CN111484480B - Polycyclic derivative inhibitor, preparation method and application thereof - Google Patents
Polycyclic derivative inhibitor, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a polycyclic derivative inhibitor, a preparation method and application thereof. In particular, the present invention relates to compounds of the general formula, methods for their preparation and pharmaceutical compositions containing them, and their use as an intracellular non-receptor tyrosine kinase, mediating the signaling and activation of various cytokines; particularly plays a key role in the biological processes of immune regulation, immune cell proliferation and the like, is closely related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and the like, and each substituent in the following general formula (I) is defined as the specification.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a polycyclic derivative inhibitor, a preparation method and application thereof.
Background
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes of JAK1, JAK2, JAK3 and TYK2, each subtype mediates different types of cytokine signal paths, and JAK-1, JAK-2 and TYK-2 are expressed in various tissue cells of a human body, and JAK-3 is mainly expressed in various hematopoietic tissue cells. A common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. When cytokine receptor is combined with ligand thereof, JAKs coupled with receptor is activated, the receptor is further phosphorylated, phosphorylated tyrosine site can be combined with STAT protein containing SH2 structural domain, thereby the STAT is recruited to the receptor and phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred into cell nucleus and activates target gene transcription thereof, and further controls various functions such as growth, activation, differentiation and the like of various cells.
TYK2 is one of the earliest subtypes found in the JAK family, mediates the functions of cytokines such as IFN-alpha, IL-6, IL-10, IL-12, IL-23 and the like, and researches show that TYK2 deletion mutation can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity, inflammation and the like. IL-23 plays a vital role in the development process of psoriasis, and recent researches show that the pathogenesis of the psoriasis is that endogenous unknown antigen-activated antigen presenting cells APC secrete IL-23, IL-23 activates Th17 cells and cytokines such as IL-17 are secreted, keratinocyte differentiation and division are induced, IL-23 is secreted, and inflammation and keratinocyte proliferation are further stimulated to produce psoriasis. TYK2 and JAK2 together mediate the downstream signaling pathway of IL-23, inhibition of JAK2 results in anemia and other blood-related side effects, and thus targeting TYK2 is a good strategy to inhibit IL-23 signaling pathway for the treatment of psoriasis.
Early TYK2 inhibitors such as Tofacitinib and the like belong to JAK non-selective inhibitors, are first oral JAK inhibitors, and have remarkable inhibitory activity on JAK1, 2 and 3 subtypes. Inhibition of the activity of other subtypes such as JAK1, JAK2 and JAK3 increases the efficacy of tofacitinib, but also brings about more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, cholesterol increase, and the like. Since JAK2 activity is associated with erythroid differentiation and lipid metabolism, the above-mentioned partial adverse reactions such as anemia are considered to be associated with insufficient selectivity of Tofacitinib for JAK-2, which is caused by nonselective inhibition of the drug. Currently, TYK2 selective inhibitors are not marketed, and early JAK inhibitors mainly compete for the binding of kinase domains to ATP and thus have a general problem of low selectivity.
The drug is between the good curative effect of JAK nonselective inhibitor and the serious side effect related to various targets, and the development of TYK2 selective inhibitor drug with higher safety for treating inflammatory diseases such as psoriasis has great clinical application potential. BMS International applications WO2015069310A1 and WO2018081488A1 report TYK2 selective inhibitors, and the developed BMS-986165 has good curative effects in the current clinical second phase and enters a clinical study in the third phase, so that the advantages of the TYK2 selective inhibitors are reflected, and the BMS-986165 has great clinical application value.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
l is a bond or NR aa ；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a,Cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 2 Selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, or a cycloalkyl group;
R aa 、R bb and R is cc Identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with a moiety selected from the group consisting of hydrogen atom, deuterium atom, 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 cycloalkylOne or more substituents selected from the group consisting of a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; and is also provided with
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), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (II):
Wherein:
ring a is selected from the group consisting of monocyclic aryl, monocyclic heteroaryl, or a double-membered ring, said double-membered ring being aryl-membered aryl, aryl-membered heteroaryl, heteroaryl-membered heteroaryl, aryl-membered heterocyclyl, heterocyclylaryl, heterocyclylalkylheteroaryl, and heteroarylalkylaryl;
R 3 one or more substituents selected 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, hydroxyl group, cyano group, oxo group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group; and is also provided with
y is an integer of 0, 1, 2, 3 or 4.
The invention also provides a preferable scheme, wherein the compounds shown in the general formula (I) and the general formula (II), stereoisomers or pharmaceutically acceptable salts thereof are characterized in that:
ring a is selected from the following groups:
the invention also provides a preferred embodiment, a compound of formula (III):
wherein:
q is a bond or NR aa ；
Ring B is selected from the group consisting of a bi-fused ring which is aryl-fused aryl, aryl-fused heteroaryl, heteroaryl-fused heteroaryl, aryl-fused heterocyclyl, heterocyclyl-fused aryl, heterocyclyl-fused heteroaryl, and heteroaryl-fused aryl;
R 4 Selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 5 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R aa 、R bb And R is cc The same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the deuterated alkyl group, the haloalkyl group, the alkoxy group, the hydroxyalkyl group, the haloalkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a hydrogen atom, a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
q is an integer of 0, 1, 2, 3 or 4; and is also provided with
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), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (IV):
Wherein:
R 6 selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, or a cycloalkyl group;
R 7 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR bb 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, 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, R 4 、q、R aa 、R bb And R is cc As described in general formula (III).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is shown in the general formula (V):
Wherein:
R 8 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 9 selected from cycloalkyl, heterocyclyl, aryl or heteroaryl groups, whereinThe cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;
r is an integer of 0, 1, 2, 3 or 4;
ring B, R 4 、q、R aa 、R bb And R is cc As described in general formula (III).
The invention also provides a preferred embodiment, a compound of formula (III):
wherein:
ring C is selected from the group consisting of double-fused rings;
R 10 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further selectedSubstituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, halogen, amino group, oxo group, thio group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;
R 11 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n1 OR aa 、-(CH 2 ) n1 NR aa R bb 、-NR aa C(O)R bb 、-NR aa C(O)NR bb R cc 、-C(O)NR aa R bb 、-NR aa S(O) m1 R bb 、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-(CH 2 ) n1 C(O)R aa 、-NR aa C(O)OR bb 、-(CH 2 ) n1 S(O) m1 R aa Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, 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, deuteroalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 12 selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, or a cycloalkyl group;
R aa 、R bb and R is cc The same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, cyano group, nitro group, hydroxyl group, amino group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl groupA group and a heteroaryl group, wherein the alkyl group, deuteroalkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a hydrogen atom, deuterium atom, a substituted or unsubstituted alkyl group, halogen, hydroxyl group, a substituted or unsubstituted amino group, oxo group, nitro group, cyano group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group;
s is an integer of 0, 1, 2, 3 or 4; and is also provided with
t is an integer of 0, 1, 2, 3 or 4.
The invention also provides a preferable scheme, wherein the compounds shown in the general formula (III) and the general formula (IV), stereoisomers or pharmaceutically acceptable salts thereof are characterized in that:
ring B is selected from the following groups:
the invention also provides a preferable scheme, wherein the compound shown in the general formula (VI), the stereoisomer or the pharmaceutically acceptable salt thereof is characterized in that:
ring B is selected from the following groups:
the invention also provides a preferable scheme, wherein the general formula (III) is further shown as a general formula (VII):
wherein:
ring D is selected from phenyl, a 5-6 membered heterocyclic group containing 1-2N or O atoms, or a 5-6 membered heteroaryl group containing 1-2N or O atoms;
preferably
M 1 、M 2 、M 3 、M 4 And M 5 Each independently selected from O, N, C (O), CR 13 、CR 13 R 14 Or NR (NR) 15 ，
R 13 And R is 14 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-3N, O or S atoms; further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyanoOxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuteromethyl, deuteroethyl, deuteropyl, 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, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azepinyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
R 15 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-3N, O or S atoms; further preferably hydrogen,Deuterium, fluoro, chloro, bromo, amino, hydroxy, cyano, oxo, thio, methyl, ethyl, propyl, ethenyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuteromethyl, deuteroethyl, deuteropyropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclohexyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
More preferably
R 16 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n2 R a 、-(CH 2 ) n2 OR a 、-(CH 2 ) n2 SR a 、-(CH 2 ) n2 NR a R b 、-(CH 2 ) n2 C(O)R a 、-(CH 2 ) n2 NR a C(O)R b 、-(CH 2 ) n2 C(O)OR a 、-(CH 2 ) n2 C(O)NR a R b 、-(CH 2 ) n2 S(O) m2 R a Or- (CH) 2 ) n2 NR a S(O) m2 R b The method comprises the steps of carrying out a first treatment on the surface of the Preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano,Oxo, thio, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, - (CH) 2 ) n2 R a 、-(CH 2 ) n2 OR a 、-(CH 2 ) n2 SR a 、-(CH 2 ) n2 NR a R b 、-(CH 2 ) n2 C(O)R a 、-(CH 2 ) n2 NR a C(O)R b 、-(CH 2 ) n2 C(O)NR a R b Or- (CH) 2 ) n2 S(O) m2 R a The method comprises the steps of carrying out a first treatment on the surface of the More preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl, 5-to 10-membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n2 R a 、-(CH 2 ) n2 OR a 、-(CH 2 ) n2 SR a 、-(CH 2 ) n2 NR a R b 、-(CH 2 ) n2 C(O)R a 、-(CH 2 ) n2 NR a C(O)R b 、-(CH 2 ) n2 C(O)NR a R b Or- (CH) 2 ) n2 S(O) m2 R a The method comprises the steps of carrying out a first treatment on the surface of the Further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuteromethyl, deuteroethyl, deuteropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxyl A group selected from the group consisting of ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, azepanyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl, naphthyl and-NHCH 3 ；
R a And R is b Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
m is an integer of 0 to 3;
m2 is an integer of 0 to 2; and is also provided with
n2 is an integer from 0 to 3.
The invention also provides a preferable scheme, wherein the general formula (III) is further shown as a general formula (VIII):
wherein:
ring E is selected from 5-6 membered heterocyclyl containing 1-2N or O atoms;
preferably
M 6 And M 7 Each independently selected from N or CR 17 ，
R 17 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-3N, O or S atoms; further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuteromethyl, deuteroethyl, deuteropyl, 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,Epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, azepinyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl or naphthyl;
more preferably
R 18 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; more preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, thioxo, C 1-3 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-3N, O or S atoms; further preferred are hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuteromethyl, deuteroethyl, deuteropyl, 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, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, epoxyheptyl, aziridinyl, azetidinyl, thienyl, pyrrolyl, pyridyl, pyranyl, piperazinyl, phenyl or naphthyl; and is also provided with
n is an integer of 0 to 3.
The present invention also provides a preferred embodiment, a process for preparing the compound of the general formula (VII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
reacting the general formula (VII-1) with the general formula (VII-2) to obtain a compound shown in the general formula (VII) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein:
X 1 selected from halogen.
The present invention also provides a preferred embodiment, a process for preparing the compound of the general formula (VIII) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized by comprising the steps of,
reacting the general formula (VII-1) with the general formula (VIII-1) to obtain the general formula (VIII-2), and further reacting the general formula (VIII-2) to obtain a compound shown in the general formula (VIII) or a stereoisomer and a pharmaceutically acceptable salt thereof;
Wherein:
X 2 selected from halogen;
X 3 selected from halogen.
The invention also relates to a technical scheme, a medicinal composition, which comprises a therapeutically effective dose of a compound shown in any one of the general formulas (I) to (IV), a stereoisomer 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 or pharmaceutically acceptable salts thereof, or the application of the pharmaceutical composition in preparing TYK2 inhibitor drugs.
The invention also relates to a technical scheme, and the compounds shown in the general formulas (I) to (IV), stereoisomers or pharmaceutically acceptable salts thereof, or the application of the pharmaceutical composition in preparing drugs for treating inflammatory diseases and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
The invention further relates to a method for preparing the compound shown in the general formulas (I) to (IV), the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof for treating inflammatory diseases.
The invention also relates to a method for the therapeutic prophylaxis and/or treatment of pre-prepared treatment of autoimmune diseases, which comprises administering to a patient a therapeutically effective dose of a compound of the general formula (I) to the general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention also provides methods of treating disease conditions, including but not limited to conditions associated with TYK2 kinase dysfunction, using the compounds or pharmaceutical compositions of the invention.
The 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 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 heart disease.
In some embodiments, the present methods involve the inflammatory and autoimmune diseases are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and crohn's disease).
The 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 invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxyA group, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:
the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having 3 to 20 membered monocyclic rings sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:
the term "fused heterocyclyl" refers to 5 to 20 membered, polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or moreThe 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 are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carboxy" means-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.
“Et 2 O "refers to 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.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
6- (Cyclopropionamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
The first step: preparation of 4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine
5-bromo-4-methoxypyridin-3-amine (2.02 g,10 mmol), bis-pinacolatyldiborane (3.05 g,12 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (816.6 mg,1 mmol), potassium acetate (2.45 g,25 mmol), and mixed in dioxane (20 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100deg.C, cooled to room temperature, the reaction solution concentrated under reduced pressure, the residue was taken up with water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine (2.1 g, 85%).
MS m/z(ESI):251.1[M+H] + .
And a second step of: preparation of 4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine
4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine (2.0 g,8 mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61 g,10 mmol), cs 2 CO 3 (7.6 g,20 mmol) tetrakis (triphenylphosphine) palladium (925 mg,0.8 mmol) was mixed with 1, 4-dioxane (40 mL) and water (5 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100℃and cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was taken up with water and CH 2 Cl 2 Separating the liquid, separating the organic phase and washing with saturated aqueous sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and subjecting to column chromatography to give the title compound 4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine (1.0 g, 61%).
MS m/z(ESI):206.1[M+H] + .
And a third step of: preparation of lithium 4, 6-dichloropyridazine-3-carboxylate
Methyl 4, 6-dichloropyridazine-3-carboxylate (2.07 g,10 mmol), lithium bromide (2.6 g,30 mmol) was dissolved in acetonitrile (20 mL) and water (2 mL), cooled to 0℃and DIPEA (5.2 mL,30 mmol) was added dropwise, the reaction was naturally warmed to room temperature for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2 mL. Times.4), the filter cake was collected and dried to give the title compound lithium 4, 6-dichloropyridazine-3-carboxylate (1.73 g, 87%).
MS m/z(ESI):193.1[M+H] + .
Fourth step: preparation of((6-chloro-4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazin-3-carbonyl) oxo) zinc
4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-amine (1.0 g,5.0 mmol), lithium 4, 6-dichloropyridazine-3-carboxylate (1.19 g,6.0 mmol) and zinc acetate (1.1 g,6.0 mmol) were mixed in isopropanol (1 mL) and water (7 mL) and reacted overnight at 65 ℃. The reaction was cooled to room temperature, water (6 mL) was added, stirring was performed for 1H, the reaction solution was filtered, the filter cake was washed with water (6 mL. Times.2) and THF (6 mL), and the filter cake was collected and dried to give the title compound ((6-chloro-4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) oxo) zinc (1.34 g, 68%).
MS m/z(ESI):362.1[M+H] + .
Fifth step: preparation of (6- (cyclopropylamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazin-3-carbonyl) zinc
((6-chloro-4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazin-3-carbonyl) oxo) zinc (157 mg,0.4 mmol), cyclopropanecarboxamide (85 mg,1.0 mmol), DBU (61 mg,0.4 mmol), potassium carbonate (110 mg,0.8 mmol), mixed in toluene (1.2 mL) and acetonitrile (0.6 mL), palladium acetate (4.5 mg,0.02 mmol) and (R) - (-) -1- [ (S) -2- (dicyclohexylphosphine) ferrocene were added ]Ethyl di-tert-butylphosphine (22 mg,0.04 mmol), the reaction was replaced with nitrogen three times and reacted overnight at 75 ℃. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, washed with petroleum ether (6 mL. Times.2), the aqueous phase was then separated, water (2 mL) was added to the aqueous phase, CH 2 Cl 2 (5 mL. Times.3) extraction, combining the organic phases, washing with saturated aqueous NaCl, separating the organic phases, drying over anhydrous sodium sulfate, and concentrating the organic solvent under reduced pressure afforded the title compound (6- (cyclopropylamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) zinc (99 mg, 56%).
MS m/z(ESI):411.2[M+H] + .
Sixth step: preparation of 6- (cyclopropanecarboxamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
(6- (Cyclopropanamido) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) pyridazine-3-carbonyl) zinc (88 mg,0.2 mmol), deuterated methylamine hydrochloride (71 mg,1.0 mmol), DIPEA (258 mg,2.0 mmol) were mixed in DMF (1 mL), HATU (380 mg,1.0 mmol) was added and reacted overnight at 40 ℃. The reaction was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was used with CH 2 Cl 2 Separating, washing the organic phase with saturated aqueous NaCl solution, drying with anhydrous sodium sulfate, concentrating the organic solvent under reduced pressure, and column chromatography to obtain the title compound 6- (cyclopropylamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-3-yl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxamide (44 mg, 52%).
MS m/z(ESI):427.2[M+H] + .
Example 2
6- (Cyclopropionamide) -4- ((3-methoxy-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-4-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((3-methoxy-2- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-4-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):427.2[M+H] + .
Example 3
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):427.2[M+H] + .
Example 4
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) amino) -N- (methyl-d) 3 ) Pyridazine-3-carboxylic acidThe preparation of the amine is described in example 1.
MS m/z(ESI):432.2[M+H] + .
Example 5
6- (Cyclopropionamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-3-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-3-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):432.2[M+H] + .
Example 6
6- (Cyclopropionamide) -4- ((4-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-5-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((4-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-5-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):433.2[M+H] + .
Example 7
6- (Cyclopropionamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-3-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) isothiazol-3-yl) amino) -N- (methyl-d) 3 ) Pyridazine (PYRIZE)Preparation of 3-carboxamide reference example 1.
MS m/z(ESI):433.2[M+H] + .
Example 8
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) naphthalen-2-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((3-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) naphthalen-2-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):476.2[M+H] + .
Example 9
6- (Cyclopropionamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-6-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-6-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H] + .
Example 10
6- (Cyclopropionamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzo [ b)]Thiophen-6-yl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((5-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzo [ b)]Thiophen-6-yl) amino) -N- (methyl-d 3 ) 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-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (cyclopropanecarboxamide) -4- ((6-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-7-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H] + .
Example 12
6- (Cyclopropionamide) -4- ((6-methoxy-7- (1-methyl-1H-1, 2, 4-triazol-3-yl) indolizin-5-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((6-methoxy-7- (1-methyl-1H-1, 2, 4-triazol-3-yl) indolizin-5-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):465.2[M+H] + .
Example 13
6- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of 4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) pyridazine-3-carboxamide
6- (cyclopropylamide) -N- (methyl-d) 3 ) -4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazole-3)-yl) amino) pyridazine-3-carboxamide preparation was described in reference to example 1.
MS m/z(ESI):386.2[M+H] + .
Example 14
6- (Cyclopropionamide) -4- ((5-methoxy-1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-4-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((5-methoxy-1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-4-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):416.2[M+H] + .
Example 15
6- (Cyclopropionamide) -4- ((4-methoxy-1-methyl-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) -N- (methyl-d) 3 ) Preparation of pyridazine-3-carboxamides
6- (Cyclopropionamide) -4- ((4-methoxy-1-methyl-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-pyrazol-3-yl) amino) -N- (methyl-d) 3 ) 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
The first step: preparation of ethyl 2- (bromomethyl) -4, 6-dichloropropionate
CCl to ethyl 4, 6-dichloro-2-methylnicotinate (2.00 g,8.54 mmol) 4 NBS (1.67 g,9.40 mmol), AIBN (140 mg,0.854 mmol) and AIBN were added sequentially to the solution (40 mL), followed by stirring overnight at 92℃and cooling to room temperature, and the organic solvent was concentrated under reduced pressure to give the crude product which was used directly in the next step.
MS m/z(ESI):311.9[M+H] + .
And a second step of: preparation of 2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one
To an acetonitrile solution (30 mL) of ethyl 2- (bromomethyl) -4, 6-dichloropycinate (crude product of the previous step) were added successively deuterated methylamine hydrochloride (390 mg,5.58 mmol) and DIPEA (6.60 mL,40 mmol), followed by stirring at room temperature for 2 hours, concentrating the organic solvent under reduced pressure, and separating the title compound 2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one (400 mg, two step yield: 23%) by column chromatography.
MS m/z(ESI):220.0[M+H] + .
And a third step of: preparation of N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) cyclopropanecarboxamide
2, 4-dichloro-6- (methyl-d 3) -6, 7-dihydro-5H-pyrrolo [3,4-b]Pyridin-5-one (100 mg,0.454 mmol), cyclopropionamide (36 mg,0.410 mmol) and Potassium carbonate (188 mg,1.36 mmol) were mixed in 1, 4-dioxane (4 mL), nitrogen sparged for 5 min, then Pd was added sequentially 2 (dba) 3 (41 mg,0.0454 mmol) and Xantphos (52 mg,0.0908 mmol), microwave 90Stirring at the temperature of 2 hours, cooling the reaction solution to room temperature, concentrating the organic solvent under reduced pressure, and separating by column chromatography to obtain the title compound N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3, 4-b)]Pyridin-2-yl) cyclopropanecarboxamide (20 mg, 16%).
MS m/z(ESI):269.1[M+H] + .
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
N- (4-chloro-6- (methyl-d 3) -5-carbonyl-6, 7-dihydro-5H-pyrrolo [3, 4-b)]Pyridin-2-yl) cyclopropanecarboxamide (20 mg,0.074 mmol), 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (17 mg,0.082 mmol) and potassium carbonate (31 mg,0.223 mmol) were mixed in 1, 4-dioxane (3 mL), nitrogen sparged for 5 minutes, then Pd was added sequentially 2 (dba) 3 (20 mg,0.0223 mmol) and Xantphos (28 mg,0.0446 mmol), stirring at 95℃for 2 hours, cooling the reaction solution to room temperature, concentrating the organic solvent under reduced pressure, and then preparing a thin layer for separation and purification 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) ]Pyridin-2-yl) cyclopropanecarboxamide (13 mg, 29%).
1 H NMR(400MHz,CD 3 OD)δ0.83-0.91(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
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-dihydro-oxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide
Preparation of N- (7- ((2-hydroxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -2-carbonyl-2, 3-dihydro-oxazolo [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-dihydro-oxazolo [4,5-b ] pyridin-5-yl) cyclopropanecarboxamide
Preparation of N- (7- ((4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2- (methylsulfonyl) phenyl) amino) -2-carbonyl-2, 3-dihydro-oxazolo [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
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
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
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
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
The first step: preparation of 2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
3-bromo-2-methoxyaniline (2.02 g,10 mmol), bis-pinacolatyldiborane (3.05 g,12 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (816.6 mg,1 mmol), potassium acetate (2.45 g,25 mmol), and mixed in dioxane (20 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100deg.C, cooled to room temperature, the reaction solution concentrated under reduced pressure, the residue was taken up with water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0 g, 80%).
1 H NMR(400MHz,CDCl 3 )δ1.36(s,12H),3.83(s,3H),6.92-6.99(m,2H),7.16-7.20(m,2H)；
MS m/z(ESI):250.1[M+H] + .
And a second step of: preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (2.0 g,8 mmol), 3-bromo-1-methyl-1H-1, 2, 4-triazole (1.61 g,10 mmol), cs 2 CO 3 (7.6 g,20 mmol) tetrakis (triphenylphosphine) palladium (924.5 mg,0.8 mmol) was mixed with 1, 4-dioxane (40 mL) and water (5 mL), the reaction system was replaced with nitrogen three times, reacted overnight at 100℃and cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was taken up with water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to give the title compound 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.14 g, 70%).
1 H NMR(400MHz,CDCl 3 )δ3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H),8.1(s,1H)；
MS m/z(ESI):205.1[M+H] + .
And a third step of: preparation of 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-nitropyridine-2, 4-diamine
2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (1.0 g,4.9 mmol), 5-bromo-4-chloro-3-nitropyridin-2-amine (3.71 g,14.7 mmol), N, N-diisopropylethylamine (2.26 g,19.6 mmol) were dissolved in DMF (10 mL) and heated to 125℃with microwaves for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was taken up in water and CH 2 Cl 2 The organic phase was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, collected by filtration, and concentrated under reduced pressure, followed by 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 (1.1 g, yield 53%).
MS m/z(ESI):420.1[M+H] + .
Fourth step: preparation of 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridin-2, 3, 4-triamine
5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -3-nitropyridine-2, 4-diamine (480 mg,1.14 mmol), iron powder (428 mg,11.42 mmol), ammonium chloride (122 mg,2.28 mmol) were dissolved in ethanol (10 mL) and water (2 mL), the reaction mixture was filtered after heating to 85℃in an oil bath, cooled to room temperature, and the filtrate was concentrated under reduced pressure and separated by column chromatography to give the title compound 5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridine-2, 3, 4-triamine (395 mg, 89% yield).
MS m/z(ESI):390.1[M+H] + .
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
5-bromo-N4- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) pyridine-2, 3, 4-triamine (399mg, 1.01 mmol), ethylcyclomethylimino acid ester hydrochloride (454 mg,3.04 mmol) was dissolved in methanol (5 mL) and glacial acetic acid (1 mL), and the mixture was heated to 70℃with microwaves, and reacted for 1 hour with microwaves to 130℃with microwaves again. Cooled to room temperature, the reaction was concentrated under reduced pressure, and the residue was taken up in water and CH 2 Cl 2 Separating the liquid, separating the organic phase and washing with saturated aqueous sodium chloride, drying the 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 (130 mg, 29%).
MS m/z(ESI):440.2[M+H] + .
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
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 (130 mg,0.3 mmoL) was dissolved in tetrahydrofuran, di-tert-butyl dicarbonate (193 mg,0.89 mmol), 4-dimethylaminopyridine (11 mg,0.088 mmol) was added, heated to 70℃for 5 hours, cooled to room temperature, the reaction mixture was concentrated under reduced pressure, the residue was taken up with water and CH 2 Cl 2 Separating the liquid, separating the organic phase and washing with saturated aqueous sodium chloride, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain the title compound 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 (150 mg, yield 79%).
MS m/z(ESI):640.2[M+H] + .
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
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 (65 mg,0.1 mmol) 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (35 mg,0.06 mmol), triethylamine (30 mg,0.3 mmol), molybdenum hexacarbonyl (80 mg,0.3 mmol), trans-bis-mu (M) -bis [2- (di-o-tolylphosphine) benzyl]Dipalladium acetate (28 mg,0.03 mmol) was mixed with acetonitrile (0.5 mL), methanol (2 mL), deoxygenated with nitrogen for 5 min, methylamine in THF (0.5 mL) was added, heated to 150℃with microwaves for 15 min, cooled to room temperature, and concentrated under reduced pressureShrinking the reaction solution, using water and CH as residues 2 Cl 2 Separating the liquid, separating the organic phase and washing with saturated aqueous sodium chloride, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the 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 (8 mg, 19% yield).
1 H NMR(400MHz,CDCl 3 )δ0.88-1.17(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
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
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
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
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
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 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-dihydro-oxazolo [4,5-b ] pyridine-6-carboxamide
Preparation of 7- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methyl-2-carbonyl-2, 3-dihydro-oxazolo [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
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
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
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-methylpyrrolo [1,2-b ] pyridazine-3-carboxamide
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Preparation of 4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyrro [1,2-b ] pyridazine-3-carboxamide reference example 24.
1 H NMR(400MHz,DMSO-d 6 )δ2.80(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
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-d) 3 ) -7H-imidazo [4,5-c]Preparation of pyridazine-3-carboxamides
6-cyclopropyl-4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d) 3 ) -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-carboxamide
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- (cyclopropylamide) -N- (methyl-d) 3 ) -4- ((2-carbonyl-2H- [1,2' -bipyridine)]-3-yl) amino) pyridazine-3-carboxamide preparation
6- (cyclopropylamide) -N- (methyl-d) 3 ) -4- ((2-carbonyl-2H- [1,2' -bipyridine)]-3-yl) amino) pyridazine-3-carboxamide preparation was described in reference to example 1.
MS m/z(ESI):409.2[M+H] + .
Example 39
6- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of 4- ((2- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) pyridin-3-yl) amino) pyridazine-3-carboxamide
6- (cyclopropylamide) -N- (methyl-d) 3 ) 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- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of-4- ((3-methyl-4-carbonyl-3, 4-dihydroquinazolin-8-yl) amino) pyridazine-3-carboxamide
6- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of-4- ((3-methyl-4-oxo-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
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- (cyclopropylamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-pyrrolo [3,2-c ] pyridine-7-carboxamide
Preparation of 4- (cyclopropylamide) -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- (cyclopropylamide) -1- (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -N-methyl-1H-imidazo [4,5-c ] pyridine-7-carboxamide
Preparation of 4- (cyclopropylamide) -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- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of 4- (5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-indol-2-yl) pyridazine-3-carboxamide
6- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of 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- (cyclopropylamide) -N- (methyl-d) 3 ) -4- (4- (1-methyl-1H-1, 2, 4-triazol-3-yl) -1H-)Preparation of indol-2-yl) pyridazine-3-carboxamide
6- (cyclopropylamide) -N- (methyl-d) 3 ) Preparation of 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
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
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
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
The 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 is described in reference example 1.
MS m/z(ESI):390.2[M+H] + .
Example 50
Preparation of 6- (cyclopropanecarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N-methylpyridazine-3-carboxamide
Preparation of 6- (cyclopropanecarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N-methylpyridazine-3-carboxamide reference example 1.
1 H NMR(400MHz,CD 3 OD)δ0.90-1.02(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-difluoro-ring)Propane-1-carbonyl) -3, 8-diazabicyclo [3.2.1]Octane-3-yl) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
6- (cyclopropanecarboxamide) -4- (8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):438.2[M+H] + .
Example 52
6- (cyclopropylamido) -4- (((1R, 3R, 5S) -8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -8-azabicyclo [ 3.2.1)]Octane-3-yl) amino) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
6- (cyclopropylamido) -4- (((1R, 3R, 5S) -8- ((S) -2, 2-difluorocyclopropane-1-carbonyl) -8-azabicyclo [ 3.2.1)]Octane-3-yl) amino) -N- (methyl-d 3 ) 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- (cyclopropanecarboxamide) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamides
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4- ((1S, 4S) -5- (2-cyanoacetyl) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) -6- (cyclopropanecarboxamide) -N- (methyl-d 3 ) Preparation of pyridazine-3-carboxamide reference example 1.
MS m/z(ESI):387.2[M+H] + .
Example 54
6- (cyclopropylamido) -N- (methyl-d) 3 ) Preparation of-4- ((1- (1-methyl-1H-1, 2, 4-triazol-3-yl) -2-carbonyl-1, 2-dihydropyridin-3-yl) amino) pyridazine-3-carboxamide
6- (cyclopropylamido) -N- (methyl-d) 3 ) Preparation of 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- (Cyclopropanamido) -N- (methyl-d 3) -4- ((6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) pyridazin-3-carboxamide
The preparation of 6- (cyclopropylamido) -N- (methyl-d 3) -4- ((6- (1-methyl-1H-1, 2, 4-triazol-3-yl) pyridin-2-yl) amino) pyridazine-3-carboxamide was described in example 1.
MS m/z(ESI):397.2[M+H] + .
Example 56
6- (cyclopropylamido) -4- ((3- (4-cyclopropyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((3- (4-cyclopropyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was according to example 1.
MS m/z(ESI):451.2[M+H] + .
Example 57
6- (cyclopropylamido) -4- ((2-methoxy-3- (4- (oxetan-3-yl) -1H-imidazol-2-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide
The preparation of 6- (cyclopropylamido) -4- ((2-methoxy-3- (4- (oxetan-3-yl) -1H-imidazol-2-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide was described in reference 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
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The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
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 the procedure described in example 16 is followed.
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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
The 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 is described in 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
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The 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 is described in 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
The 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 is described in 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
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 the procedure is as described in 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
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 the procedure is 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
The 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 is described in 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 ] pyridin-3, 4, 6-triamine
The 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 ] pyridin-3, 4, 6-triamine is described in 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
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 invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 measurement of the inhibitory Effect of the Compound of the present invention on cellular TYK2 Signal pathway
The purpose of the experiment is as follows: the purpose of this test case is to test compounds for their activity against inhibition of cellular TYK2 signaling pathways.
Experimental instrument: the centrifuge (5702R) was purchased from Eppendorf company, the pipettor was purchased from Eppendorf company, and the microplate reader was purchased from BioTek company, USA under the model number SynergyH1 full function microplate reader.
The experimental method comprises the following steps: the experiment adopts a U266 cell line expressing TYK2, activates a TYK2 signal path through INF-alpha stimulation, detects the inhibitory activity of a compound on downstream STAT3 phosphorylation of the compound, and obtains half inhibition concentration IC of the compound on the activity of the TYK2 signal path 50 。
The specific experimental operation is as follows:
u266 is paved into 384-hole detection plates for 3-12 mu L, the number of cells in each hole is 100-300K, 2 mu L of compound solution which is diluted in a gradient way is added, and the mixture is incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. Mu.L of INF-alpha was added and the final concentration of INF-alpha was 1000U/mL and shaken at room temperature for 20min. 2-5. Mu.L (5X) LANCE Ultra Lysis Buffer 2 solution was added and the mixture was shaken at room temperature for 2 hours. After 2h, 5. Mu.L of LANCE Ultra Eu-labeled Anti-STAT5 (Y694/Y699) Antibody (PerkinElmer) at a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT5 Antibody (PerkinElmer) at a final concentration of 20nM were added and incubated overnight at room temperature. The enzyme-labeled instrument measures 665nm fluorescence signal value of each plate hole, the inhibition rate is calculated through the fluorescence signal value, and the IC of the compound is obtained through curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate]/(positive control value-negative control value) ×100}. Calculation of IC using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4 parameter nonlinear logic formula 50 Values.
Conclusion of experiment:
the activity test data for inhibition of the TYK2 signaling pathway of the compounds of the present invention in cells obtained by the above protocol are shown in the following table:
conclusion of experiment: the compound of the invention shows good inhibition effect in an activity test of inhibiting a cell TYK2 signal channel.
Test example 2 measurement of the inhibitory Effect of the Compound of the present invention on the cell JAK2 Signal pathway
The purpose of the experiment is as follows: the purpose of this test case is to test compounds for their activity against cellular JAK2 signaling pathway inhibition.
Experimental instrument: the centrifuge (5702R) was purchased from Eppendorf company, the pipettor was purchased from Eppendorf company, and the microplate reader was purchased from BioTek company, USA under the model number SynergyH1 full function microplate reader.
The experimental method comprises the following steps: the test uses TF-1 cell line, activates JAK2 signal path through IL6 stimulation, detects the inhibition activity of compound on downstream STAT3 phosphorylation, and obtains half inhibition concentration IC of compound on JAK2 signal path activity 50 。
The specific experimental operation is as follows:
TF-1 cells are paved into 384-hole detection plates with 3-12 mu L, the number of each hole of cells is 100-300K, 2 mu L of compound solution which is diluted in a gradient way is added, and the cells are incubated for 2 hours in a carbon dioxide incubator. After 2 hours, 2. Mu.L of IL6 was added, the final concentration of IL6 was 30ng/mL, and the mixture was shaken at room temperature for 20 minutes. 2-5. Mu.L (5X) LANCE Ultra Lysis Buffer2 solution was added and shaken at 4℃for 2h. After 2h, 5. Mu.L of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr 705) Antibody (PerkinElmer) at a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) at a final concentration of 20nM were added and incubated overnight at room temperature. The enzyme-labeled instrument measures 665nm fluorescence signal value of each plate hole, the inhibition rate is calculated through the fluorescence signal value, and the IC of the compound is obtained through curve fitting according to the inhibition rates of different concentrations 50 。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate]/(positive control value-negative control value) ×100}. Calculation of IC using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4 parameter nonlinear logic formula 50 Values.
Conclusion of experiment:
the activity test data for inhibition of the JAK2 signaling pathway of the compounds of the present invention in cells obtained by the above protocol are shown in the following table:
conclusion of experiment: from the data in the table, it can be seen that the compounds of the examples have a certain selectivity for JAK2 cell activity compared to TYK2 cell activity.
Test example 3, balb/C mouse pharmacokinetic assay
1. Study purposes:
the pharmacokinetic behavior of the example compounds was studied in plasma in mice orally administered at a dose of 5mg/kg using Balb/C mice as the test animals.
2. Test protocol
2.1 test drug:
according to the embodiment of the invention, the home-made product is prepared.
2.2 test animals:
Balb/C Mouse 6/example, male, shanghai Jieshike laboratory animal Co., ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.3 administration:
Balb/C mice, males; after one night of fasting, the dosages were 5mg/kg, respectively, and the dosing volumes were 10mL/kg.
2.4 sample collection:
mice were bled with 0.1mL of orbital blood at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, and placed in EDTA-K before and after dosing 2 In a test tube, plasma was separated by centrifugation at 6000rpm at 4℃for 6min and stored at-80 ℃.
2.5 sample treatment:
1) The plasma sample was precipitated by adding 160. Mu.L acetonitrile to 40. Mu.L, and centrifuged at 3500 Xg for 5 to 20 minutes after mixing.
2) 100. Mu.L of the treated supernatant was taken and subjected to LC/MS/MS analysis for the concentration of the test compound.
2.6 liquid phase analysis
Liquid phase conditions: shimadzu LC-20AD pump
Mass spectrometry conditions AB Sciex API 4000 Mass spectrometer
Chromatographic column: phenomenex Gemiu 5um C18.times.4.6 mm
Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
Flow rate: 0.8mL/min
Elution time: 0-4.0 minutes, the eluent is as follows:
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 6.1 and the results of the mouse drug substitution experiments are shown in the following table:
| compounds of formula (I) | t max (h) | C max (ng/mL) | AUC 0-t (ng/mL*h) | t 1/2 (h) | MRT 0-∞ (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 |
Conclusion of experiment: as can be seen from the results of the mouse drug generation experiments in the table, the compound of the embodiment of the invention shows good metabolic properties, exposure AUC and maximum blood concentration C max All perform well.
Claims (8)
1. A compound represented by the general formula (VII) or a pharmaceutically acceptable salt thereof, characterized in that:
wherein:
ring D is selected from
R 16 Selected from hydrogen, deuterium, halogen, amino, hydroxy, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl or-NHCH 3 ；
When ring D isWhen R is 16 Not hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl;
when ring D isWhen R is 16 Not C 1-3 Deuterated alkyl;
m is an integer of 0 to 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 16 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, oxo, thio, methyl, ethyl, propyl, deuteromethyl, deuteroethyl, deuteropyropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, or-NHCH 3 。
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring D is selected from the group consisting of
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the general formula is selected from the group consisting of:
5. a process for preparing a compound of the general formula (VII) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises the steps of,
reacting the general formula (VII-1) with the general formula (VII-2) to obtain a compound shown in the general formula (VII) or pharmaceutically acceptable salt thereof;
wherein:
X 1 selected from halogen.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula as shown in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
7. Use of a compound of general formula (la) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the preparation of a TYK2 inhibitor drug.
8. Use of a compound of general formula (la) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for the treatment of inflammatory and autoimmune diseases; wherein the inflammatory and autoimmune diseases are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease.
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| US11691971B2 (en) * | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
| US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
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| WO2022046989A1 (en) | 2020-08-27 | 2022-03-03 | Incyte Corporation | Tricyclic urea compounds as jak2 v617f inhibitors |
| WO2022083560A1 (en) * | 2020-10-19 | 2022-04-28 | 南京药石科技股份有限公司 | Tyk2 selective inhibitor and use thereof |
| TW202227430A (en) * | 2020-11-17 | 2022-07-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | Nitrogen-containing derivatives, their preparation method and their medical use |
| MX2023006504A (en) * | 2020-12-02 | 2023-06-21 | Shenzhen Chipscreen Biosciences Co Ltd | Hydroxamate compound, preparation method therefor and application thereof. |
| CN116547276A (en) * | 2020-12-08 | 2023-08-04 | 正大天晴药业集团股份有限公司 | TYK2 inhibitor compounds containing an amide group and a heterocycloalkyl group |
| US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
| US20240124440A1 (en) * | 2020-12-23 | 2024-04-18 | Sudo Biosciences Limited | Tyk2 inhibitors and uses thereof |
| BR112023016590A2 (en) | 2021-02-19 | 2023-11-14 | Sudo Biosciences Ltd | TYK2 INHIBITORS AND THEIR USES |
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