CN111107848B - 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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CN111107848B
CN111107848B CN201980004523.4A CN201980004523A CN111107848B CN 111107848 B CN111107848 B CN 111107848B CN 201980004523 A CN201980004523 A CN 201980004523A CN 111107848 B CN111107848 B CN 111107848B
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pharmaceutical composition
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pyridin
imidazol
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CN111107848A (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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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 in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and application of the compound as an ASK1 inhibitor in treating neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.

Description

Pharmaceutical composition containing amide derivatives, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a pharmaceutical composition containing amide derivatives, 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, are key signaling pathways for cell mitosis and apoptosis. MAPKs are classified into three major classes, namely mitotically activated protein kinase (MAP 3K), mitotically activated protein kinase (MAP 2K), and Mitotically Activated Protein Kinase (MAPK), and MAP3K is activated under environmental signal stimulation, so that MAP2K is activated, MAP2K further activates MAPK, and MAPK mediates corresponding cellular effects by phosphorylating its downstream substrates such as transcription factors and the like.
Apoptosis signal regulating kinase 1 (ASK 1), also known as mitotically activated protein kinase 5 (MAP 3K 5), belongs to a member of the MAPK family, mediates activation of MAPK signaling pathways, ASK1 can be activated by autophosphorylation in states of stress response including oxidative stress, endoplasmic reticulum stress, calcium influx and the like, thereby activating downstream MAP2K (e.g., MKK3/6 and MKK4/7), further activating c-Jun N-terminal kinase (JNK) and p38 mitotically activated protein kinase, leading to apoptosis and related cellular effects, ASK1 activation and signaling pathways thereof play an important role in the processes of neuroretirement diseases, cardiovascular diseases, inflammation, autoimmunity, metabolic diseases and the like.
The incidence of nonalcoholic steatohepatitis (NASH) is high, with about 2% -5% of NASH patients worldwide or domestically, and the market size is estimated to reach 350-400 billion dollars in 2025. At present, NASH is not clinically approved to be used as a medicament on the market, NASH targets in early research treatment comprise FXR, PPAR, GLP and the like, but the FXR and the PPAR targets have a large safety problem, the GLP belongs to early diabetes treatment targets, the curative effect is not yet verified by exact clinical end points, and the peptide medicament needs to be subcutaneously administered every day. ASK1 is becoming a new mechanism and new target in the field of NASH treatment, and its signaling pathway plays an important role in NASH development process by promoting liver tissue inflammation and fibrosis. ASK1 inhibitors have great potential for clinical treatment of NASH and potential application value for treatment of other disease fields including neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases and the like.
Published inhibitor patent applications for selectively inhibiting ASK1 include WO2011008709, WO2016025474, WO2012003387, WO2016105453, WO2016106384 and WO2008008375, among others.
The ASK1 inhibitor has good application prospect in the pharmaceutical industry as a medicament, provides a novel structure selective ASK1 inhibitor composition, and discovers that the compound with the structure has excellent effects and actions in the aspects of pharmaceutical 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 or a pharmaceutically acceptable salt thereof, and has the following structure:
Figure GPA0000286075210000031
wherein:
M 1 、M 2 、M 3 and M 4 Each independently selected from N or-CR 6 ；
X and Y are each independently selected from the group consisting of a bond,
Figure GPA0000286075210000032
-NR 7 -、-CR 7 R 8 -、-S(O) m -、/>
Figure GPA0000286075210000033
Figure GPA0000286075210000034
Ring a is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further substituted with a member selected from deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 1 the same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents;
R 2 the same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 ；
R 3 Selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, said alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group optionally being further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 ；
Alternatively, R 3 And M 3 、M 3 And M 4 The linking groups each form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with a substituent selected from the group consisting of deuterium, alkyl, deuteroalkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
or, R 1 And X or Y, M 1 And 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 moiety selected from the group consisting of deuterium atom, alkyl, deuteroalkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 6 、R 7 and R is 8 The same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents;
R 9 Selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuteriumSubstituted alkyl, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents;
R 10 and R is 11 And are 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, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Substituted by one or more substituents；
R 12 And R is 13 The same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, an alkyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, a cyano group, an ester group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a 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 also provided with
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%, still 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 to 120mg, preferably 1 to 100mg, more preferably 1 to 50mg, still more preferably 1 to 30mg.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the group consisting of compounds of formula (II):
Figure GPA0000286075210000051
wherein:
R 4 selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents;
R 3 and R is 4 Linking to form a heterocyclic or heteroaromatic ring, wherein said heterocyclic or heteroaromatic ring is optionally further substituted with a member selected from the group consisting of deuterium atom, alkyl, deuteroalkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
alternatively, R 3 And R is 4 A heterocycle or heteroaryl ring linked to form, any two substituents on the heterocycle or heteroaryl ring may form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl ring is optionally further substituted with a substituent selected from the group consisting of deuterium atom, alkyl, deuteroalkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
ring A, M 1 、M 2 、X、Y、R 1 -R 3 And x, y, m and n are as shown in the general 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 GPA0000286075210000061
Ring B is selected from heterocyclyl or heteroaryl; wherein the heterocyclyl preferably comprises 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, the heterocyclyl further preferably comprises 3 to 12 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen and phosphorus, the remaining ring atoms are carbon, the heterocyclyl more preferably comprises 3 to 8 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen, the remaining ring atoms are carbon, the heterocyclyl most preferably comprises 5 to 7 ring atoms, wherein 1 to 2 ring atoms are selected from nitrogen, oxygen, the remaining ring atoms are carbon, the heterocyclyl further most preferably is selected from pyrrole, piperidine, azepane, morpholine, piperazine; heteroaryl preferably comprises 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, heteroaryl further preferably comprises 5 to 10 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus, the remaining ring atoms are carbon, heteroaryl most preferably comprises 5 or 6 ring atoms, wherein 1 to 2 atoms are selected from nitrogen, oxygen;
R a Selected from the group consisting of a hydrogen atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Preferably from hydrogen atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy group,Halogen, amino, nitro, hydroxy, cyano, C 1-8 Alkenyl, C 1-8 Alkynyl, C 3-8 Cycloalkyl, C 3-12 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 More preferably from the group consisting of hydrogen atoms, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Most preferably selected from the group consisting of hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethylOxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, ethylene, propylene, butylene, acetylene, propyne, butyne, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, C (O) CH 3 ；
Wherein R is a Optionally further substituted with a member selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents, preferably deuterium atoms, C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents, more preferably by deuterium atoms, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Most preferably substituted with one or more substituents of 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, propyne, butyne, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, One or more substituents selected from oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl;
alternatively, any two R's on ring B a Substituents form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the heteroatom is 1 to 4, preferably any two Ra substituents form C, selected from nitrogen, oxygen, sulphur, phosphorus 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl and C 5-14 Heteroaryl, wherein the heteroatoms are 1 to 3, more preferably any two R's selected from nitrogen, oxygen, sulfur, phosphorus a Substituents form C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl and C 5-10 Heteroaryl, wherein the heteroatoms are 1 to 2, most preferably any two R, selected from nitrogen, oxygen a Substituents forming cyclopropyl, cyclobutyl, cyclopentyl, C 3-5 Heterocyclyl, C 6-7 Aryl and C 5-7 Heteroaryl, wherein the heteroatoms are 1 to 2 selected from nitrogen, oxygen;
Wherein, any two R a The 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) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl and C 5-14 Heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents selected from the group consisting of a hydrogen atom, a deuterium atom, and C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-7 Aryl and C 5-7 Heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents; most preferably methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluoro, chloro, bromo, iodo, 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, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, 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 GPA0000286075210000091
wherein:
M 5 is O, -CR 6 or-NR 7 ；
R 6 、R 7 Identical or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxyGroup, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Preferably from hydrogen atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-8 Cycloalkyl, C 3-12 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 More preferably from the group consisting of hydrogen atoms, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Most preferably selected from the group consisting of hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
Wherein R is as follows 6 、R 7 Optionally further substituted with a member selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; preferably selected from deuterium atoms, C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-8 Alkoxy, halo C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl and C 5-14 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents selected from deuterium atoms, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl and C 5-10 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Substituted with one or more substituents, most preferably 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, hydroxyl, 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, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, 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 (V):
Figure GPA0000286075210000111
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:
M 1 、M 2 each independently selected from N or-CR 6 Optionally M 1 、M 2 Different;
x and Y are each independently selected from the group consisting of a bond,
Figure GPA0000286075210000112
-NR 7 -、-CR 7 R 8 -、-S(O) m -、/>
Figure GPA0000286075210000113
Figure GPA0000286075210000114
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 or fused polycyclic ring, preferably 6 to 10 membered, more preferably phenyl or naphthyl; the heteroaryl group preferably comprises 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, the heteroaryl group further preferably comprises 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, the heteroaryl group more preferably comprises 5 to 10 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen, phosphorus, the remaining ring atoms are carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole or pyrazinyl,
Figure GPA0000286075210000115
Figure GPA0000286075210000121
Heteroaryl groups further most preferably contain 5 or 6 ring atoms, wherein 1 to 2 atoms are selected from nitrogen, oxygen;
wherein the ring A is optionally further substituted with a member 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 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents, preferably selected from deuterium atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl and C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents selected from deuterium atoms, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl and C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Substituted with one or more substituents selected from deuterium atoms, methyl, ethyl, n-propyl, and most preferably,Isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, 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, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl,
Figure GPA0000286075210000122
Figure GPA0000286075210000123
Figure GPA0000286075210000124
Is substituted by one or more substituents;
R 2 the same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Preferably selected from hydrogen atom, deuterium atom, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the More preferably from hydrogen atom, deuterium atom, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Most preferably selected from the group consisting of a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a deuteromethyl group, a deuteroethyl group, a deuteropyropyl 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 methoxy group, and an ethoxy group A group, a propoxy group, a fluoromethoxy group, a fluoroethoxy group, a fluoropropoxy group, a chloromethoxy group, a chloroethoxy group, a chloropropoxy group, a hydroxy-substituted methyl group, a hydroxy-substituted ethyl group, a hydroxy-substituted propyl group, a fluorine group, a chlorine group, a bromine group, an iodine group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an oxetane group, a pyrrolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dihydroimidazolyl group, a dihydrofuranyl group, a dihydropyrazolyl group, a dihydropyrrolyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a homopiperazinyl group, a pyranyl group, a phenyl 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, 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 GPA0000286075210000131
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 GPA0000286075210000141
wherein,,
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 and the remaining ring atoms are carbon, preferably a 5 membered heterocyclyl containing 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 has the following structure:
Figure GPA0000286075210000142
R b Selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Deuterated alkyl or C 1-8 Haloalkyl
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: r is R 1 Identical or different and are each independently selected from hydrogen atoms, deuterium atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 ；
Wherein said R 1 Optionally further substituted with a member selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents selected from the group consisting of a hydrogen atom, a deuterium atom, and C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Substituted by one or more substituents, most preferably ethyl, hydroxy-substituted propyl, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, fluorine, chlorine bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, 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: r is R 1 Identical or different and are each independently selected from the group consisting of hydrogen atoms, deuterium atoms, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said R 1 Optionally further substituted.
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: the method is characterized in that: r is R 1 Selected from the group consisting of hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl; optionally methyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy-taken ethyl, hydroxy-substituted propyl, fluoro, chloro, bromo, iodo, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, One or more substituents selected from pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and 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 GPA0000286075210000161
R 5 selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Preferably from hydrogen atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, C 1-8 Hydroxyalkyl, cyano, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 More preferably from the group consisting of hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, C 1-6 Hydroxyalkyl, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Most preferably selected from the group consisting of hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, 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, hydroxy-substituted butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, and the like A group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole, a pyrazinyl group;
wherein R is 5 Optionally further substituted with a member selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents, preferably deuterium atoms, C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 1-8 Alkoxy, halo C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; more preferably by deuterium atoms, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; most preferably one or more of 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, hydroxyl, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, hydroxy-substituted butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, 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 GPA0000286075210000171
M 5 is O, -CR 6 or-NR 7 ；
R 6 、R 7 The same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Preferably from hydrogen atoms, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halo C 1-8 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-8 Cycloalkyl, C 3-12 Heterocyclyl, C 6-14 Aryl, C 5-14 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 More preferably from the group consisting of hydrogen atoms, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, halogen, amino, nitro, hydroxy, cyano, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl, C 5-10 Heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Most preferably selected from the group consisting of hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuteromethyl, deuteroethyl, deuteropyropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
Wherein R is as follows 6 、R 7 Optionally further substituted with a member selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitro group, cyano group, hydroxyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; preferably selected from deuterium atoms, C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-8 Alkoxy, halo C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl and C 5-14 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents selected from deuterium atoms, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 6-10 Aryl and C 5-10 Heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Most preferably one or more substituents selected from the group consisting of 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, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, triazolyl, and 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 GPA0000286075210000191
/>
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 formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the group consisting of compounds of formula (VII):
Figure GPA0000286075210000192
wherein:
ring B is selected from heterocyclyl or heteroaryl;
R 5 selected from the group consisting of hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; preferably cyclopropyl;
R a selected from the group consisting of hydrogen atoms, deuterium atoms, Alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 12 、-(CH 2 ) n SR 12 、-(CH 2 ) n C(O)R 12 、-(CH 2 ) n C(O)OR 12 、-(CH 2 ) n S(O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C(O)NR 12 R 13 、-(CH 2 ) n C(O)NHR 13 、-(CH 2 ) n NR 13 C(O)R 12 And- (CH) 2 ) n NR 13 S(O) m R 12 Is substituted by one or more substituents; preferably C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Cycloalkyl;
alternatively, any two R's on ring B a The substituents may form new cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said new cycloalkyl, aryl, heterocyclyl or heteroaryl groups are optionally further selected from the group consisting of hydrogen atoms, deuteriumAtom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
x-1 is an integer of 1, 2, 3 or 4; and is also provided with
z is an integer of 0, 1, 2, 3, 4 or 5;
ring A, M 1 、M 2 、X、Y、R 1 -R 5 And x, y, m and n are as shown in the general formula (I).
In a preferred embodiment of the invention, the pharmaceutical composition is characterized in that ring B, when selected from heterocyclyl, preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) t, t being 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 containing 5 to 7 ring atoms, 1 to 2 of which are heteroatoms selected from nitrogen, oxygen; when ring B is selected from heteroaryl, 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 ring B has the preferred structure:
Figure GPA0000286075210000211
in a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the group consisting of compounds of formula (VIII):
Figure GPA0000286075210000212
Wherein: ring a, ring B, M 1 、M 2 、R 1 、R 2 、R 5 、R a X-1, y and z are as defined in formula (I).
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the group consisting of compounds of formula (IX):
Figure GPA0000286075210000213
wherein:
ring B, R 1 、R 5 、R a X-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 formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compounds of formula (X-a) as follows:
Figure GPA0000286075210000221
wherein:
M 5 is O, -CR 6 or-NR 7 ；
R 1 Selected from hydrogen atoms, C 1-8 Alkyl or halogen;
R 5 selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl or 3-6 membered heterocyclyl;
R a the same or different, each independently selected from hydrogen atom, cyano group, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, - (CH) 2 ) n OR 9 、-(CR 9 R 10 ) n -or- (CH) 2 ) n C(O)R 9 Wherein said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, halo C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy and C 3-8 Cycloalkyl groups optionally further being selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-8 Alkyl, C 1-8 Hydroxyalkyl or C 1-8 One or more substituents in the alkoxy group; or any two R a Substituents form C 3-8 Cycloalkyl or C 3-8 A heterocyclic group;
R 9 and R is 10 The same or different are each independently selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl or C 1-8 An alkoxy group;
x-1 is an integer of 1, 2, 3 or 4;
q is 0, 1 or 2; and is also provided with
z 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 formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the compounds of formula (XI):
Figure GPA0000286075210000222
o is an integer of 0, 1, 2, 3, 4 or 5; and is also provided with
R 1 、R 5 、R a And x and z are as described in formula (VI).
In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the group consisting of compounds of formula (XII):
Figure GPA0000286075210000231
wherein:
R a the same or different, each independently selected from hydrogen atom, cyano group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, - (CH) 2 ) n OR 9 Or- (CR) 9 R 10 ) n -, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl groups are optionally further selected from hydrogen atoms, halogen, cyano, hydroxy, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group; or any two R a The substituents may form 3-6 membered cycloalkyl groups, and
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), its stereoisomer or its pharmaceutically acceptable salt is selected from the compounds of formula (XIII-a) below:
Figure GPA0000286075210000232
wherein:
M 5 selected from S or CH;
R 3 selected from C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl and 3-10 membered heterocyclyl, wherein said C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups are optionally further substituted with a member selected from the group consisting of hydrogen, deuterium, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Haloalkyl, halogen, amino, hydroxy, cyano, C 1-8 Alkoxy, C 1-8 Hydroxyalkyl, C 3-8 One or more substituents selected from cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
R 4 selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl or 3-10 membered heterocyclyl;
or R is 3 And R is 4 A 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring formed by linking, wherein said 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further substituted with a moiety selected from the group consisting of deuterium atom, alkyl, deuteroalkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, - (CR) 9 R 10 ) n -、-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C(O)NR 10 R 11 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 And- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R b selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Deuterated alkyl or C 1-8 A haloalkyl group; wherein R is b May be substituted at the oxo ring or at M 5 Ring substitution;
p is an integer of 0, 1, 2, 3 or 4; and is also provided with
q is an integer of 0 or 1.
In a more preferred embodiment of the present invention, the pharmaceutical composition, formula (XIII-A) is characterized in that ring C is a 4-7 membered heterocyclyl or heteroaryl, preferably a 5 membered heterocyclyl, most preferably ring C has the structure:
Figure GPA0000286075210000241
in a more preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the compounds of formula (XIII-B) below:
Figure GPA0000286075210000242
wherein:
ring C is a 4 to 7 membered heterocyclyl or heteroaryl, preferably a 5 membered heterocyclyl;
R a the same or different, each independently selected from hydrogen atom, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, - (CH) 2 ) n OR 9 、-(CR 9 R 10 ) n -or- (CH) 2 ) n C(O)R 9 Or any two R a The substituents may form a 3-6 membered cycloalkyl group;
R b selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Deuterated alkyl or C 1-8 A haloalkyl group;
R 9 and R is 10 Independently selected from hydrogen atoms or C 1-8 An alkyl group;
z is an integer of 0, 1, 2, 3 or 4; and is also provided with
p is 0, 1 or 2.
In a preferred embodiment of the invention, each of the formulae shown, stereoisomers thereof, or pharmaceutically acceptable salts thereof, is characterized by R 1 Selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, 5-to 10-membered heteroaryl and halogen, preferably 5-to 6-membered heteroaryl, halogen, C 1-6 Alkyl groups, more preferably pyrazole, fluorine atoms, methyl groups.
In a preferred embodiment of the invention, each of the formulae shown, stereoisomers thereof, or pharmaceutically acceptable salts thereof, is characterized by R a Selected from hydrogen atoms, cyano groups, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl-and cyano-substituted C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, - (CH) 2 ) n OR 9 、-(CR 9 R 10 ) n -or- (CH) 2 ) n C(O)R 9 Preferably from hydrogen, cyano, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Haloalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl; most preferred is methyl, ethyl, vinyl, ethynyl or trifluoromethyl.
In a preferred embodiment of the invention, each of the formulae shown, stereoisomers thereof, or pharmaceutically acceptable salts thereof, is characterized in that optionally any two of R a Forming a 3-6 membered cycloalkyl group, preferably cyclopropyl.
In a preferred embodiment of the invention, each of the formulae shown, stereoisomers thereof, or pharmaceutically acceptable salts thereof, is characterized by R 5 Selected from hydrogen atoms, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, halogen, C 3-8 Cycloalkyl, 3-to 10-membered heterocyclic groups, preferably selected from hydrogen atoms, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl; r is R 5 Most preferably cyclopropyl, isopropyl, hydroxyisopropyl, tert-butyl, trifluoromethyl or
Figure GPA0000286075210000251
The invention also relates to a method of treatment for preventing and/or treating a disease that prevents ASK 1-mediated pathologies, 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 application of the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing ASK1 inhibitor medicines.
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, preferably nonalcoholic steatohepatitis (NASH).
The invention further relates to the pharmaceutical composition, and a method for preparing the pharmaceutical composition for treating non-alcoholic steatohepatitis (NASH).
The invention also relates to a method of treatment for preventing and/or treating diseases of neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, 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: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing 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, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to 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 hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, 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.
The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring 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. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in preparing aqueous suspensions also may be formulated by the addition of water to provide the active ingredient in combination with dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. 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 emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. 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 composition may be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that may be used 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 an 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 it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus 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 this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.
The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic 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 stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used 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 will therefore 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 amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health 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, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of compound (I) of formula (I) 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, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-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, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group, various branched isomers thereof, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like, the above substituents may be linked to different carbon atoms to form a carbon chain, or may be linked to one carbon atom to form a cycloalkyl group. 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. vinyl, 1-Propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 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 monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring manner; the heterocyclic group may be Optionally substituted or unsubstituted, when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure GPA0000286075210000291
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furanyl, 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 attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure GPA0000286075210000292
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. 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, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenyl, preferably alkenyl containing 2 to 8 carbon atoms, more preferably alkenyl containing 2 to 6 carbon atoms, and most preferably alkenyl containing 2 to 3 carbon atoms; wherein said alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡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, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carboxy" means-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "refers to diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
"stereoisomers" include three classes of geometric (cis-trans) isomerism, optical isomerism, conformational isomerism.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure GPA0000286075210000321
The first step: preparation of 5-amino-2-fluoro-4-methylbenzonitrile
Figure GPA0000286075210000322
5-bromo-4-fluoro-2-methylaniline (10.0 g,49.0 mmol), cuprous cyanide (8.78 g,98.0 mmol) was mixed in NMP (50 mL), stirred at 180℃for 1 hour under nitrogen protection, and then stirred at 100℃overnight. After cooling, 28wt% 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, then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column-chromatographed to give the title compound, 5-amino-2-fluoro-4-methylbenzonitrile (5.70 g, 78%).
MS m/z(ESI)：151.1[M+H] + .
And a second step of: preparation of 5- ((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile
Figure GPA0000286075210000323
5-amino-2-fluoro-4-methylbenzonitrile (5.70 g,38.0 mmol), K 2 CO 3 (6.30 g,45.6 mmol), KI (0.630 g,3.80 mmol), 2-bromo-1-cyclopropylEthane-1-one (7.43 g,45.6 mmol) was mixed in DMF (50 mL) and stirred at 80℃for 90 min under nitrogen. After cooling the reaction, 2-bromo-1-cyclopropylethan-1-one (3.00 g,18.4 mmol), K was added 2 CO 3 (2.54 g,18.4 mmol) and stirred at 75℃for 1 hour. Cooled to room temperature, water was added to the reaction flask, left to stand for 15 minutes, and then filtered, and the filter cake was washed with water and dried to give crude title compound 5- ((2-cyclopropyl-2-carboxyethyl) amino) -2-fluoro-4-methylbenzonitrile (6.80 g, 77%).
MS m/z(ESI)：233.1[M+H] + .
And a third step of: preparation of 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure GPA0000286075210000331
A solution of 5- ((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile (6.80 g,29.3 mmol) in acetic acid (100 mL) of KSCN (5.69 g,58.6 mmol) was stirred at 110℃for 4 hours, cooled, concentrated and added with CH 2 Cl 2 And water, separating out an organic phase, and reusing the aqueous phase with CH 2 Cl 2 Extracting once. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 8.00g of crude 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile, which was used directly in the next reaction.
MS m/z(ESI)：274.1[M+H] + .
Fourth step: preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure GPA0000286075210000332
To a solution of the crude acetic acid (160 mL) and water (32 mL) at 50℃was slowly added dropwise hydrogen peroxide (30 wt%,10.0 mL), and the mixture was stirred at this temperature for one hour. Cooled to room temperature, and then Na is slowly added 2 SO 3 Aqueous solution (20 wt%,100 mL) and then stirred for 30 minutes. Concentrating to remove organic mattersSolvent, CH for aqueous phase 2 Cl 2 Extraction was performed twice. The organic phases were combined, washed successively with saturated aqueous sodium hydrogencarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, followed by column chromatography to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile (3.3 g, two-step yield 47%).
MS m/z(ESI)：242.1[M+H] + .
Fifth step: synthesis of 6-aminomethylpyridine hydrazide
Figure GPA0000286075210000333
Methyl 6-aminomethyl pyridine acid ester (2.0 g,13 mmol) was dissolved in ethanol (60 mL) at room temperature, and hydrazine hydrate (4.1 g,66 mmol) was added. The reaction was heated to 80℃and stirred at this temperature for 5 hours, after slowly cooling to room temperature, the solid precipitated in the reaction solution was filtered, and the cake was collected to give the title compound 6-aminomethylpyridine hydrazide (1.6 g, 80%).
MS m/z(ESI)：153.2[M+H] + .
Sixth step: synthesis of 6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure GPA0000286075210000334
6-Aminomethylpyridine hydrazide (300 mg,1.97 mmol) was dissolved in 2-pentanol (5 mL) and acetic acid (1 mL) at room temperature, and 5-methoxy-3, 4-dihydro-2H-pyrrole (195 mg,1.97 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) extraction, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentrating, and column chromatography to obtain the title compound 6- (6, 7-dihydro-5H-pyrrolo [2, 1-c)][1，2，4]Triazol-3-yl) pyridin-2-amine (360 mg, 91%).
MS m/z(ESI)：202.1[M+H] + .
Seventh step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure GPA0000286075210000341
5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile (1.8 g,7.47 mmol) was dissolved in 30mL of concentrated hydrochloric acid, stirred overnight under heating and refluxing, cooled and concentrated, and dried to give 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (2 g, crude product) which was used directly in the next step.
The above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (100 mg, above crude product) was dissolved in thionyl chloride (5 mL) at room temperature, stirred under reflux for 2 hours under heating, cooled and concentrated under reduced pressure to give a pale yellow solid product which was directly used for the next reaction.
Eighth step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure GPA0000286075210000342
6- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (43 mg,0.22 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100 mg, crude product above) in THF (5 mL) and pyridine (5 mL) at room temperature, followed by 4-dimethylaminopyridine (11 mg,0.09 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then water (5 mL) was added dropwise, dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (60 mg, 63%).
1 H NMR(400MHz，CDCl 3 )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, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) benzamide
Figure GPA0000286075210000351
The preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) benzamide is described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000352
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The 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 is described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000353
The 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 is described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000361
The 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 is described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000362
The 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 is described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000371
The 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 was described in example 1.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000372
First step Synthesis of (R) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000373
To a solution of (R) -5-methylpyrrolidin-2-one (1.7 g,17.2 mmol) in methylene chloride (40 mL) was added, in portions, trimethyloxonium tetrafluoroboric acid (3.55 g,24.0 mmol) under an ice bath. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, 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 GPA0000286075210000374
6-Aminomethylpyridine hydrazide (2.35 g,15.4 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL) at room temperature, and (R) -5-methoxy-2-methyl-3, 4-dihydro-2H-pyrrole (1.93 g,17.1 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) extraction, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentrating, and column chromatography to obtain the title compound (R) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1，2，4]Triazol-3-yl) pyridin-2-amine (1.62 g, 49% yield in two steps).
1 H NMR(400MHz，CDCl 3 )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] + .
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 GPA0000286075210000381
(R) -6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (139 mg,0.65 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (298 mg,1.07 mmol) in THF (10 mL) and pyridine (10 mL) at room temperature, followed by 4-dimethylaminopyridine (12 mg,0.097 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then water (5 mL), dichloromethane (50 mL. Times.2) were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography 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 (151 mg, yield 51%).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000382
The 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 was described in example 8.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000391
First step Synthesis of 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000392
To a solution of 5, 5-dimethylpyrrolidin-2-one (0.36 g,3.2 mmol) in methylene chloride (30 mL) was added, in portions, trimethyloxonium tetrafluoroboric acid (0.66 g,4.45 mmol) under an ice bath. The reaction was then allowed to slowly warm to room temperature and stirred at this temperature for 5 hours, followed by addition of saturated NaHCO 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, 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 GPA0000286075210000393
6-Aminomethylpyridine hydrazide (435 mg,2.86 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (2 mL) at room temperature, 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole (404 mg,3.2 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) extraction, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentrating and column chromatography to obtain the title compound 6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1，2，4]Triazol-3-yl) pyridin-2-amines380mg, 52% yield in two steps).
MS m/z(ESI)：230.1[M+H] + .
Step three Synthesis of 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 GPA0000286075210000394
6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (35 mg,0.15 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (70 mg,0.25 mmol) in THF (5 mL) and pyridine (5 mL) at room temperature, 4-dimethylaminopyridine (4.6 mg,0.04 mmol) was added. The reaction was heated to 45℃and stirred at this temperature for 2 hours, then quenched with water (5 mL), extracted with dichloromethane (50 mL. Times.2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography 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) -2-fluoro-4-methylbenzamide (39 mg, 54% yield).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000401
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000402
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000411
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000412
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000413
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000421
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000422
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 GPA0000286075210000423
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 GPA0000286075210000431
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 is made to 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 GPA0000286075210000432
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 is made to 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 GPA0000286075210000433
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 Process reference 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 GPA0000286075210000441
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 Process reference 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 GPA0000286075210000442
The 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 was described in 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 GPA0000286075210000443
The 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 was described in 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 GPA0000286075210000444
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 the procedure described in example 8 was followed.
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 GPA0000286075210000451
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 Process reference 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 GPA0000286075210000452
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000453
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000461
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000462
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000471
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 described in example 8.
MS m/z(ESI)：470.2[M+H] + .
Example 32
5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (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 GPA0000286075210000472
The preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000473
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000481
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000482
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000483
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000491
Synthesis of (S) -5-vinylpyrrolidin-2-one is described in J.Org.chem.2017, 82, 532-540.
MS m/z(ESI)：112.2[M+H] + .
The first step: synthesis of (S) -5-methoxy-2-vinyl-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000492
To (S) -5-vinylpyrrolidin-2-one (0.26 g,2.34 mmol) was dissolved in dichloromethane (60 mL) under ice-bath, and trimethyloxonium tetrafluoroboric acid (0.48 g,3.28 mmol) was added in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, and the organic solvent was concentrated under reduced pressure to give crude product which was used directly in the next reaction.
MS m/z(ESI)：126.1[M+H] + .
And a second step of: synthesis of (S) -6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure GPA0000286075210000493
6-Aminomethylpyridine hydrazide (321 mg,2.11 mmol) was dissolved in a mixed solvent of 2-pentanol (10 mL) and acetic acid (1 mL) at room temperature, and (S) -5-methoxy-2-vinyl-3, 4-dihydro-2H-pyrrole (293 mg,2.34 mmol) was added. The reaction was heated to 125℃and stirred at this temperature for 12 hours, cooled to room temperature, the organic solvent was concentrated under reduced pressure, and saturated NaHCO was then added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) extraction, washing of the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentration of the organic solvent, and 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 (240 mg, 50% yield in two steps).
MS m/z(ESI)：228.1[M+H] + .
And a third step of: 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 GPA0000286075210000501
(S) -6- (5-vinyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (44 mg,0.19 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (90 mg,0.33 mmol) in THF (5 mL) and pyridine (5 mL) at room temperature, followed by 4-dimethylaminopyridine (5.9 mg,0.048 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then water (5 mL) was added dropwise, dichloromethane (50 mL. Times.2) was 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 (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 (53 mg, yield 58%).
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000502
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 reference example 37.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000511
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.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000512
The first step: synthesis of (S) -5-methoxy-2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000513
(S) -5- (trifluoromethyl) pyrrolidin-2-one (0.6 g,3.92 mmol) was dissolved in methylene chloride (40 mL) under ice-bath and trimethyloxonium tetrafluoroboric acid (0.81 g,5.5 mmol) was added in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, and the organic solvent was concentrated under reduced pressure to give crude product which was used directly in the next reaction.
MS m/z(ESI)：168.2[M+H] + .
And a second step of: synthesis of (S) -6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure GPA0000286075210000514
6-Aminomethylpyridine hydrazide (620 mg,3.71 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL) at room temperature, and (S) -5-methoxy-2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrole (650 mg,3.89 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) extraction, washing of the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentration of the organic solvent, and 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 (560 mg, 56% yield in two steps).
MS m/z(ESI)：270.2[M+H] + .
And a third step of: 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 GPA0000286075210000521
(S) -6- (5- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (43 mg,0.22 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100 mg,0.36 mmol) in THF (5 mL) and pyridine (5 mL) at room temperature, followed by 4-dimethylaminopyridine (11 mg,0.09 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then quenched with water (5 mL), extracted with dichloromethane (50 mL. Times.2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in an organic solvent followed by column chromatography to isolate 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 (51 mg, 62% yield).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000522
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 reference example 40.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000531
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 reference example 40.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000532
Synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylate is described in Org. Lett.2011, 13, 2634-2637
The first step: synthesis of S-ethyl (S) -5-carbonyl pyrrolidine-2-methyl sulfate
Figure GPA0000286075210000533
Under ice bath, (S) -5-carbonyl pyrrolidine-2-carboxylic acid (20 g,150 mmol) was dissolved in CH 2 Cl 2 (300 mL) and DMF (160 mL) were then added DMAP (1.85 g,15.0 mmol) and ethanethiol (13.8 mL,180 mmol) in sequence, DCC (40.5 g,180 mmol). The reaction was slowly warmed to room temperature, stirred at this temperature for 16 hours, saturated NaHCO was added 3 Aqueous (20 mL), dichloromethane (100 mL. Times.2) was used for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, followed by column chromatography to give the title compound S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (18.5 g, 69%).
MS m/z(ESI)：174.1[M+H] + .
And a second step of: synthesis of tert-butyl (S) -2- ((ethylsulfanyl) carbonyl) -5-carbonylpyrrolidine-1-carboxylate
Figure GPA0000286075210000534
S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (6 g,34.6 mmol) was dissolved in MeCN (35 mL) under ice-bath followed by the sequential addition of Boc2O (8.28 mL,35.0 mmol) and DMAP (470 mg,3.46 mmol). The reaction was slowly warmed to room temperature, stirred at this temperature for 2 hours, saturated NaHCO was added 3 Aqueous (20 mL), ethyl acetate (100 mL. Times.2) extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, reduced pressure concentration, column chromatography separation of the title compound S-ethyl (S) -5-carbonyl pyrrolidine-2-methyl sulfate (7.3 g, 77%).
MS m/z(ESI)：296.1[M+Na] + .
And a third step of: synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylate
Figure GPA0000286075210000541
S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (1.0 g,3.66 mmol) was dissolved in acetone (15 mL) under ice-bath followed by Pd/C (160 mg), etOH (1.28 g,10.98 mmol) added sequentially. The reaction was slowly warmed to room temperature, stirred at this temperature for 1 hour, then filtered through celite, and the filtrate was concentrated under reduced pressure to give an oily product (0.72 g) which was used directly in the next step.
1 H NMR(400MHz，CDCl 3 )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] + .
Fourth step: synthesis of (S) -5-carbonyl pyrrolidine-2-carbaldehyde
Figure GPA0000286075210000542
Tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester (0.72 g,3.38 mmol) was dissolved in CH under ice bath 2 Cl 2 To (10 mL) was then added TFA (2.5 mL) in sequence. 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 (400 mg) as an oil which was used directly in the next step.
MS m/z(ESI)：114.1[M+H] + .
Fifth step: synthesis of (S) -5-ethynyl pyrrolidin-2-one
Figure GPA0000286075210000543
Under ice bath, (S) -5-carbonyl-pyrrolidine-2-carbaldehyde (400 mg, crude product from the previous step) was dissolved in MeOH (15 mL) followed by K 2 CO 3 (931 mg,6.74 mmol), (1-diazo-2)Dimethyl oxopropyl phosphonate (1.01 g,4.04 mmol). The reaction mixture was slowly warmed to room temperature, stirred at this temperature for 12 hours, and saturated brine (20 mL) was added thereto, followed by using CH 2 Cl 2 (100 mL. Times.2) extraction, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography gave the title compound (S) -5-ethynyl pyrrolidin-2-one (260 mg, 71%).
1 H NMR(400MHz，CDCl 3 )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] + .
Sixth step: synthesis of (S) -2-ethynyl-5-methoxy-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000551
(S) -5-Acetylylpyrrolidin-2-one (0.26 g,2.38 mmol) was dissolved in CH under ice 2 Cl 2 To a solution (10 mL) was added trimethyloxonium tetrafluoroboric acid (0.67 g,4.53 mmol) in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous solution (5 mL) with CH 2 Cl 2 (50 mL. Times.2) extraction, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, addition of glacial acetic acid (5 mL), and concentration of the organic solvent under reduced pressure gave crude product (315 mg) which was used directly in the next reaction.
MS m/z(ESI)：124.2[M+H] + .
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 GPA0000286075210000552
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6-Aminomethylpyridinyl hydrazide (320 mg,2.1 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL) at room temperature, and (S) -2-ethynyl-5-methoxy-3, 4-dihydro-2H was addedPyrrole (315 mg, crude product of the previous step). The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) extraction, washing of the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentration of the organic solvent, and column chromatography to give the title compound (S) -6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2, 1-c) ][1，2，4]Triazol-3-yl) pyridin-2-amine (362 mg, 46% yield in 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 GPA0000286075210000553
(S) -6- (5-ethynyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (80 mg,0.36 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (220 mg,0.79 mmol) in THF (25 mL) and pyridine (35 mL) at room temperature, followed by 4-dimethylaminopyridine (15 mg,0.12 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then quenched with water (5 mL), extracted with dichloromethane (50 mL. Times.2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in an organic solvent followed by column chromatography to isolate 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 (122 mg, 73% yield).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000561
Reference example 43 refers to 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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000562
(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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000571
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000572
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000573
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 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 GPA0000286075210000581
The 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 is described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000582
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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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000591
The first step: synthesis of (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000592
To (S) -5- (fluoromethyl) pyrrolidin-2-one (0.7 g,6.0 mmol) in dichloromethane (60 mL) was added, in portions, trimethyloxonium tetrafluoroboric acid (1.24 g,8.4 mmol) under ice-bath. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, and the organic solvent was concentrated under reduced pressure to give crude product which was used directly in the next reaction.
MS m/z(ESI)：132.2[M+H] + .
And a second step of: synthesis of (S) -6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure GPA0000286075210000593
6-Aminomethylpyridine hydrazide (900 mg,6.0 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL) at room temperature, and (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole (783 mg,6.0 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated and subjected to 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 (430 mg, 55% yield in two steps).
1 H NMR(400MHz，CDCl 3 )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] + .
And a third step of: synthesis of (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 GPA0000286075210000594
(S) -6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (195 mg,0.84 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (390 mg,1.4 mmol) in THF (15 mL) and pyridine (15 mL) at room temperature, followed by 4-dimethylaminopyridine (26 mg,0.21 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then quenched with water (5 mL), extracted with dichloromethane (50 mL. Times.2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure followed by column chromatography to isolate 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 (179 mg, 45% yield).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000601
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000602
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The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000611
The 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 was described in example 8.
1 H NMR(400MHz，CD 3 OD)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 GPA0000286075210000612
The first step: preparation of (S) - (5-carbonyl pyrrolidin-2-yl) methyl 4-methylbenzenesulfonate
Figure GPA0000286075210000613
(S) -5- (hydroxymethyl) pyrrolidin-2-one (5.0 g,43.5 mmol), p-toluenesulfonyl chloride (13.3 g,71.7 mmol), triethylamine (13.2 g,130.6 mmol) were dissolved in dichloromethane (60 mL) at room temperature in this order, reacted overnight at room temperature, dichloromethane (80 mL) was added to dilute, the organic phase was washed with 1N HCl, dried over anhydrous sodium sulfate, filtered and the organic solvent was concentrated under reduced pressure, and crude product was purified by column chromatography to give (S) - (5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (8.3 g, yield: 71%).
1 H NMR(400MHz，CDCl 3 )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] + .
And a second step of: preparation of (R) -5-ethylpyrrolidin-2-one
Figure GPA0000286075210000621
Under ice bath condition, cuprous iodide (1.06 g,5.6 mmol) is dissolved in tetrahydrofuran (6 mL), nitrogen is replaced three times, methyl lithium (7.4 mL,11.1 mmol) is added dropwise, the reaction is stirred for 45min at 0 ℃, cooled to-20 ℃, solution of (S) - (5-carbonyl pyrrolidine-2-yl) methyl 4-methylbenzenesulfonate (500 mg,1.9 mmol) in tetrahydrofuran (6 mL) is added dropwise to the reaction system, stirring is continued for 45min at-20 ℃, the reaction is gradually carried out until room temperature is reached overnight, saturated ammonium chloride is added, extraction is carried out by ethyl acetate, the organic phase is dried by anhydrous sodium sulfate, the organic solvent is concentrated under reduced pressure after filtration, and (R) -5-ethylpyrrolidin-2-one (185 mg, yield: 86%) is obtained after crude product column chromatography purification.
1 H NMR(400MHz，CD 3 OD)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] + .
And a third step of: preparation of (R) -2-ethyl-5-methoxy-3, 4-dihydro-2H-pyrrole
Figure GPA0000286075210000622
To a solution of (R) -5-ethylpyrrolidin-2-one (180 mg,1.59 mmol) in dichloromethane (10 mL) under ice bath was added trimethyl in portionsAnd (c) an alkoxynium tetrafluoroborate (226 mg,1.59 mmol). The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, 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] + .
Fourth step: synthesis of 6-aminomethylpyridine hydrazide
Figure GPA0000286075210000623
Methyl 6-aminomethyl pyridine acid ester (2.0 g,13 mmol) was dissolved in ethanol (60 mL) at room temperature, and hydrazine hydrate (4.1 g,66 mmol) was added. The reaction was heated to 80℃and stirred at this temperature for 5 hours, after slowly cooling to room temperature, the solid precipitated in the reaction solution was filtered, and the cake was collected to give the title compound 6-aminomethylpyridine hydrazide (1.6 g, 80%).
MS m/z(ESI)：153.2[M+H] + .
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 GPA0000286075210000631
6-Aminomethylpyridine hydrazide (243 mg,1.59 mmol) was dissolved in 2-pentanol (5 mL) and acetic acid (2 mL) at room temperature, and (R) -2-ethyl-5-methoxy-3, 4-dihydro-2H-pyrrole (202 mg,1.59 mmol) was added. The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) extraction, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, concentrating, and column chromatography to obtain the title compound (R) -6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2, 1-c)][1，2，4]Triazol-3-yl) pyridin-2-amine (70 mg, 19% yield).
MS m/z(ESI)：230.2[M+H] + .
Sixth step: synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure GPA0000286075210000632
The above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoic acid hydrochloride (154 mg,0.594 mmol) was dissolved in thionyl chloride (5 mL) at room temperature, stirred under heating and refluxing for 2 hours, cooled and concentrated under reduced pressure to give a pale yellow solid product which was directly used in the next reaction.
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 GPA0000286075210000633
(R) -6- (5-ethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-amine (68 mg, 0.293 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (165 mg,0.594 mmol) in THF (6 mL) and pyridine (4 mL) at room temperature, followed by 4-dimethylaminopyridine (15 mg,0.119 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then water (5 mL), dichloromethane (50 mL. Times.2) were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography 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 (26 mg, yield 19%).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000641
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 Using example 55.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000642
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000651
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.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000652
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 Using the method of example 55.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000661
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 Process reference example 55.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000662
The first step: synthesis of 5-methoxy-4-azaspiro [2.4] hept-4-ene
Figure GPA0000286075210000663
Under ice bath, 4-azaspiro [2.4]]To a solution of heptane-5-one (1.7 g,17.2 mmol) in dichloromethane (60 mL) was added trimethyloxonium tetrafluoroboric acid (3.55 g,24.0 mmol) in portions. The reaction was slowly warmed to room temperature, stirred at this temperature for 5 hours, then saturated NaHCO was added 3 Aqueous (5 mL), dichloromethane (50 mL. Times.2) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, glacial acetic acid (5 mL) was added, 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] + .
And a second step of: synthesis of 6- (6 ',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-amine
Figure GPA0000286075210000664
6-Aminomethylpyridinyl hydrazide (500 mg,4.5 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL) at room temperature, 5-methoxy-4-azaspiro [2.4 ] was added]Hept-4-ene (930 mg,6.3 mmol). The reaction was heated to 125 ℃, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then saturated NaHCO is added 3 Aqueous solution (5 mL), dichloromethane (50 mL. Times.2) extraction, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating the organic solvent, and separating by column chromatography to obtain the title compound 6- (6 ',7' -dihydrospiro [ cyclopropane-1, 5' -pyrrolo [2,1-c ])][1，2，4]Triazole compounds]-3′-Pyridin-2-amine (515 mg, 50% yield in two steps).
1 H NMR(400MHz，CDCl 3 )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] + .
And a third step of: 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 GPA0000286075210000671
6- (6 ',7' -Dihydropiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-amine (39 mg,0.17 mmol) was added to a solution of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (80 mg,0.29 mmol) in THF (5 mL) and pyridine (5 mL) at room temperature, followed by 4-dimethylaminopyridine (5.3 mg,0.043 mmol). The reaction was heated to 45℃and stirred at this temperature for 2 hours, then water (5 mL), dichloromethane (50 mL. Times.2) were added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in an organic solvent followed by column chromatography to isolate the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6 ',7' -dihydrospiro [ cyclopropan-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-fluoro-4-methylbenzamide (51 mg, 63% yield).
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000672
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.
1 H NMR(400MHz，CDCl 3 )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, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one
Figure GPA0000286075210000681
The first step: preparation of methyl 5-amino-2-cyano-4-methylbenzoate
Figure GPA0000286075210000682
Methyl 5-amino-2-bromo-4-methylbenzoate (900 mg,3.69 mmol), cuCN (657 mg,7.38 mmol) was mixed in NMP (10 mL), stirred at 180℃for 2 hours, cooled, added with water, filtered and the filter cake dried to give crude methyl 5-amino-2-cyano-4-methylbenzoate (1.5 g) as the title compound, which was used directly in the next step.
MS m/z(ESI)：191.1[M+H] + .
And a second step of: preparation of 6-amino-5-methylisoindolin-1-one
Figure GPA0000286075210000683
The crude product was dissolved in methanol (20 mL) and Raney Ni (about 100 mg) was added to the solution at H 2 Stirring 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 column chromatographed to give the title compound 6-amino-5-methylisoindolin-1-one (800 mg, crude).
MS m/z(ESI)：163.1[M+H] + .
And a third step of: preparation of 6- ((2-cyclopropyl-2-carbonylethyl) amino) -5-methylisoindolin-1-one
Figure GPA0000286075210000684
6-amino-5-methylisoindolin-1-one (370 mg,2.28 mmol), 2-bromo-1-cyclopropylethane-1-one (09 mg,2.51 mmol), KI (38.0 mg,0.228 mmol), K 2 CO 3 (378 mg,2.74 mmol) was mixed in DMF (5 mL) and stirred at 55deg.C for 2 hours. Cooled, water was added to the mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed three times with saturated brine, dried and the organic solvent was removed under reduced pressure, and the crude product was used directly in the next step.
MS m/z(ESI)：245.1[M+H] + .
Fourth step: preparation of 6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -5-methylisoindolin-1-one
Figure GPA0000286075210000691
The crude product of the third step was dissolved in AcOH (10 mL), then KSCN (442 mg,4.56 mmol) was added to the solution, followed by stirring at 120℃for 2 hours. After cooling, the reaction solution was concentrated and the crude product was used directly in the next step.
MS m/z(ESI)：286.1[M+H] + .
Fifth step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisoindolin-1-one
Figure GPA0000286075210000692
The crude product of the fourth step was dissolved in a mixed solvent of AcOH (10 mL) and water (2 mL), stirred, and hydrogen peroxide (30 wt%,10.0g,87.8 mmol) was slowly added dropwise to the solution at 50 ℃. After the completion of the dropwise addition, stirring was continued at this temperature for 1 hour. The reaction solution was cooled and 20wt% Na was slowly added 2 SO 3 The aqueous solution (30 mL) was stirred at room temperature for 30 min. The organic solvent was removed under reduced pressure and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium hydrogencarbonate and 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-methylisoindolin-1-one (180 mg, five-step yield: 42%).
MS m/z(ESI)：254.1[M+H] + .
Sixth step: preparation of 3- (6-chloropyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole
Figure GPA0000286075210000693
Preparation of 3- (6-chloropyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole reference is made to the fifth and sixth steps of example 1.
MS m/z(ESI)：221.1[M+H] + .
Seventh step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one
Figure GPA0000286075210000694
6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisoindolin-1-one (50 mg, 0.197mmol), 2-chloro-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (48 mg,0.22 mmol), cesium carbonate (86 mg,0.30 mml) were mixed in 1, 4-dioxane (4 mL), deoxygenated with nitrogen for 5 minutes, and Pd was added 2 (dba) 3 (18 mg,0.02 mmol) was deoxygenated with nitrogen for 5 minutes, xantphos (23 mg,0.04 mmol) was added, deoxygenation with nitrogen was continued for 5 minutes, and then stirring was continued for two days at 120 ℃. Cooled, concentrated, and partitioned 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, 7-dihydro-5H-pyrrolo [2, 1-c) ][1，2，4]Triazol-3-yl) pyridin-2-yl) -5-methylisoindolin-1-one (43 mg, yield: 50%).
1 H NMR(400MHz，CDCl 3 )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-methylisoindolin-1-one
Figure GPA0000286075210000701
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 example 63.
1 H NMR(400MHz，CDCl 3 )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 GPA0000286075210000702
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.
1 H NMR(400MHz，CDCl 3 )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 invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
1. Test ASK1 enzymatic experiments
The test adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition of the compound on ASK1 kinase activity and obtains the half inhibition concentration IC of the compound on ASK1 kinase activity 50 。
1) 1-5 uLASK1 enzyme solution is added into 384-well plate, and the final concentration of enzyme is 0.2-20 nM.
2) Adding 1-5 uL of compound solution which is diluted in a gradient way.
3) 1-5 uL of substrate mixed solution is added, and the final concentration of substrate polypeptide is 100-5000 nM and the final concentration of ATP is 100-1000 uM.
4) Incubating for 0.5-5 hours at room temperature.
5) 10uL of EDTA and a detection solution containing a labeled antibody are added, and the mixture is incubated for 2 to 24 hours at room temperature.
6) The microplate reader measures fluorescence signal values at about 615nm and 665nm for each plate well.
7) The inhibition ratio was calculated from the fluorescence signal values.
8) IC of compounds by curve fitting based on inhibition ratios at different concentrations 50 。
The enzymatic activity of the compounds of the examples of the present invention is shown in Table 1.
TABLE 1 enzymatic Activity of the Compounds of the examples in the present invention
Figure GPA0000286075210000711
/>
Figure GPA0000286075210000721
The compounds of the above examples can all remarkably inhibit the enzymatic activity of ASK1 kinase, and part of the compounds have strong inhibition effect on ASK1 kinase, and IC for inhibiting kinase enzymatic activity 50 Less than 10nM, these compounds have great potential for use as potent inhibitors of ASK1 in the treatment of NASH.
2. Mouse PK assay
The pharmacokinetic experiments in mice of the preferred embodiments of the present invention were performed using Balb/c male mice (Shanghai Jieshijie laboratory animal Co., ltd.).
■ The administration mode is as follows: single gastric lavage administration.
■ Dosage of administration: 5 mg/10 ml/kg.
■ Formulation recipe: CMC-Na 0.5% and dissolved by ultrasound.
■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■ Sample treatment:
1) The orbit is sampled by 0.1mL and placed in K 2 In EDTA test tube, the plasma is separated by centrifugation at 1000-3000 Xg for 5-20 min at room temperature and stored at-80 ℃.
2) The plasma sample 40uL was precipitated by adding 160uL acetonitrile, and after mixing, it was centrifuged at 500 to 2000 Xg for 5 to 20 minutes.
The concentration of the test compound was analyzed by LC/MS/MS by taking 100uL of the supernatant solution after the treatment.
■ LC-MS/MS analysis:
● Liquid phase conditions: shimadzu LC-20AD pump
● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
● Chromatographic column: phenomenex Gemiu 5um C18.times.4.6 mm
● Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
● Flow rate: 0.8mL/min
● Elution time: gradient elution for 0-3.5 min
■ Pharmacokinetics:
the main parameters were calculated with WinNonlin 6.1 and the results of the mouse drug substitution experiments are shown in table 2 below:
TABLE 2
Figure GPA0000286075210000731
/>
Figure GPA0000286075210000741
From the results of the mouse drug substitution experiments in the table, it can be seen that: the compounds of the examples of the present invention exhibit good metabolic properties, exposure AUC and maximum blood concentration C max All perform well.
3. Rat PK assay
The pharmacokinetic experiments in rats according to the preferred embodiments of the present invention were performed using SD male rats (Shanghai jetsche laboratory animals limited).
■ The administration mode is as follows: single gastric lavage administration.
■ Dosage of administration: 5 mg/10 ml/kg.
■ Formulation recipe: 5% EtOH-75% PG-10% Kolliphor-10% water, sonicated.
■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■ Sample treatment:
2) Vein blood sampling 0.2mL placed in K 2 In EDTA test tube, the plasma is separated by centrifugation at 1000-3000 Xg for 5-20 min at room temperature and stored at-80 ℃.
3) The plasma sample 40uL was precipitated by adding 160uL acetonitrile, and after mixing, it was centrifuged at 500 to 2000 Xg for 5 to 20 minutes.
4) The concentration of the test compound was analyzed by LC/MS/MS by taking 100uL of the supernatant solution after the treatment.
■ Liquid phase analysis:
● Liquid phase conditions: shimadzu LC-20AD pump
● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
● Chromatographic column: phenomenex Gemiu 5um C18.times.4.6 mm
● Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
● Flow rate: 0.8mL/min
● Elution time: gradient elution for 0-3.5 min
■ Pharmacokinetics:
the main parameters were calculated with WinNonlin 6.1 and rat drug substitution experimental results are shown in table 3 below:
TABLE 3 Table 3
Figure GPA0000286075210000751
From the results of the rat drug substitution experiments in the table, it can be seen that: compared with the prior art, the compound of the embodiment of the invention shows good metabolic property, exposure dose AUC and maximum blood concentrationDegree C max All perform well.
4. The compound of the invention has the advantages of HFD (high fat feed) +CCl 4 Effects of induced ALT and AST levels in non-alcoholic steatohepatitis mice
1) The purpose of the experiment is as follows:
the purpose of this test example was to determine whether the compounds of the invention were able to down-regulate ALT and AST levels in serum of non-alcoholic steatohepatitis mice.
2) Experimental raw materials and instruments:
the glutamic pyruvic transaminase (ALT/GPT) test box was used: nanjing established technology Co.Ltd
Glutamic oxaloacetic transaminase (AST/GOT) test box: nanjing established technology Co.Ltd
96-well plates: corning Co Ltd
BioTek Synergy H1 microplate reader: bioTek Co., USA
3) The experimental steps are as follows:
after C57BL/6 mice were subjected to adaptive feeding for 3-7 days in SPF (specific pathogen free) barrier, HFD feed feeding was changed for 8 weeks, HFD feeding was performed for five weeks, mice after HFD induction were randomly grouped according to animal weight, and CCl was orally administered twice a week 4 Induction, and lasting for 4 weeks; administration of CCl 4 Modeling the day of oral dosing, dosing frequency once per day, for 28 days continuously; the solvent control group is given with the solvent corresponding to the test sample, and the administration volume is 10mL/kg; CCl (CCl) 4 48 hours after the last administration, CO 2 The mice were euthanized, non-anticoagulated venous blood of the animals was collected from the hearts, whole blood was left at room temperature for at least 30 minutes, centrifuged at 4℃for 5 minutes at 5000 rpm, serum was separated, split into two parts, and filled into 1.5mL EP tubes for storage at-80℃for further use.
Mouse serum ALT and AST levels were tested using the glutamic pyruvic transaminase (ALT/GPT) and glutamic oxaloacetic transaminase (AST/GOT) test cassettes. Placing ALT (or AST) detection matrix solution into a 37 ℃ incubator for preheating; adding 20uL of matrix liquid into a 96-well plate, adding 5uL of serum into the 96-well plate to serve as a measuring hole, uniformly mixing, and placing into a 37 ℃ incubator for incubation for 30min by using a sealing film sealing plate; preparing an ALT (or AST) standard curve, sucking 25uL and adding the ALT standard curve 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, uniformly mixing, placing the holes into a constant temperature box at 37 ℃ for incubation for 20min by using a sealing film sealing plate, adding 200uL of 0.4M NaOH solution into each hole, placing the holes into a shaking plate instrument for shaking for 15min, reading the plate on a BioTek Synergy H1 instrument by using a detection OD program, and calculating an absolute OD value according to the OD value of each hole, wherein the wavelength is 510 nm. Absolute OD = assay well OD-control well OD; and (3) bringing the absolute OD value into a standard curve to obtain the ALT (or AST) content in the sample, wherein the sample beyond the standard curve range is detected again after serum is diluted to a proper concentration.
And (3) data processing: (% ALT reduction) = (vehicle control group-test compound)/vehicle control group x 100%;
(% AST reduction) = (vehicle control group-test compound)/vehicle control group x 100%.
4) The experimental results are shown in table 4 below:
TABLE 4 Table 4
Figure GPA0000286075210000761
Figure GPA0000286075210000771
5) Conclusion of experiment:
the compounds of the present invention show good results in down-regulating the levels of ALT and AST in serum of non-alcoholic steatohepatitis mice compared to the prior art.
5. Dose test of the Compounds of the examples of the invention administered to SD rats by gavage for 7 days
1) The purpose of the experiment is as follows:
examples 9 and 43 of the present invention, male SD rats were given repeated 1 time daily by gavage at 10, 30, 100mg/kg doses for 7 consecutive days to evaluate the possible toxic response and metabolic status in vivo.
2) Experimental equipment and reagents:
Figure GPA0000286075210000772
3) The experimental method and the treatment are as follows:
prior to administration, the compound formulated with vehicle 0.5% cmc-Na (control) was placed on a magnetic stirrer for at least 15 minutes and stirring was continued during the administration. The compound/control is taken in the required volume according to the measured body weight and administered orally and gastrographically.
At least twice daily (1 each of morning and afternoon) during the trial, about 4 hours of continuous observation after the first administration, observations including but not limited to mental state, behavioral activity, skin, hair, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, breath; animals in each group were weighed 2 times per week.
All animals were scheduled on day 8 to euthanize the anterior abdominal aorta and collect blood samples for cytometry, clotting function, and blood biochemical tests, each in EDTA-K-containing 2 Anticoagulant (blood cell count), sodium citrate (clotting function), and seperate gel + procoagulant (blood biochemistry). The blood analyzer, the automatic blood coagulation analyzer and the full-automatic biochemical analyzer are respectively used for detecting blood cell count, coagulation function and blood biochemical index, and the electrolyte analyzer is used for electrolyte detection. Pathology was observed in general anatomically, and further visualized by staining the prepared pathological sections after fixation of the liver and lungs.
The toxico-kinetic blood samples are collected before the first and the last administration and after the administration for 0.5h, 1h, 2h, 4h, 8h, 12h and 24h respectively; EDTA-K is contained before blood collection 2 Placing the centrifuge tube in a refrigerator with the temperature of 2-8 ℃ or in ice bath for temporary storage; adding the collected blood into the marked centrifuge tube, manually reversing for at least 5 times, and temporarily storing in an ice bath; centrifugation conditions: centrifuging at 4deg.C for 10min at 1500g, transferring the centrifuged blood plasma into a new labeled centrifuge tube, and preserving at below-70deg.C.
4) Experimental results
(1) Animal death: during the test period, no death or moribund phenomenon was seen in each group of animals.
(2) Clinical observation: during the trial, example 43 showed that individual animals were Mao Pengsong at 100mg/kg dose at days 7-8, respectively, after dosing, and no abnormal changes were seen in clinical observations for each group of animals for the remaining time periods.
(3) Weight of: during the test period, the body weight of each group of male mice showed a continuous trend of increasing.
(4) Clinical pathology: on the eighth day, examples 9 and 43 showed no toxicologically significant changes in blood cell count, clotting function, and blood biochemical index in male mice at doses of 10, 30, and 100mg/kg compared to vehicle control.
(5) General and histopathological examination: in this test, examples 9 and 43 showed no substantial changes in the 10, 30, 100mg/kg dose, nor in the histopathological examination of the lungs and liver.
(6) Toxicological kinetics: no accumulation was seen in the plasma of the male rats in examples 9 and 43 at a dose ranging from 10 to 100 mg/kg.
5) Conclusion of experiment:
examples 9 and 43 were given to SD male mice by repeated gavage at doses of 10, 30, 100mg/kg, respectively, 1 time per day for 7 days of continuous administration, and animals were well tolerated with a Maximum Tolerated Dose (MTD) of 100mg/kg and good safety.

Claims (19)

1. A pharmaceutical composition comprising a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, as shown below:
Figure FDA0004067931910000011
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier; the weight percentage of the active ingredients is 1-95% based on the total weight of the composition.
2. The pharmaceutical composition according to claim 1, wherein the weight percentage of active ingredient is 5% to 85% based on the total weight of the composition.
3. The pharmaceutical composition according to claim 1, wherein the weight percentage of active ingredient is 10% to 60% based on the total weight of the composition.
4. The pharmaceutical composition according to claim 1, wherein the weight percentage of active ingredient is 10% to 50% based on the total weight of the composition.
5. The pharmaceutical composition according to claim 1, wherein the dosage is in the range of 0.5-120mg.
6. The pharmaceutical composition according to claim 1, wherein the dosage is in the range of 1-100mg.
7. The pharmaceutical composition according to claim 1, wherein the dosage is in the range of 1-50mg.
8. The pharmaceutical composition according to claim 1, wherein the dosage is in the range of 1-30mg.
9. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 8, wherein the compound, stereoisomer or pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier to prepare the product.
10. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 8, wherein the compound, stereoisomer or pharmaceutically acceptable salt thereof is admixed with excipients, solvents or other pharmaceutically acceptable carriers.
11. The pharmaceutical composition according to any one of claims 1-8, characterized by the use in the preparation of ASK1 inhibitor drugs.
12. Use of a pharmaceutical composition according to any one of claims 1-8 for the preparation of a medicament for the treatment of neurodegenerative disorders, cardiovascular disorders, inflammatory disorders, metabolic disorders.
13. The use according to claim 12, wherein the inflammatory disorder is selected from the group consisting of non-alcoholic steatohepatitis.
14. The pharmaceutical composition according to any one of claims 1-8, which is in a form suitable for oral, intramuscular and subcutaneous administration, in the form of a sterile injectable aqueous or oily suspension, an oil-in-water emulsion.
15. The pharmaceutical composition of claim 14, wherein the oral form is selected from the group consisting of tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; the oil phase is vegetable oil or mineral oil in the form of oil-in-water emulsion; the sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration are in the form of sterile injectable solutions or suspensions prepared in parenterally acceptable non-toxic diluents or solvents.
16. The pharmaceutical composition of claim 15, wherein 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 which is a solution prepared in 1, 3-butanediol.
17. The pharmaceutical composition of claim 15, wherein said lozenge is selected from the group consisting of troches.
18. The pharmaceutical composition according to any one of claims 1-8, which is in a form suitable for use selected from sterile injectable aqueous solutions.
19. The pharmaceutical composition of claim 18, wherein the sterile injectable aqueous solution is in a vehicle or solvent selected from the group consisting of water, ringer's solution and isotonic sodium chloride solution.
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