CN110511213B - Immunomodulator - Google Patents

Abstract

The invention discloses an immunomodulator, and particularly relates to a compound for inhibiting IL-17A and application thereof as an immunomodulator in preparation of a medicament. The invention discloses a compound shown as a formula I or a derivative thereofThe isomer or the pharmaceutically acceptable salt thereof can be used for preparing the medicines for inhibiting the IL-17A class, and a new choice is provided for clinically screening and/or preparing the medicines for treating diseases related to the IL-17A activity.

Description

Immunomodulator

Technical Field

The invention relates to an immunomodulator and application thereof in preparing a medicament.

Background

IL-17 (interleukin-17) is a proinflammatory cytokine, playing a role in the induction of other inflammatory cytokines, chemokines and adhesion factors. The IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. IL-17A is expressed by TH17 cells, and is involved in the pathogenesis of inflammatory and autoimmune diseases. Human IL-17A is a glycoprotein having a molecular weight of about 17000 daltons. IL-17A signals intracellular through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. journal of immunology,2008,181: 2799-2805). The primary functions of IL-17A are to coordinate local tissue inflammation by upregulation of pro-and neutrophil migratory cytokines and chemokines (including IL-6, G-CSF, TNF- α, IL-1, CXCL1, CCL2, CXCL2), and matrix metalloproteases to allow activated T cells to penetrate the extracellular matrix. There are studies that have shown that IL-17A plays a major role in severe asthma and Chronic Obstructive Pulmonary Disease (COPD), and those patients generally do not respond or respond poorly to currently available drugs (Al-Ramli et Al J Allergy Clin Immunol,2009,123: 1185-1187). Upregulation of IL-17A levels has been implicated in a number of diseases including Rheumatoid Arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma and multiple sclerosis (Gaffen, SL et al.

Targeting the binding of IL-17A to IL-17RA is an effective strategy for the treatment of IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with IL-17A neutralizing antibodies reduces disease incidence and severity in autoimmune encephalomyelitis (Komiyama Y et al J. Immunol.,2006,177: 566-573). Clinical trials with IL-17A antibodies have shown good results in IL-7A-mediated inflammatory diseases including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis. The IL-17A antibody (Cosentyx/secukinumab from Novartis) was approved by the FDA for the treatment of psoriasis 1 month 2015.

Despite the existence of a variety of IL-17A antibodies, few small molecule specific inhibitors of IL-17 have been studied for oral bioavailability. In view of the cost consideration of antibody production and the limitation of administration route, the development of IL-17A small-molecule inhibitor drugs has good development prospect.

Disclosure of Invention

The invention provides a compound shown as a formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

x is selected from O, S, NR^1’；

R¹、R²Are respectively and independently selected from hydrogen and C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, -S (O)₂R⁶、-S(O)R⁶、-S(O)₂NR⁶R⁷、-S(O)NR⁶R⁷、 -C(O)R⁶、-C(O)OR⁶、-C(O)NR⁶R⁷、-P(O)(OR⁷)R⁶、-P(O)R⁶ R⁷、-P(O)R⁶(NR⁶ R⁷)、-P(O)(NR⁶ R⁷)(NR⁶ R⁷)、-P(O)(OR⁷)(NR⁶ R⁷)、P(O)(OR⁷)(OR⁷) (ii) a Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted by m R^cSubstitution;

R⁶、R⁷are respectively and independently selected from hydrogen and C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted by m R^cSubstitution;

R³、R^3’are independently selected from hydrogen, -OR^d、-SR^d、-NR^dR^dHalogen, C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring; wherein R is^dAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring by m R^cSubstitution; or, R³And R^3’Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl;

R^dselected from hydrogen, C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring;

the B ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaromatic ring is substituted by m R^cSubstitution;

R^1’selected from hydrogen, C_1～10An alkyl group;

L¹is selected from

r is 0, 1,2, 3;

R⁸and R⁹Are respectively and independently selected from hydrogen, halogen and C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are defined by m R^cSubstitution;

or, R⁸And R⁹Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl ring are substituted by m R^cSubstitution;

L²selected from-C (O) NR¹⁰-、-NR¹⁰C(O)-、-C(O)-、-C(O)O-、-S(O)₂NR¹⁰-、-S(O)NR¹⁰-、 -NR¹⁰S(O)₂-、-NR¹⁰S(O)-、-P(O)NR¹⁰-、-NR¹⁰P (O) -or none;

R¹⁰selected from hydrogen, C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are substituted with m R^cSubstitution;

R⁴and R⁵Are respectively and independently selected from hydrogen, halogen and C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, -CN, -NO₂、-OR^a、-OC(O)R^a、-OC(O)NR^aR^b、 -OS(O)₂R^a、-SR^a、-S(O)₂R^a、-S(O)₂NR^aR^b、-OS(O)₂NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、 -NR^aR^b、-NR^aC(O)R^b、-NR^aC(O)OR^b、-NR^aC(O)NR^aR^b、-NR^aS(O)₂R^b、-NR^aS(O)₂NR^aR^b(ii) a Wherein R is^a、R^bAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted with m R^cSubstitution;

or, R⁴And R⁵Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl are substituted by m R^cSubstitution;

X¹selected from the group consisting of CR¹¹Or N;

X²selected from NR¹²O, S or- (CR)¹³＝CR¹⁴)-；

X⁴Is selected from N or CH;

R¹¹selected from hydrogen, halogen, -CN, -NO₂、C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, C_1～10Haloalkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, -OR^a、-NR^aR^b；

R¹²Selected from hydrogen, C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, -S (O)₂R^a、-S(O)₂NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b；

R¹³、R¹⁴Are independently selected from hydrogen, halogen, -CN, -NO₂、C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, C_1～10Haloalkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, -OR^a、-NR^aR^b(ii) a Wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl are defined by m R^cSubstitution;

m is 0, 1,2, 3 or 4;

R^a、R^bare respectively and independently selected from hydrogen and C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, -S (O)₂R^d、-S(O)R^d、-P(O)₂R^d、 -P(O)R^d3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring are defined by m R^cSubstitution;

R^care respectively independently selected from C_1～10Alkyl, ═ S, ═ O, halogen, -CN, -NO₂、-OR^a、-OC(O)R^a、-OS(O)₂ R^a、-SR^a、-S(O)₂R^a、-S(O)₂NR^aR^b、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aR^b、-NR^aC(O)R^b、 -NR^aS(O)₂R^b3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, wherein the alkyl group, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle are substituted with 0 to 3 carbon atoms_1～10Alkyl, halogen, -NR^aR^b、-OR^d、-C(O)NR^aR^b3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle.

Further, the air conditioner is provided with a fan,

R¹、R²are respectively and independently selected from hydrogen and C_1～6Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, -S(O)₂R⁶、-S(O)R⁶、-S(O)₂NR⁶R⁷、-C(O)R⁶、-C(O)OR⁶、-C(O)NR⁶R⁷(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted by m R^cSubstitution;

R⁶、R⁷are respectively and independently selected from hydrogen and C_1～6An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic ring, a 5-to 10-membered aromatic heterocycle; wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted by m R^cSubstitution;

R³、R^3’are independently selected from hydrogen, -OR^dHalogen, C_1～6An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group, a 5-to 10-membered aromatic ring; wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring are substituted by m R^cSubstitution; or, R³And R^3’Connecting to form 3-10 membered cycloalkyl;

R^dselected from hydrogen, C_1～10Alkyl radical, C_2～10Alkenyl radical, C_2～10Alkynyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered aromatic ring, 5-to 10-membered heteroaromatic ring;

R⁸and R⁹Are respectively and independently selected from hydrogen, halogen and C_1～6An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group; wherein alkyl, cycloalkyl, heterocycloalkyl are substituted by m R^cSubstitution;

or, R⁸And R⁹Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl ring may be further substituted by m R^cSubstitution;

R¹⁰selected from hydrogen, C_1～6Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl are substituted with m R^cSubstitution;

R⁴and R⁵Are respectively and independently selected from hydrogen, halogen and C_1～6Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-memberedAromatic heterocycles, -CN, -NO₂、-OR^a、-OC(O)R^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、 -NR^aR^b、-NR^aC(O)R^b、-NR^aC(O)NR^aR^b、-NR^aS(O)₂R^b、-NR^aS(O)₂NR^aR^b、-S(O)₂R^a、 -S(O)₂NR^aR^b(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are substituted by m R^cSubstitution;

or, R⁴And R⁵Are connected to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl are substituted by m R^cSubstitution;

R¹¹selected from hydrogen, halogen, C_1～6An alkyl group;

R¹²selected from hydrogen, C_1～6An alkyl group;

R¹³、R¹⁴are respectively and independently selected from hydrogen, halogen and C_1～6Alkyl radical, C_2～6An alkenyl group; wherein the alkyl and alkenyl groups are represented by m R^cSubstitution;

m is 0, 1,2 or 3;

R^a、R^bare respectively and independently selected from hydrogen and C_1～6Alkyl radical, C_2～6Alkenyl radical, C_2～6Alkynyl, -S (O)₂R^d、-S(O)R^d、-P(O)₂R^d、 -P(O)R^d3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring are defined by m R^cAnd (4) substitution.

Further, the air conditioner is provided with a fan,

R¹、R²are each independently selected from hydrogen, -S (O)₂R⁶、-S(O)R⁶、-S(O)₂NR⁶R⁷、-C(O)R⁶、-C(O)OR⁶、 -C(O)NR⁶R⁷；

R⁶、R⁷Are respectively independentSelected from hydrogen, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or heteroaromatic ring is substituted by m R^cSubstitution;

R³、R^3’are independently selected from hydrogen, -OR^d、C_1～6An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group, a 5-to 10-membered aromatic ring; wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring are substituted by m R^cSubstitution; or, R³And R^3’Connecting to form 3-8 membered cycloalkyl;

R⁸and R⁹Are respectively and independently selected from hydrogen and C_1～6An alkyl group, a 3-to 10-membered cycloalkyl group, a 3-to 10-membered heterocycloalkyl group;

or, R⁸And R⁹Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring;

R⁴and R⁵Are respectively and independently selected from hydrogen and C_1～6Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring, 5-to 10-membered aromatic heterocycle, -OR^a、-C(O)R^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aR^b、-NR^aC(O)R^b、 -NR^aC(O)NR^aR^b、-NR^aS(O)₂R^b、-NR^aS(O)₂NR^aR^b、-S(O)₂R^a、-S(O)₂NR^aR^bStarting the process; wherein the alkylcycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by m R^cSubstitution;

or, R⁴And R⁵Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by m R^cSubstitution;

R¹¹selected from hydrogen, C_1～6An alkyl group;

R¹²selected from hydrogen, C_1～6An alkyl group;

R¹³、R¹⁴are respectively and independently selected from hydrogen and C_1～6Alkyl radical, C_2～6An alkenyl group; wherein the alkyl and alkenyl groups are represented by m R^cSubstitution;

m is 0, 1, 2.

Further, the compound of formula I is represented by formula IIa:

wherein the content of the first and second substances,

R^a’is selected from C_1～6Alkyl group of (1).

Further, the compound shown in the formula IIa is shown in the formula IIa-1 or IIa-2:

wherein the content of the first and second substances,

R^a’is selected from C_1～6Alkyl group of (1).

Further, the compound represented by formula IIa-1 is represented by formula IIIa-1 or IIIa-2:

further, R^5’Is halogen, CN; n is selected from 0, 1 and 2; l is²is-C (O) NR¹⁰-、-NR¹⁰C (O) -, -C (O) O-, or none.

Further, the compound shown in the formula IIIa-1 or IIIa-2 is specifically as follows:

further, R^5’Is halogen and 5-10 membered heteroaromatic ring, wherein 5-10 membered heteroaromatic ring can be further substituted by 0-3C_1～10Alkyl substitution, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle substitution;

n is selected from 0, 1,2 and 3; l is²is-C (O) NR¹⁰-、-NR¹⁰C (O) -, -C (O) O-, or none.

Further, the compound shown in the formula IIIa-1 or IIIa-2 is specifically as follows:

further, R^5’Is halogen and-OR^a(ii) a n is selected from 0, 1,2 and 3; l is²Is absent.

Further, the compound shown in the formula IIIa-1 or IIIa-2 is specifically as follows:

further, the compound represented by formula IIa-1 is represented by formula IIIb-1 or IIIb-2:

wherein the content of the first and second substances,

R^a’selected from substituted or unsubstituted C_1～6Alkyl groups of (a); r^5’Hydrogen, halogen; n is selected from 0, 1 and 2; l is²is-C (O) NR¹⁰-、 -NR¹⁰C (O) -, -C (O) O-, or none.

Further, the compound represented by the formula IIIb-1 or IIIb-2 is specifically:

further, the compound of formula IIa-1 is of formula IIIc:

R^a’、R^care respectively selected from C_1～6Alkyl groups of (a); r^5’Hydrogen, halogen; n is selected from 0, 1 and 2; l is²is-C (O) NR¹⁰-、 -NR¹⁰C (O) -, -C (O) O-, or none.

Further, the compound represented by the formula IIIc is specifically:

further, the compound of formula IIa-2 is of formula IIId:

wherein the content of the first and second substances,

R^a’selected from substituted or unsubstituted C_1～6Alkyl groups of (a); r^5’Hydrogen, halogen; n is selected from 0, 1 and 2; l is²is-C (O) NR¹⁰-、 -NR¹⁰C (O) -, -C (O) O-, or none.

Further, the compound represented by the formula IIId is specifically:

further, compounds of formula I are of formula IIb:

wherein the content of the first and second substances,

R^a’is selected from C_1～6Alkyl group of (1).

Further, the compound represented by formula IIb is specifically:

the invention also provides application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing medicines for treating IL-17A mediated diseases.

IL-17A mediated diseases as defined in the present invention are diseases in which IL-17A plays an important role in the pathogenesis of the disease. The primary function of IL-17A is to coordinate local tissue inflammation and thus play a role in a variety of diseases. IL-17A mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndrome.

"cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the body's ability of affected cells to spread to other sites either locally or through the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and/or molecular features. "cancer cells" refers to cells that undergo multiple stages of early, intermediate or late stage tumor progression. The cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer. In some embodiments, the compound of formula I is used to treat a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, graves 'disease, celiac disease, crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, gillyre syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the invention relate to the treatment of autoimmune diseases such as psoriasis or multiple sclerosis.

Inflammatory diseases include a variety of conditions characterized by pathological inflammation of the tissue. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, house dust mite-induced airway inflammation, and interstitial cystitis. There is a significant overlap between inflammatory and autoimmune diseases. Some embodiments of the invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, manifested in allergic reactions and in some myopathies, many of which cause abnormal inflammation. IL-17A mediated diseases also include autoimmune inflammatory diseases.

The invention also provides a medicament which is a preparation prepared from the compound, or the stereoisomer or the pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C_a～bAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C_1～4The alkyl group means an alkyl group having 1 to 4 carbon atoms.

"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁～C₆Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C₁～C₆An alkoxy group.

"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:

dicyclohexyl and

a dicyclohexyl group.

"alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least 1 site of vinyl unsaturation (> C ═ C <). For example, (Ca-Cb) alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.

"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, and the like.

"halogen" is fluorine, chlorine, bromine or iodine.

"haloalkyl" means an alkyl group in which the hydrogen atom may be replaced by one or more halogen atoms. E.g. C_1～4The haloalkyl group means an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms.

"heterocycle", "heterocycloalkyl" refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

"heteroaromatic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

"stereoisomers" includes enantiomers and diastereomers;

the term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.

The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

The novel compound shown in the formula I shows good IL-17A inhibitory activity, and provides a novel medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker AvanceII)I400 and Bruker Avance 300) NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl)₃) Deuterated methanol (CD3OD) with internal standard Tetramethylsilane (TMS).

LC-MS was measured using Shimadzu LC-MS 2020 (ESI).

HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).

MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used.

The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

In the examples, M is mole per liter, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

DMF refers to N, N-dimethylformamide.

DMSO refers to dimethyl sulfoxide.

DIPEA: refers to diisopropylethylamine.

Boc is tert-butyloxycarbonyl.

TFA refers to trifluoroacetic acid.

DBU is 1, 8-diazabicycloundec-7-ene.

HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

HBTU is O-benzotriazole-tetramethyluronium hexafluorophosphate.

EDCI 1-Ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride.

HOAT 1-hydroxy-7-azobenzotriazol.

EXAMPLE 1 preparation of intermediate 1

Step 1 preparation of intermediate 1-1

Ethyl nitroacetate (28.5g, 130mmol) and 5-bromo-2-chlorobenzaldehyde (17.3g, 130mmol) were dissolved in anhydrous tetrahydrofuran (400mL), titanium tetrachloride (28.5mL, 260.0mmol) was slowly added dropwise at 0 ℃ under nitrogen protection, and after the addition was completed, the reaction was stirred at 0 ℃ for 1 hour. N-methylmorpholine (57.8mL, 520.0mmol) was slowly added dropwise to the reaction mixture, after the addition was complete, the temperature was slowly raised to room temperature, and the reaction was continued for 2 hours with stirring. Adding distilled water to quench the reaction, extracting with ethyl acetate, combining organic phases, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying by column chromatography (eluent: petroleum ether: ethyl acetate: 20: 1) to obtain intermediate 1-1(23.6g, 71mmol, 54% yield). MS M/z 335(M +1)⁺。

Step 2 preparation of intermediates 1-2

Anhydrous zinc chloride (14.4g, 106.0mmol) was dissolved in anhydrous tetrahydrofuran (100mL), and 2M isopropyl magnesium chloride in tetrahydrofuran (53mL, 106.0mmol) was slowly added dropwise at 0 ℃ under nitrogen, and the reaction was stirred at 0 ℃ for 1 hour after the addition was completed. Slowly dripping the obtained isopropyl magnesium zinc bromide into anhydrous tetrahydrofuran (100mL) solution of intermediate 1-1(23.6g, 70.5mmol) at 0 ℃ under the protection of nitrogen, and continuously stirring and reacting at 0 ℃ for 2 hours after dripping. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate 20: 1) to give intermediate 1-2(18.6g, 49.1mmol, yield 70%). MS M/z 379(M +1)⁺。

Step 3 preparation of intermediates 1-3

Intermediate 1-2(18.6g, 49.1mmol) was dissolved in glacial acetic acid (300mL), zinc powder (16.0 g, 245.5mmol) was added in portions at 0 deg.C, and the reaction was stirred at room temperature for 12 hours. The zinc powder was removed by filtration, the solvent was evaporated under reduced pressure, and purified by column chromatography (eluent: petroleum ether: ethyl acetate 10: 1) to give intermediate 1-3(7.6g, 21.8mmol, yield 44%). MS M/z 350(M +1)⁺.

Step 4 preparation of intermediates 1-4

The intermediate 1-3(3.8g,10.9mmol) was dissolved in dichloromethane (60mL), triethylamine (4.6 mL, 32.7mmol) and di-tert-butyl dicarbonate (3.8mL, 16.4mmol) were added dropwise in this order at 0 deg.C, and the reaction was allowed to warm to room temperature and stirred for 1 hour after the addition. The solvent was evaporated under reduced pressure and purified by column chromatography (eluent: petroleum ether: ethyl acetate: 20: 1) to give intermediate 1-4(4.5g, 92% yield). MS M/z 350(M-99)⁺，394(M-55)⁺。

Step 5 preparation of intermediate 1

Dissolving intermediates 1-4(4.5g, 10.0mmol) in a mixed solvent of tetrahydrofuran (15mL), water (15mL) and methanol (5mL), adding sodium hydroxide (2.0g, 50.0mmol) in portions at 0 deg.C, heating to room temperature after adding, and stirringThe reaction was carried out for 4 hours. And (3) evaporating the solvent under reduced pressure, dropwise adding 1N HCl under ice bath to adjust the pH to 4, separating out a solid, filtering, and drying in vacuum to obtain a crude product, wherein the crude product is separated by an SFC chiral separation column to respectively obtain four single chiral isomers 1-a,1-b,1-c and 1-d of the intermediate 1, and the four single chiral isomers are respectively 0.8g and the yield is 19%. MS M/z 322(M-99)⁺，366(M-55)⁺。

Example 2 preparation of intermediate 2

Referring to the method for preparing the intermediate 1 in example 1, four single chiral isomers 2-a,2-b,2-c,2-d of the intermediate 2 can be respectively obtained by using o-chlorobenzaldehyde as a starting material, performing condensation, Grignard reaction, nitro reduction, amino protection by Boc, hydrolysis and separation by an SFC chiral separation column. MS M/z 242[ M-99 ]]⁺，286[M-55]⁺。

EXAMPLE 3 preparation of intermediate 3

Referring to the method for preparing the intermediate 1 in example 1, m-chlorobenzaldehyde is used as a starting material, and four single chiral isomers 3-a,3-b,3-c,3-d of the intermediate 3 can be respectively obtained by condensation, Grignard reaction, nitro reduction, amino protection by Boc, hydrolysis and separation by an SFC chiral separation column. MS M/z 242[ M-99 ]]⁺，286[M-55]⁺。

Example 4 preparation of intermediate 4

Referring to example 1, the intermediate 1 was prepared by condensation, Grignard reaction, nitro reduction, Boc protection of amino group, hydrolysis using 2-chloro-5-fluorobenzaldehyde as starting material, and separation by SFC chiral separation column to obtain four intermediates 4The single chiral isomer 4-a,4-b,4-c, 4-d. MS M/z 257[ M-99 ]]⁺，304[M-55]⁺。

EXAMPLE 5 preparation of intermediate 5

Referring to the method for preparing the intermediate 1 in example 1, four single chiral isomers 5-a,5-b,5-c,5-d of the intermediate 5 can be respectively obtained by using 2-chloro-5-methoxybenzaldehyde as a starting material, performing condensation, Grignard reaction, nitro reduction, amino protection by Boc, hydrolysis and separation by an SFC chiral separation column. MS M/z 257[ M-99 ]]⁺，316[M-55]⁺。

EXAMPLE 6 preparation of intermediate 6

Referring to example 1, the intermediate 1 was prepared from 2-chloro-5-cyanobenzaldehyde as a starting material by condensation, grignard reaction, nitro reduction, amino protection with Boc, hydrolysis, and separation with SFC chiral separation column to obtain four single chiral isomers 6-a,6-b,6-c,6-d of the intermediate 6. MS M/z 267[ M-99 ]]⁺，311[M-55]⁺。

Example 7 preparation of intermediate 7

Step 1 preparation of intermediate 7-1

Referring to example 1, intermediate 2-1 was obtained by reacting o-chlorobenzaldehyde with ethyl nitroacetate, intermediate 2-1(5g,19.56mmol) was dissolved in methanol (50mL) at room temperature, sodium methoxide (4.23g,78.23 mmol) was added, the reaction was stirred at room temperature for 2 hours, TLC showed disappearance of the starting material, the solvent was removed by concentration under reduced pressure, saturated aqueous ammonium chloride solution was added to 20mL, ethyl acetate (20mL × 2) was extracted, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was separated by silica gel column (petroleum ether/ethyl acetate 4: 1) to give intermediate 7-1(3g,10.43mmol, 53.32% yield), a pale yellow liquid, Rf ═ 0.5(Hexanes/EtOAc ═ 8: 1).

Step 2 preparation of intermediate 7-2

The intermediate 7-1(1.58g,5.48mmol) was dissolved in 10mL of glacial acetic acid, zinc powder (1.79g,27.41mmol) was added, the reaction was stirred at room temperature for 2 hours, filtered, washed with a small amount of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure, and the crude product was isolated by silica gel column (petroleum ether/ethyl acetate 2: 1) to give intermediate 7-2(0.83g,3.22mmol, 58.76% yield), as a pale yellow solid, MS M/z:258[ M +1].

Step 3 preparation of intermediate 7-3

Intermediate 7-2(0.83g,3.22mmol) was dissolved in a mixed solution of THF (3mL) and water (1mL), and NaHCO was added separately₃(541.11mg,6.44mmol) and (Boc)₂O (737.20mg,3.38mmol), stirring at room temperature for 12 hours, adding ethyl acetate (15mL) and water (15mL) for washing, washing the organic phase with water, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, separating the crude product with silica gel column (petroleum ether/ethyl acetate 4: 1) to obtain intermediate 7-3(1.1g,3.07mmol, 95.45% yield), light yellow liquid, MS M/z:302[ M-55].

Step 4 preparation of intermediate 7

Intermediate 7-3(1.23g,3.44mmol) was dissolved in a mixed solution of methanol (15mL) and water (15mL), and lithium hydroxide monohydrate (1.20g,28.53mmol) was added to stir the reaction at room temperature for 4 hours. The solvent was evaporated under reduced pressure, 0.5N HCl was added dropwise to adjust pH to 4 under ice bath, ethyl acetate extraction-tetrahydrofuran 5:1 extraction, organic phase was concentrated under reduced pressure to obtain pale yellow liquid intermediate 7(1.1g,3.34mmol, 97.04% yield). MS M/z 274[ M-55].

EXAMPLE 8 preparation of intermediate 8

Referring to the method for preparing the intermediate 7 of example 7, the intermediate 8 can be obtained by reacting the intermediate 2-1 with sodium ethoxide, then performing nitro reduction, protecting amino group with Boc, and hydrolyzing. MS M/z 288[ M-55]]⁺。

EXAMPLE 9 preparation of intermediate 9

Referring to the method for preparing the intermediate 7 of example 7, the intermediate 9 can be obtained by reacting the intermediate 2-1 with sodium isopropoxide, performing nitro reduction, protecting amino group with Boc, and hydrolyzing. MS M/z 302[ M-55]]⁺。

EXAMPLE 10 preparation of intermediate 10

Referring to the method of example 7 for preparing intermediate 7, intermediate 10 was obtained by reacting intermediate 2-1 with cyclopropanol in the presence of potassium tert-butoxide, followed by nitro reduction, amino protection with Boc, and hydrolysis. MS M/z 300[ M-55]]⁺。

EXAMPLE 11 preparation of intermediate 11

Referring to the method for preparing the intermediate 1 in example 1, propionaldehyde is used as a starting material, and is condensed with ethyl nitroacetate, subjected to Grignard reaction with o-chlorophenyl magnesium bromide, reduced by nitrozinc powder, protected by Boc amino group, subjected to alkaline hydrolysis, and finally separated by an SFC chiral separation column to prepare four single chiral isomers 11-a,11-b,11-c and 11-d of the intermediate 11. MS M/z 228[ M-99 ]]⁺，272[M-55]⁺。

EXAMPLE 12 preparation of intermediate 12

Referring to the method for preparing the intermediate 1 in example 1, cyclopropanecarboxaldehyde is used as a starting material, and four single chiral isomers 12-a,12-b,12-c and 12-d of the intermediate 12 can be respectively obtained by condensation with ethyl nitroacetate, Grignard reaction with o-chlorophenyl magnesium bromide, reduction with nitrozinc powder, Boc protection of amino group, alkaline hydrolysis and separation by an SFC chiral separation column. MS M/z 228[ M-99 ]]⁺，272[M-55]⁺。

EXAMPLE 13 preparation of intermediate 13

Referring to the method for preparing the intermediate 1 in example 1, the four single chiral isomers 13-a,13-b,13-c,13-d of the intermediate 13 can be respectively obtained by taking cyclobutane formaldehyde as a starting material, condensing with ethyl nitroacetate, carrying out Grignard reaction with o-chlorophenyl magnesium bromide, reducing with nitro zinc powder, protecting amino with Boc, carrying out alkaline hydrolysis, and finally separating by an SFC chiral separation column. MS M/z 254[ M-99 ]]⁺，298[M-55]⁺。

EXAMPLE 14 preparation of intermediate 14

Referring to the method for preparing the intermediate 1 in example 1, cyclohexyl formaldehyde is used as a starting material, and four single chiral isomers 14a,14-b,14-c and 14-d of the intermediate 14 can be respectively obtained by condensation with ethyl nitroacetate, Grignard reaction with o-chlorophenyl magnesium bromide, reduction with nitro zinc powder, Boc protection of amino groups, alkaline hydrolysis and separation by an SFC chiral separation column. MS M/z 282[ M-99 ]]⁺，326[M-55]⁺。

EXAMPLE 15 preparation of intermediate 15

Adding dichloromethane activated resin to FMOC-D-CHA-OH (2.00g,5.08mmol) and DIPEA (1.97g, 15.24mmol,2.66mL) in DMF (40.00mL), shaking for 12 hours, filtering, adding DCM/MeOH/DIPEA (85/10/5) to the resin, shaking for 30min, filtering, adding DCM (50X 10mL), DMF (50X 10mL), washing with DCM (50X 10mL), adding HFIP (20% in DCM) (913.89mg,5.08mmol, 40.00mL) to the resin, shaking for a while, filtering, adding HFIP (20% DCM in) (913.89mg,5.08mmol, 40.00mL) to the resin, shaking, combining filtrates, concentrating to obtain cyclohexyl-D-glycine (870.00mg,5.08 mmol, 100.00% yield), adding 500mg (2.92mmol), adding water (1.00 mmol, 618.98 mg, 1-20 mL) and THF (1mL), 5.84mmol) and Boc2O (954.84mg,4.38mmol), stirring at room temperature overnight, removing most of the organic solvent under reduced pressure, adjusting pH to 4 with 6N HCl, extracting with ethyl acetate (3X 10ml), combining the organic phases, concentrating under reduced pressure to obtain crude intermediate 15 (0.78 g), MS M/z:272[ M +1] M +1]⁺。

EXAMPLE 16 preparation of intermediate 16

Referring to example 7, the intermediate 7 was prepared by condensing cyclohexylformaldehyde as a starting material with ethyl nitroacetate, reacting with sodium methoxide,Then, four single chiral isomers 16-a,16-b,16-c and 16-d of the intermediate 16 can be respectively obtained by nitro reduction, amino protection by Boc, hydrolysis and separation by an SFC chiral resolution column. MS M/z 302[ M +1]]⁺。

EXAMPLE 17 preparation of intermediate 17

Referring to the method for preparing the intermediate 7 in example 7, the intermediate 2-1 reacts with 4-methylpyrazole in a potassium carbonate-DMF system, and then the four single chiral isomers 17-a,17-b,17-c and 17-d of the intermediate 17 can be obtained respectively by reduction with nitro zinc powder, amino protection with Boc, hydrolysis and separation with an SFC chiral separation column. MS M/z 324[ M-55]]⁺。

EXAMPLE 18 preparation of intermediate 18

Step 1 preparation of intermediate 18-1

4-pyrazole boronic acid pinacol ester (5g,25.8mmol) and cesium carbonate (16.9g, 51.5 mmol) were added to a three-necked flask with DMF (100mL) under ice bath and nitrogen blanket, methyl iodide (5.68g, 40mmol) was added, and the temperature was raised to room temperature. Stirring at room temperature for 8 hr, filtering, distilling under reduced pressure to remove most solvent, extracting with water and ethyl acetate, extracting the water phase with ethyl acetate twice, mixing the organic phases, distilling under reduced pressure to remove solvent to obtain crude intermediate 18-1 (4.85g, 23.3mmol, yield 90%), MS M/z 209[ M + 1% ]]⁺。

Step 2 preparation of intermediate 18

Under nitrogen protection, intermediates 1-4(710mg,1.63mmol), intermediate 18-1(509.69mg,2.45 mmol), Pd (PPh3)4(94.31mg,81.66umol) and Na2CO3 (519.33) of example 1mg,4.90mmol) was suspended in a mixed solvent of 1, 4-dioxane (3mL) and H2O (0.3mL) and degassed by ultrasound for 15min, the reaction solution was heated to 80 ℃ for overnight reaction, concentrated to dryness under reduced pressure, and the residue was isolated and purified by silica gel column to give the coupled product (0.45g,1.03mmol, 63.21% yield), MS M/z:435[ M + 1: (M): 435)]⁺. The coupling product is hydrolyzed by alkali and separated by SFC chiral separation column to obtain four single chiral isomers 18-a,18-b,18-c,18-d of the intermediate 18, MS M/z:422 [ M + 1%]⁺。

EXAMPLE 19 preparation of intermediate 19

Step 1 preparation of intermediate 19-1

4-Pyrazoleboronic acid pinacol ester (5g,25.8mmol) and cesium carbonate (16.9g, 51.5 mmol) were added to DMF (100mL) under ice bath and nitrogen blanket, 2-iodopropane (6.1g, 36mmol) was added, and the temperature was raised to room temperature. Stirring at room temperature for 8 hr, filtering, evaporating most of the solvent under reduced pressure, extracting with water and ethyl acetate, extracting the aqueous phase twice with ethyl acetate, combining the organic phases, and evaporating the solvent under reduced pressure to obtain crude intermediate 19-1 (5.5g, 23.3mmol, yield 90%). MS M/z 237[ M +1]]⁺。

Step 2 preparation of intermediate 19

Referring to the method of step 2 of example 18, intermediates 1-4 and 19-1 were coupled, then hydrolyzed with base, and finally separated by SFC chiral separation column to prepare four single chiral isomers 19-a,19-b,19-c,19-d of intermediate 19, respectively. MS M/z 450[ M +1]]⁺。

EXAMPLE 20 preparation of intermediate 20

Referring to example 18, step 1, an N-substitution reaction of 4-pyrazoleboronic acid pinacol ester with N-Boc-4-iodopiperidine gave intermediate 20, MS M/z:378[ M +1]]⁺。

EXAMPLE 21 preparation of intermediate 21

Referring to the method of step 2 of example 18, the intermediates 1 to 4 were coupled with 2-methoxypyridine-4-valerylboronic acid, then hydrolyzed with base, and finally separated by SFC chiral separation column to obtain the intermediate 21, which is four single chiral isomers 21-a,21-b, 21-c,21-d, respectively. MS M/z 449[ M +1]]⁺。

EXAMPLE 22 preparation of intermediate 22

According to the preparation method of the example 1, 2-chloro-4-bromobenzaldehyde is used as a starting material, condensed with ethyl nitroacetate, subjected to Grignard reaction of cyclopropyl magnesium bromide, subjected to nitro reduction and amino Boc protection, coupled with the intermediate 19-1 according to the coupling method of the example 19, then subjected to alkaline hydrolysis, and finally separated by an SFC chiral separation column to prepare the intermediate 22, namely four single chiral isomers 22-a,22-b,22-c and 22-d. MS M/z 448[ M +1]]⁺。

EXAMPLE 23 preparation of intermediate 23

Step 1 preparation of intermediate 23-1

Ethyl p-nitrophenylacetate (156g,745.71mmol) in dry DMF (700mL) at 0 ℃ under nitrogenAdding Cs2CO3(290.82g,894.85mmol), heating to room temperature and stirring for 1 hour, then cooling to 0 ℃ and slowly dropwise adding methyl iodide (116.43g,820.28mmol), reacting overnight, filtering, diluting the filtrate with 2L ethyl acetate, washing with saturated saline (3X 1.5L), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain intermediate 23-1(165g,739.16mmol, 99.12% yield), MS M/z:224[ M +1]]⁺The crude product was used directly in the next step.

Step 2 preparation of intermediate 23-2

Dissolving intermediate 23-1(2.30g,10.30mmol) in EtOH (20mL), replacing with nitrogen, adding 10% Pd/C (0.5g), stirring under hydrogen atmosphere at normal pressure for reaction overnight, filtering with diatomaceous earth after the raw material disappears, washing with ethanol, concentrating the filtrate under reduced pressure to dryness, separating and purifying with silica gel column to obtain intermediate 23-2(1.30g,6.73mmol, 65.31% yield), MS M/z: 194[ M +1]]⁺。

Step 3 preparation of intermediate 23-3

Dissolving intermediate 23-2(2.70g,13.97mmol) in acetic anhydride (10mL), cooling to 0 deg.C, stirring for 15min, slowly adding HNO3(1.76g,27.94mmol, 68% mass fraction) dropwise, stirring for 30min, removing raw material, pouring the reaction solution into ice water, extracting with ethyl acetate (2X 30mL), mixing organic phases, washing with saturated sodium carbonate, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness to obtain intermediate 23-3 crude product (3.45g,12.32mmol, 88% yield), and MS M/z 281[ M + 1mmol)]⁺。

Step 4 preparation of intermediate 23-4

Intermediate 23-3(3.45g,12.32mmol) was dissolved in 20ml ethanol and SOCl was added₂(4.40g,36.96mmol, 2.68mL), heating to 50 deg.C and stirring for 1 hr, LC-MS shows disappearance of raw material, concentrating the reaction solution under reduced pressure to dryness, adding CH₂Cl₂(150mL) and H₂O (150mL), with saturated NaHCO₃Adjusting the pH value to 8, and passing the water phase through CH₂Cl₂(2X 150mL), the combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude intermediate 23-4(2.89g,12.07mmol, 98% yield), MS M/z:239[ M +1]]⁺The product was used directly in the next reaction without purification.

Step 5 preparation of intermediate 23

Dissolving intermediate 23-4(2.89g,12.07mmol) in 10ml ethanol, adding Pd/C (0.5g) under nitrogen atmosphere, hydrogenating at normal pressure overnight, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reverse phase column to obtain intermediate 23(2.13g,10.26mmol, 85% yield), MS M/z:209[ M + 1%]⁺.

EXAMPLE 24 preparation of intermediate 24

Referring to the method of example 23, steps 1 to 5, p-nitroacetoacetate was used as a raw material, and benzylation, p-nitro reduction, M-nitration and simultaneous p-amino acetylation were performed with iodoethane under the catalysis of DMF-cesium carbonate, followed by deacetylation and hydrogenation reduction to obtain intermediate 24, MS M/z:223[ M +1]⁺.

EXAMPLE 25 preparation of intermediate 25

The method according to steps 1 to 5 of example 23 was repeated toEthyl nitrophenylacetate as raw material is alkylated with 2-bromopropane in benzyl position under the catalysis of DMF-potassium carbonate, reduced in para-nitro group, nitrified in meta position and acetylated in para-amino group, deacetylated and hydrogenated to obtain intermediate 25, MS M/z is 237[ M +1]]⁺.

EXAMPLE 26 preparation of intermediate 26

Step 1 preparation of intermediate 26-1

Adding Cs2CO3(2.73kg,8.37mol) into a dry DMF (2L) solution of ethyl p-nitrophenylacetate (350g,1.67mol L) under the protection of nitrogen at 0 ℃, raising the temperature to room temperature and stirring for 1 hour, then slowly dropwise adding methyl iodide (1.19kg, 8.37mol), reacting at room temperature overnight after dropwise adding, filtering, diluting the filtrate with 10L ethyl acetate, washing with saturated saline (3X 10L), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain an intermediate 26-1(320g,1.24mol, 74.17% yield), MS M/z:238[ M +1], and]⁺the crude product was used directly in the next step.

Step 2-5 preparation of intermediate 26

Referring to the method of example 23, steps 2 to 5, the intermediate 26-1 of step 1 was subjected to reduction of para-nitro group, meta-nitration and simultaneous acetylation of para-amino group, followed by deacetylation and hydrogenation reduction to obtain intermediate 26, MS M/z:223[ M +1]]⁺.

EXAMPLE 27 preparation of intermediate 27

Referring to the method of example 23, ethyl 2-F-4-nitrophenylacetate as starting material is benzyldouble methylated with iodomethane under the catalysis of DMF-cesium carbonate to obtain para-nitro nitrateReducing, nitrifying in meta position while acetylating in para-amino group, deacetylating, and hydrogenating to obtain intermediate 27, MS M/z 241M +1]⁺.

EXAMPLE 28 preparation of intermediate 28

Referring to the method of example 23, using ethyl 2-fluoro-4-nitrophenylacetate as the starting material, benzyl double methylation with methyl iodide under the catalysis of DMF-cesium carbonate, para nitro reduction, meta (3-position) nitration and simultaneous para amino acetylation, deacetylation, hydrogenation reduction to obtain intermediate 28, MS M/z:241[ M +1]]⁺.

EXAMPLE 29 preparation of intermediate 29

Referring to the method of example 23, using ethyl 2-fluoro-4-nitro-5-bromobenzoate as starting material, the intermediate 29, MS M/z 241[ M + 1: 241, was obtained by benzylation with iodomethane under the catalysis of DMF-cesium carbonate, 4-nitro reduction, M (3) nitration with simultaneous acetylation of the para-amino group, deacetylation, hydrogenation reduction and simultaneous elimination of the 5-bromo group]⁺.

EXAMPLE 30 preparation of intermediate 30

Step 1 preparation of intermediate 30-1

P-isopropylaniline (15.6g,115.38mmol) was dissolved in acetic anhydride (100mL), cooled to 0 deg.C and stirred for 15min, and HNO was slowly added dropwise₃(21.81g,346.14mmol, 68% mass fraction), stirring for 12 hr, removing raw materials, pouring the reaction solution into ice water, extracting with ethyl acetate (2 × 300mL), mixing organic phases, washing with saturated sodium carbonate, and adding anhydrous sodium sulfateDrying, filtering, and concentrating under reduced pressure to dryness to obtain crude intermediate 30-1 (16g,64.79mmol, 56.16% yield), MS M/z:223[ M +1]]⁺。

Step 2 preparation of intermediate 30-2

Dissolving intermediate 30-1(15g,67.49mmol) in ethanol (150mL), adding NaOH (4.05g,101.24 mmol), heating to 80 ℃ for reaction for 2 hours, LC-MS shows that the raw materials have reacted, pouring the reaction solution into water, DCM (100mL x 3) extracting, combining organic phases, washing the organic phases with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness to obtain crude intermediate 30-2 (10g,49.94mmol, 74.00% yield), directly using in the next step, MS M/z:181[ M +1]]⁺。

Step 3 preparation of intermediate 30

Referring to step 23, the nitro reduction method, intermediate 30-2 is reduced by Pd/C hydrogenation, and then purified by MPLC reverse phase to obtain intermediate 30, MS M/z 151[ M +1]]⁺。

EXAMPLE 31 preparation of intermediate 31

Referring to the method of example 23, step 1-5, ethyl p-nitroacetoacetate as a raw material was subjected to benzylation with 1, 2-dibromoethane under DMF-Na hydrogen, reduction of p-nitro group, M-nitration with simultaneous acetylation of p-amino group, deacetylation, and hydrogenation reduction to obtain intermediate 31, MS M/z is 221[ M +1]]⁺.

EXAMPLE 32 preparation of intermediate 32

Referring to the method of example 23, steps 1-5, ethyl p-nitroacetoacetate as a raw material was subjected to benzylcyclobutylation, p-nitro reduction, M-nitration with simultaneous acetylation of p-amino groups, deacetylation, and hydrogenation reduction with 1, 3-diiodopropane under the catalysis of DMF-cesium carbonate to obtain intermediate 32, MS M/z:235[ M +1]]⁺.

EXAMPLE 33 preparation of intermediate 33

Referring to the method of example 23, steps 1-5, ethyl p-nitroacetoacetate as a raw material was subjected to benzyl-position introduction of cyclopentyl with bromocyclopentane under the catalysis of DMF-cesium carbonate, reduction of p-nitro group, M-position nitration and simultaneous acetylation of p-amino group, followed by deacetylation and hydrogenation reduction to obtain intermediate 33, MS M/z:263[ M +1]⁺.

EXAMPLE 34 preparation of intermediate 34

Step 1 preparation of intermediate 34-1

Adding 2-nitro-4-bromoaniline (5.00g,23.04mmol), ethyl acrylate (4.61g,46.08mmol) and DIPEA (8.94g,23.04mmol,12.50mL) into 100mL acetonitrile in sequence, ultrasonically degassing for 5min under nitrogen bubbling, then adding Pd (PPh3)4(2.60g,23.04mmol), heating to 90 ℃ under nitrogen protection for reaction overnight, cooling to room temperature after reaction, adding water for dilution, extracting with ethyl acetate (3x200mL), combining organic phases, drying and filtering with anhydrous sodium sulfate, concentrating the filtrate to dryness, separating and purifying the crude product by silica gel column chromatography to obtain intermediate 34-1(2.20g,9.31mmol, 40.42% yield), MS M/z:237[ M + 1[ (+ 1)]⁺.

Step 2 preparation of intermediate 34-2

Dissolving intermediate 34-1(3.20g,13.55mmol) in 30ml ethanol, adding Pd/C (0.2g) under nitrogen atmosphere, hydrogenating overnight at normal pressure, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reverse phase column to obtain intermediate 34-2(1.76g,8.53mmol, 62.95% yield), MS M/z:207[ M +1]]⁺.

Step 3 preparation of intermediate 34

Dissolving intermediate 34-2(640.00mg,3.10mmol) in 30ml methanol, adding PtO2 (60.00mg) under nitrogen atmosphere, hydrogenating overnight at normal pressure, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reversed phase column to obtain intermediate 34(620.00mg,2.98mmol, 96.13% yield), MS M/z:209[ M +1]]⁺.

EXAMPLE 35 preparation of intermediate 35

Referring to the procedure of step 2 of example 18, after coupling 2-nitro-4-bromoaniline with 3, 5-dimethylpyrazole-4-boronic acid pinacol ester, intermediate 35, MS M/z:203[ M +1] M/z, was obtained by the carbon reduction method of nitropalladium in example 23]⁺.

EXAMPLE 36 preparation of intermediate 36

Referring to the procedure of step 2 of example 18, after coupling 2-nitro-4-bromoaniline with 3, 5-dimethylisoxazole-4-boronic acid pinacol ester, intermediate 36, MS M/z: 204[ M +1] M/z, was obtained by the nitro palladium on carbon reduction method of example 23]⁺.

EXAMPLE 37 preparation of intermediate 37

Step 1 preparation of intermediate 37-1

Adding 3, 5-dimethylisoxazole-4-boronic acid pinacol ester (1g,4.50mmol), 1-bromo-2-methoxyethane (688.41mg, 4.95mmol) and cesium carbonate (2.93g,9.01mmol) into 10mL of DMF, stirring at room temperature for reaction for 24 hours, adding 100mL of water, extracting with ethyl acetate (100mL of 3), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying a crude product by a silica gel column (petroleum ether/ethyl acetate 3: 1-1: 1) to obtain a yellowish green intermediate 37-1, (1.12g,4.0mmol, 89% yield), MS M/z 281[ M + 1: [ M +1]]⁺.

Step 2 preparation of intermediate 37

Referring to the procedure of step 2 of example 18, after coupling 2-nitro-4-bromoaniline with pinacol borate 37-1, intermediate 37, MS M/z:261[ M +1] was obtained by the nitro-palladium on carbon reduction method of example 23]⁺.

EXAMPLE 38 preparation of intermediate 38

Step 1 preparation of intermediate 38-1

4-Bromophenylenediamine (5.00g,26.73mmol), pinacol diboron (20.37g,80.20mmol) and KOAc (10.48g,106.93mmol) were added successively to 100ml dioxane, ultrasonic degassing was conducted under nitrogen bubbling for 5min, and Pd (dppf) Cl was subsequently added₂(586.25mg,801.98umol), heating to 100 ℃ under the protection of nitrogen, reacting for 20 hours, cooling to room temperature after the reaction is finished, filtering through a short silica gel column, concentrating the filtrate under reduced pressure, and separating and purifying the crude product through silica gel column chromatography(Petroleum Ether/Ethyl acetate 2: 1) to intermediate 38-1(86mg,367.36umol, 6.87% yield), MS M/z:235[ M +1]]⁺.

Step 2 preparation of intermediate 38-2

Dissolving methyl 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) acetate (660mg,2,83mmol) in 15ml of 7M ammonia water-ethanol solution, stirring at room temperature for 20 hours, and concentrating under reduced pressure to dryness to obtain an intermediate 38-2(574mg,2,63 mmol, 93% yield), MS M/z 232[ M +1]]⁺.

Step 3 preparation of intermediate 38

With reference to the procedure of step 2 of example 18, coupling of pinacol boronic acid ester 38-1 from step 1 with 38-2 from step 2 gave intermediate 38, MS M/z:246[ M +1]]⁺.

EXAMPLE 39 preparation of intermediate 39

Intermediate 39 was obtained by coupling pinacol borate ester 38-1 obtained in step 1 of example 38 with 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) ethylamine by the method described in step 2 of example 18, MS M/z:218[ M +1]⁺.

EXAMPLE 40 preparation of intermediate 40

Step 1 preparation of intermediate 40-1

O-methanesulfonic acid ethyl lactate (1.24g,6.30mmol) and cesium carbonate (3.08g,9.46mmol) were added to 3, 5-dimethylpyrazole-4-boronic acid pinacol at room temperatureAlcohol ester (0.7g,3.15mmol) in 10ml acetonitrile, reaction at 60 deg.C for 10 hours, vacuum concentration, water and ethyl acetate extraction, organic phase concentration, silica gel column chromatography separation purification (petroleum ether/methyl tert-butyl ether 1:1) to obtain intermediate 40-1(700mg,2.17mmol, 68.93% yield), MS M/z: 323[ M +1]⁺.

Step 2 preparation of intermediate 40-2

Intermediate 40-1(0.7g,2.17mmol) was dissolved in THF/EtOH/H2O ═ 4/1/1(10mL), LiOH monohydrate (260.16mg,10.86mmol) was added, stirred at room temperature for 3 hours, adjusted to pH 5 with 1N HCl, extracted with ethyl acetate, and the organic phase was concentrated to give crude intermediate 40-2 (500mg,1.70mmol, 78.24% yield) which was used in the next step without purification, MS M/z:295[ M + 1: []⁺.

Step 3 preparation of intermediate 40-3

Dissolving intermediate 40-2(0.5g,1.70mmol) in 10ml DCM, adding HBTU (647.29 mg,2.55mmol), DIEA (1.10g,8.50mmol) and methylamine (105.58mg,3.40mmol) at room temperature, stirring the reaction solution at 50 deg.C for 10 hr, concentrating under reduced pressure, extracting with water and ethyl acetate, drying the organic phase, concentrating under reduced pressure, separating and purifying with silica gel column chromatography (DCM/MeOH: 20/1) to obtain intermediate 40-3(80mg,260.42umol, 15.32% yield), MS M/z 308[ M +1 mmol: [ M + 308 ]]⁺.

Step 4 preparation of intermediate 40

Referring to the method of step 2 of example 18, after coupling 2-nitro-4-bromoaniline with pinacol borate 40-3, the intermediate was obtained by the nitro palladium on carbon reduction method of example 23Intermediate 40, MS M/z 288[ M +1]]⁺.

EXAMPLE 41 preparation of Compound 41

Step 1 preparation of intermediate 41-1

Referring to the method of step 1 to 5 of example 23, intermediate 41-1, MS M/z 195[ M +1] M +1, was obtained by reducing ethyl p-nitroacetoacetate as a raw material by p-nitro reduction, M-nitration and simultaneous acetylation of p-amino group, followed by deacetylation and hydrogenation reduction]⁺.

Step 2 preparation of intermediate 41-2

Dissolving 1-ethyl-1H-pyrazole-5-carboxylic acid (1.40g,9.99 mmol) in 5mL DMF, sequentially adding HOAt (2.27g,9.99mmol), DIPEA (1.29g,9.99mmol,1.74mL) and EDCI (2.23g,9.99mmol) at 0 deg.C, after 5min, adding (S) - (-) -cyclohexylalanine methyl ester (2.22g,11.99mmol), stirring at room temperature for 2 hr, after reaction, adding water and ethyl acetate, extracting, washing organic phase with saturated ammonium chloride, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, purifying crude product by silica gel column chromatography to obtain intermediate 41-2(1.70g,5.53mmol, 55.36% yield), MS M/z 308[ M + 1: (M/z) ] [ M + 1(M + 1/z) ], wherein]⁺.

Step 3 preparation of intermediate 41-3

Adding the intermediate 41-2(1.40g,4.55mmol) and LiOH (218.16mg,9.11mmol) into 10ml of THF-water (1:1), stirring at room temperature for 4 hours, concentrating under reduced pressure, adjusting pH to 4 with 1N HCl, extracting with DCM (2X 20ml), combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain intermediate 41-3(700.00mg,2.39 mmol, 52.44% yield), and directly using the crude product without purificationNext reaction, MS M/z 294[ M +1]]⁺.

Step 4 preparation of intermediate 41-4 mixture of structural isomers

Dissolving the intermediate 41-3(280.92mg,957.60umol) and HATU (1.31g,3.46mmol) in 5mL DCM under ice bath, stirring for a while, sequentially adding diamine 41-1(194mg,1.0mmol) and DIPEA (1.03g,7.98 mmol), reacting at room temperature for 3 hours, adding water for quenching, removing most of the organic solvent under reduced pressure, extracting with ethyl acetate (20mL, 3), combining the organic phases, respectively washing with saturated common salt water, drying with anhydrous sodium sulfate, spin-drying under reduced pressure, and purifying and separating the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 1:1) to obtain a structural isomer mixture (992.00mg,2.11mmol, 79.22% yield), MS M/z:470(M +1) of the intermediate 41-4⁺And the two were not separated and used for the next step.

Step 5 preparation of intermediates 41-5

The intermediate 41-4 mixture obtained in step 4 (992.00mg,2.11mmol) was added to AcOH (10mL) and reacted at 55 ℃ for 12h, concentrated under reduced pressure and dried, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 1:1) to give intermediate 41-5(800mg,1.82mmol, 86.3% yield), MS m/z: 452(M +1)⁺。

Step 6 preparation of intermediates 41-6

Intermediate 41-5(800mg,1.82mmol) was dissolved in 10mL THF-H2O (1:1), LiOH (438mg, 18.3mmol) was added, stirred at room temperature for 3 hours, adjusted to pH 5 with 1N HCl, extracted with ethyl acetate, and the organic phase was concentrated to give crude intermediate 41-6 (500mg,1.18mmol, 64.5% yield), which was used without purification directly in the reaction mixtureNext, MS M/z 424[ M +1]]⁺.

Step 7 intermediate 41 preparation

Under ice bath, the crude product of intermediate 41-6 (500mg,1.18mmol), HOAt (293.42mg,2.16mmol) and EDCI (412.08mg,2.16mmol) in 10mL DCM mixture are stirred for a while, methylamine hydrochloride (239mg,3.54mmol) and DIPEA (697.08mg,5.39mmol,939.46uL) are added in turn, the mixture is cooled to room temperature for 3 hours, water is added for quenching, most of the organic solvent is removed under reduced pressure, ethyl acetate (20mL x 3) is extracted, the organic phases are combined, then saturated ammonium chloride and saturated common salt are respectively washed with water, anhydrous sodium sulfate is dried, the mixture is dried under reduced pressure, and the crude product is purified and separated by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain compound 41(0.44g,0.1mmol, 85% yield), MS M/z:437(M +1)

EXAMPLE 42 preparation of Compound 42

Step 1 preparation of intermediate 42-1

Referring to step 7 of example 41, intermediate 41-6 was condensed with D-leucine tert-butyl ester hydrochloride to give intermediate 42-1, MS M/z:593(M +1)⁺.

Step 2 preparation of Compound 42

Dissolving intermediate 42-1(600mg,1.01mmol) in 4mL dichloromethane, adding 4mL trifluoroacetic acid under ice bath, stirring for 3 hours under ice bath, reacting, concentrating under reduced pressure, purifying the crude product with MPLC reversed phase C18 column to obtain compound 42(26.85mg,47.03umol, 4.66% yield), MS M/z:537(M +1)⁺.

EXAMPLE 43 preparation of Compound 43

Referring to step 7 of example 41, intermediate 41-6 was condensed with isoamylamine to give compound 43, MS M/z:493(M +1)⁺.

EXAMPLE 44 preparation of Compound 44

Referring to steps 2-7 of example 41, compound 44 was obtained by condensation of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid with (S) - (-) -cyclohexylalanine methyl ester, hydrolysis of methyl ester, condensation with o-phenylenediamine, closing of imidazole ring, hydrolysis of ethyl ester, and condensation with amine, MS M/z:451[ M +1]]⁺。

EXAMPLE 45 preparation of Compound 45

Referring to steps 4-7 of example 41, a compound 45 was obtained by condensing an intermediate 41-3 with an o-phenylenediamine 30 as an intermediate in example 30 and closing the imidazole ring in the order mentioned above, MS M/z:408[ M +1]]⁺。

EXAMPLE 46 preparation of Compound 46

Referring to steps 4-7 of example 41, a compound 46, MS M/z:451[ M +1] M +1, was obtained by condensing the intermediate 41-3 with the intermediate o-phenylenediamine 23 of example 23, closing the imidazole ring, hydrolyzing the ethyl ester, and finally condensing with methylamine]⁺.

EXAMPLE 47 preparation of Compound 47

Referring to steps 4-7 of example 41, intermediate 41-3 was condensed with o-phenylenediamine 24, the intermediate of example 24, imidazole ring was closed, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 47, MS M/z:465[ M + 1: step 4: 4-4: 7: 4: 7]⁺.

EXAMPLE 48 preparation of Compound 48

Referring to steps 4-7 of example 41, intermediate 41-3 was condensed with o-phenylenediamine 25, an imidazole ring was closed, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 48, MS M/z:479[ M +1]]⁺.

EXAMPLE 49 preparation of Compound 49

Referring to steps 4-7 of example 41, a compound 49, MS M/z 505[ M +1] was obtained by condensation of an intermediate 41-3 with o-phenylenediamine 33, which is an intermediate in example 33, closing imidazole ring, hydrolyzing ethyl ester, and finally condensing with methylamine]⁺.

EXAMPLE 50 preparation of Compound 50

Referring to steps 4-7 of example 41, a compound 50, MS M/z:463[ M +1] M +1 was obtained by condensing the intermediate 41-3 with the intermediate o-phenylenediamine 31 of example 31, closing the imidazole ring, hydrolyzing the ethyl ester, and finally condensing with methylamine]⁺.

EXAMPLE 51 preparation of Compound 51

Referring to steps 4-7 of example 41, intermediate 41-3 was condensed with o-phenylenediamine 32, an imidazole ring was closed, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 51, MS M/z:477[ M +1] in sequence]⁺.

EXAMPLE 52 preparation of Compound 52

Referring to steps 4-7 of example 41, intermediate 41-3 was condensed with o-phenylenediamine 26, an imidazole ring was closed, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 52, MS M/z:465[ M + 1: (M +1) ]]⁺.

EXAMPLE 53 preparation of Compound 53

Referring to steps 4-7 of example 41, intermediate 41-3 was condensed with intermediate 2-bromo-4, 5-o-phenylenediamine ethyl acetate (obtained from ethyl 2-bromo-4-nitrophenylacetate according to the method of example 23, steps 2-5), imidazole ring was closed, ethyl ester was hydrolyzed, and finally, condensation with methylamine was performed to obtain compound 53, MS M/z:515[ M + 1: [ M +1]]⁺.

EXAMPLE 54 preparation of Compound 54

Example 53 Compound 53(89mg,0.173mmol), 2-Phenylvinylboronic acid (33.5mg,0.227 mmol), K₂CO₃(71.6mg,0.519mmol) was added successively to a mixed solution of 1, 4-dioxane (2ml) and water (0.3ml), sonicated under nitrogen bubbling for 10min, followed by addition of Pd (dppf) Cl₂(25mg,35.00umol), stirring overnight at 80 ℃, cooling to room temperature after the reaction is finished, adding water for dilution, extracting with ethyl acetate, washing an organic phase with water, washing with saturated sodium chloride, and using anhydrous sulfuric acidDrying sodium, filtering, concentrating the filtrate under reduced pressure to dryness, separating and purifying the crude product by silica gel column chromatography to obtain intermediate compound 54(20.7mg,38.4umol, 22.21% yield), MS M/z:539[ M +1]]⁺.

EXAMPLE 55 preparation of Compound 55

Dissolving compound 54(10.00mg,0.019mmol) in 5ml methanol, adding 10% Pd/C (3.00 mg) under nitrogen atmosphere, hydrogenating overnight at normal pressure, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reversed phase column to obtain compound 55(9.85mg,0.018mmol, 96% yield), MS M/z:541[ M +1]]⁺.

EXAMPLE 56 preparation of Compound 56

Step 1 intermediate 56-1 preparation

Dissolving 4-pyrazole ethyl formate (1.00g,7.14mmol) in 20ml of anhydrous THF under ice bath, adding NaH (430.00mg,17.92mmol) in batches, stirring for 1 hour under the protection of nitrogen, then adding bromoethyl methyl ether (1.20g,8.64 mmol), allowing the reaction to naturally rise to room temperature, after 2 hours, adjusting the pH to 5 with 1N HCl after the reaction is finished, extracting with ethyl acetate, washing with saturated saline, drying with organic phase anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain an intermediate 56-1(1.20g,6.05mmol, 84.79% yield), MS M/z:199[ M +1]]⁺.

Step 2 preparation of intermediate 56-2

Referring to step 6 of example 41, intermediate 56-2, MS M/z:171[ M +1], was obtained by hydrolyzing intermediate 56-1 with lithium hydroxide]⁺.

Step 3 preparation of Compound 56

Referring to steps 2-7 of example 41, similarly, (S) - (-) -cyclohexylalanine methyl ester was condensed with intermediate 56-2, methyl ester was hydrolyzed, condensed with intermediate 26, imidazole ring was closed, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 56, MS M/z:495[ M +1)]⁺.

EXAMPLE 57 preparation of Compound 57

Step 1 preparation of intermediate 57-1 structural isomer mixture

By condensing intermediate 15 with intermediate 26 according to the method of step 4 of example 41, intermediate 57-1 (mixture of structural isomers), MS M/z:476(M +1)⁺And the two were not separated and used for the next step.

Step 2 preparation of intermediate 57-2

Referring to the procedure of example 41, step 5, heating intermediate 57-1 (mixture of structural isomers) in acetic acid to imidazole ring gave intermediate 57-2, MS M/z:458(M +1)⁺。

Step 3 preparation of intermediate 57-3

Dissolving intermediate 57-2(1.2g,2.62mmol) in 5mL dichloromethane, adding 5mL trifluoroacetic acid under ice bath, stirring for 3 hr under ice bath, reacting, concentrating under reduced pressure, and purifying the crude product with MPLC reversed phase C18 column to obtain compound 42(800mg,2.24mol, 85%yield)，MS m/z:358(M+1)⁺.

Step 4 preparation of intermediate 57-4

Referring to the procedure of example 41, step 2, intermediate 57-4, MS M/z:466(M +1) was obtained by condensing intermediate 57-3 with 1-methyl-1H-pyrazole-5-carboxylic acid⁺。

Step 5 preparation of intermediate 57-5

Referring to the procedure of step 6 of example 41, intermediate 57-5, MS M/z: 438(M +1) was obtained from intermediate 57-4 by hydrolysis with LiOH⁺。

Step 6 preparation of Compound 57

Referring to the procedure of example 41, step 7, condensation of intermediate 57-5 with (2R) -2-amino-N, N-dimethyl-propionamide gave compound 57, MS M/z:536(M +1)⁺The amount of, white solid,¹H NMR(400MHz,DMSO-d₆)δ7.70– 7.57(m,2H),7.51(d,J＝2.1Hz,1H),7.35(d,J＝8.5Hz,1H),7.04(d,J＝2.1Hz,1H),5.44 (dd,J＝8.8,6.7Hz,1H),4.66(q,J＝6.8Hz,1H),4.03(s,3H),2.95(s,3H),2.78(s,3H),2.00 (t,J＝7.1Hz,2H),1.84–1.56(m,6H),1.52(s,6H),1.32–1.21(m,2H),1.20–0.92(m,9H).

EXAMPLE 58 preparation of Compound 58

With reference to example 57, condensation of 57-5 with (2R) -2-amino-N-methyl-propionamide affords compound 58, MS M/z 522(M +1)⁺White, whiteA colored solid, which is a solid,¹H NMR(400MHz,DMSO-d₆)δ7.70–7.60(m,2H),7.52 (d,J＝2.1Hz,1H),7.40(d,J＝8.8Hz,1H),7.05(d,J＝2.1Hz,1H),5.45(dd,J＝9.5,5.9Hz, 1H),4.23(q,J＝7.1Hz,1H),4.03(s,3H),2.07–1.96(m,2H),1.84–1.72(m,2H),1.66(s, 2H),1.61(s,1H),1.53(s,6H),1.35–1.23(m,1H),1.16(dd,J＝19.5,9.0Hz,6H),1.02 (dt,J＝17.4,7.8Hz,3H).

EXAMPLE 59 preparation of Compound 59

By condensing 57-5 with (2R) -2-amino-propionamide, according to the method of example 57, compound 59, MS M/z:508 (M +1)⁺The amount of, white solid,¹H NMR(400MHz,DMSO-d₆)δ7.57(d,J＝8.1Hz,2H),7.48(d,J＝ 2.0Hz,1H),7.37–7.16(m,1H),7.05(t,J＝6.7Hz,1H),5.51–5.34(m,1H),4.20(d,J＝7.1 Hz,1H),4.02(s,3H),1.97(t,J＝7.0Hz,2H),1.75(t,J＝14.3Hz,2H),1.64(s,2H),1.53 (t,J＝16.2Hz,6H),1.37(s,1H),1.31–1.22(m,3H),1.22–0.89(m,7H).

EXAMPLE 60 preparation of Compound 60

Referring to step 4-7 of example 41, compound 60 was obtained by condensing intermediate 41-3 with intermediate 34 of example 34, closing imidazole ring, hydrolyzing ethyl ester, condensing with D-leucine tert-butyl ester hydrochloride, and finally hydrolyzing tert-butyl ester with trifluoroacetic acid in this order, MS M/z:551[ M +1]]⁺.

EXAMPLE 61 preparation of Compound 61

Referring to step 4-7 of example 41, the intermediate 41-3 was condensed with o-phenylenediamine 26, an imidazole ring was closed, ethyl ester was hydrolyzed, and D-leucine was added in that order to obtain a mixtureCondensation of tert-butyl ester hydrochloride of amino acid, and final hydrolysis of tert-butyl ester with trifluoroacetic acid to obtain compound 61 with MS M/z of 565M +1]⁺.¹H NMR(400MHz,DMSO-d₆)δ9.11(d,J＝7.2Hz,1H), 7.57～7.63(m,2H),7.54(d,J＝2.4Hz,1H),7.41(d,J＝8Hz,1H),7.33(d,J＝8Hz,),7.03(dd, J1＝1.6Hz,J2＝2Hz,1H),5.45(dd,J¹＝7.6Hz,J²＝14.8Hz,1H),4.39～4.54(m,2H),4.23～4.28(m, 1H),1.99(t,J＝7.2Hz,2H),1.72～1.84(m,2H),1.65～1.71(m,2H),1.57～1.62(m,2H),1.52(d, J＝2.8Hz,6H),1.34～1.46(m,3H),1.28(t,J＝6.8Hz,3H),1.11～1.21(m,3H),0.92～1.06(m,2H), 0.78(t,J＝5.6Hz,6H).

EXAMPLE 62 preparation of Compound 62

First, referring to the procedure of example 38, intermediate 38-1 was coupled with methyl 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) acetate, then referring to the procedure of example 57, step 1-6, the coupled product was condensed with intermediate 15 of example 15, imidazole ring was closed, Boc was removed, 2-methyl-1H-pyrazoloyl group was introduced, ester was hydrolyzed, and finally condensed with cyclopentylamine to obtain compound 62, MS M/z:557[ M +1] of]⁺.

EXAMPLE 63 preparation of Compound 63

First, referring to the procedure of example 38, intermediate 38-1 was coupled with methyl 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) acetate, then referring to the procedure of example 57, steps 1 to 6, the coupled product was condensed with intermediate 15 of example 15, imidazole ring was closed, Boc was removed, 2-methyl-1H-pyrazoloyl group was introduced, ester hydrolysis was performed, and finally condensation with 2-propylamine was carried out to obtain compound 63, MS M/z:531[ M +1] in]⁺.

EXAMPLE 64 preparation of Compound 64

Referring to steps 4-7 of example 41, a compound 64, MS M/z:460[ M +1] was obtained by condensing the intermediate 41-3 with the intermediate o-phenylenediamine 35 of example 35 and closing the imidazole ring]⁺.

EXAMPLE 65 preparation of Compound 65

Step 1 preparation of intermediate 65-1

2-methyl-6, 7-dihydropyrazole [1,5-a ]]Dissolving pyrazine-5 (4H) -benzyloxycarbonyl (110mg,0.405mmol) in 1mL DMF, adding NBS (72mg,0.405mmol), stirring at room temperature for 3 hours, separating and purifying by silica gel column chromatography to obtain bromo intermediate 65-1, MS M/z:350[ M +1]]⁺.

Step 2 preparation of intermediate 65-2

Referring to the method of example 38, intermediate 65-2, MS M/z:378[ M +1] was obtained by coupling pinacol borate 38-1 with bromide 65-1 obtained in step 2 of example 65]⁺.

Step 3 preparation of Compound 65

Referring to steps 1-6 of example 57, compound 65, MS M/z:487[ M +1] M +1, was prepared by condensing intermediate 15 of example 15 with intermediate 65-2 of example 65, closing the imidazole ring, removing Boc, introducing 2-methyl-1H-pyrazoloyl, and removing the Cbz protecting group by hydrogenation]⁺.

EXAMPLE 66 preparation of Compound 66

Dissolving compound 65(20mg,41.10umol) of example in 1ml DCM, adding 1ml dichloromethane solution of cyclopentyl isocyanate (4.57mg, 41.10umol) dropwise, reacting at room temperature for 4 hours after dropwise addition, concentrating, and separating and purifying the crude product by MPLC reversed phase C18 column to obtain compound 66, MS M/z:598[ M + 1[ ]]⁺.

EXAMPLE 67 preparation of Compound 67

Referring to example 57, Steps 1-6, four isomer mixtures of intermediate 14 of example 14 (before resolution) were condensed with intermediate 41-1 of example 41, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazol-5-yl was introduced, ester was hydrolyzed, and finally condensed with methylamine hydrochloride to give compound 67, MS M/z:548[ M + 1-acyl chloride]⁺.

EXAMPLE 68 preparation of Compound 68

Referring to example 57, Steps 1-6, single stereoisomer 14a of intermediate 14 of example 14 was condensed with intermediate 41-1 of example 41, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazole-5-acyl was introduced, ester was hydrolyzed, and finally condensed with methylamine hydrochloride to give compound 68, MS M/z:548[ M +1] M +1]⁺.

EXAMPLE 69 preparation of Compound 69

Referring to example 57, Steps 1-6, single stereoisomer 14d of intermediate 14 of example 14 was condensed with intermediate 41-1 of example 41, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazole-5-acyl was introduced, ester was hydrolyzed, and finally condensed with methylamine hydrochloride to give compound 69, MS M/z:548[ M +1] M +1]⁺.

EXAMPLE 70 preparation of Compound 70

Referring to example 57, Steps 1-6, single stereoisomer 14b of intermediate 14 of example 14 was condensed with intermediate 41-1 of example 41, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazole-5-acyl was introduced, ester was hydrolyzed, and finally condensed with methylamine hydrochloride to give compound 70, MS M/z:548[ M +1] M +1]⁺.

EXAMPLE 71 preparation of Compound 71

Referring to example 57, Steps 1-6, single stereoisomer 14c of intermediate 14 of example 14 was condensed with intermediate 41-1 of example 41, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazole-5-acyl was introduced, ester was hydrolyzed, and finally condensed with methylamine hydrochloride to give compound 71, MS M/z:548[ M +1] M +1]⁺.

EXAMPLE 72 preparation of Compound 72

Referring to example 57, steps 1-6, the four isomer mixture of intermediate 16 of example 16 (before resolution) was condensed with intermediate 26 of example 26, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazol-5-yl was introduced, ethyl ester was hydrolyzed, and finally condensed with (2R) -2-amino-N-methyl-propionamide to give compound 72, MS M/z:552[ M + 1-methyl-propionamide: (M +1) ]]⁺。

EXAMPLE 73 preparation of Compound 73

Step 1 preparation of intermediate 73-1 mixture of structural isomers

Referring to the procedure of example 41, step 4, the condensation of the starting o-chloro-D-Boc-phenylalanine with intermediate 34 gave intermediate 73-1 (mixture of structural isomers), MS M/z:490(M +1)⁺And the two were not separated and used for the next step.

Step 2 preparation of intermediate 73-2

Referring to the procedure of example 41, step 5, heating intermediate 73-2 (mixture of structural isomers) in acetic acid to form imidazole ring gave intermediate 73-2, MS M/z:472(M +1)⁺。

Step 3-6 preparation of Compound 73

Referring to steps 3-6 of example 57, compound 73 was obtained by sequential Boc removal from intermediate 73-2, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, ethyl ester hydrolysis, condensation with D-leucine tert-butyl ester hydrochloride, and finally hydrolysis of tert-butyl ester with trifluoroacetic acid, MS M/z 579[ M + 1: 3-6 in each of example 57, all of which shall be as shown in each of which are intermediate 73: 73-6, 3-6, sequentially via intermediate 73: 73-6, respectively]⁺.

EXAMPLE 74 preparation of Compound 74

Step 1 preparation of intermediate 74-1

Ethyl 2-methyl-2- (4-nitrophenyl) propionate (40.0g, 168.6mmol) was dissolved in ethanol (600mL), and sodium hydroxide (10.1g, 252.9mmol) was added portionwise at room temperature, after which the reaction was stirred at 80 ℃ for 2 hours. The solvent was evaporated under reduced pressure, 1N HCl solution was added dropwise under ice bath to adjust pH to 4, ethyl acetate was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give intermediate 74-1(33.5g, 160.2mmol, 95% yield). MS M/z 210 [ M ]+1]⁺.

Step 2 preparation of intermediate 74-2

Intermediate 74-1(33.5g, 160.2mmol) was dissolved in DMF (500mL), HBTU (72.9 g, 192.2mmol), N, N-diisopropylethylamine (45.5g, 352.4mmol) and ammonium chloride (12.9g, 240.3mmol) were added under ice-bath, and the reaction was stirred at room temperature for 2 hours. Extraction was then carried out with water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give crude intermediate 74-2(29.0g, 139.3mmol, 87% yield). MS M/z 209[ M +1]]⁺.

Step 3 preparation of intermediate 74-3

Intermediate 74-2(29.0g, 139.3mmol) was dissolved in methanol (300mL), palladium on carbon (2.9g, palladium content 10%) was added, the reaction system was replaced three times with hydrogen, and stirred under a hydrogen atmosphere (1atm) for 12 hours. The reaction was filtered through celite and the solvent was evaporated under reduced pressure to give intermediate 74-3(22.4g, 125.4mmol, 90% yield). MS M/z 179[ M +1]]⁺.

Step 4 preparation of intermediate 74-4

Intermediate 74-3(22.4g, 125.4mmol) was dissolved in tetrahydrofuran (300mL), and 1M borane tetrahydrofuran solution (627.0mL, 627.0mmol) was added dropwise under ice bath, and the reaction was stirred at 60 ℃ for 12 hours under nitrogen protection after the addition was complete. Quenching the reaction by adding saturated ammonium chloride solution, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, evaporating off the solvent under reduced pressure, purifying with MPLC (eluent gradient: acetonitrile: water 0:100 to 40:60, 20 min, 0.005% formic acid in water) and thenIntermediate 74-4(12.4g, 75.2mmol, 60% yield) was obtained. MS M/z 165[ M +1]]⁺.

Step 5 preparation of intermediate 74-5

Intermediate 74-4(12.4g, 75.2mmol) was dissolved in tetrahydrofuran (500mL) and triethylamine (30.4 g, 300.8mmol) and benzyloxycarboximoyl succinimide (39.4g, 157.9mmol) were added at 0 ℃. Then, the reaction mixture was warmed to room temperature and stirred for 1 hour. Purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 5:1) afforded intermediate 74-5(30.6g, 70.7mmol, 94% yield). MS M/z 433[ M +1]]⁺.

Step 6 preparation of intermediate 74-6

Intermediate 74-5(30.6g, 70.7mmol) was dissolved in acetic anhydride (300mL), nitric acid (6.3mL, 141.4mmol) was added dropwise at 0 deg.C, and the reaction was allowed to stir at 0 deg.C for 5 hours. Purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 3:1) afforded intermediate 74-6(22.3g, 46.7mmol, 66% yield). MS M/z 478[ M +1]]⁺.

Step 7 preparation of intermediate 74-7

Intermediate 74-6(22.3g, 46.7mmol) was dissolved in ethanol (400mL), sodium hydroxide (1.9g, 46.7mmol) was added portionwise at room temperature, and the reaction was stirred at 70 ℃ for 1 hour after the addition. Extraction with water and ethyl acetate then followed by extraction of the aqueous phase twice with ethyl acetate, combination of the organic phases, drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure gave crude intermediate 74-7 (15.4g, 44.8mmol, 96% yield). MS M/z 344[ M +1]]⁺.

Step 8 preparation of intermediates 74-8

The crude intermediate 74-7 (15.4g, 44.8mmol) was dissolved in methanol (600mL), zinc powder (14.6 g, 224.0mmol) and ammonium chloride (239.6g, 448.0mmol) were added under ice-bath, and the reaction was stirred at room temperature for 1 hour after the addition. Filtration to remove zinc dust, evaporation of solvent under reduced pressure and purification by MPLC (eluent gradient acetonitrile: water 0:100 to 50:50, 20 min, 0.005% formic acid in water) afforded intermediate 74-8(12.5g, 40mmol, 89% yield), MS M/z:314[ M + 1: (M + 1): intermediate)]⁺.

Step 9 preparation of intermediates 74-9

Referring to steps 1 to 4 of example 57, intermediate 74-9, MS M/z 627[ M +1] 627, M/z:627, was prepared by condensing single stereoisomer 2-c of intermediate 2 of example 2, which was used as a starting material, with intermediate 74-9, which was obtained by condensation of o-phenylenediamine 74-8, an intermediate of example 74, closing an imidazole ring, removing a Boc, and condensing with 1-methyl-1H-pyrazole-5-carboxylic acid]⁺.

Step 10 preparation of intermediates 74-10

Intermediate 74-9(1.25g, 2.0mmol) was dissolved in methanol (20mL) and palladium on carbon (140.0mg, palladium content 10%) was added at room temperature. The reaction system was replaced with hydrogen three times, and stirred under a hydrogen atmosphere (1atm) for 12 hours. The reaction was filtered through celite, and the solvent was evaporated under reduced pressure to give crude intermediate 74-10 (0.935g, 1.9mmol, 96% yield). MS M/z 493[ M +1]]⁺.

Step 11 preparation of Compound 74

Referring to the procedure of example 41, step 7, condensation of intermediate 74-10 with acetyl chloride gave compound 74, MS M/z:535(M +1)⁺.

EXAMPLE 75 preparation of Compound 75

Referring to example 74, compound 75, MS M/z:535(M +1), was obtained as a single stereoisomer 2-d of intermediate 2 of example 2 by condensation with o-phenylenediamine 74-8, an intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 76 preparation of Compound 76

Referring to example 74, compound 76, MS M/z:535(M +1), was prepared from single stereoisomer 2-b of intermediate 2 of example 2 by condensation with o-phenylenediamine 74-8, intermediate 74, ring closure, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation to remove Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 77 preparation of Compound 77

Referring to example 74, compound 77, MS M/z:535(M +1), was obtained by condensation of the single stereoisomer 2-a of intermediate 2 of example 2 with o-phenylenediamine 74-8, intermediate 74, ring closure, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, Cbz hydrogenation, and acetyl chloride⁺.

EXAMPLE 78 preparation of Compound 78

Referring to example 74, compound 78, MS M/z:547(M +1) was prepared by condensation of the single stereoisomer 13-a of intermediate 13 of example 13 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.¹HNMR(400MHz, DMSO-d₆)δ12.67(s,1H),8.79(s,1H),8.42(s,1H),7.58(t,J＝4.0Hz,1H),7.52(s,2H), 7.42(t,J＝9.6,2H),7.36-7.32(m,2H),7.24–7.19(m,2H),6.67(d,J＝2.0Hz,1H),5.59(t,J ＝10.0Hz,1H),4.13(t,J＝10.0Hz,1H),3.83(s,3H),2.69-2.63(m,1H),2.36-2.33(m,1H), 1.78(s,3H),1.56-1.49(m,2H),1.46-1.39(m,2H),1.30(s,6H),1.25-1.15(m,2H).

EXAMPLE 79 preparation of Compound 79

Referring to example 74, starting from the single stereoisomer 13-d of intermediate 13 from example 13, the reaction was performed by condensation with o-phenylenediamine 74-8, an intermediate from example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and finally condensation with acetyl chloride to give compound 79, MS M/z:547(M +1)⁺.

EXAMPLE 80 preparation of Compound 80

Referring to example 74, compound 80, MS M/z:547(M +1) was prepared by condensation of the single stereoisomer 13-b of intermediate 13 of example 13 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 81 preparation of Compound 81

Referring to example 74, compound 81, MS M/z:547(M +1) was prepared by condensation of the single stereoisomer 13-c of intermediate 13 of example 13 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.¹HNMR(400MHz, DMSO-d₆)δ12.10(s,1H),8.93(s,1H),7.54(t,J＝5.6Hz,1H),7.48(d,J＝2.0Hz,1H), 7.45-7.41(m,1H),7.35(d,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,2H),7.23(t,J＝7.2Hz,1H), 7.16-7.09(m,2H),7.07(d,J＝2.0Hz,1H),5.73(t,J＝8.8Hz,1H),4.27(t,J＝8.8Hz,1H), 4.01(s,3H),3.27-3.25(m,2H),2.97-2.87(m,1H),1.89-1.79(m,2H),1.76(s,3H),1.69(dd,J₁＝8.4,J₂＝18.0,1H),1.59-1.46(m,3H),1.25(s,6H).

EXAMPLE 82 preparation of Compound 82

Step 1 preparation of intermediate 82-1

Referring to the method for preparing the intermediate 1 in example 1, benzaldehyde is used as a starting material, and four single chiral isomers 82-1a,82-1b,82-1c and 82-1d of the intermediate 82-1 can be respectively obtained by condensation, Grignard reaction, nitro reduction, Boc protection of amino, hydrolysis and separation by an SFC chiral separation column. MS M/z 320[ M +1]]⁺。

Step 2 preparation of Compound 82

Referring to example 74, the single chiral isomer 81-1b of intermediate 82-1 of example 82 was used as a starting material to prepare a compound by condensation with o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation to remove Cbz, and condensation with cyclopropanecarbonyl chloride82，MS m/z:539(M+1)⁺.

EXAMPLE 83 preparation of Compound 83

Referring to example 74, compound 83, MS M/z:539(M +1) was prepared by condensation of the single chiral isomer 81-1c of intermediate 82-1 of example 82 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation to remove Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 84 preparation of Compound 84

Referring to example 74, compound 84, MS M/z:539(M +1) was prepared by condensation of the single chiral isomer 81-1a of intermediate 82-1 of example 82 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation to remove Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 85 preparation of Compound 85

Referring to example 74, compound 85, MS M/z:539(M +1) was obtained by condensation of the single chiral isomer 81-1d of intermediate 82-1 of example 82 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation to remove Cbz, and finally with cyclopropanecarbonyl chloride⁺.

EXAMPLE 86 preparation of Compound 86

Referring to example 74, compound 86, MS M/z:573(M +1) was prepared by condensation of the single chiral isomer 13-b of intermediate 13 of example 13 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 87 preparation of Compound 87

Referring to example 74, starting from the single chiral isomer 13-c of intermediate 13 of example 13, condensation with o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride gave compound 87, MS M/z:573(M +1)⁺.¹H NMR(400MHz, DMSO-d₆)δ12.44(s,1H),8.67(d,J＝10.0Hz,1H),7.79(t,J＝6.0Hz,1H),7.60-7.48(m, 2H),7.44-7.29(m,5H),7.26-7.19(m,2H),6.65(d,J＝2.0Hz,1H),5.58(t,J＝6.0Hz,1H), 4.12(t,J＝5.6Hz,1H),3.83(s,3H),2.71-2.63(m,1H),1.65-1.40(m,6H),1.31(s,6H), 0.63-0.56(m,5H).

EXAMPLE 88 preparation of Compound 88

Referring to example 74, starting from the single chiral isomer 13-a of intermediate 13 of example 13, compound 88, MS M/z:573(M +1), was prepared by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 89 preparation of Compound 89

Referring to example 74, starting from the single chiral isomer 13-d of intermediate 13 of example 13, compound 89, MS M/z:573(M +1), was prepared by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 90 preparation of Compound 90

Referring to example 74, starting from the single chiral isomer 19-b of example 19 intermediate 19, compound 90, MS M/z:643(M +1) was obtained by condensation with the intermediate o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 91 preparation of Compound 91

Referring to example 74, starting from the single chiral isomer 19-d of example 19 intermediate 19, compound 91, MS M/z:643(M +1), was obtained by condensation with the intermediate o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 92 preparation of Compound 92

Referring to example 74, starting from the single chiral isomer 19-a of intermediate 19 of example 19, the compound 92, MS M/z:643(M +1), was obtained by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 93 preparation of Compound 93

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to condense with o-phenylenediamine 74-8, a ring was closed, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, Cbz was removed by hydrogenation, and finally, condensation with acetyl chloride gave compound 93, MS M/z:643(M +1)⁺.¹HNMR(400MHz,CD₃OD) δ＝8.42(br,1H),8.05(s,1H),7.86(s,1H),7.61～7.69(m,2H),7.56(d,J＝8.4Hz,1H), 7.33～7.44(m,4H),6.48(s,1H),6.10(d,J＝10.0Hz,1H),4.17～4.24(m,1H),3.87(s,3H),3.47(s, 2H),1.92～2.03(m,1H),1.88(s,3H),1.55(d,J＝6.4Hz,6H),1.30～1.41(m,6H),1.01(d,J＝6.4Hz, 3H),0.90(d,J＝6.8Hz,3H).

EXAMPLE 94 preparation of Compound 94

Step 1 preparation of intermediate 94-1

Referring to the method for preparing the intermediate 1 in example 1, benzaldehyde is used as a starting material, and four single chiral isomers 94-1a,94-1b,94-1c and 94-1d of the intermediate 94-1 can be respectively obtained by condensation, Grignard reaction, nitro reduction, amino protection by Boc, hydrolysis and separation by an SFC chiral separation column. MS M/z 308[ M +1]]⁺。

Step 2 preparation of Compound 94

Referring to the method of example 74, the single chiral isomer 94-1b of the intermediate 94-1 in step 1 is used as a raw material to be condensed with the o-phenylenediamine 74-8 as the intermediate of example 74, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, Cbz removal by hydrogenation,finally condensing with cyclopropanecarbonyl chloride to obtain compound 94, MS M/z 527(M +1)⁺.¹H NMR(400MHz, MeOD):δ7.54(s,1H),7.48(d,J＝8.7Hz,1H),7.37(d,J＝7.6Hz,1H),7.27–7.12(m,7H), 6.33(d,J＝2.1Hz,1H),5.86(d,J＝9.8Hz,1H),4.97(d,J＝3.2Hz,1H),4.16(t,J＝6.1Hz, 1H),3.52–3.44(m,1H),3.42–3.33(m,3H),3.13(dd,J＝11.5,6.9Hz,1H),1.78(ddd,J＝ 19.2,12.0,6.5Hz,2H),1.60(dt,J＝13.1,6.5Hz,1H),1.36–1.27(m,6H),0.83(d,J＝6.7Hz, 3H),0.77(d,J＝6.7Hz,3H),0.64(dt,J＝5.8,3.8Hz,2H),0.56(ddd,J＝10.2,6.6,3.8Hz, 2H).

EXAMPLE 95 preparation of Compound 95

Referring to the procedure of example 74, starting from the single chiral isomer 94-1c of intermediate 94-1 of step 1 of example 94, compound 95, MS M/z:527(M +1) was obtained by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation removal of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 96 preparation of Compound 96

Referring to example 74, compound 96, MS M/z 527(M +1) was prepared by condensation of step 1, intermediate 94-1, the single chiral isomer 94-1a, with example 74, intermediate o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation to remove Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 97 preparation of Compound 97

Referring to the procedure of example 74, intermediate 94-1 was synthesized as a single chiral isomer of step 1The structure 94-1d is prepared from the raw material through condensation with o-phenylenediamine 74-8 as an intermediate in example 74, ring closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl addition, hydrogenation to remove Cbz, and condensation with cyclopropanecarbonyl chloride to obtain compound 97, MS M/z 527(M +1)⁺.

EXAMPLE 98 preparation of Compound 98

Referring to example 74, starting from the single chiral isomer 1-b of intermediate 1 of example 1, the compound 98, MS M/z:579(M +1), was obtained by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, removal of 1-methyl-1H-pyrazole-5-acyl, removal of Cbz from hydrobromic acid-acetic acid, and final condensation with acetyl chloride⁺.

EXAMPLE 99 preparation of Compound 99

Referring to example 74, starting from the single chiral isomer 1-c of intermediate 1 of example 1, the compound 99, MS M/z:579(M +1), can be obtained by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, removal of 1-methyl-1H-pyrazole-5-acyl, removal of Cbz from hydrobromic acid-acetic acid, and final condensation with acetyl chloride⁺.

EXAMPLE 100 preparation of Compound 100

Referring to example 74, the single chiral isomer 1-c of intermediate 1 of example 1 was used as a starting material to prepare compound 100, MS M/z:627(M +1), by condensation with o-phenylenediamine 74-8, ring closure, Boc removal, 1-ethyl-1H-pyrazole-5-acyl, hydrobromic acid-acetic acid removal of Cbz, and final condensation with acetyl chloride, as described in example 74⁺.

EXAMPLE 101 preparation of Compound 101

Referring to example 74, starting from the single chiral isomer 1-a of intermediate 1 of example 1, condensation with o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, removal of Cbz from hydrobromic acid-acetic acid, and final condensation with acetyl chloride gave 101, MS M/z:579(M +1)⁺.

EXAMPLE 102 preparation of Compound 102

Referring to example 74, compound 102, MS M/z 579(M +1), was prepared by condensation of the single chiral isomer 1-d of intermediate 1 of example 1 with o-phenylenediamine 74-8, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl, hydrobromic acid-acetic acid removal of Cbz, and finally with acetyl chloride as starting material in example 74⁺.

EXAMPLE 103 preparation of Compound 103

Referring to example 74, compound 103, MS M/z:615(M +1) was obtained by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with acetyl chloride⁺.

EXAMPLE 104 preparation of Compound 104

Referring to the procedure of example 74, starting from the single chiral isomer 18-c of intermediate 18 of example 18The material was condensed with o-phenylenediamine 74-8, an intermediate in example 74, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, hydrogenation to remove Cbz, and finally condensation with 3-tetrahydrofuranic acid to give compound 104, MS M/z:671(M +1)⁺.

EXAMPLE 105 preparation of Compound 105

Referring to example 74, compound 105, MS M/z:641(M +1), was prepared by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 106 preparation of Compound 106

Referring to example 74, compound 106, MS M/z:641(M +1), was prepared by condensation of the single chiral isomer 18-b of intermediate 18 of example 18, starting with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 107 preparation of Compound 107

Referring to example 74, compound 107, MS M/z:641(M +1), was prepared by condensation of the single chiral isomer 18-a of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 108 preparation of Compound 108

Referring to example 74, the single chiral isomer 18-c of example 18 intermediate 18 was used as a starting material to prepare compound 108 by condensation with o-phenylenediamine 74-8 of example 74 intermediate, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation of Cbz, condensation with 1-Boc-pyrrolidine-3-carboxylic acid, and final Boc removal with trifluoroacetic acid (M +1), MS M/z:670 (M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ0.79(d,J＝8.4Hz,3H)0.84(d,J＝6.8Hz,3H)1.32(d, J＝4.0Hz,6H)1.66～1.76(m,1H)1.83～1.91(m,1H)1.97～2.06(m,1H)3.02～3.07(m,3H) 3.17～3.21(m,2H)3.78(s,3H)3.87(s,3H)4.11～4.22(m,2H)6.07(t,J＝9.2Hz,1H)6.60(s,1H) 7.32～7.38(m,5H)7.55～7.61(m,3H)7.83(s,1H)7.96(t,J＝6.4Hz,1H)8.09(s,1H) 8.73～8.96(brs,3H)。

EXAMPLE 109 preparation of Compound 109

Referring to example 74, the single chiral isomer 18-c of example 18 intermediate 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, Cbz hydrogenation removal, and finally condensation with cyclobutanecarboxylic acid to give compound 109, MS M/z:655(M +1)⁺.

EXAMPLE 110 preparation of Compound 110

Referring to example 74, a compound 110 can be obtained by using the single chiral isomer 18-c of the intermediate 18 of example 18 as a raw material and condensing with o-phenylenediamine 74-8 of example 74, ring closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl addition, Cbz hydrogenation removal, and finally condensation with cyclopentanecarboxylic acid, wherein MS m/z is 669(M+1)⁺.

EXAMPLE 111 preparation of Compound 111

Step 1 preparation of intermediate 111-1

Referring to the method for preparing the intermediate 1 in example 1, acetaldehyde is used as a starting material, and is condensed with ethyl nitroacetate, subjected to Grignard reaction with o-chlorophenyl magnesium bromide, reduced with nitro zinc powder, protected with amino by Boc, hydrolyzed with alkali, and finally separated by an SFC chiral separation column to prepare four single chiral isomers 111-1a,111-1b,111-1c and 111-1d which can respectively obtain the intermediate 111-1. MS M/z 314[ M +1]]⁺。

Step 2 preparation of Compound 111

Referring to example 74, a single chiral isomer 111-1c of intermediate 111-1 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, Cbz hydrogenation removal, and finally condensation with cyclopropanecarbonyl chloride to give compound 111, MS M/z:533(M +1)⁺.

EXAMPLE 112 preparation of Compound 112

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl addition, hydrogenation Cbz removal, and finally condensation with n-butyric acid to give compound 112, MS M/z:643(M +1)⁺.

EXAMPLE 113 preparation of Compound 113

Referring to example 74, the single chiral isomer 18-c of example 18 intermediate 18 was used as a starting material to condense with example 74 intermediate o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation removal of Cbz, condensation with 1-Boc-pyrrolidine-3-acetic acid, and final removal of Boc with trifluoroacetic acid to give compound 113, MS M/z:684 (M +1)⁺.

EXAMPLE 114 preparation of Compound 114

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, Cbz hydrogenation removal, and finally condensation with cyclopropylacetic acid to give compound 114, MS M/z:655(M +1)⁺.

EXAMPLE 115 preparation of Compound 115

Referring to example 74, compound 115, MS M/z:669(M +1), was prepared by condensation of the single chiral isomer 19-c of intermediate 19 of example 19 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, hydrogenation removal of Cbz, and finally condensation with cyclopropylacetic acid⁺.¹H NMR(400MHz, DMSO):δ＝12.64(s,1H),8.36(s,1H),8.16(s,1H),7.83(s,1H),7.78(s,1H),7.58(s,1H),7.46 (s,1H),7.40(d,J＝2.4Hz,2H),7.29(d,J＝2.0Hz,2H),6.55(d,J＝2.0Hz,1H),6.02(t,J＝10.0Hz, 1H),4.55-4.51(m,1H),4.28(d,J＝11.2Hz,1H),3.77(s,3H),2.68(t,J＝1.6Hz,1H),2.34(t, J＝2.0Hz,1H),1.85(s,1H),1.63(m,1H),1.47(d,J＝6.4Hz,6H),1.31(s,6H),1.25(s,1H), 0.81(t,J＝8.0Hz 6H),0.63-0.57(m,4H).

EXAMPLE 116 preparation of Compound 116

Referring to example 74, compound 116, MS M/z:671(M +1), was prepared by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with 4-methylvaleric acid⁺.

EXAMPLE 117 preparation of Compound 117

Referring to example 74, starting from the single chiral isomer 18-c of intermediate 18 of example 18, compound 117, MS M/z:643(M +1), was obtained by condensation with o-phenylenediamine 74-8, the intermediate of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation removal of Cbz, and condensation with isobutyric acid⁺.¹H NMR(400MHz, DMSO-d₆)δ12.57(s,1H),8.88(s,1H),8.08(s,1H),7.81(d,J＝0.8Hz,1H),7.56(s,2H), 7.52-7.43(m,2H),7.43-7.34(m,2H),7.29(d,J＝0.8Hz,1H),7.26-7.23(m,1H),6.53(d,J＝ 2.0Hz,1H),6.00(t,J＝10.0Hz,1H),4.26(dd,J₁＝4.0Hz,J₂＝10.8Hz,1H),3.89(s,3H), 3.76(s,3H),2.45-2.31(m,1H),2.05-1.95(m,1H),1.90-1.75(m,1H),1.30(s,6H),0.93(d,J＝ 6.8Hz,6H),0.81(d,J＝6.8Hz,6H).

EXAMPLE 118 preparation of Compound 118

Referring to the method of example 74, the single chiral isomer 18-c of the intermediate 18 of example 18 is used as a raw material to be condensed with the o-phenylenediamine 74-8 of the intermediate 74 of example, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl,hydrogenation to remove Cbz, and condensation with 3-methylbutyric acid to give compound 118, MS M/z:657(M +1)⁺.

EXAMPLE 119 preparation of Compound 119

By following the procedure of example 74, starting from the single chiral isomer 1-c of intermediate 1 of example 1, condensation with o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, removal of Cbz from hydrobromic acid-acetic acid, condensation with cyclopropanecarbonyl chloride, coupling with intermediate 20 of example 20 by following the procedure of example 18, step 2, and final removal of Boc protecting group from trifluoroacetic acid gave compound 119, MS M/z:710(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.92(d,J＝6.4Hz,1H),8.18(s,1H),7.89(s,1H),7.79(t,J＝5.2Hz, 1H),7.59(s,1H),7.46～7.56(m,2H),7.41(m,2H),7.25～7.29(m,2H),6.54(s,1H),6.02(t, J＝10.4Hz,1H),4.43(s,1H),4.26(dd,J1＝3.2Hz,J2＝11.6Hz,1H),3.76(s,3H),2.94(s,2H), 2.11～2.23(m,3H),1.94～2.11(m,3H),1.76～1.91(m,2H),1.58～1.67(m,2H),1.31(s,6H),1.24(s, 1H),0.81(d,J＝5.2Hz,6H),0.57～0.63(m,4H).

EXAMPLE 120 preparation of Compound 120

Referring to example 74, compound 120, MS M/z 666(M +1) was obtained by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, Cbz hydrogenation, and N-methylaminosulfonyl chloride⁺.

EXAMPLE 121 preparation of Compound 121

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, Cbz hydrogenation removal, and condensation with nicotinic acid to give compound 121, MS M/z:678(M +1)⁺.

EXAMPLE 122 preparation of Compound 122

Referring to example 74, compound 122, MS M/z:681(M +1), was prepared by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, Cbz hydrogenation, and final condensation with 1-methylpyrazole-4-carboxylic acid⁺.

EXAMPLE 123 preparation of Compound 123

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl addition, Cbz hydrogenation removal, and final condensation with cyclopropylchloroformate to give compound 123, MS M/z:657(M +1)⁺.

EXAMPLE 124 preparation of Compound 124

Referring to example 74, the single chiral isomer 18-c of example 18 intermediate 18 was used as a starting material to prepare a compound which was condensed with the intermediate o-phenylenediamine 74-8 of example 74, ring-closed, Boc-removed, 1-methyl-1H-pyrazole-5-acyl-removed, Cbz-removed by hydrogenation, and finally condensed with oxazole-2-carboxylic acidCompound 124, MS M/z 668(M +1)⁺.

EXAMPLE 125 preparation of Compound 125

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, Cbz hydrogenation removal, and finally condensation with cyclopropylsulfonyl chloride to give compound 125, MS M/z:677(M +1)⁺.

EXAMPLE 126 preparation of Compound 126

Referring to example 74, compound 126, MS M/z 644(M +1) was obtained by condensation of the single chiral isomer 18-c of intermediate 18 of example 18 with o-phenylenediamine 74-8, intermediate 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with N, N-dimethylformyl chloride⁺.

EXAMPLE 127 preparation of Compound 127

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl addition, Cbz hydrogenation removal, and finally condensation with methanesulfonyl chloride to give compound 127, MS M/z:651(M +1)⁺.

EXAMPLE 128 preparation of Compound 128

Step 1 preparation of intermediate 128-1

Referring to example 74, the single chiral isomer 18-c of example 18 intermediate 18 was used as a starting material to condense with o-phenylenediamine 74-8, the intermediate was subjected to ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, hydrogenation to remove Cbz to obtain an amino intermediate, the intermediate (100mg,174.48umol) was dissolved in 3ml of methanol, ethyl glyoxylate (17.81mg,174.48umol) was added and stirred at 60 ℃ for 1 hour, NaBH3CN (32.89mg,523.44umol) was added and stirred at 60 ℃ overnight, water was added for quenching, ethyl acetate extraction was performed, concentration was performed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain intermediate 128-1, MS M/z:659(M +1)⁺.

Step 2 preparation of Compound 128

Intermediate 128-1(13mg,19.72umol) was dissolved in 1ml of acetic acid, potassium cyanate (1.92mg,23.66umol) was added thereto, the reaction was stirred at room temperature overnight, and after concentration, the product was isolated and purified by MPLC 18 column to obtain compound 128(5.01mg,7.40 umol, 37.52% yield, 96.9% purity), MS M/z:656(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ＝12.71(s,1H),8.90(s,1H),8.30(s,1H),8.06(s,1H),7.81(s,1H),7.55(s,2H),7.41-7.33(m, 2H),7.31-7.18(m,2H),6.53(d,J＝1.6Hz,1H),6.01(t,J＝10.4Hz,1H),4.28-4.21(m,1H), 3.88(s,3H),3.78(s,3H),3.46(s,2H),1.85(s,1H),1.36(s,4H),1.29(s,2H),0.83-0.77(m, 6H).

EXAMPLE 129 preparation of Compound 129

Referring to example 74, starting from the single chiral isomer 18-c of example 18 intermediate 18, the product was condensed with the example 74 intermediate o-phenylenediamine 74-8, ring-closed, Boc-removed, 1-methyl-1H-pyrazol-5-yl, hydrogenated to remove Cbz, and then the product was subjected to the reference example128 step 1 Process, reductive amination with 4-methyl-2-oxopentanoic acid to give the Compound 129, MS M/z:687(M +1)⁺.¹H NMR(400MHz,MeOD):δ7.98(s,1H),7.86(s,1H),7.71(s, 1H),7.63-7.65(m,1H),7.28-7.46(m,5H),6.472-6.476(d,1H,J＝1.6Hz),6.094-6.12(d,1H, J＝10Hz),4.21-4.27(m,1H),3.96(s,3H),3.86(s,3H),3.71-3.79(m,1H),3.40-3.50(m,1H), 1.64-1.80(m,3H),1.57-1.59(d,5H,J＝5.2Hz),1.38-1.41(m,3H),0.99-1.01(d,2H,J＝7.2Hz), 0.89-0.93(m,9H).

EXAMPLE 130 preparation of Compound 130

Step 1 preparation of intermediate 130-1

Compound 129(20mg,29.10umol) was dissolved in 10ml of methanol, and a catalytic amount of concentrated sulfuric acid (285.42ug,2.91 umol,1.55 e) was added^-1uL), stirring at 60 deg.C for 12 hr, LC-MS tracking the disappearance of raw material, concentrating the reaction solution, adding water, extracting with ethyl acetate, concentrating, separating and purifying by silica gel column chromatography (MeOH: DCM ═ 1:10), and subjecting the crude product to high performance liquid chromatography (water: ACN ═ 1:1) to obtain intermediate 130-1(20mg,25.67umol, 88.20% yield), MS M/z:701(M +1)⁺.

Step 2 preparation of Compound 130

Referring to example 128, step 2, compound 130, MS M/z:712(M +1) was obtained by reacting 130-1 with potassium cyanate in acetic acid to close the ring⁺.¹H NMR(400MHz,MeOD):δ8.52(s,1H),7.98(s,1H),7.86(s,1H), 7.63(s,2H),7.34-7.48(m,3H),6.49(s,1H),6.09-6.12(m,1H),4.63(s,2H),4.19-4.21(m, 1H),3.88-3.96(m,6H),3.34-3.40(m,2H),1.96-2.00(m,1H),1.60-1.66(m,1H),1.46-1.50(d,4H, J＝16Hz),1.24-1.27(m,2H),1.02-1.03(d,3H,J＝6Hz),0.89-0.91(d,3H,J＝6.8Hz),0.73-0.75(t, 3H,J＝6Hz),0.35-0.37(d,3H,J＝6.4Hz).

EXAMPLE 131 preparation of Compound 131

Step 1 preparation of intermediate 131-1

Referring to the method for preparing the intermediate 1 in example 1, four single chiral isomers 131-1a,131-1b,131-1c and 131-1d of the intermediate 131-1 can be respectively obtained by using acetaldehyde as a starting material, condensing with ethyl nitroacetate, carrying out a Grignard reaction with o-chlorophenyl magnesium bromide, reducing with nitrozinc powder, protecting amino with Boc, carrying out alkaline hydrolysis, and finally separating by an SFC chiral separation column. MS M/z 214[ M-99 ]]⁺，258[M-55]⁺。

Step 2 preparation of Compound 131

Referring to example 74, the single chiral isomer 131-c of intermediate 131-1 of example 131 was condensed with o-phenylenediamine 74-8 of example 74, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation to remove Cbz, and finally condensation with cyclopropanecarbonyl chloride gave compound 131, MS M/z:533(M +1)⁺.¹H NMR(400 MHz,DMSO-d₆):δ＝7.83(s,1H),7.64(s,1H),7.46-7.36(m,6H),7.21(t,J＝8.0Hz,2H),6.54 (s,1H),6.47(s,1H),5.90(s,1H),5.63(s,1H),4.89(d,J＝4.4Hz,1H),4.84(d,J＝4.0Hz,1H),4.43 (s,2H),3.83(s,2H),3.33(d,J＝6.0Hz,2H),1.74(s,1H),1.60(s,1H),1.43(s,1H),1.27(s,6H), 1.25(s,1H),0.63-0.58(m,4H).

EXAMPLE 132 preparation of Compound 132

Referring to the method of example 74, the single chiral isomer 11-c of the intermediate 11 of example 11 is used as a raw material to be condensed with the o-phenylenediamine 74-8 of the intermediate 74 of example, ring closure and ring removalBoc, adding 1-methyl-1H-pyrazole-5-acyl, hydrogenating to remove Cbz, and finally condensing with cyclopropanecarbonyl chloride to obtain compound 132, MS M/z:547(M +1)⁺.¹H NMR(400MHz, DMSO-d₆)δ8.87(d,J＝8.8Hz,1H),7.78(t,J＝5.6Hz,1H),7.49～7.62(m,2H),7.47(d,J＝7.6Hz, 1H),7.42(d,J＝8Hz,1H),7.31～7.37(m,2H),7.20～7.26(m,2H),6.3(d,J＝1.6Hz,1H),5.70(s, 1H),4.00～4.15(m,1H),3.83(s,3H),3.35(s,2H),1.46～1.66(m,3H),1.31(s,6H),1.24(s,1H), 0.56～0.65(m,7H).

EXAMPLE 133 preparation of Compound 133

Referring to example 74, compound 133, MS M/z:547(M +1) was prepared by condensation of the single chiral isomer 11-a of intermediate 11 of example 11 with o-phenylenediamine 74-8 of example 74, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz, and final condensation with cyclopropanecarbonyl chloride⁺.¹H NMR(400MHz, DMSO-d6)δ9.42(d,J＝7.6Hz,1H),7.82(t,J＝6Hz,1H),7.57(s,1H),7.55(s,1H),7.53(d,J＝2Hz, 1H),7.51(s,1H),7.43(d,J＝8.8Hz,1H),7.33(t,J＝7.2Hz,1H),7.27～7.29(m,1H),7.15～7.21(m, 1H),7.12(d,J＝2Hz,1H),5.71(s,1H),4.09～4.18(m,1H),3.97(s,3H),3.32(d,J＝6Hz,2H), 1.96～2.11(m,2H),1.82～1.94(m,1H),1.52～1.58(m,1H),1.27(d,J＝2Hz,6H),0.71(t,J＝7.6Hz, 3H),0.53～0.57(m,4H).

EXAMPLE 134 preparation of Compound 134

Referring to example 74, the single chiral isomer 11-d of intermediate 11 of example 11 was condensed with o-phenylenediamine 74-8 of example 74, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl addition, hydrogenation to remove Cbz, and finally condensation with cyclopropanecarbonyl chloride gave 134, MS M/z:547(M +1)⁺.

EXAMPLE 135 preparation of Compound 135

Referring to example 74, the single chiral isomer 11-b of intermediate 11 of example 11 was condensed with o-phenylenediamine 74-8, ring-closed, Boc-removed, 1-methyl-1H-pyrazol-5-yl group added, Cbz removed by hydrogenation, and finally condensed with cyclopropanecarbonyl chloride to give compound 135, MS M/z:547(M +1)⁺.

EXAMPLE 136 preparation of Compound 136

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was condensed with o-phenylenediamine 74-8, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl addition, Cbz hydrogenation removal, and final condensation with cyclopropanecarbonyl chloride to give compound 136, MS M/z:560(M +1)⁺.¹HNMR(400MHz, DMSO-d₆)δ12.21(s,1H),8.99(d,J＝8.4Hz,1H),7.76(t,J＝5.6Hz,1H),7.56(d,J＝6.4Hz, 1H),7.49(d,J＝1.6Hz,1H),7.44-7.22(m,4H),7.17-7.12(m,2H),7.10(s,1H),5.95(t,J＝ 8.8Hz,1H),4.00(s,3H),3.53-3.50(m,2H),3.32-3.30(m,2H),1.64-1.59(m,1H),1.42-1.31 (m,1H),1.26(s,6H),0.62-0.56(m,4H),0.44-0.39(m,2H),0.31-0.23(m,1H),-0.02--0.05(m, 1H).

EXAMPLE 137 preparation of Compound 137

Referring to the procedure of example 74, the single chiral isomer 12-a of intermediate 12 of example 12 was used as a starting material to undergo condensation with o-phenylenediamine 74-8, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, hydrogenation to remove Cbz, and finally reaction with cyclopropylmethylCondensation of the acid chloride gives the compound 137, MS M/z:560(M +1)⁺.¹H NMR(400MHz, DMSO-d₆)δ9.42(d,J＝7.6Hz,1H),7.82(t,J＝6Hz,1H),7.57(s,1H),7.55(s,1H),7.53(d,J＝2Hz, 1H),7.51(s,1H),7.43(d,J＝8.8Hz,1H),7.33(t,J＝7.2Hz,1H),7.27～7.29(m,1H),7.15～7.21(m, 1H),7.12(d,J＝2Hz,1H),5.71(s,1H),4.09～4.18(m,1H),3.97(s,3H),3.32(d,J＝6Hz,2H), 1.96～2.11(m,2H),1.82～1.94(m,1H),1.52～1.58(m,1H),1.27(d,J＝2Hz,6H),0.71(t,J＝7.6Hz, 3H),0.53～0.57(m,4H).

EXAMPLE 138 preparation of Compound 138

Referring to example 74, compound 138, MS M/z:560(M +1), was prepared by condensation of the single chiral isomer 12-d of intermediate 12 of example 12 with o-phenylenediamine 74-8, intermediate 74, ring closure, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, hydrogenation of Cbz removal, and final condensation with cyclopropanecarbonyl chloride⁺.

EXAMPLE 139 preparation of Compound 139

Referring to example 74, a single chiral isomer 12-b of intermediate 12 of example 12 was used as a starting material to condense with o-phenylenediamine 74-8, a ring was closed, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, Cbz was removed by hydrogenation, and finally, the resulting product was condensed with cyclopropanecarbonyl chloride to give compound 139, MS M/z:560(M +1)⁺.¹HNMR(400MHz, DMSO-d₆)δ12.62(s,1H),8.87(s,1H),7.80(t,J＝6.0Hz,1H),7.59-7.47(m,4H),7.40(dd,J₁＝1.2Hz,J₂＝8.0Hz,1H),7.35-7.19(m,4H),6.65(d,J＝2.0Hz,1H),5.86(s,1H),3.84(s, 3H),1.66-1.59(m,1H),1.31(s,6H),0.65-0.56(m,4H),0.24-0.17(m,1H),0.14-0.07(m,1H), 0.02--0.02(m,1H).

EXAMPLE 140 preparation of Compound 140

Referring to example 74, the single chiral isomer 1-c of intermediate 1 of example 1 was used as a starting material to condense with o-phenylenediamine 74-8, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, Cbz was removed with hydrobromic acid, and finally, the resulting product was condensed with cyclopropanecarbonyl chloride to give compound 140, MS M/z:639(M +1)⁺.

EXAMPLE 141 preparation of Compound 141

By following the procedure of example 18, step 2, the coupling of compound 140 from example 140 with 2-fluoropyridin-5-boronic acid ester gave compound 141, MS M/z:656(M +1)⁺.

EXAMPLE 142 preparation of Compound 142

The compound 141 from example 141 was reacted with N, N-dimethylethylenediamine in tetrahydrofuran in the presence of triethylamine to give the compound 142, MS M/z:724(M +1)⁺.

EXAMPLE 143 preparation of Compound 143

By referring to the procedure of step 2 of example 18, compound 143, MS M/z:655(M +1) was obtained by coupling compound 140 of example 140 with 1, 5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester⁺.

EXAMPLE 144 preparation of Compound 144

By referring to the procedure of step 2 of example 18, compound 144, MS M/z:655(M +1) was obtained by coupling compound 140 of example 140 with 1, 3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester⁺.

EXAMPLE 145 preparation of Compound 145

Referring to example 74, compound 145, MS M/z:666(M +1) was obtained by condensation of the single chiral isomer 18-b of intermediate 18 of example 18 with o-phenylenediamine 74-8, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl addition, hydrogenation to remove Cbz, and finally with methanesulfonyl chloride, which is an intermediate of example 74⁺.¹H NMR(400MHz, DMSO-d₆)δ12.47(d,J＝10.0Hz,1H),8.84(dd,J＝24.4,9.6Hz,1H),8.08(s,1H),7.82(s, 1H),7.64–7.57(m,2H),7.48(d,J＝8.4Hz,1H),7.39(s,2H),7.30–7.24(m,2H),6.63(d,J ＝5.2Hz,2H),6.52(s,1H),6.02(t,J＝10.4Hz,1H),4.27(s,1H),3.89(s,3H),3.77(s,3H), 3.00(d,J＝6.8Hz,2H),2.34(d,J＝4.8Hz,3H),1.84(s,1H),1.36(s,6H),0.81(d,J＝6.4Hz, 6H).

EXAMPLE 146 preparation of Compound 146

Step 1 preparation of intermediate 146-1

Referring to the method of example 23, ethyl p-nitrophenylacetate was hydrogenated, nitrated to introduce a nitro group at the meta position, deacetylated, and hydrogenated to reduce to obtain intermediate 146-1, MS M/z:195(M +1)⁺.

Step 2 preparation of Compound 146

Referring to example 74, the single chiral isomer 2-b of intermediate 2 of example 2 was used as a starting material to condense with o-phenylenediamine 146-1, the intermediate of example 146, ring closure, removal of Boc, addition of 1-ethyl-1H-pyrazol-5-yl, further referring to example 41, steps 6-7, alkaline hydrolysis, and finally condensation with methylamine hydrochloride to give compound 146, MS M/z:507(M +1)⁺.¹HNMR(400MHz,MeOD):δ7.51(d,J＝2.0,1H),7.37-7.35(m,2H),7.24-7.21(m,2H), 7.17-7.13(m,1H),7.09-7.05(m,2H),6.90(d,J＝2.0,1H),5.92(d,J＝10.0,1H),4.58-4.51(m, 2H),4.24-4.20(m,1H),3.54(s,2H),2.69(s,3H),2.45-2.40(m,1H),1.37(t,J＝7.2,3H),1.05 (d,J＝6.8,3H),0.94(d,J＝8.4,3H)

EXAMPLE 147 preparation of Compound 147

Referring to example 74, using single chiral isomer 2-a of intermediate 2 of example 2 as raw material, the compound 147, MS M/z:507(M +1) was obtained by condensation with o-phenylenediamine 146-1, the ring was closed, Boc was removed, 1-ethyl-1H-pyrazol-5-yl group was added, referring to example 41, Steps 6-7, base hydrolysis, and finally condensation with methylamine hydrochloride⁺.

EXAMPLE 148 preparation of Compound 148

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 148, MS M/z:507(M +1), by condensation with o-phenylenediamine 146-1, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, referring to example 41, steps 6 to 7, base hydrolysis, and condensation with methylamine hydrochloride⁺.¹HNMR(400MHz,MeOD):δ8.51(s,1H),7.51(d,J＝6.8,3H),7.38-7.31(m,3H),7.24-7.19 (m,2H),6.47(s,1H),5.99(d,J＝9.6,1H),4.40-4.29(m,2H),4.20-4.17(m,1H),3.61(s,2H), 2.72(s,3H),1.91-1.86(m,1H),1.23(t,J＝7.2,3H),0.96(d,J＝6.8,3H),0.85(d,J＝6.8,3H).

EXAMPLE 149 preparation of Compound 149

Referring to example 74, the single chiral isomer 2-d of intermediate 2 of example 2 was used as a starting material to prepare compound 149, MS M/z 507(M +1) by condensation with o-phenylenediamine 146-1, the intermediate of example 146, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 150 preparation of Compound 150

Referring to example 74, the single chiral isomer 3-b of intermediate 3 of example 3 was used as a starting material to prepare compound 150, MS M/z 507(M +1), by condensation with o-phenylenediamine 146-1, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, referring to example 41, steps 6 to 7, base hydrolysis, and condensation with methylamine hydrochloride⁺.

EXAMPLE 151 preparation of Compound 151

Referring to example 74, the single chiral isomer 3-a of intermediate 3 of example 3 was used as a starting material to prepare compound 151, MS M/z 507(M +1) by condensation with o-phenylenediamine 146-1, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, referring to example 41, steps 6 to 7, base hydrolysis, and condensation with methylamine hydrochloride⁺.

EXAMPLE 152 preparation of Compound 152

Referring to example 74, the single chiral isomer 3-c of intermediate 3 of example 3 was used as a starting material to condense with o-phenylenediamine 146-1, the intermediate of example 146, ring closure, removal of Boc, addition of 1-ethyl-1H-pyrazol-5-yl, further referring to example 41, steps 6-7, base hydrolysis, and finally condensation with methylamine hydrochloride to give compound 152, MS M/z:507(M +1)⁺.

EXAMPLE 153 preparation of Compound 153

Referring to example 74, the single chiral isomer 3-d of intermediate 3 of example 3 was used as a starting material to prepare compound 153, MS M/z:507(M +1) by condensation with o-phenylenediamine 146-1, the intermediate of example 146, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6 to 7, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 154 preparation of Compound 154

Referring to example 74, starting from the single chiral isomer 2-b of intermediate 2 of example 2, compound 154, MS M/z:535(M +1), was obtained by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with methylamine hydrochloride⁺. ¹HNMR(400MHz,MeOD):δ7.57-7.48(m,3H),7.37-7.30(m,3H),7.24-7.19(m,3H),6.45 (s,1H),5.97(d,J＝10.0,1H),4.36-4.29(m,2H),4.22-4.18(m,1H),2.67(d,J＝4.0,3H), 1.89-1.85(m,1H),1.59(s,6H),1.22(t,J＝7.2,3H),0.94(d,J＝5.6,3H),0.85(d,J＝6.4,3H).

EXAMPLE 155 preparation of Compound 155

Referring to example 74, the single chiral isomer 2-a of intermediate 2 of example 2 was used as a starting material to prepare compound 155, MS M/z:535(M +1), by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6 to 7, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 156 preparation of Compound 156

Referring to example 74, starting from the single chiral isomer 2-c of intermediate 2 of example 2, compound 156, MS M/z:535(M +1) was obtained by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with methylamine hydrochloride⁺. ¹HNMR(400MHz,MeOD):δ7.50(d,J＝2.0,1H),7.42-7.35(m,2H),7.27-7.21(m,2H), 7.18-7.04(m,3H),6.69(d,J＝2.0,1H),5.91(d,J＝10.4,1H),4.56-4.49(m,2H),4.26-4.22(m, 1H),2.62(s,3H),2.45-2.40(m,1H),1.52(s,6H),1.35(t,J＝7.2,3H),1.03(d,J＝6.4,3H), 0.94(d,J＝6.8,3H).

Preparation of the Compound 157 of example 157

Referring to example 74, starting from the single chiral isomer 2-d of intermediate 2 of example 2, the compound 157, MS M/z:535(M +1) was obtained by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 158 preparation of Compound 158

Referring to example 74, starting from the single chiral isomer 18-c of intermediate 18 of example 18, compound 158, MS M/z:615(M +1) was obtained by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-ethyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 159 preparation of Compound 159

Referring to example 74, the single chiral isomer 21-c of intermediate 21 of example 21 was condensed with o-phenylenediamine 26, ring-closed, Boc removed, 1-ethyl-1H-pyrazol-5-yl, step 6-7 of example 41, base hydrolysis, and finally condensation with methylamine hydrochloride to give compound 159, MS M/z:642(M +1)⁺.

EXAMPLE 160 preparation of Compound 160

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 26, ring-closed, Boc removed, and then 1-methyl-1H-pyrazole-5-acyl group was added thereto as a starting material, followed by basic hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally basic hydrolysis of methyl ester to give compound 160, MS M/z:701(M +1), in accordance with example 41, steps 6-7⁺.

EXAMPLE 161 preparation of Compound 161

Referring to example 74, the single chiral isomer 18-D of example 18 intermediate 18 was used as a starting material and condensed with the intermediate o-phenylenediamine 26 of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, Steps 6-7, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally alkaline hydrolysis of the methyl ester to give compound 161, MS M/z:701(M +1)⁺.

EXAMPLE 162 preparation of Compound 162

Step 1 preparation of intermediate 162-1

Boc-D-leucine (2.49g, 10mmol) was dissolved in DMF (25mL), HBTU (4.17 g,11 mmol), DBU (2.58g, 20mmol) and methylsulfonamide (1.9g, 20mmol) were added in ice bath, and the reaction was stirred at room temperature for 5 h. Extraction with water and ethyl acetate followed by extraction of the aqueous phase twice with ethyl acetate, combination of the organic phases, drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure gave crude intermediate 162-1(1.5g,6.5mmol, 50% yield). MS M/z 309(M +1)⁺.

Step 2 preparation of intermediate 162-2

Intermediate 162-1(1.5g,6.5mmol) was added to dichloromethane (20mL), trifluoroacetic acid (10mL) was added under ice-bath, stirred for 1 hour under ice-bath, and the solvent was evaporated under reduced pressure to give crude intermediate 9 (0.68g,11.9mmol, yield 80%), MS M/z 209(M +1)⁺.

Step 3 preparation of Compound 162

Reference is made to the procedure in example 74 as an intermediate to example 1818 single chiral isomer 18-c as raw material was condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, step 6-7 of example 41, base hydrolysis, and finally condensation with intermediate 162-2 of example 162, step 2, to give compound 162, MS M/z:778(M +1)⁺.

EXAMPLE 163 preparation of Compound 163

Step 1 preparation of intermediate 163-1

Referring to the procedure of example 162, steps 1-2, sulfonylation from Boc-D-leucine as a starting material with ethylsulfonyl chloride and removal of Boc protecting group gave intermediate 163-1, MS M/z:223(M +1)⁺.

Step 2 preparation of Compound 163

Referring to example 74, starting from the single chiral isomer 18-c of example 18, intermediate 18, through condensation with the intermediate o-phenylenediamine 26 of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, reference example 41, steps 6-7, base hydrolysis, and final condensation with intermediate 163-1 of example 163, step 1, compound 163, MS M/z:792(M +1)⁺.¹HNMR(400MHz,DMSO-d₆)δ＝12.63(s,1H),8.94(d,J＝8.8 Hz,1H),8.27(s,4H),8.08(s,1H),7.82(s,1H),7.56(s,2H),7.44-7.34(m,1H),7.28(d,J＝ 2.0Hz,1H),7.17(d,J＝8.8Hz,1H),6.53(s,1H),6.02(t,J＝10.4Hz,1H),4.31-4.25(m,1H), 4.05-3.99(m,1H),3.89(s,3H),3.76(s,3H),2.88-2.76(m,2H),1.85(s,1H),1.52(d,J＝6.8 Hz,6H),1.47-1.39(m,2H),1.36-1.28(m,1H),0.97(t,J＝7.2Hz,3H),0.83-0.78(m,12H).

EXAMPLE 164 preparation of Compound 164

Step 1 preparation of intermediate 164-1

Referring to example 162, step 1-2, sulfonylation and Boc-protecting group removal from Boc-D-leucine as a starting material with cyclopropylsulfonyl chloride gave intermediate 164-1, MS M/z:235(M +1)⁺.

Step 2 preparation of Compound 164

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 26, ring-closed, Boc removed, 1-methyl-1H-pyrazole-5-yl group, which was intermediate 26 of example 26, followed by base hydrolysis in steps 6-7 of example 41, and finally condensed with intermediate 164-1 of example 163, step 1 to give compound 164, MS M/z:804(M +1)⁺.

EXAMPLE 165 preparation of Compound 165

Step 1 preparation of intermediate 165-1

Boc-D-leucine (2.49g, 10mmol) was dissolved in DMF (25mL), HBTU (4.17 g,11 mmol), DBU (2.58g, 20mmol) and ammonium chloride (1.07g, 20mmol) were added under ice-bath, and the reaction was stirred at room temperature for 5 hours. Then extracted with water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give crude intermediate 165-1(1.5g,6.5 mmol, 50% yield). MS M/z 231(M +1)⁺.

Step 2 preparation of intermediate 165-2

Intermediate 165-1(1.5g, 6.5)mmol) is added into DMF (20mL), cyanuric chloride (0.7g, 3.9mmol) is added under ice bath, stirred for 10 hours at room temperature, the solvent is distilled off under reduced pressure to obtain crude intermediate 165-2(0.64g,3mmol, yield 46%), MS M/z 213(M +1)⁺.

Step 3 preparation of intermediate 165-3

Adding intermediate 165-2(0.64g,3mmol) into DMF (20mL), adding sodium azide (0.29g, 4.5mmol) and ammonium chloride (0.24g, 4.5mmol), stirring at 100 ℃ for 10 hours, and removing the solvent by evaporation under reduced pressure to obtain crude intermediate 165-3(0.51g,2mmol, 66% yield), MS M/z:256(M +1)⁺.

Step 4 preparation of intermediate 165-4

Adding intermediate 165-3(0.51g,2mmol) into dichloromethane (20mL), adding trifluoroacetic acid (10mL) under ice bath, stirring for 1 hour under ice bath, and evaporating the solvent under reduced pressure to obtain crude intermediate 11 (0.28g,1.8mmol, yield 90%), MS M/z:156(M +1)⁺.

Step 5 preparation of Compound 165

Referring to example 74, a single chiral isomer 18-c of intermediate 18 of example 18 was used as a starting material to prepare compound 165, MS M/z:725(M +1), by condensation with o-phenylenediamine 26, cyclization, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, referring to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with intermediate 165-4⁺.¹HNMR(400MHz,DMSO-d₆)δ＝8.86(d,J＝9.2Hz,1H),8.07(s,1H),7.81(s,1H), 7.55(s,1H),7.49(t,J＝6.4Hz,3H),7.38(s,2H),7.28(d,J＝2Hz,1H),7.11(d,J＝8.8Hz,1H), 6.51(d,J＝1.6Hz,1H),6.00(t,J＝10.4Hz,1H),5.24(dd,J¹＝7.6Hz,J²＝14.4Hz,1H),4.25(d, J＝10.8Hz,1H),3.88(s,3H),3.75(s,3H),1.77～1.86(m,1H),1.70～1.75(m,1H),1.58(t,J＝7Hz, 1H),1.52(d,J＝6.4Hz,6H),1.29～1.39(m,1H),0.81(s,4H),0.78(s,6H),0.77(s,2H)

EXAMPLE 166 preparation of Compound 166

Referring to example 74, the single chiral isomer 4-c of intermediate 4 of example 4 was used as a starting material to condense with o-phenylenediamine 30, the intermediate of example 30, ring closure, Boc removal, and 1-methyl-1H-pyrazole-5-acyl to give compound 166, MS M/z:482(M +1)⁺.¹H NMR(400MHz,DMSO-d₆):δ12.55(s,1H),8.89-8.94(t,1H), 7.08-7.56(m,6H),6.563-6.568(d,J＝1.5Hz,1H),5.84-5.89(t,1H),4.23-4.26(m,1H),3.87(s, 3H),2.98-3.03(m,1H),1.82-1.83(m,1H),1.25-1.27(d,J＝6.8Hz,5H),0.78-0.79(d,J＝7.2 Hz,5H).

EXAMPLE 167 preparation of Compound 167

Referring to example 74, the single chiral isomer 4-b of intermediate 4 of example 4 was used as a starting material to condense with o-phenylenediamine 30, the intermediate of example 30, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl to give compound 167, MS M/z:482(M +1)⁺.¹H NMR(400MHz,DMSO-d₆):δ12.15(s,1H),9.10-9.12(d,J＝8.8 Hz,1H),8.21(s,1H),6.97-7.47(m,8H),5.81-5.86(t,J＝1.5Hz,1H),4.26-4.30(m,1H),4.06(s, 3H),3.87(s,1H),2.91-2.94(m,1H),2.40-2.46(m,1H),1.19-1.27(d,J＝6.8Hz,6H), 0.84-0.91(d,J＝7.2Hz,6H).

EXAMPLE 168 preparation of Compound 168

Referring to example 74, the single chiral isomer 94-1c of intermediate 94-1 from step 1 of example 94 was condensed with o-phenylenediamine 26 as an intermediate of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to steps 6-7 of example 41, alkaline hydrolysis, condensation with D-leucine tert-butyl ester hydrochloride, and finally hydrolysis of tert-butyl ester with trifluoroacetic acid gave compound 168, MS M/z:587(M +1)⁺.

EXAMPLE 169 preparation of Compound 169

Referring to example 74, the single chiral isomer 94-1c of intermediate 94-1 from step 1 of example 94 was condensed with o-phenylenediamine 26 as an intermediate in example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further, referring to steps 6-7 of example 41, alkaline hydrolysis, and condensation with intermediate 162-2 from example 162 to give compound 169, MS M/z:664(M +1)⁺.

EXAMPLE 170 preparation of Compound 170

Referring to example 74, Boc-L-3, 3-diphenylalanine was used as a starting material and subjected to condensation with o-phenylenediamine 26, an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further reference to examples 41, steps 6 to 7, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally alkaline hydrolysis of methyl ester to give compound 170, MS M/z: 621(M +1)⁺.

EXAMPLE 171 preparation of Compound 171

Step 1 preparation of intermediate 171-1

Referring to example 1, the intermediate 1 was prepared from 1-methyl-1H-indazole-6-carbaldehyde as a starting material by condensation with ethyl nitroacetate, grignard reaction with isopropyl magnesium chloride, reduction with nitrozinc powder, protection of amino groups with Boc, basic hydrolysis, and separation with an SFC chiral separation column to give four single chiral isomers 171-1a, 171-1b,171-1c,171-1d of intermediate 171-1. MS M/z 362[ M +1]]⁺。

Step 2 preparation of Compound 171

Referring to example 74, the single chiral isomer 171-1c of intermediate 171-1 from step 1, example 171 was condensed with o-phenylenediamine 26, example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, step 6-7, example 41, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and alkaline hydrolysis of methyl ester to give compound 171, MS M/z:641(M +1)⁺.

EXAMPLE 172 preparation of Compound 172

Referring to example 74, the single chiral isomer 171-1b of intermediate 171-1 from step 1, example 171 was used as a starting material, which was condensed with o-phenylenediamine 26, example 26, ring-closing, Boc removal, and 1-methyl-1H-pyrazole-5-acyl, followed by steps 6-7 of example 41, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and alkaline hydrolysis of methyl ester to give compound 172, MS M/z:641(M +1)⁺.

EXAMPLE 173 preparation of Compound 173

Step 1 preparation of intermediate 173-1

Ethyl nitroacetate (9.50g,71.34mmol) and cyclobutanone (5g,71.34mmol) were dissolved in anhydrous tetrahydrofuran (200mL), titanium tetrachloride (27.06g,142.67mmol) was slowly added dropwise at 0 ℃ under nitrogen, and after the addition was complete, the reaction was stirred at 0 ℃ for 1 hour. N-methylmorpholine (28.82g,285.35mmol) was slowly added dropwise to the reaction mixture, after the addition was complete, the temperature was slowly raised to room temperature, and the reaction was stirred for 2 hours. Adding distilled water to quench the reaction, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying by column chromatography (eluent: petroleum ether: ethyl acetate: 50: 1) to obtain intermediate 173-1(10g,54.00mmol, 75.70% yield).

Step 2 preparation of intermediate 173-2

Referring to example 1, intermediate 173-2a and 173-2b, MS M/z 306[ M + 1: M +1, were prepared by Grignard reaction of intermediate 173-1 with phenylmagnesium bromide, nitro reduction, Boc protection of amino group, basic hydrolysis of ethyl ester, and separation with SFC chiral separation column]⁺。

Step 3 preparation of Compound 173

Referring to example 74, using the single chiral isomer 173-2a of intermediate 173-2 from step 2 of example 173 as the starting material, the compound 173, MS M/z:585(M +1) was prepared by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl, further reference to steps 6-7 of example 41, base hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally base hydrolysis of methyl ester⁺.

EXAMPLE 174 preparation of Compound 174

Referring to example 74, the single chiral isomer 173-2b of intermediate 173-2 from step 2 of example 173 was condensed with o-phenylenediamine 26 as an intermediate in example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to steps 6-7 of example 41, followed by basic hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally basic hydrolysis of methyl ester to give compound 174, MS M/z:585(M +1)⁺.

EXAMPLE 175 preparation of Compound 175

Step 1 preparation of intermediate 175-1

Referring to the method for preparing intermediate 1 of example 1, intermediate 173-1 and o-chlorophenyl magnesium bromide are subjected to Grignard reaction, nitro reduction, Boc protection of amino group, ethyl ester alkaline hydrolysis, and finally separation by SFC chiral separation column to prepare two single chiral isomers 175-1a and 175-1b which can respectively obtain intermediate 175-1, MS M/z is 340[ M + 1[ ] -M +/z]⁺。

Step 2 preparation of Compound 175

Referring to example 74, using single chiral isomer 175-1a of intermediate 175-1 of step 2 of example 173 as raw material, through condensation with o-phenylenediamine 26, cyclization, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to steps 6-7 of example 41, through alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally through alkaline hydrolysis of methyl ester, compound 175 is obtained, MS M/z:619(M +1)⁺.

EXAMPLE 176 preparation of Compound 176

Referring to example 74, the single chiral isomer 175-1b of intermediate 175-1 of step 2, example 173, was used as a starting material to prepare compound 176, MS M/z:619(M +1), by condensation with o-phenylenediamine 26, example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, further reference to steps 6-7, example 41, base hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally base hydrolysis of methyl ester⁺.

EXAMPLE 177 preparation of Compound 177

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to prepare compound 177, MS M/z:805(M +1), by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further reference to example 41, steps 6 to 7, alkaline hydrolysis, and further condensation with intermediate 162-2 of example 162⁺.¹H NMR(400MHz,DMSO-d₆)δ＝11.77(s,1H),8.80(d,J＝8.8Hz, 1H),8.17(s,1H),7.83(s,1H),7.59-7.54(m,3H),7.42–7.30(m,4H),7.15(d,J＝8.4Hz,1H), 6.55(s,1H),6.02(t,J＝10.0Hz,1H),4.55–4.49(m,1H),4.37-4.31(m,1H),4.22-4.21(m, 1H),3.77(s,3H),3.21(d,J＝1.6Hz,3H),1.87(s,1H),1.55–1.45(m,12H),1.25(s,1H),0.85 –0.76(m,12H).

EXAMPLE 178 preparation of Compound 178

Referring to example 74, intermediate 19 (mixture of enantiomers 19-c and 19-D) from example 19 was condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closed, Boc-removed, 1-methyl-1H-pyrazole-5-acyl, step 6-7 of reference example 41, base hydrolyzed, and condensed with D-leucine methyl ester hydrochloride, and finallyThen hydrolyzing the methyl ester with alkali to obtain compound 178, MS M/z:729(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ12.50(s,2H), 8.81-8.79(d,J＝9.2Hz,1H),8.13-8.11(d,J＝8.4Hz,1H),7.80(s,1H),7.63–7.45(t,J＝29.6 Hz,3H),7.37–7.36(t,J＝2.8Hz,2H),7.26–7.25(m,2H),7.13-7.11(d,J＝8.4Hz,1H),6.50 (s,1H),6.01-5.96(t,J＝10Hz,1H),4.53-4.46(m,1H),4.23-4.21(d,J＝10Hz,2H),4.23(s, 3H),1.81(s,1H),1.59-1.25(m,15H),0.80–0.75(m,11H).

EXAMPLE 179 preparation of Compound 179

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, steps 6-7, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and finally alkaline hydrolysis of methyl ester to give compound 179, MS M/z:729(M +1)⁺.¹HNMR(400MHz,MeOD):δppm 12.20-13.13(m, 1.5H),8.86-8.88(d,J＝9.2Hz,1H),8.15-8.17(m,1H),7.82(s,1H),7.34-7.57(m,5H), 7.22-7.27(m,2H),7.12-7.14(m,1H),6.52-6.53(m,1H),5.93-6.03(m,1H),4.46-4.56(m, 1H),4.22-4.26(m,2H),4.22-4.26(m,2H),3.76(s,3H),1.80-1.84(m,1H),1.49-1.52(d,J＝ 9.6Hz,6H),1.44-1.46(d,J＝6.4Hz,1H),0.77-0.85(m,11H)。

EXAMPLE 180 preparation of Compound 180

Referring to the procedure of example 74, a compound was prepared by condensing the single chiral isomer 19-c of intermediate 19 of example 19 with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to steps 6 to 7 of example 41, base hydrolysis, condensation with D-leucine methyl ester hydrochloride, ester hydrolysis and aminolysis180，MS m/z:728(M+1)⁺.

Preparation of example 181 Compound 181

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, referring to examples 41, steps 6-7, base hydrolysis, condensation with D-N-methyl-gamma-hydroxy leucine methyl ester, and ester hydrolysis to give compound 181, MS M/z:745(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.76(d,J＝8.4 Hz,1H),8.27(s,1H),7.93(t,J＝8.0Hz,2H),7.70(t,J＝4.0Hz,3H),7.66(s,1H),7.47(dd,J 1＝ 1.6Hz,J 2＝8.4Hz,1H),7.41–7.39(m,2H),7.34(d,J＝8.4Hz,1H),6.69(d,J＝2.0Hz,1H), 6.14(t,J＝8.8Hz,1H),4.02(t,J＝8.0Hz,1H),3.84(s,3H),2.23(dd,J＝11.9,9.6Hz,1H), 2.11–2.02(m,2H),1.53–1.34(m,18H),0.98(d,J＝6.4Hz,3H),0.79(d,J＝6.8Hz,3H).

EXAMPLE 182 preparation of Compound 182

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, referring to example 41, Steps 6 to 7, basic hydrolysis, condensation with D-cyclopropylalanine methyl ester, and ester hydrolysis gave compound 182, MS M/z:727(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.06(s,1H),7.87(s,1H),7.68 (dd,2H),7.59(dd,1H),7.44-7.42(d,J＝2.1Hz,1H),7.37–7.33(m,3H),6.50(s,1H),6.11 (d,J＝9.5Hz,1H),4.59(dt,J＝13.6,6.7Hz,2H),4.43(dd,J＝7.4,4.9Hz,1H),4.19(dd,J＝ 8.3,6.4Hz,1H),3.883(s,3H),3.53–3.48(m,1H),1.98(dd,J＝12.0,7.5Hz,1H),1.66(d,J＝ 12.0Hz,6H),1.56(d,J＝12.0Hz,6H),1.39–1.23(m,3H),1.03(d,J＝6.9Hz,3H),0.89(d,J＝ 6.9Hz,3H),0.61–0.48(m,1H),0.30(ddd,J＝11.5,7.7,3.9Hz,2H).

Preparation of the Compound 183 of example 183

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to prepare compound 183, MS M/z:713(M +1) by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, further referring to examples 41, Steps 6-7, base hydrolysis, condensation with D-cyclopropylglycine methyl ester, and final ester hydrolysis⁺.¹H NMR(400MHz,MeOD)δ8.06(s,1H),7.87(s,1H),7.65 (d,J＝2.9Hz,2H),7.57(d,J＝8.4Hz,1H),7.43(dd,J＝8.3,2.0Hz,1H),7.38–7.31(m,3H), 6.51(d,J＝2.2Hz,1H),6.12(d,J＝9.2Hz,1H),4.59(m,J＝11.8,5.9Hz,2H),4.23–4.14(m, 2H),3.89(s,3H),3.82(d,J＝9.4Hz,1H),1.99(d,J＝4.6Hz,2H),1.65(d,J＝7.3Hz,6H), 1.56(d,J＝6.7Hz,6H),1.04(d,J＝5.9Hz,3H),0.89(d,J＝6.8Hz,3H),0.54(m,J＝12.2, 5.0Hz,1H),0.46–0.40(m,2H),0.28–0.22(m,1H).

EXAMPLE 184 preparation of Compound 184

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to prepare compound 184, MS M/z:713(M +1) by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, Steps 6-7, basic hydrolysis, condensation with D-proline methyl ester, and final ester hydrolysis⁺.¹H NMR(400MHz,DMSO-d₆):δ＝8.38-8.33(m,1H),8.15(s,1H), 7.81(s,1H),7.57-7.50(m,2H),7.37-7.33(m,1H),7.27-7.24(m,1H),6.64-6.61(m,1H), 6.07-5.98(m,1H),4.54-4.52(m,1H),4.27-4.19(m,2H),3.79(s,3H),2.70-2.68(m,3H), 2.03-2.01(m1H),1.87-1.85(m,1H),1.66-1.59(m,3H),1.53-1.44(m,13H),1.27-1.24(m, 1H),0.80(s,6H)。

EXAMPLE 185 preparation of Compound 185

Step 1 preparation of intermediate 185-1

Referring to the procedure of step 2 of example 18, intermediates 1-4 were coupled with 1-cyclopropylpyrazole-4-boronic acid pinacol ester, then hydrolyzed, and finally separated by SFC chiral resolution column to prepare four single chiral isomers 185-1a,185-1b,185-1c,185-1d of intermediate 185-1, respectively. MS M/z 448[ M +1]]⁺。

Step 2 preparation of Compound 185

Referring to example 74, the single chiral isomer 185-1c of intermediate 185-1 was used as a starting material to condense with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, steps 6-7, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and final ester hydrolysis to give compound 185, MS M/z:727(M +1)⁺.

EXAMPLE 186 preparation of Compound 186

Step 1 preparation of intermediate 186-1

Referring to example 1, intermediate 186-1, MS M/z:446[ M +1] was obtained by condensing 2-chloro-5-bromobenzaldehyde as a starting material with ethyl nitroacetate, Grignard reaction with cyclopropylmagnesium chloride, reduction with nitrozinc powder, and protection of amino group with Boc]⁺。

Step 2 preparation of intermediate 186-2

Referring to the procedure of step 2 of example 18, intermediate 186-1 was coupled with 1-isopropylpyrazole-4-boronic acid pinacol ester, then hydrolyzed, and finally separated by SFC chiral resolution column to prepare four single chiral isomers 186-2a,186-2b,186-2c,186-2d of intermediate 186-1, respectively. MS M/z 448[ M +1]]⁺。

Step 3 preparation of Compound 186

Referring to example 74, single chiral isomer 186-2c of intermediate 186-2 was used as a starting material to undergo condensation with o-phenylenediamine 26, an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, steps 6-7, alkaline hydrolysis, condensation with D-leucine methyl ester hydrochloride, and final ester hydrolysis to give compound 186, MS M/z:727(M +1)⁺.¹H NMR(400MHz,Methanol-d₄)δ8.04(s,1H),7.80(m,1H), 7.73-7.67(s,2H),7.59(d,J＝8.5Hz,1H),7.43–7.33(m,4H),6.63(s,1H),5.95-5.93(m,1H), 4.61-4.54(m,1H),4.48-4.45(m,1H),3.87(s,3H),1.68-1.66(m,3H),1.64-1.62(m,3H), 1.60-1.58(m,2H),1.55(d,J＝6.7Hz,6H),1.51–1.46(m,1H),1.31-1.29(m,1H),0.90–0.83 (m,6H),0.38-0.32(m,1H),0.29-0.22(m,1H),0.15–0.07(m,1H),-0.17--0.23(m,1H).

EXAMPLE 187 preparation of Compound 187

Referring to the method of example 74, single chiral isomer 186-2c of intermediate 186-2 is used as raw material to be condensed with o-phenylenediamine 26 as an intermediate of example 26, ring closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, and reference implementation is carried outExample 41 Steps 6-7, alkaline hydrolysis, condensation with D-cyclopropylglycine methyl ester, and final ester hydrolysis gave compound 187, MS M/z 711(M +1) +.¹H NMR(400MHz,DMSO-d₆)δ8.19(s,1H),7.85(s,1H),7.76(s,1H), 7.66(d,J＝7.9Hz,2H),7.48–7.42(m,1H),7.41–7.31(m,3H),6.63(s,1H),5.96(s,1H), 4.58–4.46(m,1H),3.80(s,3H),3.48–3.40(m,1H),1.59–1.54(m,3H),1.54(s,3H),1.47–1.45(m,3H),1.44(s,3H),1.33–1.21(m,1H),1.16–1.04(m,1H),0.56–0.44(m,1H),0.41 –0.24(m,3H),0.23–-0.10(m,5H),-0.18–-0.34(m,1H).

EXAMPLE 188 preparation of Compound 188

Referring to example 74, the single chiral isomer 186-2c of intermediate 186-2 was used as the starting material to undergo condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, step 6-7, alkaline hydrolysis, condensation with D-cyclopropylalanine methyl ester, and final ester hydrolysis to give compound 188, MS M/z:725(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.22(s,1H),7.87(s,1H),7.80(s,1H), 7.74–7.64(m,2H),7.52–7.33(m,4H),6.66(s,1H),6.03(s,1H),4.52(dt,J＝13.3,6.6Hz, 1H),4.29(dd,J＝9.3,4.7Hz,1H),3.82(s,3H),1.69–1.61(m,1H),1.58(s,3H),1.56(s,3H), 1.47(s,3H),1.46(s,3H),1.33–1.22(m,1H),0.62–0.48(m,1H),0.36–0.21(m,3H),0.19– 0.10(m,1H),0.09–-0.03(m,3H),-0.04–-0.13(m,1H),-0.16–-0.32(m,1H).

EXAMPLE 189 preparation of Compound 189

Referring to the procedure of example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to undergo condensation with the intermediate o-phenylenediamine 26 of example 26, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group, and further reference was made toEXAMPLE 41 Steps 6-7, alkaline hydrolysis, condensation with (S) -3-aminotetrahydrofuran-3-carboxylic acid methyl ester, and finally ester hydrolysis gave compound 189, MS M/z:729(M +1)⁺.¹H NMR(401MHz,MeOD)δ8.04–8.02(m,1H), 7.85–7.83(m,1H),7.64–7.60(m,2H),7.55–7.51(m,1H),7.39(s,1H),7.31(s,4H),6.49– 6.46(s,1H),6.11–6.06(m,1H),4.60–4.53(m,1H),4.21–4.15(m,2H),3.86(s,3H),2.42– 2.19(m,2H),2.03–1.93(m,1H),1.61(s,6H),1.54(d,J＝6.8Hz,6H),1.00(s,3H),0.87 (d,J＝6.6Hz,3H).

EXAMPLE 190 preparation of Compound 190

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to example 41, steps 6-7, base hydrolysis, condensation with ethyl 3-aminooxetane-3-carboxylate, and ester hydrolysis to give compound 190, MS M/z:715(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.07(s,1H),7.88(s, 1H),7.74(d,J＝5.8Hz,1H),7.64(d,J＝9.0Hz,1H),7.45–7.33(m,3H),6.50–6.48(m, 1H),6.10(s,1H),4.30(d,J＝6.6Hz,1H),4.12(m,2H),3.86(m,2H),1.67(s,2H),1.56 (d,J＝6.8Hz,2H),1.26(t,J＝7.1Hz,2H),1.22(s,1H),1.00(t,J＝7.4Hz,3H),0.94–0.86 (m,3H).

EXAMPLE 191 preparation of Compound 191

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material, which was condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc-removal, 1-methyl-1H-pyrazole-5-acyl group, and further, referring to examples 41, steps 6 to 7, basic hydrolysis, condensation with 1-aminocyclopropanecarboxylic acid methyl ester, and ester hydrolysis to give compound 191,MS m/z:699(M+1)⁺.¹H NMR(400MHz,MeOD)δ8.04(s,1H),7.85(s,1H),7.62 (s,2H),7.52(d,J＝8.4Hz,1H),7.41(dd,J＝8.3,2.0Hz,1H),7.31(ddd,J＝10.4,9.7,5.0Hz, 3H),6.47(s,1H),6.08(d,J＝9.5Hz,1H),4.56(m,1H),4.20–4.14(m,1H),3.86(s,3H),2.00 –1.91(m,1H),1.59(s,6H),1.53(d,J＝6.7Hz,6H),1.45(dd,J＝7.8,4.6Hz,2H),1.01 (d,J＝3.8Hz,2H),1.00–0.96(m,3H),0.87(d,J＝6.8Hz,3H).

EXAMPLE 192 preparation of Compound 192

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, steps 6-7, alkaline hydrolysis, condensation with L-leucine methyl ester hydrochloride, and finally alkaline hydrolysis of methyl ester to give compound 192, MS M/z:729(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.09(s,1H),7.89(s,1H), 7.69(d,J＝1.3Hz,1H),7.67(d,J＝1.3Hz,3H),7.66(d,J＝1.2Hz,1H),7.64(d,J＝1.6Hz, 2H),7.40(d,J＝8.2Hz,2H),7.37(d,J＝1.7Hz,1H),6.54(s,1H),6.15(d,J＝8.9Hz,1H), 4.58(dd,J＝13.4,6.7Hz,1H),4.48(d,J＝4.8Hz,1H),4.18(s,1H),3.91(s,3H),2.04(s,1H), 1.66(d,J＝15.1Hz,6H),1.56(d,J＝6.7Hz,6H),1.32–1.29(m,3H),1.07(d,J＝6.1Hz, 3H),0.90(d,J＝6.5Hz,3H),0.88–0.83(m,6H).

EXAMPLE 193 preparation of Compound 193

Referring to example 74, starting from the single chiral isomer 19-c of intermediate 19 of example 19, the product was condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl, further, referring to example 41, steps 6-7, base hydrolysis, condensation with D-proline methyl ester, and final ester hydrolysis with ammoniaThe decomposition gives the compound 193, MS M/z:712(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.82(d,J＝5.1Hz,1H),7.53– 7.44(m,4H),7.29(s,2H),7.17(d,J＝7.9Hz,1H),7.10(d,J＝14.2Hz,1H),6.93(s,1H), 6.01(d,J＝7.5Hz,1H),4.63(s,1H),4.49(s,1H),4.42–4.36(m,1H),4.13(s,3H),2.83(s, 2H),2.58–2.41(m,2H),2.10–1.99(m,1H),1.76–1.56(m,5H),1.51(d,J＝5.4Hz,6H), 1.34–1.30(m,2H),1.24–1.19(m,3H),0.92(s,3H).

Preparation of example 194 Compound 194

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to examples 41, steps 6 to 7, alkaline hydrolysis, condensation with D-cis-3-hydroxyproline methyl ester, and ester hydrolysis to give compound 194, MS M/z:729(M +1)⁺.¹H NMR(400MHz,Methanol-d₄)δ8.04(s,1H),7.85(s,1H), 7.62(s,1H),7.57-7.56(m,1H),7.42-7.40(m,1H),7.36–7.27(m,3H),7.24(d,J＝8.6Hz, 1H),6.47(s,1H),6.10(d,J＝8.5Hz,1H),4.60-4.51(m,1H),4.45-4.42(m,1H),4.20-4016(m, 1H),4.10(s,1H),3.94-3.91(m,1H),3.86(s,3H),3.50–3.41(m,1H),3.14–3.05(m,1H), 2.83–2.74(m,1H),2.29-2.25(m,1H),1.98-1.95(m,1H),1.72-1.68(m,1H),1.61(s,2H),1.58 (s,2H),1.53(d,J＝6.7Hz,6H),1.50-1.47(m,1H),1.02(d,J＝6.7Hz,2H),0.88(d,J＝6.7 Hz,4H).

EXAMPLE 195 preparation of Compound 195

Referring to the procedure of example 74, starting from the single chiral isomer 19-c of intermediate 19 of example 19, the product was condensed with o-phenylenediamine 26, the intermediate of example 26 was ring-closed, Boc was removed, and 1-methyl-1H-pyrazole-5-acyl was added, followed by the procedure of example 416-7, hydrolyzing with alkali, condensing with azacycloheptane-2-methyl formate, and hydrolyzing to obtain 195 MS M/z 729(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.06(s,1H),7.87(s,1H),7.61 (d,J＝29.3Hz,3H),7.51(s,1H),7.43(dd,J＝8.3,1.9Hz,1H),7.34(d,J＝8.4Hz,2H),7.27 (d,J＝7.9Hz,1H),7.19(d,J＝8.4Hz,1H),6.53(s,1H),6.13(d,J＝8.6Hz,1H),4.59(dt,J＝ 13.4,6.8Hz,1H),4.49(s,1H),4.28(s,1H),4.13(s,2H),3.91(d,J＝5.4Hz,3H),2.19(d,J＝ 16.9Hz,1H),2.02(s,2H),1.87(s,2H),1.62(d,J＝15.2Hz,6H),1.56(d,J＝6.7Hz,6H), 1.44(s,2H),1.22(d,J＝18.8Hz,2H),1.08(s,3H),0.88(d,J＝6.7Hz,3H).

EXAMPLE 196 preparation of Compound 196

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, referring to example 41, Steps 6-7, basic hydrolysis, condensation with D-trans-3-hydroxyproline methyl ester, and ester hydrolysis gave compound 196, MS M/z:729(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ8.14(s,1H),7.93(s,1H), 7.79-7.73(d,J＝4.1Hz,3H),7.58-7.50(m,3H),7.44–7.38(m,3H),7.36–7.29(m,3H), 7.27-7.25(m,2H),6.69(t,J＝4.1Hz,1H),6.28(d,J＝7.4Hz,1H),4.63-4.56(m,2H),4.45– 4.33(m,2H),4.14–4.05(m,2H),3.99(d,J＝1.9Hz,4H),3.76–3.61(m,3H),2.29(dd,J＝ 13.6,6.9Hz,2H),1.67(d,J＝3.2Hz,2H),1.62(d,J＝3.9Hz,2H),1.56(dd,J＝6.5,4.5Hz, 8H),1.44(d,J＝18.4Hz,10H),1.32–1.18(m,6H),1.13–1.00(m,7H),0.91(d,J＝6.5Hz, 3H),0.79(dd,J＝16.2,6.7Hz,4H).

EXAMPLE 197 preparation of Compound 197

With reference to the method of example 74 of the present invention,the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, Steps 6-7, alkaline hydrolysis, condensation with (R) -morpholine-3-carboxylic acid methyl ester hydrochloride, and final ester hydrolysis to give compound 197, MS M/z:729(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ8.14(s,1H),7.92(s, 1H),7.80(d,J＝11.0Hz,2H),7.72(d,J＝6.5Hz,1H),7.67–7.57(m,2H),7.57–7.45(m, 2H),7.44–7.28(m,2H),6.71(s,1H),6.33(dd,J＝8.4,3.5Hz,1H),4.59(d,J＝10.4Hz,2H), 4.16(d,J＝12.9Hz,2H),3.97(d,J＝9.0Hz,3H),3.03–2.91(m,1H),2.76(dd,J＝11.4,3.8 Hz,1H),2.31–2.08(m,2H),1.90(d,J＝4.4Hz,1H),1.80–1.45(m,14H),1.18(d,J＝6.5 Hz,3H),1.06(d,J＝2.7Hz,1H),0.91(d,J＝6.6Hz,3H).

EXAMPLE 198 preparation of Compound 198

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to prepare compound 198, MS M/z:699(M +1), by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6-7, base hydrolysis, condensation with (R) - -cyclobutylamine-2-carboxylic acid methyl ester, and final ester hydrolysis⁺.¹H NMR(400MHz,Methanol-d4)δ8.06(s,1H),7.87(s,1H), 7.68–7.54(m,3H),7.54–7.40(m,2H),7.40–7.27(m,4H),6.52(d,J＝2.2Hz,1H),6.13 (d,J＝9.2Hz,1H),4.62–4.53(m,2H),4.13(s,2H),3.90(s,3H),2.10–1.76(m,3H),1.71– 1.44(m,16H),1.31(s,1H),1.25-1.21(m,1H),1.06(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz, 4H).

EXAMPLE 199 preparation of Compound 199

Reference is made to the example 74 method forEXAMPLE 19 Single chiral isomer 19-c of intermediate 19 was prepared by condensation with o-phenylenediamine 26, the intermediate of EXAMPLE 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, Steps 6-7, base hydrolysis, condensation with trans-4-fluoro-L-proline methyl ester, and final ester hydrolysis to give compound 199, MS M/z:731(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.06(s,1H),7.87(s,1H), 7.66(d,J＝12.4Hz,1H),7.59(d,J＝8.1Hz,2H),7.43(dd,J＝8.3,1.9Hz,1H),7.38–7.33 (m,2H),7.28(d,J＝9.4Hz,1H),6.50(s,1H),6.12(d,J＝9.4Hz,1H),4.59(dt,J＝13.5,6.9 Hz,2H),4.18(s,1H),3.89(s,3H),2.55–2.36(m,2H),2.00(d,J＝5.1Hz,2H),1.88(s,1H), 1.62(d,J＝8.6Hz,6H),1.56(d,J＝6.7Hz,6H),1.05(d,J＝6.0Hz,3H),0.90(d,J＝6.7Hz, 3H).

EXAMPLE 200 preparation of Compound 200

Referring to example 74, using the single chiral isomer 186-2c of example 186 intermediate 186-2 as the starting material, through condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, steps 6-7, alkaline hydrolysis, and condensation with D-cyclopropylglycine methyl ester, compound 187 was obtained, MS M/z:725(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.19(d,J＝2.0Hz,1H),7.84 (d,J＝0.8Hz,1H),7.73-7.68(m,1H),7.58(d,J＝7.2Hz,1H),7.44–7.41(m,1H), 7.38-7.35(m,2H),7.21(d,J＝8.4Hz,1H),6.63(d,J＝4.0Hz,1H),5.95(s,1H),4.55–4.49 (m,1H),3.80(s,H),3.62(s,3H),3.61–3.60(m,2H),1.54–1.45(m,12H),1.16–1.08(m,2H), 0.52–0.48(m,1H),0.41–-0.02(m,7H),-0.29(s,1H).

EXAMPLE 201 preparation of Compound 201

Referring to the procedure of example 74, intermediate 186-2 is of single chiralityThe isomer 186-2c was obtained by condensation with o-phenylenediamine 26, which is the intermediate in example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further refer to steps 6-7 of example 41, hydrolysis with alkali, and condensation with D-cyclopropylalanine methyl ester to give compound 201, MS M/z:739(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.21(s,1H),7.87(s,1H),7.79(s,1H),7.74(d,J＝8.6Hz, 1H),7.69(d,J＝1.2Hz,1H),7.47(dd,J＝8.3,2.1Hz,1H),7.44–7.36(m,3H),6.65(s,1H), 6.02(s,1H),4.57–4.47(m,1H),4.35–4.28(m,1H),3.81(s,3H),1.69–1.61(m,1H),1.56 (s,3H),1.55(s,3H),1.48–1.46(m,3H),1.46–1.43(m,3H),1.32–1.21(m,1H),0.63–0.52 (m,1H),0.36–0.25(m,3H),0.20–0.10(m,1H),0.09–-0.03(m,3H),-0.04–-0.11(m,1H), -0.16–-0.30(m,1H).

EXAMPLE 202 preparation of Compound 202

Referring to example 74, the single chiral isomer 19-c of intermediate 19 of example 19 was used as a starting material to condense with o-phenylenediamine 23, the intermediate of example 23, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to examples 41, Steps 6-7, alkaline hydrolysis, and finally condensation with methylamine to give compound 202, MS M/z:615(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.50(s,1H),8.03(s,1H),7.84(s,1H),7.61(s,1H),7.56(s, 1H),7.54–7.47(m,1H),7.43–7.38(m,1H),7.38–7.29(m,2H),7.29–7.22(m,1H),6.47(s, 1H),6.08(d,J＝9.7Hz,1H),4.21–4.13(m,1H),3.84(s,3H),3.78–3.71(m,1H),2.69(s, 3H),1.93(d,J＝7.1Hz,1H),1.57–1.46(m,9H),0.99(d,J＝6.2Hz,3H),0.87(d,J＝6.8Hz, 3H).

EXAMPLE 203 preparation of Compound 203

Referring to the procedure of example 74, starting from the single chiral isomer 19-d of intermediate 19 of example 19After condensation with o-phenylenediamine 23, the intermediate of example 23, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further reference example 41, Steps 6 to 7, alkaline hydrolysis, and finally condensation with methylamine, Compound 203 was obtained, MS M/z:615(M +1)⁺.¹H NMR(400MHz,CD₃OD)δ＝7.69(s,1H),7.52-7.44(m,4H),7.29-7.25(m, 3H),7.13-7.08(d,J＝22.0,1H),6.95(s,1H),6.02-5.99(d,J＝8.8,1H),4.50-4.32(m,1H), 4.21-4.14(m,1H),4.11(s,3H),3.74-3.68(m,1H),2.7-2.68(d,J＝2.8,3H),2.53-2.45(m, 1H),1.50-1.44(m,9H),1.21-1.18(t,J＝6.8,3H),0.95-0.92(m,3H).

EXAMPLE 204 preparation of Compound 204

Referring to example 74, the single chiral isomer 6-c of intermediate 6 of example 6 was used as a starting material to condense with o-phenylenediamine 41-1, the intermediate of example 41, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, steps 6-7, alkaline hydrolysis, and finally condensation with methylamine to give compound 204, MS M/z:518(M +1)⁺.

EXAMPLE 205 preparation of Compound 205

Referring to example 74, compound 205, MS M/z:493(M +1) was obtained by condensation of single chiral isomer 2-c of intermediate 2 of example 2 with o-phenylenediamine 146-1, cyclization, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl group, referring to steps 6-7 of example 41, base hydrolysis, and condensation with methylamine hydrochloride⁺.

EXAMPLE 206 preparation of Compound 206

Referring to example 74, compound 206 was obtained by condensation of (single chiral isomer 2-c) of intermediate 2 of example 2 with o-phenylenediamine 146-1, the intermediate of example 146, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, further reference to example 41, steps 6-7, base hydrolysis, and final condensation with R-N-methyl-2-amino-propionamide (M +1), MS M/z: 564(M +1)⁺.

EXAMPLE 207 preparation of Compound 207

Referring to example 74, compound 207, MS M/z:550 (M +1), was obtained by condensation of single chiral isomer 2-c of intermediate 2 of example 2 with o-phenylenediamine 146-1, ring closure, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl group, referring to example 41, steps 6-7, base hydrolysis, and final condensation with R-2-amino-propionamide as starting material⁺.

EXAMPLE 208 preparation of Compound 208

With reference to the procedure of example 74, starting from the single chiral isomer 5-c of intermediate 5 of example 5, by condensation with the intermediate o-phenylenediamine 30 of example 30, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group, compound 208, MS M/z:494(M +1)⁺.

EXAMPLE 209 preparation of Compound 209

Referring to example 74, compound 209, MS M/z:482(M +1), was prepared from the single chiral isomer 4-c of intermediate 4 of example 4 by condensation with o-phenylenediamine 30, the intermediate of example 30, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group⁺.

EXAMPLE 210 preparation of Compound 210

Referring to example 74, compound 210, MS M/z:482(M +1), was prepared from the single chiral isomer 4-d of intermediate 4 of example 4 by condensation with o-phenylenediamine 30, the intermediate of example 30, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group⁺.

EXAMPLE 211 preparation of Compound 211

Referring to example 74, a compound 211, MS M/z:574(M +1), was obtained by condensing the single chiral isomer 2-d of intermediate 2 of example 2 with the intermediate o-phenylenediamine 37 of example 37, ring-closing, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group⁺.

EXAMPLE 212 preparation of Compound 212

Referring to example 74, compound 212, MS M/z:574(M +1), was prepared by condensing the single chiral isomer 2-c of example 2, intermediate 2, with o-phenylenediamine 37, intermediate 37, ring-closing, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl group, as in example 37⁺.

EXAMPLE 213 preparation of Compound 213

Referring to the method of example 74, the intermediate 2 (four unresolved chiral isomer mixture) of example 2 is used as a raw material to perform condensation, ring closing, Boc removal and 1-methyl addition with the intermediate o-phenylenediamine 35 of example 35-1H-pyrazole-5-acyl to give compound 213, MS M/z:516(M +1)⁺.

EXAMPLE 214 preparation of Compound 214

Step 1 preparation of intermediate 214-1

Referring to example 38, intermediate 214-1, MS M/z:261(M +1) was obtained by coupling intermediate 38-1 with methyl 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) acetate⁺.

Step 2 preparation of Compound 214

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with an intermediate o-phenylenediamine 214-1, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, further referring to example 41, steps 6-7, alkaline hydrolysis, and finally condensation with 2-propylamine to give compound 214, MS M/z 601(M +1)⁺.

EXAMPLE 215 preparation of Compound 215

Referring to example 74, the single chiral isomer 2-b of intermediate 2 of example 2 was used as a starting material and condensed with an intermediate o-phenylenediamine 214-1, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further reference example 41, steps 6-7, alkaline hydrolysis, and finally condensation with cyclopentylamine gave compound 215, MS M/z:627(M +1)⁺.

EXAMPLE 216 preparation of Compound 216

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with an intermediate o-phenylenediamine 214-1, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6-7, alkaline hydrolysis, and finally condensation with cyclopentylamine gave compound 216, MS M/z:627(M +1)⁺.

EXAMPLE 217 preparation of Compound 217

Step 1 preparation of intermediate 217-1

Referring to the procedure of example 38, intermediate 38-1 was reacted with bromopyrazole "6-benzyl-4-methyl-3-bromo-2-methyl-4, 5,7, 8-tetrahydro-6H-pyrazolo [1,5-d]Coupling of diazepine-4, 6-dicarboxylate to give the intermediate 217-1, MS M/z:450(M +1)⁺.

Step 2 preparation of Compound 217

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 217, MS M/z: 682(M +1) by condensation with the intermediate o-phenylenediamine 217-1, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further reference to example 41, steps 6-7, base hydrolysis, condensation with cyclopentylamine, and final palladium on charcoal hydrogenation to remove the benzyloxycarbonyl protecting group⁺.

EXAMPLE 218 preparation of Compound 218

Step 1 preparation of intermediate 218-1

Referring to the procedure of example 38, intermediate 38-1 was reacted with bromopyrazole "methyl-3-bromo-2-methyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Oxazacycloheptane-4-carboxylic acid ester "couplingIntermediate 218-1, MS M/z:317(M +1) can be obtained⁺.

Step 2 preparation of Compound 218

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 218, MS M/z:683(M +1) by condensation with o-phenylenediamine 218-1 as an intermediate, ring closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, steps 6-7, base hydrolysis, and condensation with cyclopentylamine⁺.

EXAMPLE 219 preparation of Compound 219

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with the intermediate o-phenylenediamine 217-1, ring-closed, Boc-removed, 1-methyl-1H-pyrazole-5-acyl group added, and carbobenzoxy protecting group removed by hydrogenation over palladium to give compound 219, MS M/z:629(M +1)⁺.

EXAMPLE 220 preparation of Compound 220

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 40, which is an intermediate of example 40, to ring-close, remove Boc, and add 1-methyl-1H-pyrazole-5-acyl to give compound 220, MS M/z:601(M +1)⁺.¹H NMR(400MHz,MeOD):δ＝7.67-7.61(m,1H),7.53-7.51(m, 1H),7.47-7.34(m,3H),7.27-7.21(m,2H),6.49(s,1H),6.02(d,J＝9.6Hz,1H),5.03-4.98(m, 1H),4.73(s,1H),4.24-4.16(m,1H),3.93(s,3H),2.79(s,3H),2.26(d,J＝6.4Hz,4H),2.16(d, J＝3.6Hz,2H),1.99-1.93(m,1H),1.76(d,J＝7.2Hz,3H),0.99(d,J＝6.8Hz,2H),0.89(d,J＝6.8 Hz,3H)。

EXAMPLE 221 preparation of Compound 221

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, step 6-7 of example 41, base hydrolysis, condensation with methyl 4-aminotetrahydropyran-4-carboxylate, ester hydrolysis and aminolysis gave compound 221, MS M/z:632(M +1)⁺.

EXAMPLE 222 preparation of Compound 222

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-yl group was added, referring to example 41, Steps 6 to 7, alkaline hydrolysis and condensation with 3- (R) -aminopiperidin-2-one gave compound 222, MS M/z:602 (M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.91(s,1H),7.81-7.76(m,2H),7.69-7.67(m, 2H),7.62-7.52(m,2H),7.49–7.37(m,4H),7.34-7.30(m,2H),6.67(s,1H),5.96-5.91(m,1H), 4.28-4.21(m,1H),3.95(s,3H),3.31–3.28(m,2H),1.94–1.83(m,4H),1.67(d,J＝5.2Hz, 6H),0.68-.055(m,1H),0.25-0.19(m,2H),-0.02-0.08(m,1H).

EXAMPLE 223 preparation of Compound 223

Referring to the method of example 74, the single chiral isomer 12-c of the intermediate 12 of example 12 was used as a starting material to undergo condensation, ring closure, ring removal with the o-phenylenediamine 26 as the intermediate of example 26Boc, 1-methyl-1H-pyrazole-5-acyl, then example 41, steps 6-7, alkaline hydrolysis, and condensation with (2R,4S) -trans-4-fluoro-D-prolinamide gave compound 223, MS M/z:620(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.57(d,J＝8.1Hz,1H),7.41(d,J＝2.1 Hz,2H),7.39(s,1H),7.36–7.30(m,2H),7.28(s,1H),7.26(s,1H),7.23(d,J＝6.9Hz,1H), 6.63(s,1H),5.84(s,1H),5.02(s,1H),4.64–4.58(m,2H),3.91(d,J＝1.1Hz,3H),3.14– 3.51(m,1H),1.66(s,3H),1.60(s,3H),0.91(m,J＝13.5,7.5Hz,3H),0.33(m,J＝13.1,8.7, 4.0Hz,2H),0.24(s,2H),0.07–0.00(m,2H),-0.25(s,2H).

EXAMPLE 224 preparation of Compound 224

Referring to example 74, a single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-carbonyl group was added, referring to example 41, Steps 6 to 7, basic hydrolysis and condensation with 1-aminocyclopropanecarboxamide gave compound 224, MS M/z:588 (M +1)⁺.¹H NMR(400MHz,MeOD)δ7.90(d,J＝1.1Hz,1H),7.79(d,J＝8.7Hz,1H), 7.69(dd,J＝8.8,1.7Hz,1H),7.60–7.54(m,1H),7.48(dd,J＝7.9,1.3Hz,1H),7.44(d,J＝ 2.2Hz,1H),7.40(td,J＝7.6,1.3Hz,1H),7.32(ddd,J＝7.5,4.8,1.7Hz,1H),6.67(t,J＝2.5 Hz,1H),5.95(s,1H),3.96(s,3H),3.45(s,1H),2.88(s,1H),1.65(s,6H),1.51(q,J＝7.9,4.6 Hz,2H),1.06(q,J＝7.9,4.6Hz,2H),0.97–0.85(m,1H),0.51–0.41(m,1H),0.40–0.30(m, 1H),0.25–0.14(m,1H),-0.04(s,1H).

EXAMPLE 225 preparation of Compound 225

Referring to the procedure of example 74, starting from the single chiral isomer 12-c of intermediate 12 of example 12, the product was condensed with the intermediate o-phenylenediamine 26 of example 26Ring-opened, Boc-removed, 1-methyl-1H-pyrazole-5-acyl, which was subjected to alkaline hydrolysis in accordance with steps 6 to 7 of example 41 and then condensed with D-cyclopropylalaninamide to give compound 225, MS M/z:616(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.85(d,J＝1.3Hz,1H),7.81(s,1H),7.78(s,1H), 7.66(dd,J＝8.8,1.7Hz,1H),7.56(dd,J＝6.4,4.9Hz,1H),7.48(dd,J＝8.0,1.3Hz,1H), 7.45(d,J＝2.2Hz,1H),7.40(t,J＝7.4Hz,1H),7.36–7.30(m,1H),7.17(dd,J＝7.7,4.1Hz, 1H),5.94–5.85(m,1H),4.58–4.37(m,1H),3.59–3.45(m,2H),3.27–2.95(m,1H),1.70 (d,J＝3.2Hz,6H),1.59–1.50(m,2H),0.68–0.60(m,2H),0.51–0.43(m,1H),0.43–0.35 (m,3H),0.18(dd,J＝9.9,5.4Hz,2H),0.08–0.02(m,2H).

EXAMPLE 226 preparation of Compound 226

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group addition, referring to examples 41, steps 6 to 7, alkaline hydrolysis, and ammonolysis with aqueous ammonia to give compound 226, MS M/z:505(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.84(d,J＝1.2Hz,1H),7.80(dd,J＝8.4,0.8Hz,1H), 7.68-7.65(m,1H),7.60–7.55(m,1H),7.48(dd,J＝8.0 1.2Hz,1H),7.44(d,J＝2.0Hz,1H), 7.42-7.38(m,1H),7.32-7.28(m,1H),6.66(d,J＝2.0Hz,1H),5.94(s,1H),3.96(s,3H),3.52 –3.45(m,1H),1.68(s,6H),1.63(s,1H),1.31(s,1H),0.48–0.42(m,1H),0.40-0.33(m,1H), 0.21-0.16(m,1H),-0.04(s,1H).

EXAMPLE 227 preparation of Compound 227

Referring to the method of example 74, the single chiral isomer 12-c of the intermediate 12 of example 12 is used as a raw material to be condensed with the o-phenylenediamine 26 as the intermediate of example 26,cyclization, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, Steps 6-7, alkaline hydrolysis, and condensation with 3- (R) -amino-2-pyrrolidinone gave compound 227, MS M/z:588 (M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.93(s,1H),7.81(d,J＝8.8Hz,1H),7.71 (dd,J＝8.4,1.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.47(dd,J＝8.0,1.6Hz,1H),7.43–7.42(m, 1H),7.39(dd,J＝7.6,1.6Hz,1H),7.34-7.30(m,1H),6.67(d,J＝2.0Hz,1H),6.00(s,1H), 4.46(t,J＝8.8Hz,1H),3.96(s,3H),3.38(dd,J＝9.6,2.8Hz,2H),2.47–2.39(m,1H), 2.14-2.02(m,1H),1.68(d,J＝2.4Hz,6H),1.31(s,1H),0.48–0.35(m,2H),0.22-0.16(m,1H), -0.06(s,1H).

EXAMPLE 228 preparation of Compound 228

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-carbonyl addition, according to example 41, steps 6-7, base hydrolysis, and condensation with 1-amino-1-cyclopenta-carboxamide to give compound 228, MS M/z:616(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.87(d,J＝1.6Hz,1H),7.81(d,J＝8.8Hz, 1H),7.66-7.63(m,1H),7.59–7.54(m,1H),7.48-7.46(m,1H),7.44-7.42(m,1H),7.40-7.37(m, 1H),7.34-7.30(m,1H),6.67(d,J＝2.0Hz,1H),6.00(s,1H),3.96(s,3H),3.45(s,1H), 2.18-2.13(m 2H),2.00–1.94(m,2H),1.76–1.50(m,12H),1.30(s,1H),0.49-0.42(m,1H), 0.38-0.31(m,1H),0.22–0.16(m,1H).

EXAMPLE 229 preparation of Compound 229

Referring to the procedure of example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material to undergo condensation, ring closure, Boc removal, and addition of 1-methyl-1-carbonyl group with o-phenylenediamine 26, an intermediate of example 26H-pyrazole-5-acyl, according to the steps 6 to 7 of example 41, which was subjected to alkaline hydrolysis and condensation with R-2-amino-2-cyclopropylacetamide to give 229, MS M/z:602 (M +1)⁺.¹H NMR(400MHz,DMSO-d6)δ7.57–7.46(m,3H),7.43–7.34(m,2H),7.38 –7.20(m,2H),7.24–7.11(m,1H),6.65-6.64(m,1H),5.90-5.81(m,1H),3.82(s,3H),3.81–3.70(m,2H),1.56–1.44(m,8H),1.53(d,J＝4.8Hz,3H),1.21(d,J＝6.6Hz,4H),1.02-0.95 (m,1H),0.38-0.28(m,3H),0.23-0.18(m,1H),0.14-0.08(m,2H),0.01--0.09(m, 1H)-0.33--0.41(m,1H).

EXAMPLE 230 preparation of Compound 230

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-carbonyl group was added, referring to example 41, Steps 6 to 7, basic hydrolysis and condensation with 3-aminotetrahydrofuran-3-carboxamide to give compound 230, MS M/z:618(M +1)⁺.¹H NMR(400MHz,Methanol-d₄)δ7.58(s,2H),7.41–7.39(m,2H),7.33–7.30 (m,2H),7.25(dd,J＝7.8,1.6Hz,1H),6.63(s,1H),5.84(s,1H),4.21(d,J＝9.4Hz,1H),3.90 (s,3H),3.86(dd,J＝9.5,2.4Hz,1H),3.79–3.69(m,1H),2.44-2.37(m,1H),2.26-2.17(m, 1H),1.68-1.61(m,7H),1.31(s,3H),0.91(d,J＝9.2Hz,1H),0.34–0.23(m,3H),0.04 (dd,J＝9.6,4.8Hz,1H).

EXAMPLE 231 preparation of Compound 231

Referring to the procedure of example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was used as a starting material to undergo condensation with o-phenylenediamine 26, which is an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to the procedure of example 41, steps 6 to 7, basic hydrolysis, and condensation with 1-aminocyclobutanecarboxamide, thus obtaining the compoundThe compound 231, MS M/z:602 (M +1) can be obtained⁺.¹H NMR(400MHz,Methanol-d4)δ7.64–7.52(m,3H),7.41-7.39(m,2H), 7.35-7.31(m,2H),7.28–7.21(m,1H),6.63(s,1H),5.84(s,1H),3.90(s,3H),2.63–2.56(m, 2H),2.20-2.12(m,2H),1.93–1.86(m,3H),1.66(s,7H),1.31-1.24(m,1H),0.435–0.21(m, 2H),0.07-0.03(m,1H).

EXAMPLE 232 preparation of Compound 232

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was condensed with o-phenylenediamine 26, ring-closed, Boc removed, 1-methyl-1H-pyrazole-5-carbonyl group added as an intermediate in example 26, followed by basic hydrolysis, condensation with methyl 1-aminocyclobutanecarboxylate, and ester hydrolysis to give compound 232, MS M/z:603(M +1) in example 41, steps 6-7⁺.¹H NMR(400MHz,Methanol-d4)δ7.69(s,1H),7.59(d,J＝8.4 Hz,2H),7.43–7.20(m,8H),6.65(s,1H),5.87(s,1H),3.90(s,3H),3.62(s,1H),3.19–3.12 (m,1H),3.00(s,1H),2.84(s,1H),2.57–2.35(m,5H),1.94(s,18H),1.78(d,J＝3.6Hz,1H), 1.65(s,6H),1.37–1.20(m,4H),0.36–0.18(m,2H).

EXAMPLE 233 preparation of Compound 233

Referring to example 74, the single chiral isomer 12-c of intermediate 12 of example 12 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-carbonyl group addition, referring to examples 41, steps 6 to 7, alkaline hydrolysis, and condensation with D-leucinamide to give compound 233, MS M/z:618(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.85(s,1H),7.79(d,J＝8.8Hz,1H),7.65-7.62(m,3H), 7.49–7.40(m,3H),7.32-7.23(m,2H),6.65(d,J＝2.0Hz,1H),5.93(s,1H),4.49(dd,J＝10.4, 4.4Hz,1H),3.96(s,3H),3.54–3.45(m,1H),1.69(s,6H),0.92-0.87(m,6H),0.49-0.42(m, 1H),0.37(s,1H),0.21-0.15(m,1H).

EXAMPLE 234 preparation of Compound 234

Referring to example 74, intermediate 9 of example 9 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group addition, as shown in example 41, steps 6 to 7, alkaline hydrolysis, and condensation with R-2-amino-2-cyclobutyl-N-methylacetamide to give compound 234, MS M/z:648(M +1) +

EXAMPLE 235 preparation of Compound 235

Referring to example 74, intermediate 10 of example 10 was used as a starting material and subjected to condensation with o-phenylenediamine 26 of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl group, further referring to steps 6 to 7 of example 41, alkaline hydrolysis, and condensation with R-2-amino-2-cyclobutyl-N-methylacetamide to obtain compound 235, MS M/z:648(M +1)⁺.¹H NMR(400M,MeOD)δ7.70-7.79(m,2H),7.65-7.69(m,1H),7.50-7.60(m,3H), 7.43-7.49(m,1H),7.35-7.42(m,2H),7.18-7.28(m,1H),6.89-7.01(m,2H),6.06-6.10(m,1H), 5.71-5.73(m,1H),5.67-5.70(m,1H),4.28-4.35(m,1H),4.00(s,1H),3.90(s,2H),2.71-2.72(m, 3H),2.49-2.60(m,1H),1.82-1.98(m,4H),1.74-1.81(m,1H),1.63-1.69(m,6H), 0.60-0.67(m,1H),0.45-0.54(m,2H),0.31-0.43(m,2H).

EXAMPLE 236 preparation of Compound 236

Referring to the procedure of example 74, the intermediate 8 of example 8 was used as a starting material to react with the intermediate o-phenylenediamine of example 2626 condensation, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, base hydrolysis, and condensation with R-2-amino-2-methyl-N-methylacetamide as in example 41, Steps 6-7, to give compound 236, MS M/z:594(M +1)⁺.

EXAMPLE 237 preparation of Compound 237

Referring to example 74, intermediate 8 of example 8 was used as a starting material and subjected to condensation with o-phenylenediamine 26 of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with R-2-amino-2-isopropyl-N-methylacetamide to give compound 237, MS M/z:622(M +1)⁺.

EXAMPLE 238 preparation of Compound 238

Referring to example 74, intermediate 7 of example 7 was used as a starting material and subjected to condensation with o-phenylenediamine 26, which is an intermediate of example 26, ring closure, removal of Boc, and addition of 1-methyl-1H-pyrazole-5-acyl group, according to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with R-2-amino-2-methyl-acetamide to give compound 238, MS M/z:566(M +1)⁺.¹H NMR (400M,CDCl₃)δ8.18(s,1H),7.88-8.06(m,1H),7.58-7.67(m,1H),7.50-7.57(m,1H), 7.38-7.48(m,2H),7.30-7.38(m,2H),7.14-7.28(m,4H),6.78-6.90(m,1H),6.34-6.43(m,1H), 5.84-6.09(m,3H),5.71-5.78(m,1H),5.54-5.60(m,1H),5.31-5.39(m,1H),4.49-4.57(m,1H), 4.00-4.07(m,2H),3.94-3.98(m,1H),3.35-3.42(m,2H),3.24(s,1H),1.58-1.72(m, 6H),1.23-1.32(m,3H).

Preparation of example 239 Compound 239

Referring to example 74, intermediate 7 of example 7 was used as a starting material and subjected to condensation with o-phenylenediamine 26 as an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with R-2-amino-2-methyl-N-methylacetamide to give compound 239, MS M/z:580(M +1)⁺.¹H NMR(400M,CDCl₃)δ8.14(s,1H),7.61-7.72(m,2H),7.50-7.59(m,2H),7.46-7.49(m, 1H),7.41-7.45(m,1H),7.30-7.37(m,3H),7.14-7.26(m,4H),6.81-6.89(m,1H),6.28-6.41(m, 2H),6.01-6.10(m,1H),5.82-5.95(m,2H),5.55-5.61(m, 1H),5.31-5.41(m,1H),4.39-4.55(m,2H),4.03-4.13(m,3H),3.95-4.02(m,2H),3.36-3.48(m, 3H),3.24(s,2H),2.70-2.83(m,5H),1.66(s,9H),1.17-1.36(m,6H).

EXAMPLE 240 preparation of Compound 240

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to examples 41, Steps 6-7, alkaline hydrolysis, and condensation with N, N-dimethylethylenediamine to give compound 240, MS M/z:578 (M +1)⁺.

EXAMPLE 241 preparation of Compound 241

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, steps 6-7, base hydrolysis, and condensation with N- (2-aminoethyl) morpholine to give 241, MS M/z:620(M +1)⁺.

EXAMPLE 242 preparation of Compound 242

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 242, MS M/z: 621(M +1), by condensation with o-phenylenediamine 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, Steps 6-7, alkaline hydrolysis, condensation with D-leucine methyl ester, and final ester hydrolysis⁺.¹HNMR(400MHz,MeOD):δ＝8.52(s,1H),7.98(s,1H),7.86(s,1H),7.63(s,2H), 7.34-7.48(m,3H),6.49(s,1H),6.09-6.12(m,1H),4.63(s,2H),4.19-4.21(m,1H),3.88-3.96(m, 6H),3.34-3.40(m,2H),1.96-2.00(m,1H),1.60-1.66(m,1H),1.46-1.50(d,4H,J＝16Hz), 1.24-1.27(m,2H),1.02-1.03(d,3H,J＝6Hz),0.89-0.91(d,3H,J＝6.8Hz),0.73-0.75(t,3H,J＝6 Hz),0.35-0.37(d,3H,J＝6.4Hz)

Preparation of compound 243 of example 243

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, alkaline hydrolysis, and further condensation with intermediate 162-2 of example 162 to give compound 243, MS M/z: 698(M +1)⁺。

EXAMPLE 244 preparation of Compound 244

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to undergo condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, referring to example 41, steps 6 to 7, and addition of aqueous alkaliThe resulting product was condensed with intermediate 165-4 of example 165 to give compound 244, MS M/z: 645(M +1)⁺。

Preparation of compound 245 of example 245

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to condense with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference example 41, Steps 6-7, alkaline hydrolysis, and further condensation with intermediate 164-1 of example 164 to give compound 245, MS M/z:724(M +1)⁺。

EXAMPLE 246 preparation of Compound 246

Referring to example 74, a compound 246, MS M/z:712(M +1), was prepared by condensation of the single chiral isomer 2-c of intermediate 2 of example 2, starting with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, reference example 41, steps 6-7, base hydrolysis, and condensation with intermediate 163-1 of example 163⁺。

EXAMPLE 247 preparation of Compound 247

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to examples 41, steps 6 to 7, alkaline hydrolysis, and condensation with D-leucinamide to give compound 247, MS M/z:620(M +1)⁺.

EXAMPLE 248 preparation of Compound 248

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to examples 41, steps 6-7, base hydrolysis, condensation with R-2-cyclopropyl-glycine methyl ester, and ester hydrolysis to give compound 248, MS M/z:605(M +1)⁺。

EXAMPLE 249 preparation of Compound 249

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and 1-methyl-1H-pyrazole-5-acyl group was added, followed by basic hydrolysis, condensation with R-2-amino-2-cyclopropylmethyl-ethyl acetate, and ester hydrolysis to give compound 249, MS M/z:619(M +1), in accordance with example 41, step 6-7⁺.

EXAMPLE 250 preparation of Compound 250

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and 1-methyl-1H-pyrazole-5-acyl group was added, followed by basic hydrolysis, condensation with D-proline methyl ester, and ester hydrolysis to give compound 250, MS M/z:605(M +1) in example 41, steps 6-7⁺.¹H NMR(400MHz,MeOD)δ7.58–7.55(m,2H),7.53–7.50(m,1H),7.37 (dd,J＝14.5,5.8Hz,3H),7.28–7.22(m,2H),6.52(s,1H),6.02(d,J＝9.0Hz,1H),4.45(m, 1H),4.18(s,1H),3.95(s,3H),2.94–2.88(m,2H),2.13(m,2H),1.96(m,1H),1.82–1.68(m, 2H),1.61(d,J＝6.8Hz,6H),1.02(d,J＝5.7Hz,3H),0.87(d,J＝6.8Hz,3H).

Preparation of example 251 Compound 251

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to examples 41, Steps 6-7, base hydrolysis, condensation with D-proline methyl ester, ester hydrolysis and aminolysis gave 251, MS M/z:604(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.60–7.48(m,3H),7.39(dm,3H),7.24 (m,2H),6.51(s,1H),6.02(d,J＝9.0Hz,1H),4.44(m,1H),4.18(s,1H),3.94(s,3H),2.92(m, 2H),1.96(m,1H),1.80–1.68(m,2H),1.65(s,3H),1.57(s,3H),1.54–1.42(m,2H),0.99 (d,J＝17.1Hz,3H),0.87(d,J＝6.4Hz,3H).

EXAMPLE 252 preparation of Compound 252

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, basic hydrolysis, condensation with methyl 1-aminocyclopropanecarboxylate, and further ester hydrolysis to give 252, MS M/z:591(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.61(s,1H),7.54–7.46(m,2H), 7.39–7.34(m,1H),7.34–7.26(m,2H),7.25–7.13(m,2H),6.46(s,1H),5.96(d,J＝9.5Hz, 1H),4.27–4.12(m,1H),4.09(s,1H),3.90(s,3H),1.95-1.81(m 1H),1.59(s,6H),1.52(s, 2H),1.47-1.39(m,2H),1.00–0.91(m,6H),0.84(d,J＝6.8Hz,3H).

EXAMPLE 253 preparation of Compound 253

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with 3- (R) -amino-2-pyrrolidone to give compound 253, MS M/z:590(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.65(s,1H),7.57–7.49(m,3H),7.42–7.31(m,4H), 7.27–7.21(m,2H),6.48(s,1H),5.99(d,J＝9.5Hz,1H),4.45–4.36(m,1H),4.30–4.17(m, 1H),3.92(s,3H),2.48–2.35(m,2H),2.08–1.85(m,3H),1.64(d,J＝6.5Hz,6H),0.96 (t,J＝6.5Hz,3H),0.87(d,J＝6.8Hz,3H).

EXAMPLE 254 preparation of Compound 254

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to examples 41, steps 6 to 7, basic hydrolysis and condensation with R-2-amino-2-cyclopropylmethyl-acetamide gave compound 254, MS M/z:618(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.55-7047(m,2H),7.43-7.38(m,2H),7.34– 7.29(m,2H),7.26–7.14(m,2H),6.86(d,J＝8.4Hz,1H),6.48-6.47(m,1H),5.88(d,J＝11.0 Hz,1H),4.31–4.19(m,2H),3.82(s,3H),1.80-1.68(m,1H),1.54(d,J＝7.3Hz,6H), 1.40-1.33(m,1H),0.80-0.75(m,6H),0.52-0.44(m,1H),0.26-0.22(m,2H),-0.03--0.13(m, 3H).

EXAMPLE 255 preparation of Compound 255

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, Steps 6-7, basic hydrolysis and condensation with R-2-amino-2-cyclopentanecarboxamide gave compound 255, MS M/z:618(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.64–7.46(m,3H),7.44-7.39(m,2H),7.37– 7.29(m,2H),7.25-7.21(m,1H),7.13(d,J＝8.6Hz,1H),6.90(s,1H),6.49-6.44(m,1H),5.88 (d,J＝9.6Hz,1H),3.82(s,3H),1.98-1.92(m,3H),1.84-1.75(m,4H),1.52(s,6H),1.45-1.41 (m,2H),0.78(d,J＝6.9Hz,6H).

EXAMPLE 256 preparation of Compound 256

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to condense with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, steps 6-7, alkaline hydrolysis, and final ammonolysis to give 256, MS M/z:507(M +1)⁺.¹H NMR(400 MHz,DMSO-d₆)δ12.53(d,J＝14.8Hz,1H),8.76(dd,J＝31.2,9.4Hz,1H),7.61–7.56(m, 1H),7.47–7.40(m,3H),7.34–7.20(m,2H),7.25–7.16(m,2H),6.87-6.80(m,2H),6.50 (d,J＝2.4Hz,1H),5.90(t,J＝10.0Hz,1H),4.32–4.24(m,1H),4.12(d,J＝7.6Hz,1H),3.83 (s,3H),3.18(d,J＝4.4Hz,1H),1.78(d,J＝9.2Hz,1H),1.50(s,6H),0.78(t,J＝7.2Hz,6H).

EXAMPLE 257 preparation of Compound 257

Referring to the method of example 74, the single chiral isomer 2-c of the intermediate 2 of example 2 is used as a raw material to be condensed with the intermediate o-phenylenediamine 26 of example 26, ring closure, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, and then reference is made to the factEXAMPLE 41 Steps 6-7, alkaline hydrolysis, condensation with methylamine hydrochloride gave compound 257, MS M/z:521(M +1)⁺.

EXAMPLE 258 preparation of Compound 258

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, remove Boc, and add 1-methyl-1H-pyrazole-5-acyl, referring to example 41, Steps 6-7, and then subjected to basic hydrolysis and condensation with R-2-amino-2-cyclopropyl-acetamide to give compound 258, MS M/z:604(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.56(d,J＝13.5Hz,2H),7.43(dd,J＝8.0,2.4Hz, 2H),7.38–7.28(m,2H),7.26–7.21(m,1H),7.18(d,J＝8.6Hz,1H),6.51(s,1H),5.92 (d,J＝11.2Hz,1H),4.25(d,J＝10.9Hz,1H),3.84(s,3H),3.80–3.73(m,1H),2.68(dd,J＝3.7,1.8Hz,1H),2.34(dt,J＝3.6,1.8Hz,1H),1.81(s,1H),1.53(s,6H),1.46(d,J＝8.5Hz, 1H),1.00(dt,J＝11.0,4.1Hz,1H),0.81(t,J＝11.9Hz,6H),0.44–0.28(m,3H),0.16(d,J＝ 3.7Hz,1H),-0.05(s,1H).

Preparation of the Compound 259 of example 259

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 as an intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, steps 6 to 7, base hydrolysis, and condensation with 1-aminocyclopropanecarboxamide to give 259, MS M/z:590(M +1)⁺.

EXAMPLE 260 preparation of Compound 260

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, remove Boc, and then subjected to 1-methyl-1H-pyrazole-5-acyl group, referring to steps 6 to 7 of example 41, basic hydrolysis, and condensation with 3-aminotetrahydrofuran-3-carboxamide to give compound 260, MS M/z:620(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.78(s,1H),7.75–7.66(m,3H),7.65–7.57 (m,3H),7.54–7.43(m,5H),7.38(d,J＝8.0Hz,1H),7.34–7.28(m,2H),7.24(dd,J＝8.0, 1.2Hz,1H),7.16–7.12(m,1H),7.08(d,J＝2.0Hz,1H),6.71(s,1H),6.14(d,J＝8.0Hz,1H), 5.92(d,J＝11.4Hz,1H),4.45(dd,J＝11.4,5.2Hz,1H),4.27–4.21(m,2H),4.08(s,3H), 3.99(s,3H),3.92(qd,J＝8.4,4.8Hz,2H),3.85–3.69(m,4H),2.61(dt,J＝12.8,6.4Hz,1H), 2.40(dq,J＝13.2,8.4Hz,2H),2.29-2.24(m,3H),1.63(dd,J＝27.46 2.4Hz,11H),1.35–1.31 (m,1H),1.13(d,J＝6.8Hz,3H),1.02(dd,J＝15.6,6.8Hz,5H),0.87(d,J＝6.8Hz,4H).

Preparation of compound 261 of example 261

Referring to example 74, starting from the single chiral isomer 2-c of intermediate 2 of example 2, the compound 261, MS M/z:634(M +1), was obtained by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference to example 41, steps 6-7, base hydrolysis, condensation with methyl 4-aminotetrahydropyran-4-carboxylate, final ester hydrolysis and aminolysis⁺.

EXAMPLE 262 preparation of Compound 262

Referring to the method of example 74, the single chiral isomer 2-c of the intermediate 2 of example 2 is used as a raw material to be condensed with the o-phenylenediamine 26 of the intermediate 26 of example 26, and the ring is closed, Boc is removed, and the 1-methyl is addedYl-1H-pyrazole-5-acyl, which was obtained by basic hydrolysis and condensation with 3- (R) -aminopiperidin-2-one in steps 6 to 7 of example 41 to give compound 262, MS M/z:604(M +1)⁺.¹H NMR(400MHz,Methanol-d4)δ7.83(s,1H),7.73-7.69(m,2H),7.65-7.62(m, 2H),7.57–7.53(m,2H),7.45(s,2H),7.40-7.37(m,1H),7.34–7.24(m,3H),6.68(s,1H), 6.13-6.09(m,1H),5.82-5.87(m,1H),4.43-4.37(m,1H),4.24-4.18(m,3H),4.08(s,2H),3.99 (s,3H),3.30-3.27(m,3H),2.20-2.11(m,2H),1.98-1.95(m,3H),1.93–1.80(m,6H),1.67-1.63 (m,6H),1.60-1.57(m,5H),1.33(t,J＝7.3Hz,3H),1.12(d,J＝6.5Hz,3H),1.05-1.01(m,3H), 0.88(d,J＝6.7Hz,3H).

EXAMPLE 263 preparation of Compound 263

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to examples 41, steps 6 to 7, basic hydrolysis and condensation with 1-aminocyclobutanecarboxamide gave compound 263, MS M/z:604(M +1)⁺.

EXAMPLE 264 preparation of Compound 264

Step 1 preparation of intermediate 264-1

Dissolving 4-bromo-2-nitro-phenol (4.36g,20.00mmol) and 4-methoxybenzyl bromide (8.04g,40.00mmol) in DMF (40.00mL) reaction solution, heating to 80 ℃ and stirring for 2 hours, cooling to room temperature after the reaction is finished, adding water for dilution, DCM for extraction (2X 60mL), combining organic phases, washing with water (3X 60mL), washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying a crude product by silica gel column chromatography (petroleum ether/ethyl acetate 30: 1) to obtain an intermediate 264-1(3.70g,10.94mmol, 54.70% yield), and LC-MS does not respond.

Step 2 preparation of intermediate 264-2

Dissolving intermediate 264-1(6.00g,17.74mmol) and ethyl acrylate (5.33g,53.22mmol) in acetonitrile (50mL), heating to 90 ℃ under the protection of nitrogen, stirring for 12 hours, cooling to room temperature, concentrating under reduced pressure, diluting with water, extracting with DCM (2X 60mL), combining organic phases, washing with water (3X 60mL), washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 20: 1) to obtain intermediate 264-2(3.50g,9.79mmol, 55.21% yield), MS M/z:358(M +1)⁺.

Step 3 preparation of intermediate 264-3

Dissolving intermediate 264-2(1.50g,4.20mmol) in 30ml methanol, adding PtO2(50 mg) under nitrogen atmosphere, hydrogenating overnight at normal pressure, adding 10% Pd/C (50mg) after the raw material disappears, hydrogenating overnight at normal pressure, filtering with diatomaceous earth, concentrating the filtrate under reduced pressure to dryness, purifying the crude product with MPLC 18 reverse phase column to obtain intermediate 264-3 (800.00mg,3.82mmol, 91.03% yield), MS M/z:210(M +1)⁺.

Step 3 preparation of intermediate 264-4

Intermediate 264-3(300.00mg,1.43mmol) was dissolved in DCM (10mL), intermediates 41-3(419.50mg,1.43mmol), EDCI (273.13mg,1.43mmol), HOAT (194.48mg,1.43mmol) and DIPEA (553.41mg,4.29mmol) from example 41 were added in that order, the reaction mixture was stirred at room temperature for 2 hours, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified over silica gelColumn chromatography separation and purification (dichloromethane/methanol 20: 1) to obtain intermediate 264-4(544mg,1.14mmol, 80% yield), MS M/z:485(M +1)⁺.

Step 5 preparation of intermediate 264-5

Dissolving intermediate 264-4(500.00mg,1.03mmol) in 15mL toluene, adding TsOH (268.26mg,5.15 mmol), heating to 100 ℃ and stirring for 15 hours, after the reaction is finished, concentrating under reduced pressure, separating and purifying by silica gel column chromatography (dichloromethane/methanol 30: 1) to obtain intermediate 264-5(130.00mg,278.63umol, 27.05% yield), MS M/z:467(M +1)⁺.

Step 6 preparation of intermediate 264-6

Dissolving the intermediate 264-6(100.00mg,214.33umol) in 5ml ethanol, adding NaOH (17.15mg, 428.66umol), stirring overnight at room temperature, adjusting the pH value to 6 with 1N HCl after the reaction is finished, extracting with ethyl acetate, and concentrating under reduced pressure to dryness to obtain a crude product (93.00mg,212.08umol, 98.95% yield) of the intermediate 264-6, which is directly used in the next step without purification. MS M/z 439(M +1)⁺.

Step 7 preparation of intermediate 264-7

Dissolving intermediate 264-6(50.00mg,114.02umol) in DCM (5mL), sequentially adding D-leucine tert-butyl ester (23.49mg,125.42umol), EDCI (26.13mg,136.82umol), HOAT (18.61mg,136.82umol) and DIPEA (73.54mg,570.10umol), stirring the reaction solution at room temperature for 2 hours, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the crude product by silica gel column chromatography (dichloromethane/methanol 30: 1) to obtain intermediate 264-7(40.00mg,65.81umol, 57).72％yield)，MS m/z:608(M+1)⁺.

Step 8 preparation of Compound 264

Dissolving intermediate 264-7(40.00mg,65.81umol) in 2mL dichloromethane, adding 2mL trifluoroacetic acid under ice bath, dripping, stirring under ice bath for 3 hours, reacting, concentrating under reduced pressure, purifying the crude product with MPLC reversed phase C18 column to obtain compound 264(5.10mg,8.80umol, 13.37% yield), MS M/z:552(M +1)⁺.

EXAMPLE 265 preparation of Compound 265

Referring to example 74, starting from the single chiral isomer 2-c of intermediate 2 of example 2, the product was condensed with o-phenylenediamine 26, example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, step 6-7 of example 41, base hydrolysis, and addition of (R) -7-amino-5-azaspiro [2.4 ]]Condensation of the hepta-4-one gives the compound 265, MS M/z:604(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.60-7.55(m,1H),7.53-7.47(m,1H), 7.47–7.38(m,3H),7.35–7.29(m,2H),7.25-7.19(m,1H),7.13-7.08(m,1H),6.49-6.47(m, 1H),5.88(d,J＝11.1Hz,1H),4.51-4.43(m,1H),4.28-4.17(m,1H),3.82(s,3H),3.11-3.05(m, 1H),1.78-1.71(m,1H),1.57–1.42(m,6H),0.87–0.68(m,8H),0.52-0.42(m,2H).

EXAMPLE 266 preparation of Compound 266

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 27, ring-closing, Boc removal, and then 1-methyl-1H-pyrazole-5-acyl group was added theretoEXAMPLE 41 Steps 6-7, alkaline hydrolysis, condensation with R-2-amino-2-cyclopropyl-acetamide gave compound 266, MS M/z:622(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.54–7.30(m,8H),7.24(d,J＝7.6Hz,2H),6.65 (s,1H),6.48(s,1H),5.90(d,J＝11.2Hz,2H),4.27(t,J＝6.8Hz,1H),3.82(s,3H),1.80(s, 2H),1.57-1.41(m,8H),1.24(s,3H),0.98(d,J＝6.4Hz,2H),0.90–0.72(m,9H),0.39–0.30 (m,4H),0.16(s,2H).

EXAMPLE 267 preparation of Compound 267

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 267, MS M/z:578 (M +1) by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to examples 41, Steps 6-7, basic hydrolysis, and condensation with (R) -2-amino-propionamide⁺.¹H NMR(400MHz,DMSO-d₆)δ7.69(d,J＝8.9Hz,2H),7.55–7.46(m,1H),7.46 –7.34(m,4H),7.28(td,J＝7.7,1.6Hz,1H),6.61(d,J＝1.8Hz,1H),6.02(d,J＝9.6Hz,1H), 4.26–4.20(m,1H),4.15(dd,J＝9.4,5.9Hz,1H),3.86(s,3H),1.92(dd,J＝13.1,6.3Hz,1H), 1.53(s,6H),1.17(d,J＝7.1Hz,3H),0.90(d,J＝6.6Hz,3H),0.77(d,J＝6.7Hz,3H).

EXAMPLE 268 preparation of Compound 268

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group, referring to examples 41, steps 6 to 7, alkaline hydrolysis, and condensation with (R) -3-amino-3-methyl-2-pyrrolidone to give compound 268, MS M/z:604(M +1)⁺.

EXAMPLE 269 preparation of Compound 269

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with o-phenylenediamine 26, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, referring to example 41, Steps 6 to 7, basic hydrolysis was performed, and condensation with (R) -2-amino-N-methylpropanamide was carried out to obtain compound 269, MS M/z:592(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝8.9Hz,2H),7.47(d,J＝7.5Hz, 1H),7.44–7.30(m,4H),7.26(dd,J＝12.1,4.6Hz,1H),6.56(s,1H),5.97(d,J＝9.7Hz,1H), 4.25–4.20(m,1H),4.16(s,1H),3.84(s,3H),1.87(s,1H),1.51(d,J＝9.5Hz,6H),1.14 (d,J＝7.1Hz,3H),0.86(d,J＝6.5Hz,3H),0.77(d,J＝6.7Hz,3H).

EXAMPLE 270 preparation of Compound 270

Referring to example 74, a compound 270, MS M/z:648(M +1), was prepared from the single chiral isomer 2-c of intermediate 2 of example 2 by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further reference to example 41, steps 6-7, base hydrolysis, condensation with (R) -2-amino-propionic acid methyl ester, ester hydrolysis, and finally condensation with 3-aminotetrahydrofuran⁺.¹H NMR(400MHz,DMSO-d₆)δ7.68–7.60 (m,2H),7.47(d,J＝7.4Hz,1H),7.43–7.30(m,4H),7.29–7.22(m,1H),6.56(s,1H),5.98 (d,J＝9.5Hz,1H),4.26–4.21(m,1H),4.21–4.10(m,3H),3.84(s,3H),2.06–1.98(m,1H), 1.90–1.83(m,1H),1.53(d,J＝9.0Hz,6H),1.14(dd,J＝7.1,1.4Hz,3H),0.86(d,J＝6.6Hz, 3H),0.78(d,J＝6.8Hz,3H).

EXAMPLE 271 preparation of compound 271

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with (R) -2-amino-N, N' -dimethylpropionamide to give compound 271, MS M/z:606 (M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.66(d,J＝8.4Hz,2H),7.49(d,J＝7.7Hz, 1H),7.45–7.32(m,4H),7.28(t,J＝6.9Hz,1H),6.58(s,1H),5.98(d,J＝9.7Hz,1H),4.73– 4.61(m,1H),4.16(dd,J＝9.9,6.0Hz,1H),3.85(s,3H),3.00–2.89(m,3H),2.78(dd,J＝ 13.6,6.7Hz,3H),1.94–1.83(m,1H),1.57–1.44(m,6H),1.12(t,J＝9.7Hz,3H),0.88 (d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H).

EXAMPLE 272 preparation of Compound 272

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, remove Boc, and add 1-methyl-1H-pyrazole-5-acyl, referring to examples 41, Steps 6-7, alkaline hydrolysis, and condensation with (R) -2-amino-N-ethylpropionamide to give compound 272, MS M/z:606 (M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.68(d,J＝7.9Hz,2H),7.55–7.46(m,1H),7.46 –7.33(m,4H),7.32–7.24(m,1H),6.59(s,1H),6.00(d,J＝9.9Hz,1H),4.27–4.12(m,2H), 3.85(s,3H),3.08–2.95(m,2H),1.93–1.83(m,1H),1.51(dd,J＝28.2,6.2Hz,6H),1.15 (d,J＝9.7Hz,3H),0.99–0.91(m,3H),0.89(d,J＝10.6,4.5Hz,3H),0.78(d,J＝6.7Hz,3H).

EXAMPLE 273 preparation of Compound 273

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group, referring to steps 6 to 7 of example 41, alkaline hydrolysis, and condensation with (R) -2-amino-N-isopropylacrylamide gave compound 273, MS M/z:620(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.77–7.64(m,2H),7.51(d,J＝7.2Hz,1H), 7.41(dt,J＝13.7,6.9Hz,4H),7.30(dd,J＝10.7,4.5Hz,1H),6.59(s,1H),6.00(d,J＝9.7Hz, 1H),4.23–4.11(m,2H),3.85(s,3H),1.91(d,J＝6.2Hz,1H),1.62–1.46(m,6H),1.15 (d,J＝7.1Hz,3H),1.04–0.92(m,6H),0.90(d,J＝6.6Hz,3H),0.78(d,J＝6.7Hz,3H).

EXAMPLE 274 preparation of Compound 274

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to condense with o-phenylenediamine 26, the intermediate of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, Steps 6-7, alkaline hydrolysis, and condensation with (R) -2-amino-N-cyclopropylpropionamide gave 274, MS M/z:618(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.67(s,2H),7.48(d,J＝7.6Hz,1H),7.37 (d,J＝14.2Hz,4H),7.30–7.23(m,1H),6.57(s,1H),5.98(d,J＝9.6Hz,1H),4.20–4.08(m, 2H),1.94–1.80(m,1H),1.47(dd,J＝28.3,9.5Hz,6H),1.11(d,J＝7.1Hz,3H),0.86(d,J＝ 6.2Hz,3H),0.76(d,J＝6.5Hz,3H),0.56(d,J＝5.4Hz,2H),0.27(s,2H).

EXAMPLE 275 preparation of Compound 275

Referring to the method of example 74, the single chiral isomer 2-c of the intermediate 2 of example 2 is used as a raw material to be condensed with the o-phenylenediamine 26 as the intermediate of example 26,cyclization, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, and condensation with (R) -2-amino-N-cyclopropylmethylpropanamide, by basic hydrolysis, according to steps 6-7 of example 41, gave compound 275, MS M/z:632(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.76–7.60(m,2H),7.56–7.46(m,1H),7.46 –7.32(m,4H),7.30–7.21(m,1H),6.58(d,J＝1.6Hz,1H),6.00(d,J＝10.0Hz,1H),4.29– 4.22(m,1H),4.21–4.13(m,1H),3.85(s,3H),2.97–2.85(m,2H),1.92–1.81(m,1H),1.51 (d,J＝28.5,7.6Hz,6H),1.17(d,J＝7.1Hz,3H),0.87(d,J＝6.6Hz,3H),0.78(d,J＝6.7Hz, 3H),0.39–0.27(m,2H),0.12–0.02(m,2H).

EXAMPLE 276 preparation of Compound 276

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group, referring to steps 6 to 7 of example 41, followed by basic hydrolysis, and condensation with (R) -2-amino-N- (4-aminotetrahydropyran) propionamide to give compound 276, MS M/z:662(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.62(d,J＝8.6Hz,2H),7.47 (d,J＝7.9Hz,1H),7.42–7.23(m,5H),6.54(s,1H),5.94(d,J＝9.7Hz,1H),4.24–4.20(m, 1H),4.18(s,2H),3.83(s,3H),3.33–3.24(m,2H),1.85(s,2H),1.59(s,2H),1.54(t,J＝15.7 Hz,6H),1.25(d,J＝22.6Hz,3H),1.14(d,J＝7.2Hz,3H),0.85(d,J＝6.3Hz,3H),0.77 (d,J＝6.8Hz,3H).

EXAMPLE 277 preparation of Compound 277

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to undergo condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl, and referring to example 41Step 6-7, the compound 277 is obtained by alkali hydrolysis and condensation with (R) -3-methyl-2-carbonyl piperazine, MS M/z:604(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.67(d,J＝9.2Hz,1H),7.82(s,1H),7.66(d,J＝ 8.4Hz,1H),7.57–7.32(m,5H),7.24(dd,J＝9.2,4.4Hz,1H),7.10(d,J＝6.4Hz,1H),6.59 (s,1H),5.98(t,J＝9.6Hz,1H),4.71(s,1H),4.19(s,1H),3.87(s,3H),2.74(d,J＝46.4Hz, 4H),1.92(s,1H),1.51(d,J＝26.0Hz,6H),1.31–1.16(m,3H),0.82(dd,J＝34.4,6.4Hz, 6H).

EXAMPLE 278 preparation of Compound 278

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to example 41, steps 6-7, base hydrolysis, and condensation with R-2-amino-N-methyl-3-methylbutanamide gave compound 278, MS M/z:620(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.65(d,J＝9.2Hz,1H),7.84(s,1H),7.64 (d,J＝9.2Hz,2H),7.47-7.38(m,4H),7.33–7.20(m,2H),6.70(s,2H),6.58(s,1H),5.98(s, 1H),4.18(s,2H),4.11–4.04(m,1H),3.85(s,3H),1.86(dd,J＝13.6,6.8Hz,3H),1.55(d,J＝ 7.6Hz,5H),0.91–0.61(m,10H),0.01(s,1H).

Preparation of compound 279 of example 279

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, steps 6-7, base hydrolysis, and condensation with R-2-amino-3-methylbutanamide gave compound 279, MS M/z:606 (M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.64(d,J＝7.6Hz,1H),7.66(d,J＝10.0Hz,2H), 7.49(d,J＝7.2Hz,1H),7.42-7.25(m,5H),7.02(s,1H),6.70–6.55(m,2H),6.00(s,1H), 4.20–4.07(m,2H),3.87(s,3H),1.90(dt,J＝13.2,6.8Hz,2H),1.55(d,J＝4.0Hz,5H),0.89 (d,J＝6.0Hz,2H),0.79(dd,J＝10.4,6.8Hz,5H),0.68(d,J＝6.8Hz,3H).

EXAMPLE 280 preparation of Compound 280

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, step 6-7, alkaline hydrolysis, and condensation with 2-amino-2-cyclobutyl-N-methyl-acetamide to give compound 280, MS M/z:632(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.72(d,J＝10.0Hz,1H),7.71(s,1H), 7.57(s,4H),7.42(d,J＝8.0Hz,2H),7.33(d,J＝2.0Hz,2H),7.22(dd,J＝14.4,7.2Hz,3H), 6.70(s,2H),6.53(s,1H),5.93(s,1H),4.25(t,J＝8.4Hz,3H),3.84(s,3H),2.42–2.33(m, 3H),1.87–1.44(m,14H),1.26(dd,J＝12.4,5.54Hz,3H),0.78(d,J＝6.8Hz,5H).

Example 281 preparation of Compound 281

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to examples 41, steps 6 to 7, basic hydrolysis and condensation with cyclobutylglycinamide gave compound 281, MS M/z:618(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.73(d,J＝9.2Hz,2H),7.71–7.40(m,7H),7.31 (d,J＝2.0Hz,2H),7.24–7.03(m,4H),6.96(s,1H),6.51(d,J＝14.8Hz,4H),5.90(s,2H), 4.31–4.19(m,3H),3.83(s,3H),3.06(s,1H),2.34(s,1H),1.74(d,J＝38.4Hz,6H),1.53(s, 7H),1.31–1.21(m,3H),0.77(s,6H).

EXAMPLE 282 preparation of Compound 282

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 27, which is an intermediate of example 27, followed by ring closure, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to examples 41, Steps 6-7, alkaline hydrolysis, and condensation with 1-aminocyclobutanecarboxamide to give 282, MS M/z:622(M +1)⁺.¹HNMR(400MHz,MeOD):δ＝7.72-7.64(m,1H),7.52-7.51(m,1H),7.42-7.34(m, 3H),7.27-7.23(m,1H),6.48(s,1H),5.98(d,J＝9.6Hz,1H),4.60(s,1H),4.25-4.24(m,1H), 3.96(s,3H),2.62-2.55(m,2H),2.21-2.14(m,2H),1.95-1.89(m,2H),1.63(s,6H),0.99-0.97 (m,3H),0.87(d,J＝6.8Hz,3H).

EXAMPLE 283 preparation of Compound 283

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 27, which is an intermediate of example 27, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to examples 41, Steps 6-7, basic hydrolysis and condensation with 1-aminocyclobutane-N-methylformamide gave compound 283, MS M/z: 636(M +1)⁺.¹HNMR(400MHz,MeOD):δ＝7.74-7.62(m,1H),7.52-7.51(m,1H),7.42-7.31 (m,3H),7.27-7.23(m,1H),6.48(s,1H),5.98(d,J＝9.2Hz,1H),4.60(s,1H),4.25-4.23(m,1H), 3.93(s,3H),2.78(s,3H),2.60-2.53(m,2H),2.21-2.13(m,2H),1.93-1.89(m,2H),1.63(s, 6H),0.99-0.98(m,1H),0.87(d,J＝6.8Hz,3H)

EXAMPLE 284 preparation of Compound 284

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, referring to examples 41, steps 6 to 7, base hydrolysis, and condensation with 1- (1H-pyrazol-3-yl) ethylamine to give compound 284, MS M/z:601(M +1)⁺.

EXAMPLE 285 preparation of Compound 285

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, step 6-7 of example 41, base hydrolysis, and condensation with 1- (1H-imidazole) -4-ethylamine to give compound 285, MS M/z:601(M +1)⁺.

EXAMPLE 286 preparation of Compound 286

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, steps 6 to 7, alkaline hydrolysis and condensation with (1R,2R) -2-aminocyclobutane- (N-methyl) -1-carboxamide gave 286, MS M/z:618(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.56-7.53(m,2H),7.49 (d,J＝8.0Hz,1H),7.36(dd,J＝8.8,1.6Hz,1H),7.34–7.25(m,3H),7.21–7.15(m,1H), 6.53(s,1H),5.96(d,J＝8.4Hz,1H),4.06(t,J＝7.6Hz,1H),3.86(s,3H),2.59(s,3H),1.98(s, 1H),1.51(s,6H),1.19(s,1H),0.97(d,J＝6.4Hz,2H),0.91–0.88(m,1H),0.77(t,J＝6.8Hz, 3H).

EXAMPLE 287 preparation of Compound 287

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, steps 6 to 7, alkaline hydrolysis and condensation with (1S,2R) -2-aminocyclobutane- (N-methyl) -1-carboxamide gave compound 287, MS M/z:618(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.64-7.55(m,6H), 7.40-7.24(m,6H),6.54(s,1),6.04–6.00(m,1H),4.27–4.18(m,3H),3.95(s,3H),2.68(s, 2H),2.51(s,2H),2.00-1.93(m,3H),1.61(d,J＝2.4Hz,6H),1.42–1.25(m,12H), 1.04(d,J＝7.2Hz,3H),0.94-0.87(m,7H).

EXAMPLE 288 preparation of Compound 288

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to close the ring, remove Boc, and add 1-methyl-1H-pyrazole-5-acyl, referring to example 41, Steps 6-7, alkaline hydrolysis, and condensation with (1S,2R) -2-aminocyclopentane- (N-methyl) -1-carboxamide gave compound 288, MS M/z:632(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.71–7.67(m,2H),7.59(d,J＝ 7.6Hz,1H),7.48-7.38(m,4H),7.30–7.27(m,1H),6.66(s,1H),6.11(d,J＝8.4Hz,1H),4.29 (dd,J＝14.0,6.8Hz,1H),4.20(s,1H),3.98(s,3H),3.80–3.70(m,4H),3.25(q,J＝7.6Hz, 4H),2.81(d,J＝8.0Hz,1H),2.68(s,1H),2.54(s,2H),2.07(s,1H),1.93–1.78(m,3H), 1.68–1.51(m,9H),1.09(d,J＝5.6Hz,3H),0.87(d,J＝6.8Hz,3H),0.12(s,1H).

EXAMPLE 289 preparation of Compound 289

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closed, Boc-removed, 1-methyl-1H-pyrazole-5-acyl group, followed by basic hydrolysis in steps 6 to 7 of example 41, and condensed with (R) -2-amino-N- (4-methylpiperazine) propionamide to give compound 289, MS M/z:661(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.67(d,J＝8.8Hz,2H),7.52(d,J＝2.1Hz,2H),7.41(ddd,J＝13.3,9.9,8.3Hz,4H),7.30–7.24(m,2H),6.60(d,J＝1.6Hz,1H), 6.02(d,J＝10.0Hz,1H),3.86(s,3H),2.78(s,7H),1.53(d,J＝4.8Hz,6H),1.13(d,J＝6.8 Hz,3H),0.89–0.85(m,3H),0.77(d,J＝6.7Hz,3H).

EXAMPLE 290 preparation of Compound 290

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 290, MS M/z:632(M +1), by condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, steps 6 to 7, base hydrolysis, and condensation with (R) -2-amino-N-tetrahydropyrrolidinopropionamide⁺.¹H NMR(400MHz,DMSO-d₆)δ7.69(d,J＝9.0Hz,2H),7.51(dd,J＝ 12.5,4.8Hz,2H),7.43–7.37(m,4H),7.31–7.25(m,2H),6.03(d,J＝9.5Hz,1H),3.86(s, 3H),1.53(d,J＝6.6Hz,6H),1.30–1.21(m,4H),1.16–1.06(m,4H),0.92–0.87(m,4H), 0.77(d,J＝6.7Hz,3H).

EXAMPLE 291 preparation of Compound 291

Referring to the procedure of example 74, starting from the single chiral isomer 2-c of intermediate 2 of example 2, the procedure was as described in example 26Condensation of the intermediate o-phenylenediamine 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis with alkali, and condensation with (R) -2-amino-N-morpholinepropionamide, Steps 6-7 of reference example 41, to give the Compound 291, MS M/z:648(M +1)⁺.

EXAMPLE 292 preparation of Compound 292

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to example 41, steps 6 to 7, base hydrolysis, and condensation with 3-aminotetrahydrofuran-4- (N-cyclopropyl) carboxamide to give 292, MS M/z:660(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.70(dd,J＝20.0,8.4Hz,2H),7.61 (d,J＝13.2Hz,1H),7.54(dd,J＝12.4,8.4Hz,1H),7.50–7.36(m,3H),7.34–7.27(m,1H), 6.67(s,1H),6.08(d,J＝7.6Hz,1H),4.56(d,J＝4.4Hz,1H),4.17(s,1H),4.08(s,1H),3.98 (s,2H),1.69–1.61(m,4H),1.56(s,1H),1.15–0.98(m,4H),0.87(d,J＝6.8Hz,2H), 0.76–0.68(m,1H),0.51–0.42(m,1H).

EXAMPLE 293 preparation of Compound 293

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 as an intermediate of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, Steps 6-7, alkaline hydrolysis, and condensation with (3S,4R) -3-aminofuran-4- (N-cyclopropyl) carboxamide to give compound 293, MS M/z:658(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.79–7.67(m,1H),7.58(d,J＝ 21.2Hz,1H),7.54–7.38(m,2H),7.34–7.23(m,1H),6.64(s,1H),6.09(d,J＝8.0Hz,1H), 4.28(d,J＝7.2Hz,1H),4.19(s,1H),4.09(s,1H),3.98(s,2H),2.51–2.35(m,1H), 1.99–1.49(m,10H),1.40–1.26(m,4H),1.18–0.99(m,3H),0.88(d,J＝6.8Hz,3H),0.61 (d,J＝6.8Hz,2H),0.37(dd,J＝13.2,9.2Hz,2H).

EXAMPLE 294 preparation of Compound 294

Referring to example 74, using single chiral isomer 2-c of intermediate 2 of example 2 as raw material, condensing with o-phenylenediamine 26 of example 26, ring closing, removing Boc, adding 1-methyl-1H-pyrazole-5-acyl, referring to example 41, steps 6-7, hydrolyzing with alkali, condensing with 1- (2H-1,2, 4-triazole-3-yl) ethylamine to obtain compound 294, MS M/z:602 (M +1)⁺.

EXAMPLE 295 preparation of Compound 295

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group addition, referring to examples 41, steps 6 to 7, alkaline hydrolysis, and condensation with 4-aminotetrahydropyran to give 295, MS M/z:591(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.64(d,J＝8.4Hz,1H),7.58(s,1H),7.50(dd,J＝12.2, 5.3Hz,2H),7.39(dd,J＝4.9,2.8Hz,2H),7.28(d,J＝8.4Hz,2H),6.58(s,1H),5.97(d,J＝ 9.9Hz,1H),3.85(s,3H),3.36–3.22(m,4H),2.07(s,6H),1.89(s,1H),1.56(d,J＝13.0Hz, 2H),1.51(s,6H),1.43(s,2H),1.06(t,J＝7.0Hz,6H).

Preparation of example 296 Compound 296

Referring to the procedure of example 74, the single chiral isomerisation of intermediate 2 of example 2The 2-c is prepared by condensing the raw material with o-phenylenediamine 26, the intermediate of example 26, ring closing, removing Boc, adding 1-methyl-1H-pyrazole-5-acyl, further referring to the steps 6-7 of example 41, hydrolyzing with alkali, condensing with R-2-amino-2-isopropyl-N-cyclopropylacetamide to obtain 296, MS M/z:646(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.92(s,1H),7.65–7.54(m,2H),7.47 (d,J＝8.5Hz,1H),7.45–7.36(m,2H),7.31(dd,J＝7.1,4.9Hz,2H),7.22(t,J＝7.7Hz,1H), 7.13(t,J＝9.3Hz,1H),6.65–6.56(m,1H),5.90(d,J＝10.9Hz,1H),3.82(s,3H),1.86–1.73 (m,3H),1.52(d,J＝12.4Hz,7H),1.41–1.33(m,2H),1.25(dd,J＝20.6,6.9Hz,5H),0.94– 0.84(m,3H),0.78(d,J＝6.0Hz,5H),0.74(d,J＝6.8Hz,4H),0.68–0.61(m,3H),0.57 (d,J＝7.0Hz,2H),0.30(dd,J＝11.5,5.0Hz,2H).

Example 297 preparation of Compound 297

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazol-5-yl group, to steps 6 to 7 of example 41, alkaline hydrolysis, and condensation with 3- (ALPHA-aminoethyl) -5-methyl-4-H-1, 2, 4-triazole to give compound 297, MS M/z:616(M +1)⁺.

EXAMPLE 298 preparation of Compound 298

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, ring-closed, Boc removed, and then 1-methyl-1H-pyrazole-5-acyl group was added, as shown in example 41, step 6-7, followed by basic hydrolysis and condensation with D-cyclobutyl-N-methylglycinamide to give 298, MS M/z:632(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.74–7.66(m,1H),7.64–7.60(m,1H),7.59 –7.55(m,1H),7.50–7.45(m,1H),7.45–7.37(m,2H),7.35–7.28(m,2H),7.25–7.19(m, 1H),7.19–7.12(m,1H),6.71–6.58(m,2H),6.51–6.45(m,1H),5.94–5.85(m,1H),4.32– 4.17(m,3H),4.07–4.04(m,1H),3.87–3.80(m,3H),1.86–1.58(m,8H),1.53(s,7H),1.49 –1.42(m,1H),0.81–0.71(m,6H).

EXAMPLE 299 preparation of Compound 299

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, steps 6 to 7, alkaline hydrolysis, and condensation with D-cyclobutyl-N-ethylglycinamide to give compound 299, MS M/z:646(M +1)⁺.

EXAMPLE 300 preparation of Compound 300

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closed, Boc-removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group addition, referring to example 41, steps 6-7, alkaline hydrolysis, and condensation with R-2-amino-3-methyl-N-ethylbutanamide to give 300, MS M/z:634(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.82(s,1H),7.63(s,1H),7.57(d,J＝7.9Hz,1H), 7.47(d,J＝8.5Hz,1H),7.41(t,J＝7.8Hz,2H),7.31(d,J＝8.3Hz,2H),7.25–7.19(m,1H), 7.14(t,J＝9.0Hz,1H),6.64–6.50(m,2H),6.48(s,1H),5.89(d,J＝11.2Hz,1H),4.28–4.21 (m,1H),4.10–4.04(m,2H),3.83(s,3H),1.53(d,J＝9.8Hz,5H),0.95(dd,J＝13.7,7.0Hz, 3H),0.78(d,J＝5.4Hz,8H),0.69–0.63(m,3H).

EXAMPLE 301 preparation of Compound 301

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 27, ring-closed, Boc removed, and then subjected to 1-methyl-1H-pyrazole-5-acyl group addition to steps 6-7 of example 41, alkaline hydrolysis, and condensation with R-2-amino-3-methyl-N-methylbutanamide to give 301, MS M/z:638(M +1)⁺.¹HNMR(400MHz,MeOD):δ＝7.74-7.65(m,1H),7.51(d,J＝7.2Hz,1H),7.41-7.23 (m,4H),6.48(s,1H),5.98(d,J＝9.6Hz,1H),4.27-4.20(m,1H),4.16(d,J＝7.6Hz,1H),3.93(s, 3H),2.71(s,3H),1.96-1.85(m,2H),1.63(s,5H),0.98(d,J＝6.8Hz,3H),0.90-0.87(m,6H), 0.82(d,J＝6.4Hz,3H).

EXAMPLE 302 preparation of Compound 302

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to examples 41, steps 6 to 7, basic hydrolysis and condensation with 4-aminopyrazole gave compound 302, MS M/z:573(M +1)⁺. ¹HNMR(400MHz,MeOD):δ＝7.68(s,1H),7.60-7.58(m,1H),7.54-7.49(m,2H),7.39-7.34 (m,3H),7.26-7.23(m,1H),6.50(s,1H),6.01(d,J＝9.6Hz,1H),5.36(t,d＝4.8Hz,1H), 4.21-4.19(m,1H),3.93(s,3H),2.21(t,J＝7.6Hz,1H),2.06-2.03(m,4H),1.72(s,3H), 1.65-1.61(m,1H),1.00-0.99(m,2H),0.94-0.90(m,2H),0.86(d,J＝6.8Hz,2H)

EXAMPLE 303 preparation of Compound 303

Referring to the procedure of example 74, intermediate 2 of example 2The single chiral isomer 2-c as the raw material was condensed with o-phenylenediamine 27, which is an intermediate in example 27, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, followed by basic hydrolysis in steps 6 to 7 of example 41, and condensation with R-cyclobutyl-N-methylglycinamide to give 303, MS M/z:650(M +1)⁺.¹HNMR(400MHz,MeOD):δ＝7.73-7.64(m,1H),7.51(d,J＝7.6Hz,1H),7.41-7.23(m,4H), 6.48(s,1H),5.98(d,J＝9.6Hz,1H),4.34(d,d＝8.8Hz,1H),4.27-4.22(m,1H),3.93(s,3H), 2.70(s,3H),2.52-2.49(m,1H),2.26-2.19(m,1H),1.93-1.71(m,5H),1.63(d,J＝8.0Hz,6H), 0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.8Hz,3H).

EXAMPLE 304 preparation of Compound 304

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to condense with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, further referring to example 41, Steps 6-7, alkaline hydrolysis, and condensation with (R) -cyclobutyl-N-morpholinoglycinamide to give compound 304, MS M/z:688(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.82(s,2H),8.34(s,1H),7.63(s,1H),7.56 (d,J＝7.4Hz,1H),7.47(s,1H),7.44–7.37(m,2H),7.31(d,J＝8.5Hz,2H),7.23–7.10(m, 4H),6.49(s,1H),5.93–5.86(m,2H),4.68(t,J＝8.4Hz,2H),4.24(s,2H),3.82(s,3H),3.54 –3.37(m,8H),1.84–1.57(m,9H),1.57–1.47(m,6H),0.80–0.69(m,6H).

EXAMPLE 305 preparation of Compound 305

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to undergo condensation with o-phenylenediamine 26, an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, steps 6-7, alkaline hydrolysis, and (R) -cyclobutadineCondensation of the base-N- (4-methylpiperazine) glycinamide to give the compound 305, MS M/z:701(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.82(s,2H),8.34(s,1H),7.63(s,1H), 7.56(d,J＝7.4Hz,1H),7.47(s,1H),7.44–7.37(m,2H),7.31(d,J＝8.5Hz,2H),7.23–7.10 (m,4H),6.49(s,1H),5.93–5.86(m,2H),4.68(t,J＝8.4Hz,2H),4.24(s,2H),3.82(s,3H), 3.54–3.37(m,8H),1.84–1.57(m,9H),1.57–1.47(m,6H),0.80–0.69(m,6H).

EXAMPLE 306 preparation of Compound 306

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to examples 41, steps 6 to 7, basic hydrolysis and condensation with (R) -cyclobutyl-N- (1-methylpiperidin-4-yl) glycinamide gave compound 306, MS M/z:715(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.20(s,1H),7.62(s,2H),7.51 –7.38(m,4H),7.31(s,2H),7.23(d,J＝7.8Hz,1H),7.15(s,2H),6.49(s,1H),5.96–5.86(m, 2H),4.32–4.21(m,3H),3.83(s,3H),2.13(s,3H),1.97–1.87(m,3H),1.85–1.56(m,10H), 1.56–1.44(m,6H),0.78(d,J＝4.6Hz,5H).

EXAMPLE 307 preparation of Compound 307

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to example 41, steps 6 to 7, alkaline hydrolysis and condensation with (R) -cyclobutyl-N- (1-methyltetrahydropyrrole-3R-yl) glycinamide gave compound 307, MS M/z:701(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.74(s,1H),7.69(d,J＝8.8 Hz,1H),7.59(d,J＝7.2Hz,1H),7.53–7.50(m,1H),7.41(d,J＝9.2Hz,2H),7.34(d,J＝8.0 Hz,1H),7.27(t,J＝7.6Hz,1H),7.07(t,J＝16.0Hz,1H),6.71(s,1H),6.12(d,J＝8.0Hz, 1H),4.37(s,1H),4.24-4.18(m,1H),4.14–4.10(m,1H),3.97(s,3H),2.94(s,3H),2.54(d,J＝ 7.6Hz,2H),2.14–1.78(m,8H),1.63(d,J＝7.2Hz,7H),1.28(s,1H),1.10(d,J＝5.2Hz,3H), 0.84(d,J＝6.8Hz,3H).

EXAMPLE 308 preparation of Compound 308

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to examples 41, steps 6 to 7, alkaline hydrolysis and condensation with (R) -cyclobutyl-N- (1-methylpiperidin-3S-yl) glycinamide gave compound 308, MS M/z:715(M +1)⁺.¹HNMR(400MHz,MeOD):δ＝8.43(s,1H),7.64(s,1H), 7.57-7.51(m,2H),7.39-7.34(m,2H),7.31-7.23(m,2H),6.51(s,1H),6.01(d,J＝9.2Hz,1H), 4.32-4.19(m,2H),3.93(m,J＝2.0Hz,3H),3.22-3.08(m,2H),2.67(d,J＝3.6Hz,3H), 2.58-2.41(m,2H),2.02-1.95(m,1H),1.94-1.81(m,5H),1.64(d,J＝5.6Hz,6H),1.48-1.41(m, 2H),1.01-0.98(m,3H),0.86(d,J＝6.8Hz,3H)

Example 309 preparation of Compound 309

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to examples 41, steps 6 to 7, alkaline hydrolysis and condensation with (R) -cyclobutyl-N- (1-methylpiperidin-3R-yl) glycinamide gave compound 309, MS M/z:715(M +1)⁺.

EXAMPLE 310 preparation of Compound 310

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazol-5-yl group was added, and then, referring to example 41, steps 6 to 7, basic hydrolysis and condensation with (R) -2-amino-N- (1-methyltetrahydropyrrole-3S-yl) propionamide gave compound 310, MS M/z:661(M +1)⁺.¹H NMR(400M,MeOD)δ7.77-7.82(m,1H),8.31-8.45(m, 1H),7.22-7.67(m,6H),6.51(s,1H),5.92-6.06(m,1H),5.51(s,1H),4.12-4.40(m,3H), 3.89-3.98(m,2H),3.38-3.57(m,2H),3.11-3.28(m,2H),2.81-2.93(m, 2H),2.67-2.80(m,1H),2.32-2.51(m,2H),1.86-2.07(m,2H),1.54-1.72(m,4H),1.23-1.33(m, 2H),0.94-1.04(m,2H),0.81-0.92(m,2H).

EXAMPLE 311 preparation of Compound 311

Referring to example 74, a compound 311, MS M/z:689(M +1), was prepared by condensing the single chiral isomer 2-c of intermediate 2 of example 2 with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, addition of 1-methyl-1H-pyrazol-5-yl, referring to steps 6-7 of example 41, base hydrolysis, and condensation with (R) -2-amino-3-methyl-N- (1-methyltetrahydropyrrole-3S-yl) butanamide⁺.

EXAMPLE 312 preparation of Compound 312

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to undergo condensation with o-phenylenediamine 26, the intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, referring to example 41, steps 6 to 7, and addition of aqueous alkaliHydrolyzing, condensing with (R) -cyclobutyl-N- (1-methyl tetrahydropyrrole-3R-group) glycinamide to obtain compound 312, MS M/z:701(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.43(s,1H),7.64(s,1H), 7.54(dd,J＝17.6,8.0Hz,2H),7.39–7.34(m,3H),7.31–7.23(m,2H),6.52(s,1H),6.00 (d,J＝8.8Hz,1H),4.34(s,1H),4.28–4.25(m,1H),4.22-4.17(m,1H),3.94(s,3H), 3.51-3.40(s,2H),3.23-3.12(m,3H),2.86(d,J＝12.4Hz,3H),2.60–2.52(m,3H),2.00-1.75 (m,8H),1.64(d,J＝7.6Hz,8H),1.41(d,J＝11.2Hz,2H),1.30(d,J＝9.3Hz,7H),0.99(s, 4H),0.86(d,J＝6.8Hz,3H).

EXAMPLE 313 preparation of Compound 313

Referring to example 74, a compound 313, MS M/z:689(M +1), was prepared by condensing o-phenylenediamine 26, which is the intermediate 2 of example 2, with 2-c, which is a single chiral isomer of example 2, as a starting material, closing the ring, removing Boc, adding 1-methyl-1H-pyrazol-5-yl, referring to example 41, steps 6 to 7, performing alkaline hydrolysis, and condensing with (R) -2-amino-3-methyl-N- (1-methyltetrahydropyrrole-3R-yl) butanamide⁺.¹H NMR(400MHz,MeOD)δ8.48(s,1H),7.64(s, 1H),7.56(d,J＝8.0Hz,1H),7.52(d,J＝4.0Hz,1H),7.42–7.32(m,3H),7.30–7.22 (m,2H),6.52(s,1H),6.01(d,J＝8.0Hz,1H),4.35(s,1H),4.19(s,1H),4.14–4.07(m,1H), 3.94(d,J＝1.2Hz,3H),3.37(s,1H),3.15–3.02(m,2H),2.78(d,J＝17.6Hz,3H),2.47–2.34 (m,1H),2.02–1.86(m,3H),1.65(s,6H),1.00(d,J＝5.2Hz,3H),0.94–0.82(m,6H),0.82– 0.72(m,3H).

EXAMPLE 314 preparation of Compound 314

Referring to the method of example 74, the single chiral isomer 2-c of the intermediate 2 of example 2 is used as raw material to be condensed with the intermediate o-phenylenediamine 26 of example 26, the ring is closed, Boc is removed, 1-methyl-1H-pyrazole-5-acyl is added, and then reference is made toExample 41 Steps 6-7 were performed with alkaline hydrolysis and condensation with (R) -2-amino-N- (1-methyltetrahydropyrrole-3R-yl) propionamide to give compound 314, MS M/z:661(M +1)⁺.¹H NMR(400M,MeOD)δ7.77-7.82(m,1H),7.69-7.75(m, 1H),7.56-7.65(m,2H),7.43-7.49(m,2H),7.36-7.40(m,1H),7.26-7.34(m,1H), 6.70-6.77(m,1H),6.11-6.16(m,1H),4.39-4.44(m,1H),4.23-4.32(m,1H),4.14-4.21(m, 1H),4.00(s,3H),3.78-3.88(m,1H),3.58-3.67(m,1H),3.12-3.19(m,1H),2.93-3.02(m,3H), 2.51-2.62(m,1H),2.31-2.43(m,1H),2.02-2.22(m,3H),1.58-1.71(m,6H),1.28-1.34(m,3H), 1.09-1.18(m,3H),0.84-0.91(m,3H).

EXAMPLE 315 preparation of Compound 315

Referring to example 74, a compound 315, MS M/z:638(M +1), obtained by condensation of O-phenylenediamine 29, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition to the intermediate of example 29, step 6-7 of example 41, base hydrolysis, and condensation with R-2-amino-3-methyl-N-methylbutanamide⁺.¹H NMR(400MHz,MeOD)δ7.54(d,J＝8.0Hz,1H),7.46(d,J＝1.2 Hz,1H),7.43–7.37(m,4H),7.28–7.24(m,2H),7.13–7.10(m,1H),6.62(s,1H),6.07 (d,J＝8.4Hz,1H),4.14-4.10(m,3H),3.97(s,3H),2.71(d,J＝3.2Hz,4H),2.03–1.89(m, 3H),1.64(d,J＝0.8Hz,6H),1.58(d,J＝1.6Hz,1H),1.07(d,J＝6.4Hz,3H),1.01(t,J＝6.4 Hz,2H),0.89–0.84(m,6H),0.80(d,J＝6.8Hz,3H),0.75(d,J＝6.8Hz,1H).

EXAMPLE 316 preparation of Compound 316

Referring to the procedure of example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to undergo condensation with the intermediate o-phenylenediamine 29 of example 29, ring closure, Boc removal, and addition of 1-methyl-1H-pyrazole-5-acyl groupWith reference to steps 6-7 of example 41, the compound 316, MS M/z:650(M +1), was obtained by hydrolysis with alkali and condensation with (R) -cyclobutyl-N-methylglycinamide⁺.¹H NMR(400MHz,MeOD)δ7.53(d,J＝8.0Hz,1H),7.43(d,J＝1.2Hz,1H), 7.42(d,J＝2.0Hz,1H),7.39(s,1H),7.37(s,1H),7.26(s,1H),7.09(dd,J＝12.4,1.2Hz,1H), 6.60(s,1H),6.05(d,J＝8.0Hz,1H),4.32–4.29(m,1H),4.16-4.11(m,1H),3.97(s,3H),2.70 (s,3H),2.57–2.51(m,1H),2.04–1.73(m,8H),1.64(t,J＝5.2Hz,7H),1.31(s,4H),1.07 (d,J＝6.4Hz,3H),0.86(d,J＝6.8Hz,3H).

EXAMPLE 317 preparation of Compound 317

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material and condensed with o-phenylenediamine 28, a ring was closed, Boc was removed, 1-methyl-1H-pyrazole-5-yl group was added, as shown in example 41, steps 6 to 7, base hydrolysis was performed, and condensation with (R) -cyclobutyl-N-methylglycinamide gave compound 317, MS M/z:650(M +1)⁺.¹H NMR(400MHz,MeOD)δ7.53(d,J＝8.4Hz,1H),7.47-7.43(m,2H),7.41 (d,J＝2.0Hz,1H),7.38–7.32(m,2H),7.26–7.22(m,1H),6.62(s,1H),6.05(d,J＝8.0Hz, 1H),4.33–4.29(m,1H),4.07(t,J＝7.2Hz,1H),3.95(s,3H),2.68(s,3H),2.48(dd,J＝ 15.2,6.8Hz,1H),2.01–1.68(m,8H),1.60(d,J＝14.0Hz,6H),1.07(d,J＝6.4Hz,3H),0.82 (d,J＝6.8Hz,3H).

EXAMPLE 318 preparation of Compound 318

Referring to the procedure of example 74, starting from the single chiral isomer 2-c of intermediate 2 of example 2, the product was condensed with o-phenylenediamine 26, which is an intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, referring to the procedure of example 41, steps 6 to 7, base hydrolysis, and condensation with 1- (5-methyl-1H-pyrazol-3-yl) isobutylamineThus, compound 318, MS M/z 643(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.65–7.61(m,1H),7.48–7.35(m, 4H),7.35–7.27(m,3H),7.24–7.16(m,2H),7.15–7.08(m,2H),6.56–6.44(m,3H),5.97–5.82(m,3H),5.81–5.64(m,3H),4.78–4.50(m,5H),4.38–4.19(m,4H),3.83(s,3H),2.92 –2.88(m,1H),2.15–2.04(m,4H),2.02–1.86(m,3H),1.86–1.74(m,3H),1.60–1.44(m, 7H),0.83–0.75(m,5H),0.71–0.59(m,6H).

EXAMPLE 319 preparation of Compound 319

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 as an intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, referring to examples 41, steps 6 to 7, base hydrolysis, and condensation with 1- (5-methyl-1H-pyrazol-3-yl) cyclobutanemethylamine to give compound 319, MS M/z:655(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.96–8.70(m,2H),8.37–8.04(m, 3H),7.67–7.50(m,2H),7.50–7.36(m,3H),7.36–7.28(m,2H),7.28–7.19(m,1H),7.19– 7.08(m,1H),7.08–6.85(m,2H),6.56–6.47(m,1H),5.95–5.82(m,2H),5.72–5.65(m, 1H),5.03–4.74(m,3H),4.38–4.17(m,2H),3.83(s,3H),2.13–2.03(m,3H),1.81–1.59(m, 6H),1.56–1.40(m,6H),1.03(d,J＝6.5Hz,11H),0.78–0.69(m,4H).

EXAMPLE 320 preparation of Compound 320

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, referring to example 41, step 6-7, base hydrolysis, and condensation with N-methyl- (1-tetrahydrofuran-3R-yl) acetamide to give the compoundCompound 320, MS M/z:648(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.83(s,1H),7.68(s,1H),7.63–7.54 (m,1H),7.47(d,J＝8.5Hz,1H),7.41(t,J＝7.3Hz,2H),7.31(dd,J＝7.1,5.4Hz,2H),7.22 (t,J＝6.9Hz,1H),7.17–6.93(m,3H),6.47(s,1H),5.88(d,J＝11.1Hz,1H),4.28–4.16(m, 2H),3.81(s,3H),3.58(dd,J＝10.7,5.2Hz,2H),3.35(d,J＝7.3Hz,1H),1.75(s,3H),1.52 (d,J＝8.1Hz,6H),0.77(d,J＝6.3Hz,6H).

EXAMPLE 321 preparation of Compound 321

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26 as an intermediate of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazol-5-yl group addition, referring to examples 41, steps 6 to 7, base hydrolysis, and condensation with (R) -cyclobutyl-N- (1-methyl-1-cyclopropanol) glycinamide to give compound 321, MS M/z:688(M +1)⁺.

EXAMPLE 322 preparation of Compound 322

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, steps 6 to 7, alkaline hydrolysis and condensation with (R) -cyclobutyl-N- (1-methyl-1-epoxycyclopropane) glycinamide gave compound 322, MS M/z:702(M +1)⁺.

EXAMPLE 323 preparation of Compound 323

Referring to the procedure of example 74, intermediate 2 of example 2 was prepared using a single handSex isomer 2-c as raw material was condensed with o-phenylenediamine 26, which is the intermediate in example 26, ring-closing, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to steps 6 to 7 in example 41, alkali hydrolysis, and further condensation with (R) -N-methyl- (1-tetrahydrofuran-3S-yl) acetamide to obtain compound 323, MS M/z:648(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ7.83(s,1H),7.68(s,1H),7.63 –7.54(m,1H),7.47(d,J＝8.5Hz,1H),7.41(t,J＝7.3Hz,2H),7.31(dd,J＝7.1,5.4Hz,2H), 7.22(t,J＝6.9Hz,1H),7.17–6.93(m,3H),6.47(s,1H),5.88(d,J＝11.1Hz,1H),4.28–4.16 (m,2H),3.81(s,3H),3.58(dd,J＝10.7,5.2Hz,2H),3.35(d,J＝7.3Hz,1H),1.75(s,3H), 1.52(d,J＝8.1Hz,6H),0.77(d,J＝6.3Hz,6H).

EXAMPLE 324 preparation of Compound 324

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 26, which is an intermediate of example 26, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, steps 6 to 7, alkaline hydrolysis and condensation with (R) -cyclobutyl-N- (1-methyl-1-F cyclopropane) glycinamide gave compound 324, MS M/z:690(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.89–8.67(m,3H),8.23(s, 1H),8.12(s,2H),7.63(s,1H),7.57(d,J＝8.5Hz,1H),7.54–7.37(m,4H),7.31(t,J＝7.2Hz, 3H),7.27–7.18(m,2H),7.18–7.07(m,2H),6.70(dd,J＝22.6,8.2Hz,2H),6.49(s,2H), 5.96–5.85(m,2H),4.33(t,J＝8.6Hz,1H),4.26(d,J＝7.6Hz,2H),3.83(s,3H),1.85–1.59 (m,8H),1.52(s,7H),1.24(s,1H),0.89(d,J＝19.0Hz,3H),0.78(d,J＝6.5Hz,6H),0.62 (d,J＝8.7Hz,3H).

EXAMPLE 325 preparation of Compound 325

Referring to the procedure of example 74, intermediate 2 of example 2The single chiral isomer 2-c as the raw material was condensed with o-phenylenediamine 26, which is the intermediate in example 26, ring-closing, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl, further referring to example 41, Steps 6-7, alkali hydrolysis, condensation with (R) -cyclobutyl-N- (2-fluoroethyl) glycinamide to give compound 325, MS M/z:664(M +1)⁺.¹H NMR(400MHz,MeOD)δ8.25(s,1H),7.64(s,1H),7.58(s,1H), 7.56–7.49(m,1H),7.45–7.29(m,4H),7.25(dd,J＝10.7,4.5Hz,1H),6.74(d,J＝8.0Hz, 1H),6.52(s,2H),6.01(d,J＝9.2Hz,1H),4.50–4.42(m,1H),4.41–4.30(m,2H),4.19(s, 1H),3.94(s,3H),3.58(s,1H),3.50(s,1H),3.47–3.41(m,1H),2.64–2.41(m,3H),2.04– 1.76(m,7H),1.76–1.59(m,7H),1.53–1.37(m,3H),1.31(s,1H),1.00(d,J＝6.3Hz,4H), 0.88(t,J＝13.7Hz,4H).

EXAMPLE 326 preparation of Compound 326

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material to prepare compound 326, MS M/z:592(M +1) by condensation with o-phenylenediamine 23, the intermediate of example 23, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, further referring to example 41, Steps 6-7, base hydrolysis, and condensation with (R) -2-amino-N, N' -dimethylpropionamide⁺.

Example 327 preparation of Compound 327

Referring to example 74, the single chiral isomer 2-c of intermediate 2 of example 2 was condensed with o-phenylenediamine 23, which is an intermediate of example 23, to ring-close, Boc was removed, 1-methyl-1H-pyrazole-5-acyl group was added, and then, referring to example 41, steps 6 to 7, basic hydrolysis and condensation with (R) -cyclobutyl-N-methylglycinamide gave compound 327, MS M/z:618(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ8.95(s,1H),8.42(s,1H),8.06–7.76(m,2H), 7.65–7.36(m,4H),7.36–7.26(m,2H),7.24-7.19(m,2H),6.54(s,1H),5.90(t,J＝7.2Hz, 1H),4.35–4.14(m,2H),3.83(d,J＝3.2Hz,3H),2.57(d,J＝4.4Hz,1H),2.48(d,J＝4.4Hz, 2H),1.97–1.43(m,8H),1.38-1.35(m,3H),0.77-0.74(d,J＝6.1Hz,6H).

EXAMPLE 328 preparation of Compound 328

Referring to example 74, a single chiral isomer 2-c of intermediate 2 of example 2 was used as a starting material, which was condensed with o-phenylenediamine 26, an intermediate of example 26, ring-closing, Boc-protecting group-removal, condensation with 1, 6-dihydro-1-methyl-6-oxo-2-pyridinecarboxylic acid, and further, referring to example 41, step 6-7, basic hydrolysis, condensation with 1-amino-1-cyclobutylformamide gave compound 328, MS M/z:631(M +1)⁺.¹H NMR(400MHz,DMSO-d₆)δ9.42(d,J＝8.8 Hz,1H),7.64(d,J＝29.6Hz,3H),7.48(d,J＝8.0Hz,2H),7.40(t,J＝7.2Hz,1H),7.28 (dd,J＝9.2,7.2Hz,3H),6.83(s,1H),6.55(s,1H),6.38(dd,J＝9.2,1.0Hz,1H),5.95-5.85(m, 1H),5.73(d,J＝6.4Hz,1H),4.22(dd,J＝11.2,4.4Hz,1H),2.85(s,3H),2.06(d,J＝14.4Hz, 3H),1.76(d,J＝8.0Hz,3H),1.54(s,6H),0.79(t,J＝6.4Hz,5H).

EXAMPLE 329 preparation of Compound 329

Referring to example 74, the single chiral isomer 18-c of intermediate 18 of example 18 was condensed with o-phenylenediamine 26 of example 26, ring-closing, Boc removal, 1-methyl-1H-pyrazole-5-acyl group addition, according to example 41, steps 6-7, base hydrolysis, and condensation with D-2-amino-4-methylpentamamide to give compound 329, MS M/z: 700(M +1)⁺.

EXAMPLE 330 preparation of Compound 330

Referring to example 74, compound 330, MS M/z:493(M +1) was obtained by condensation of single chiral isomer 2-c of intermediate 2 of example 2 with o-phenylenediamine 146-1, cyclization, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl group, referring to steps 6-7 of example 41, base hydrolysis, and final condensation with methylamine hydrochloride⁺.

EXAMPLE 331 preparation of Compound 331

With reference to the procedure of example 74, starting from the single chiral isomer 5-a of intermediate 5 of example 5, through condensation with o-phenylenediamine 30, the intermediate of example 30, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazole-5-acyl group, compound 331, MS M/z:494(M +1)⁺.

EXAMPLE 332 preparation of Compound 332

Referring to the method of example 57, Steps 1-6, intermediate 15 was condensed with intermediate 26 of example 26, imidazole ring was closed, Boc was removed, 1-ethyl-1H-pyrazol-5-yl was introduced, ethyl ester was hydrolyzed, and finally condensed with methylamine to obtain compound 332, MS M/z:465[ M + 1: [ ] -M]⁺。

EXAMPLE 333 preparation of Compound 333

Referring to the procedure of example 74, starting from intermediate 171-1 (four undissociated isomer mixture) of step 1 of example 171, which was subjected to condensation with o-phenylenediamine 26, an intermediate of example 26, ring closure, removal of Boc, addition of 1-methyl-1H-pyrazol-5-yl, further referring to steps 6-7 of example 41, hydrolysis with alkali,finally condensing with R-2-amino-propionamide to obtain a compound 333, MS M/z:598(M +1)⁺.

EXAMPLE 334 preparation of Compound 334

Referring to steps 4-7 of example 41, compound 334 was obtained by condensation of intermediate 41-3 with intermediate 34-2 of example 34, imidazole ring closure, ethyl ester hydrolysis, condensation with D-leucine tert-butyl ester hydrochloride, and finally hydrolysis of tert-butyl ester with trifluoroacetic acid, MS M/z:549[ M +1] (MS M/z: M +1)]⁺.

EXAMPLE 335 preparation of Compound 335

Referring to steps 4-7 of example 41, a compound 335 was obtained by condensing intermediate 41-3 with intermediate 36 of example 36 and closing the imidazole ring, MS M/z:461[ M +1]]⁺.

EXAMPLE 336 preparation of intermediate 336

Step 1 preparation of intermediate 336-1

Referring to step 3 of example 38, intermediate 336-1 was obtained by coupling intermediate 38-1 with methyl 2- (4-bromo-1, 3-dimethyl-1H-pyrazol-5-yl) acetate, MS M/z:275[ M +1]]⁺

Step 2 preparation of Compound 336

Referring to the procedure of example 74, intermediate 2 of example 2 (mixture of enantiomers 2-c and 2-d) was used as starting material which was condensed with intermediate o-phenylenediamine 336-1Closing the ring, removing Boc, adding 1-methyl-1H-pyrazole-5-acyl, performing alkaline hydrolysis according to steps 6-7 of example 41, and condensing with cyclopentylamine to obtain 336, MS M/z:641(M +1)⁺。

In order to illustrate the advantageous effects of the present invention, the present invention provides the following test examples.

Test example 1IL-17 enzyme-linked immunosorbent assay (ELISA) test

The inhibition of receptor-ligand binding by IL-17a inhibitors was quantitatively determined by competitive ELISA. IL-17a (Nano Biological incc. Cat #12047-H07B) at 0.2. mu.g/ml was incubated in 96-well plates at 37 degrees for 30 minutes at 100. mu.l per well. The plate was washed 4 times with PBST (PBS, 0.05% Tween-20), 200. mu.l each well, and 200. mu.l of 5% skim milk was added and incubated for 30 minutes on a 25-degree shaker. 100X concentrations of test compound were prepared, ranging from 0.003. mu.M to 30. mu.M. The plates were washed 4 times with PBST (PBS, 0.05% Tween-20), mixed with 89. mu.l PBST and 1. mu.l of 100 Xconcentration test compound and preincubated for 10min at 25 ℃. Add 10. mu.l of 16nM IL-17R and incubate for 30min on a 25 degree shaker. After washing the plate 4 times, 100. mu.l of anti-Fc-tag HRP-conjugated antibody was added and incubated for 30 minutes on a 25 ℃ shaker. After washing the plate 4 times, 100. mu.l of TMB substrate solution was added and incubated at 25 ℃ in the dark. After addition of 20% HCl, the light absorption was measured at a wavelength of 450nm using a microplate reader.

The compounds prepared in the examples were tested for IL-17A inhibitory activity according to the methods described above, and the results are shown in Table 1, in which the IC of each compound was determined₅₀Sorted by description, in table 1:

"+" denotes IC₅₀The measured value is greater than 1uM and less than 100 μ M;

"+ +" denotes IC₅₀Measured at less than 1uM and greater than 250 nM;

"+ + + +" denotes IC₅₀The assay was less than 250nM.

TABLE 1 inhibitory Activity of Compounds on IL-17A

Experiments show that the compounds of the embodiment of the invention have good IL-17A inhibitory activity and can be effectively used for treating diseases with abnormal IL-17A activity.

In conclusion, the novel compound shown in the formula I shows good IL-17A inhibitory activity, and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

Claims (6)

1. A compound of formula IIIa-1 or IIIa-2, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R^1’selected from hydrogen;

R^a’is selected from C_1～6Alkyl groups of (a);

R³、R^3’are independently selected from hydrogen, -OR^d、C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group, and a 5-to 10-membered aromatic ring; or, R³And R^3’Connecting to form 3-10 membered cycloalkyl;

R^dselected from hydrogen, C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group;

R^5’is halogen, n is selected from 0, 1 and 2; or, R^5’Is halogen and 5-10 membered heteroaromatic ring, n is selected from 2 and 3, wherein the heteroaromatic ring can be further substituted by 0-3C_1～10Alkyl substitution, 5-10-membered aromatic ring, 5-10-membered aromatic heterocycle substitution;

r is 0, 1;

R⁸and R⁹Are respectively and independently selected from hydrogen and C_1～10Alkyl, 3-10 membered cycloalkyl; or, R⁸And R⁹Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaromatic ring; wherein the heterocycloalkyl or heteroaromatic ring is substituted by 0, 1 or 2 carbon atoms_1～10Alkyl substituted, wherein the alkyl may be substituted with 0 to 3-OR^dSubstitution;

L²is-C (O) NR¹⁰-、-NR¹⁰C (O) -, -C (O) -or none, R¹⁰Selected from hydrogen;

R⁴and R⁵Are respectively and independently selected from hydrogen and C_1～10Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered heteroaromatic ring, -S (O)₂NR^aR^b、-C(O)OR^a、-C(O)NR^aR^b(ii) a Wherein alkyl is substituted by 0, 1, 2R^cSubstitution; wherein the heterocycloalkyl group is substituted by 0, 1, 2C_1～10Alkyl, ═ O, -C (O) NH₂Substitution; wherein the cycloalkyl group is substituted by 0, 1, 2-C (O) NH₂Substituted, wherein the aromatic heterocycle is substituted by 0, 1,2, 3 methyl groups;

R^a、R^bare respectively and independently selected from hydrogen and C_1～10Alkyl, -S (O)₂R^d3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; wherein, alkyl is substituted by 0, 1,2 cyclopropyl, -OH, methoxy, halogen; wherein heterocycloalkyl is substituted with 0, 1,2, 3 methoxy groups;

R^cselected from the group consisting of ═ O, -OH, -c (O) OH, cyclopropyl, N-dimethylamino, and 5 to 10 membered aromatic heterocycle, wherein the aromatic heterocycle is substituted with 0 to 3 methyl groups;

or, R⁴And R⁵Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl radical is substituted by 0, 1,2, 3C_1～10Alkyl, ═ O, -OH, halogen, -C (O) OH, -C (O) NR^aR^bAnd (4) substitution.

2. A compound of formula IIIb-1 or IIIb-2, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R¹、R^1’selected from hydrogen;

R^a’is selected from C_1～6Alkyl groups of (a); r³、R^3’Are independently selected from hydrogen, -OR^d、C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group, and a 5-to 10-membered aromatic ring; or, R³And R^3’Connecting to form 3-10 membered cycloalkyl;

R^dselected from hydrogen, C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group;

R⁴and R⁵Are respectively and independently selected from hydrogen and C_1～10Alkyl, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 5-to 10-membered heteroaromatic ring, -S (O)₂NR^aR^b、-C(O)OR^a、-C(O)NR^aR^b(ii) a Wherein alkyl is substituted by 0, 1, 2R^cSubstitution; wherein the heterocycloalkyl group is substituted by 0, 1, 2C_1～10Alkyl, ═ O, -C (O) NH₂Substitution; wherein the cycloalkyl group is substituted by 0, 1, 2-C (O) NH₂Substituted, wherein the aromatic heterocycle is substituted by 0, 1,2, 3 methyl groups;

R^a、R^bare respectively and independently selected from hydrogen and C_1～10Alkyl, -S (O)₂R^d3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; wherein, alkyl is substituted by 0, 1,2 cyclopropyl, -OH, methoxy, halogen; wherein heterocycloalkyl is substituted with 0, 1,2, 3 methoxy groups;

R^cselected from the group consisting of ═ O, -OH, -c (O) OH, cyclopropyl, N-dimethylamino, and 5 to 10 membered aromatic heterocycle, wherein the aromatic heterocycle is substituted with 0 to 3 methyl groups;

or, R⁴And R⁵Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl radical is substituted by 0, 1,2, 3C_1～10Alkyl, ═ O, -OH, halogen、-C(O)OH、-C(O)NR^aR^bSubstitution;

R^5’is hydrogen or halogen, n is selected from 0, 1 and 2;

r is 0, 1;

R⁸and R⁹Are respectively and independently selected from hydrogen and C_1～10Alkyl, 3-10 membered cycloalkyl; or, R⁸And R⁹Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaromatic ring; wherein the heterocycloalkyl or heteroaromatic ring is substituted by 0, 1 or 2 carbon atoms_1～10Alkyl substituted, wherein the alkyl may be substituted with 0 to 3-OR^dSubstitution;

L²is-C (O) NR¹⁰-、-NR¹⁰C (O) -, -C (O) -or none;

R¹⁴selected from hydrogen, halogen, C_1～10Alkyl radical, C_2～10An alkenyl group; wherein the alkyl and alkenyl are substituted by 1-10 aromatic ring.

3. A compound represented by the following structural formula:

4. use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an IL-17A mediated disease.

5. Use according to claim 4, characterized in that: the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.

6. A medicament, characterized by: the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and pharmaceutically acceptable auxiliary materials.