolved in acetonitrile (20m L) and water (2m L), cooled to 0 ℃, DIPEA (5.2m L, 30mmol) was added dropwise, the reaction mixture was allowed to naturally rise to room temperature and reacted for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2m L× 4), the filter cake was collected and dried to give the title compound, lithium 4, 6-dichloropyridazine-3-carboxylate (1.73g, 87%).
MS m/z(ESI):193.1[M+H]+.
The fourth step: preparation of ((6-chloro-4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) oxo) zinc
Figure BDA0002377299080000232
4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine (1.0g,5.0mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (1.19g,6.0mmol) and zinc acetate (1.1g,6.0mmol) were mixed in isopropanol (1m L) and water (7m L) and reacted overnight at 65 ℃.
MS m/z(ESI):362.1[M+H]+.
The fifth step: preparation of (6- (cyclopropylcarboxamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) zinc
Figure BDA0002377299080000233
((6-chloro-4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) oxo) Zinc (157mg,0.4mmol), Cyclopropanecarboxamide (85mg,1.0mmol), DBU (61mg,0.4mmol), Potassium carbonate (110mg,0.8mmol) was mixed in toluene (1.2m L) and acetonitrile (0.6m L) and Palladium acetate (4.5mg,0.02mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added]Ethyl di-tert-butylphosphine (22mg,0.04mmol), reaction three times with nitrogen substitution, reaction at 75 ℃ overnight, cooling to room temperature, addition of water (4m L) and acetic acid (2m L), washing with petroleum ether (6m L× 2), separation of the aqueous phase, addition of water (2m L), CH2Cl2(5m L× 3) and the organic phases were combined and washed with saturated aqueous NaCl solution, the separated organic phase was dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure to give the title compound (6- (cyclopropylcarboxamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) zinc (99mg, 56%).
MS m/z(ESI):411.2[M+H]+.
And a sixth step: preparation of 6- (cyclopropylcarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Figure BDA0002377299080000241
(6- (Cyclopropanecarboxamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) Zinc (88mg,0.2mmol), deuterated methylamine hydrochloride (71mg,1.0mmol), DIPEA (258mg,2.0mmol) mixed in DMF (1m L), HATU (380mg,1.0mmol) added, reaction overnight at 40 ℃ reaction cooled to room temperature, reaction cooled to room temperature with saturated aqueous sodium bicarbonate solution and CH2Cl2Separating the solution, washing the organic phase with saturated aqueous NaCl solution, drying with anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure, and performing column chromatography to obtain the title compound 6- (cyclopropylcarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazole-3-Yl) pyridin-3-yl) amino) -N- (methyl-d3) Pyridazine-3-carboxamide (44mg, 52%).
MS m/z(ESI):427.2[M+H]+.
Example 2
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-4-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000251
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-4-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):427.2[M+H]+.
Example 3
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000252
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):427.2[M+H]+.
Example 4
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000253
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) amino) -N- (methyl-d3) Reference for preparation of pyridazine-3-carboxamideExample 1.
MS m/z(ESI):432.2[M+H]+.
Example 5
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000261
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):432.2[M+H]+.
Example 6
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-5-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000262
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-5-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):433.2[M+H]+.
Example 7
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000263
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):433.2[M+H]+.
Example 8
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) naphthalen-2-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000271
6- (Cyclopropanecarboxamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) naphthalen-2-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):476.2[M+H]+.
Example 9
6- (Cyclopropanecarboxamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-6-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000272
6- (Cyclopropanecarboxamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-6-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H]+.
Example 10
6- (Cyclopropanecarboxamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzo [ b]Thien-6-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000281
6- (Cyclopropanecarboxamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzo [ b]Thien-6-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):482.2[M+H]+.
Example 11
6- (Cyclopropanecarboxamide) -4- ((6-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-7-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000282
6- (Cyclopropanecarboxamide) -4- ((6-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-7-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H]+.
Example 12
6- (Cyclopropanecarboxamide) -4- ((6-methoxy-7- (1-methyl-1H-1, 2, 4-triazol-3-yl) indolizin-5-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000291
6- (Cyclopropanecarboxamide) -4- ((6-methoxy-7- (1-methyl-1H-1, 2, 4-triazol-3-yl) indolizin-5-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H]+.
Example 13
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000292
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):386.2[M+H]+.
Example 14
6-(Cyclopropanecarboxamide) -4- ((5-methoxy-1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-4-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000293
6- (Cyclopropanecarboxamide) -4- ((5-methoxy-1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-4-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):416.2[M+H]+.
Example 15
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-1-methyl-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000301
6- (Cyclopropanecarboxamide) -4- ((4-methoxy-1-methyl-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):430.2[M+H]+.
Example 16
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000302
The first step is as follows: preparation of ethyl 2- (bromomethyl) -4, 6-dichloronicotinate
Figure BDA0002377299080000303
Add to CCl of Ethyl 4, 6-dichloro-2-methyl nicotinate (2.00g,8.54mmol)4NBS (1.67g,9.40mmol), AIBN (140mg, 0.854mmol) were added to the solution (40m L) in this order, followed by stirring overnight at 92 deg.C, cooling the reaction to room temperature, and concentrating the organic solvent under reduced pressure to give the crude product which was used directly in the next step.
MS m/z(ESI):311.9[M+H]+.
The second step is that: preparation of 2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Figure BDA0002377299080000304
To an acetonitrile solution (30m L) of ethyl 2- (bromomethyl) -4, 6-dichloronicotinate (crude product in the previous step) were added deuterated methylamine hydrochloride (394mg, 5.58mmol) and DIPEA (6.60m L, 40mmol) in this order, followed by stirring at room temperature for 2 hours, concentration of the organic solvent under reduced pressure, and column chromatography to give the title compound 2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one (400mg, two-step yield: 23%).
MS m/z(ESI):220.0[M+H]+.
The third step: preparation of N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000311
2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3, 4-b)]Pyridin-5-one (100mg, 0.454mmol), Cyclopropanecarboxamide (36mg, 0.410mmol) and potassium carbonate (188mg, 1.36mmol) were mixed in 1, 4-dioxane (4m L), bubbled with nitrogen for 5 minutes, then Pd was added successively2(dba)3(41mg,0.0454mmol) and Xantphos (52mg, 0.0908mmol), stirring at 90 ℃ for 2 hours under microwave, cooling the reaction mixture to room temperature, concentrating the organic solvent under reduced pressure and then subjecting to column chromatography to give the title compound N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] -pyrrolo [3]Pyridin-2-yl) cyclopropanecarboxamide (20mg, 16%).
MS m/z(ESI):269.1[M+H]+.
The fourth step: preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000312
N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3, 4-b)]Pyridin-2-yl) Cyclopropanecarboxamide (20mg, 0.074mmol), 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (17mg, 0.082mmol) and potassium carbonate (31mg, 0.223mmol) were mixed in 1, 4-dioxane (3m L), nitrogen bubbled for 5 minutes, then Pd was added successively2(dba)3(20mg,0.0223mmol) and Xantphos (28mg, 0.0446mmol), stirring at 95 ℃ for 2 hours under microwave, cooling the reaction to room temperature, concentrating the organic solvent under reduced pressure and purifying by preparative thin layer separation to give the title compound N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] p]Pyridin-2-yl) cyclopropanecarboxamide (13mg, 29%).
1H NMR(400MHz,CD3OD)0.83-0.91(m,4H),1.74-1.83(m,1H),3.66(s,3H),4.01(s,3H),4.33(s,2H),7.18-7.20(m,1H),7.52(dd,J＝8.0,3.2Hz,1H),7.78(s,1H),8.07(d,J＝8.0Hz,1H),8.47(s,1H)；
MS m/z(ESI):437.2[M+H]+.
Example 17
Preparation of N- (5- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazin-7-yl) cyclopropanecarboxamide
Figure BDA0002377299080000321
Preparation of N- (5- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazin-7-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):484.2[M+H]+.
Example 18
Preparation of N- (7- ((2-hydroxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide
Figure BDA0002377299080000322
Preparation of N- (7- ((2-hydroxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):408.2[M+H]+.
Example 19
Preparation of N- (7- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide
Figure BDA0002377299080000331
Preparation of N- (7- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):470.2[M+H]+.
Example 20
Preparation of N- (4- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000332
Preparation of N- (4- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):453.2[M+H]+.
Example 21
Preparation of N- (3-methyl-4- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000333
Preparation of N- (3-methyl-4- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):467.2[M+H]+.
Example 22
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000341
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):420.2[M+H]+.
Example 23
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000342
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):434.2[M+H]+.
Example 24
Preparation of 2-cyclopropyl-7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-3H-imidazo [4,5-b ] pyridine-6-carboxamide
Figure BDA0002377299080000343
The first step is as follows: preparation of 2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
Figure BDA0002377299080000351
3-bromo-2-methoxyaniline (2.02g,10mmol), bis-pinacolylboron (3.05g,12mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (816.6mg,1mmol), potassium acetate (2.45g,25mmol) were mixed in dioxane (20m L), the reaction system was replaced with nitrogen three times, reacted at 100 ℃ overnight, cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0g, 80%).
1H NMR(400MHz,CDCl3)1.36(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]+.
The second step is that: preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
Figure BDA0002377299080000352
2-methoxy-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0g,8mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61g,10mmol), Cs2CO3(7.6g,20mmol) and tetrakis (triphenylphosphine) palladium (924.5mg,0.8mmol) were mixed with 1, 4-dioxane (40m L) and water (5m L), the reaction system was replaced with nitrogen three times, the mixture was reacted at 100 ℃ overnight, the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2Separating the liquid, separating the organic phase and washing with saturated aqueous sodium chloride solutionThe organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.14g, 70%).
1H NMR(400MHz,CDCl3)3.77(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]+.
The third step: preparation of 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-nitropyridine-2, 4-diamine
Figure BDA0002377299080000361
2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.0g,4.9mmol), 5-bromo-4-chloro-3-nitropyridin-2-amine (3.71g,14.7mmol), N, N-diisopropylethylamine (2.26g,19.6mmol) was dissolved in DMF (10m L), heated to 125 ℃ by microwave, reacted for 2 hours, cooled to room temperature, the reaction was concentrated under reduced pressure, the residue was taken up with water and CH2Cl2The organic phase was dried over anhydrous sodium sulfate, collected by filtration, concentrated under reduced pressure and subjected to column chromatography to give the title compound 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-nitropyridine-2, 4-diamine (1.1g, yield 53%).
MS m/z(ESI):420.1[M+H]+.
The fourth step: preparation of 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridine-2, 3, 4-triamine
Figure BDA0002377299080000362
5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-nitropyridine-2, 4-diamine (480mg,1.14mmol), iron powder (638mg,11.42mmol), ammonium chloride (122mg,2.28mmol) were dissolved in ethanol (10m L) and water (2m L), the oil bath was heated to 85 ℃ for reaction for 6 hours, the reaction solution was cooled to room temperature, and after filtering the reaction solution, the filtrate was concentrated under reduced pressure and column chromatography was performed to isolate the title compound 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridine-2, 3, 4-triamine (395mg, yield 89%).
MS m/z(ESI):390.1[M+H]+.
The fifth step: preparation of 6-bromo-2-cyclopropyl-N- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3H-imidazo [4,5-b ] pyridin-7-amine
Figure BDA0002377299080000363
5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridine-2, 3, 4-triamine (395mg,1.01mmol), ethylcyclopropanecarboximidic acid (454mg,3.04mmol) were dissolved in methanol (5m L) and glacial acetic acid (1m L), heated to 70 ℃ by microwave for 1 hour, heated to 130 ℃ by microwave for 3 hours, cooled to room temperature, concentrated under reduced pressure, washed with water and CH to give a residue, and concentrated under reduced pressure2Cl2Separating, separating organic phase, washing with saturated aqueous solution of sodium chloride, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain the title compound 6-bromo-2-cyclopropyl-N- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3H-imidazo [4,5-b]Pyridin-7-amine (130mg, 29%).
MS m/z(ESI):440.2[M+H]+.
And a sixth step: preparation of tert-butyl 6-bromo-7- ((tert-butoxycarbonyl) (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-cyclopropyl-3H-imidazo [4,5-b ] pyridine-3-carboxylate
Figure BDA0002377299080000371
6-bromo-2-cyclopropyl-N- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3H-imidazo [4,5-b]Pyridin-7-amine (130mg,0.3 mmol L) was dissolved in tetrahydrofuran, di-tert-butyl dicarbonate (193mg,0.89mmol), 4-dimethylaminopyridine (11mg,0.088mmol) were added, the mixture was heated to 70 ℃ to react for 5 hours, cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was washed with water and CH2Cl2Separating liquid and organic matterAnd the combined phases were washed with a saturated aqueous solution of sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure after filtration, and the title compound was isolated by column chromatography, tert-butyl 6-bromo-7- ((tert-butoxycarbonyl) (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-cyclopropyl-3H-imidazo [4,5-b]Pyridine-3-carboxylic acid ester (150mg, yield 79%).
MS m/z(ESI):640.2[M+H]+.
The seventh step: preparation of 2-cyclopropyl-7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-3H-imidazo [4,5-b ] pyridine-6-carboxamide
Figure BDA0002377299080000372
Tert-butyl 6-bromo-7- ((tert-butoxycarbonyl) (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-cyclopropyl-3H-imidazo [4, 5-b)]Pyridine-3-carboxylic acid ester (65mg,0.1mmol)4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (35mg,0.06mmol), triethylamine (30mg,0.3mmol), molybdenum hexacarbonyl (80mg,0.3mmol), trans-bis (M) U (M) -bis [2- (di-o-tolylphosphine) benzyl]Dipalladium acetate (28mg,0.03mmol) was mixed in acetonitrile (0.5m L), methanol (2m L), deoxygenated with nitrogen for 5 minutes, methylamine in THF (0.5m L) was added, the reaction was heated to 150 ℃ with microwave for 15 minutes, cooled to room temperature, the reaction was concentrated under reduced pressure, the residue was taken up with water and CH2Cl2Separating, separating organic phase, washing with saturated sodium chloride aqueous solution, drying organic phase with anhydrous sodium sulfate, filtering, concentrating organic solvent under reduced pressure, and separating by column chromatography to obtain the title compound 2-cyclopropyl-7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-3H-imidazo [4,5-b]Pyridine-6-carboxamide (8mg, yield 19%).
1H NMR(400MHz,CDCl3)0.88-1.17(m,4H),1.78-1.84(m,1H),3.01(s,3H),3.42(s,3H),4.03(s,3H),6.67(s,1H),7.38-7.45(m,2H),7.79-7.86(m,2H),8.12-8.22(m,2H),9.59(s,1H)；
MS m/z(ESI):419.2[M+H]+.
Example 25
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide
Figure BDA0002377299080000381
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):379.2[M+H]+.
Example 26
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 3-dimethyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide
Figure BDA0002377299080000382
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 3-dimethyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):393.2[M+H]+.
Example 27
Preparation of 3-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide
Figure BDA0002377299080000391
Preparation of 3-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):419.2[M+H]+.
Example 28
Preparation of 3-ethyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide
Figure BDA0002377299080000392
Preparation of 3-ethyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrazolo [3,4-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):407.2[M+H]+.
Example 29
Preparation of 5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazine-6-carboxamide
Figure BDA0002377299080000401
Preparation of 5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazine-6-carboxamide reference is made to example 24.
MS m/z(ESI):410.2[M+H]+.
Example 30
Preparation of 7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridine-6-carboxamide
Figure BDA0002377299080000402
Preparation of 7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-2-carbonyl-2, 3-dihydrooxazolo [4,5-b ] pyridine-6-carboxamide reference example 24.
MS m/z(ESI):396.2[M+H]+.
Example 31
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrrolo [2,3-b ] pyridine-5-carboxamide
Figure BDA0002377299080000403
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-1H-pyrrolo [2,3-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):378.2[M+H]+.
Example 32
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 2-dimethyl-1H-pyrrolo [2,3-b ] pyridine-5-carboxamide
Figure BDA0002377299080000411
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 2-dimethyl-1H-pyrrolo [2,3-b ] pyridine-5-carboxamide reference example 24.
MS m/z(ESI):392.2[M+H]+.
Example 33
Preparation of 7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 2-dimethyl-3H-imidazo [4,5-b ] pyridine-6-carboxamide
Figure BDA0002377299080000412
Preparation of 7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N, 2-dimethyl-3H-imidazo [4,5-b ] pyridine-6-carboxamide reference example 24.
MS m/z(ESI):393.2[M+H]+.
Example 34
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrrolido [1,2-b ] pyridazine-3-carboxamide
Figure BDA0002377299080000421
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrrolido [1,2-b ] pyridazine-3-carboxamide reference example 24.
1H NMR(400MHz,DMSO-d6)2.80(d,J＝4.4Hz,3H),3.69(s,3H),3.93(s,3H),5.54(dd,J＝4.5,1.6Hz,1H),6.48(dd,J＝4.5,2.6Hz,1H),7.24(t,J＝7.8Hz,1H),7.36(dd,J＝7.8,1.7Hz,1H),7.67(dd,J＝2.7,1.6Hz,1H),7.81(dd,J＝7.8,1.8Hz,1H),8.37(s,1H),8.42-8.50(m,1H),8.55(s,1H),11.71(s,1H)；
MS m/z(ESI):378.1[M+H]+.
Example 35
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-N- (methyl-d)3) -7H-imidazo [4,5-c]Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000422
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-N- (methyl-d)3) -7H-imidazo [4,5-c]Preparation of pyridazine-3-carboxamide reference example 24.
MS m/z(ESI):397.2[M+H]+.
Example 36
6-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -7H-imidazo [4,5-c]Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000431
6-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d3) -7H-imidazo [4,5-c]Preparation of pyridazine-3-carboxamide reference example 24.
MS m/z(ESI):423.2[M+H]+.
Example 37
N- (methyl-d)3) -7- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -3H-imidazo [4,5-b]Preparation of pyridine-6-carboxamides
Figure BDA0002377299080000432
N- (methyl-d)3) -7- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -3H-imidazo [4,5-b]Preparation of pyridine-6-carboxamide reference example 24.
MS m/z(ESI):430.2[M+H]+.
Example 38
6- (Cyclopropanecarboxamide) -N- (methyl-d3) -4- ((2-carbonyl-2H- [1,2' -bipyridine)]Preparation of (E) -3-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000433
6- (Cyclopropanecarboxamide) -N- (methyl-d3) -4- ((2-carbonyl-2H- [1,2' -bipyridine)]Preparation of (E) -3-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):409.2[M+H]+.
Example 39
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- ((2- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) pyridin-3-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000441
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of-4- ((2- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) pyridin-3-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):439.2[M+H]+.
Example 40
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- ((3-methyl-4-carbonyl-3, 4-dihydroquinazolin-8-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000442
6- (Ring)Propanecarboxamide) -N- (methyl-d3) Preparation of-4- ((3-methyl-4-carbonyl-3, 4-dihydroquinazolin-8-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):397.2[M+H]+.
EXAMPLE 41
Preparation of N- (6-amino-9- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -9H-purin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000443
Preparation of N- (6-amino-9- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -9H-purin-2-yl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):406.1[M+H]+.
Example 42
Preparation of 4- (cyclopropylcarboxamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-pyrrolo [3,2-c ] pyridine-7-carboxamide
Figure BDA0002377299080000451
Preparation of 4- (cyclopropylcarboxamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-pyrrolo [3,2-c ] pyridine-7-carboxamide reference example 1.
MS m/z(ESI):446.2[M+H]+.
Example 43
Preparation of 4- (cyclopropylcarboxamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-imidazo [4,5-c ] pyridine-7-carboxamide
Figure BDA0002377299080000452
Preparation of 4- (cyclopropylcarboxamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-imidazo [4,5-c ] pyridine-7-carboxamide reference example 1.
MS m/z(ESI):447.2[M+H]+.
Example 44
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- (5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-2-yl) pyridazine-3-carboxamide
Figure BDA0002377299080000461
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- (5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-2-yl) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):420.2[M+H]+.
Example 45
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- (4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-2-yl) pyridazine-3-carboxamide
Figure BDA0002377299080000462
6- (Cyclopropanecarboxamide) -N- (methyl-d3) Preparation of (E) -4- (4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-2-yl) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):420.2[M+H]+.
Example 46
Preparation of N- (1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-carbonyl-2, 3-dihydro-1H-pyrazolo [4,3-c ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000463
Preparation of N- (1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-carbonyl-2, 3-dihydro-1H-pyrazolo [4,3-c ] pyridin-6-yl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):406.2[M+H]+.
Example 47
Preparation of N- (5- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -4-carbonyl-4, 5-dihydro-1H-pyrazolo [4,3-c ] pyridin-3-yl) cyclopropanecarboxamide
Figure BDA0002377299080000471
Preparation of N- (5- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -4-carbonyl-4, 5-dihydro-1H-pyrazolo [4,3-c ] pyridin-3-yl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):406.2[M+H]+.
Example 48
Preparation of N- (4- (3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -5-carbonyl-4, 5-dihydro-1H-pyrazolo [4,3-b ] pyridin-3-yl) cyclopropanecarboxamide
Figure BDA0002377299080000472
Preparation of N- (4- (3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -5-carbonyl-4, 5-dihydro-1H-pyrazolo [4,3-b ] pyridin-3-yl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):376.2[M+H]+.
Example 49
Preparation of N- (5- (2-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000473
Preparation of N- (5- (2-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):390.2[M+H]+.
Example 50
Preparation of 6- (cyclopropylcarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -N-methylpyridazine-3-carboxamide
Figure BDA0002377299080000481
Preparation of 6- (cyclopropylcarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -N-methylpyridazine-3-carboxamide reference is made to example 1.
1H NMR(400MHz,CD3OD)0.90-1.02(m,4H),1.76-2.15(m,7H),2.95-3.21(m,6H),3.47-3.61(m,2H),4.57-4.74(m,2H),7.94(d,J＝5.4Hz,1H)；
MS m/z(ESI):435.2[M+H]+.
Example 51
6- (Cyclopropanecarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000482
6- (Cyclopropanecarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):438.2[M+H]+.
Example 52
6- (Cyclopropanecarboxamido) -4- (((1R,3R,5S) -8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -8-azabicyclo [3.2.1]Octane-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000491
6- (Cyclopropanecarboxamido) -4- (((1R,3R,5S) -8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -8-azabicyclo [3.2.1]Octane-3-yl) amino) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):452.2[M+H]+.
Example 53
4- ((1S,4S) -5- (2-cyanoacetyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) -6- (cyclopropylcarboxamide) -N- (methyl-d3) Preparation of pyridazine-3-carboxamides
Figure BDA0002377299080000492
4- ((1S,4S) -5- (2-cyanoacetyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-yl) -6- (cyclopropylcarboxamide) -N- (methyl-d3) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):387.2[M+H]+.
Example 54
6- (Cyclopropanecarboxamido) -N- (methyl-d3) Preparation of (E) -4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2-carbonyl-1, 2-dihydropyridin-3-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000493
6- (Cyclopropanecarboxamido) -N- (methyl-d3) Preparation of (E) -4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2-carbonyl-1, 2-dihydropyridin-3-yl) amino) pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):413.2[M+H]+.
Example 55
6- (Cyclopropanecarboxamido) -N- (methyl-d 3) -4- ((6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) pyridazine-3-carboxamide
Figure BDA0002377299080000501
Preparation of 6- (cyclopropylcarboxamido) -N- (methyl-d 3) -4- ((6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):397.2[M+H]+.
Example 56
6- (Cyclopropanecarboxamido) -4- ((3- (4-cyclopropyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Figure BDA0002377299080000502
Preparation of 6- (cyclopropylcarboxamido) -4- ((3- (4-cyclopropyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):451.2[M+H]+.
Example 57
6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (4- (oxetan-3-yl) -1H-imidazol-2-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
Figure BDA0002377299080000511
Preparation of 6- (cyclopropylcarboxamido) -4- ((2-methoxy-3- (4- (oxetan-3-yl) -1H-imidazol-2-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide reference is made to example 1.
MS m/z(ESI):467.2[M+H]+.
Example 58
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000512
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):434.2[M+H]+.
Example 59
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000513
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):448.2[M+H]+.
Example 60
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -3- (methylamino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000521
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -3- (methylamino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):434.2[M+H]+.
Example 61
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6-dihydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000522
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6-dihydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):446.2[M+H]+.
Example 62
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6-dihydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000531
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6-dihydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):432.2[M+H]+.
Example 63
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6-dihydropyrido [2,3-d ] pyridazin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000532
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-5-carbonyl-5, 6-dihydropyrido [2,3-d ] pyridazin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):447.2[M+H]+.
Example 64
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6-dihydropyrido [2,3-d ] pyridazin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000533
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -5-carbonyl-5, 6-dihydropyrido [2,3-d ] pyridazin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):433.2[M+H]+.
Example 65
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -3-methyl-4-carbonyl-3, 4-dihydropyrido [2,3-d ] pyrimidin-7-yl) cyclopropanecarboxamide
Figure BDA0002377299080000541
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -3-methyl-4-carbonyl-3, 4-dihydropyrido [2,3-d ] pyrimidin-7-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):447.2[M+H]+.
Example 66
N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -4-carbonyl-3, 4-dihydropyrido [2,3-d ] pyrimidin-7-yl) cyclopropanecarboxamide
Figure BDA0002377299080000542
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -4-carbonyl-3, 4-dihydropyrido [2,3-d ] pyrimidin-7-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):433.2[M+H]+.
Example 67
N- (5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylquinolin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000551
Preparation of N- (5-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylquinolin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):447.2[M+H]+.
Example 68
N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-1, 5-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000552
Preparation of N- (4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-1, 5-naphthyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):430.2[M+H]+.
Example 69
N- (7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-methyl-2H-pyrazolo [4,3-b ] pyridin-5-yl) cyclopropanecarboxamide
Figure BDA0002377299080000553
Preparation of N- (7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-methyl-2H-pyrazolo [4,3-b ] pyridin-5-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):419.2[M+H]+.
Example 70
N- (3-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -1H-pyrrolo [2,3-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000561
Preparation of N- (3-fluoro-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -1H-pyrrolo [2,3-b ] pyridin-6-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):422.2[M+H]+.
Example 71
N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -3-fluoro-1H-pyrrolo [2,3-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000562
Preparation of N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -3-fluoro-1H-pyrrolo [2,3-b ] pyridin-6-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):448.2[M+H]+.
Example 72
N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -3- (methylamino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide
Figure BDA0002377299080000571
Preparation of N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -3- (methylamino) -1H-pyrazolo [3,4-b ] pyridin-6-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):460.2[M+H]+.
Example 73
N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methyl-5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000572
Preparation of N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methyl-5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):460.2[M+H]+.
Example 74
N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methyl-5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide
Figure BDA0002377299080000573
Preparation of N- (4- ((3- (1-cyclopropyl-1H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methyl-5-carbonyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) cyclopropanecarboxamide reference is made to example 16.
MS m/z(ESI):474.2[M+H]+.
Example 75
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-2- (pyridin-2-ylamino) -7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one
Figure BDA0002377299080000581
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-2- (pyridin-2-ylamino) -7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one proceeds according to example 16.
MS m/z(ESI):457.2[M+H]+.
Example 76
4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-2- (pyridin-2-ylamino) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
Figure BDA0002377299080000582
Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methyl-2- (pyridin-2-ylamino) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one is as described in example 16.
MS m/z(ESI):443.2[M+H]+.
Example 77
3-fluoro-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N6- (pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridine-4, 6-diamine
Figure BDA0002377299080000591
Preparation of 3-fluoro-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N6- (pyridin-2-yl) -1H-pyrrolo [2,3-b ] pyridine-4, 6-diamine reference example 16.
MS m/z(ESI):431.2[M+H]+.
Example 78
N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N3-methyl-N6- (pyridin-2-yl) -1H-pyrazolo [3,4-b ] pyridine-3, 4, 6-triamine
Figure BDA0002377299080000592
Preparation of N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N3-methyl-N6- (pyridin-2-yl) -1H-pyrazolo [3,4-b ] pyridine-3, 4, 6-triamine reference example 16.
MS m/z(ESI):443.2[M+H]+.
Example 79
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazin-7-yl) cyclopropanecarboxamide
Figure BDA0002377299080000593
Preparation of N- (5- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-carbonyl-1, 4-dihydro-2H-pyrido [2,3-d ] [1,3] oxazin-7-yl) cyclopropanecarboxamide reference example 16.
MS m/z(ESI):436.2[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of the inhibitory Effect of the Compound of the present invention on the cellular TYK2 Signal pathway
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds on inhibition of the cellular TYK2 signaling pathway.
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf corporation, the pipettor is purchased from Eppendorf corporation, and the microplate reader is purchased from BioTek corporation, USA, and the model is SynergyH1 full-function microplate reader.
The experimental method is characterized in that a U266 cell line expressing TYK2 is adopted in the experiment, the INF- α stimulates and activates a TYK2 signal channel, the inhibitory activity of the compound on downstream STAT3 phosphorylation is detected, and the compound on the TYK2 signal is obtainedMedian inhibitory concentration of signal pathway activity IC50。
The specific experimental operations were as follows:
spreading U266 fine 3-12 μ L in 384-well detection plate, the number of cells per well is 100-300K, adding 2 μ L gradient diluted compound solution, incubating in carbon dioxide incubator for 2 hours, adding 2 μ L0 INF- α - α final concentration 1000U/m L1 after 2 hours, shaking for 20min at room temperature, adding 2-5 μ L2 (5X) L ANCE Ultra L ysis Buffer2 solution, shaking for 2h at room temperature, adding 5 μ L final concentration 2nM L ANCE Ultra Eu-labeled Anti-STAT5(Y694/Y699) Antilock PerkinElmer and L ANCE Ultra U L light-weighted-labeled Anti-STAT5 Antimer solution at room temperature, incubating in signal analyzer for 20nM, and calculating the inhibition ratio by fluorescence inhibition IC curve according to different concentrations of the ELISA signals at room temperature, determining the overnight signal values, calculating the inhibition ratio by fluorescence curve of different concentrations of the compounds50。
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 was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plate](Positive control value-negative control value) × 100} IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the activity test data of the compounds of the present invention in inhibiting the cell TYK2 signaling pathway obtained by the above protocol are shown in the following table:
Figure BDA0002377299080000601
Figure BDA0002377299080000611
and (4) experimental conclusion: the compound of the invention shows good inhibition effect in activity test of cell TYK2 signal channel inhibition.
Test example 2 measurement of inhibitory Effect of the Compound of the present invention on the cellular JAK2 Signal pathway
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds on inhibition of the cellular JAK2 signaling pathway.
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf corporation, the pipettor is purchased from Eppendorf corporation, and the microplate reader is purchased from BioTek corporation, USA, and the model is SynergyH1 full-function microplate reader.
The experimental method comprises the steps of adopting TF-1 cell line in the experiment, stimulating and activating a JAK2 signal channel through I L6, detecting the inhibition activity of the compound on downstream STAT3 phosphorylation, and obtaining the half inhibition concentration IC of the compound on the activity of the JAK2 signal channel50。
The specific experimental operations were as follows:
spreading TF-1 cells 3-12 mu L in 384-well detection plate, wherein the number of cells in each well is 100-300K, adding 2 mu L gradient diluted compound solution, incubating in carbon dioxide incubator for 2 hours, adding 2 mu L0I L16 after 2 hours, adding I L26 to obtain final concentration of 30ng/m L, shaking for 20min at room temperature, adding 2-5 mu L (5X) L ANCE Ultra L ysis Buffer2 solution, shaking for 2 hours at 4 degrees, adding 5 mu L to obtain final concentration of 2nM L ANCE Ultra Eu-labelled Anti-STAT3 (Tyr) Anti (PerkinElmer) solution, adding L ANCE Ultra U L light-labelled Anti-3 Anti (TKmer) solution at 4 nM after 2 hours, measuring room temperature signal value of 20nM, measuring overnight signal value of each well, calculating inhibition ratio by different STAT IC ratios according to different STAT signal concentration curve50。
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 was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plate](Positive control value-negative control value) × 100} IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the activity test data of the compound shown in the invention in inhibiting the cell JAK2 signal channel are shown in the following table:
Figure BDA0002377299080000612
and (4) experimental conclusion: as can be seen from the data in the table, the example compounds have some selectivity for JAK2 cellular activity compared to TYK2 cellular activity.
Test example 3 pharmacokinetic assay of Balb/C mice
1. The research aims are as follows:
Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of the examples, orally administered at a dose of 5mg/kg to the plasma in the mice.
2. Test protocol
2.1 test drugs:
the embodiment of the invention is self-made.
2.2 test animals:
Balb/C Mouse 6 per example, male, Shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013) 0006N 0.311620400001794).
2.3 administration:
Balb/C mice, male, fasted overnight at a p.o. dose of 5mg/kg, administered at a volume of 10m L/kg.
2.4 sample collection:
mice were bled at 0.1m L using orbital bleeds at 0.5, 1,2,4, 6, 8 and 24 hours before and after dosing, and placed in EDTA-K2The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.
2.5 sample treatment:
1) plasma samples 40 mu L were precipitated by adding 160 mu L acetonitrile, mixed and centrifuged at 3500 × g for 5-20 minutes.
2) The treated supernatant solution (100 mu L) was subjected to L C/MS/MS analysis to determine the concentration of the test compound.
2.6 liquid phase analysis
Liquid phase conditions Shimadzu L C-20AD Pump
Mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy
Phenomenex Gemiu 5um C1850 × 4.6.6 mm chromatographic column
The mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
Flow rate 0.8m L/min
Elution time: 0-4.0 min, eluent as follows:
Figure BDA0002377299080000621
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in the following table:
compound (I) tmax(h) Cmax(ng/mL) AUC0-t(ng/mL*h) t1/2(h) MRT0-∞(h)
Example 16 0.5 1156 3654 2.5 3.0
Example 24 1.0 980 2984 2.1 2.8
Example 33 1.0 781 2500 2.0 2.6
And (4) experimental conclusion: as can be seen from the results of the mouse pharmacokinetic experiments in the table, the compounds of the embodiment of the invention have good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.

Claims (17)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002377299070000011
wherein:
l is a bond or NRaa；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R2selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group or a cycloalkyl group;
Raa、Rbband RccThe same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, 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; and is
x is an integer of 0, 1,2, 3 or 4.
2. A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by general formula (II):
Figure FDA0002377299070000021
wherein:
ring a is selected from monocyclic aryl, monocyclic heteroaryl, or a bicyclic ring which is aryloaryl, heteroaryloaryl, aryloaterocyclyl, heterocycloaryl, heterocycloateroaryl, and heteroaryloaryl;
R3one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, mercapto group, nitro group, hydroxyl group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; and is
y is an integer of 0, 1,2, 3 or 4.
3. A compound according to any one of claims 1 to 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that:
ring a is selected from the following groups:
Figure FDA0002377299070000022
4. a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002377299070000023
wherein:
q is a bond or NRaa；
Ring B is selected from bicyclic;
R4selected from hydrogen atom, deuterium atom, alkyl, deuterated alkyl and alkyl halideAlkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R5selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Raa、Rbband RccThe same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, 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;
q is an integer of 0, 1,2, 3 or 4; and is
z is an integer of 0, 1,2, 3 or 4.
5. The compound of claim 4, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the formula (III) is further represented by formula (IV):
Figure FDA0002377299070000041
wherein:
R6selected from hydrogen atomsDeuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, or cycloalkyl group;
R7selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
p is an integer of 0, 1,2, 3 or 4;
ring B, R4、q、Raa、RbbAnd RccAs claimed in claim 4.
6. The compound of claim 4, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the formula (III) is further represented by formula (V):
Figure FDA0002377299070000042
wherein:
R8selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R9selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
r is an integer of 0, 1,2, 3 or 4;
ring B, R4、q、Raa、RbbAnd RccAs claimed in claim 4.
7. A compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002377299070000051
wherein:
ring C is selected from bicyclic;
R10selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R11selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1ORaa、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1RaaOr- (CH)2)n1NRaaS(O)m1RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R12selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group or a cycloalkyl group;
Raa、Rbband RccThe same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl, deuterated alkyl, 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 atoms, deuterium atoms, substituted or unsubstituted alkyl groups, halogen, hydroxyl, 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;
s is an integer of 0, 1,2, 3 or 4; and is
t is an integer of 0, 1,2, 3 or 4.
8. A compound, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 4 to 6, characterized in that:
ring B is selected from the following groups:
Figure FDA0002377299070000061
9. the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claim 7, characterized in that:
ring C is selected from the following groups:
Figure FDA0002377299070000071
10. the compound of claim 4, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the formula (III) is further represented by formula (VII):
Figure FDA0002377299070000072
wherein:
ring D is selected from phenyl, 5-6 membered heterocyclic group containing 1-2N or O atoms or 5-6 membered heteroaryl group containing 1-2N or O atoms;
preference is given to
Figure FDA0002377299070000073
M1、M2、M3、M4And M5Each independently selected from O, N, C (O), CR13、CR13R14Or NR15，
R13And R14Each is independentSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthaleneThe base group is a group of a compound,
R15selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano,Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
more preferably
Figure FDA0002377299070000081
R16Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)ORa、-(CH2)n2C(O)NRaRb、-(CH2)n2S(O)m2RaOr- (CH)2)n2NRaS(O)m2Rb(ii) a Preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)NRaRbOr- (CH)2)n2S(O)m2Ra(ii) a More preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl, 5-10 membered heteroaryl containing 1-3N, O or S atoms, - (CH)2)n2Ra、-(CH2)n2ORa、-(CH2)n2SRa、-(CH2)n2NRaRb、-(CH2)n2C(O)Ra、-(CH2)n2NRaC(O)Rb、-(CH2)n2C(O)NRaRbOr- (CH)2)n2S(O)m2Ra(ii) a Further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl, naphthyl or-NHCH3；
RaAnd RbEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein said alkyl, deuterated alkyl, 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;
m is an integer of 0 to 3;
m2 is an integer of 0-2; and is
n2 is an integer from 0 to 3.
11. The compound of claim 4, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the formula (III) is further represented by formula (VIII):
Figure FDA0002377299070000101
wherein:
ring E is selected from a 5-6 membered heterocyclic group containing 1-2N or O atoms;
preference is given to
Figure FDA0002377299070000102
M6And M7Each independently selected from N or CR17，
R17Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preference is given to hydrogen, deuterium, halogen, amino,Hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
more preferably
Figure FDA0002377299070000103
R18Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C1-3Alkyl radical, C2-5Alkenyl radical, C2-5Alkynyl, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy, C3-6Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C6-10Aryl or 5-10 membered heteroaryl containing 1-3N, O or S atoms; further preferred is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, glycidyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepinyl, thienyl, pyrrolyl, cyclopentyl, cyclohexylmethyl, pyrrolyl, cyclopentyloxy, azetidinyl, cyclopentyloxy, azetidinyl, azacycloheptyloxy, thienyl, pyrrolyl, amino, hydroxyl, cyano, Pyridyl, pyranyl, piperazinyl, phenyl or naphthyl; and is
n is an integer of 0 to 3.
12. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the general formula is selected from the group consisting of:
Figure FDA0002377299070000111
Figure FDA0002377299070000121
Figure FDA0002377299070000131
Figure FDA0002377299070000141
13. a process for the preparation of a compound of formula (VII) or stereoisomers and pharmaceutically acceptable salts thereof according to claim 10, comprising the steps of,
Figure FDA0002377299070000142
reacting the general formula (VII-1) with the general formula (VII-2) to obtain a compound shown as the general formula (VII) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
X1selected from halogens.
14. A process for preparing a compound of the general formula (VIII) according to claim 11 or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of,
Figure FDA0002377299070000151
the general formula (VII-1) reacts with the general formula (VIII-1) to obtain a general formula (VIII-2), and the general formula (VIII-2) further reacts to obtain a compound shown as the general formula (VIII) or a stereoisomer and pharmaceutically acceptable salts thereof;
wherein:
X2selected from halogens;
X3selected from halogens.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (la), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.
16. Use of a compound of formula (la), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 15, for the manufacture of a TYK2 inhibitor medicament.
17. Use of a compound of general formula (la), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 15 for the treatment of inflammatory and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease.
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