CN111107848A - Pharmaceutical composition containing amide derivatives, and preparation method and application thereof - Google Patents

Pharmaceutical composition containing amide derivatives, and preparation method and application thereof Download PDF

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CN111107848A
CN111107848A CN201980004523.4A CN201980004523A CN111107848A CN 111107848 A CN111107848 A CN 111107848A CN 201980004523 A CN201980004523 A CN 201980004523A CN 111107848 A CN111107848 A CN 111107848A
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alkyl
heteroaryl
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CN111107848B (en
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高鹏
孙广俊
王少宝
张福军
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

A pharmaceutical composition containing amide derivatives, and its preparation method and application are provided. In particular to a pharmaceutical composition, which comprises a compound shown as a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and application of the pharmaceutical composition as an ASK1 inhibitor in treating neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmunity and metabolic diseases.

Description

Pharmaceutical composition containing amide derivatives, and preparation method and application thereof Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a pharmaceutical composition containing an amide derivative, and a preparation method and application thereof.
Background
Mitotically Activated Protein Kinase (MAPK) signaling pathways mediate a variety of different cellular functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and are key signaling pathways for cell mitosis and apoptosis. MAPK is divided into three major types, namely mitotically activated protein kinase (MAP3K), mitotically activated protein kinase (MAP2K) and Mitotically Activated Protein Kinase (MAPK), MAP3K is activated under the stimulation of environmental signals, so that MAP2K is activated, MAP2K further activates MAPK, and MAPK mediates corresponding cellular effects by phosphorylating downstream substrates thereof, such as transcription factors and the like.
Apoptosis signal-regulated kinase 1(ASK1), also called mitotically activated protein kinase 5(MAP3K5), belongs to a member of the MAPK family, mediates activation of MAPK signal pathways, ASK1 can be activated by autophosphorylation under stress reactions including oxidative stress, endoplasmic reticulum stress and calcium influx, so as to activate MAP2K (such as MKK3/6 and MKK4/7) downstream thereof, further activate c-Jun N-terminal kinase (JNK) and p38 mitotically activated protein kinase, cause apoptosis and other related cellular effects, ASK1 activation and its signal pathways play an important role in the processes of neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases, and the like.
The incidence rate of nonalcoholic steatohepatitis (NASH) is high, about 2-5 percent of NASH patients are globally or domestically, and the market scale is estimated to reach 350-400 billion dollars in 2025. At present, NASH has no clinical approval for marketed drugs, the early-stage researched NASH treatment targets comprise FXR, PPAR, GLP and the like, but the FXR and PPAR targets have a greater safety problem, the GLP belongs to the early-stage diabetes treatment target, the curative effect is not proved by an exact clinical endpoint, and the peptide drugs need daily subcutaneous injection administration. ASK1 is becoming a new mechanism and a new target in the field of NASH treatment, and its signaling pathway plays an important role in the development of NASH by promoting inflammation and fibrosis of liver tissues. The ASK1 inhibitor has great potential for clinical treatment of NASH, and has potential application value in other disease fields including treatment of neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, metabolic diseases and the like.
Disclosed inhibitor patent applications that selectively inhibit ASK1 include, among others, WO2011008709, WO2016025474, WO2012003387, WO2016105453, WO2016106384, and WO 2008008375.
The ASK1 inhibitor has good application prospect in the pharmaceutical industry, the invention provides a selective ASK1 inhibitor composition with a novel structure, and the finding shows that the compound with the structure has excellent effect and action in the aspects of pharmacokinetic activity and pharmacodynamic activity.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition, which comprises a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and has the following structure:
Figure PCTCN2019099971-APPB-000001
wherein:
M1、M2、M3and M4Each independently selected from N or-CR6；
X and Y are each independently selected from the group consisting of a bond,
Figure PCTCN2019099971-APPB-000002
-NR7-、-CR7R8-、-S(O)m-、
Figure PCTCN2019099971-APPB-000003
Figure PCTCN2019099971-APPB-000004
Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
R1are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
R2are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、 -(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
R3Selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
Or, R3And M3、M3And M4The linkage forms a cycloalkyl, heterocyclyl, aryl or heteroaryl group, respectively, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
or alternatively, R1And X or Y, M1And X or Y are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, respectively, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
R6、R7and R8Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
R9selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyl groups, amino groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
R10and R11The same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
R12and R13The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, ester group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group, wherein said alkyl 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 deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, ester group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;
x is an integer of 0, 1,2, 3 or 4;
y is an integer of 0, 1 or 2;
m is an integer of 0, 1 or 2; and is
n is an integer of 0, 1,2, 3,4 or 5.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, and even more preferably 10% to 50%.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the dosage is in the range of 0.5-120mg, preferably 1-100mg, more preferably 1-50mg, and even more preferably 1-30 mg.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (II):
Figure PCTCN2019099971-APPB-000005
wherein:
R4selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
R3and R4Linked to form a heterocycle or heteroaryl ring, wherein said heterocycle or heteroaryl ring is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
or, R3And R4Linking the formed heterocycle or heteroaryl ring, any two substituents on the heterocycle or heteroaryl ring can form cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, aromatic, heterocyclyl, or heteroaryl ring is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
ring A, M1、M2、X、Y、R1-R3X, y, m and n are as described in formula (I).
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (III):
Figure PCTCN2019099971-APPB-000006
ring B is selected from heterocyclyl or heteroaryl; wherein heterocyclyl preferably comprises 3 to 20 ring atoms, wherein one or more ring atoms is selected from nitrogen, oxygen, phosphorus or S (O) t and the remaining ring atoms are carbon, heterocyclyl further preferably comprises 3 to 12 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen and phosphorus and the remaining ring atoms are carbon, heterocyclyl further preferably comprises 3 to 8 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen and the remaining ring atoms are carbon, heterocyclyl most preferably comprises 5 to 7 ring atoms, wherein 1 to 2 ring atoms are selected from nitrogen, oxygen and the remaining ring atoms are carbon, heterocyclyl further most preferably is selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine; heteroaryl preferably comprises 5 to 14 ring atoms of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or s (o) t and the remaining ring atoms are carbon, heteroaryl further preferably comprises 5 to 10 ring atoms of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or s (o) t and the remaining ring atoms are carbon, heteroaryl more preferably comprises 5 to 10 ring atoms of which 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus and the remaining ring atoms are carbon, heteroaryl most preferably comprises 5 or 6 ring atoms of which 1 to 2 atoms are selected from nitrogen, oxygen;
Raselected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C1-8Alkenyl radical, C1-8Alkynyl, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, propyl group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, ethylene group, propylene group, butene group, acetylene group, propyne group, butyne group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, pyrazolyl group, Imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, C (O) CH3；
Wherein R isaOptionally further substituted by a substituent selected from the group consisting of deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxy group, alkenyl group, alkynyl group,Alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents of (1), preferably by deuterium atom, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, cyano, hydroxy, C2-8Alkenyl, C2-8Alkynyl, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1), more preferably deuterium atom, C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, cyano, hydroxy, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl-(CH2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by deuterium, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, ethylene, propylene, butene, acetylene, propynyl, butynyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
or, any two R on ring BaThe substituents form cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein the heteroatom is 1 to 4, preferably any two, R selected from nitrogen, oxygen, sulphur, phosphorusaThe substituents forming C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, wherein the heteroatom is 1 to 3 selected from nitrogen, oxygen, sulfur, phosphorus, more preferably any two RaThe substituents forming C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, wherein the heteroatom is 1 to 2 selected from nitrogen, oxygen, most preferably any two RaThe substituents form cyclopropyl, cyclobutyl, cyclopentyl, C3-5Heterocyclic group, C6-7Aryl and C5-7Heteroaryl, wherein the heteroatoms are 1 to 2 selected from nitrogen, oxygen;
wherein any two R areaThe ring formed by the substituents is optionally further substituted with a substituent selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is preferably substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、 -(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-7Aryl and C5-7Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1); most preferably by hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, ethylene, propylene, butene, acetylene, propyne, butyne, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrakis-propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, and the likeHydrogen furyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
z is an integer of 0, 1,2, 3,4 or 5;
t is 0, 1 or 2.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (IV):
Figure PCTCN2019099971-APPB-000007
wherein:
M5is O, -CR6or-NR7；
R6、R7Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy radicalHalogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine, chlorine, bromine, iodine, amino group, nitro group, hydroxy group, cyano groupCyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
wherein, R is6、R7Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably selected from deuterium atoms, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, difluoromethyl, trifluoromethyl, chloroethyl, chloropropyl, amino, nitro, chloro-ethoxy, chloro-propoxy, Imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinylSubstituted with one or more substituents of (a);
q is 0, 1 or 2.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (V):
Figure PCTCN2019099971-APPB-000008
wherein:
o is an integer of 0, 1,2, 3,4 or 5.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that:
M1、M2each independently selected from N or-CR6Optional M1、M2Different;
x and Y are each independently selected from the group consisting of a bond,
Figure PCTCN2019099971-APPB-000009
-NR7-、-CR7R8-、-S(O)m-、
Figure PCTCN2019099971-APPB-000010
Figure PCTCN2019099971-APPB-000011
Optionally X and Y are different;
ring A is selected from aryl or heteroaryl; the aryl group is a 6 to 14-membered all-carbon monocyclic ring or a fused polycyclic ring, preferably 6 to 10-membered, more preferably phenyl or naphthyl; preferably said heteroaryl group comprises 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms being carbon, further preferably said heteroaryl group comprises 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms being carbon, more preferably said heteroaryl group comprises 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus, the remaining ring atoms being carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole or pyrazinyl,
Figure PCTCN2019099971-APPB-000012
Figure PCTCN2019099971-APPB-000013
even more most preferably the heteroaryl group comprises 5 or 6 ring atoms, wherein 1 to 2 atoms are selected from nitrogen, oxygen;
wherein said ring A is optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is preferably substituted by one or more substituents selected from deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably by one or more substituents selected from the group consisting of deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, methoxy, ethoxy, propoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl,Pyrimidinyl, thiadiazoles, pyrazinyl,
Figure PCTCN2019099971-APPB-000014
Figure PCTCN2019099971-APPB-000015
Figure PCTCN2019099971-APPB-000016
Is substituted with one or more substituents of (1);
R2are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Preferably selected from hydrogen atoms, deuterium atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a More preferably from hydrogen atoms, deuterium atoms, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Most preferably selected from the group consisting of hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, hydroxypropoxy group, hydroxy-substituted methyl group, hydroxy-substituted ethyl group, hydroxy-substituted propyl group, fluoro group, chloro group, bromo group, iodo group, amino group, nitro group, hydroxy group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenylA group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, and a pyrazinyl group.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (III-A):
Figure PCTCN2019099971-APPB-000017
in a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (III-A1) or formula (III-A2):
Figure PCTCN2019099971-APPB-000018
wherein the content of the first and second substances,
ring C is a 4-7 membered heterocyclyl or heteroaryl group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or s (o) t, the remaining ring atoms are carbon, preferably a 5 membered heterocyclyl group comprising 1-2 nitrogen or oxygen atoms; the heteroaryl group preferably comprises 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, preferably a 5-or 6-membered heteroaryl group comprising 1 to two heteroatoms of nitrogen or oxygen; preferably, ring C is of the structure:
Figure PCTCN2019099971-APPB-000019
Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8Haloalkyl group
t is 0, 1 or 2.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: the method is characterized in that: r1Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
Wherein R is1Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、 -(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloro ethoxy group, chloroPropoxy, methyl substituted with hydroxy, ethyl substituted with hydroxy, propyl substituted with hydroxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: r1Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein R is1Optionally further substituted.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: the method is characterized in that: r1Selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, and trifluoromethylA group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoropropoxy group, chloromethoxy group, chlorompropoxy group, fluorine, chlorine, bromine, iodine, amino group, nitro group, hydroxyl group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrazolyl group, oxazolyl group, pyrrolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, thiadiazole, pyrazinyl group; optionally substituted with a group selected from hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloropropoxy group, hydroxy-substituted methyl group, hydroxy-substituted ethyl group, hydroxy-substituted propyl group, fluoro group, chloro group, bromo group, iodo group, amino group, nitro group, hydroxy group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidyl group, piperidinyl group, and the, Piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (VI-A) or formula (VI-B):
Figure PCTCN2019099971-APPB-000020
R5selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, C1-8Hydroxyalkyl, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy、C1-6Hydroxyalkyl, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, hydroxyl-substituted methyl group, hydroxyl-substituted ethyl group, hydroxyl-substituted propyl group, hydroxyl-substituted butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
wherein R is5Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents of (1), preferably by deuterium atom, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, cyano, hydroxy, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); more preferably by deuterium atom, C1-6Alkyl, halo C1-6Alkyl, halogen, amino, nitro, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); most preferably deuterium atom-, methyl-, ethyl-, n-propyl-, isopropyl-, difluoromethyl-, trifluoromethyl-, fluoroethyl-, fluoropropyl-, dichloromethyl-, trichloromethyl-, chloroethyl-, chloropropyl-, methoxy-, ethoxy-, propoxy-, fluoromethoxy-, fluoroethoxy-, fluoropropoxy-, chloromethoxy-, chloroethoxy-, chloropropoxy-, fluoropropoxy-, fluorine-, chlorine-, bromine-, iodine-, amino-, nitro-, hydroxy-, cyano-, hydroxy-substituted methyl-, hydroxy-substituted ethyl-, hydroxy-substituted propyl-, hydroxy-substituted butyl-, cyclopropyl-, cyclobutyl-, cyclopentyl-, oxetanyl-, pyrrolidinyl-, imidazolidinyl-, tetrahydrofuranyl-, tetrahydrothienyl-, dihydroimidazolyl-, dihydrofuranyl-, dihydropyrazolyl-, dihydropyrrolyl-, piperidinyl-, piperazinyl-, morpholinyl-, thiomorpholinyl-, homopiperazinyl-, pyranyl-, phenyl-, imidazolyl-, etc, Furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
x-1 is an integer of 1,2, 3 or 4.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (VI-A1) or formula (VI-B1):
Figure PCTCN2019099971-APPB-000021
M5is O, -CR6or-NR7；
R6、R7The same or different and each is independently selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro groupHydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、 -(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, propyl group, fluoromethyl group, fluoroethyl group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrazolyl group, Oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
wherein, R is6、R7Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably selected from deuterium atoms, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroEthyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, propoxy, fluoromethoxy, fluoroethoxy, fluoro-ethoxy, fluoropropoxy, chloro-propoxy, chloro-methoxy, chloro-propoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, thiadiazole or pyrazinyl;
q is 0, 1 or 2.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I) is represented by formula (VI-A2) or formula (VI-B2):
Figure PCTCN2019099971-APPB-000022
o is an integer of 0, 1,2, 3,4 or 5.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (VII):
Figure PCTCN2019099971-APPB-000023
wherein:
ring B is selected from heterocyclyl or heteroaryl;
R5selected from hydrogen atom, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogenElements, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably a cyclopropyl group;
Raselected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably C1-8Alkyl radical, C1-8Alkoxy radical, C1-8A cycloalkyl group;
or, any two R on the B ringaThe substituents may form new cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said forming new cycloalkyl, aromatic, heterocyclyl or heteroaryl groups is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
x-1 is an integer of 1,2, 3 or 4; and is
z is an integer of 0, 1,2, 3,4 or 5;
ring A, M1、M2、X、Y、R1-R5X, y, m and n are as described in formula (I).
In a preferred embodiment of the present invention, the pharmaceutical composition, when ring B is selected from heterocyclyl, preferably comprises 3 to 20 ring atoms, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen or s (o) t, t is 0, 1 or 2, and the remaining ring atoms are carbon; more preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen, oxygen; most preferably 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen, oxygen; when ring B is selected from heteroaryl, it is preferably a heteroaryl group comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, more preferably a 5 to 10 membered heteroaryl group comprising 1 to 2 heteroatoms, wherein the heteroatoms are selected from oxygen and nitrogen, most preferably a 5 or 6 membered heteroaryl group comprising 1 to 2 heteroatoms, wherein the heteroatoms are selected from oxygen and nitrogen;
further preferred structures of ring B are as follows:
Figure PCTCN2019099971-APPB-000024
in a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (VIII):
Figure PCTCN2019099971-APPB-000025
wherein: ring A, ring B, M1、M2、R1、R2、R5、RaX-1, y and z are as described in formula (I).
In a preferred embodiment of the present invention, the pharmaceutical composition, characterized in that the compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds of the general formula (IX):
Figure PCTCN2019099971-APPB-000026
wherein:
ring B, R1、R5、RaX-1 and z are as described in formula (I).
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of the following general formula (X-a):
Figure PCTCN2019099971-APPB-000027
wherein:
M5is O, -CR6or-NR7；
R1Selected from hydrogen atoms, C1-8Alkyl or halogen;
R5is selected from C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Haloalkyl, C1-8Hydroxyalkyl or 3-6 membered heterocyclyl;
Rathe same or different, each independently selected from hydrogen atom, cyano, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Haloalkyl, C1-8HydroxyalkanesBase, C1-8Alkoxy radical, C3-8Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Wherein said C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo C1-8Alkyl radical, C1-8Hydroxyalkyl, C1-8Alkoxy and C3-8Cycloalkyl is optionally further substituted by a group selected from hydrogen atom, deuterium atom, halogen, cyano, hydroxy, C1-8Alkyl radical, C1-8Hydroxyalkyl or C1-8Substituted with one or more substituents of alkoxy; or any two RaThe substituents forming C3-8Cycloalkyl or C3-8A heterocyclic group;
R9and R10The same or different, each independently selected from hydrogen atom, C1-8Alkyl radical, C1-8Haloalkyl, C1-8Hydroxyalkyl or C1-8An alkoxy group;
x-1 is an integer of 1,2, 3 or 4;
q is 0, 1 or 2; and is
z is an integer of 0, 1,2, 3,4 or 5.
In a preferred embodiment of the present invention, the pharmaceutical composition, characterized in that the compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds of the general formula (XI):
Figure PCTCN2019099971-APPB-000028
o is an integer of 0, 1,2, 3,4 or 5; and is
R1、R5、RaX and z are as described for formula (VI).
In a preferred embodiment of the present invention, the pharmaceutical composition, wherein the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds of formula (XII):
Figure PCTCN2019099971-APPB-000029
wherein:
Rathe same or different, each independently selected from hydrogen atom, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, - (CH)2)nOR9Or- (CR)9R10)n-, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy and C3-6Cycloalkyl is optionally further substituted by a group selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkyl or C1-6Substituted with one or more substituents of alkoxy; or any two RaThe substituents may form a 3-to 6-membered cycloalkyl group, an
z is an integer of 0, 1,2 or 3.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (XIII-a) as follows:
Figure PCTCN2019099971-APPB-000030
wherein:
M5selected from S or CH;
R3is selected from C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-8Cycloalkyl and 3-10 membered heterocyclyl, wherein said C is1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-8Cycloalkyl and 3-10 membered heterocyclyl are optionally further selected from the group consisting of hydrogen atom, deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, halogen, amino, hydroxy, cyano, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl;
R4selected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-8Cycloalkyl or 3-10 membered heterocyclyl;
or R3And R4Linked to form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, wherein said 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further substituted with one or more substituents selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, halogen groups, amino groups, nitro groups, hydroxy groups, cyano groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (a);
Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group; wherein R isbMay be substituted at oxo ring or at M5Ring substitution;
p is an integer of 0, 1,2, 3 or 4; and is
q is an integer of 0 or 1.
In a more preferred embodiment of the present invention, the pharmaceutical composition of formula (XIII-A) is characterized in that ring C is a 4-7 membered heterocyclic or heteroaryl group, preferably a 5 membered heterocyclic group, most preferably ring C has the structure:
Figure PCTCN2019099971-APPB-000031
in a more preferred embodiment of the present invention, the pharmaceutical composition, characterized in that the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds of formula (XIII-B):
Figure PCTCN2019099971-APPB-000032
wherein:
ring C is a 4-to 7-membered heterocyclyl or heteroaryl group, preferably a 5-membered heterocyclyl group;
Rathe same or different, each independently selected from hydrogen atom, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Or any two RaThe substituents may form 3-6 membered cycloalkyl;
Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group;
R9and R10Independently selected from a hydrogen atom or C1-8An alkyl group;
z is an integer of 0, 1,2, 3 or 4; and is
p is 0, 1 or 2.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R is1Is selected from C1-8Alkyl radical, C3-8Cycloalkyl, 5-10 membered heteroaryl and halogen, preferably 5-6 membered heteroaryl, halogen, C1-6Alkyl groups, more preferably pyrazole, fluorine atoms and methyl groups.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R isaSelected from hydrogen atom, cyano, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Haloalkyl, C1-8Hydroxyalkyl, cyano-substituted C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Preferably from hydrogen atoms, cyano groups, hydroxy groups, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl radical, C1-6Haloalkyl, 3-to 6-membered heterocyclic group, C3-6A cycloalkyl group; most preferred is methyl, ethyl, vinyl, ethynyl or trifluoromethyl.
In a preferred embodiment of the present invention, each of the formulae shown, stereoisomers thereof or pharmaceutically acceptable salts thereof, is characterized by optionally any two of R whereinaTo form a 3-6 membered cycloalkyl group, preferably cyclopropyl.
In a preferred embodiment of the invention, each of the formulae depicted, stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein R is5Selected from hydrogen atoms, C1-8Alkyl radical, C1-8Haloalkyl, C1-8Hydroxyalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, halogen, C3-8Cycloalkyl, 3-to 10-membered heterocyclic group, preferably selected from hydrogen atom, C1-6Alkyl, hydroxy C1-6Alkyl radical C1-6Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl; r5Most preferably cyclopropyl, isopropyl, hydroxyisopropyl, tert-butyl, trifluoromethyl or
Figure PCTCN2019099971-APPB-000033
The invention also relates to a method for the treatment and/or prophylaxis of diseases with pathological features mediated by ASK1, comprising administering to a patient a therapeutically effective dose of a pharmaceutical composition.
The invention further relates to the pharmaceutical composition, which is characterized in that the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition thereof in preparing ASK1 inhibitor drugs.
The invention further relates to the use of said pharmaceutical composition for the preparation of a medicament for the treatment of neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders and ASK1, said inflammatory disorders preferably being non-alcoholic steatohepatitis (NASH).
The invention further relates to the pharmaceutical composition and a method for preparing the pharmaceutical composition for treating nonalcoholic steatohepatitis (NASH).
The invention also relates to a method for the therapeutic prevention and/or treatment of diseases that are pre-prepared for the treatment of neurodegenerative, cardiovascular, inflammatory, metabolic disorders, comprising administering to a patient a therapeutically effective dose of a pharmaceutical composition.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol, or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4And the substituent groups can be connected to different carbon atoms to form a carbon chain, and can also be connected to one carbon atom to form a cycloalkyl. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthioAlkyl, amino, halogen, mercapto, hydroxyl, 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 8 carbon atoms, more 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 "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or are further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring; the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyanoCycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2019099971-APPB-000034
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2019099971-APPB-000035
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Alkoxy groups having 1 to 8 carbon atoms are preferred, alkoxy groups having 1 to 6 carbon atoms are more preferred, and alkoxy groups having 1 to 3 carbon atoms are most preferred. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" means alkenyl, also known as alkenyl, preferably alkenyl containing 2 to 8 carbon atoms, more preferably alkenyl of 2 to 6 carbon atoms, most preferably alkenyl of 2 to 3 carbon atoms; wherein said alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" means (CH.ident.C-), preferably alkynyl containing 2 to 8 carbon atoms, more preferably alkynyl of 2 to 6 carbon atoms, most preferably alkynyl of 2 to 3 carbon atoms. Wherein said alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3"means tris (dibenzylidene)Mesityl oxide) dipalladium.
"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
"stereoisomerism" encompasses geometric isomerism (cis-trans isomerism), optical isomerism, conformational isomerism, and the like.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco 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. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai 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 present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000036
The first step is as follows: preparation of 5-amino-2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-APPB-000037
5-bromo-4-fluoro-2-methylaniline (10.0g,49.0mmol), cuprous cyanide (8.78g,98.0mmol) were mixed in NMP (50mL), stirred at 180 ℃ for 1h under nitrogen, then at 100 ℃ overnight. After cooling, 28 wt% aqueous ammonia was added, stirred for 15 minutes and extracted three times with EtOAc. The organic phases were combined, washed three times with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 5-amino-2-fluoro-4-methylbenzonitrile (5.70g, 78%).
MS m/z(ESI):151.1[M+H]+.
The second step is that: preparation of 5- ((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-APPB-000038
5-amino-2-fluoro-4-methylbenzonitrile (5.70g,38.0mmol), K2CO3(6.30g,45.6mmol), KI (0.630g,3.80mmol), 2-bromo-1-cyclopropylethane-1-one (7.43g,45.6mmol) were mixed in DMF (50mL) and stirred at 80 ℃ for 90 min under nitrogen. After the reaction is cooled, the 2-bromo-1-cyclopropylethane-1-Ketone (3.00g,18.4mmol), K2CO3(2.54g,18.4mmol) and further stirred at 75 ℃ for 1 hour. After cooling to room temperature, water was added to the reaction flask, and after standing for 15 minutes, filtration was carried out, the filter cake was washed with water, and dried to give crude title compound 5- ((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile (6.80g, 77%).
MS m/z(ESI):233.1[M+H]+.
The third step: preparation of 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-APPB-000039
A solution of 5- ((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile (6.80g,29.3mmol), KSCN (5.69g,58.6mmol) in acetic acid (100mL) was stirred at 110 ℃ for 4h, cooled, concentrated, and CH was added2Cl2And water, separating out the organic phase, and reusing the aqueous phase with CH2Cl2And extracting once. The organic phases are combined, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain 8.00g of crude 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile which is directly used for the next reaction.
MS m/z(ESI):274.1[M+H]+.
The fourth step: preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-APPB-000040
To a solution of the above crude product in acetic acid (160mL) and water (32mL) was slowly added dropwise hydrogen peroxide (30 wt%, 10.0mL) at 50 ℃ and stirred at that temperature for one hour. Cooling to room temperature, and slowly adding Na2SO3Aqueous solution (20 wt%, 100mL) and then stirred for 30 minutes. Concentrating to remove organic solvent, and collecting water phase with CH2Cl2The extraction was performed twice. Mixing the organic phases, sequentially adding saturated sodium bicarbonate water solution and saturated foodWashed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile (3.3g, 47% yield over two steps).
MS m/z(ESI):242.1[M+H]+.
The fifth step: synthesis of 6-aminomethyl pyridine hydrazide
Figure PCTCN2019099971-APPB-000041
Methyl 6-aminomethylpyridyl ester (2.0g,13mmol) was dissolved in ethanol (60mL) at room temperature, and hydrazine hydrate (4.1g,66mmol) was added. The reaction was heated to 80 ℃ and stirred at that temperature for 5 hours, and after slowly cooling to room temperature, the solid precipitated in the reaction solution was filtered and the filter cake was collected to give the title compound 6-aminomethylpyridine hydrazide (1.6g, 80%).
MS m/z(ESI):153.2[M+H]+.
And a sixth step: synthesis of 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000042
6-Aminomethylpyridinohydrazide (300mg,1.97mmol) was dissolved in 2-pentanol (5mL) and acetic acid (1mL) at room temperature, and 5-methoxy-3, 4-dihydro-2H-pyrrole (195mg,1.97mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentration and column chromatography to afford the title compound 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (360mg, 91%).
MS m/z(ESI):202.1[M+H]+.
The seventh step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure PCTCN2019099971-APPB-000043
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile (1.8g,7.47mmol) was dissolved in 30mL concentrated hydrochloric acid, heated under reflux and stirred overnight, cooled, concentrated and dried to give 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (2g, crude) which was used directly in the next step.
The above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (100mg, crude product above) was dissolved in thionyl chloride (5mL) at room temperature, stirred under heating reflux for 2 hours, cooled and concentrated under reduced pressure to give a pale yellow solid product which was used directly in the next reaction.
Eighth step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000044
6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (43mg,0.22mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100mg, crude from the above step) in THF (5mL) and pyridine (5mL) at room temperature, followed by 4-dimethylaminopyridine (11mg,0.09 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then water (5mL) was added dropwise, dichloromethane (50mL × 2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (60mg, 63%).
1H NMR(400MHz,CDCl3)δ9.05(d,J＝15.1Hz,1H),8.34(d,J＝8.2Hz,1H),8.13-8.02(m,2H),7.88(t,J＝8.0Hz,1H),7.48(m,1H),7.20(d,J＝12.4Hz,1H),6.80(m,1H),4.53-4.34(m,2H),3.04(t,J＝7.7Hz,2H),2.96-2.74(m,2H),2.30(s,3H),1.98-1.82(m,1H),0.90(m,2H),0.88-0.76(m,2H)；
MS m/z(ESI):444.1[M+H]+.
Example 2
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000045
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) benzamide reference is made to example 1.
1H NMR(400MHz,CDCl3)δ9.00(d,J＝14.9Hz,1H),8.29(d,J＝0.8Hz,1H),7.99(d,J＝7.3Hz,1H),7.92-7.90(m,1H),7.83(t,J＝7.9Hz,1H),7.43(d,J＝1.0Hz,1H),7.12(d,J＝12.3Hz,1H),6.73(m,1H),4.57(m,2H),3.03-3.01(m,2H),2.22(s,3H),1.85(m,3H),1.81(m,2H),1.74(m,2H),0.85-0.82(m,2H),0.79-0.76(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 3
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000046
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) benzamide the procedure was followed as in example 1.
1H NMR(400MHz,CDCl3)δ8.98(d,J＝14.6Hz,1H),8.27(d,J＝8.2Hz,1H),7.99(t,J＝7.5Hz,2H),7.81(t,J＝8.0Hz,1H),7.39(s,1H),7.12(d,J＝12.3Hz,1H),6.72(s,1H),4.41(t,J＝6.0Hz,2H),3.00(t,J＝6.4Hz,2H),2.22(s,3H),2.03-1.95(m,2H),1.93-1.87(m,2H),1.85-1.79(m,1H),0.88-0.79(m,2H),0.78-0.70(m,2H)；
MS m/z(ESI):458.2[M+H]+.
Example 4
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000047
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference is made to example 1.
1H NMR(400MHz,CDCl3)δ9.08(d,J＝14.7Hz,1H),8.41-8.35(m,1H), 8.13-8.07(m,1H),8.05(d,J＝7.3Hz,1H),7.91(t,J＝8.0Hz,1H),7.48(d,J＝1.2Hz,1H),7.20(d,J＝12.3Hz,1H),6.80(d,J＝1.2Hz,1H),5.06(s,2H),4.59(t,J＝5.2Hz,2H),4.09(t,J＝5.3Hz,2H),2.30(s,3H),1.95-1.86(m,1H),0.95-0.87(m,2H),0.87-0.78(m,2H)；
MS m/z(ESI):460.2[M+H]+.
Example 5
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000048
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) benzamide the procedure was followed as in example 1.
1H NMR(400MHz,CDCl3)δ9.01(d,J＝14.5Hz,1H),8.29(d,J＝8.3Hz,1H),7.99(t,J＝8.3Hz,2H),7.83(d,J＝8.0Hz,1H),7.42(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H),4.45(t,J＝5.5Hz,2H),4.27(s,2H),3.24(t,J＝5.5Hz,2H),2.33(s,1H),2.22(s,3H),1.84-1.82(m,1H),0.87-0.80(m,2H),0.78-0.75(m,2H)；
MS m/z(ESI):459.2[M+H]+.
Example 6
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000049
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) benzamide the procedure is as in example 1.
1H NMR(400MHz,CDCl3)δ8.98(d,J＝14.8Hz,1H),8.29(d,J＝8.2Hz,1H),8.01(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H),4.49(t,J＝5.5Hz,2H),3.80(s,2H),2.83(t,J＝5.5Hz,2H),2.48(s,3H),2.22(s,3H),1.85(m,1H),0.85-0.82(m,2H),0.79-077(m,2H)；
MS m/z(ESI):473.2[M+H]+.
Example 7
4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (3- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) phenyl) picolinamide
Figure PCTCN2019099971-APPB-000050
Preparation of 4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (3- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) phenyl) picolinamide reference is made to example 1.
1H NMR(400MHz,CDCl3)δ10.16(s,1H),8.68(d,J＝5.4Hz,1H),8.49(s,1H),8.27(d,J＝2.1Hz,1H),8.01(d,J＝1.0Hz,1H),7.92-7.64(m,2H),7.63-7.41(m,2H),7.22(d,J＝1.0Hz,1H),4.35(t,J＝7.1Hz,2H),3.08-3.04(m,2H),2.89-2.84(m,2H),1.94-1.90(m,1H),0.95-0.91(m,2H),0.87-0.84(m,2H)；
MS m/z(ESI):412.2[M+H]+.
Example 8
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000051
First step synthesis of (R) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000052
Trimethyloxonium tetrafluoroborate (3.55g,24.0mmol) was added portionwise to a solution of (R) -5-methylpyrrolidin-2-one (1.7g,17.2mmol) in dichloromethane (40mL) under ice-bath. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3The aqueous solution (5mL), dichloromethane (50 mL. times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, added with glacial acetic acid (5mL), and concentrated under reduced pressure to give the crude product which was used directly in the next reaction.
MS m/z(ESI):114.1[M+H]+.
Second step synthesis of (R) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000053
6-Aminomethylpyridinohydrazide (2.35g,15.4mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL) at room temperature, and (R) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole (1.93g,17.1mmol) was added. The reaction is heated to 125 ℃, stirred for 12 hours at the temperature, cooled to room temperature,concentrating under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound (R) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (1.62g, 49% yield over two steps).
1H NMR(400MHz,CDCl3)δ7.65(m,1H),7.61-7.42(m,1H),6.54(m,1H),5.17-4.88(m,1H),3.18-2.77(m,3H),2.43-2.31(m,1H),1.53-1.37(m,3H)；
MS m/z(ESI):216.1[M+H]+.
The third step is the synthesis of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000054
(R) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (139mg,0.65mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (298mg,1.07mmol) in THF (10mL) and pyridine (10mL) at room temperature, followed by 4-dimethylaminopyridine (12mg,0.097 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then water (5mL), dichloromethane (50mL × 2) was added and extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and column-chromatographed to give the title compound (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (151mg, 51% yield).
1H NMR(400MHz,CDCl3)δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5.03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1.90(m,1H),1.56(d,J＝6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H)；
MS m/z(ESI):458.1[M+H]+.
Example 9
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000055
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CDCl3)δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5.03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1.90(m,1H),1.56(d,J＝6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H)；
MS m/z(ESI):458.1[M+H]+.
Example 10
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000056
First step synthesis of 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000057
Trimethyloxonium tetrafluoroborate (0.66g,4.45mmol) was added portionwise to a solution of 5, 5-dimethylpyrrolidin-2-one (0.36g,3.2mmol) in dichloromethane (30mL) under ice-bath. The reaction was then slowly brought to room temperature and stirred at this temperature for 5 hours, and thenThen saturated NaHCO is added3The aqueous solution (5mL), dichloromethane (50 mL. times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, added with glacial acetic acid (5mL), and concentrated under reduced pressure to give the crude product which was used directly in the next reaction.
MS m/z(ESI):128.2[M+H]+.
Second step synthesis of 6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000058
6-Aminomethylpyridinohydrazide (435mg,2.86mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL) at room temperature, and 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole (404mg,3.2mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound 6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (380mg, 52% yield over two steps).
MS m/z(ESI):230.1[M+H]+.
Step three, synthesizing 5- (4-cyclopropyl-1H-imidazole-1-yl) -N- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridine-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000059
To a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (70mg,0.25mmol) in THF (5mL) and pyridine (5mL) was added 6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (35mg,0.15mmol) at room temperature, 4-dimethylaminopyridine (4.6mg,0.04mmol) was added. The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then quenched by addition of water (5mL), extracted with dichloromethane (50mL × 2), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (39mg, 54% yield).
1H NMR(400MHz,CDCl3)δ9.05(d,J＝16.6Hz,1H),8.29-8.27(m,1H),8.09-7.94(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.2Hz,1H),6.73(s,1H),3.10-2.86(m,2H),2.60-2.45(m,2H),2.22(s,3H),1.88-1.82(m,1H),1.72(s,6H),0.87-0.82(m,2H),0.78-0.75(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 11
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000060
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CDCl3)δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7.49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m,1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2.82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H)；
MS m/z(ESI):488.2[M+H]+.
Example 12
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000061
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CDCl3)δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7.49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m,1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2.82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H)；
MS m/z(ESI):488.2[M+H]+.
Example 13
(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000062
Preparation of (R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ9.22(d,J＝1.4Hz,1H),8.45(d,J＝8.2Hz,1H),8.10(t,J＝8.0Hz,1H),8.05-7.97(m,2H),7.66(s,1H),7.50(d,J＝10.9Hz,1H),5.57-5.45(m,1H),3.47-3.36(m,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.59(d,J＝6.5Hz,3H),1.43(d,J＝6.9Hz,6H)；
MS m/z(ESI):460.2[M+H]+.
Example 14
(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000063
Preparation of (S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ9.21(s,1H),8.55-8.30(m,1H),8.18-7.96(m,3H),7.67(s,1H),7.51(d,J＝9.8Hz,1H),5.54-5.34(m,1H),3.34(s,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.57(d,J＝5.8Hz,3H),1.42(d,J＝6.9Hz,6H)；
MS m/z(ESI):460.2[M+H]+.
Example 15
(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000064
Preparation of (R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure was followed in example 8.
1H NMR(400MHz,CD3OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H),5.64(s,1H), 3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J＝5.5Hz,3H),1.48(s,9H)；
MS m/z(ESI):474.2[M+H]+.
Example 16
(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000065
Preparation of (S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure was followed in example 8.
1H NMR(400MHz,CD3OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H),5.64(s,1H),3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J＝5.5Hz,3H),1.48(s,9H)；
MS m/z(ESI):474.2[M+H]+.
Example 17
(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000066
Preparation of (S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference is made to example 8.
MS m/z(ESI):490.2[M+H]+.
Example 18
(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000067
Preparation of (R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference is made to example 8.
MS m/z(ESI):490.2[M+H]+.
Example 19
(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000068
Preparation of (S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
MS m/z(ESI):504.2[M+H]+.
Example 20
(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000069
Preparation of (R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
MS m/z(ESI):504.2[M+H]+.
Example 21
(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-APPB-000070
Preparation of (R) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide the procedure is as in example 8.
MS m/z(ESI):486.2[M+H]+.
Example 22
(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-APPB-000071
Preparation of (S) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide the procedure is as in example 8.
MS m/z(ESI):486.2[M+H]+.
Example 23
(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-APPB-000072
Preparation of (R) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide reference was made to example 8.
MS m/z(ESI):474.2[M+H]+.
Example 24
(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-APPB-000073
Preparation of (S) -2-fluoro-4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide reference was made to example 8.
MS m/z(ESI):474.2[M+H]+.
Example 25
(R) -2-fluoro-5- (4- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000074
Preparation of (R) -2-fluoro-5- (4- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide reference is made to example 8.
MS m/z(ESI):476.2[M+H]+.
Example 26
(S) -2-fluoro-5- (4- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000075
Preparation of (S) -2-fluoro-5- (4- (2-hydroxypropan-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide reference is made to example 8.
MS m/z(ESI):476.2[M+H]+.
Example 27
N- (6- (7-acetyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000076
N- (6- (7-acetyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide was prepared as in example 1.
1H NMR(400MHz,CDCl3)δ9.00(d,J＝15.0Hz,1H),8.31(m,1H),8.15-7.94(m,2H),7.84(t,J＝8.0Hz,1H),7.47-7.37(m,1H),7.14(m,1H),6.74(s,1H),4.95(m,2H),4.62-4.44(m,2H),3.93(m,2H),2.22(s,3H),2.19(s,3H),1.85(m,1H),0.88-0.81(m,2H),0.78-0.75(m,2H)；
MS m/z(ESI):501.2[M+H]+.
Example 28
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000077
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ8.20(d,J＝8.1Hz,1H),7.87(t,J＝7.9Hz,1H),7.83-7.78(m,1H),7.68-7.62(m,2H),7.25(d,J＝11.2Hz,1H),6.96(s,1H),4.58-4.50(m,1H),4.34-4.23(m,1H),3.35-3.26(m,1H),2.94-2.86(m,1H),2.38-2.28(m,1H),2.17(s,3H),1.84-1.77(m,1H),1.35(d,J＝7.0Hz,3H), 0.81-0.77(m,2H),0.68-0.62(m,2H)；
MS m/z(ESI):458.2[M+H]+.
Example 29
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (6-methoxy-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000078
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (6-methoxy-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.11(s,1H),8.35(s,1H),8.11-7.90(m,3H),7.60(s,1H),7.50(d,J＝10.3Hz,1H),4.71-4.62(m,2H),3.46(s,3H),3.39-3.35(m,2H),3.15-3.03(m,1H),2.35(s,3H),2.13-2.06(m,1H),1.19-1.13(m,2H),0.97-0.88(m,2H)；
MS m/z(ESI):474.2[M+H]+.
Example 30
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6-cyclopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000079
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6-cyclopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ8.22(d,J＝8.1Hz,1H),7.88(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.64(d,J＝6.6Hz,1H),7.58(d,J＝1.2Hz,1H),7.27(d,J＝11.1Hz,1H),6.94(d,J＝1.1Hz,1H),4.70-4.63(m,1H),4.18-4.14(m,1H),3.13-3.07(m,1H),2.79-2.72(m,1H),2.55-2.43(m,1H),2.17(s,3H),1.82-1.77(m,1H),1.01-0.91(m,1H),0.81-0.74(m,2H),0.67-0.62(m,2H),0.53-0.47(m,2H),0.28-0.16(m,2H)；
MS m/z(ESI):484.2[M+H]+.
Example 31
N- (6- (5'H,7' H-spiro [ cyclopropane-1, 6 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000080
The preparation of N- (6- (5'H,7' H-spiro [ cyclopropane-1, 6 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide is as per example 8.
MS m/z(ESI):470.2[M+H]+.
Example 32
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000081
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ8.36-8.28(m,2H),8.00-7.86(m,2H),7.77(d,J＝5.9Hz,1H),7.37(d,J＝10.8Hz,1H),7.12(s,1H),4.31(s,2H),2.87(s,2H),2.29(s,3H),1.97-1.88(m,1H),1.35(s,6H),0.96-0.89(m,2H),0.80-0.74(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 33
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000082
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)；
MS m/z(ESI):458.2[M+H]+.
Example 34
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000083
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)；
MS m/z(ESI):458.2[M+H]+.
Example 35
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000084
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)；
MS m/z(ESI):458.2[M+H]+.
Example 36
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- ((R) -5- ((R) -1-methoxyethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000085
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- ((R) -5- ((R) -1-methoxyethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
1H NMR(400MHz,CDCl3)δ8.96(d,J＝15.6Hz,1H),8.31(m,1H),8.01(m,2H),7.83(t,J＝8.0Hz,1H),7.41(s,1H),7.12(d,J＝12.6Hz,1H),6.73(s,1H),5.08(m,1H),4.03-3.92(m,1H),3.36(s,3H),2.96-2.87(m,2H),2.87-2.64(m,3H),2.21(s,3H),0.85-0.79(m,7H)；
MS m/z(ESI):502.2[M+H]+.
Example 37
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000086
For the synthesis of (S) -5-vinylpyrrolidin-2-one see J.org.chem.,2017,82, 532-540.
MS m/z(ESI):112.2[M+H]+.
The first step is as follows: synthesis of (S) -5-methoxy-2-vinyl-3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000087
To (S) -5-vinylpyrrolidin-2-one (0.26g,2.34mmol) was dissolved in dichloromethane (60mL) under ice-bath and trimethyloxonium tetrafluoroborate (0.48g,3.28mmol) was added portionwise. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase with saturated brine washing, anhydrous sodium sulfate drying, adding glacial acetic acid (5mL), decompression concentration of organic solvent, crude product directly used in the next reaction.
MS m/z(ESI):126.1[M+H]+.
The second step is that: synthesis of (S) -6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000088
6-Aminomethylpyridinohydrazide (321mg,2.11mmol) was dissolved in a mixed solvent of 2-pentanol (10mL) and acetic acid (1mL) at room temperature, and (S) -5-methoxy-2-vinyl-3, 4-dihydro-2H-pyrrole (293mg,2.34mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, after cooling to room temperature, the organic solvent was concentrated under reduced pressure and then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating the organic solvent and separating by column chromatography to give the title compound (S) -6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (240mg, two)Step yield 50%).
MS m/z(ESI):228.1[M+H]+.
The third step: synthesis of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000089
(S) -6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (44mg,0.19mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (90mg,0.33mmol) in THF (5mL) and pyridine (5mL) at room temperature, followed by 4-dimethylaminopyridine (5.9mg,0.048 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then water (5mL) was added dropwise, dichloromethane (50mL × 2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated and column-chromatographed to give the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (53mg, 58% yield).
1H NMR(400MHz,CD3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)；
MS m/z(ESI):470.1[M+H]+.
Example 38
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000090
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide refers to example 37.
1H NMR(400MHz,CD3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)；
MS m/z(ESI):470.1[M+H]+.
Example 39
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000091
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide reference example 37.
1H NMR(400MHz,CD3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)；
MS m/z(ESI):470.1[M+H]+.
Example 40
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000092
The first step is as follows: synthesis of (S) -5-methoxy-2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000093
(S) -5- (trifluoromethyl) pyrrolidin-2-one (0.6g,3.92mmol) was dissolved in dichloromethane (40mL) under ice-bath and trimethyloxonium tetrafluoroborate (0.81g,5.5mmol) was added portionwise. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase with saturated brine washing, anhydrous sodium sulfate drying, adding glacial acetic acid (5mL), decompression concentration of organic solvent, crude product directly used in the next reaction.
MS m/z(ESI):168.2[M+H]+.
The second step is that: synthesis of (S) -6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000094
6-Aminomethylpyridinohydrazide (620mg,3.71mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL) at room temperature, and (S) -5-methoxy-2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrole (650mg, 3.89mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating the organic solvent, and separating by column chromatography to give the title compound (S) -6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (560mg, 56% yield over two steps).
MS m/z(ESI):270.2[M+H]+.
The third step: synthesis of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000095
(S) -6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (43mg,0.22mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100mg,0.36mmol) in THF (5mL) and pyridine (5mL) at room temperature, followed by 4-dimethylaminopyridine (11mg,0.09 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then the reaction was quenched by addition of water (5mL), extracted with dichloromethane (50mL × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and then isolated by column chromatography to give the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (51mg, 62% yield).
1H NMR(400MHz,CDCl3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)；
MS m/z(ESI):512.2[M+H]+.
EXAMPLE 41
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000096
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide refers to example 40.
1H NMR(400MHz,CDCl3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)；
MS m/z(ESI):512.2[M+H]+.
Example 42
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000097
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide refers to example 40.
1H NMR(400MHz,CDCl3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)；
MS m/z(ESI):512.2[M+H]+.
Example 43
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000098
Synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylate is described in org.Lett.2011,13,2634-
The first step is as follows: synthesis of S-ethyl (S) -5-carbonyl pyrrolidine-2-methylsulfate
Figure PCTCN2019099971-APPB-000099
(S) -5-Carbonylpyrrolidine-2-carboxylic acid (20g,150mmol) was dissolved in CH under ice bath2Cl2(300mL) and DMF (160mL) were added DMAP (1.85g,15.0mmol) followed by ethanethiol (13.8mL,180mmol) and DCC (40.5g,180 mmol). The reaction was slowly warmed to room temperature, stirred at this temperature for 16 hours, and saturated NaHCO was added3Aqueous solution (20mL), dichloromethane (100 mL. times.2) extraction, organic phase with saturated brine, dried over anhydrous sodium sulfate, reduced pressure concentration and column chromatography to give the title compound S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (18.5g, 69%).
MS m/z(ESI):174.1[M+H]+.
The second step is that: synthesis of tert-butyl (S) -2- ((ethylthio) carbonyl) -5-carbonylpyrrolidine-1-carboxylate
Figure PCTCN2019099971-APPB-000100
S-Ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (6g,34.6mmol) was dissolved in MeCN (35mL) in ice bath, followed by the sequential addition of Boc2O (8.28mL,35.0mmol), DMAP (470mg,3.46 mmol). The reaction was slowly warmed to room temperature, stirred at this temperature for 2 hours, and saturated NaHCO was added3Aqueous solution (20mL), ethyl acetate (100 mL. times.2) extraction, organic phase with saturated brine, drying over anhydrous sodium sulfate, vacuum concentration and column chromatography separation to get the title compound S-ethyl (S) -5-carbonyl pyrrolidine-2-methyl sulfate (7.3g, 77%).
MS m/z(ESI):296.1[M+Na]+.
The third step: synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylate
Figure PCTCN2019099971-APPB-000101
S-Ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (1.0g,3.66mmol) was dissolved in acetone (15mL) under ice-bath, followed by the addition of Pd/C (160mg), EtSiH (1.28g,10.98mmol) in that order. The reaction was allowed to slowly warm to room temperature, after stirring at this temperature for 1 hour, it was filtered through celite, and the filtrate was concentrated under reduced pressure to give an oily product (0.72g) which was used directly in the next step.
1H NMR(400MHz,CDCl3)δ9.58(s,1H),4.63-4.41(m,1H),2.54-2.48(m,2H),2.28-2.15(m,1H),2.07-2.01(m,1H),1.46(s,9H)；
MS m/z(ESI):214.1[M+H]+.
The fourth step: synthesis of (S) -5-carbonyl pyrrolidine-2-formaldehyde
Figure PCTCN2019099971-APPB-000102
Tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylate (0.72g,3.38mmol) was dissolved in CH under ice bath2Cl2To (10mL) was added TFA (2.5mL) in that order. The reaction was slowly warmed to room temperature, stirred at this temperature for 2 hours, and concentrated under reduced pressure to give the crude product (400mg) as an oil which was used directly in the next step.
MS m/z(ESI):114.1[M+H]+.
The fifth step: synthesis of (S) -5-ethynylpyrrolidin-2-one
Figure PCTCN2019099971-APPB-000103
(S) -5-Carbonylpyrrolidine-2-carbaldehyde (400mg, crude product from above) was dissolved in MeOH (15mL) in an ice bath, followed by the sequential addition of K2CO3(931mg,6.74mmol), (1-diazo-2-oxopropyl) phosphonic acid dimethyl ester (1.01g,4.04 mmol). The reaction was slowly warmed to room temperature, stirred at that temperature for 12 hours, and saturated brine (20mL) was added with CH2Cl2(100 mL. times.2), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatographyThe title compound (S) -5-ethynylpyrrolidin-2-one (260mg, 71%) was isolated.
1H NMR(400MHz,CDCl3)δ6.68(s,1H),4.38-4.35(m,1H),2.50-2.40(m,2H),2.37(d,J＝2.2Hz,1H),2.33-2.26(m,1H),2.22-2.15(m,1H)；
MS m/z(ESI):110.1[M+H]+.
And a sixth step: synthesis of (S) -2-ethynyl-5-methoxy-3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000104
(S) -5-ethynylpyrrolidin-2-one (0.26g,2.38mmol) was dissolved in CH under ice-bath2Cl2To the solution (10mL) was added trimethyloxonium tetrafluoroborate (0.67g,4.53mmol) in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3Aqueous solution (5mL) with CH2Cl2(50 mL. times.2) and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5mL) was added and the organic solvent was concentrated under reduced pressure to give the crude product (315mg) which was used directly in the next reaction.
MS m/z(ESI):124.2[M+H]+.
The seventh step: synthesis of (S) -6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000105
6-Aminomethylpyridinohydrazide (320mg,2.1mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL) at room temperature, and (S) -2-ethynyl-5-methoxy-3, 4-dihydro-2H-pyrrole (315mg, crude product from above) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase with saturated brine washing, anhydrous sodium sulfate drying, organic solvent concentration and columnThe title compound (S) -6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2, 1-c) is obtained by chromatographic separation][1,2,4]Triazol-3-yl) pyridin-2-amine (362mg, 46% yield over two steps).
MS m/z(ESI):226.2[M+H]+.
Eighth step: synthesis of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000106
(S) -6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (80mg,0.36mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (220mg,0.79mmol) in THF (25mL) and pyridine (35mL) at room temperature, followed by 4-dimethylaminopyridine (15mg,0.12 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then the reaction was quenched by addition of water (5mL), extracted with dichloromethane (50mL × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and then isolated by column chromatography to give the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (122mg, 73% yield).
1H NMR(400MHz,CDCl3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H), 8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)；
MS m/z(ESI):468.2[M+H]+.
Example 44
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000107
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference example 43.
1H NMR(400MHz,CDCl3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)；
MS m/z(ESI):468.2[M+H]+.
Example 45
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000108
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference example 43.
1H NMR(400MHz,CDCl3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)；
MS m/z(ESI):468.2[M+H]+.
Example 46
(S) -N- (6- (5-cyano-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000109
Preparation of (S) -N- (6- (5-cyano-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.17-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H)；
MS m/z(ESI):469.1[M+H]+.
Example 47
(R) -N- (6- (5-cyano-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000110
Preparation of (R) -N- (6- (5-cyano-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.17-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H)；
MS m/z(ESI):469.1[M+H]+.
Example 48
(S) -N- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000111
Preparation of (S) -N- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6 Hz,1H),5.80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H),2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H)；
MS m/z(ESI):483.2[M+H]+.
Example 49
(S) -N- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000112
Preparation of (R) -N- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide reference is made to example 8.
1H NMR(400MHz,CD3OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6Hz,1H),5.80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H),2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H)；
MS m/z(ESI):483.2[M+H]+.
Example 50
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000113
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
1H NMR(400MHz,CDCl3)δ9.06(d,J＝15.6Hz,1H),8.28-8.16(m,1H),8.04(d,J＝7.2Hz,1H),7.79-7.65(m,2H),7.42(t,J＝4.0Hz,1H),7.19(d,J＝12.2Hz,1H),6.79(s,1H),4.97-4.83(m,1H),4.47(m,1H),4.05-3.87(m,1H),3.30-3.15(m,1H),3.00-2.75(m,3H),2.29(s,3H),1.94-1.75(m,2H),0.94-0.86(m,2H),0.86-0.70(m,2H)；
MS m/z(ESI):474.1[M+H]+.
Example 51
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000114
First step (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole synthesis
Figure PCTCN2019099971-APPB-000115
To (S) -5- (fluoromethyl) pyrrolidin-2-one (0.7g,6.0mmol) was dissolved in dichloromethane (60mL) under ice-bath, and trimethyloxonium tetrafluoroborate (1.24g,8.4mmol) was added in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase with saturated brine washing, anhydrous sodium sulfate drying, adding glacial acetic acid (5mL), decompression concentration of organic solvent, crude product directly used in the next reaction.
MS m/z(ESI):132.2[M+H]+.
The second step is the synthesis of (S) -6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000116
6-Aminomethylpyridinohydrazide (900mg,6.0mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL) at room temperature, and (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole (783mg,6.0mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating the organic solvent, and column chromatography to give the title compound (S) -6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (430mg, 55% yield over two steps).
1H NMR(400MHz,CDCl3)δ7.69(m,1H),7.66-7.51(m,1H),6.60-6.47(m,1H),5.21-5.04(m,1H),4.94(m,0.5H),4.82(m,1H),4.70(m,0.5H),3.20-2.92(m,3H),2.85-2.70(m,1H)；
MS m/z(ESI):234.2[M+H]+.
Step three, synthesizing (S) -5- (4-cyclopropyl-1H-imidazole-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000117
(S) -6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (195mg,0.84mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (390mg,1.4mmol) in THF (15mL) and pyridine (15mL) at room temperature, followed by 4-dimethylaminopyridine (26mg,0.21 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then quenched by addition of water (5mL), extracted with dichloromethane (50mL × 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide was isolated by column chromatography after concentrating the organic solvent under reduced pressure (179mg, 45% yield).
1H NMR(400MHz,CDCl3)δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8.0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87(m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H)；
MS m/z(ESI):476.2[M+H]+.
Example 52
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000118
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 51.
1H NMR(400MHz,CDCl3)δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8.0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87(m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H)；
MS m/z(ESI):476.2[M+H]+.
Example 53
(R) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000119
Preparation of (R) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27-6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H)；
MS m/z(ESI):474.1[M+H]+.
Example 54
(S) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000120
Preparation of (S) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide the procedure is as in example 8.
1H NMR(400MHz,CD3OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27-6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H)；
MS m/z(ESI):474.1[M+H]+.
Example 55
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000121
The first step is as follows: preparation of (S) - (5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate
Figure PCTCN2019099971-APPB-000122
(S) -5- (hydroxymethyl) pyrrolidin-2-one (5.0g,43.5mmol), p-toluenesulfonyl chloride (13.3g,71.7mmol), and triethylamine (13.2g,130.6mmol) were dissolved in this order in dichloromethane (60mL) at room temperature, reacted overnight at room temperature, diluted with dichloromethane (80mL), washed with 1N HCl, the organic phase was dried over anhydrous sodium sulfate, filtered, the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to give (S) - (5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (8.3g, yield: 71%).
1H NMR(400MHz，CDCl3)δ7.79(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),6.26(s,1H),4.06-4.03(m,1H),3.97-3.84(m,2H),2.46(s,3H),2.36-2.19(m,3H),1.83-1.72(m,1H)；
MS m/z(ESI):270.1[M+H]+.
The second step is that: preparation of (R) -5-ethylpyrrolidin-2-one
Figure PCTCN2019099971-APPB-000123
Under the ice bath condition, cuprous iodide (1.06g,5.6mmol) is dissolved in tetrahydrofuran (6mL), nitrogen is replaced three times, methyllithium (7.4mL,11.1mmol) is added dropwise, the reaction is stirred at 0 ℃ for 45min, the reaction system is cooled to-20 ℃, a tetrahydrofuran (6mL) solution of (S) - (5-carbonyl-pyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (500mg,1.9mmol) is added dropwise into the reaction system, the reaction system is stirred at-20 ℃ for 45min, the reaction system is gradually raised to room temperature for overnight, saturated ammonium chloride is added, ethyl acetate is used for extraction, an organic phase is dried by anhydrous sodium sulfate, an organic solvent is concentrated by reduced pressure after filtration, and crude product is purified by column chromatography to obtain (R) -5-ethyl-pyrrolidin-2-one (185mg, yield: 86%).
1H NMR(400MHz，CD3OD)δ3.54-3.45(m,1H),2.24-2.19(m,2H),2.18-2.09(m,1H),1.66-1.57(m,1H),1.53-1.43(m,1H),1.42-1.32(m,1H),0.84(t，J＝7.5Hz,3H)；
MS m/z(ESI):114.2[M+H]+.
The third step: preparation of (R) -2-ethyl-5-methoxy-3, 4-dihydro-2H-pyrrole
Figure PCTCN2019099971-APPB-000124
Trimethyloxonium tetrafluoroborate (226mg,1.59mmol) was added portionwise to a solution of (R) -5-ethylpyrrolidin-2-one (180mg,1.59mmol) in dichloromethane (10mL) under ice-bath. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3The aqueous solution (5mL), dichloromethane (50 mL. times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, added with glacial acetic acid (5mL), and concentrated under reduced pressure to give the crude product which was used directly in the next reaction.
MS m/z(ESI):128.2[M+H]+.
The fourth step: synthesis of 6-aminomethyl pyridine hydrazide
Figure PCTCN2019099971-APPB-000125
Methyl 6-aminomethylpyridyl ester (2.0g,13mmol) was dissolved in ethanol (60mL) at room temperature, and hydrazine hydrate (4.1g,66mmol) was added. The reaction was heated to 80 ℃ and stirred at that temperature for 5 hours, and after slowly cooling to room temperature, the solid precipitated in the reaction solution was filtered and the filter cake was collected to give the title compound 6-aminomethylpyridine hydrazide (1.6g, 80%).
MS m/z(ESI):153.2[M+H]+.
The fifth step: preparation of (R) -6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000126
6-Aminomethylpyridinohydrazide (243mg,1.59mmol) was dissolved in 2-pentanol (5mL) and acetic acid (2mL) at room temperature, and (R) -2-ethyl-5-methoxy-3, 4-dihydro-2H-pyrrole (202mg,1.59mmol) was added. The reaction was heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Aqueous solution (5mL), dichloromethane (50 mL. times.2) extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and column chromatographed to give the title compound (R) -6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-amine (70mg, 19% yield).
MS m/z(ESI):230.2[M+H]+.
And a sixth step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure PCTCN2019099971-APPB-000127
The above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (154mg,0.594mmol) was dissolved in thionyl chloride (5mL) at room temperature, stirred under heating reflux for 2 hours, cooled and concentrated under reduced pressure to give a pale yellow solid product which was used directly in the next reaction.
The seventh step: preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000128
(R) -6- (5-Ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (68mg, 0.297mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (165mg,0.594mmol) in THF (6mL) and pyridine (4mL) at room temperature, followed by 4-dimethylaminopyridine (15mg,0.119 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then water (5mL), dichloromethane (50mL × 2) was added and extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and column-chromatographed to give the title compound (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (26mg, 19% yield).
1H NMR(400MHz,CDCl3)δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz,1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.08-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 56
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000129
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide reference is made to example 55.
1H NMR(400MHz,CDCl3)δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz,1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.08-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 57
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000130
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
1H NMR(400MHz,CDCl3)δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H), 2.22(s,3H),1.85(m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H)；
MS m/z(ESI):486.2[M+H]+.
Example 58
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000131
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide reference example 8.
1H NMR(400MHz,CDCl3)δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H),2.22(s,3H),1.85(m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H)；
MS m/z(ESI):486.2[M+H]+.
Example 59
(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000132
Preparation of (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide refers to example 55.
1H NMR(400MHz,CDCl3)δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89(m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.63(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H)；
MS m/z(ESI):486.2[M+H]+.
Example 60
(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-APPB-000133
Preparation of (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide refers to example 55.
1H NMR(400MHz,CDCl3)δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89(m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.63(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H)；
MS m/z(ESI):486.2[M+H]+.
Example 61
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000134
The first step is as follows: synthesis of 5-methoxy-4-azaspiro [2.4] hept-4-ene
Figure PCTCN2019099971-APPB-000135
Under ice-bath, 4-azaspiro [2.4] is added]To a solution of heptan-5-one (1.7g,17.2mmol) in dichloromethane (60mL) was added trimethyloxonium tetrafluoroborate (3.55g,24.0mmol) in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, and then saturated NaHCO was added3The aqueous solution (5mL), dichloromethane (50 mL. times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, added with glacial acetic acid (5mL), and concentrated under reduced pressure to give the crude product which was used directly in the next reaction.
MS m/z(ESI):126.2[M+H]+.
The second step is that: synthesis of 6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-amine
Figure PCTCN2019099971-APPB-000136
6-Aminomethylpyridinohydrazide (500mg,4.5mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL) at room temperature, and 5-methoxy-4-azaspiro [2.4] was added]Hept-4-ene (930mg,6.3 mmol). Inverse directionIt is heated to 125 ℃ and stirred at this temperature for 12 hours, cooled to room temperature and concentrated under reduced pressure. Then saturated NaHCO was added3Extracting with water solution (5mL), dichloromethane (50mL × 2), washing organic phase with saturated brine, drying with anhydrous sodium sulfate, concentrating organic solvent, and separating by column chromatography to obtain title compound 6- (6',7' -dihydrospiro [ cyclopropane-1, 5' -pyrrolo [2, 1-c)][1,2,4]Triazole compounds]-3' -yl) pyridin-2-amine (515mg, 50% yield over two steps).
1H NMR(400MHz,CDCl3)δ7.60-7.44(m,2H),6.57-6.47(m,1H),4.31(s,2H),3.21-3.05(m,2H),2.79-2.67(m,2H),2.13-2.05(m,2H),0.86-0.79(m,2H)；
MS m/z(ESI):228.2[M+H]+.
The third step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-APPB-000137
6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-amine (39mg,0.17mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (80mg,0.29mmol) in THF (5mL) and pyridine (5mL) at room temperature, followed by 4-dimethylaminopyridine (5.3mg,0.043 mmol). The reaction was heated to 45 ℃ and stirred at that temperature for 2 hours, then water (5mL), dichloromethane (50mL × 2) was added and extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated and then column chromatographed to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (51mg, 63% yield).
1H NMR(400MHz,CDCl3)δ9.05(d,J＝16.6Hz,1H),8.33-8.31(m,1H),8.09(d,J＝7.4Hz,1H),8.06-7.99(m,1H),7.86(t,J＝8.0Hz,1H),7.46(s,1H),7.21(d,J＝12.6Hz,1H),6.80(s,1H),3.17(t,J＝7.6Hz,2H),2.80(t,J＝7.8Hz,2H),2.30(s,3H),2.19-2.05(m,2H),1.98-1.84(m,1H),1.00-0.87(m,4H),0.87-0.78(m,2H)；
MS m/z(ESI):470.2[M+H]+.
Example 62
N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methylbenzamide
Figure PCTCN2019099971-APPB-000138
Preparation of N- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methylbenzamide reference example 61.
1H NMR(400MHz,CDCl3)δ9.06(d,J＝16.6Hz,1H),8.31(m,1H),8.05(m,2H),7.86(t,J＝8.0Hz,1H),7.57(s,1H),7.22(d,J＝12.4Hz,1H),6.77(s,1H),3.17(t,J＝7.6Hz,2H),2.99(m,1H),2.80(t,J＝7.8Hz,2H),2.31(s,3H),2.19-2.12(m,2H),1.33(d,J＝6.8Hz,6H),0.98(m,2H)；
MS m/z(ESI):472.2[M+H]+.
Example 63
6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one
Figure PCTCN2019099971-APPB-000139
The first step is as follows: preparation of methyl 5-amino-2-cyano-4-methylbenzoate
Figure PCTCN2019099971-APPB-000140
Methyl 5-amino-2-bromo-4-methylbenzoate (900mg,3.69mmol), CuCN (657mg,7.38mmol) were mixed in NMP (10mL), stirred at 180 ℃ for 2 hours, cooled, then water was added, filtered, and the filter cake was dried to give the title compound methyl 5-amino-2-cyano-4-methylbenzoate crude product (1.5g), which was used directly in the next step.
MS m/z(ESI):191.1[M+H]+.
The second step is that: preparation of 6-amino-5-methylisoindoline-1-one
Figure PCTCN2019099971-APPB-000141
The crude product was dissolved in methanol (20mL) and Raney Ni (ca. 100mg) was added in H2Stirring overnight under the conditions of atmosphere (2-3 atm) and normal temperature. The catalyst was removed by filtration through Celite, and the filtrate was concentrated and subjected to column chromatography to give the title compound, 6-amino-5-methylisoindoline-1-one (800mg, crude product).
MS m/z(ESI):163.1[M+H]+.
The third step: preparation of 6- ((2-cyclopropyl-2-carbonylethyl) amino) -5-methylisoindoline-1-one
Figure PCTCN2019099971-APPB-000142
6-amino-5-methylisoindoline-1-one (370mg,2.28mmol), 2-bromo-1-cyclopropylethane-1-one (409mg,2.51mmol), KI (38.0mg,0.228mmol), K2CO3(378mg,2.74mmol) was mixed in DMF (5mL) and stirred at 55 ℃ for 2 h. After cooling, water was added to the mixture, which was extracted twice with dichloromethane. The organic phases were combined, washed three times with saturated brine, dried and the organic solvent removed under reduced pressure, and the crude product was used directly in the next step.
MS m/z(ESI):245.1[M+H]+.
The fourth step: preparation of 6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -5-methylisoindoline-1-one
Figure PCTCN2019099971-APPB-000143
The crude product of the third step was dissolved in AcOH (10mL), and KSCN (442mg,4.56mmol) was added to the solution, followed by stirring at 120 ℃ for 2 hours. After cooling, the reaction was concentrated and the crude product was used directly in the next step.
MS m/z(ESI):286.1[M+H]+.
The fifth step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisoindoline-1-one
Figure PCTCN2019099971-APPB-000144
The crude product from the fourth step was dissolved in a mixed solvent of AcOH (10mL) and water (2mL), stirred, and to this solution was slowly added dropwise hydrogen peroxide (30 wt%, 10.0g,87.8mmol) at 50 ℃. After the addition was complete, stirring was continued at this temperature for 1 hour. The reaction solution was cooled and 20 wt% Na was slowly added2SO3The aqueous solution (30mL) was stirred at room temperature for 30 minutes. The organic solvent was removed under reduced pressure and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to give the title compound 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisoindoline-1-one (180mg, five-step yield: 42%).
MS m/z(ESI):254.1[M+H]+.
And a sixth step: preparation of 3- (6-chloropyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole
Figure PCTCN2019099971-APPB-000145
Preparation of 3- (6-chloropyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole refers to the fifth and sixth steps of example 1.
MS m/z(ESI):221.1[M+H]+.
The seventh step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one
Figure PCTCN2019099971-APPB-000146
6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisoindolin-1-one (50mg,0.197mmol), 2-chloro-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (48mg,0.22mmol), cesium carbonate (86mg, 0.30 mmol) were mixed in 1, 4-dioxane (4mL), nitrogen was deoxygenated for 5 minutes, Pd was added2(dba)3(18mg,0.02mmol), deoxygenated under nitrogen for an additional 5 minutes, followed by the addition of Xantphos (23mg,0.04mmol), deoxygenated under nitrogen for an additional 5 minutes, followed by stirring at 120 ℃ for two days. Cooled, concentrated and separated with dichloromethane and water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by preparative thin layer chromatography to give the title compound 6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1,2,4]Triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one (43mg, yield: 50%).
1H NMR(400MHz,CDCl3)δ8.63(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.84(t,J＝8.0Hz,1H),7.76(s,1H),7.48(s,1H),6.84(s,1H),5.08(s,2H),4.48(t,J＝7.2Hz,2H),2.88(m,2H),2.35(s,3H),1.93(m,1H),0.91(m,2H),0.85(m,2H)；
MS m/z(ESI):438.2[M+H]+.
Example 64
6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -5-methylisoindoline-1-one
Figure PCTCN2019099971-APPB-000147
Preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -5-methylisoindolin-1-one reference is made to example 63.
1H NMR(400MHz,CDCl3)δ8.70(d,J＝8.0Hz,1H),7.95(d,J＝7.2Hz,1H),7.87(t,J＝8.0Hz,1H),7.78(s,1H),7.56(s,1H),7.49(s,1H),6.63(s,1H),5.13(s,2H),3.19(t,J＝7.6Hz,2H),2.80(t,J＝7.6Hz,2H),2.35(s,3H),1.93(m,3H),1.01(m,2H),0.88(m,4H)；
MS m/z(ESI):464.2[M+H]+.
Example 65
(S) -6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methyl-2- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) isoindolin-1-one
Figure PCTCN2019099971-APPB-000148
Preparation of (S) -6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methyl-2- (6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) isoindolin-1-one reference example 63.
1H NMR(400MHz,CDCl3)δ8.67(d,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H), 7.85(t,J＝8.0Hz,1H),7.77(s,1H),7.56(s,1H),7.50(s,1H),6.84(s,1H),5.58(m,1H),5.10(d,J＝13.2Hz,1H),4.91(d,J＝13.2Hz,1H),3.19(m,2H),3.00(m,2H),2.35(s,3H),1.94(m,1H),0.90(m,4H)；
MS m/z(ESI):506.2[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
1. Testing ASK1 enzymological experiments
The experiment adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition effect of the compound on the ASK1 kinase activity, and obtains the half inhibition concentration IC of the compound on the ASK1 kinase activity50。
1) Adding 1-5 uL ASK1 enzyme solution into a 384-well plate, wherein the final concentration of the enzyme is 0.2-20 nM.
2) And adding 1-5 uL of the compound solution diluted in a gradient manner.
3) Adding 1-5 uL of substrate mixed solution containing 100-5000 nM of substrate polypeptide and 100-1000 uM of ATP final concentration.
4) And incubating for 0.5-5 hours at room temperature.
5) And adding 10uL of EDTA and detection solution containing a labeled antibody, and incubating at room temperature for 2-24 hours.
6) The microplate reader measures the fluorescence signal at approximately 615nm and 665nm for each plate well.
7) The inhibition rate was calculated from the fluorescence signal value.
8) Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
The enzymatic activities of the compounds of the examples of the present invention are shown in Table 1.
TABLE 1 enzymatic Activity of the Compounds exemplified in the present invention
Compound numbering ASK1 IC 50(nM)
Example 1 6.0
Example 2 9.3
Example 3 13.4
Example 4 47.8
Example 7 19.6
Example 8 1.8
Example 9 5.0
Example 10 1.0
Example 11 10.6
Example 13 2.7
Example 14 9.0
Example 15 1.4
Example 16 4.1
Example 30 11.4
Example 31 10.9
Example 32 4.9
Example 33 7.2
Example 34 5.2
Example 36 9.1
Example 37 3.5
Example 38 4.1
Example 40 1.9
EXAMPLE 41 7.7
Example 43 1.9
Example 44 3.6
Example 48 6.1
Example 50 9.6
Example 51 4.9
Example 53 8.2
Example 55 1.9
Example 56 5.0
Example 59 2.9
Example 60 6.6
Example 61 1.9
Example 62 3.0
Example 63 8.4
Example 64 5.5
Example 65 9.4
The compounds of the above examples can obviously inhibit the enzymatic activity of ASK1 kinase, part of the compounds have strong inhibition effect on ASK1 kinase, and the IC of kinase enzyme activity inhibition50Less than 10nM, these compounds have great potential as potent inhibitors of ASK1 for the treatment of NASH.
2. Mouse PK analysis
The mouse pharmacokinetic experiments of the preferred embodiment of the invention were performed using Balb/c male mice (Shanghai Jitsie laboratory animals Co., Ltd.).
■ administration mode is single intragastric administration.
■ at a dose of 5 mg/10 ml/kg.
■ the preparation is prepared by dissolving 0.5% CMC-Na with ultrasound.
■ sample points 0.5, 1,2,4, 6, 8 and 24 hours post-dose.
■ sample treatment:
1) 0.1mL of blood is collected in orbit and placed in K2Centrifuging the plasma in an EDTA test tube at the room temperature of 1000-3000 Xg for 5-20 min, and storing the plasma at-80 ℃.
2) Adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, and centrifuging for 5-20 minutes at 500-2000 Xg after mixing.
Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.
■ LC-MS/MS analysis:
● liquid phase conditions: shimadzu LC-20AD pump
● Mass Spectrometry conditions: AB Sciex API 4000 mass spectrometer
● column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm
● mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
● flow rate: 0.8mL/min
● elution time: gradient elution for 0-3.5 min
■ pharmacokinetics:
the main parameters were calculated using WinNonlin 6.1, and the mouse pharmacokinetic experimental results are shown in table 2 below:
TABLE 2
Figure PCTCN2019099971-APPB-000149
Figure PCTCN2019099971-APPB-000150
As can be seen from the results of the mouse pharmacokinetic experiments in the table: the inventionThe compounds of the examples show good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.
3. Rat PK analysis
Rat pharmacokinetic experiments in the preferred embodiment of the invention were performed using SD male rats (Shanghai Jitsie laboratory animals Co., Ltd.).
■ administration mode is single intragastric administration.
■ at a dose of 5 mg/10 ml/kg.
■ formulation 5% EtOH-75% PG-10% Kolliphor-10% Water, dissolved by sonication.
■ sample points 0.5, 1,2,4, 6, 8 and 24 hours post-dose.
■ sample treatment:
2) collecting blood in vein of 0.2mL, and placing in K2Centrifuging the plasma in an EDTA test tube at the room temperature of 1000-3000 Xg for 5-20 min, and storing the plasma at-80 ℃.
3) Adding 160uL acetonitrile into 40uL of the plasma sample for precipitation, and centrifuging for 5-20 minutes at 500-2000 Xg after mixing.
4) Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.
■ liquid phase analysis:
● liquid phase conditions: shimadzu LC-20AD pump
● Mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy
● column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm
● mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
● flow rate: 0.8mL/min
● elution time: gradient elution for 0-3.5 min
■ pharmacokinetics:
the main parameters were calculated using WinNonlin 6.1, and the rat pharmacokinetic experimental results are shown in table 3 below:
TABLE 3
Figure PCTCN2019099971-APPB-000151
As can be seen from the results of the rat pharmacokinetic experiments in the table: compared with the prior art, the compounds of the embodiment of the invention show good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.
4. The compound of the invention is used for HFD (high fat diet) + CCl4Effect of induced non-Alcoholic steatohepatitis mice ALT and AST levels
1) Purpose of the experiment:
the purpose of this test example was to determine whether the compounds of the present invention could down-regulate the levels of ALT and AST in serum of nonalcoholic steatohepatitis mice.
2) Experimental raw materials and instruments:
using a glutamic-pyruvic transaminase (ALT/GPT) test kit: nanjing technology Co Ltd
Aspartate aminotransferase (AST/GOT) test kit: nanjing technology Co Ltd
96-well plate: corning Ltd
BioTek Synergy H1 microplate reader: BioTek, USA
3) The experimental steps are as follows:
c57BL/6 mice were acclimatized in SPF (specific pathogen free) barrier for 3-7 days, then fed with replacement HFD feed for 8 weeks, fed with HFD for the fifth week, randomly divided into groups according to animal body weight, and orally administered twice a week with CCl4Induction, and lasting for 4 weeks; administration of CCl4Modeling the oral administration beginning on the day, wherein the administration frequency is once a day and the administration is continuously carried out for 28 days; the solvent control group is given with the corresponding solvent of the test sample, and the administration volume is 10 mL/kg; CCl448 hours after the last administration, with CO2Euthanizing a mouse, collecting animal non-anticoagulated venous blood from a heart, placing whole blood at normal temperature for at least 30 minutes, centrifuging under the condition of 4-5000 r 5 minutes of centrifugation, separating serum, subpackaging into two parts, and placing into an EP (ethylene propylene) tube with the volume of 1.5mL for storage at-80 ℃ for later use.
Serum ALT and AST levels were measured in mice using alanine aminotransferase (ALT/GPT) and aspartate aminotransferase (AST/GOT) test cassettes. Preheating ALT (or AST) detection matrix liquid in a 37 ℃ thermostat; adding 20uL of matrix solution into a 96-well plate, adding 5uL of serum into the 96-well plate as a measurement hole, uniformly mixing, and placing the mixture into a 37 ℃ incubator by using a sealing membrane sealing plate for incubation for 30 min; preparing an ALT (or AST) standard curve, sucking 25uL and adding into a 96-well plate; then 20uL of plasma is sucked and added into a 96-well plate to be used as a control hole; adding 20uL of 2, 4-dinitrophenylhydrazine solution into each hole, mixing uniformly, placing the mixture into a thermostat at 37 ℃ by using a sealing film sealing plate, incubating for 20min, adding 200uL of 0.4M NaOH solution into each hole, placing the holes on a plate shaking instrument, shaking for 15min, reading the plates by using an OD detection program on a BioTek Synergy H1 instrument, wherein the wavelength is 510nm, and calculating an absolute OD value according to the OD value of each hole. Absolute OD value-assay well OD value-control well OD value; and (3) substituting the absolute OD value into a standard curve to obtain the ALT (or AST) content in the sample, and detecting the sample beyond the standard curve after diluting the serum to a proper concentration.
Data processing: (% ALT reduction) ═ vehicle control-test compound)/vehicle control group x 100%;
(% AST reduction) ═ vehicle control-test compound)/vehicle control x 100%.
4) The results of the experiments are shown in table 4 below:
TABLE 4
ALT (U/L) reduction rate AST (U/L) reduction rate
Vehicle control - -
GS-4997 40％ 35％
Example 8 56％ 58％
Example 9 69％ 67％
Example 10 50％ 46％
Example 15 54％ 58％
Example 34 67％ 60％
Example 37 57％ 62％
Example 40 50％ 65％
Practice ofExample 43 65％ 58％
Example 55 56％ 55％
Example 61 50％ 54％
Example 64 51％ 47％
Example 65 46％ 52％
5) And (4) experimental conclusion:
compared with the prior art, the compound shows good effect in the down-regulation of the ALT and AST levels in the serum of the nonalcoholic steatohepatitis mouse.
5. The compounds of the examples of the invention were subjected to a 7-day gavage dosing test in SD rats
1) Purpose of the experiment:
examples 9 and 43 of the present invention were repeatedly gavaged to male SD rats 1 time a day for 7 consecutive days at doses of 10, 30, 100mg/kg to evaluate possible toxic reactions and in vivo metabolism.
2) Experimental equipment and reagents:
blood analyzer
Figure PCTCN2019099971-APPB-000152
Series of
Automatic blood coagulation analyzer
Figure PCTCN2019099971-APPB-000153
Full-automatic biochemical analyzer TBA-120FR
Electrolyte analyzer easy lyte
Sodium carboxymethylcellulose (CMC-Na) Chemicals group chemical Co., Ltd
Jiangsu health medical products Limited company of blood biochemical blood collection tube
EDTA-K2Jiangsu health medical products Limited of centrifuge tubes
3) Experimental methods and treatments:
prior to dosing, the compound formulated with vehicle 0.5% CMC-Na (control) was placed on a magnetic stirrer and stirred for at least 15 minutes with constant stirring during dosing. The compound/control was extracted exactly the required volume based on the measured body weight and administered by oral gavage.
The test period was observed at least twice daily (1 observation in each of the morning and afternoon) for about 4 hours after the first dose, and the observations included, but not limited to, mental state, behavioral activity, skin, coat, eye, ear, nose, abdomen, external genitalia, anus, limbs, feet, respiration; animals in each group were weighed 2 times per week.
All animals were scheduled to euthanasia on day 8 before abdominal aorta blood was collected for blood cell count, coagulation function, blood biochemistry examination, each in the presence of EDTA-K2Anticoagulant (blood cell count), sodium citrate (blood coagulation function), separation gel and coagulant (blood biochemistry). The blood analyzer, the automatic blood coagulation analyzer and the full-automatic biochemical analyzer are respectively used for blood cell counting, blood coagulation function and blood biochemical index detection, and the electrolyte analyzer is used for electrolyte detection. The pathology was observed in gross anatomy, and after fixation of liver and lung, pathological sections were made and stained for further observation.
The toxokinetic blood samples are respectively taken before the first administration and the last administration, 0.5h, 1h after the first administration,Collecting for 2h, 4h, 8h, 12h and 24 h; before blood collection, EDTA-K is contained2The centrifugal tube is placed in a refrigerator at the temperature of 2-8 ℃ or in an ice bath for temporary storage; adding the collected blood into the marked centrifugal tube, manually reversing for at least 5 times, and temporarily storing in an ice bath; centrifugation conditions: centrifuging at 4 deg.C and 1500g for 10min, completing centrifugation within 2 hr, transferring centrifuged plasma to a new labeled centrifuge tube, and storing at-70 deg.C or below.
4) Results of the experiment
① animal death No death or dying phenomenon was observed in each group of animals during the test period.
② clinical observations during the trial, it was observed that individual animals were fluffy at the dose of 100mg/kg on days 7-8 after administration, and the clinical observations of the animals in the remaining time periods did not change abnormally.
③ body weight the weight average of each group of male mice showed a continuously increasing trend during the test period.
④ clinical pathology on day eight compared with vehicle control group, the blood cell count, blood coagulation function and blood biochemical index of male mice are not changed in toxicological significance under the dosage of 10, 30 and 100mg/kg in examples 9 and 43.
⑤ gross and histopathological examination in this trial, examples 9 and 43, at doses of 10, 30, 100mg/kg, no gross changes were observed, and no associated changes were observed in the histopathological examination of the lungs and liver.
⑥ pharmacokinetics-No accumulation was observed in male mouse plasma in either of examples 9 and 43 in the 10-100mg/kg dose range.
5) And (4) experimental conclusion:
examples 9 and 43 were repeatedly gavaged to SD male mice at doses of 10, 30, and 100mg/kg, respectively, 1 time per day for 7 days, and the animals were well tolerated, had a Maximum Tolerated Dose (MTD) of 100mg/kg, and were safe.

Claims (36)

  1. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2019099971-APPB-100001
    wherein:
    M1、M2、M3and M4Each independently selected from N or-CR6；
    X and Y are each independently selected from the group consisting of a bond,
    Figure PCTCN2019099971-APPB-100002
    -NR7-、-CR7R8-、-S(O)m-、
    Figure PCTCN2019099971-APPB-100003
    Figure PCTCN2019099971-APPB-100004
    Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    R1are the same or different and are each 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 haloalkoxy group, a halogen, an amino group, a substituted alkoxy group, a substituted,Nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
    R2are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、 -(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
    R3Selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
    Or, R3And M3、M3And M4Each linkage forming a cycloalkyl, aromatic, heterocyclic or heteroaromatic ring, wherein said cycloalkyl, aromatic, heterocyclic or heteroaromatic ring is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    or alternatively, R1And X or Y, M1And X or Y are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, respectively, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    R6、R7and R8Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
    R9selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, hydroxyl groups, amino groups, alkoxy groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
    R10and R11The same or different and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
    R12and R13The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, ester group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group, wherein said alkyl 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 deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, ester group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;
    x is an integer of 0, 1,2, 3 or 4;
    y is an integer of 0, 1 or 2;
    m is an integer of 0, 1 or 2; and is
    n is an integer of 0, 1,2, 3,4 or 5;
    the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  2. The pharmaceutical composition according to claim 1, wherein the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, and even more preferably 10% to 50% based on the total weight of the composition.
  3. The pharmaceutical composition according to claim 1, wherein the dose is in the range of 0.5-120mg, preferably 1-100mg, more preferably 1-50mg, even more preferably 1-30 mg.
  4. The pharmaceutical composition of claim 1, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of formula (II):
    Figure PCTCN2019099971-APPB-100005
    wherein:
    R4selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals areOptionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1);
    R3and R4Linked to form a heterocyclic or heteroaromatic ring, wherein said heterocyclic or heteroaromatic ring is optionally further selected from the group consisting of alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    or, R3And R4Linking the formed heterocycle or heteroaryl ring, any two substituents on the heterocycle or heteroaryl ring can form cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, aromatic, heterocyclic ringThe radical or heteroaryl ring radical is optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    ring A, M1、M2、X、Y、R1-R3X, y, m and n are as defined in claim 1.
  5. The pharmaceutical composition of claim 4, wherein the compound of formula (I) is represented by formula (III):
    Figure PCTCN2019099971-APPB-100006
    ring B is selected from heterocyclyl or heteroaryl; wherein heterocyclyl preferably comprises 3 to 20 ring atoms, wherein one or more ring atoms is selected from nitrogen, oxygen, phosphorus or s (o) t and the remaining ring atoms are carbon, heterocyclyl further preferably comprises 3 to 12 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen and phosphorus and the remaining ring atoms are carbon, heterocyclyl further preferably comprises 3 to 8 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen and the remaining ring atoms are carbon, heterocyclyl most preferably comprises 5 to 7 ring atoms, wherein 1 to 2 ring atoms are selected from nitrogen, oxygen and the remaining ring atoms are carbon, heterocyclyl further preferably is selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine; heteroaryl preferably comprises 5 to 14 ring atoms of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or s (o) t and the remaining ring atoms are carbon, heteroaryl further preferably comprises 5 to 10 ring atoms of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or s (o) t and the remaining ring atoms are carbon, heteroaryl more preferably comprises 5 to 10 ring atoms of which 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus and the remaining ring atoms are carbon, heteroaryl most preferably comprises 5 or 6 ring atoms of which 1 to 2 atoms are selected from nitrogen, oxygen;
    Raselected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C1-8Alkenyl radical, C1-8Alkynyl, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, propyl group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, ethylene group, propylene group, butene group, acetylene group, propyne group, butyne group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, pyrazolyl group, Imidazolyl, furyl, thienyl,Thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, or C (O) CH3；
    Wherein R isaOptionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、 -(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents of (1), preferably by deuterium atom, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, cyano, hydroxy, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1), more preferably deuterium atom, C1-3Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C1-3Alkyl, halogen, amino, nitro, cyano, hydroxy, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by deuterium, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, ethylene, propylene, butene, acetylene, propynyl, butynyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    or, any two R on ring BaThe substituents form cycloalkyl, heterocyclyl, aryl andheteroaryl, wherein the heteroatom is 1 to 4, preferably any two R selected from nitrogen, oxygen, sulfur, phosphorusaThe substituents forming C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, wherein the heteroatom is 1 to 3 selected from nitrogen, oxygen, sulfur, phosphorus, more preferably any two RaThe substituents forming C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, wherein the heteroatom is 1 to 2 selected from nitrogen, oxygen, most preferably any two RaThe substituents form cyclopropyl, cyclobutyl, cyclopentyl, C3-5Heterocyclic group, C6-7Aryl and C5-7Heteroaryl, wherein the heteroatoms are 1 to 2 selected from nitrogen, oxygen;
    wherein any two R areaThe ring formed by the substituents is optionally further substituted with a substituent selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is preferably substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaromatic compoundsRadical, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-7Aryl and C5-7Heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1); most preferably by a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a deuterated methyl group, a deuterated ethyl group, a deuterated propyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a fluoropropyl group, a dichloromethyl group, a trichloromethyl group, a chloroethyl group, a chloropropyl group, a fluoromethoxy group, a fluoroethoxy group, a fluoropropoxy group, a chloromethoxy group, a chloroethoxy group, a chloropropoxy group, a fluoropropoxy group, a chloromethoxy groupChlorine, bromine, iodine, amino, nitro, hydroxy, cyano, ethylene, propylene, butene, acetylene, propyne, butyne, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    z is an integer of 0, 1,2, 3,4 or 5;
    t is 0, 1 or 2.
  6. The pharmaceutical composition of claim 5, wherein the compound of formula (I) is represented by formula (IV):
    Figure PCTCN2019099971-APPB-100007
    wherein:
    M5is O, -CR6or-NR7；
    R6、R7Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、 -(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, and di-ethyl groupFluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, fluoropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    wherein, R is6、R7Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably selected from deuterium atoms, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dibutenyl, tetrahydrofuranyl, propargyl, trifluoromethyl, fluoromethyl, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propylHydrogen imidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    q is 0, 1 or 2.
  7. The pharmaceutical composition of claim 5, wherein the compound of formula (I) is represented by formula (V):
    Figure PCTCN2019099971-APPB-100008
    wherein:
    o is an integer of 0, 1,2, 3,4 or 5.
  8. The pharmaceutical composition according to any one of claims 5 to 7,
    M1、M2each independently selected from N or-CR6Optional M1、M2Different;
    x and Y are each independently selected from the group consisting of a bond,
    Figure PCTCN2019099971-APPB-100009
    -NR7-、-CR7R8-、-S(O)m-、
    Figure PCTCN2019099971-APPB-100010
    Figure PCTCN2019099971-APPB-100011
    Optionally X and Y are different;
    ring A is selected from aryl or heteroaryl; the aryl group is a 6 to 14-membered all-carbon monocyclic ring or a fused polycyclic ring, preferably 6 to 10-membered, more preferably phenyl or naphthyl; preferably said heteroaryl group comprises 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms being carbon, further preferably said heteroaryl group comprises 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms being carbon, more preferably said heteroaryl group comprises 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus, the remaining ring atoms being carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole or pyrazinyl,
    Figure PCTCN2019099971-APPB-100012
    even more most preferably the heteroaryl group comprises 5 or 6 ring atoms, wherein 1 to 2 atoms are selected from nitrogen, oxygen;
    wherein said ring A is optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is preferably substituted by one or more substituents selected from deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably by one or more substituents selected from the group consisting of deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, methoxy, ethoxy, propoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinylThiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazinyl, pyridinylyl, pyridinyl, and the like,
    Figure PCTCN2019099971-APPB-100013
    Figure PCTCN2019099971-APPB-100014
    Figure PCTCN2019099971-APPB-100015
    Is substituted with one or more substituents of (1);
    R2are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Preferably selected from hydrogen atoms, deuterium atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a More preferably from hydrogen atoms, deuterium atoms, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Most preferably selected from the group consisting of hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, hydroxypropoxy group, hydroxy-substituted methyl group, hydroxy-substituted ethyl group, hydroxy-substituted propyl group, fluoro group, chloro group, bromo group, iodo group, amino group, nitro group, hydroxy group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrakis groupHydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl.
  9. The pharmaceutical composition of claim 5, wherein the compound of formula (I) is represented by formula (III-A):
    Figure PCTCN2019099971-APPB-100016
  10. the pharmaceutical composition of claim 9, wherein the compound of formula (I) is represented by formula (III-a1) or formula (III-a 2):
    Figure PCTCN2019099971-APPB-100017
    wherein the content of the first and second substances,
    ring C is a 4-7 membered heterocyclyl or heteroaryl group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or s (o) t, the remaining ring atoms are carbon, preferably a 5 membered heterocyclyl group comprising 1-2 nitrogen or oxygen atoms; the heteroaryl group preferably comprises 1 to 4 heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, preferably a 5-or 6-membered heteroaryl group comprising 1 to two heteroatoms of nitrogen or oxygen; preferably, ring C is of the structure:
    Figure PCTCN2019099971-APPB-100018
    Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group;
    t is 0, 1 or 2.
  11. The pharmaceutical composition of claim 10, wherein: r1Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9；
    Wherein R is1Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl groupA group selected from the group consisting of fluoro-propyl, dichloro-methyl, trichloromethyl, chloro-ethyl, chloro-propyl, methoxy, ethoxy, propoxy, fluoro-methoxy, fluoro-ethoxy, fluoro-propoxy, chloro-methoxy, chloro-ethoxy, chloro-propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, propoxy, fluoro-ethoxy, fluoro-propoxy, chloro-ethoxy, chloro-propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, fluoro-imidazolyl, Thiadiazole, pyrazinyl.
  12. The pharmaceutical composition of claim 11, wherein: r1Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein R is1Optionally further substituted.
  13. The pharmaceutical composition of claim 12, wherein: r1Selected from the group consisting of hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxy group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, Pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl; optionally substituted with a group selected from hydrogen atom, deuterium atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, fluoropropoxy group, chloromethoxy group, chloropropoxy group, hydroxy-substituted methyl group, hydroxy-substituted ethyl group, hydroxy-substituted propyl group, fluoro group, chloro group, bromo group, iodo group, amino group, nitro group, hydroxy group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidyl group, piperidinyl group, and the, Piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl.
  14. The pharmaceutical composition of claim 10, wherein the compound of formula (I) is represented by formula (VI-a) or formula (VI-B):
    Figure PCTCN2019099971-APPB-100019
    R5selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, C1-8Hydroxyalkyl, cyano, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-6Alkyl, deuterated C1-6Alkyl, halo C1-6Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, C1-6Hydroxyalkyl, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, chloropropyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, fluoroethoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, hydroxyl group-substituted methyl group, hydroxyl group-substituted ethyl group, hydroxyl group-substituted propyl group, hydroxyl group-substituted butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetane group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, thiomorpho, Homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    wherein R is5Optionally further substituted with one or more substituents selected from deuterium atoms, alkyl groups, alkyl halidesRadical, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is preferably substituted by one or more substituents of (1), preferably by deuterium atom, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, cyano, hydroxy, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); more preferably by deuterium atom, C1-6Alkyl, halo C1-6Alkyl, halogen, amino, nitro, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); most preferably deuterium atom-, methyl-, ethyl-, n-propyl-, isopropyl-, difluoromethyl-, trifluoromethyl-, fluoroethyl-, fluoropropyl-, dichloromethyl-, trichloromethyl-, chloroethyl-, chloropropyl-, methoxy-, ethoxy-, propoxy-, fluoromethoxy-, fluoroethoxy-, fluoropropoxy-, chloromethoxy-, chloroethoxy-, chloropropoxy-, fluoropropoxy-, fluorine-, chlorine-, bromine-, iodine-, amino-, nitro-, hydroxy-, cyano-, hydroxy-substituted methyl-, hydroxy-substituted ethyl-, hydroxy-substituted propyl-, hydroxy-substituted butyl-, cyclopropyl-, cyclobutyl-, cyclopentyl-, oxetanyl-, pyrrolidinyl-, imidazolidinyl-, tetrahydrofuranyl-, tetrahydrothienyl-, dihydroimidazolyl-, dihydrofuranyl-, dihydropyrazolyl-, dihydropyrrolyl-, piperidinyl-, piperazinyl-, morpholinyl-, thiomorpholinyl-, homopiperazinyl-, pyranyl-, phenyl-, imidazolyl-, etc, Furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    x-1 is an integer of 1,2, 3 or 4.
  15. The pharmaceutical composition of claim 14, wherein the compound of formula (I) is represented by formula (VI-a1) or formula (VI-B1):
    Figure PCTCN2019099971-APPB-100020
    M5is O, -CR6or-NR7；
    R6、R7Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Preferably from hydrogen atoms, C1-8Alkyl, deuterated C1-8Alkyl, halo C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-8Cycloalkyl radical, C3-12Heterocyclic group, C6-14Aryl radical, C5-14Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9More preferably selected from hydrogen atom, C1-3Alkyl, deuterated C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, halogen, amino, nitro, hydroxy, cyano, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl radical, C5-10Heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Most preferably selected from the group consisting of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, deuterated methyl group, deuterated ethyl group, deuterated propyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, fluoropropyl group, dichloromethyl group, trichloromethyl group, chloroethyl group, propyl group, fluoromethyl group, fluoroethyl group, fluoropropoxy group, chloromethoxy group, chloroethoxy group, chloropropoxy group, fluorine group, chlorine group, bromine group, iodine group, amino group, nitro group, hydroxyl group, cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuryl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, phenyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrazolyl group, Oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    wherein, R is6、R7Optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably selected from deuterium atoms, C1-8Alkyl, halo C1-8Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-8Alkoxy, halo C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C6-14Aryl and C5-14Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、 -(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents selected from deuterium atom, C1-3Alkyl, halo C1-3Alkyl, halogen, amino, nitro, hydroxy, cyano, C1-3Alkoxy, halo C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-6Cycloalkyl radical, C3-6Heterocyclic group, C6-10Aryl and C5-10Heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Most preferably by methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, difluoromethyl, trifluoromethyl, chloroethyl, chloropropyl, amino, nitro, chloro-ethoxy, chloro-propoxy, Imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    q is 0, 1 or 2.
  16. The pharmaceutical composition of claim 14, wherein the compound of formula (I) is represented by formula (VI-a2) or formula (VI-B2):
    Figure PCTCN2019099971-APPB-100021
    o is an integer of 0, 1,2, 3,4 or 5.
  17. The pharmaceutical composition according to claim 1, characterized in that the compound of general formula (I), its stereoisomers or its pharmaceutically acceptable salts are selected from the following compounds of general formula (VII):
    Figure PCTCN2019099971-APPB-100022
    wherein:
    ring B is selected from heterocyclyl or heteroaryl;
    R5selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably a cyclopropyl group;
    Raselected from hydrogen atom, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl and cyanoAlkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9(ii) a Wherein said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nOR12、-(CH2)nSR12、-(CH2)nC(O)R12、-(CH2)nC(O)OR12、-(CH2)nS(O)mR12、-(CH2)nNR12R13、-(CH2)nC(O)NR12R13、-(CH2)nC(O)NHR13、-(CH2)nNR13C(O)R12And- (CH)2)nNR13S(O)mR12Is substituted with one or more substituents of (1); preferably C1-8Alkyl radical, C1-8Alkoxy radical, C1-8A cycloalkyl group;
    or, any two R on ring BaThe substituents form cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said cycloalkyl, aromatic, heterocyclyl or heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, heteroaryl, and mixtures,Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    x-1 is an integer of 1,2, 3 or 4; and is
    z is an integer of 0, 1,2, 3,4 or 5;
    ring A, M1、M2、X、Y、R1、R2Y, m and n are as defined in claim 1.
  18. Pharmaceutical composition according to claim 17, wherein ring B, when selected from heterocyclyl, preferably comprises 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or s (o) t, t is 0, 1 or 2, the remaining ring atoms being carbon; more preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen, oxygen; most preferably 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen, oxygen; when ring B is selected from heteroaryl, it is preferably a heteroaryl group comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, more preferably a 5 to 10 membered heteroaryl group comprising 1 to 2 heteroatoms, wherein the heteroatoms are selected from oxygen and nitrogen, most preferably a 5 or 6 membered heteroaryl group comprising 1 to 2 heteroatoms, wherein the heteroatoms are selected from oxygen and nitrogen;
    further preferred structures of ring B are as follows:
    Figure PCTCN2019099971-APPB-100023
  19. the pharmaceutical composition according to any one of claims 1-2, 4, 17-18, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of formula (VIII):
    Figure PCTCN2019099971-APPB-100024
    wherein:
    ring A, ring B, M1、M2、R1、R2、R5、RaX-1, y and z are as defined in claim 17.
  20. The pharmaceutical composition according to any one of claims 1-2, 4, 17, 19, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of formula (IX):
    Figure PCTCN2019099971-APPB-100025
    wherein:
    ring B, R1、R5、RaX-1 and z are as defined in claim 19.
  21. The pharmaceutical composition according to claims 1-2, 4, 17, 19-20, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (X-a) as follows:
    Figure PCTCN2019099971-APPB-100026
    wherein:
    M5is O, -CR6or-NR7；
    R1Is selected fromHydrogen atom, C1-8Alkyl or halogen;
    R5is selected from C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-8Haloalkyl, C1-8Hydroxyalkyl or 3-6 membered heterocyclyl;
    Rathe same or different, each independently selected from hydrogen atom, cyano, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Haloalkyl, C1-8Hydroxyalkyl, C1-8Alkoxy radical, C3-8Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Wherein said C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo C1-8Alkyl radical, C1-8Hydroxyalkyl, C1-8Alkoxy and C3-8Cycloalkyl is optionally further substituted by a group selected from hydrogen atom, deuterium atom, halogen, cyano, hydroxy, C1-8Alkyl radical, C1-8Hydroxyalkyl or C1-8Substituted with one or more substituents of alkoxy; or any two RaThe substituents forming C3-8Cycloalkyl or C3-8A heterocyclic group;
    R9and R10The same or different, each independently selected from hydrogen atom, C1-8Alkyl radical, C1-8Haloalkyl, C1-8Hydroxyalkyl or C1-8An alkoxy group;
    x-1 is an integer of 1,2, 3 or 4;
    q is 0, 1 or 2; and is
    z is an integer of 0, 1,2, 3,4 or 5.
  22. The pharmaceutical composition of claims 1-2, 4, 17, 19-21, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (XI) as follows:
    Figure PCTCN2019099971-APPB-100027
    wherein:
    Raselected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR)9R10)n-and- (CH)2)nOR9(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and- (CH)2)nOR12Is substituted with one or more substituents of (1); preferably C1-8Alkyl radical, C1-8Alkoxy radical, C1-8A cycloalkyl group;
    or, any two RaThe substituents may form cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said cycloalkyl, aromatic, heterocyclyl or heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    o is an integer of 0, 1,2, 3,4 or 5; and is
    R1、R5X-1 and z are as defined in claim 21.
  23. The pharmaceutical composition of claims 1-2, 4, 17, 19-22, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of formula (XII):
    Figure PCTCN2019099971-APPB-100028
    wherein:
    Rathe same or different, each independently selected from hydrogen atom, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, - (CH)2)nOR9Or- (CR)9R10)n-, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy and C3-6Cycloalkyl is optionally further substituted by a group selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkyl or C1-6Substituted with one or more substituents of alkoxy;
    or any two RaThe substituents may form a 3-to 6-membered cycloalkyl group, an
    z is an integer of 0, 1,2 or 3.
  24. The pharmaceutical composition of claim 1, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (XIII-a) as follows:
    Figure PCTCN2019099971-APPB-100029
    wherein:
    R3and R4Linked to form a 3-to 10-membered heterocyclic ring or a 5-to 10-membered heteroaromatic ring, whereinOptionally further substituted with a 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring selected from deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, halogen, amino, nitro, hydroxy, cyano, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, - (CR)9R10)n-、-(CH2)nOR9、-(CH2)nSR9、-(CH2)nC(O)R9、-(CH2)nC(O)OR9、-(CH2)nS(O)mR9、-(CH2)nNR10R11、-(CH2)nC(O)NR10R11、-(CH2)nC(O)NHR10、-(CH2)nNR10C(O)R9And- (CH)2)nNR10S(O)mR9Is substituted with one or more substituents of (1);
    Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group;
    R1selected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group;
    x-1 is an integer of 0, 1,2 or 3;
    p is an integer of 0, 1,2, 3 or 4.
  25. The pharmaceutical composition of claim 24, wherein ring C is a 4-7 membered heterocyclyl or heteroaryl, preferably a 5 membered heterocyclyl, most preferably ring C has the structure:
    Figure PCTCN2019099971-APPB-100030
  26. the pharmaceutical composition of claim 1, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (XIII-B):
    Figure PCTCN2019099971-APPB-100031
    wherein:
    ring C is a 5-7 membered heterocyclyl or heteroaryl group, preferably a 5 membered heterocyclyl group;
    Rathe same or different, each independently selected from hydrogen atom, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Or any two RaThe substituents may form 3-6 membered cycloalkyl;
    Rbselected from hydrogen atoms, C1-8Alkyl radical, C1-8Deuterated alkyl or C1-8A haloalkyl group;
    R9and R10Independently selected from a hydrogen atom or C1-8An alkyl group;
    z is an integer of 0, 1,2, 3 or 4; and is
    p is 0, 1 or 2.
  27. The pharmaceutical composition according to claims 1,4, 17, 19-22 and 24, characterized in that it comprises a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R is1Is selected from C1-8Alkyl radical, C3-8Cycloalkyl, 5-10 membered heteroaryl and halogen, preferably 5-6 membered heteroaryl, halogen, C1-6Alkyl groups, more preferably pyrazole, fluorine atoms or methyl groups.
  28. The pharmaceutical composition of claims 17, 19-23, 26, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R isaSelected from hydrogen atom, cyano, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Haloalkyl, C1-8Hydroxyalkyl, cyano-substituted C1-8Alkyl radical, C1-8Alkoxy radical, C3-8Cycloalkyl, - (CH)2)nOR9、-(CR9R10)n-or- (CH)2)nC(O)R9Preferably from hydrogen atoms, cyano groups, hydroxy groups, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl, halogeno C1-6Alkyl, 3-6 membered heterocyclic group, C3-6A cycloalkyl group; most preferred is methyl, ethyl, vinyl, ethynyl or trifluoromethyl.
  29. The pharmaceutical composition of claims 17, 19-23, 26, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, optionally wherein any two R areaTo form a 3-6 membered cycloalkyl group, preferably cyclopropyl.
  30. The pharmaceutical composition of claims 17 and 19-22, wherein the compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R is5Selected from hydrogen atoms, C1-8Alkyl, halo C1-8Alkyl, hydroxy C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkoxy, halogen, C3-8Cycloalkyl, 3-to 10-membered heterocyclic group, preferably selected from hydrogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, 3-6 membered heterocyclyl or C3-6A cycloalkyl group; r5Most preferably cyclopropyl, isopropyl, hydroxyisopropyl, tert-butyl, trifluoromethyl or
    Figure PCTCN2019099971-APPB-100032
  31. The pharmaceutical composition according to claims 1-30, wherein the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds:
    Figure PCTCN2019099971-APPB-100033
    Figure PCTCN2019099971-APPB-100034
    Figure PCTCN2019099971-APPB-100035
  32. a process for the preparation of a pharmaceutical composition according to claims 1-31, wherein the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier to prepare the product, preferably wherein the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, is admixed with an excipient, a solvent or another pharmaceutically acceptable carrier.
  33. The pharmaceutical composition according to claims 1-31, for use in the manufacture of a medicament for the inhibition of ASK 1.
  34. Use of a pharmaceutical composition according to claims 1-31 for the manufacture of a medicament for the treatment of neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders and ASK 1; the inflammatory disorder is preferably non-alcoholic steatohepatitis (NASH).
  35. The pharmaceutical composition according to claims 1-31, where applicable, in a form selected from the group consisting of sterile injectable aqueous or oleaginous suspensions for oral, intramuscular and subcutaneous administration, oil-in-water emulsions and sterile injectable aqueous solutions.
  36. The pharmaceutical composition of claim 35 in oral form selected from the group consisting of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; the oil-in-water emulsion is in the form of vegetable oil or mineral oil; the sterile injection aqueous solution form is characterized in that a solvent or a solvent is selected from water, ringer's solution and isotonic sodium chloride solution; the sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration is in the form of a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent, preferably a solution prepared in 1, 3-butanediol.
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