WO2020143385A1 - Arylamide inhibitor, preparation method therefor and application thereof - Google Patents

Abstract

Disclosed by the present invention is an apoptosis signal regulating kinase 1 (ASK1) inhibitor. Provided are an arylamide compound having the structure represented by formula (I), and a stereoisomer, a tautomer or a pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof; and also provided is a pharmaceutical composition of the pharmaceutically acceptable salt of said compound. The present arylamide compound may be used to treat and prevent non-alcoholic steatohepatitis and related diseases.

Description

Arylamide inhibitors, preparation method and application thereof Technical field

The invention belongs to the field of drug synthesis, and particularly relates to an arylamide inhibitor, its preparation method and application.

Background technique

The mitotic activated protein kinase signaling (MAPK) pathway is a key signaling pathway for cell mitosis and apoptosis. There are three main types of MAPK, including mitotic activated protein kinase kinase kinase (MAP3K), mitotic activated protein kinase kinase (MAP2K) and mitotic activated protein kinase kinase kinase (MAPK). Under the stimulation of corresponding environmental signals, MAP3K, MAP2K and MAPK are activated sequentially, and finally MAPK phosphorylates downstream substrates to produce corresponding cell effects, such as cell growth, differentiation, survival and apoptosis.

The balance between cell survival and apoptosis is the key to the normal development of the human body. If these imbalances will cause various diseases (such as cancer, autoimmune diseases, heart diseases and metabolic diseases, etc.). Hepatocyte apoptosis is currently considered to be one of the important causes of liver disease progression. Although this is a common process, its role in liver fibrosis is closely related to viral hepatitis, alcoholic and non-alcoholic liver disease (inflammatory). In animal experiments, it was found that hepatic fibrosis can be reduced by regulating hepatocyte apoptosis (Alexander J. Kovalic, Sanjaya K. Satapathy, Naga Chalasani; Hepatology International 2018, 12: 97–106).

Non-alcoholic fatty liver disease affects about 10% to 30% of ordinary adults and 60-80% of patients with type 2 diabetes. In the United States, the incidence of NAFLD accounts for about 10-46% of the total population, and about 10-30% of patients will develop non-alcoholic steatohepatitis (NASH, nonalcoholic steatohepatitis). Non-alcoholic steatohepatitis (NASH) manifests as inflammation and steatosis of liver cell damage, which can lead to major diseases such as advanced liver fibrosis, cirrhosis, liver failure, and liver tumors. By 2025, its medications are expected to exceed US$35-40 billion. Early research targets include PPAR, FXR, GLP, ACC, THR, etc., but so far, NASH has not been clinically approved for therapeutic drugs.

Apoptosis signal kinase 1 (ASK1) is one of the members of the mitogen-activated protein kinase kinase family and plays a key role in cytokine and stress-induced apoptosis (Paul Yosuke Kawarazaki, Hidenori Ichijo, Isao Naguro, Expert Opin. Ther. Targets 2014 18(6):651-664). Numerous animal and human experiments have shown that the ASK1 pathway is overexpressed in hepatocytes of obese and non-alcoholic fatty liver patients, and is closely related to steatosis, insulin resistance and inflammation. Therefore, the specific inhibitor of apoptosis signal kinase 1 is expected to become a new generation of drugs for the treatment of inflammatory and metabolic diseases (such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis). Therefore, ASK1 inhibitors have very good development and application prospects as pharmaceuticals in the pharmaceutical industry.

In summary, there is an urgent need in the art to develop a new ASK1 inhibitor with excellent effects.

Summary of the invention

The object of the present invention is to provide a class of compounds with novel structures, which can be used as selective ASK1 inhibitors, have selective inhibitory effects on apoptosis signal kinase 1, excellent pharmacodynamic properties and the like.

In the first aspect of the present invention, there is provided an arylamide compound having the structure of general formula (I), or a stereoisomer, tautomer, racemate, or polymorph thereof, or Pharmaceutically acceptable salts, hydrates, solvates, or prodrugs;

In the formula:

M ₁ and M ₂ are each independently selected from: N or CR ₇ ;

Ring A is selected from the group consisting of substituted or unsubstituted C3-C20 carbocycles (preferably, C3-C10 carbocycles), substituted or unsubstituted 3-20 membered heterocycles (preferably, 3-12 membered heterocycles) Ring), substituted or unsubstituted C6-C20 aromatic ring (preferably, C6-C12 aromatic ring) or substituted or unsubstituted 5-20 membered heteroaromatic ring (preferably, 5 to 12 membered heteroaromatic ring) ; In ring A, the substitution means that ring A is substituted by oxo, thio, or -(CH ₂ ) _n- (that is, two hydrogen atoms connected to the same carbon atom on the group are replaced by the group), Or H on ring A is substituted with one or more (preferably 1 to 3) substituents selected from the group consisting of deuterium atoms, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, Halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n O(CH ₂ ) _o R ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C (O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ;

Each R ₁ is the same or different, and each independently is a group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n R ₁₀ , -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n CH(R ₁₀ )(CH ₂ ) _o NR ₁₁ R ₁₂ (including: -(CH ₂ ) _n CH(OH)(CH ₂ ) _o NHR ₁₁ ), -(CH ₂ ) _n O(CH ₂ ) _o R ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S (O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ , -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ or -( CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ , -(CH ₂ ) _n N(R ₁₁ )(CH ₂ ) _o R ₁₀ (including -(CH ₂ ) _n NH(CH ₂ ) _o R ₁₀ );

R ₂ , each of R ₃ and R ₅ are independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (preferably -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and- (CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ;

R _{4 is} selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, hydroxyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; alternatively, R ₄ and M ₃ together with the N atom connected to them form a ring selected from the group consisting of substituted or unsubstituted heterocycle, substituted or unsubstituted Substituted heteroaromatic ring;

M ₃ and M ₄ are each independently selected from N or CR ₇ ; or M ₃ and M ₄ and their adjacent chemical bonds together constitute a group selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group;

M _{5 is} selected from the group: N or CR ₇ ;

-NR ₈-、CR ₈R ₉-、-S(O) _m-、

X and Y are independently selected from: bond,

-NR ₈ -, CR ₈ R ₉ -, -S(O) _m -,

Alternatively, X and/or Y and M ₁ , M ₂ or M ₅ and the chemical bonds to which they are connected together form a ring selected from the group consisting of substituted or unsubstituted carbocycles, substituted or unsubstituted heterocycles, substituted or unsubstituted Aromatic ring, substituted or unsubstituted heteroaromatic ring;

R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ;

Unless otherwise specified, the above-mentioned substitution refers to the substitution of one or more (preferably 1-3) hydrogen atoms on the group with substituents selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, Haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n R ₁₀ , -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ , or -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ;

R _{10 is} independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, cyano group, substituted or unsubstituted cycloalkyl group, substitution Or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;

R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, substituted or unsubstituted cycloalkyl group, substitution Or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; or, R ₁₁ and R ₁₂ and the N atom to which they are connected together constitute a ring selected from the group consisting of: substituted or unsubstituted Substituted heterocycle, or substituted or unsubstituted heteroaromatic ring;

Wherein, in said R ₁₀ , R ₁₁ and R ₁₂ , substitution means that one or more (preferably 1-3) hydrogen atoms on the group are replaced by substituents selected from the group consisting of deuterium atoms, alkanes Group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH ₂ ) _n R ₁₃ , -(CH ₂ ) _n OR ₁₃ , -(CH ₂ ) _n SR ₁₃ , -(CH ₂ ) _n COR ₁₃ , -(CH ₂ ) _n C(O)OR ₁₃ , -(CH ₂ ) _n S(O) _m R ₁₃ , -(CH ₂ ) _n NR ₁₃ R ₁₄ , -(CH ₂ ) _n C(O)NR ₁₃ R ₁₄ , (including -(CH ₂ ) _n C(O)NHR ₁₄ ), -(CH ₂ ) _n NR ₁₄ C(O)R ₁₃ and -(CH ₂ ) _n NR ₁₄ S(O) _m R ₁₃ ;

R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, ester group, substituted or unsubstituted cycloalkane Group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; wherein, in R ₁₃ and R ₁₄ , the substitution refers to one or more groups on the group (Preferably 1-3) hydrogen atoms are substituted with substituents selected from the group consisting of deuterium atoms, alkyl groups, alkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, ester groups;

x is 0, 1, 2, 3 or 4; y is 0, 1 or 2; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5;

o is 0, 1, 2, 3, 4 or 5;

Unless otherwise specified, in the above formulas, 0-3 hydrogens in "(CH ₂ ) _n "or "(CH ₂ ) _o " are substituted by C1-C6 alkyl groups; each of the cycloalkyl groups is C3-C20 ring Alkyl (preferably C3-C10 cycloalkyl); each of said heterocyclic groups is a 3-20 membered heterocyclic group (preferably 3-10 membered heterocyclic group); each said aryl group is C6 -C20 aryl group (preferably C6-C12 aryl group); each of said heteroaryl groups is 5-20 membered heteroaryl groups (preferably 5 to 12 membered heteroaryl groups) each said alkyl group is C1 -C18 alkyl (preferably C1-C6 alkyl); each alkoxy group is C1-C18 alkoxy (preferably C1-C6 alkoxy); each ester group is C2- C10 ester group (preferably C2-C6 ester group); each of the carbocycles is a C3-C20 carbocycle (preferably C3-C10 carbocycle); each of the heterocycles is a 3-20 membered heterocycle (Preferably 3-10 membered heterocyclic ring); each of said aromatic rings is C6-C20 aromatic ring (preferably C6-C12 aromatic ring); each of said heteroaromatic ring is 5-20 membered heteroaromatic ring (Preferably a 5- to 12-membered heteroaromatic ring).

In another preferred example, R ₂ , each R ₃ and R ₅ are independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, halogen, amino group , Nitro, hydroxy, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; preferably, each is independent Selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group; more preferably, each independently selected from the group consisting of hydrogen atom, Deuterium atom.

In another preferred example, R ₂ is a hydrogen atom or a deuterium atom.

In another preferred example, R ₅ is a hydrogen atom or a deuterium atom.

In another preferred example, each R _{1 is} independently selected from the following group: substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, -(CH ₂ ) _n R ₁₀ , -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n CH(R ₁₀ )(CH ₂ ) _o NR ₁₁ R ₁₂ (including: -(CH ₂ ) _n CH(OH)(CH ₂ ) _o NHR ₁₁ ), -(CH ₂ ) _n O(CH ₂ ) _o R ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ , -(CH ₂ ) _n NR ₁₁ C( O)R ₁₀ or -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ , -(CH ₂ ) _n N(R ₁₁ )(CH ₂ ) _o R ₁₀ (including -(CH ₂ ) _n NH(CH ₂ ) _o R ₁₀ ).

In another preferred example, each R _{1 is} independently a substituted or unsubstituted group selected from the group consisting of:

-C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl,

Wherein, the substitution means that one or more (preferably 1-3) hydrogens on the group are replaced by a substituent selected from the group consisting of deuterium atom, halogen, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 deuterated alkyl.

In another preferred example, each R _{1 is} independently a corresponding group in a specific compound.

In another preferred example, when M ₅ is CR ₇ , R _{7 in} M ₅ is selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, Halogen (preferably F or Cl), amino, nitro, hydroxyl, cyano (more preferably, R ₇ is halogen).

In another preferred example, when M ₅ is CR ₇ , R _{7 in} M ₅ is fluorine or chlorine.

In another preferred example, M ₅ is N.

或-S(O) _m-(较佳地-S(O)-或-S(O) ₂-)，较佳地Y或X为

且 In another preferred example, Y or X is

Or -S(O) _m- (preferably -S(O)- or -S(O) ₂ -), preferably Y or X is

And

X or Y is -NR ₈ -.

In another preferred example, when X is -NR ₈ -, (i) R _{8 is} selected from a hydrogen atom or a deuterium atom; or, (ii) X, Y, and M ₅ and the chemical bonds connected thereto form a group selected from the group consisting of Ring: substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl.

In another preferred example, M ₁ is CR ₇ and M ₂ is N, or M ₂ is CR ₇ and M ₁ is N.

In another preferred example, when M ₁ is CR ₇ and M ₂ is N, or M ₂ is CR ₇ and M ₁ is N, R ₇ in the M ₁ or M ₂ group is selected from the group consisting of hydrogen atoms , Deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano; preferably, R ₇ in the M ₁ or M ₂ group is hydrogen Atom or deuterium atom.

In another preferred example, M ₃ is CR ₇ .

In another preferred example, M ₄ is N.

In another preferred example, x is 0, 1, or 2; more preferably, x is 0 or 1.

In another preferred example, R ₃ is a hydrogen atom or a deuterium atom.

In another preferred example, the compound is a compound represented by the general formula (II):

In the formula, R _{6 is} selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -( CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ , -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; where the substitution refers to a group One or more (preferably 1-3) hydrogen atoms on the are replaced by a substituent selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, halogens , Amino, nitro, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₁₃ , -(CH ₂ ) _n SR ₁₃ , -(CH ₂ ) _n COR ₁₃ , -(CH ₂ ) _n C(O) OR ₁₃ , -(CH ₂ ) _n S(O) _m R ₁₃ , -(CH ₂ ) _n NR ₁₃ R ₁₄ , -(CH ₂ ) _n C(O )NR ₁₃ R ₁₄ (including -(CH ₂ ) _n C(O)NHR ₁₄ ), -(CH ₂ ) _n NR ₁₄ C(O)R ₁₃ and -(CH ₂ ) _n NR ₁₄ S(O) _m R ₁₃ ; or, R ₄ and the N atom connected to it, together with R ₆ and the C atom connected to it, constitute a substituted or unsubstituted heterocyclic ring, or a substituted or unsubstituted heteroaromatic ring;

Unless otherwise specified, substitutions, rings A, M ₁ , M ₂ , M ₅ , X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R _14. The definitions of x and y are as described above.

In another preferred embodiment, R ₄ and R ₆ are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, and halogenated alkyl; or

R ₄ and its connected N atom, together with R ₆ and its connected C atom, form a substituted or unsubstituted heterocycle (preferably, there is only one N heteroatom on the heterocyclic ring); wherein, the substitution It means that one or more (preferably 1-3) hydrogen atoms on the group are replaced by substituents selected from the group consisting of deuterium atoms, halogens, alkyl groups, deuterated alkyl groups, and halogenated alkyl groups.

In another preferred example,

其中，V ₁和V ₂各自独立地选自键、O、-NR ₈-、CR ₈R ₉或-S(O) _m-，各个V各自独立地选自：CH ₂、

R ₈、R ₉的定义如前所述； Ring A is

Wherein, V ₁ and V ₂ are each independently selected from a bond, O, -NR ₈ -, CR ₈ R ₉ or -S(O) _m -, and each V is independently selected from: CH ₂ ,

The definitions of R ₈ and R ₉ are as described above;

其中，V ₃、V ₄和V ₅各自独立地选自下组：O、-NR ₈-、CR ₈R ₉、-S(O) _m、

R ₈、R ₉的定义如前所述 Or, ring A is

Among them, V ₃ , V ₄ and V ₅ are each independently selected from the group consisting of: O, -NR ₈ -, CR ₈ R ₉ , -S(O) _m ,

R ₈ and R ₉ are as defined above

Alternatively, ring A is selected from the group:

选自下组： In another preferred example,

Choose from the following groups:

The definition of R ₁ is as described above.

In another preferred example, the compound is a compound represented by the general formula (III);

Among them, the definitions of rings A, M ₁ , M ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , x and y are as described above.

In another preferred example, the compound is a compound represented by the general formula (X);

Wherein, M ₆ and M ₇ are each independently selected from the group consisting of CH, CH ₂ , N, NH, O; Rings A, M ₁ , M ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , The definitions of R ₆ , x and y are as described above.

In another preferred example, the compound is a compound represented by the general formula (XII);

Wherein, M _{8 is} selected from the group consisting of: CH ₂ , NH, O; ring A, M ₁ , M ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , x and y are as defined above Said.

In another preferred example, the compound is a compound represented by the general formula (IV);

Among them, the definitions of rings A, R ₁ , R ₄ , R ₆ and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (V);

Among them, the definitions of rings A, R ₁ , R ₄ , R ₆ and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (VI);

Wherein, V ₁ and V ₂ are each independently selected from: bond, O, -NR ₈ -, CR ₈ R ₉ or -S(O) _m -; R ₁ , R ₄ , R ₈ , R ₉ , R ₆ , The definitions of m and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (VII);

Wherein, V ₁ and V ₂ are each independently selected from: bond, O, -NR ₈ -, CR ₈ R ₉ or -S(O) _m -; R ₁ , R ₄ , R ₈ , R ₉ , R ₆ , The definitions of m and x are as described above.

In another preferred example, V ₁ and V _{2 are} not both bonds.

In another preferred example, V ₁ and V ₂ are each independently selected from: O, -NH-, -S(O) _m -, CH ₂ .

In another preferred example, the compound is a compound represented by the general formula (VIII);

R ₁、R ₄、R ₈、R ₉、R ₆、m和x的定义如前所述。 Wherein, V ₃ , V ₄ and V ₅ are each independently selected from: O, -NR ₈ -, CR ₈ R ₉ , -S(O) _m ,

The definitions of R ₁ , R ₄ , R ₈ , R ₉ , R ₆ , m, and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (IX);

R ₁、R ₄、R ₈、R ₉、R ₆、m和x的定义如前所述。 Wherein, V ₃ , V ₄ and V ₅ are each independently selected from O, -NR ₈ -, CR ₈ R ₉ , -S(O) _m ,

The definitions of R ₁ , R ₄ , R ₈ , R ₉ , R ₆ , m, and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (XI);

Among them, the definitions of rings A, M ₆ , M ₇ , R ₁ , R ₄ , R ₆ and x are as described above.

In another preferred example, the compound is a compound represented by the general formula (XIII);

Among them, the definitions of rings A, M ₈ , R ₁ , R ₄ , R ₆ and x are as described above. In another preferred example, the compound is selected from the following group:

In a second aspect of the present invention, there is provided a method for preparing a compound according to the first aspect, the compound is a compound represented by the general formula (III), and the preparation method includes the following steps:

The compound of the general formula (X-A) and the compound of the general formula (X-B) are coupled to obtain the compound of the general formula (III).

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier, and (ii) the compound according to the first aspect, or a stereoisomer thereof , Tautomers, racemates, or polymorphs thereof, or pharmaceutically acceptable salts thereof, or hydrates thereof, or solvates thereof, or prodrugs.

In another preferred example, the pharmaceutical composition further includes additional therapeutic drugs; the additional therapeutic drugs are drugs for treating or preventing diseases selected from the group consisting of cardiovascular diseases, metabolic diseases, and immunity Disease, inflammation, cancer, or a combination thereof.

In another preferred example, the dosage form of the pharmaceutical composition includes, but is not limited to: injections, tablets, capsules, aerosols, suppositories, films, pills, external rubs, or controlled release or sustained release Type or nano preparations.

In another preferred example, the additional therapeutic agents include: bile acid receptor (FXR) agonist (such as Obeticholic acid, Tropifexor, GS-9674), peroxisome proliferator-activated receptor (PPAR) Agonists (such as Elafibranor, Saroglitazar, Remogliflozin and Etabonate), thyroid hormone receptor beta (THRβ) agonists (such as MGL-3196), diacylglycerol-O-acyl transferase (DGAT) inhibitors (such as Pradigastat, PF-06865571 ), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (such as Vismodegib), half Galectin inhibitors (e.g. GR-MD-02), CC chemokine receptor type 2 and type 5 (CCR2 and CCR5) dual antagonists (e.g. Cenicriviroc), hexanokinase (KHK) inhibitors (PF -06835919), glucagon-like peptide-1 (GLP-1) receptor agonist (such as liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibody (such as simtuzumab) , Cholic acid and arachidonic acid complex Aramchol, or a combination thereof.

In a fourth aspect of the present invention, there is provided a method for preparing the pharmaceutical composition according to the third aspect, comprising the step of: combining a pharmaceutically acceptable carrier with the compound according to the first aspect, or a stereogenic difference Mixtures of tautomers, tautomers, racemates, or their polymorphs, or their pharmaceutically acceptable salts, or their hydrates, or their solvates, or prodrugs, are mixed to form Pharmaceutical composition.

In a fifth aspect of the present invention, there is provided a compound according to the first aspect, or a stereoisomer, tautomer, racemate, or polymorphic form thereof, or a pharmaceutically acceptable thereof The use of a salt, or a hydrate thereof, or a solvate thereof, or a prodrug is used to prepare a pharmaceutical composition having selective inhibitory effect on ASK1.

In a sixth aspect of the present invention, there is provided a compound according to the first aspect, or the use of the pharmaceutical composition according to the third aspect,

(i) For the preparation of ASK1 inhibitor drugs;

(ii) for the preparation of a medicament for the treatment and/or prevention of ASK1-mediated diseases; and/or

(iii) For the treatment and/or prevention of ASK1-mediated diseases;

Wherein, the diseases mediated by ASK1 include inflammation, cardiovascular diseases, infections, immune diseases, metabolic diseases, or a combination thereof.

In another preferred example, the inflammatory or metabolic diseases include but are not limited to: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, gallstones, primary biliary cirrhosis, primary Sclerosing cholangitis, liver cirrhosis, diabetes, atherosclerosis, obesity, or a combination thereof.

In another preferred example, the inflammation is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or a combination thereof.

In a seventh aspect of the present invention, there is provided a method for preventing and/or treating ASK1-mediated diseases, comprising the steps of:

Administration of a compound as described in the first aspect, or a stereoisomer, tautomer, racemate, or polymorph thereof, or a pharmaceutically acceptable salt thereof, or hydration thereof to a subject in need of treatment Substances, or solvates thereof, or prodrugs; or administering the pharmaceutical composition as described in the third aspect to a subject in need of treatment.

In another preferred example, ASK1-mediated diseases include: inflammation, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.

It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other, thereby forming a new or preferred technical solution. Due to space limitations, I will not repeat them here.

detailed description

The inventor has gone through extensive and in-depth research. For the first time, an arylamide compound with a novel structure was developed. The arylamide compounds have excellent selective inhibitory activity against apoptosis signal-regulated kinase 1 (ASK1), and the present invention has been completed based on this.

the term

The term "alkyl" refers to a straight-chain or branched-chain alkane group, containing 1-18 carbon atoms, especially 1-6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentane Group, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and so on. The term "(C ₁ -C ₆ )alkyl" refers to a linear or branched alkyl group, including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, Tert-butyl, isobutyl. "Substituted alkyl" means that one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, alkyl, cycloalkyl Group, alkenyl group, cycloalkenyl group, alkynyl group, heterocyclic ring or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms, at least one carbon-carbon double bond substituent. Typical groups include vinyl or allyl. The term "(C ₂ -C ₆ )alkenyl" refers to a linear or branched group containing 2-6 carbon atoms and having at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl , (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl , 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (Z)-1-hexenyl, (E)-2 -Pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3 -Hexenyl, (E)-3-hexenyl and (E)-1,3-hexadienyl. "Substituted alkenyl" means that one or more positions in the alkenyl group are substituted, especially 1-4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms, at least one carbon-carbon triple bond substituent. Typical groups include ethynyl. The term "(C ₂ -C ₆ )alkynyl" refers to a linear or branched group containing 2-6 carbon atoms and having at least one carbon-carbon double bond, such as ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl. "Substituted alkynyl" means that one or more positions in the alkynyl group are substituted, especially 1-4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents can be optionally substituted.

The term "carbocycle" refers to a saturated or unsaturated cyclic hydrocarbon compound group, such as cycloalkyl, cycloalkenyl, etc., including 1-4 rings, each ring containing 3-8 carbon atoms. The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl" or "substituted carbocycle" means that one or more positions in the cycloalkyl are substituted, especially 1 to 4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycles (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged-ring heterocycles (excluding heteroaromatic rings), fused cycloalkyl groups, fused cycloalkenyl groups, fused ring heterocyclic groups or fused ring aromatic ring groups, the above-mentioned cycloalkyl groups, cycloalkenyl groups, heterocyclic groups and heterocyclic aromatic groups The group may be optionally substituted.

The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon compound group, including 1-4 rings, each ring containing 3-8 carbon atoms. Typical cycloalkenyl groups such as cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include spirocyclic or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), fused cycloalkyl, fused cycloalkenyl, fused ring hetero A cyclic group or a fused ring aromatic ring group, the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group and heterocyclic aryl group may be optionally substituted.

The term "heterocyclyl" or "heterocycle" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered Tricyclic system), in which at least one heteroatom exists in a ring with at least one carbon atom. Each heterocycle containing a heteroatom may carry 1, 2, 3, or 4 heteroatoms. These heteroatoms are selected from nitrogen, oxygen, or sulfur atoms. The nitrogen or sulfur atoms can be oxidized, and the nitrogen atoms can also be It is quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule. Typical monocyclic heterocycles include but are not limited to azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine , Thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl, 4-piperidone, tetrahydropyranyl, morpholino, thiomorpholino, thiomorpholine sulfoxide, thiomorpholine sulfoxide, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through the ring Any two or more atoms on the ring are further connected with other cycloalkyl, heterocyclic, aryl and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted, when substituted, The substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate groups.

The term "aryl" or "aromatic ring" refers to an aromatic cyclic hydrocarbon compound group having 1 to 5 rings, especially to monocyclic and bicyclic groups such as phenyl, biphenyl, or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or Cl ₃ -containing alkyl groups), nitrile, nitro, oxo (e.g., = O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR _a, SR _a, S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C (=O) NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , where R _{a present here} may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R _b , R _c and R _d independently represent hydrogen, deuterium, alkyl, cycloalkyl, or aromatic heterocyclic ring, or R _b and R _c with the N atom may form a heterocyclic ring; R _e independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl groups, fused ring alkenyl groups, fused ring heterocyclic groups or fused ring aromatic ring groups, the above mentioned cycloalkyl groups, cycloalkenyl groups, heterocyclic groups and heterocyclic aromatic groups The group may be optionally substituted.

The term "heteroaryl" or "heteroaryl ring" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered group, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Sulfur, oxo, carboxyl and carboxylate groups.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

Unless otherwise stated, it is assumed that any hetero atom with a dissatisfied valence state has enough hydrogen atoms to supplement its valence state.

The possible salts of the compounds of the present invention are also within the scope of the present invention. Unless otherwise stated, the compounds in the present invention are understood to include salts thereof. The term "salt" as used herein refers to an acidic or basic salt formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("internal salts") that may be formed are included in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in the separation or purification steps of the preparation process. The compounds of the present invention may form salts. For example, Compound I reacts with a certain amount, such as an equivalent amount of acid or base, to be salted out in a medium, or lyophilized in an aqueous solution.

The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can be salted include acetate (eg, with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipic acid salt, alginate, ascorbate, aspartate, benzoate , Besylate, bisulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerol phosphate, hemisulfate, enanthate, hexanoate, hydrochloride, hydrobromide, hydroiodide, isethionate (Eg, 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, tosylate such as p-toluenesulfonate, dodecanoate, etc.

Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and organic base-forming salts (such as organic amines) such as benzathine and dicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (Eg dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long-chain halides (eg decyl, dodecyl, tetradecyl and tetradecyl chloride, bromide And iodide), aralkyl halides (such as benzyl and phenyl bromide) and so on.

The prodrugs and solvates of the compounds of the present invention are also covered. The term "prodrug" here refers to a compound that produces a compound, salt, or solvate of the present invention through chemical transformations of metabolism or chemical processes when treating related diseases. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates in the present invention may exist in tautomeric forms (eg amides and imine ethers). All these tautomers are part of the present invention.

The stereoisomers of all compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric and diastereomeric forms, are within the scope of the present invention. The independent stereoisomers of the compounds in the present invention may not co-exist with other isomers (for example, as a pure or substantially pure optical isomer has a special activity), or may be a mixture, such as Racemate, or a mixture with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations of S or R, which were defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be solved by physical methods, such as fractional crystallization, or separation and crystallization by derivatization to diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with optically active acids and recrystallization.

The compound of the present invention, the compound obtained by preparation, separation and purification in sequence has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text Listed. Here, such "very pure" compounds of the invention also form part of the invention.

All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure forms. The definition of the compound of the present invention includes both cis (Z) and return (E) olefin isomers, and carbocyclic and heterocyclic cis and trans isomers.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

The definition of specific functional groups and chemical terms are detailed below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, all of which are included in the reference list.

Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, exo Spin the mixture and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and their mixtures are included in the present invention.

According to the invention, the ratio of isomer mixtures containing isomers can be varied. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios easily understood by those of ordinary skill in the art, as well as ratios of mixtures of more complex isomers, are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, one or more atoms are usually replaced by atoms with different atomic weight or mass number. Examples of compound isotopes that can be listed as the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein isotopes or other other isotope atoms containing the above compounds are within the scope of the present invention . Certain isotopically-labeled compounds in the present invention, such as ³ H and ¹⁴ C radioisotopes, are also among them, and are useful in the tissue distribution experiments of drugs and substrates. Tritium, that is, ³ H and carbon-14, that is, ¹⁴ C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, ie ² H, have advantages in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in the body, therefore, priority may be given in certain circumstances. Isotope-labeled compounds can be prepared by a general method by replacing easily-available isotope-labeled reagents with non-isotopic reagents using the schemes disclosed in the examples.

If a specific enantiomer synthesis of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with chiral adjuvants, the resulting diastereomeric mixture is separated, and the chiral adjuvant is removed The pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, which can then be separated by crystallization or chromatography. Separation by conventional means, and then the pure enantiomer is obtained.

As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their scope of inclusion. In general, whether the term "substitution" occurs before or after the term "optional", the general formula including substituents in the formulation of the present invention refers to the replacement of hydrogen radicals with a specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, each position of the substituent may be the same or different. The term "substitution" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, nitrogen such as a heteroatom may have a hydrogen substituent or any allowable organic compound described above to supplement its valence state. Furthermore, the present invention is not intended to limit the substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. The term "stable" here refers to a compound with stability, which is tested for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above purpose.

Metabolites of the compounds and pharmaceutically acceptable salts involved in this application, as well as prodrugs that can be converted into the structure of the compounds and pharmaceutically acceptable salts involved in this application, are also included in the claims of this application in.

Pharmaceutical composition and method of administration

Since the compound of the present invention has excellent selective inhibitory activity of apoptosis signal-regulated kinase 1 (ASK1), the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and The pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for the treatment, prevention and alleviation of diseases mediated by apoptotic signal-regulated kinase 1 (ASK1). According to the prior art, the compounds of the present invention can be used to treat the following diseases: inflammation, cardiovascular disease, infection, immune disease or metabolic disease.

The pharmaceutical composition of the present invention contains a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier in a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound/dose of the present invention, and more preferably, 10-500 mg of the compound/dose of the present invention. Preferably, the "one dose" is a capsule or tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween

), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When co-administered, the original drug administration mode and dosage can be kept unchanged, while the compound of formula I is taken at the same time or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time may be preferably used. Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drugs may be lower than the dose of them alone.

Drugs or active ingredients that can be used in combination with the compounds of the present invention include, but are not limited to: bile acid receptor (FXR) agonists (eg, Obeticholic acid, Tropifexor, GS-9674), peroxisome proliferator activation Receptor (PPAR) agonist (eg Elafibranor, Saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor β (THR _β ) agonist (eg MGL-3196), diacylglycerol-O-acyltransferase (DGAT) inhibitor ( Such as Pradigastat, PF-06865571), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (E.g. Vismodegib), galectin inhibitors (e.g. GR-MD-02), CC chemokine receptor type 2 and type 5 (CCR2 and CCR5) dual antagonists (e.g. Cenicriviroc), hexanokinase ( KHK) inhibitor (PF-06835919), glucagon-like peptide-1 (GLP-1) receptor agonist (eg liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) Aramchol, a complex of monoclonal antibodies (such as simtuzumab), cholic acid, and arachidonic acid.

The inflammation, cardiovascular disease, infection, immune disease, metabolic disease or cancer involved in this application include (but are not limited to): primary cholestatic cirrhosis (PBC), primary sclerosing cholecystitis ( PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), or liver fibrosis; arteriosclerosis, blood lipids Disorders, hypercholesterolemia or hypertriglyceridemia; type I diabetes, type II diabetes or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer Or colorectal cancer.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose when administered is a pharmaceutically effective dose, for a person of 60 kg body weight, daily The dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.

Arylamides

The object of the present invention is to provide a new class of compounds that have selective inhibitory effect on apoptosis signal-regulated kinase 1 (ASK1) or better pharmacodynamic properties and uses thereof.

Specifically, the compound of the present invention has a structure represented by formula (I)

Here, the definition of each group or ring is as described above.

The main advantages of the present invention include:

(a) The compound of the present invention has excellent selective inhibitory activity against apoptosis signal-regulated kinase 1 (ASK1).

(b) The compound of the present invention exhibits excellent metabolic properties.

(c) The compound of the present invention exhibits excellent activity in vivo.

(d) The compounds of the present invention have low inhibitory activity against CYP3A4 and other CYP enzymes, thereby avoiding possible drug-drug interactions and increasing drug safety.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are generally based on conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid-mass spectrometry (LC-MS).

NMR was detected using Bruker AVANCE-400 nuclear magnetic instrument, and the measurement solvent included deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol CD ₃ OD), etc., the internal standard uses tetramethylsilane (TMS), the chemical shift is measured in parts per million (ppm).

Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. HPLC was measured using an Agilent 1100 high-pressure chromatograph (Microsorb 5micron C18 100x 3.0mm chromatographic column).

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20mm, and the preparation thin layer chromatography uses 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be used or synthesized according to the literature reported in the art.

Unless otherwise specified, all reactions of the present invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is in degrees Celsius.

Example 1

7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(2-methoxyethyl)- Preparation of 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Step 1: Preparation of methyl 2,4-difluoro-5-nitrobenzoate

Thionyl chloride (18 mL, 242 mmol) was added dropwise to a solution of 2,4-difluoro-5-nitrobenzoic acid (10 g, 49 mmol) in methanol (150 mL) at room temperature. After the dropwise addition, the reaction solution was stirred at room temperature for 4 hours, and then the reaction solution was concentrated under reduced pressure below 40°C. Ethyl acetate (200mL) and water (200mL) were added to the residue to separate the layers. After the organic phase was collected, it was washed with aqueous sodium bicarbonate solution (5%wt, 2x100mL), water (100mL) and saturated brine (100mL), It is then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure below 40°C to obtain the target product (crude product 9.5 g, crude yield 92%), which was directly used in the next reaction without purification.

Step 2: Preparation of methyl 2-fluoro-4-benzyloxy-5-nitrobenzoate

Sodium hydride (-60% wt, 950 mg, 24 mmol) was added portionwise to a solution of benzyl alcohol (2.4 g, 22 mmol) in N,N-dimethylformamide (30 mL) at 0-5°C. After completion of the dropwise addition, the reaction solution was stirred at 0-5°C for 30 min, and then N,N-dimethylformamide (10 mL) of methyl 2,4-difluoro-5-nitrobenzoate (4.0 g, 18 mmol) was added dropwise. ) Solution. After the dropwise addition, the reaction solution was naturally raised to room temperature, and stirred at room temperature for 12 hours. The resulting reaction liquid was separated with ethyl acetate (150 mL) and water (150 mL). The aqueous phase was separated and extracted with ethyl acetate (2x50 mL). The organic phases were combined, washed with water (2x100 mL) and saturated brine (2x100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried at 40°C under reduced pressure to obtain the target product (crude product 4.2g), which was directly used in the next reaction without purification.

Step 3: Preparation of methyl 2-fluoro-4-hydroxy-5-aminobenzoate

Palladium carbon (10% palladium content, 50% water, 1.0g) was added to a solution of methyl 2-fluoro-4-benzyloxy-5-nitrobenzoate (4.2g) in methanol (50mL) under a nitrogen atmosphere. in. Subsequently, the reaction solution was stirred at room temperature for 12 h under a hydrogen atmosphere. The resulting reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure below 40°C to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target product (1.35 g).

LC-MS: m/z 184(MH) ^-

Step 4: Preparation of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester

N,N-Dimethyl 2-fluoro-4-hydroxy-5-aminobenzoate (1.35g, 7.3mmol), dibromoethane (1.5g, 8.1mmol), potassium carbonate (3.0g, 21.7mmol) The mixed solution of methylformamide (30 mL) was stirred at 60-65°C for 12 h. After cooling, the resulting reaction liquid was separated with ethyl acetate (100 mL) and water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with water (3x70 mL) and saturated brine (70 mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried under reduced pressure below 40°C to obtain the target product (crude product 880 mg), which was directly used in the next step without purification.

LC-MS: m/z 212(M+H) ⁺

Step 5: Preparation of 7-fluoro-4-(2-methoxyethyl) 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid

7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester (440 mg, 2.1 mmol), bromoethyl methyl ether (440 mg, 3.2 mmol) and A mixed solution of potassium carbonate (440 mg, 3.2 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80-90°C for 12 h. After cooling, the resulting reaction solution was separated with ethyl acetate (50 mL) and water (50 mL). After adjusting the pH of the aqueous phase to 3 to 4 with dilute hydrochloric acid (2N), it was extracted with ethyl acetate (50 mL). The combined organic phases were washed with water (3x50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure below 40°C. To the resulting residue, methanol (20 mL) and aqueous sodium hydroxide solution (2N, 10 mL) were added. After the reaction was stirred at room temperature for 4 h, the pH was adjusted to 3 to 4 with dilute hydrochloric acid (2N), and ethyl acetate (50 mL) and water (50 mL) were added to separate layers. After the organic phase was separated, it was washed with water (2x50 mL) and saturated brine (50 mL) in this order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried under reduced pressure below 40°C to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target product (220 mg).

LC-MS: m/z 254 (MH) ^- .

Step 6 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(2-methoxyethyl Radical)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Oxalyl chloride (200 mg, 1.6 mmol) was added dropwise to 7-fluoro-4-(2-methoxyethyl)3,4-dihydro-2H-benzo[b][1,4]oxo at room temperature Azine-6-carboxylic acid (200 mg, 0.78 mmol) in dichloromethane (5 mL). The reaction solution was reacted at room temperature for 1 hour, and then concentrated under reduced pressure at 40°C. The resulting residue was dissolved in dichloromethane (10 mL), followed by the addition of diisopropylethylamine (300 mg, 2.3 mmol) and 6-(4-isopropyl-4H-1,2,4-triazole-3 -Yl)pyridin-2-amine (160 mg, 0.79 mmol). The resulting mixture was stirred at room temperature for 3 h, and then separated with ethyl acetate (50 mL) and water (50 mL). After collecting the organic phase, it was washed with water (30 mL) and saturated brine (30 mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the target product (90 mg, yield 26%).

LC-MS: m/z 439.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (d, 1H), 8.43 (d, 2H), 8.04 (d, 1H), 7.89 (t, 1H), 7.41 (d, 1H), 6.64 (d, 1H), 5.53 (m, 1H), 4.30 (t, 2H), 3.63 (t, 2H), 3.54 (t, 2H), 3.44 (t, 2H), 3.36 (s, 3H), 1.61 (d, 6H ).

Example 2

7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(methoxymethyl)-2, Preparation of 3-dihydrobenzo[b][1,4]dioxin-6-carboxamide

Step 1: Preparation of 1-bromo-2-fluoro-4,5-dimethoxybenzene

Bromine (9.3g, 1.1eq) was added dropwise to methylene chloride (160mL) of 4-fluoro-1,2-dimethoxybenzene (7g) and iron powder (0.15g, 0.05eq) at 0°C Mixed solution. The reaction solution was reacted at 0°C overnight, then washed with water, dried and concentrated to obtain the target product (crude product 9.5 g), which was directly used in the next reaction without purification.

Step 2: Preparation of methyl 2-fluoro-4,5-dimethoxybenzoate

1-Bromo-2-fluoro-4,5-dimethoxybenzene (5g), 1,1'-bis(triphenylphosphine) ferrocene (5g) and palladium acetate (5g) in methanol (20mL) , DMF (20mL) and triethylamine (10mL) in a mixed solution under CO atmosphere (2Mpa) at 100 ℃ for 24h. The resulting mixture was concentrated under reduced pressure, and the residue was separated with water and ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel quasi-chromatography to obtain the target product (2.9 g).

LC-MS: m/z 215 (M+H) ⁺ .

Step 3: Preparation of 2-fluoro-4,5-dihydroxybenzoic acid

Boron tribromide (12.8 g) was slowly added dropwise to a solution of methyl 2-fluoro-4,5-dimethoxybenzoate (2.9 g) in DCM (15 mL) at 0°C. After the addition, the reaction solution was reacted at room temperature overnight. The resulting mixture was carefully quenched with ice water and concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic phases are combined and dried with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain the target product (crude product 2.2g), which was directly used in the next reaction without purification.

LC-MS: m/z 173 (M+H) ⁺ .

Step 4: Preparation of methyl 2-fluoro-4,5-dihydroxybenzoate

2-Fluoro-4,5-dihydroxybenzoic acid (0.56g) was reacted in a hydrogen chloride methanol solution (4N, 20mL) at 80°C under reflux overnight, cooled to room temperature and concentrated under reduced pressure to obtain the target product (crude product 0.75g) It is used directly in the next reaction without purification.

LC-MS: m/z 187 (M+H) ⁺ .

Step 5: Preparation of 7-fluoro-3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester

A mixed solution of 2-fluoro-4,5-dihydroxybenzoic acid methyl ester (2g) and potassium carbonate (1.49g) in acetone (20mL) was stirred at room temperature for 30min, followed by dropwise addition of propylene oxide bromide (1.5g). The resulting mixture was reacted at 80°C overnight, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target product (0.94 g).

LC-MS: m/z 243 (M+H) ⁺ .

Step 6: Preparation of 7-fluoro-3-(methylsulfonyloxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester

Methanesulfonyl chloride (445mg, 3.87mmol) was added dropwise to 7-fluoro-3-(hydroxymethyl)-2-3-dihydrobenzo[b][1,4]dioxin-6- at room temperature Methyl carboxylate (780 mg, 3.2 mmol) and diisopropylethylamine (623 mg, 4.8 mmol) in THF (5 mL). The resulting mixed solution was stirred at room temperature for 2 to 3 hours, and then dichloromethane (50 mL) and water (50 mL) were added for liquid separation. After collecting the organic phase, it was washed with water (50 mL) and saturated brine (50 mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure below 40°C to obtain the target product (crude product 920 mg), which was directly used in the next reaction without purification.

Step 7: Preparation of 7-fluoro-3-(methoxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid

Add sodium methoxide (465mg, 8.61mmol) to 7-fluoro-3-(methylsulfonylhydroxymethyl)-2-3-dihydrobenzo[b][1,4]dioxin-6 at room temperature -Methyl carboxylate (920 mg, 2.87 mmol) in methanol (10 mL). The reaction solution was stirred and refluxed for 2 h, and then cooled to room temperature, and then water (10 mL) and NaOH (20% wt, 10 mL) were added. The resulting mixed liquid was cooled to room temperature after reacting at 50°C for 1 hour, adjusted to pH 6-7 with dilute hydrochloric acid (1N), and then concentrated under reduced pressure. The residue was separated with an acidic aqueous solution (pH=2-3, 50 mL) and dichloromethane (50 mL). The aqueous phase was separated and extracted with dichloromethane (2x50 mL). The organic phases were combined and washed with saturated brine (2x50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain the target product (400 mg).

LC-MS: m/z 241 (MH) ^- .

Step 8: 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(methoxymethyl ) Preparation of 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamide

Add (chloromethylene) dimethyl ammonium chloride (400 mg, 4.34 mmol) to 7-fluoro-3-(methoxymethyl)-2-3-dihydrobenzo under a nitrogen atmosphere at room temperature [b] [1,4] Dioxin-6-carboxylic acid (400 mg, 1.58 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 h, then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (400 mg, 1.97 mmol) and diethylisopropyl were added Amine (600 mg, 5.21 mmol). The resulting mixture was stirred at room temperature for 3 h, and then separated with ethyl acetate (50 mL) and water (50 mL). After the organic phase was collected, it was washed with water (2x50 mL) and saturated brine (50 mL) in this order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated at 40°C under reduced pressure to obtain a crude product, which was then purified by preparative chromatography to obtain the target product (180 mg, yield 26%).

LC-MS: m/z 426.31 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (d, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.05 (d, 1H), 7.90 (t, 1H), 7.76 (d, 1H), 6.77 (d, 1H), 5.54 (m, 1H), 4.43 (dd, 1H), 4.34 (m, 1H), 4.18 (dd, 1H), 3.66 (m, 2H), 3.46 (s, 3H ), 1.61 (d, 6H).

Example 2A

(S)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(methoxymethyl ) Preparation of 2,3-dihydrobenzo[b][1,4]diox-6-carboxamide

Step 1: Preparation of 7-fluoro-3(S)-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid methyl ester

Dissolve methyl 2-fluoro-4,5-dihydroxybenzoate (8.0 g, 43 mmol) in N,N-dimethylformamide (150 mL), then add R-anhydroglycerol p-valent benzenesulfonate (9.8 g , 43mmol) and potassium carbonate (7.2g, 52mmol). The mixture was heated to 70-75°C for 8 h, and then ethyl acetate (400 mL) and water (400 mL) were added to separate layers. After collecting the organic layer, it was washed with water (2x300 mL) and saturated sodium chloride (2x200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain the target product (6.1 g, yield 58%).

LC-MS: m/z 241.49 (MH) ^- .

Step 2: Preparation of 7-fluoro-3(S)-methylsulfonylhydroxymethyl-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid methyl ester

At room temperature, 7-fluoro-3(S)-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid methyl ester (2.0g, 8.26mmol) And diisopropylethylamine (1.6 g, 12.3 mmol) were dissolved in dichloromethane (20 mL), and then methanesulfonyl chloride (1.14 g, 9.91 mmol) was added dropwise. The resulting reaction solution was stirred at room temperature for 2 to 3 hours, and then dichloromethane (20 mL) and water (50 mL) were added to separate layers. The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), then dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (2.4 g, crude yield 90%), which was directly used in the next reaction without purification.

Step 3: Preparation of 7-fluoro-3(S)-methoxymethyl-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxylic acid

Dissolve 7-fluoro-3(S)-methylsulfonylhydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxylate methyl ester (900 mg, 2.8 mmol) Methanol (10 mL) followed by sodium methoxide (400 mg, 7.4 mmol). The reaction solution was reacted at reflux for 2h, and then the reaction solution was cooled to room temperature, and then water (10 mL) and aqueous NaOH solution (20%, 10 mL) were added. The resulting mixed solution was heated to 50°C for 1 hour, then cooled to room temperature, and then the pH of the reaction system was adjusted to 5 to 6 with dilute hydrochloric acid (1N). The resulting mixture was concentrated under reduced pressure, followed by addition of dilute hydrochloric acid (50 mL, pH=2-3) and dichloromethane (50 mL) for separation. The aqueous phase was separated and extracted with dichloromethane (2x50 mL). All organic phases were combined and washed with saturated brine (2x50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain the target product (450 mg, yield 66%).

LC-MS: m/z 241.41 (MH) ^- .

Fourth step: 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3(S)-methoxy Preparation of methyl-2,3-dihydrobenzo[B][1,4]diox-6-carboxamide

Dissolve 7-fluoro-3(S)-methoxymethyl-2,3-dibenzo[b][1,4]dioxo-6-carboxylic acid (400 mg, 1.58 mmol) in a nitrogen atmosphere Dichloromethane (10 mL), followed by (chloromethylene) dimethyl ammonium chloride (400 mg, 4.34 mmol). The reaction solution was stirred at room temperature for 1 h, and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (400 mg, 1.97 mmol) and diethylisopropyl were added Amine (600 mg, 5.21 mmol). The resulting mixture was stirred at room temperature for 3 h, then ethyl acetate (50 mL) and water (50 mL) were added to separate layers. The organic phase was washed with water (2x50mL) and saturated brine (50mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was depressurized, and the resulting crude product was purified by preparative chromatography to obtain the target product (220 mg, yield 31%).

LC-MS: m/z 426.21 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, 1H), 8.90 (s, 1H), 8.47 (d, 1H), 8.07 (d, 1H), 7.93 (t, 1H), 7.76 (d, 1H), 6.75 (d, 1H), 5.58 (m, 1H), 4.41 (dd, 1H), 4.33 (m, 1H), 4.18 (m, 1H), 3.66 (m, 2H), 3.45 (s, 3H ), 1.65 (d, 6H).

According to the method of the above example, the following compounds are synthesized with different starting materials:

Example 2B

(R)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(methoxymethyl )-2,3-dihydrobenzo[b][1,4]diox-6-carboxamide

LC-MS: m/z 426.21 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, 1H), 8.90 (s, 1H), 8.47 (d, 1H), 8.07 (d, 1H), 7.93 (t, 1H), 7.76 (d, 1H), 6.75 (d, 1H), 5.58 (m, 1H), 4.41 (dd, 1H), 4.33 (m, 1H), 4.18 (m, 1H), 3.66 (m, 2H), 3.45 (s, 3H ), 1.65 (d, 6H).

Example 3A

(S)-3-((benzyloxy)methyl)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Group)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxamide

LC-MS: m/z 504 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (d, J=17.1 Hz, 1H), 8.67 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.03 (d, J=7.6 Hz , 1H), 7.90 (dd, J = 13.6, 5.6 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.42-7.30 (m, 5H), 6.72 (dd, J = 14.4, 4.9 Hz, 1H), 5.63–5.46 (m, 1H), 4.61 (s, 2H), 4.47–4.27 (m, 2H), 4.18 (m, 1H), 3.88–3.62 (m, 2H), 1.63 (t, J= 7.2Hz, 6H.

Example 3B

(R)-3-((benzyloxy)methyl)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine-2- Group)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxamide

LC-MS: m/z 504 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (d, J=17.3 Hz, 1H), 8.77 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.05 (d, J=7.6 Hz , 1H), 7.92 (t, J = 8.0Hz, 1H), 7.74 (d, J = 7.7Hz, 1H), 7.42-7.29 (m, 5H), 6.73 (d, J = 12.8Hz, 1H), 5.68 –5.50(m,1H), 4.60(s,2H), 4.47–4.27(m,2H), 4.18(m,1H), 3.86–3.62(m,2H),1.64(t,J=7.2Hz,6H ).

Example 4A

(R)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(morpholinomethyl) -2,3-dihydrobenzo[b][1,4]diox-6-carboxamide

Step 1: Preparation of 7-fluoro-3(R)-(N-morphinylmethyl)-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid

Dissolve 7-fluoro-3(R)-methanesulfonylhydroxymethyl-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxylic acid methyl ester (500 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL), followed by the addition of morpholine (180 mg, 2.1 mmol) and diisopropylethylamine (250 mg, 1.9 mmol). The reaction solution was stirred at 75-80°C for 8h and then cooled to room temperature, and then methanol (10 mL) and aqueous NaOH solution (20%, 10 mL) were added. The mixed solution was heated to 40-50°C for 1 hour, then cooled to room temperature, and then the pH of the reaction system was adjusted to 5 to 6 with dilute hydrochloric acid (1N). The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target product (350 mg, yield 75%)

LC-MS: m/z 296.41 (MH) ^- .

Step 2: (R)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(morphine Of morpholino)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxamide

Under a nitrogen atmosphere, 7-fluoro-3(R)-(N-morpholinylmethyl)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxylic acid (350 mg, 1.18 mmol) was dissolved in dichloromethane (10 mL), followed by (chloromethylene) dimethyl ammonium chloride (300 mg, 3.25 mmol). The reaction solution was stirred at room temperature for 1 h, and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (300 mg, 1.47 mmol) and diisopropyl ethyl were added Amine (400 mg, 3.47 mmol). After the resulting mixture was stirred at room temperature for 3 h, ethyl acetate (50 mL) and water (50 mL) were added and the layers were separated. After the organic phase was collected, it was washed with water (2x50 mL) and saturated brine (50 mL) in this order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative chromatography to obtain the target product (180 mg, yield 32%).

LC-MS: m/z 481.21 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.08 (d, 1H), 8.39 (m, 2H), 8.04 (d, 1H), 7.91 (t, 1H), 7.72 (d, 1H), 6.77 (d, 1H), 5.50 (m, 1H), 4.45 (d, 1H), 4.13 (m, 1H), 3.92 (m, 5H), 2.89 (m, 6H), 1.60 (m, 6H).

According to the method of the above example, the following compounds are synthesized with different starting materials:

Example 4B

(S)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(morpholinomethyl) -2,3-dihydrobenzo[b][1,4]diox-6-carboxamide

LC-MS: m/z 481.21 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, 1H), 8.40 (m, 2H), 8.03 (d, 1H), 7.91 (t, 1H), 7.74 (d, 1H), 6.76 (d, 1H), 5.50 (m, 1H), 4.44 (d, 1H), 4.11 (m, 1H), 3.84 (m, 5H), 2.83 (m, 6H), 1.60 (m, 6H).

Example 5A

(R)-3-((dimethylamino)methyl)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- 2-yl)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxamide

LCMS m/z 439.45 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (d, 1H), 8.42 (d, 1H), 8.37 (s, 1H), 8.03 (d, 1H), 7.90 (t, 1H), 7.76 (d, 1H), 6.75 (d, 1H), 5.51 (m, 1H), 4.41 (dd, 1H,), 4.33 (m, 1H), 4.08 (m, 1H), 2.65 (m, 2H), 2.38 (s, 6H), 1.60 (d, 6H).

Example 5B

(S)-3-((dimethylamino)methyl)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- 2-yl)-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxamide

LCMS m/z 439.45 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (d, 1H), 8.42 (d, 1H), 8.37 (s, 1H), 8.05 (d, 1H), 7.90 (t, 1H), 7.76 (d, 1H), 6.75 (d, 1H), 5.51 (m, 1H), 4.41 (dd, 1H), 4.32 (m, 1H), 4.08 (m, 1H), 2.65 (m, 2H), 2.38 (s, 6H ), 1.60 (d, 6H).

Example 6

13-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3,5,6,8,9- Hexahydrobenzo[b][1,4,7,10]tetraoxycyclododecane-12-carboxamide

Step 1: Preparation of 13-fluoro-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxycyclododecane-12-carboxylic acid

Triethylene glycol bis(p-toluenesulfonate) (2.5 g, 5.5 mmol) and potassium carbonate (1.5 g, 11 mmol) were added to methyl 2-fluoro-4,5-dihydroxybenzoate (1.0 g, 5.4 mmol) in N,N-dimethylformamide (50 mL) solution. The mixture was heated at 70-75°C and stirred for 8 h, then cooled to room temperature, and then ethyl acetate (200 mL) and water (200 mL) were added to separate layers. After the organic layer was collected, it was washed with water (2x200mL) and saturated sodium chloride (2x100mL) in sequence, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (10 mL) and aqueous NaOH (4N, 10 mL). The mixture was stirred at room temperature for 2-3h, adjusted to pH 4-5 with dilute hydrochloric acid (2N), and concentrated under reduced pressure. The resulting residue was separated with ethyl acetate (20 mL) and water (20 mL). The organic phase was collected and washed with saturated sodium chloride (2x20 mL), then concentrated under reduced pressure. The captured residue was purified by silica gel column chromatography to obtain the target product (800 mg, yield 52%).

LC-MS: m/z 285.31 (MH) ^- .

The second step: 13-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3,5,6, Preparation of 8,9-hexahydrobenzo[b][1,4,7,10]tetraoxycyclododecane-12-carboxamide

Under a nitrogen atmosphere, (chloromethylene) dimethyl ammonium chloride (400 mg, 4.34 mmol) was added to 13-fluoro-2,3,5,6,8,9-hexahydrobenzo[b][ 1,4,7,10] tetraoxododecane-12-carboxylic acid (600 mg, 2.1 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 1 h, then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (400 mg, 1.97 mmol) and diethylisopropyl were added Amine (800 mg, 6.2 mmol). The resulting mixture was continued to be stirred at room temperature for 3 h, and ethyl acetate (50 mL) and water (50 mL) were added to separate layers. After the organic phase was collected, it was washed with water (2x50 mL) and saturated brine (50 mL) in this order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain the target product (210 mg, yield 21%).

LC-MS: m/z 470.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (d, 1H, J=16 Hz), 8.60 (s, 1H), 8.44 (d, J=8 Hz, 1H), 8.06 (d, J=8 Hz, 1H) , 7.90 (m, 1H), 7.84 (d, J = 8Hz, 1H), 6.77 (d, J = 12Hz, 1H), 5.53 (m, 1H), 4.25 (m, 4H), 3.94 (m, 2H) , 3.78 (m, 6H), 1.63 (d, 6H).

Example 7

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxyethyl) -3a,7a-dihydro-1H-indole-6-amide preparation

The first step: 6-bromo-5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole

Chloroethyl methyl ether (1.06g, 0.01mol) and cesium carbonate (6g) were added to N,N-dimethylformamide of 5-fluoro-6-bromoindole (2.0g, 0.009mol) at room temperature (16mL) in solution. The reaction mixture was reacted at 80°C for 24h, then cooled to room temperature, diluted with water (10mL) and extracted with ethyl acetate (2x20mL). The combined organic phase was washed sequentially with water (10 mL) and saturated brine (10 mL), then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 2.4g), which was directly used in the next reaction without purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.89 (d, 1H), 7.48 (d, 1H), 7.45 (d, 1H), 6.45 (s, 1H), 4.34 (m, 2H), 3.62 ( m, 2H), 3.20 (s, 3H).

Step 2: Preparation of methyl 5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole-6-carboxylic acid

At room temperature, combine 6-bromo-5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole (1.4g, 0.005mol), N,N-dimethyl Carboxamide (10 mL), methanol (10 mL), triethylamine (10 mL) and PdCl ₂ (dppf) (1 g) were sequentially added to the autoclave. The reaction solution was reacted at 100° C. overnight under a CO atmosphere (2.5 MPa), and the resulting mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target compound (1.1 g).

¹ HNMR (400MHz, DMSO-d ₆ ) δ: 7.98 (d, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 6.45 (s, 1H), 4.31 (s, 2H), 3.95 (s , 3H), 3.69 (m, 2H), 3.30 (s, 3H).

Step 3: Preparation of 5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole-6-carboxylic acid

5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole-6-carboxylic acid methyl ester (1.0g, 0.004mol) and sodium hydroxide (0.5g, 0.012mol ) A mixed solution of methanol (15 mL) and water (6 mL) was reacted at room temperature overnight. The resulting mixture was concentrated and adjusted to pH 2 with dilute HCl (1N, 10 mL), and then extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 0.75g), which was directly used in the next reaction without purification.

LC-MS: m/z 238 (M+H) ⁺ .

Fourth step: 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxy Of ethyl)-3a,7a-dihydro-1H-indole-6-amide

Thionyl chloride (0.1g, 0.0014mol) was added dropwise to 5-fluoro-1-(2-methoxyethyl)-3a,7a-dihydro-1H-indole-6-carboxylic acid ( 0.1g, 0.0004mol) in dichloromethane (1mL) solution. The reaction solution was reacted at room temperature for 1h, and then 6-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (0.08g, 0.00045mol) and triethylamine ( 0.2g, 0.225mol) in dichloromethane (1mL). The resulting mixture was reacted at room temperature overnight and then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain the target compound (0.023 g).

LC-MS: m/z 423 (M+H) ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ: 9.38 (d, 1H), 8.48 (d, 1H), 8.40 (s, 1H), 8.28 (d, 1H), 8.06 (d, 1H), 7.95 (d, 1H ), 7.41 (s, 1H), 7.40 (s, 1H), 5.55 (m, 1H), 4.39 (m, 2H), 3.76 (m, 2H), 3.32 (s, 3H), 1.64 (d, 6H) .

The following compounds were synthesized according to the method of Example 7 with different starting materials:

Example 8

1-benzyl-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-6- Formamide

LC-MS: m/z 455 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.62 (d, J=3.2 Hz, 1H), 8.87 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.89 (dd, J = 9.1, 6.8 Hz, 2H), 7.79 (d, J = 3.1 Hz, 1H), 7.51 (d, J = 11.6 Hz, 1H), 7.44-7.13 (m, 5H), 6.59 (d, J = 3.0 Hz, 1H), 5.65 (m, 1H), 5.53 (s, 2H), 1.42 (d, J = 6.7 Hz, 6H).

Example 9

1-(2-(benzyloxy)ethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -1H-indole-6-formamide

LC-MS: m/z 499(M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.87 (s, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.14–7.99 (m, 2H), 7.88 (d, J = 7.6Hz, 1H), 7.64 (d, J = 3.1Hz, 1H), 7.49 (d, J = 11.7Hz, 1H), 7.23 (dt, J = 12.5, 7.5Hz, 5H), 6.54 (t, J = 7.4 Hz, 1H), 5.73–5.59 (m, 1H), 4.65–4.35 (m, 4H), 3.78 (t, J=5.0 Hz, 2H), 1.43 (d, J=6.7 Hz, 6H).

Example 10

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-1H-indole-6- Formamide

LC-MS: m/z 379 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.03 (dd, J = 10.1, 6.5 Hz, 2H), 7.87 (d, J = 7.6 Hz, 1H), 7.42 (m, 2H), 6.51 (d, J=3.0 Hz, 1H), 5.73–5.59 (m, 1H), 3.89 (s, 3H), 1.57 (d, J=6.7 Hz ,6H).

Example 11

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-ethyl-1H-indole-6- Formamide

LC-MS: m/z 393 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.03 (t, J=7.1 Hz, 2H), 7.87 (d, J=7.6 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.40 (d, J = 12.9 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 5.79–5.55 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.57 (d, J = 6.7 Hz, 6H), 1.46 (t, J = 7.5 Hz, 3H).

Example 12

5-fluoro-1-isopropyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-6 -Formamide

LC-MS: m/z 407 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.11–7.95 (m, 2H), 7.85 (d, J=7.6 Hz, 1H ), 7.61 (d, J = 3.1 Hz, 1H), 7.36 (d, J = 12.9 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 5.74–5.49 (m, 1H), 4.89–4.70 (m, 1H), 1.55 (dd, J=10.5, 6.7Hz, 12H).

Example 13

1-cyclopropylmethyl-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole- 6-formamide

LC-MS: m/z 419 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.18–7.97 (m, 2H), 7.87 (d, J=7.6 Hz, 1H ), 7.58 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 12.9 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 5.75–5.55 (m, 1H), 4.12 (d , J = 6.9Hz, 2H), 1.57 (d, J = 6.7Hz, 6H), 1.32 (m, 1H), 0.62 (m, 2H), 0.44 (m, 2H).

Example 14

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyridin-2-ylmethyl)- 1H-indole-6-formamide

LC-MS: m/z 456 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) delta 9.35 (d, J=19.2 Hz, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.50 (s, 1H), 8.46 (d, J=8.4 Hz , 1H), 8.24 (d, J = 6.0Hz, 1H), 8.06 (d, J = 7.6Hz, 1H), 7.92 (t, J = 8.0Hz, 1H), 7.70 (t, J = 7.6Hz, 1H) ), 7.51 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 13.6 Hz, 1H), 7.31 (t, J = 5.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 5.64 (s, 2H), 5.57 (m, 1H), 1.63 (d, J = 6.4 Hz, 6H).

Example 15

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-indole-6-formamide

LC-MS: m/z 456 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.65 (d, J=2.4 Hz, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 8.47 (d, J=4.8 Hz, 1H) , 8.25 (d, J = 8.4 Hz, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.98 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 11.6 Hz, 1H), 7.34 (dd, J = 4.8 Hz, J = 8.0 Hz, 1H) ), 6.60 (d, J = 3.2 Hz, 1H), 5.62-5.69 (m, 1H), 5.59 (s, 2H), 1.42 (d, J = 6.8 Hz, 6H).

Example 16

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(pyridin-4-ylmethyl)- 1H-indole-6-formamide

LC-MS: m/z 456 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.62 (d, J=2.8 Hz, 1H), 8.86 (s, 1H), 8.49 (d, J=6.0 Hz, 2H), 8.23 (d, J= 8.4Hz, 1H), 8.01(t, J=8.0Hz, 1H), 7.86-7.88(m, 2H), 7.80(d, J=3.2Hz, 1H), 7.54(d, J=11.6Hz, 1H) , 7.08 (d, J = 5.6 Hz, 2H), 6.64 (d, J = 3.2 Hz, 1H), 5.62-5.67 (m, 3H), 1.42 (d, J = 6.8 Hz, 6H).

Example 17

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-phenethyl-1H-indole-6 -Formamide

LC-MS: m/z 469 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 9.45 (d, J=20 Hz, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.26 (d, J=4.0 Hz, 1H), 8.18 (d, J = 7.6Hz, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.39 (d, J = 14.4Hz, 1H), 7.23-7.29 (m, 2H), 7.09 ( d, J = 2.8Hz, 1H), 7.04 (d, J = 7.2Hz, 2H), 6.45 (d, J = 2.8Hz, 1H), 5.81 (m, 1H), 4.46 (t, J = 7.2Hz, 2H), 3.15 (t, J = 7.2 Hz, 2H), 1.81 (d, J = 6.8 Hz, 6H).

Example 18

N-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxyethyl)-3a,7a-di Preparation of Hydrogen-1H-pyrrole[3,4-c]pyridine-6-amide

Step 1: Preparation of 1-(2-methoxyethyl)-1H-pyrrole[3,2-c]pyridine-6-carboxylic acid-(2-methoxyethyl) ester

N,N- of 1H-pyrrole[3,2-c]pyridine-6-carboxylic acid (0.25g, 0.0015mol), cesium carbonate (1.0g, 0.0030mol) and chloroethyl methyl ether (0.5g, 0.0045mol) A solution of dimethylformamide (3 mL) was reacted at 85°C overnight. The resulting reaction liquid was cooled to room temperature and quenched with water (10 mL), and then extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 0.4g), which was directly used in the next reaction without purification.

LC-MS: m/z 279 (M+H) ⁺ .

Step 2: Preparation of 1-(2-methoxyethyl)-3a,7a-dihydro-1H-pyrrole[3,2-c]pyridine-6-carboxylic acid

1-(2-methoxyethyl)-1H-pyrrole[3,2-c]pyridine-6-carboxylic acid-(2-methoxyethyl) ester (0.4g, 0.0014mol) and sodium hydroxide ( A mixed solution of 0.17 g, 0.0042 mol) of methanol (6 mL) and water (2 mL) was reacted at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was adjusted to pH 2 with dilute HCl (1N, 10 mL), and then extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 0.3g), which was directly used in the next reaction without purification.

LC-MS: m/z 221 (M+H) ⁺ .

Step 3: N-6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1–(2-methoxyethyl)-3a ,7a-dihydro-1H-pyrrole[3,4-c]pyridine-6-amide preparation

Thionyl chloride (0.1g, 0.0014mol) was added dropwise to 1-(2-methoxyethyl)-3a,7a-dihydro-1H-pyrrole[3,2-c]pyridine-6 at room temperature -A solution of methyl carboxylate (0.1 g, 0.00045 mol) in dichloromethane (1 mL). The reaction solution was reacted at room temperature for 1h, and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (0.05g, 0.00045mol) and triethylamine were added dropwise (0.2g, 0.225mol) in dichloromethane (1mL). The resulting mixture was reacted at room temperature overnight, then concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound (0.005 g).

LC-MS: m/z 406 (M+H) ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ: 12.31 (brs, 1H), 8.96 (s, 1H), 8.52 (m, 3H), 8.11 (m, 1H), 7.95 (m, 1H), 7.52 (s , 1H), 6.8 (s, 1H), 5.36 (m, 1H), 4.42 (s, 2H), 3.76 (m, 2H), 3.37 (s, 3H), 1.25 (d, 6H).

Example 19

1-(2-(benzyloxy)ethyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole [3,2-c]pyridine-6-formamide

LC-MS: m/z 482 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 9.00 (s, 1H), 8.94 (s, 1H), 8.54 (s, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.78 (d, J = 2.4Hz, 1H), 7.18-7.26 (m, 3H), 7.14 ( d, J = 8.0 Hz, 2H), 6.83 (d, J = 2.0 Hz, 1H), 5.48 (m, 2H), 4.62 (t, J = 4.8 Hz, 2H), 4.46 (s, 2H), 3.81 ( t, J=5.2 Hz, 1H), 1.53 (d, J=6.4 Hz, 6H).

Example 20

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxyethyl)1H -Indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-( 2-methoxyethyl) 1H-indazole-6-formamide

Step 1: Preparation of methyl 5-fluoro-1H-indazole-6-carboxylate

N,N-dimethylmethyl 5-fluoro-6-bromo-1H-indazole (750 mg, 3.5 mmol), Pd(dppf)Cl ₂ (150 mg, 0.02 mmol) and potassium carbonate (1.0 g, 7.2 mmol) A mixed solution of amide (15 mL) and methanol (30 mL) was reacted at 90-100° C. for 8-12 h under a carbon monoxide atmosphere (2 MPa). The resulting mixture was cooled to room temperature and then concentrated under reduced pressure below 40°C. The residue was separated with ethyl acetate (100 mL) and water (100 mL). The organic phase was collected, washed sequentially with water (3x50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure below 40°C to obtain a crude product (700 mg), which was directly used in the next reaction without purification.

LC-MS: m/z 193 (MH) ^- .

Step 2: Preparation of 5-fluoro-1-(methoxyethyl)-indazole-6-carboxylic acid and 5-fluoro-2-(methoxyethyl)-indazole-6-carboxylic acid

Sodium hydride (420 mg, 7.0 mmol) was added to a solution of methyl 5-fluoro-1H-indazole-6-carboxylate (700 mg, about 3.5 mmol) in N,N-dimethylformamide (10 mL) at room temperature. in. After the reaction mixture was stirred at room temperature for 30 min, bromoethyl methyl ether (650 mg, 4.7 mmol) was added, and then stirred at 50° C. for 8 to 10 h. After the resulting mixture was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added and the layers were separated. The organic phase was collected and washed with water (2x50 mL), then concentrated under reduced pressure. Methanol (20 mL) and aqueous NaOH solution (10% wt, 20 mL) were added to the resulting residue, and then stirred at room temperature for 2 h. The resulting mixture was adjusted to pH 2 to 3 with dilute hydrochloric acid (1N), and ethyl acetate (100 mL) and water (100 mL) were added to separate layers. The aqueous layer was separated and extracted with ethyl acetate (2x30 mL). After the organic phases were combined, they were washed sequentially with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5-fluoro-1-(methoxyethyl)-indazole-6-carboxylic acid and 5-fluoro-2-(methoxyethyl)-ind A mixture of oxazole-6-carboxylic acid (350 mg).

LC-MS: m/z 237.25(MH) ^-

The third step: 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxy (Ethyl) 1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) Preparation of -2-(2-methoxyethyl) 1H-indazole-6-carboxamide

Under a nitrogen atmosphere, (chloromethylene) dimethyl ammonium chloride (270 mg, 2.92 mmol) was added to the 5-fluoro-1-(methoxyethyl)-indazole-6-carboxylic acid obtained in the previous step and A mixture of 5-fluoro-2-(methoxyethyl)-indazole-6-carboxylic acid (350 mg, 1.46 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 1 h, and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (350 mg, 1.52 mmol) and diethylisopropyl were added Amine (335 mg, 2.92 mmol). The resulting mixture was stirred at room temperature for 3 h, and then separated with ethyl acetate (50 mL) and water (50 mL). After the organic phase was collected, it was washed with water (2x50 mL) and saturated brine (50 mL) in this order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 40°C, and the residue was purified by preparative chromatography to obtain two isomers 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3 -Yl)pyridin-2-yl)-1-(2-methoxyethyl) 1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1 , 2,4-triazol-3-yl)pyridin-2-yl)-2-(2-methoxyethyl) 1H-indazole-6-carboxamide.

Isomer 20A (110 mg, yield 18%). LC-MS: m/z 422.37 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, 1H), 8.49 (t, 2H), 8.43 (d, 1H), 8.07 (m, 2H), 7.94 (t, 1H), 7.50 (d, 1H), 5.54 (m, 1H), 4.65 (t, 2H), 3.88 (t, 2H), 3.31 (s, 3H), 1.63 (d, 6H).

Isomer 20B (100 mg, 16% yield). LC-MS: m/z 422.39 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, 1H), 8.67 (d, 1H), 8.50 (d, 1H), 8.40 (s, 1H), 8.05 (t, 2H), 7.93 (t, 1H), 7.41 (d, 1H), 5.54 (m, 1H), 4.64 (t, 2H), 3.90 (t, 2H), 3.36 (s, 3H), 1.60 (d, 6H).

Using Example 5 as a general method, the following compounds were synthesized using different starting materials.

Example 21

1-(2-isopropoxyethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -1H-indazole-6-carboxamide and 2-(2-isopropoxyethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridin-2-yl)-2H-indazole-6-carboxamide

Isomer 21A

LCMS m/z 448.48 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J=16 Hz, 1H), 8.49 (d, J=8 Hz, 1H), 8.43-8.41 (m, 2H), 8.07 (t, J=8 Hz, 1H), 8.05 (s, 1H), 7.95 (t, J = 8Hz, 1H), 7.52 (d, J = 12Hz, 1H), 5.54 (m, 1H), 4.62 (t, J = 4Hz, 2H), 3.99 (t, J = 4 Hz, 2H), 3.25 (m, 1H), 1.61 (d, J = 4 Hz, 6H), 0.40 (m, 4H).

Isomer 21B

LCMS m/z 448.47 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=16 Hz, 1H), 8.50 (d, J=8 Hz, 1H), 8.42 (d, J=8 Hz, 1H), 8.06 (m, 2H) , 7.95 (m, 1H), 7.52 (d, J = 8Hz, 1H), 7.44 (d, J = 8Hz, 1H), 5.57 (m, 1H), 4.62 (t, J = 4Hz, 2H), 3.99 ( t, J = 4 Hz, 2H), 3.25 (m, 1H), 1.61 (d, J = 8 Hz, 6H), 0.40 (m, 4H).

Example 22

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(3-methoxypropyl)- 1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2- (3-methoxypropyl)-2H-indazole-6-formamide

Isomer 22A

LCMS m/z 436.50 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J=16 Hz, 1H), 8.49 (d, J=8 Hz, 1H), 8.41 (s, 1H), 8.40 (d, J=8 Hz, 1H) , 8.08-8.06 (m, 2H), 7.94 (t, J = 8Hz, 1H), 7.53 (d, J = 12Hz, 1H), 5.56 (m, 1H), 4.58 (t, J = 4Hz, 2H), 3.33 (m, 5H), 2.28 (m, 2H), 1.61 (d, J = 4 Hz, 6H).

Isomer 22B

LCMS m/z 436.49 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=16 Hz, 1H), 8.63 (d, J=8 Hz, 1H), 8.47 (d, J=8 Hz, 1H), 8.38 (s, 1H) , 8.02 (m, 2H), 7.91 (t, J = 8Hz, 1H), 7.42 (d, J = 12Hz, 1H), 5.57 (m, 1H), 4.58 (t, J = 4Hz, 2H), 3.33 ( s, 3H), 3.30 (t, J = 4 Hz, 2H), 2.22 (m, 2H), 1.59 (d, J = 8 Hz, 6H).

Example 23

1-(cyclopropylmethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H- Indazole-6-carboxamide and 2-(cyclopropylmethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine -2-yl)-2H-indazole-6-carboxamide

Isomer 23A

LCMS m/z 418.48 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (d, J=16 Hz, 1H), 8.49 (d, J=8 Hz, 1H), 8.40-8.39 (m, 2H), 8.10 (d, J=8 Hz, 1H), 8.03 (s, 1H), 7.95 (t, J = 8Hz, 1H), 7.55 (d, J = 12Hz, 1H), 5.54 (m, 1H), 4.37 (d, J = 8Hz, 2H), 1.61 (d, J = 8 Hz, 6H), 1.39 (m, 1H), 0.62 (m, 2H), 0.45 (m, 2H).

Isomer 23B

LCMS m/z 418.48 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=16 Hz, 1H), 8.68 (d, J=8 Hz, 1H), 8.53-8.49 (m, 2H), 8.11 (s, 1H), 8.08 (t, J = 8 Hz, 1H), 7.93 (t, J = 8 Hz, 1H), 7.45 (d, J = 16 Hz, 1H), 5.58 (m, 1H), 4.35 (d, J = 8 Hz, 2H), 1.61 (d, J = 8 Hz, 6H), 1.45 (m, 1H), 0.77 (d, J = 8 Hz, 2H), 0.51 (m, J = 8 Hz, 2H).

Example 24

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-1H-indazole-6- Formamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-methyl-2H-indazole -6-Formamide

Isomer 24A

LCMS m/z 378.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J=20 Hz, 1H), 8.51-8.36 (m, 3H), 8.04 (s, 1H), 7.95 (t, J=8 Hz, 1H), 7.61 -7.40 (m, 2H), 5.56 (m, 1H), 4.19 (s, 3H), 1.62 (d, J = 8 Hz, 6H).

Isomer 24B

LCMS m/z 378.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=20 Hz, 1H), 8.67 (d, J=8 Hz, 1H), 8.50 (d, J=8 Hz, 1H), 8.38 (s, 1H) , 8.05 (s, 1H), 7.93 (s, 1H), 7.56-7.40 (m, 2H), 5.54 (m, 1H), 4.29 (s, 3H), 1.61 (d, J = 8 Hz, 6H).

Example 25

1-(2-(benzyloxy)ethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -1H-indazole-6-carboxamide and 2-(2-(benzyloxy)ethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole -3-yl)pyridin-2-yl)-2H-indazole-6-carboxamide mixture (1:1)

LC-MS: m/z 500.8 (M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ 9.30-9.17 (m, 1H), 8.67-8.46 (m, 2H), 8.39 (s, 1H), 8.10-8.04 (m, 2H), 7.97-7.91 (m , 1H), 7.53-7.41(m, 1H), 7.31-7.30(m, 1H), 7.29-7.14(m, 4H), 5.58-5.51(m, 1H), 4.69-4.65(m, 2H), 4.50 -4.45 (m, 2H), 4.00-3.91 (m, 2H), 1.62-1.60 (m, 6H).

Example 26

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-((4-methylmorpholine-2 -Yl)methyl)-1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridine- 2-yl)-2-((4-methylmorpholin-2-yl)methyl)-2H-indazole-6-formamide mixture (1:1)

LC-MS: m/z 479.5 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ 9.33-9.16 (m, 1H), 8.66-8.44 (m, 2H), 8.38 (d, 1H), 8.09-8.05 (m, 2H), 7.97-7.91 (m , 1H), 7.53-7.41 (m, 1H), 5.57-5.50 (m, 1H), 4.60-4.48 (m, 2H), 4.08-3.99 (m, 1H), 3.91-3.84 (m, 1H), 3.68 -3.56(m,1H),2.81-2.73(m,1H),2.65-2.59(m,1H),2.28-2.27(d,3H),2.13-2.07(m,1H),1.94-1.81(m, 1H), 1.62-1.59 (m, 6H).

Example 27

(S)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(1-methoxy Propan-2-yl)-1H-indazole-6-carboxamide and (S)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3- Yl)pyridin-2-yl)-2-(1-methoxypropan-2-yl)-2H-indazole-6-carboxamide mixture (1:1)

LCMS m/z 436.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J=16 Hz, 0.6H), 9.21 (d, J=16 Hz, 0.4H), 8.68-8.39 (m, 3H), 8.09-7.92 (m, 3H), 7.53 (d, J = 12 Hz, 0.6H), 7.43 (d, J = 12 Hz, 0.4H), 5.54 (m, 1H), 5.02-4.80 (m, 1H), 3.90-3.84 (m, 1H ), 3.78-3.71 (m, 1H), 3.31-3.27 (m, 3H) 1.71-1.59 (m, 9H).

Example 28

(R)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(1-methoxy Propan-2-yl)-1H-indazole-6-carboxamide and (R)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3- Yl)pyridin-2-yl)-2-(1-methoxypropan-2-yl)-2H-indazole-6-carboxamide mixture (1:1)

LCMS m/z 436.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J=16 Hz, 0.6H), 9.20 (d, J=16 Hz, 0.4H), 8.68-8.40 (m, 3H), 8.09-7.90 (m, 3H), 7.53 (d, J = 12Hz, 0.6H), 7.43 (d, J = 12Hz, 0.4H), 5.54 (m, 1H), 5.02-4.80 (m, 1H), 3.89-3.83 (m, 1H ), 3.77-3.71 (m, 1H), 3.31-3.26 (m, 3H) 1.70-1.59 (m, 9H).

Example 29

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxypropyl)- 1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2- (2-Methoxypropyl)-2H-indazole-6-formamide mixture (1:1)

LCMS m/z 436.46 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=16 Hz, 1H), 8.41 (d, J=8 Hz, 1H), 8.36 (d, J=8 Hz, 1H), 8.31 (s, 1H) , 7.98 (m, 2H), 7.86 (t, J = 8Hz, 1H), 7.44 (d, J = 12Hz, 1H), 5.46 (m, 1H), 4.38 (m, 2H), 3.79 (m, 1H) , 3.15 (s, 3H), 1.52 (d, J = 4 Hz, 6H), 1.13 (d, J = 4 Hz, 3H).

Example 30

6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(2-methoxyethyl)- Preparation of 1-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazole-5-carboxamide

Step 1: Preparation of 2-fluoro-4-methylamino-5-nitrobenzoic acid

An aqueous solution of methylamine (30% wt, 5 g, 48.4 mmol) was added dropwise to a solution of 2-fluoro-4-methylamino-5-nitrobenzoic acid (5.0 g, 24.6 mmol) in tetrahydrofuran (50 mL) under an ice bath. in. After the dropwise addition, the reaction solution was naturally raised to room temperature and stirred at room temperature for 12 hours. The resulting mixture was quenched with water (50 mL), and then concentrated under reduced pressure at 30 to 35°C. The obtained residue was filtered, and the filter cake was rinsed with a small amount of water and then air-dried at 40-50° C. to obtain the target product (crude product 2.3 g), which was directly used in the next reaction without purification.

LC-MS: m/z 213(MH) ^-

Step 2: Preparation of 2-fluoro-4-methylamino-5-aminobenzoic acid

Pd/C (10% Pd, 50% water, 0.3 g) was added to methanol (30 mL) of 2-fluoro-4-methylamino-5-nitrobenzoic acid (2.3 g, 10.7 mmol) under a nitrogen atmosphere. In solution. The reaction was stirred under hydrogen atmosphere for 4 hr, then filtered through celite, and the filter cake was rinsed with methanol. The filtrates were collected together and concentrated under reduced pressure below 40°C to obtain the target product (crude product 1.9g), which was directly used in the next reaction without purification.

LC-MS: m/z 183(MH) ^-

Step 3: Preparation of 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid

At room temperature, triphosgene (0.5 g, 1.7 mmol) was added to a solution of 2-fluoro-4-methylamino-5-aminobenzoic acid (0.5 g, 2.7 mmol) in acetic acid (10 mL). The reaction solution was stirred at room temperature for 3 h, and then concentrated under reduced pressure below 40° C. The obtained residue was purified by silica gel column chromatography to obtain the target product (170 mg).

LC-MS: m/z 211(M+H) ⁺

The fourth step: 6-fluoro-3-(2-methoxyethyl)-1-methyl-2-oxo-2-3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid preparation

Sodium carbonate (276 mg, 2 mmol) and chloroethyl methyl ether (150 mg, 1.6 mmol) were added to 6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo at room temperature [d] Imidazole-5-carboxylic acid (170 mg, 0.81 mmol) in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 80-85°C for 12 h, and then cooled to room temperature, and then ethyl acetate (30 mL) and dilute hydrochloric acid (0.5 N, 30 mL) were added for separation. After the aqueous phase was separated, it was extracted with ethyl acetate (20 mL). The organic phases were combined, washed with water (30 mL) and saturated brine (30 mL) in this order, and then concentrated under reduced pressure at 40°C. To the resulting concentrated residue were added tetrahydrofuran (10 mL) and aqueous sodium hydroxide solution (4N, 10 mL), and then stirred at room temperature for 12 h. The resulting mixture was adjusted to pH 3-4 with dilute hydrochloric acid (2N), and then extracted with ethyl acetate (3x20 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo at 40°C to obtain the target product (110 mg), which was directly used in the next reaction without purification.

LC-MS: m/z 267(MH) ^-

Step 5: 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(2-methoxy Preparation of ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazole-5-carboxamide

Add (chloromethylene) dimethyl ammonium chloride (100 mg, 0.78 mmol) to 6-fluoro-3-(2-methoxyethyl)-1-methyl-2-oxo under a nitrogen atmosphere 2-3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (110 mg, 0.4 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature for 1 h, and then 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (82 mg, 0.4 mmol) and diethylisopropyl were added Amine (155 mg, 1.2 mmol). The resulting mixture was stirred at room temperature for 3 h, then ethyl acetate (50 mL) and water (50 mL) were added and the layers were separated. After collecting the organic phase, it was washed with water (50 mL) and saturated brine (50 mL) in that order, then dried over anhydrous sodium sulfate and filtered. The filtrate was vacuum-depressurized at 40°C, and the residue was purified by preparative chromatography to obtain the target product (80 mg).

LC-MS: m/z 452.35 (MH) ^- . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, 1H), 8.44 (m, 1H), 8.40 (s, 1H), 8.06 (d, 1H), 7.93 (m, 2H), 6.80 (d, 1H), 5.52 (m, 1H), 4.12 (t, 2H), 4.71 (t, 2H), 3.46 (s, 3H), 3.35 (s, 3H), 1.62 (d, 6H).

The following compounds were synthesized with different starting materials according to the method of Example 1 above:

Example 31

4-(2-(benzyloxy)ethyl)-7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl )-3,4-dihydro-2H-benzo[b][1,4]azine-6-carboxamide

LC-MS: m/z 517 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.15 (d, J=18.1 Hz, 1H), 8.53–8.32 (m, 2H), 8.06 (d, J=7.6 Hz, 1H), 7.92 (t, J= 8.0Hz, 1H), 7.43(d, J=7.7Hz, 1H), 7.37–7.15(m, 5H), 6.63(t, J=16.7Hz, 1H), 5.54(dd, J=13.5, 6.7Hz, 1H), 4.55 (s, 2H), 4.32 (dd, J = 15.9, 11.6 Hz, 2H), 3.86-3.72 (m, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.51-3.39 (m , 2H), 1.70–1.56 (m, 6H).

The following compounds were synthesized according to the method of Example 7 with different starting materials:

Example 32

1-(2,2-difluoroethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -1H-indole-6-formamide

LC-MS: m/z 429 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.39 (d, J = 19.1 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 8.30 (d, J = 6.2 Hz , 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 13.5 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H) ), 6.64 (d, J = 2.8 Hz, 1H), 6.08 (m, 1H), 5.58 (dt, J = 13.4, 6.7 Hz, 1H), 4.58 (td, J = 14.2, 3.8 Hz, 2H), 1.64 (d, J=6.7Hz, 6H).

Example 33

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2,2,2-trifluoroethane Group)-1H-indole-6-formamide

LC-MS: m/z 447(M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (d, J = 18.9 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.41 (s, 1H), 8.29 (t, J = 9.0 Hz , 1H), 8.09 (d, J = 7.6Hz, 1H), 7.95 (t, J = 8.0Hz, 1H), 7.43 (t, J = 12.4Hz, 1H), 7.37 (d, J = 3.1Hz, 1H ), 6.67 (d, J = 3.1 Hz, 1H), 5.57 (dt, J = 13.0, 6.4 Hz, 1H), 4.78 (q, J = 8.4 Hz, 2H), 1.64 (d, J = 6.7 Hz, 6H) ).

Example 34

5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H- Indole-6-formamide

LC-MS: m/z 435 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J = 19.5 Hz, 1 H), 8.51 (d, J = 8.2 Hz, 1 H), 8.41 (s, 1 H), 8.36 (d, J = 6.4 Hz , 1H), 8.09 (d, J = 7.4Hz, 1H), 7.95 (t, J = 8.0Hz, 1H), 7.53 (d, J = 3.2Hz, 1H), 7.41 (d, J = 13.7Hz, 1H) ), 6.59 (d, J = 3.1 Hz, 1H), 5.74–5.43 (m, 1H), 5.24 (td, J = 5.4, 2.8 Hz, 1H), 4.27–4.16 (m, 2H), 4.11 (dd, J=10.0, 5.6Hz, 1H), 4.01 (td, J=8.8, 5.9Hz, 1H), 2.62 (dt, J=14.4, 7.7Hz, 1H), 2.20 (ddd, J=13.6, 8.2, 2.9Hz , 1H), 1.64 (d, J=6.7Hz, 6H).

Example 35

1-(2-(benzyloxy)ethyl)-6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -1H-benzo[d]imidazole-5-carboxamide and 1-(2-(benzyloxy)ethyl)-5-fluoro-N-(6-(4-isopropyl-4H-1,2, 4-triazol-3-yl)-1H-benzo[d]imidazole-6-carboxamide

Example 35A

LC-MS: m/z 500 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (t, J=16.4 Hz, 1H), 8.60 (d, J=7.0 Hz, 1H), 8.47 (d, J=8.2 Hz, 1H), 8.37 (d , J = 5.6 Hz, 1H), 8.05 (d, J = 13.1 Hz, 1H), 7.99 (t, J = 11.0 Hz, 1H), 7.93–7.81 (m, 1H), 7.32–7.19 (m, 3H) , 7.19–7.10(m, 2H), 5.60–5.40(m, 1H), 4.47(d, J=9.9Hz, 2H), 4.38–4.30(m, 2H), 3.79(dt, J=7.8, 5.1Hz , 2H), 1.57 (t, J=8.7Hz, 6H).

Example 35B

LC-MS: m/z 500 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 (t, J = 18.3 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 10.9 Hz, 1H), 8.28 (d , J = 6.6Hz, 1H), 8.23-8.15 (m, 1H), 8.13-7.99 (m, 1H), 7.97-7.82 (m, 1H), 7.60 (t, J = 14.1Hz, 1H), 7.36- 7.07 (m, 4H), 5.60–5.46 (m, 1H), 4.47 (d, J = 8.4 Hz, 2H), 4.43 (t, J = 4.9 Hz, 2H), 3.82 (t, J = 4.9 Hz, 2H ), 1.58 (dd, J = 15.7, 8.8 Hz, 6H).

Example 36

1-(2-(benzyloxy)ethyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-imidazole [4,5-c]pyridine-6-carboxamide and 3-(2-(benzyloxy)ethyl)-N-(6-(4-isopropyl-4H-1,2,4-triazole- 3-yl)pyridin-2-yl)-3H-imidazole[4,5-c]pyridine-6-carboxamide mixture (6:4)

LC-MS: m/z 483 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.74 (m, 1H), 9.16 (m, 1H), 8.92 (s, 1H), 8.70–8.46 (m, 2H), 8.41 (d, J=8.3 Hz, 1H ), 8.10 (td, J = 8.0, 3.6 Hz, 1H), 7.88 (dd, J = 7.6, 3.4 Hz, 1H), 7.20 (m, 5H), 5.48 (tt, J = 13.5, 6.8 Hz, 1H) , 4.68 (t, J = 4.6 Hz, 2H), 4.48 (d, J = 2.8 Hz, 2H), 3.84 (dt, J = 14.0, 5.0 Hz, 2H), 1.53 (d, J = 6.7 Hz, 6H) .

Example 37

1-(2-(benzyloxy)ethyl)-6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) -2-methyl-1H-phenylpropyl[d]imidazole-5-carboxamide and 1-(2-(benzyloxy)ethyl)-5-fluoro-N-(6-(4-isopropyl-4H -1,2,4-triazol-3-yl)pyridin-2-yl)-2-methyl-1H-phenylpropyl[d]imidazole-6-carboxamide

Example 37A

LC-MS: m/z 514 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=18.4 Hz, 1H), 8.50–8.31 (m, 2H), 8.26 (d, J=6.4 Hz, 1H), 8.10 (d, J= 7.6Hz, 1H), 7.94 (t, J = 8.0Hz, 1H), 7.63 (d, J = 12.7Hz, 1H), 7.25 (d, J = 7.7Hz, 4H), 7.15-7.04 (m, 2H) , 5.55 (dt, J = 13.3, 6.7 Hz, 1H), 4.54-4.34 (m, 4H), 3.83 (t, J = 4.8 Hz, 2H), 2.80 (s, 3H), 1.61 (t, J = 9.2 Hz, 6H).

Example 37B

LC-MS: m/z 514 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, J=15.0 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H), 8.51–8.36 (m, 2H), 8.05 (d, J= 7.6Hz, 1H), 7.92(t, J=8.0Hz, 1H), 7.26(s, 5H), 7.13–7.04(m, 2H), 5.52(dd, J=13.4, 6.7Hz, 1H), 4.45( m, 2H), 4.38 (m, 2H), 3.81 (m, 2H), 2.80 (s, 3H), 1.61 (t, J=8.5Hz, 6H).

Biological test evaluation

The following biological test examples further describe and explain the present invention, but these examples are not meant to limit the scope of the present invention

In Vitro Experiment of Inhibition of Compounds on Apoptosis Signal Regulatory Kinase 1 (ASK1)

Reagents:

hASK1 enzyme: GST-ASK1 (654-971)

Substrate: MKK6; HIS-Avi-MKK6

Kit: ADP-Glo ^TM Kinase Assay 10,000 tests;

Culture plate: Corning 3573

DTT: Sigma-Aldrich;

ATP: Ultra Pure ATP, 100mM. Included in kit.

Magnesium acetate tetrahydrate: Sigma-Aldrich;

MOPS: Ambion;

NP-40: Thermo Scientific Pierce;

BSA: Equitech-Bio Inc;

Glycerol: Sigma-Aldrich;

experiment procedure:

1. Buffer: 10 mM MOPS pH 7.0; 10 mM Mg-Acetate; 1 mM DTT (added before use); 0.025% NP-40; 0.05% BSA; 1.5% glycerol.

2. Pre-prepared ASK1+MKK6 solution (2x): dilute hASK1 enzyme and MKK6 with buffer to a final concentration of 0.25nM hASK1, 300nM MKK6;

3. Pre-prepared ATP solution (2x): dilute ATP with buffer to a final concentration of 100uM;

4. Add the compound to the 384-well plate at a gradient concentration, and use the HP D300 automatic pipette to replenish DMSO to a total volume of 5 nL/well. The minimum control column: substrate + ATP + 0.1% DMSO; the maximum control column: enzyme + substrate + ATP + 0.1% DMSO.

5. Add the ASK1-MKK6 mixture (2x) to the 384-well plate to which the corresponding compound has been added in step 4, 2.5 μL/well, mix by shaking, and incubate at room temperature for 15 min.

6. Add ATP solution (2x) to the 384-well plate of step 5, 2.5 μL/well, mix by shaking and centrifuge, incubate at room temperature for 30 min.

7. Then add ADP-Glo reagent at 5 μL/well to inactivate ATP, and incubate at room temperature for 40 min.

8. Then add kinase detection reagent at 10 μL/well to convert ADP to ATP and incubate at room temperature for 60 min.

9. Read fluorescence data

10. Use Graphpad Prism to calculate the four-parameter inhibitor response curve

The enzymatic activities of the compounds of the examples in the present invention are shown in Table 1.

Table 1 Examples of enzymatic activities of the compounds of the present invention

Compound number ASK1IC ₅₀ (nM) Example 1 11.5 Example 2 5 Example 2A 4.1 Example 2B 7.3 Example 3A 6.0 Example 3B 12.4 Example 4B 27.4 Example 6 7.9 Example 7 6.7 Example 8 15.4 Example 9 1.2 Example 18 6 Example 20A 42.6 Example 20B 55.3 Example 21A 17.7 Example 21B 11.2 Example 22A 74.5 Example 22B 22.7 Example 23A 61.0 Example 23B 26.2 Example 24A 24.0 Example 24B 26.3 Example 25 8.1 Example 26 70 Example 27 114 Example 28 64.5 Example 29 202 Example 30 27.7 Example 31 3.3 Example 32 19.9 Example 33 75.4 Example 34 10.2 Example 35A 9.3 Example 35B 0.9 Example 36 0.8

Pharmacokinetic test evaluation

Male SD rats, weighing about 200 g, were fasted overnight, and then given 5 mg/kg of the compound solution of the present invention [DMSO/PEG400 as a carrier] by intragastric administration. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24 and 36 h after administration, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.

Experimental results: The compounds of the present invention exhibit better metabolic properties in rats, including higher plasma exposure AUC, maximum plasma concentration C _max and half-life t _1/2 .

In vivo pharmacodynamic test

Pharmacodynamic evaluation of a non-alcoholic steatohepatitis mouse model induced by high fat feed (HFD) and carbon tetrachloride (CCl ₄ )

Experimental procedure: C57BL/6 mice were adapted to feed for 3-7 days in a SPF barrier and then switched to HFD feed for 8 weeks. Starting at the fifth week of HFD feeding, the mice were randomly divided into groups according to body weight. The grouped mice were given oral CCl ₄ twice a week for four weeks. The oral administration was started once a day on the day of CCl ₄ modeling and continued for 28 days. The vehicle control group was given a vehicle corresponding to the test article, and the administration volume was 10 mL/Kg. 48 hours after the last CCl ₄ administration, the mice were euthanized with CO ₂ . The non-coagulated venous blood was collected from the heart of the mouse, and the whole blood was placed at room temperature for more than 30 minutes, and then centrifuged under the centrifugal condition of 5000 rpm for 5 minutes at 4 degrees Celsius. After separation, the obtained serum was divided into two portions, filled into 1.5mL EP tubes, and stored at -80 degrees Celsius for later use. The alanine aminotransferase kit and aspartate aminotransferase kit were used to detect the ALT and AST levels in the serum of mice, and to score liver cell degeneration, necrosis, balloon-like degeneration, and inflammatory cell infiltration.

Experimental results: The compound of the present invention has an excellent therapeutic effect on high-fat feed (HFD) and CCl ₄ induced liver vascularization.

CYP inhibitory test

CYP3A4 inhibitory test (midazolam)

The test compound was mixed with human liver microsomes (0.1 mg/mL) and NADPH (1 mM) at 7 concentrations (0.14, 0.41, 1.23, 3.70, 11.11, 33.33, 100 uM in DMSO) on the probe substrate midazolam Incubate at 37°C for 5 minutes in the presence of (2.5uM). A selective CYP3A4 inhibitor (ketoconazole, Ketoconazole) was used as a positive reference to conduct experiments with the test compound.

CYP3A4 inhibitory test (testosterone, testosterone)

Test compounds were tested at 7 concentrations (0.14, 0.41, 1.23, 3.70, 11.11, 33.33, 100 uM in DMSO) with human liver microsomes (0.1 mg/mL) and NADPH (1 mM) on the probe substrate testosterone (50 uM) Incubate for 5 minutes at 37°C in the presence of. A selective CYP3A4 inhibitor (ketoconazole, Ketoconazole) was used as a positive reference to conduct experiments with the test compound.

The structure of the control compound GS-4997 is as follows:

The experimental results are shown in Table 2:

Table 2

The results show that the compounds of the present invention have low inhibitory activity against CYP3A4 and other CYP enzymes, thereby reducing the possibility of drug-drug interaction and increasing drug safety.

All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that, after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

An arylamide compound having the structure of general formula (I), or its stereoisomers, tautomers, racemates, or polymorphs thereof, or pharmaceutically acceptable salts, hydrates thereof , Solvates, or prodrugs;

In the formula: M ₁ and M ₂ are each independently selected from: N or CR ₇ ; Ring A is selected from the group consisting of substituted or unsubstituted C3-C20 carbocycle, substituted or unsubstituted 3-20 membered heterocyclic ring, substituted or unsubstituted C6-C20 aromatic ring or substituted or unsubstituted 5-20 membered Heteroaromatic ring; in ring A, the substitution means that ring A is substituted with oxo, thio, or -(CH ₂ ) _n -, or H on ring A is selected from one or more of the following groups (preferably 1-3) substituted by substituents: deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted cycloalkane Group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n O(CH ₂ ) _o R ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O) R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; Each R ₁ is the same or different, and each independently is a group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n R ₁₀ , -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n CH(R ₁₀ )(CH ₂ ) _o NR ₁₁ R ₁₂ (including: -(CH ₂ ) _n CH(OH)(CH ₂ ) _o NHR ₁₁ ), -(CH ₂ ) _n O(CH ₂ ) _o R ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S (O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ , -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ or -( CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ , -(CH ₂ ) _n N(R ₁₁ )(CH ₂ ) _o R ₁₀ (including -(CH ₂ ) _n NH(CH ₂ ) _o R ₁₀ ); R ₂ , each of R ₃ and R ₅ are independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (preferably -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and- (CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; R _{4 is} selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, hydroxyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; alternatively, R ₄ and M ₃ together with the N atom connected to them form a ring selected from the group consisting of substituted or unsubstituted heterocycle, substituted or unsubstituted Substituted heteroaromatic ring; M ₃ and M ₄ are each independently selected from N or CR ₇ ; or M ₃ and M ₄ and their adjacent chemical bonds together constitute a group selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; M _{5 is} selected from the group: N or CR ₇ ; X and Y are independently selected from: bond,

-NR ₈ -, CR ₈ R ₉ -, -S(O) _m -,

Alternatively, X and/or Y and M ₁ , M ₂ or M ₅ and the chemical bonds to which they are connected together form a ring selected from the group consisting of substituted or unsubstituted carbocycles, substituted or unsubstituted heterocycles, substituted or unsubstituted Aromatic ring, substituted or unsubstituted heteroaromatic ring; R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; Unless otherwise specified, the above-mentioned substitution refers to the substitution of one or more (preferably 1-3) hydrogen atoms on the group with substituents selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, Haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n R ₁₀ , -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C(O)NR ₁₁ R ₁₂ (including -(CH ₂ ) _n C(O)NHR ₁₁ ), -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ , or -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; R _{10 is} independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, cyano group, substituted or unsubstituted cycloalkyl group, substitution Or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group; R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, substituted or unsubstituted cycloalkyl group, substitution Or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; or, R ₁₁ and R ₁₂ and the N atom to which they are connected together constitute a ring selected from the group consisting of: substituted or unsubstituted Substituted heterocycle, or substituted or unsubstituted heteroaromatic ring; Wherein, in said R ₁₀ , R ₁₁ and R ₁₂ , substitution means that one or more (preferably 1-3) hydrogen atoms on the group are replaced by substituents selected from the group consisting of deuterium atoms, alkanes Group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH ₂ ) _n R ₁₃ , -(CH ₂ ) _n OR ₁₃ , -(CH ₂ ) _n SR ₁₃ , -(CH ₂ ) _n COR ₁₃ , -(CH ₂ ) _n C(O)OR ₁₃ , -(CH ₂ ) _n S(O) _m R ₁₃ , -(CH ₂ ) _n NR ₁₃ R ₁₄ , -(CH ₂ ) _n C(O)NR ₁₃ R ₁₄ , (including -(CH ₂ ) _n C(O)NHR ₁₄ ), -(CH ₂ ) _n NR ₁₄ C(O)R ₁₃ and -(CH ₂ ) _n NR ₁₄ S(O) _m R ₁₃ ; R ₁₃ and R ₁₄ are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, ester group, substituted or unsubstituted cycloalkane Group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; wherein, in R ₁₃ and R ₁₄ , the substitution refers to one or more groups on the group (Preferably 1-3) hydrogen atoms are substituted with substituents selected from the group consisting of deuterium atoms, alkyl groups, alkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, ester groups; x is 0, 1, 2, 3 or 4; y is 0, 1 or 2; m is 0, 1, or 2; and n is 0, 1, 2, 3, 4 or 5; o is 0, 1, 2, 3, 4 or 5; Unless otherwise specified, in the above formulas, 0-3 hydrogens in "(CH ₂ ) _n "or "(CH ₂ ) _o " are substituted with C1-C6 alkyl; Each said cycloalkyl is C3-C20 cycloalkyl (preferably C3-C10 cycloalkyl); Each said heterocyclic group is a 3-20 membered heterocyclic group (preferably 3-10 membered heterocyclic group); Each aryl group is C6-C20 aryl (preferably C6-C12 aryl); Each of the heteroaryl groups is 5-20 membered heteroaryl (preferably 5 to 12 membered heteroaryl) Each said alkyl group is C1-C18 alkyl (preferably C1-C6 alkyl); Each of the alkoxy groups is C1-C18 alkoxy (preferably C1-C6 alkoxy); Each said ester group is a C2-C10 ester group (preferably a C2-C6 ester group); Each of the carbocycles is C3-C20 carbocycle (preferably C3-C10 carbocycle); Each said heterocycle is a 3-20 membered heterocycle (preferably 3-10 membered heterocycle); Each of the aromatic rings is a C6-C20 aromatic ring (preferably a C6-C12 aromatic ring); Each of the heteroaromatic rings is a 5-20 membered heteroaromatic ring (preferably a 5 to 12 membered heteroaromatic ring). The compound according to claim 1, wherein the compound is a compound represented by the general formula (II):

In the formula, R _{6 is} selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH ₂ ) _n OR ₁₀ , -(CH ₂ ) _n SR ₁₀ , -(CH ₂ ) _n COR ₁₀ , -(CH ₂ ) _n C(O)OR ₁₀ , -(CH ₂ ) _n S(O) _m R ₁₀ , -(CH ₂ ) _n NR ₁₁ R ₁₂ , -(CH ₂ ) _n C( O)NR ₁₁ R ₁₂ , -(CH ₂ ) _n NR ₁₁ C(O)R ₁₀ and -(CH ₂ ) _n NR ₁₁ S(O) _m R ₁₀ ; wherein, the substitution refers to one on the group Or more (preferably 1-3) hydrogen atoms are substituted with a substituent selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, halogenated alkoxy groups, halogens, amino groups, Nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH ₂ ) _n OR ₁₃ , -(CH ₂ ) _n SR ₁₃ , -(CH ₂ ) _n COR ₁₃ , -(CH ₂ ) _n C(O)OR ₁₃ , -(CH ₂ ) _n S(O) _m R ₁₃ , -(CH ₂ ) _n NR ₁₃ R ₁₄ , -(CH ₂ ) _n C(O)NR ₁₃ R ₁₄ (including -(CH ₂ ) _n C(O)NHR ₁₄ ), -(CH ₂ ) _n NR ₁₄ C(O)R ₁₃ and -(CH ₂ ) _n NR ₁₄ S(O) _m R ₁₃ ; or , R ₄ and its attached N atom, together with R ₆ and its connected C atom, constitute: substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaromatic ring; Unless otherwise specified, substitutions, rings A, M ₁ , M ₂ , M ₅ , X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R _14. The definitions of x and y are as described in claim 1. The compound according to claim 2, wherein the compound is a compound represented by the general formula (III), (X) or (XII);

Wherein, M ₆ and M ₇ are each independently selected from the following group: CH, CH ₂ , N, NH, O; M _{8 is} selected from the following group: CH ₂ , NH, O; Rings A, M ₁ , M ₂ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , x and y are as described in claim 2. The compound according to claim 2, wherein the compound is a compound represented by general formula (IV) or general formula (V);

Among them, the definition of ring A, R ₁ , R ₄ , R ₆ and x is as described in claim 2. The compound according to claim 2, wherein the compound is a compound represented by general formula (VI), general formula (VII), general formula (VIII) or general formula (IX);

among them, V ₁ and V ₂ are each independently selected from a bond, O, -NR ₈ -, CR ₈ R ₉ or -S(O) _m -; V ₃ , V ₄ and V ₅ are each independently selected from O, -NR ₈ -, CR ₈ R ₉ , -S(O) _m ,

R ₁ , R ₄ , R ₈ , R ₉ , R ₆ , m and x are as defined in claim 2. The compound according to claim 2, wherein the compound is a compound represented by general formula (XI) or general formula (XIII);

Wherein, M ₆ and M ₇ are each independently selected from the following group: CH, CH ₂ , N, NH, O; M _{8 is} selected from the following group: CH ₂ , NH, O; Rings A, R ₁ , R ₄ , R ₆ and x are as described in claim 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

A method for preparing a compound according to claim 3, wherein the compound is a compound represented by the general formula (III), and the preparation method includes the following steps:

Coupling the compound of general formula (X-A) and the compound of general formula (X-B) to obtain the compound of general formula (III); Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , M ₁ , M ₂ , M ₅ , x and y are as defined in claim 3. A pharmaceutical composition, characterized in that the composition comprises (i) a pharmaceutically acceptable carrier, and (ii) the compound of claim 1, or a stereoisomer or tautomer thereof , Racemates, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, or prodrugs. The compound according to claim 1, or a stereoisomer, tautomer, racemate, or polymorph thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvent thereof Use of a compound, or a prodrug, or a pharmaceutical combination according to claim 9, characterized in that (i) for the preparation of ASK1 inhibitors; and/or (ii) for the preparation of a medicament for the treatment and/or prevention of ASK1-mediated diseases: wherein the ASK1-mediated diseases are selected from the group consisting of inflammation, cardiovascular diseases, infections, immune diseases, metabolic diseases, or combination.