RU2823231C1 - Pd-l1 antagonist compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a PD-L1 antagonist compound, specifically to a compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof. In Formula (I): L₁ is selected from: -CR^AR^B- and -C(O)-; L₂, L₃, are selected from: -(CR^CR^D)_p, -(CR^CR^D)_p-NR^z-(CR^CR^D)_q-, -(CR^CR^D)_p-O-(CR^CR^D)_q- and -C(O)-; W₁, W₂ each independently represents CR^L or N; R¹ each independently represents hydrogen or -NR^aR^b, or -O(C₁-C₆ alkyl), -O(C₀-C₆ alkylene)(C₃-C₆ cycloalkyl) or -O(C₀-C₆ alkylene)(3–6-membered heterocycloalkyl containing one nitrogen atom) substituted with 0, 1, 2 or 3 substitutes; R² represents hydrogen, halogen, nitro, cyano, -NR^aR^b, -SO₂R^a, -S(O)R^a, C₁-C₆ alkyl, -O(C₁-C₆ alkyl), -O(C₃-C₆ cycloalkyl), halogen(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl; R³ and R⁴ each independently represents hydrogen or halogen; R⁵ is independently hydrogen, halogen, cyano, C₁-C₆ alkyl, halogen(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl; Cy is a benzene ring or six-membered heteroaryl substituted with 0, 1, 2 or 3 R⁶, wherein the six-membered heteroaryl can optionally contain 1 or 2 nitrogen atoms; R⁶ is hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or -O(C₁-C₆ alkyl), substituted with 0, 1, 2 or 3 halogens, -O(C₀-C₆ alkylene)(C₃-C₆ cycloalkyl) or -O(C₀-C₆ alkylene)(3–6 membered heterocycloalkyl); R^L is hydrogen, -O(C₁-C₆ alkyl), -O(C₃-C₆ cycloalkyl), halogen or cyano; T is -(C₁-C₆ alkyl), -(C₀-C₆ alkylene)-(C₃-C₁₂ cycloalkyl) or -(C₀-C₆ alkylene)-(3–12-membered heterocycle containing at least one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom) substituted with 0, 1, 2 or 3 substituents; A is -(C₁-C₆ alkyl), -(C₀-C₆ alkylene)-(C₃-C₁₂ cycloalkyl), -(C₀-C₆ alkylene)-(3–12-membered heterocycle containing at least one nitrogen atom), -(C₀-C₆ alkylene)-(C₆-C₁₀ aryl) or -(C₀-C₆ alkylene)-(5–10 membered heteroaryl containing at least one nitrogen atom), substituted with 0, 1, 2 or 3 substitutes; m, o each independently represents 0, 1 or 2; and p, q each independently represents 0, 1, 2 or 3; values R^A, R^B, R^C, R^D, R^a and R^b are defined in the claims. Also disclosed is a compound selected from a group of individual compounds, a pharmaceutical composition, use of said compounds or a pharmaceutical composition, a method of treating and a method of inhibiting binding of PD-L1 with PD-1.

EFFECT: disclosed compounds have inhibitory activity on PD-L1/PD-1 and can be used to treat/prevent disorders responsive to inhibition of PD-L1 binding with PD-1.

29 cl, 1 tbl, 173 ex

Description

Technical field

The present invention relates to a PD-L1 antagonist compound and a method of using it for the treatment/prevention of immunization-related disorders.

Prior Art

Tumor immunotherapy was named the most important scientific breakthrough of the year in 2013 by Science magazine due to its superior efficacy and innovation. Tumor immunotherapy is expected to be an innovation in the treatment of tumors following surgery, chemotherapy, radiation therapy and targeted therapy. Tumor immunotherapy is the application of immunological principles and techniques to improve tumor cell immunogenicity and sensitivity to effector cell killing, stimulate and enhance the body's antitumor immune response, and use immune cells and effector molecules to target the host into the body. The immune system kills tumors and suppresses their growth. Tumor immunotherapy has recently attracted much attention and is the focus of attention in the field of tumor therapy. The good news regarding tumor immunotherapy has continued in recent years. Currently, immunotherapy has demonstrated strong antitumor activity in the treatment of several tumor types, such as melanoma and non-small cell lung cancer, and several tumor immunotherapy drugs have been approved by the US Food and Drug Administration (FDA) for clinical use.

PD-1 (programmed death receptor 1, programmed death 1) is a member of the CD28 superfamily. Immunomodulation targeting PD-1 is of great importance in antitumor, anti-infective, anti-autoimmune diseases and organ transplant survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role. PD-L1 (programmed cell death ligand 1) is a 40 kDa type 1 transmembrane protein. Normally, the immune system responds to foreign antigens that accumulate in the lymph nodes or spleen, promoting the proliferation of antigen-specific T cells. The combination of PD-1 and PD-L1 can transmit inhibitory signals and reduce T cell proliferation.

One way tumor cells avoid destruction by T cells is by producing PD-L1 on their surface. When PD-1 on the surface of T cells recognizes PD-L1, it can transmit inhibitory signals, and T cells cannot detect tumor cells and send attack signals to tumor cells. PD-1 is a new immunotherapy that evades the immune system by disarming tumor cells. The mechanism of action of PD-1 immunotherapy is to develop specific protein antibodies against PD-1 or PD-L1, block the process of recognizing PD-1 and PD-L1, and partially restore T cell function so that the T cells can kill tumor cells.

PD-1 is expressed on activated T cells, B cells, myeloid cells and has two ligands, PD-L1 and PD-L2. Both PD-L1/L2 are expressed in antigen-presenting cells, and PD-L1 is also expressed in various tissues. PD-1 binding to PD-L1 mediates a coinhibitory T cell activation signal, regulates T cell activation and proliferation, and plays a negative regulatory role similar to CTLA-4. The laboratory of Chinese scientist Chen Leiping first discovered that PD-L1 is highly expressed in tumor tissue and regulates the function of tumor-infiltrating CD8 T cells. Therefore, immunomodulation targeting PD-1/PD-L1 is of great importance for tumor control. Several therapeutic monoclonal antibodies (mAbs) targeting the PD-1/PD-L1 interaction have been approved by the US FDA. In addition to the development of related monoclonal antibodies, the search for oral small molecule compounds convenient for cancer patients to target and inhibit immune checkpoints is also a frontier area of tumor immunotherapy. Low molecular weight compounds can penetrate the cell membrane and act on intracellular targets, so they have a wide range of applications. Second, chemically modified small molecules often have good bioavailability and pliability, effectively avoiding degradation and enzyme inactivation in the digestive tract. Third, small molecule research is also quite advanced in terms of manufacturing process, dosage form design, and administration methods.

Most monoclonal antibodies (mAbs) are administered by intravenous injection at high doses. Small molecule drugs that are more suitable for oral administration may reduce serious immune-related side effects. Compared to monoclonal antibodies, small molecule drug inhibitors have many other advantages, such as lower production cost, better stability, and better penetration into organs and tumors. Given the many advantages of the kinetic properties of small molecule drugs, this will allow dosing flexibility for monotherapy or other combination regimens. The small molecule compounds of the present invention may provide a more superior therapeutic option for patients and physicians.

Brief Disclosure of the Present Invention

The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, isomer, solvate or metabolite thereof:

In this case, L ₁ is selected from the groups: - CR ^A R ^B - and - C(O)-;

L ₂ , L ₃ selected from the groups: -(CR ^C R ^D ) _p , -(CR ^C R ^D ) _p -NR ^a -(CR ^C R ^D ) _q -, -(CR ^C R ^D ) _p -O- (CR ^C R ^D ) _q - and -C(O)-;

W ₁ and W ₂ are each independently CR ^L or N;

Each R ¹ is independently hydrogen, halogen, nitro, cyano or -NR ^a R ^b or C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene)(C ₅ -C ₁₀ aryl), -O(C ₀ -C ₆ alkylene)(5-10-membered heteroaryl), -O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl ) or -O(C ₀ -C ₆ alkylene)(3-6-membered heterocycloalkyl); where the substituents are selected from: -OR ^a , cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₁ -C ₆ alkylene)OR ^a , cyano C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₈ cycloalkyl, -C(O)R ^a , -(C ₁ -C ₆ alkylene)C(O)R ^a , -C(O)OR ^a , -(C ₁ -C ₆ alkyl)C(O )OR ^a , -NR ^a R ^b , -(C ₁ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -SO ₂ R ^a , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b ;

R ² , R ³ , R ⁴ , R ⁵ are each independently hydrogen, halogen, nitro, cyano, -NR ^a R ^b , -SO ₂ R ^a , -S(O)R ^a , -P(O)R ^a R ^b , C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen(C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl;

Cy represents a benzene ring or a six-membered heteroaryl substituted with 0, 1, 2 or 3 R ⁶ , where the six-membered heteroaryl may optionally contain 1 or 2 nitrogen atoms; where said R ⁶ represents hydrogen, halogen, nitro, cyano, -NR ^a R ^b , -SO ₂ R ^a , -S(O)R ^a or P(O)R ^a R ^b or C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene) (C ₅ -C ₁₀ aryl), -O(C ₀ -C ₆ alkylene)(5- 10-membered heteroaryl), -O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene)(3-6-membered heterocycloalkyl), substituted with 0, 1, 2 or 3 substituents; where the substituent is selected from: -OR ^a , cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₁ -C ₆ alkylene)OR ^a , cyanoC ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₈ cycloalkyl, -C(O)R ^a , -(C ₁ -C ₆ alkylene)C(O)R ^a , -C(O)OR ^a , -(C ₁ -C ₆ alkylene)C(O) OR ^a , -NR ^a R ^b , -(C ₁ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -SO ₂ R ^a , -C(O)NR ^a SO ₂ R ^b or -NR ^a C(O)R ^b ;

In this case, R ^L represents: hydrogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen, nitro, cyano, -NR ^a R ^b , halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl;

T and A each independently represent: -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene) -(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₆ alkylene) -(3- 12-membered heterocycle), -(C ₀ -C ₆ alkylene) -(C ₆ -C ₁₀ aryl) or -(C ₀ -C ₆ alkylene)-(5-10-membered heteroaryl), substituted 0, 1, 2 or 3 substituents, and the substituents are selected from: cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , cyano C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl ), C ₃ -C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C(O)R ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl) C(O)OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and - NR ^a C(O)R ^b ;

Moreover, R ^A and R ^B each independently represent: hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkylene)(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₃ alkylene)(3 -12-membered heterocycle), halogen (C ₁ -C ₆ alkyl) or halogen, or R ^A and R ^B together with the carbon atoms to which they are attached form a 3-6 membered ring;

R ^C and R ^D are each independently: hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkylene)(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₃ alkylene)(3-12 -membered heterocycle), halogen (C ₁ -C ₆ alkyl) or halogen, or R ^C and R ^D together with the carbon atoms to which they are attached form a 3-6 membered ring;

R ^a and R ^b each independently represent: hydrogen, C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)OH, -(C ₀ -C ₃ alkylene)( C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₃ alkylene)(3-12-membered heterocycle), -(C ₀ -C ₃ alkylene) (C ₆ -C ₁₀ -aryl), -(C ₀ - C ₃ alkylene) (5-10 membered heteroaryl) or halogen (C ₁ -C ₆ alkyl), or R ^a and R ^b together with the atoms to which they are usually attached form a 3-6 membered ring;

In this case, m and o are each independently 0, 1 or 2;

In this case, p and q each independently represent 0, 1, 2 or 3.

Preferably, the compound of formula (I) has the following structure of formula (II):

In this case, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o have the values defined in the formula (I );

In this case, r represents 0, 1, 2 or 3.

Preferably, the compound of formula (I) has the following structure of formula (III):

In this case, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o have the values defined in the formula (I );

In this case, W ³ represents CR ^M or N;

In this case, R ^M represents: hydrogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen, nitro, cyano, -NR ^a R ^b , halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl;

In this case, r represents 0, 1 or 2.

Preferably, the compound of formula (I) has the following structure of formula (IV):

In this case, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o have the values defined in the formula (I );

In this case, W ₄ represents CR ^N or N;

In this case, R ^N represents: hydrogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen, nitro, cyano, -NR ^a R ^b , halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl;

In this case, r represents 0, 1 or 2.

In the compounds of the present invention, L ₁ is preferably selected from -CR ^A R ^B -, with R ^A , R ^B each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and halogen (C ₁ -C ₆ alkyl), preferably hydrogen.

In the compounds of the present invention, L ₂ and L ₃ are preferably each independently selected from -CR ^C R ^D - and -CR ^C R ^D -NR ^a -(CR ^C R ^D ) _q -, wherein q is selected from 0, 1 or 2 wherein ^RC , ^RD are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and halogen(C ₁ -C ₆ alkyl), preferably hydrogen; each R ^a is independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl) and -(C ₀ -C ₃ alkylene)C ₃ -C ₁₂ cycloalkyl.

In the compound of the present invention, W ₁ and W ₂ are preferably each independently CH or N.

In the compounds of the present invention, W ₃ is preferably CH or N.

In the compounds of the present invention, W ₄ is preferably CH or N.

In the compounds of the present invention, each T and A are preferably independently substituted with 0, 1, 2 or 3 substituents: -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene) - (C ₃ -C ₁₂ cycloalkyl ) or -(C ₀ -C ₆ alkylene)-(3-12-membered heterocycle), with substituents selected from: cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , C ₁ -C ₆ cyanoalkyl, halogen(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C(O)R ^a , -(C ₀ -C ₆ alkylene )C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O)OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b , wherein R ^a and R ^b are each independently hydrogen, C ₁ -C ₆ alkyl or halogen( C ₁ -C ₆ alkyl).

In the compounds of the present invention, each T and A preferably independently represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₁₂ cycloalkyl group or a 3-12 membered heterocycle, substituted with 0, 1 or 2 substituents, the substituents being selected from: cyano, oxo, -OR ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O)OR ^a , -NR ^a C(O)R ^b , -NR ^a SO ₂ R ^b and -C(O)NR ^a SO ₂ R ^b , wherein R ^a and R ^b are independently hydrogen, C ₁ -C ₆ alkyl or halogen (C ₁ -C ₆ alkyl).

In the compounds of the present invention, each T and A preferably independently represent the following groups: optionally substituted with 0, 1 or 2 substituents, wherein the substituents are selected from: C ₁ -C ₆ alkyl, -OR ^a , -(C ₀ -C ₆ alkylene)C(O)R ^a and -(C ₀ -C ₆ alkenyl )C(O)OR ^a , wherein R ^a is hydrogen or C ₁ -C ₆ alkyl, preferably hydrogen, wherein α is 1, 2 or 3.

In the compounds of the present invention, T and A preferably each independently represent the following groups:

In the compounds of the present invention, each T, A preferably independently represents the following groups: optionally substituted with 0, 1 or 2 substituents, wherein the substituents are selected from: C ₁ -C ₆ alkyl, -OR ^a and halogen, wherein R ^e and R ^a are each independently hydrogen or C ₁ -C ₆ alkyl; wherein α is 1, 2, 3 or 4.

In the compounds of the present invention, T and A are each preferably independently wherein R ^e represents hydrogen or C ₁ -C ₆ alkyl, wherein a represents 1, 2, 3 or 4.

In the compounds of the present invention, T and A are preferably each independently:

In the compounds of the present invention, R ¹ is preferably -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene)(C ₅ -C ₁₀ aryl), -O(C ₀ -C ₆ alkylene) (5-10 membered heteroaryl), -O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene)(3-6 membered heterocycloalkyl), substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, cyano C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl.

In the compounds of the present invention, R ² is preferably hydrogen, halogen, nitro, cyano, -SO ₂ ^Ra , C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl; wherein R ^a represents hydrogen, C ₁ -C ₆ alkyl or halogen (C ₁ -C ₆ alkyl).

In the compounds of the present invention, R ³ and R ⁴ are preferably each independently hydrogen, halogen, nitro or cyano.

In the compounds of the present invention, R ⁵ is preferably hydrogen, halogen, nitro, cyano, C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl.

In the compounds of the present invention, R ⁶ is preferably hydrogen, halogen, nitro, cyano, -SO ₂ ^Ra , C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl, or -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene) (C ₅ -C ₁₀ aryl), -O(C ₀ -C ₆ alkylene)(5-10-membered heteroaryl), - O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene) (3-6 membered heterocycloalkyl), substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, cyano C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl.

In the compounds of the present invention, R ^L is preferably hydrogen or halogen.

In the compounds of the present invention, ^RM and ^RN are preferably each independently hydrogen.

Detailed Description of the Present Invention

In particular, the present invention provides compounds having the following structures:

In addition, the present invention also provides a pharmaceutical composition containing a compound of the present invention and optionally further containing additional therapeutic agents and/or immune checkpoint inhibitors. The pharmaceutical compositions of the present invention may contain a pharmaceutically acceptable carrier.

In addition, the present invention also provides a compound of the present invention or a pharmaceutical composition containing a compound of the present invention for the manufacture of a medicament for the prevention or treatment of a disease or condition that can be treated by inhibiting the binding of PD-L1 to PD-1. Preferably, the disease is selected from tumors, cancer, viral infections, diseases associated with inflammation and autoimmune diseases.

The present invention also relates to the use of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention for the manufacture of a medicament for the prevention or treatment of a disease or condition responsive to inhibition of PD-L1 binding to PD-1. Preferably, the disease or disorder is selected from tumors, cancer, viral infections, diseases associated with inflammation and autoimmune diseases.

In addition, the present invention also provides a method of preventing or treating diseases or conditions (preferably tumors, cancer, viral infections, diseases associated with inflammation and autoimmune diseases) that can be treated by inhibiting the binding of PD-L1 to PD-1, comprising administering a compound of the present invention or a pharmaceutical composition of the present invention to a mammal in need thereof.

The present invention also provides a method of preventing or treating a disease or condition responsive to inhibition of PD-L1 binding to PD-1, comprising administering to a mammal in need thereof a compound or pharmaceutical composition of the present invention. The term "disease or disorder responsive to inhibition of PD-L1 binding to PD-1" means any disease or disorder in which the progression of the disease can be modified by inhibiting the binding of PD-L1 to PD-1, or can lead to relief, suppression, elimination and improving the consequences of diseases, conditions, disorders, etc. or the prevention of such diseases or conditions. Preferably, the disease or disorder responsive to inhibition of PD-L1 binding to PD-1 is selected from the group consisting of tumors, cancer, viral infections, inflammatory diseases and autoimmune diseases.

The present invention also provides a method of inhibiting the binding of PD-L1 to PD-1, which includes exposing said PD-L1 and/or PD-1 to a compound of the present invention or a pharmaceutical composition of the present invention.

In the above-described embodiments relating to the compounds, pharmaceutical compositions, and uses and methods of using the compounds or pharmaceutical compositions of the present invention, said compounds of the present invention particularly include the form of pharmaceutically acceptable salts thereof.

Representative examples of inflammatory, autoimmune and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritis, lupus, systemic lupus erythematosus (SLE), skin diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, pulmonary disease, pneumonia, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory pulmonary disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma , acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative tumor (MPN ), diffuse large B-cell lymphoma and follicular lymphoma.

Representative examples of cancer or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer brain, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer , papillary thyroid cancer, kidney cancer, renal parenchyma cancer, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), T-cell leukemia adult lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma , craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma or plasmacytoma.

The compounds of the present invention or pharmaceutically acceptable salts thereof may have enhanced anticancer effects when administered in combination with additional therapeutic agents or immune checkpoint inhibitors for the treatment of cancer or tumors.

Representative examples of therapeutic agents for the treatment of cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carbamoilustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, sulfhydrylpurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, mixtomycin, bleomycin, tamoxifen, flutamide, gonarelin analogues, megestrol ketones, prednisolone, dexamethasone, methylprednisolone, thalidomide, interferon, calcium folinate, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, anib, crenolanib, crizotinib, dabrafenib , dacomitinib, danucetib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, cotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nilotinib, b, oprosomib, olaparib, pazopanib , pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, cicatinib, saridegib, Sorafenib, Sunitinib, Tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vemodagi, , alemtuzumab, bevacizumab, belemumab vedotin, catuximab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumumab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and/or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, LAG3 antibody, antibody TIM-3 and anti-CTLA-4 antibody or any combination thereof.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may provide enhanced therapeutic effect when administered in combination with additional therapeutic agents useful in the treatment of inflammatory, autoimmune and immune-mediated diseases.

Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroid drugs (eg, prednisolone, prednisolone, methylprednisone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti -TNFα agents (eg, etanercept, infliximab, adalimumab, etc.), calcineurin inhibitor (eg, tacrolimus, pimecrolimus, etc.), and antihistamines (eg, diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, and etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount of 0.1 to 2000 mg/kg body weight/day in mammals, including humans (about 70 kg body weight). Preferably 1 to 1000 mg/kg body weight/day and administered as one or 4 divided doses per day or as scheduled. The dosage of the active ingredient may be adjusted according to a number of relevant factors, such as the condition of the subject being treated, the type and severity of the disease, the frequency of administration and the judgment of the physician. In some cases, amounts less than the doses indicated above may be appropriate. An amount greater than the above dose may be used as long as it does not cause adverse side effects, and the amount may be administered in several divided doses per day.

In addition, the present invention also provides a method of inhibiting PD-L1, comprising affecting PD-L1 with a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical combination of the present invention.

Definitions

It is especially noted that in this text, when referring to a “compound” having a specific structural formula, its stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopes are generally also included in derivatives, as well as pharmaceutically acceptable salts, solvates, hydrates and the like in their alternative forms. It is well known to those skilled in the art that salts, solvates and hydrates of a compound are alternative existing forms of the compound, and all of them can be converted into the compound under certain conditions, pharmaceutically acceptable salts, as well as solvates and hydrates thereof.

Likewise, when a compound is referred to herein, its prodrugs, metabolites and nitrogen oxides are generally also included.

The medicinal salts or pharmaceutically acceptable salts of the present invention can be prepared using inorganic or organic acids, and “medicinal salts” or “pharmaceutically acceptable salts” refer to such salts. Within the limits of reasonable medical judgment, they are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., which can be described as a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base or free acid with a suitable reagent as described below. For example, the free base can be reacted with a suitable acid. In addition, when the compounds of the present invention contain an acid moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts (eg, sodium or potassium salts) and alkaline earth metal salts (eg, calcium or magnesium salts). Examples of medicinal addition salts of non-toxic acids are amino groups with inorganic acids (for example, hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids) or organic acids (for example, acetic, oxalic, maleic, tartaric, citric acid, succinic acid or malonic acid), or with using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconate, heptanoate , caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate , bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonic acid salt, undecanoate, valerate, etc. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium salts, quaternary ammonium salts and ammonium cations formed by counterions, for example halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

The medicinal salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess of organic acid or aqueous mineral acid to precipitate the salt from the resulting mixture, removing the solvent and remaining free acid from it and isolating the precipitated salt.

The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, provided that the precursors or metabolites are metabolized in vivo to form compounds. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., in a reasonable ratio benefits/risks and effective for intended use. The term “prodrug” refers to a compound that undergoes rapid transformation in the body to form the parent compound of the above formula, for example, through metabolism in the body or N-demethylation of the compounds of the invention.

As used herein, the term “solvate” means the physical association of a compound of the present invention with one or more molecules of a solvent, whether organic or inorganic. This physical association involves hydrogen bonds. In some cases, such as when one or more solvent molecules are included in the crystal lattice of a crystalline solid, the solvate can be isolated. The solvent molecules in the solvate can be in a regular and/or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvates” includes both the solution phase and the isolated solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art.

“Stereoisomerism” in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (ie, optical isomerism). Conformational isomerism refers to the stereoisomeric phenomenon in which atoms or groups of atoms in a molecule have different arrangements in space due to the rotation or twisting of carbon and single carbon bonds in organic molecules with a specific configuration. Alkanes and rings are common. Alkane structures such as the chair and boat conformations that occur in the cyclohexane structure. "Stereoisomer" means that the compounds of the present invention contain one or more centers of asymmetry and are thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have centers of asymmetry, each of which will produce two optical isomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures, as well as the pure or partially pure compound. The compounds of the present invention may exist in tautomeric forms having different points of hydrogen addition due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. Enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers of all compounds of formula (I). Constructs and their mixtures, etc. all are included within the scope of the present invention.

"Isotopic derivatives" of the present invention refer to molecules in which the compounds are labeled with isotopes in this patent. The following isotopes are usually used as isotope markers: hydrogen isotopes: ² H and ³ H; carbon isotopes: ¹¹ C, ¹³ C and ¹⁴ C; chlorine isotopes: ³⁵ Cl and ³⁷ Cl; fluorine isotopes: ¹⁸ F; Iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotope: ¹³ N and ¹⁵ N; oxygen isotope: ¹⁵ O, ¹⁷ O and ¹⁸ O and sulfur isotopes ³⁵ S. These isotopically labeled compounds can be used to study the distribution of drug molecules in tissues. In particular, deuterium ^2H and carbon ^13C are more widely used because they are easier to label and detect. Substitution of certain heavy isotopes such as deuterium ( ^2H ) may improve metabolic stability, prolong half-life, and thus provide therapeutic benefits to reduce dosages. Isotopically labeled compounds are typically synthesized from labeled starting materials, and their synthesis is carried out using known synthetic methods as for non-isotopically labeled compounds.

The compounds or pharmaceutical compositions of the present invention can be prepared according to any of the conventional methods in dosage forms such as tablets, granules for oral or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection), powder, capsule, syrup, emulsion, microemulsion, solution or suspension.

The pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, solid magnesium fatty acid, calcium stearate, gelatin , talc, surfactants, suspending agents, emulsifiers and diluents. Examples of carriers used in the injectable compositions of the present invention are water, saline solutions, dextrose solutions, glucose-like solutions, alcohols, glycols, ethers (for example, polyethylene glycol 400), oils, fatty acids, esters fatty acids, glycerides, surfactants, suspending and emulsifying agents.

Other features of this invention will become apparent from the description of exemplary embodiments of this invention, which are given to illustrate the invention and not to limit it, and the following examples have been prepared using the methods disclosed in this invention.

Unless otherwise specified, terms used in this application (including description and claims) are defined as follows. It should be noted that in the specification and claims, the singular form “a” includes the plural unless the context clearly requires otherwise. Unless otherwise stated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology were used. In this application, the use of “or” or “and” means “and/or” unless otherwise indicated.

In the description and claims, the data or name must cover all stereo and optical isomers and racemates in which the above isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in compounds, and all such stable isomers are covered by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, which can be isolated as a mixture of isomers or as individual isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. All methods used to prepare the compounds of the present invention and intermediates obtained therefrom are considered part of this invention. Once enantiomeric or diastereomeric products are obtained, they can be separated by conventional methods such as chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both the free forms and the salts of these end products are included within the scope of the present invention. If desired, one form of compound can be converted into another. Free bases or acids can be converted to salts; salts can be converted into free compounds or another salt; mixtures of isomeric compounds of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms and salts, can exist in various tautomeric forms in which hydrogen atoms are transferred to other parts of the molecule and the chemical bonds between the atoms of the molecule are thus rearranged. It should be understood that all tautomeric forms that may exist are covered by the present invention.

Unless otherwise indicated, the definitions of substituents of the present invention are independent and not related, for example, for R ^a (or R ^b ) in substituents they are independent in the definitions of different substituents. In particular, choosing a definition for R ^a (or R ^b ) in one substituent does not mean that R ^a (or R ^b ) has the same definition in other substituents. More specifically, for example (to list only a partial list) for NR ^a R ^b , when the definition of R ^a (or R ^b ) is chosen from hydrogen, it does not mean that in -C(O)-NR ^a R ^b R ^a (or R ^b ) must be hydrogen.

Unless otherwise indicated, when a substituent is designated as "optionally substituted", the substituent is selected, for example, from alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino groups (where two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, and rylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, for example -SO ₂ NH ₂ , substituted sulfonamido, nitro, cyano, carboxy, carbamoyl, such as -CONH ₂ , substituted carbamoyl groups, such as -CONH alkyl, -CONH aryl, -CONH arylalkyl, or having two substituents at the nitrogen atom, selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc., and substituted heterocyclyl.

The terms "alkyl" or "alkylene" as used herein are intended to include saturated, branched and straight chain aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" means an alkyl group containing from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl base.

The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C ₂ -C ₆ alkenyl" contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C ₂ -C ₆ alkynyl" contains from two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C ₁ -C ₆ alkoxy" (or alkyloxy) is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy) and t-butoxy. Likewise, "alkylthio" or "thioalkoxy" is an alkyl group, as defined above, having the specified number of carbon atoms attached via a sulfur bridge, for example, methyl-S- and ethyl-S-.

The term "carbonyl" refers to an organic functional group (C=O) consisting of two atoms, carbon and oxygen, linked by a double bond.

The term "aryl", by itself or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring containing a total of 5 to 12 ring members, bicyclic or tricyclic ring systems , where at least one ring in the system is aromatic, and each ring in the system contains from 3 to 7 ring members. In some embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base. The term "aralkyl" or "arylalkyl" refers to an alkyl moiety attached to an aryl ring. Non-limiting examples include benzyl, phenethyl and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, dotted lines drawn from a ring system indicate that a bond can be attached to any suitable ring atom.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to straight or branched cyclic alkyl including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, propyl with a 1-methyl ring and 2-methylcyclopropyl. Bicyclic cyclic alkyl groups include bridged, spiro- or fused cycloalkyl groups.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to straight or branched cyclic alkenyl including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl, 1-methylcyclopropenyl and 2-methylcyclopropenyl. Bicyclic cyclic alkenyl groups include bridged, spiro- or cyclic fused ring alkenyl groups.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the stated number of carbon atoms and substituted by one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethylpropyl and heptachloropropyl. Examples of haloalkyl groups also include "fluoroalkyl groups", which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more fluorine atoms.

"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group, as defined above, having the specified number of carbon atoms attached via an oxygen bridge. For example, "C ₁ -C ₆ haloalkoxy" is meant to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Likewise, "haloalkylthio" or "thiohaloalkoxy" is a haloalkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge, for example, trifluoromethyl-S- and pentafluoroethyl-S-.

In the present disclosure, the expression Cx1-Cx2 is used when referring to certain substituent groups, which means that the number of carbon atoms in the substituent groups may be from x1 to x2. For example, C ₀ -C ₈ means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₁ -C ₈ means that the group contains 1, 2, 3, 4, 5, 6, 7 carbon atoms, or 8 carbon atoms, C ₂ -C ₈ means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C ₃ -C ₈ means that the group contains 3 , 4, 5, 6, 7 or 8 carbon atoms, C ₄ -C ₈ means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C ₀ -C ₆ means that the group contains 0, 1, 2 , 3, 4, 5 or 6 carbon atoms, C ₁ -C ₆ means a group contains 1, 2, 3, 4, 5 or 6 carbon atoms, Cr-Cb means a group contains 2, 3, 4, 5 or 6 carbon atoms, C ₃ -C ₆ means that the group contains 3, 4, 5 or 6 carbon atoms.

In this disclosure, the expression "x1-x2-membered ring" is used to refer to cyclic groups such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl, which refers to the ring atoms of the group. The number can be from x1 to x2. For example, a 3- to 12-membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, and the number of atoms in the ring may be 3, 4, 5, 6. , 7, 8, 9, 10, 11 or 12; 3-6 membered ring meaning that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of atoms in the ring can be 3, 4, 5 or 6; 3-8 membered ring meaning that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of atoms in the ring can be 3, 4, 5, 6, 7 or 8; 3-9 membered ring, meaning that the cyclic group may be a 3, 4, 5, 6, 7, 8 or 9 membered ring, the number of ring atoms may be 3, 4, 5, 6, 7, 8 or 9; 4-7 membered ring meaning that the cyclic group can be a 4-, 5-, 6- or 7-membered ring, and the number of atoms in the ring can be 4, 5, 6 or 7; 5-8 membered ring meaning that the cyclic group can be a 5, 6, 7 or 8 membered ring, and the number of atoms in the ring can be 5, 6, 7 or 8; 5-12 membered ring meaning that the cyclic group can be 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of atoms in the ring can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring meaning that the cyclic group can be 6, 7, 8, 9, 10, 11 or 12 membered ring, the number of atoms in the ring can be 6, 7, 8, 9, 10, 11 or 12. The ring atoms may be carbon atoms or heteroatoms, for example heteroatoms selected from N, O and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S heteroatoms.

In the context of the present invention, each of the one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

The term "heteroaryl" means stable 3-, 4-, 5-, 6- or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycles, which are fully unsaturated, partially unsaturated and contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and include any of the following polycyclic groups, wherein any heterocycle, as defined above, is fused with a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atoms are substituted or unsubstituted (ie N or NR, where R is H or, if specified, another substituent). Heterocycles can be attached to their side groups on any heteroatom or carbon atom, resulting in a stable structure. The heterocyclyl groups described herein may be substituted at the carbon or nitrogen atom if the resulting compound is stable. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in the heterocycle does not exceed one. When used, the term "heterocycle" is intended to include heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidine, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, 4aH-carbazolyl, carboline, anil, chromenil, cinnoline, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, Sh-indazolyl, imidazopyridyl, pseudoindolenyl, indolenyl, indolinyl, indolyl, ZN-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindoline, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxane oxazopyridyl, methylenedioxyphenyl, morpholinyl, naphthyl, octahydroisoquinolinyl, oxadiazolyl, ill, 1,2,4 -oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, rylene, oxindole, pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxtyl, phenoxazinyl, phthalazinyl, , piperidinyl , piperidonyl, 4-piperidinyl, piperonyl, pteridinylpyridyl, pyrazinyl, purinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyrido imidazolyl, pyridothiazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidyl, 2-pyrrolidinyl, pyrrolyl , quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, tetrahydroaclilinyl, quinuzoliline tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazole base, 1,2,5 -triazolyl, 1,3,4-triazolyl and xanthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindyldolyl, indoline, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl and 1,2,3,4-tetrahydroquinoxalinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-". ", "-pyrimidinylbiphenyl-", where the present invention also includes fused rings containing, for example, the above heterocycles and spiro compounds.

As used herein, the term “heterocycloalkyl” or “heterocycle” refers to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system, and also includes spiroheterocycle or bridged heterocycloalkyl. Monocyclic heterocycloalkyl refers to a saturated or unsaturated but non-aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S, P. Bicyclic heterocycloalkyl systems refer to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group , or to a cycloalkenyl group, or to a heterocycloalkyl group, or to a heteroaryl group. Preferably, "heterocycloalkyl" or "heterocycle" contains at least one or two heteroatoms selected from O, N and S.

The term "bridged cycloalkyl" as used herein refers to polycyclic compounds having two or more carbon atoms in common. It can be divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The first consists of two alicyclic rings having more than two carbon atoms in common, the second is a bridged cyclic hydrocarbon consisting of three or more rings.

As used herein, the term "spirocycloalkyl" refers to polycyclic hydrocarbons in which one carbon atom (called a spiro atom) is common to the monocyclic rings.

The term "bridged heterocyclic group" as used herein refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one atom selected from O, N and S. It can be divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

The term “heterospirocyclyl” as used herein refers to polycyclic hydrocarbons with one carbon atom (called a spiroatom) common to the single rings, and the ring contains at least one heteroatom selected from O, N and S.

The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound. As used herein, the term “ring double bond” is a double bond formed between two adjacent ring atoms (eg, C=C, C=N or N=N).

When nitrogen atoms (eg, amines) are present in the compounds of the present invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to produce other compounds of the present invention. Accordingly, both the nitrogen atoms shown and the claimed are intended to include both the nitrogen shown and its N-oxides for the production of derivatives of the invention.

When any variable appears more than once in any composition or formula of a compound, its definition in each occurrence is independent of its definition in each other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, the group may optionally be substituted with up to three R groups, and in each case R is independently selected from the definition of R. Additionally, combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

The term "patient" as used herein refers to an organism being treated with the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, mice, primates/monkeys, horses, cattle, pigs, dogs, cats, etc.) and most preferably humans.

The term "effective amount" as used herein means the amount of a drug or agent (ie, a compound of the invention) that will produce a biological or medical response in a tissue, system, animal or human, for example, desired by a researcher or clinician. In addition, the term “therapeutically effective amount” means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease compared to a corresponding subject not receiving such amounts or rate of disease progression. An effective amount may be administered in one or more administrations or doses and is not intended to be limited to a particular formulation or route of administration. The term also includes an amount effective to improve normal physiology.

As used herein, the term “treatment” includes its broad meaning to include therapeutic and/or prophylactic treatment of a subject. In particular, "treatment" includes any treatment that results in alleviation, inhibition, elimination and amelioration and/or prevention of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, amelioration, elimination, prevention or alleviation its symptom. Therapeutic treatment includes alleviating, inhibiting or improving symptoms or conditions of a disease, delaying the development of complications, attenuating the underlying metabolic syndrome, inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition, alleviating a disease or symptom; helps reduce disease or symptoms; relieve complications caused by a disease or symptoms, or treat symptoms caused by a disease or symptoms. Preventative treatment includes pre-treatment to prevent, block or delay, slow the onset or progression of, or reduce the severity of a disease or disorder.

Likewise, “therapeutic agents” also include agents or means that provide therapeutic and/or prophylactic treatment to a subject.

The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" are used herein to refer to those compounds, substances, compositions and/or dosage forms that, within the bounds of sound medical judgment, are suitable for contact with human and animal tissues, toxicity, irritation, allergic reactions and /or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

Some pharmacy and medical terms

The term "cancer" as used herein refers to abnormal cell growth that is uncontrolled and, under certain conditions, capable of metastasizing (spreading). This type of cancer includes, but is not limited to, solid tumors (eg, bladder, colon, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organs (eg , thyroid), prostate, skin (melanoma) or blood tumor (eg, non-leukemic leukemia).

The term "co-administration" or similar terms as used herein refer to the administration to a patient of multiple selected therapeutic agents administered in the same or different administrations at the same or different times.

The term "enhancement" or "can be enhanced" as used herein refers to the ability of a desired result to be enhanced or prolonged in either effectiveness or duration. Thus, when enhancing the therapeutic effect of a drug, the term "can be enhanced" refers to the ability of the drug to increase or prolong the activity or duration of action of the drug in the system. As used herein, the term "synergy" refers to the ability to maximize the ability of another therapeutic agent in an ideal system.

The term "immune disease" refers to a disease or condition of an adverse or harmful response to an endogenous or exogenous antigen. The result is usually cell dysfunction, or destruction and dysfunction of cells, or destruction of organs or tissues, which can cause immune symptoms.

The terms "kit" and "product packaging" are synonymous.

The terms "subject", "subject" or "patient" include mammals and non-mammals. Mammals include, but are not limited to: humans, non-human primates such as orangutans, monkeys and marmosets; farm animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; laboratory animals, including rodents. Such as rats, mice and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish and the like. In a preferred embodiment, the selected mammal is a human.

In this context, the compound or pharmaceutical composition, when administered, results in an improvement, especially a reduction in severity, delay of onset, slowing of progression, or shortening of the duration of a disease, symptom or condition. Permanent or temporary, continuous or intermittent conditions may be due to or associated with administration.

Method of administration

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal, nasal and topical routes of administration. Additionally, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal administration.

Administration of the compounds of the present invention may be local. In some specific embodiments, the depot composition is administered by implantation (eg, subcutaneously or intramuscularly) or intramuscular injection. Additionally, in another embodiment, the drug is administered using a targeted drug delivery system. For example, liposomes encapsulated with organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.

Pharmaceutical composition and dosage

The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutical substance, composition or carrier such as a liquid or solid excipient, diluent, excipient, processing aid (such as lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or substances encapsulated in a solvent which involve the transfer or transport of the compound in question from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the drug and is not harmful to the patient.

The term "pharmaceutical composition" means a composition comprising a compound of the present invention and optionally other pharmaceutically acceptable carriers. "Pharmaceutically acceptable carrier" refers to a vehicle conventional in the art for delivering a biologically active agent to an animal, particularly a mammal, including (i.e.) adjuvants, excipients or excipients such as diluents, preservatives, agents, excipients, flow modifiers , disintegrants, agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, flavorings, antibacterial agents, antifungal agents, lubricants and dispersing agents, depending on the route of administration and the nature of the dosage form.

The pharmaceutical compositions of the present invention may contain a therapeutically effective amount of one or more compounds of the present invention, formulated together, optionally, with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally with one or more other therapeutic agents. The compounds of the present invention can be administered for any of the above uses by any suitable route, for example, orally, for example, in the form of tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions ; sublingual; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (for example, in sterile injectable aqueous or non-aqueous solutions or liquid suspensions); nasally, including administration into the nasal membranes, for example, using an inhalation spray; topically, for example, in the form of a cream or ointment; or rectally, for example, in the form of a suppository; or by intratumoral injection. They can be administered separately, but are usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

Pharmaceutically acceptable carriers are formulated according to a number of factors within the control of those skilled in the art. Such factors include, but are not limited to: the type and nature of the active agent; a subject to whom the composition containing the active agent will be administered; intended route of administration of the composition; target therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid vehicles and various solid and semi-solid dosage forms.

Such carriers may include a variety of different ingredients and additives in addition to the active agent, with other ingredients being included for various reasons known to those skilled in the art, such as stabilization of the active agent, binders, and the like. Descriptions of suitable pharmaceutical carriers and factors influencing carrier selection can be found in a number of available references, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), ^22nd Edition (2012), Pharmaceutical Press.

Of course, dosage regimens of the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent, the mode and manner of its administration, the species, age, sex, health status and body weight of the individual, the recipient, the nature and severity of symptoms, type concomitant treatment, frequency of treatment, route of administration, renal and hepatic function of the patient and the desired effect. In general guidance, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably when used for the indicated effect is usually from about 0.1 mg/day to about 250 mg/day. During a constant rate infusion, the most preferred intravenous dose should be from about 0.01 mg/kg/min to about 10 mg/kg/min. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be administered in divided doses two, three or four times daily.

The compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (hereinafter referred to as pharmaceutically acceptable carriers), suitably selected in accordance with the intended form of administration (for example, oral tablets, capsules, elixirs and syrups) and in accordance with standard pharmaceutical practice as mixtures of medicinal carriers.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is typically present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and filled into size 1 gelatin capsules.

A typical injection formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) into a vial, aseptically lyophilizing and capping. To use, the contents of the bottle are mixed with 2 ml of saline to obtain an injection.

The present invention includes pharmaceutical compositions containing, either alone or in combination with a pharmaceutically acceptable carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

Regardless of the route of administration chosen, the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art. Art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response, composition, and route of administration for a particular patient without being toxic to the patient.

The dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide used, the route of administration, the time of administration, the rate of elimination of the particular compound used; rate and degree of absorption, duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical field such as age, gender, weight, condition, general health and previous medical history, etc.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve the desired therapeutic effect, a physician or veterinarian may initiate a dose of a compound of the present invention used in a pharmaceutical composition at a level below the required level and gradually increase the dose until the desired effect is achieved. In general, a suitable daily dose of a compound of the present invention will be that amount of compound that represents the lowest dose effective to produce a therapeutic effect. Such effective dose will generally depend on the factors discussed above. Typically, oral, intravenous, intracerebroventricular and subcutaneous dosages of the compounds of the invention for patients range from about 0.01 to about 50 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in a unit dosage form. In some aspects of the invention, dosing is once daily. Although the compounds of the present invention can be administered separately, it is preferable to administer the compounds in the form of a pharmaceutical composition (composition).

Kit/Product Packaging

Kit/product packaging is also described herein for use in the treatment of the above indications. These kits may consist of a conveyor, package or box of containers that can be divided into compartments to accommodate one or more containers such as vials, tubes, etc., each container containing one component according to the method described above. Suitable containers include, but are not limited to, bottles, vials, syringes and tubes. Containers are made of acceptable materials such as glass or plastic.

For example, the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in mixture with other ingredients described herein. The container may have a sterile outlet (eg, the container may be an IV pack or a bottle with a stopper that can be pierced with a hypodermic needle). Such kits may contain the compound along with instructions for use, labeling, or operating instructions as described herein.

A typical kit may include one or more containers, each containing one or more materials (such as reagents or concentrated stock solutions and/or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes with a list of contents and/or instructions for use, as well as instructions for use, inner packaging. The entire set of instructions must be included.

Labels can be displayed on the container or closely associated with it. Having a label on a container means that letters, numbers or other elements of the label are affixed, cast or engraved on the container; The label may also be on a container or shipping box containing various containers, such as on product inserts. The label may be used to indicate the specific therapeutic use of the contents. The label may also include instructions for use of the contents, such as those described in the method described above.

All features described herein (including any claims set forth in the abstract) and/or all steps included in any method or process may be present in any combination, except to the extent that certain features or steps are mutually exclusive in one and the same the same combination.

The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments can be optionally combined. All features disclosed herein may be used in combination with any composition, and each feature disclosed herein may be replaced by any alternative features that serve the same, equivalent, or similar purpose. Therefore, unless otherwise indicated, the disclosed features are only general examples of equivalent or similar features.

The present invention will be further described below in connection with specific embodiments. It should be understood that these examples are used only to illustrate the present invention and not to limit the scope of the present invention. In the following examples, experimental methods without specific conditions generally follow normal conditions or conditions suggested by the manufacturer. All percentages, ratios, ratios or parts are by weight unless otherwise noted.

The unit of mass percent in the present invention is well known to those skilled in the art, for example, it refers to the mass of the solute in 100 ml of solution. Unless otherwise specified, all professional and scientific terms used herein have the same meanings as those known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be used in the methods of the present invention. The methods and materials for the preferred embodiments described herein are presented for illustrative purposes only.

Examples

If the preparation method is not specified, suitable intermediates are commercially available (eg from Sigma Aldrich, Alfa).

General process

Commercially available reagents were used without further purification. ¹ H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values are expressed in parts per million, i.e. delta values. The following abbreviations are used for multiple NMR signals: s = unimodal, brs = broad, d = doublet, t = triplet, m = multiplet. Coupling constants are given in J values measured in Hz. NMR and mass spectrum results were corrected for background peaks. Chromatography refers to column chromatography using 100 mesh silica gel and is carried out under nitrogen pressure (flash chromatography). Reaction monitoring TLC refers to TLC performed using a specific mobile phase and Merck silica gel F254 as the stationary phase.

LC-MS experiments were performed under the following conditions:

Apparatus: Thermo U3000, ALLtech ELSD, MSQ, Combined UV ELSD and MSD detector (elution ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6×50 mm; Column temperature: 30°C. Gradient [time] (min) / solvent B to A (%)]: 0.00/5.0, 0.70/95, 1.40/95, 1.41/5, 1.50/5 (Solvent A=0.01% trifluoroacetic acid in water; Solvent B=0.01% trifluoroacetic acid in acetonitrile). UV detection: 214/254/280/300 nm; DAD detection: 200-400 nm; flow rate: 4 mL/min; MS: ESI, 100-1500 m/z

Preparative HPLC typically uses a base method (acetonitrile-water gradient with 10 mM ammonium bicarbonate in water); Thermo U3000 AFC-3000; Column: Globalsil C-18 12 nm, 250×20 mm, 10 μm, or equivalent, flow rate: 20 ml/min for separation.

Synthesis of intermediates

Receiving INT-1 connection:

2-Chloro-5-hydroxybenzoic acid (29.0 g, 168 mmol) was dissolved in tetrahydrofuran (100 ml) and borane (1.0 M in tetrahydrofuran, 336 ml) was added dropwise under nitrogen and an ice bath. After adding dropwise, the reaction solution was warmed to room temperature and stirred for 16 hours. Raw material testing TLC was completely consumed, methanol was added dropwise to the reaction solution in an ice bath to quench the reaction until no more bubbles appeared. The solvent was concentrated to give a pale yellow solid, INT-1a (26.6 g, yield: 99.8%).

Compound INT-1a (26.6 g, 168 mmol) and imidazole (11.5 g, 169 mmol) were dissolved in dichloromethane (300 ml). tert-butyldimethylsilyl chloride (25.5 g, 169 mmol), previously dissolved in dichloromethane (100 ml), was added in portions at 0°C. The mixture was heated to 30°C and stirred for 16 hours, the reaction was quenched with water (100 ml) and the aqueous phase was extracted with dichloromethane (100 ml x 2). The combined organic phases were washed with brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a pale yellow liquid INT-1b (33.4 g, yield: 73%).

Compound INT-1b (8.0 g, 29.3 mmol) was dissolved in acetonitrile (100 ml), triethylamine (14.8 g, 147 mmol), magnesium chloride (5.58 g, 58.6 mmol) and paraformaldehyde (8.80 g, 293 mmol). The mixture was heated to 90°C under a nitrogen atmosphere and stirred vigorously for 20 hours. The reaction solution was diluted with water (100 ml), adjusted to pH 3-4 with saturated aqueous citric acid and extracted with ethyl acetate (200 ml x 2). The combined organic phases were washed with brine (300 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid INT-1c (5.0 g, yield: 56.7%). ¹ H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.23 (s, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 4.72 (s, 2H), 0.96 (s , 9H), 0.14 (s, 6H).

5-Chloromethyl-3-cyanopyridine hydrochloride (3.20 g, 17.0 mmol) was dissolved in N,N-dimethylformamide (20 ml), N,N-diisopropylethylamine (5.48 g, 42.4 mmol) and potassium carbonate (5.86 g, 42.4 mmol). After stirring for 10 minutes, INT-1c (4.25 g, 14.1 mmol) and potassium iodide (234 mg, 1.41 mmol) were added to the above reaction solution. The reaction solution was stirred in an ice bath for 30 minutes, then heated to 50°C and stirred for 16 hours. The reaction solution was cooled in an ice bath. After adding 100 ml of water, a solid precipitated. The solid was filtered, washed with water and dried. The crude solid was then separated by silica gel column chromatography to obtain a white solid, INT-1d (5.00 g, yield: 84.9%). MS (ESI): m/z 417.2 (M+H) ⁺ .

Compound INT-1d (5.0 g, 12.0 mmol) was dissolved in toluene (10 ml), ethylene glycol (14.9 g, 240 mmol) and p-toluenesulfonic acid (228 mg, 1.20 mmol) were added, then trimethyl orthoformate (2.55 g, 24.0 mmol) was added dropwise. The mixture was heated to 80°C under a nitrogen atmosphere and stirred for 16 hours. The reaction solution was cooled in an ice bath, quenched with saturated aqueous sodium bicarbonate (50 ml) and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid INT-1e (5.50 g, yield: 99.5%). MS (ESI): m/z 461.2 (M+H) ⁺ .

Compound INT-1e (2.20 g, 4.77 mmol) was dissolved in tetrahydrofuran (10 ml), a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 7.16 ml) was added and the reaction solution was stirred at 30°C for half an hour. Diluted with water (30 ml), the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was suspended with a mixture of ethyl acetate and petroleum ether (v/v=3/100, 20 ml) and filtered to obtain a pale yellow solid. INT-1f (1.58 g, yield: 95.5%). MS (ESI): m/z 347.2 (M+H) ⁺ .

Compound INT-1f (1.50 g, 4.33 mmol) was dissolved in dichloromethane (30 ml), N,N-diisopropylethylamine (1.68 g, 13.0 mmol) was added, methanesulfonic acid anhydride (1.51 g, 8.65 mmol) at 0°C in a nitrogen atmosphere. A mixture of N,N-diisopropylethylamine (1.68 g, 13.0 mmol) and dioxane hydrochloride (4 M, 1.62 ml) in dichloromethane (10 ml) was then added. The reaction solution was stirred at 25°C for 16 hours. Quench with water (30 ml) and extract the aqueous phase with dichloromethane (50 ml x 2). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give a pale yellow solid INT-1g (1.40 g, yield: 88.6%). MS (ESI): m/z 365.2 (M+H) ⁺ .

Compound INT-1 g (1.36 g, 3.72 mmol), 4-bromo-1H-indazole (734 mg, 3.72 mmol) and potassium carbonate (1.03 g, 7.45 mmol) were dissolved in N ,N-dimethylformamide (10 ml). The mixture was stirred at 50°C for 16 hours. The reaction solution was cooled in an ice bath, 100 ml of water was added until a solid precipitated, filtered, washed with water and dried; The resulting crude solid was separated by silica gel column chromatography to obtain a pale yellow solid, INT-1h (1.08 g, yield: 55.2%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J=2.0 Hz, 1H), 8.82 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.70 (d, J =8.5 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 6.91 (s, 1H), 6.04 (s, 1H ), 5.71 (s, 2H), 5.16 (s, 2H), 4.04-4.01 (m, 2H), 3.97-3.89 (m, 2H); MS (ESI): m/z 525.0 (M+H) ⁺ .

Compound INT-1h (1.00 g, 1.90 mmol) was dissolved in tetrahydrofuran (20 ml), hydrochloric acid (4.0 M in water, 5.0 ml) was added. The reaction solution was stirred at 30°C for 1 hour. It was then neutralized with saturated aqueous sodium bicarbonate and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a pale yellow solid, INT-1i (900 mg, yield: 98.2%). MS (ESI): m/z 481.0 (M+H) ⁺ .

Compound INT-1i (840 mg, 1.74 mmol) was dissolved in N,N-dimethylformamide (5 ml), O-tert-butyl-L-serine tert-butyl ester (418 mg, 1.92 mmol) and acetic acid (209 mg, 3.48 mmol), the reaction mixture was stirred at 30°C for 1 hour. Sodium triacetoxyborohydride (1.48 g, 6.96 mmol) was then added to the reaction solution, and the reaction mixture was stirred at 30° C. for 1 hour. It was then quenched by adding water (50 ml) and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give pale yellow solid INT-1j (720 mg, yield: 60.5%), MS (ESI): m/z 682.1 (M+H) ⁺ .

Intermediate INT-1j (1.00 g, 1.46 mmol), pinacol diboronate (558 mg, 2.20 mmol), potassium acetate (431 mg, 4.39 mmol) and Pd(dppf)Cl ₂ (107 mg , 0.15 mmol). Mix in dioxane (15 ml). The reaction solution was heated to 90°C under nitrogen atmosphere and stirred overnight. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate (100 ml), filtered through celite, washed with 100 ml of ethyl acetate, and the resulting filtrate was concentrated. The residue was separated by silica gel column chromatography (dichloromethane/methanol, v/v=20/1) to obtain a pale yellow solid, INT-1 (600 mg, yield: 56.1%). MS (ESI): m/z 730.7 (M+H) ⁺ .

Receiving INT-2 connection:

(S)-5-Hydroxymethyl-2-pyrrolidone (10.0 g, 86.9 mmol) was dissolved in dry tetrahydrofuran (200 ml), phthalimide (12.8 g, 86.9 mmol) and triphenylphosphine (34.2 g, 130 mmol). Diisopropyl azodicarboxylate (26.4 g, 130 mmol) was slowly added dropwise to the reaction solution under ice bath conditions and a nitrogen atmosphere. The reaction solution was warmed to room temperature and stirred overnight, and the resulting precipitate was filtered and dried to give a white solid, INT-2a (11.4 g, yield: 53.7%). MS (ESI): m/z 245.1 (M+H) ⁺ .

Compound INT-2a (1.0 g, 4.09 mmol) was dissolved in ethanol (20 ml) and 80% hydrazine hydrate (512 mg, 8.19 mmol) was added. The reaction solution was heated to 85°C and stirred for 2 hours. After cooling the reaction mixture to room temperature, the formed precipitate was removed by filtration. After concentrating the filtrate, dichloromethane (50 ml) was added and the resulting filtrate was further concentrated in vacuo to obtain a yellow oily liquid INT-2 (430 mg, yield: 92.0%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.65 (s, 1H), 3.43-3.37 (m, 1H), 2.47-2.42 (m, 2H), 2.12-2.04 (m, 2H), 2.03-1.96 (m, 1H), 1.66 1.60 (m, 1H), 1.58 (s, 2H).

Receiving an INT-3 connection:

4-Formylbenzeneboronic acid pinacol ester (4.50 g, 19.4 mmol) and 1,3-dibromo-2-chlorobenzene (10.5 g, 38.8 mmol) were dissolved in a mixed solvent of dioxane and water (60 ml, v/v = 5/1), potassium carbonate (8.04 g, 58.2 mmol) and Pd(dppf)Cl ₂ (1.42 g, 1.94 mmol) were added. The reaction solution was heated to 80°C under nitrogen atmosphere and stirred for 3 hours. The reaction was quenched with water (100 ml) and the aqueous phase was extracted with ethyl acetate (200 ml x 2). The organic phases were combined, washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=4/1) to give a white solid INT-3a (3.7 g, yield: 64.6%).

Compound INT-3a (1.00 g, 3.38 mmol) was dissolved in N,N-dimethylformamide (10 ml), followed by compound INT-2 (541 mg, 4.74 mmol) and acetic acid (203 mg, 3. 38 mmol)). The resulting reaction solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was added. The resulting reaction solution was further stirred at room temperature overnight. It was quenched with saturated aqueous sodium bicarbonate (50 ml) and the aqueous phase was extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed successively with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow solid INT-3b (1.41 g, yield: 99.5%). MS (ESI): m/z 393.3 (M+H) ⁺ .

Compound INT-3b (1.41 g, 3.58 mmol) was dissolved in dichloromethane (15 ml), triethylamine (725 mg, 7.16 mmol) and di-tert-butyl dicarbonate (860 mg, 3.94 mmol) were added sequentially. . The reaction solution was stirred at room temperature for 2 hours, then diluted with 200 ml of dichloromethane; The resulting organic phase was washed successively with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane/methanol, v/v=20/1) to obtain a white solid INT-3 (1.55 g, yield: 87.6%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.78 (dd, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.44-7.25 (m, 6H), 4.53-4.39 (m, 2H), 3.80-3.70 (m, 1H), 3.26-3.10 (m, 2H), 2.17-1.99 (m, 3H), 1.76-1.66 (m, 1H), 1.38 (s, 9H); MS (ESI): m/z 493.3 (M+H) ⁺ .

Receiving an INT-4 connection:

From 1,3-dibromo-2-toluene, according to the synthesis method of compound INT-3, the white solid INT-4 can be obtained. ¹ H NMR (500 MHz, Chloroform-d) δ 7.76 (d, J=7.2 Hz, 1H), 7.28-7.22 (m, 7H), 4.53 (s, 2H), 4.05-3.67 (m, 1H), 3.42 -3.20 (m, 2H), 2.40 (s, 3H), 2.01-1.90 (m, 3H), 1.82-1.71 (m, 1H), 1.36 (s, 9H); MS (ESI): m/z 473.4 (M+H) ⁺ .

Receiving an INT-5 connection:

Compound INT-3a (1.50 g, 5.08 mmol) was dissolved in N,N-dimethylformamide (20 ml), then (R)-3-hydroxypyrrolidine hydrochloride (1.88 g, 15.2 mmol) and anhydrous sodium acetate (1.25 g, 15.2 mmol). The reaction solution was stirred at room temperature overnight. Sodium triacetoxyborohydride (4.31 g, 20.3 mmol) was then added and the reaction solution was further stirred at room temperature for 2 hours; The reaction was quenched with saturated aqueous sodium bicarbonate (100 ml) and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The organic phases were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane/methanol, v/v=20/1) to give a pale yellow solid INT-5 (1.60 g, yield: 80.6%). ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 7.71-7.67 (m, 1H), 7.46-7.41 (m, 2H), 7.38-7.33 (m, 2H), 7.32 (d, J=7.8 Hz, 1H ), 7.25 (t, J=7.8 Hz, 1H), 4.41-4.31 (m, 1H), 3.81-3.66 (m, 2H), 2.88-2.83 (m, 1H), 2.83-2.76(m, 1H), 2.64-2.58 (m, 1H), 2.56-2.51 (m, 1H), 2.22-2.12 (m, 1H), 1.79-1.70 (m, 1H); MS (ESI): m/z 366.1 (M+H) ⁺ .

Receiving an INT-6 connection:

Starting with 4-bromo-2-methoxybenzaldehyde, turn to the final esterification reaction of compound INT-1 with Suzuki boron to produce compound INT-6a.

Starting with the INT-b compound, referring to the synthesis method of the INT-3 compound to obtain the INT-6 compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.78 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.42-7.38 (m, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.11-7.03 (m, 1H), 7.02-7.00 (m, 1H), 6.98-6.93 (m, 1H), 4.47-4.34 (m, 2H), 3.81 (s, 3H), 3.77-3.71 ( m, 1H), 3.26-3.17 (m, 2H), 2.18-2.10 (m, 1H), 2.09-2.00 (m, 2H), 1.74-1.64 (m, 1H), 1.47-1.26 (m, 9H). MS (ESI): m/z 523.2 (M+H) ⁺ .

Receiving an INT-7 connection:

Intermediate INT-1i (1.00 g, 2.08 mmol), pinacol diboronate (635 mg, 2.50 mmol), potassium acetate (612 mg, 6.24 mmol) and Pd(dppf)Cl2 (152 mg, 0.21 mmol) mixed in dioxane solution (20 ml). The reaction solution was heated to 90°C under nitrogen atmosphere and stirred overnight. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate (100 ml), filtered through celite, the filter cake was further washed with ethyl acetate (100 ml), and the resulting filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=1/1) to obtain a pale yellow solid, INT-7a (940 mg, yield: 85.5%). MS (ESI): m/z 529.2 (M+H) ⁺ .

Compound INT-7a (96.4 mg, 0.18 mmol) and compound INT-3 (75.0 mg, 0.15 mmol) were dissolved in a mixed solvent of dioxane and water (11 ml, v/v=10/1 ) and potassium carbonate was added. (63.0 mg, 0.46 mmol) and Pd(dppf)Cl2 (11.1 mg, 0.015 mmol), the mixture was heated to 80°C under a nitrogen atmosphere and stirred for 3 hours. Then quench with water (50 ml) and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The organic phases were combined, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative thin layer chromatography (dichloromethane/methanol, v/v=95/5) to give a pale yellow solid, INT-7 (120 mg, yield: 96.9%). MS (ESI): m/z 815.2 (M+H) ⁺ .

Receiving an INT-8 connection:

Starting with compounds INT-1c and iodomethane, refer to the synthesis of INT-1i to obtain compound INT-8b. MS (ESI): m/z 379.1 (M+H) ⁺ .

Starting with the INT-8b compound, refer to the INT-7 compound synthesis to obtain the INT-8c compound and the INT-8 compound. Their spectral information is as follows:

INT-8c: ¹ H NMR (500 MHz, Chloroform-d) δ 10.31 (s, 1H), 8.50 (s, 1H), 7.83 (s, 1H), 7.69 (d, J=7.0 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 1H), 6.42 (s, 1H), 5.73 (s, 2H), 3.60 (s, 3H), 1.42 (s, 12H); MS (ESI): m/z 427.3 (M+H) ⁺ .

INT-8: MS (ESI): m/z 713.5 (M+H) ⁺ .

Receiving an INT-9 connection:

Starting with compound INT-8c and compound INT-6, compound INT-9 is prepared with reference to the synthesis of compound INT-8. MS (ESI): m/z 743.6 (M+H) ⁺ .

Receiving an INT-10 connection:

Starting with 3-bromo-2-chlorophenol, refer to the synthesis method for compound INT-7a to obtain compound INT-10a. MS (ESI): m/z 253.3 (MH) ^-.

Starting with the compound INT-10a and 6-chloro-2-methoxy-3-pyridaldehyde, compound INT-10b was prepared by reversing the synthesis method of compound INT-3a. MS (ESI): m/z 262.0 (M-H) ^- .

Compound INT-10b (500 mg, 1.90 mmol) was dissolved in anhydrous dichloromethane (10 ml), N,N-diisopropylethylamine (490 mg, 3.80 mmol) was added, the ice bath was cooled to 0° C., followed by slow addition of drops of trifluoromethanesulfonic acid anhydride (804 mg, 2.85 mmol). The reaction solution was gradually warmed to room temperature and stirring was continued for 2 hours. It was quenched with 50 ml of saturated aqueous ammonium chloride and the aqueous phase was extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with 50 ml brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain an orange oily substance INT-10 (482 mg, yield: 64.2%). MS (ESI): m/z 396.2 (M+H) ⁺ .

Receiving an INT-11 connection:

Dissolve (R)-1-Boc-3-carboxypyrrolidine (1.00 g, 4.65 mmol), iodomethane (1.00 g, 7.05 mmol) and potassium carbonate (2.00 g, 14.5 mmol) at 25 25°C N'N-dimethylformamide (3 ml). The reaction mixture was stirred for 3 hours. It was then diluted with water (50 ml) and extracted with ethyl acetate (50 ml x 2); The organic phases were combined, washed with 50 ml brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily substance INT-11a. (1.00 g, yield: 93.9%).

To a solution of INT-11a (1.00 g, 4.36 mmol) in dichloromethane (2 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 5 mL). The reaction solution was stirred at 25°C for 3 hours. The resulting reaction solution was concentrated to obtain a yellow solid INT-11 (700 mg, yield: 96.9%). ¹ H NMR (500 MHz, DMSO-d6) δ 9.70 (brs, 2H), 3.66 (s, 3H), 3.42-3.35 (m, 1H), 3.30-3.22 (m, 2H), 3.19-3.13 (m, 2H), 2.22-2.14 (m, 1H), 2.06-1.99 (m, 1H).

Receiving an INT-12 connection:

Starting with compound INT-8c and compound INT-5, compound INT-12 is prepared with reference to the synthesis of compound INT-8. MS (ESI): m/z 586.4 (M+H) ⁺ .

Receiving an INT-13 connection:

Add thionyl chloride (11.7 g, 98.6 mmol) to a solution of 2-hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol) in methanol (20 ml) under ice bath conditions; the reaction solution was stirred at 65°C for 16 hours. The reaction solution was concentrated, and ethyl acetate (100 ml) and water (100 ml) were added to the residue; The organic phase was washed with saturated sodium bicarbonate (100 ml), brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oil. INT-13a (5.25 g, yield: 96.1%).

To compound INT-13a (5.25 g, 31.6 mmol) in N,N-dimethylformamide (30 ml) was added iodomethane (5.83 g, 41.1 mmol) and potassium carbonate (8.73 g, 63. 2 mmol); The reaction solution was stirred at 25°C for 6 hours. The reaction solution was concentrated, and ethyl acetate (100 ml) and water (100 ml) were added to the residue. The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily substance INT-13b. (5.6 g, yield: 98.4%).

To a solution of compound INT-13b (1.0 g, 5.55 mmol) in methanol (15 ml) was added silver trifluoromethanesulfonate (1.57 g, 6.10 mmol) and iodine (1.55 g, 6.10 mmol) ; The reaction solution was stirred at 25°C for 2 hours. Then filtered, the filtrate was diluted with ethyl acetate (50 ml), washed with aqueous sodium sulfite (5% w/w, 50 ml) and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give INT -13 as an orange solid. (1.6 g, yield: 94.2%). ¹ H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.45 (s, 3H); MS (ESI): m/z 306.9 (M+H) ⁺ .

Receiving an INT-14 connection:

Thionyl chloride (185 mg, 1.55 mol) was added to a solution of trans-(N-Boc-4-aminocyclohexyl)acetic acid (100 mg, 0.39 mmol) in methanol (3 ml); The reaction solution was stirred at 70°C for 3 hours. After concentrating the reaction solution, a white solid, INT-14, was obtained. (70 mg, yield: 86.7%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.15 7.92 (m, 3H), 3.56 (s, 3H), 2.87 (s, 1H), 2.21-2.15 (m, 2H), 1.95-1.87 (m, 2H ), 1.74-1.66 (m, 2H), 1.63-1.53 (m, 1H), 1.35-1.25 (m, 2H), 1.06-0.95 (m, 2H).

Receiving an INT-15 connection:

To a solution of 4-bromo-2,6-difluorobenzaldehyde (1.10 g, 4.98 mmol) in methanol (10 mL), sodium methoxide (5.4 M in methanol, 1.11 mL) was added dropwise under bath conditions. ice). The reaction solution was stirred under the same conditions for 3 hours. The reaction was quenched with hydrochloric acid (1 M in water, 12 ml) and stirred for 10 minutes; The resulting solution was further diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with brine (150 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=10/1) to obtain a white solid INT-15a (660 mg, yield: 56.9%) and a white solid INT-15b (204 mg , yield: 16.7%).

Compound INT-15a: ¹ H NMR (500 MHz, Chloroform-d) δ 10.36 (s, 1H), 6.97-6.93 (m, 2H), 3.94 (s, 3H).

Compound INT-15b: ¹ H NMR (500 MHz, Chloroform-d) δ 10.42 (s, 1H), 6.76 (s, 2H), 3.90 (s, 6H).

Starting from compound INT-15a, related to the synthesis method of compound INT-6, compound INT-15 can be obtained. ¹ N NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 6.90-6.86 (m, 2H), 4.54-4.50 (m, 2H), 3.84 (s, 3H), 3.77-3.73 (m, 1H), 3.17 (d, J=5.3 Hz, 2H) , 2.12-2.02 (m, 3H), 1.71-1.65 (m, 1H), 1.40-1.32 (m, 9H); MS (ESI): m/z 541.5 (M+H) ⁺ .

Receiving an INT-16 connection:

Starting with compound INT-8c and compound INT-15, compound INT-16 is prepared with reference to the synthesis of compound INT-8. MS (ESI): m/z 761.7 (M+H) ⁺ .

Receiving INT-17 connection:

A solution of S-2-aminoadipic acid (5 g, 31 mmol) in acetic acid and water (25 ml, v/v=1/4) was stirred at 110°C for 16 hours. After concentrating the reaction solution, the resulting residue was dissolved in ethanol. Unreacted starting materials are not soluble in ethanol. The ethanol filtrate was concentrated to give a white solid INT-17a (3 g, yield: 67.6%). MS (ESI): m/z 142.1 (M-H) ^-

Starting with compound INT-17a and referring to the synthesis method for compound INT-13a, the colorless oil INT-17b can be obtained.

At 0°C, sodium borohydride (433 mg, 11.5 mmol) was added to a solution of compound INT-17b (450 mg, 2.9 mmol) in ethanol (10 ml); The resulting mixture was stirred at room temperature for 16 hours. A small amount of acetic acid was added to quench the reaction, the resulting reaction solution was concentrated, and the resulting residue was dissolved in dichloromethane. The organic phase was washed with a small amount of brine, dried over anhydrous sodium sulfate and concentrated to give a colorless oil, INT-17c (369 mg, yield: 99.8%). MS (ESI): m/z 130.2 (M+H) ⁺ .

Starting with compound INT-17c and referring to the synthesis method of compound INT-2, the light yellow oil INT-17 can be obtained. ¹ H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 3.22-3.06 (m, 1H), 2.59-2.42 (m, 2H), 2.18-1.98 (m, 2H), 1.75 (brs, 2H), 1.64 1.50 (m, 2H), 1.37-1.18 (m, 2H).

Receiving an INT-18 connection:

Starting from compound INT-15a, which belongs to the final stage of the Suzuki boron esterification reaction of compound INT-1, and the synthesis method of compound INT-3a, compound INT-18a can be obtained. ^1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.91-7.87 (m, 1H), 7.52-7.48 (m, 1H), 7.44-7.38 (m, 1H), 7.13-7.10 ( m, 1H), 7.04-7.00 (m, 1H), 3.96 (s, 3H).

Starting with compound INT-18a, turn to the last step of the esterification reaction of compound INT-1 with Suzuki boron to obtain compound INT-18. ¹ H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.68-7.64 (m, 1H), 7.55-7.51 (m, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.05 (s, 1H), 6.97-6.89 (m, 1H), 3.93 (s, 3H), 1.31 (s, 12H); MS (ESI): m/z 391.7 (M+H) ⁺ .

Synthesis of exemplary compounds

Example 1:

Starting with compound INT-1 and compound INT-5, refer to the synthesis of compound INT-7 to obtain compound 1a. MS (ESI): m/z 889.9 (M+H) ⁺ .

Compound 1a (20 mg, 0.022 mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added and the reaction solution was stirred at 25°C for 6 hours. After concentrating the reaction solution, the residue was purified by preparative high-performance liquid chromatography column to obtain white solid 1. (6.5 mg, yield: 37.4%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.72-7.67 (m, 1H), 7.55 -7.45 (m, 7H), 7.40 (d, J=8.0 Hz, 2H), 7.18-7.15 (m, 1H), 6.83 (s, 1H), 5.74-5.69 (m, 2H), 5.11-5.05 (m , 2H), 4.24-4.18 (m, 1H), 3.93 (d, J=14.5 Hz, 1H), 3.85 (d, J=14.5 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.61 -3.55 (m, 2H), 3.12-3.07 (m, 1H), 2.72-2.68 (m, 1H), 2.65-2.58 (m, 2H), 2.38-2.32 (m, 2H), 2.05-1.97 (m, 1H), 1.59-1.52 (m, 1H); MS (ESI): m/z 777.8 (M+H) ⁺ .

Example 2:

Starting with compound INT-1 and compound INT-4, refer to the synthesis of compound 1 to obtain compound 2. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.71-7.64 (m, 2H), 7.55 (s, 1H), 7.46-7.37 (m, 6H ), 7.34-7.31 (m, 1H), 7.28 (d, J=7.5, 1H), 7.09 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 5.71 (s, 2H), 5.14- 5.08 (m, 2H), 3.96-3.84 (m, 2H), 3.79-3.74 (m, 2H), 3.64-3.57 (m, 3H), 3.13-3.09 (m, 1H), 2.55 (d, J=6.0 Hz, 2H), 2.15-2.05 (m, 3H), 1.99 (s, 3H), 1.73-1.67 (m, 1H); MS (ESI): m/z 784.3 (M+H) ⁺ .

Example 3:

Starting with compound INT-1 and compound INT-3a, refer to the synthesis of compound INT-7 to obtain compound 3a. MS (ESI): m/z 818.4 (M+H) ⁺ .

Starting with compound 3a and morpholine, refer to the reductive amination step in the synthesis of compound INT-3b to obtain compound 3b. MS (ESI): m/z 889.9 (M+H) ⁺ .

Starting with compound 3b, refer to the last Boe deprotection step in the synthesis of compound 1 to obtain compound 3. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.33 (s , 1H), 7.86 (s, 1H), 7.72-7.67 (m, 1H), 7.56-7.45 (m, 7H), 7.41 (d, J=7.5 Hz, 2H), 7.17 (d, J=7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13-5.05 (m, 2H), 3.92 (d, J=14.0 Hz, 1H), 3.85 (d, J=14.0 Hz, 1H), 3.63-3.56 (m, 6H), 3.52 (s, 2H), 3.13-3.06 (m, 1H), 2.40 (s, 4H); MS (ESI): m/z 777.6 (M+H) ⁺ .

Example 4:

Starting with compound 3a and N-methylethanolamine, compound 4 was prepared according to the synthesis of compound 3. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 8.84 (d, J= 2.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.55-7.46 (m, 6H), 7.41 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.14-5.06 (m, 2H), 3.96 (d, J=14.0 Hz, 1H), 3.88 (d, J=14.0 Hz, 1H), 3.69-3.63 (m, 1H), 3.61-3.58 (m, 1H), 3.57 (s, 2H), 3.54 (t, J=6.5 Hz, 2H), 3.18-3.14 (m, 1H), 2.55-2.53 (m, 2H), 2.20 (s, 3H); MS (ESI): m/z 765.7 (M+H) ⁺ .

Example 5:

Starting with compound 3a and ethanolamine, refer to the synthesis of compound 3 to obtain compound 5. ¹ H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.56-7.50 (m, 3H), 7.49-7.43 (m, 6H), 7.17 (d, J=7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13-5.05 (m, 2H), 3.90 (d, J=14.0 Hz, 1H), 3.86-3.80 (m, 3H), 3.60-3.54 (m, 2H ), 3.51 (t, J=6.0 Hz, 2H), 3.10-3.05 (m, 1H), 2.65 (t, J=6.0 Hz, 2H); MS (ESI): m/z 751.4 (M+H) ⁺ .

Example 6:

Starting with compounds INT-3a and N-methylethanolamine, turn to the reductive amination step in the synthesis of compound INT-3b to obtain compound 6a. MS (ESI): m/z 354.2 (M+H) ⁺ .

To a solution of compound 6a (207 mg, 0.58 mmol) in tetrahydrofuran (5 ml) under ice bath conditions (203 mg, 1.17 mmol), N,N-diisopropylethylamine (226 mg, 1.75 mmol) was successively added and methanesulfonic acid anhydride. The reaction solution was stirred in an ice bath for half an hour, then heated to 25°C and stirred at the same temperature for 2 hours. The reaction solution was diluted with water (20 ml), the aqueous phase was extracted with dichloromethane (20 ml x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give compound 6b. To a solution of (R)-(-)-3-hydroxytetrahydrofuran (103 mg, 1.17 mmol) in tetrahydrofuran (5 ml) was added sodium hydrogen (60 wt.% in kerosene) under ice bath conditions under a nitrogen atmosphere, 46. 8 mg; The reaction solution was stirred in an ice bath for half an hour, and then the compound 6b obtained above was added. The resulting reaction solution was heated to 50°C and stirred overnight, after cooling to room temperature, the reaction solution was quenched with water (20 ml) and the aqueous phase was extracted with ethyl acetate (20 ml x 2); The combined organic phases were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative thin layer chromatography (dichloromethane/methanol, v/v=15/1) to give compound 6c as a yellow oil. (110 mg, yield: 44.4%). MS (ESI): m/z 424.3 (M+H) ⁺ .

Starting with compound INT-1 and compound 6 c, compound 6 is prepared with reference to the synthesis of compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz, 1H), 8.84 (d, J =2.0 Hz, 1H), 8.34-8.32 (m, 1H), 7.86 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.55-7.45 (m, 7H), 7.40 (d, J= 8.0 Hz, 2H), 7.20-7.15 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.12-5.05 (m, 2H), 4.12-4.08 (m, 1H), 3.89-3.77 (m, 2H), 3.73-3.68 (m, 1H), 3.67-3.62 (m, 3H), 3.57 (s, 2H), 3.55-3.48 (m, 4H), 3.02-2.94 (m, 1H), 2.55 (t, J=6.0 Hz, 2H), 2.20 (s, 3H), 1.94-1.83 (m, 2H); MS (ESI): m/z 835.7 (M+H) ⁺ .

Example 7:

Compound INT-3 (200 mg, 0.40 mmol) in tetrahydrofuran (2 mL) with sodium hydrogen (60% w/w in kerosene, 32.4 mg) was added in an ice bath and the reaction solution was further stirred for half an hour in an ice bath. Methyl iodide (86 mg, 0.61 mmol) was then added to the reaction solution at room temperature, and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water (20 ml) and the aqueous phase was extracted with ethyl acetate (20 ml x 2); The combined organic phases were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane/methanol, v/v=10/1) to obtain a yellow oily substance 7a (200 mg, yield: 97%). MS (ESI): m/z 507.4 (M+H) ⁺ .

Starting with compound INT-1 and compound 7a, refer to the synthesis of compound 1 to obtain compound 7. ¹ H NMR (500 MHz, DMSO-d6) δ 8.99-8.90 (m, 1H), 8.90-8.79 (m, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=8.5Hz, 1H), 7.57-7.43 (m, 9H), 7.17 (d, J=7.0 Hz, 1H), 6.83 (s , 1H), 5.72 (s, 2H), 5.15-5.05 (m, 2H), 3.97-3.91 (m, 1H), 3.89-3.83 (m, 1H), 3.78 (s, 2H), 3.68-3.52 (m , 3H), 3.18-3.10 (m, 1H), 2.73-2.63 (m, 5H), 2.33-2.22 (m, 1H), 2.18-2.08 (m, 1H), 2.06-1.98 (m, 1H), 1.87 1.77 (m, 1H); MS (ESI): m/z 818.6 (M+H) ⁺ .

Example 8:

Starting with compound INT-1 and compound INT-6, refer to the synthesis of compound 1 to obtain compound 8. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.74-7.68 (m, 2H), 7.57-7.49 (m, 4H), 7.48-7.45 (m , 1H), 7.42 (d, J=8.0 Hz, 1H), 7.19-7.15 (m, 1H), 7.11-7.04 (m, 2H), 6.85 (s, 1H), 5.72 (s, 2H), 5.15- 5.06 (m, 2H), 3.95 (d, J=14.5 Hz, 1H), 3.87 (d, J=14.5 Hz, 1H), 3.83 (s, 3H), 3.76-3.73 (m, 2H), 3.66-3.62 (m, 2H), 3.61-3.55 (m, 1H), 3.15-3.11 (m, 1H), 2.58-2.54 (m, 2H), 2.14-2.06 (m, 3H), 1.74-1.66 (m, 1H) ; MS (ESI): m/z 834.7 (M+H) ⁺ .

Example 9:

Starting with compounds INT-1 and 1,3-dibromo-2-chlorobenzene, turn to the Suzuki reaction, the last step in the synthesis of compound INT-7, to obtain compound 9a. MS (ESI): m/z 792.6 (M+H) ⁺ .

Starting with compound 9a, refer to the synthesis of compound INT-7a to obtain compound 9b. MS (ESI): m/z 840.6 (M+H) ⁺ .

Starting with compound 9b and 2-bromo-5-aldopyridine, refer to the Suzuki reaction, the last step in the synthesis of compound INT-7, to obtain compound 9 c. MS (ESI): m/z 819.4 (M+H) ⁺ .

Starting with compound 9c and compound INT-2, turn to the reductive amination step in the synthesis of compound INT-3b to obtain compound 9d. MS (ESI): m/z 917.8 (M+H) ⁺ .

Starting with compound 9d, referring to the last Boc deprotection step in the synthesis of compound 1, gives compound 9. ¹ H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.92-7.83 (m, 2H), 7.75-7.66 (m, 3H), 7.65-7.55 (m , 3H), 7.52-7.44 (m, 1H), 7.21-7.14 (m, 1H), 6.86 (s, 1H), 5.73 (s, 2H), 5.15-5.05 (m, 2H), 3.99-3.73 (m , 4H), 3.69-3.55 (m, 3H), 3.21-3.15 (m, 1H), 2.58-2.52 (m. 2H), 2.18-2.03 (m, 3H), 1.75-1.64 (m, 1H); MS (ESI): m/z 805.8 (M+H) ⁺ .

Example 10:

Starting with compound 9b and 5-bromo-2-pyridaldehyde, compound 10 was prepared according to the synthesis of compound 9. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.74-7.69 (m, 2H), 7.62-7.44 (m, 6H) , 7.18 (d, J=7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.14-5.05 (m, 2H), 3.93-3.73 (m, 4H), 3.68-3.50 (m , 3H), 3.03-2.94 (m, 1H), 2.58 (d, J=6.2 Hz, 2H), 2.16-2.05 (m, 3H), 1.75-1.66 (m, 1H); MS (ESI): m/z 805.3 (M+H) ⁺ .

Example 11:

Starting with compound 9b and 4-bromo-3-methoxybenzaldehyde, compound 11 was prepared according to the synthesis of compound 9. ¹ H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=2.0 Hz, 1H), 8.77 ( d, J=2.0 Hz, 1H), 8.27-8.25 (m, 1H), 7.73 (s, 1H), 7.66-7.59 (m, 2H), 7.47 (s, 1H), 7.45-7.37 (m, 3H) , 7.32-7.28 (m, 1H), 7.15-7.08 (m, 2H), 7.05 (s, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.78 (s, 1H), 5.64 (s, 2H ), 5.06-5.00 (m, 2H), 3.87-3.82 (m, 1H), 3.80-3.75 (m, 1H), 3.74-3.67 (m, 6H), 3.58-3.56 (m, 1H), 3.51-3.50 (m, 1H), 3.04-2.99 (m, 1H), 2.51-2.47 (m, 2H), 2.08-1.99 (m, 3H), 1.68-1.59 (m, 1H); MS (ESI): m/z 834.7 (M+H) ⁺ .

Example 12:

Starting with the pinacol ester of 4-formylphenylboronic acid and 1,3-dibromo-2-fluorobenzene, refer to the synthesis of compound INT-3a to obtain compound 12a. ¹ H NMR (500 MHz, Chloroform-d) δ 10.08 (s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.61 (t, J=7.0 Hz, 1H), 7.40 (t, J=7.0 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H).

Starting with compound 12a, compound INT-2 and compound INT-1, compound 12 is prepared with reference to the synthesis of compound INT-3 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=2.0 Hz , 1H), 8.84 (d, J=2.0 Hz, 1H), 8.34-8.32 (m, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.64-7.57 (m, 4H), 7.53 (s, 1H), 7.51-7.42 (m, 4H), 7.30-7.26 (m, 1H), 6.85 (s, 1H), 5.72 (s , 2H), 5.15-5.07 (m, 2H), 3.90 (d, J=14.5 Hz, 1H), 3.85-3.72 (m, 3H), 3.65-3.60 (m, 1H), 3.56 (d, J=5.5 Hz, 2H), 3.07-2.99 (m, 1H), 2.54-2.52 (m, 2H), 2.14-2.05 (m, 3H), 1.73-1.64 (m, 1H); MS (ESI): m/z 788.3 (M+H) ⁺ .

Example 13:

Starting with the pinacol ester of 4-formylphenylboronic acid and 2,6-dibromobenzonitrile, refer to the synthesis of compound INT-3a to obtain compound 13a. ¹ H NMR (500 MHz, Chloroform-d) δ 10.11 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H).

Starting with compound 13a, compound INT-2 and compound INT-1, compound 13 is prepared with reference to the synthesis of compound INT-3 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz , 1H), 8.81 (d, J=2.0 Hz, 1H), 8.31-8.29 (m, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.93-7.87 (m, 1H), 7.80-7.72 ( m, 2H), 7.70-7.63 (m, 4H), 7.56-7.45 (m, 4H), 7.37-7.33 (m, 1H), 6.70 (s, 1H), 5.78-5.73 (m, 2H), 5.06- 4.99 (m, 2H), 3.90 (d, J=15.0 Hz, 1H), 3.84-3.75 (m, 3H), 3.71 (d, J=15.0 Hz, 1H), 3.66-3.61 (m, 1H), 3.58 -3.54 (m, 1H), 3.09-3.02 (m, 1H), 2.56-2.53 (m, 2H), 2.14-2.05 (m, 3H), 1.73-1.65 (m, 1H); MS (ESI): m/z 795.7 (M+H) ⁺ .

Example 14:

Starting with the pinacol ester of 4-formylphenylboronic acid and 1-bromo-3-iodobenzene, refer to the synthesis of compound INT-3a to obtain compound 14a.

Starting with compound 14a, compound INT-2 and compound INT-1, compound 14 is prepared with reference to the synthesis of compound INT-3 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J=2.0 Hz , 1H), 8.83 (d, J=2.0 Hz, 1H), 8.32-8.30 (m, 1H), 8.21-8.18 (m, 1H), 7.96-7.94 (m, 1H), 7.76-7.71 (m, 4H ), 7.69-7.62 (m, 3H), 7.55 (s, 1H), 7.51-7.44 (m, 3H), 7.38 (d, J=7.0 Hz, 1H), 6.83 (s, 1H), 5.76-5.70 ( m, 2H), 5.16-5.08 (m, 2H), 3.94 (d, J=14.0 Hz, 1H), 3.87 (d, J=14.0 Hz, 1H), 3.79 (d, J=14.0 Hz, 1H), 3.75 (d, J=14.0 Hz, 1H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 1H), 3.15-3.12 (m, 1H), 2.54-2.52 (m, 2H), 2.13- 2.04 (m, 3H), 1.72-1.64 (m, 1H); MS (ESI): m/z 770.7 (M+H) ⁺ .

Example 15:

At room temperature, 3-bromo-4-chloroaniline (2.06 g, 9.98 mmol) was dissolved in sulfuric acid (25% w/w aqueous solution, 40 ml) and stirred for half an hour; The reaction solution was then cooled to -50°C, and an aqueous (10 mL) solution containing pre-dissolved sodium nitrite (826 mg, 12.0 mmol) was slowly added dropwise. After completion of the dropwise addition, the reaction solution was further stirred for 1 hour at -5°C; then a mixed solution of ethyl acetate and water (50 ml, v/v=3/2) with pre-dissolved potassium iodide (3.31 g, 20.0 mmol) was added dropwise, while maintaining the reaction temperature below -5°C. The aqueous phase was further extracted with ethyl acetate (50 ml x 2), the combined organic phase was washed successively with saturated sodium thiosulfate solution (100 ml x 2) and brine (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give a light yellow solid 15a. (2.05 g, yield: 64.7%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.95 (d, J=2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.17 (d, J=8.5 Hz, 1H).

4-formylphenylboronic acid pinacol ester (439 mg, 1.89 mmol) and compound 15a (500 mg, 1.58 mmol) were dissolved in a mixture of dioxane and water (10 ml, v/v = 4/1), sodium bicarbonate (397 mg, 4.73 mmol) and Pd(dppf)Cl ₂ (58 mg, 0.079 mmol). The reaction solution was heated to 80°C under nitrogen atmosphere and stirred for 3 hours. The reaction was quenched with water (50 ml) and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The organic phases were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=10/1) to give a yellow oily substance 15b (271 mg, yield: 58.2%).

Starting with compound 15b, compound INT-2 and compound INT-1, compound 15 is prepared with reference to the synthesis of compound INT-3 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.81-7.76 (m, 2H), 7.74-7.65 (m, 5H), 7.55-7.40 (m, 4H), 7.25-7.19 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.13-5.04 (m, 2H), 3.90-3.83 (m, 1H), 3.78-3.69 (m, 3H), 3.63-3.53 (m, 3H), 3.06-2.97 (m, 1H), 2.57-2.55 (m, 2H), 2.13-2.03 (m, 3H), 1.70-1.63 (m, 1H); MS (ESI): m/z 804.7 (M+H) ⁺ .

Example 16:

At room temperature, dissolved N-chlorosuccinimide (419 mg, 3.14 mmol) was added to a solution of N,N-dimethylformamide (3 mL) with 3-bromo-4-methylaniline (584 mg, 3.14 mmol). The reaction solution was heated to 80°C and stirred for 1 hour at the same temperature. Using water (50 mL), the reaction was quenched (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=10/1) to give a white solid 16a (292 mg, yield: 42.2%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.97 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 5.41 (s, 2H), 2.22 (s, 3H) .

Starting with Pinacol 4-formylphenylboronic acid and compound 16a, refer to the synthesis of compound INT-3a to obtain compound 16b.

At room temperature, dissolved tert-butyl nitrite (50 mg, 0.49 mmol) of compound 16b (100 mg, 0.41 mmol) and copper(I) bromide (91 mg, 0.63 mmol) were added in acetonitrile (1 mL). The reaction solution was heated to 60°C and stirred for 1 hour at the same temperature. The reaction was quenched with water (20 ml), the aqueous phase was extracted with ethyl acetate (20 ml × 2). The combined organic phase, brine (50 mL), was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=10/1) to give a white solid 16 s (28 mg, yield: 22.2%). ¹ H NMR (500 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.02-7.95 (m, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H ), 7.08 (d, J=8.2 Hz, 1H), 2.01 (s, 3H).

Starting with compound 16c, compound INT-2 and compound INT-1, compound 16 is prepared with reference to the synthesis of compound INT-3 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.98-8.88 (m, 1H) , 8.85-8.77 (m, 1H), 8.32-8.23 (m, 1H), 7.81 (s, 1H), 7.67-7.63 (m, 2H), 7.53 (s, 1H), 7.47-7.42 (m, 3H) , 7.42-7.39 (m, 2H), 7.27-7.21 (m, 2H), 7.14-7.09 (m, 1H), 6.82 (s, 1H), 5.69 (s, 2H), 5.11-5.04 (m, 2H) , 3.95-3.82 (m, 2H), 3.82-3.75 (m, 2H), 3.66-3.61 (m, 2H), 3.59-3.55 (m, 1H), 3.17-3.13 (m, 1H), 2.62-2.56 ( m, 2H), 2.14-2.10 (m, 1H), 2.08 (s, 3H), 2.08-2.04(m, 1H), 2.02-1.92 (m, 1H), 1.74-1.64 (m, 1H); MS (ESI): m/z 818.5 (M+H) ⁺ .

Example 17:

Starting with 3-bromo-4-chloroaniline, refer to the synthesis of compound 16 to obtain compound 17. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95-8.88 (m, 1H), 8.85-8.76 (m, 1H), 8.34-8.27 (m, 1H), 7.90-7.84 (m, 1H), 7.72-7.64 (m, 3H), 7.54 (d, J=8.3 Hz, 1H), 7.49-7.40 (m, 4H), 7.29 ( d, J=7.7 Hz, 2H), 7.14 (d, J=7.0 Hz, 1H), 6.73 (s, 1H), 5.68 (s, 2H), 5.09-4.99 (m, 2H), 3.80-3.71 (m , 2H), 3.66 (s, 2H), 3.63-3.57 (m, 1H), 3.42-3.34 (m, 2H), 3.21-3.16 (m, 1H), 2.56-2.52 (m, 2H), 2.13-2.04 (m, 3H), 1.70-1.64 (m, 1H); MS (ESI): m/z 838.2 (M+H) ⁺ .

Example 18:

Starting with 4-bromophenylethanol, compound 18a was prepared according to the synthesis of compound INT-7a. MS (ESI): m/z 249.1 (M+H) ⁺ .

Starting with compound 18a and 1,3-dibromo-2-toluene, refer to the synthesis of compound INT-3a to obtain compound 18b. MS (ESI): m/z 311.0 (M+H) ⁺ .

Starting with compound 18b, compound 18c is prepared with reference to the synthesis of compound 6b. MS (ESI): m/z 389.0 (M+H) ⁺ .

At 50°C, a solution of acetonitrile (10 ml) with compound 18c (290 mg, 0.74 mmol), (R)-3-hydroxypyrrolidine hydrochloride (138 mg, 1.12 mmol) and cesium carbonate (727 mg, 2. 23 mmol) was stirred for 16 hours. The reaction was quenched with water (30 ml). The aqueous phase was extracted with ethyl acetate (30 ml x 2). The combined organic phase was washed with brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane/methanol, v/v=10/1) to obtain a yellow oily substance 18d (140 mg, yield: 49.0%). MS (ESI): m/z 380.2 (M+H) ⁺ .

Starting with compound 18d and compound INT-1, compound 18 is prepared with reference to the synthesis of compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=2.0 Hz, 1H), 8.83 (d, J= 2.0 Hz, 1H), 8.33-8.31 (m, 1H), 7.86 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.53-7.51 (m, 2H), 7.48-7.45 (m, 2H ), 7.44-7.41 (m, 2H), 7.34-7.32 (m, 3H), 7.16 (d, J=7.0 Hz, 1H), 6.79 (s, 1H), 5.71 (s, 2H), 5.08 (d, J=3.0 Hz, 2H), 4.20-4.18(m, 1H), 3.86 3.81 (m, 2H), 3.53 3.51 (m, 2H), 2.97 (t, J=6.0 Hz, 1H), 2.80-2.76 (m , 4H), 2.68-2.63 (m, 4H), 2.00-1.96 (m, 1H), 1.57-1.53 (m, 1H); MS (ESI): m/z 791.5 (M+H) ⁺ .

Example 19:

Starting with 4-bromophenylpropanol, refer to the synthesis of compound 18 to obtain compound 19. ¹ H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H ), 8.54 (s, 1H), 8.35-8.33 (m, 1H), 7.86 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.55-7.51 (m, 2H), 7.49-7.42 ( m, 5H), 7.30 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.0 Hz, 1H), 6.75 (s, 1H), 5.70 (s, 2H), 5.13-4.98 (m, 2H ), 4.22-4.15 (m, 2H), 3.71-3.64 (m, 2H), 3.24-3.17 (m, 3H), 2.71-2.63 (m, 3H), 2.56-2.53 (m, 1H), 2.42-2.38 (m, 3H), 2.30-2.27 (m, 1H), 2.01-1.93 (m, 1H), 1.79-1.73 (m, 2H), 1.56-1.50 (m, 1H); MS (ESI): m/z 805.7 (M+H) ⁺ .

Example 20:

At 25°C, N-chlorosuccinimide (639 mg, 4.78 mmol) was added in portions to a solution of acetonitrile (20 ml) with dissolved 2,6-dibromoaniline (1.00 g, 3.99 mmol). The resulting reaction solution was stirred at the same temperature for 16 hours. After adding water to the reaction solution, a solid precipitates. The solid thus obtained was further washed with water and dried to obtain a white solid 20a (1.10 g, yield: 96.7%). ¹ H NMR (500 MHz, DMSO-d6) 6 7.53 (s, 2H), 5.48 (s, 2H).

Starting with compound 20a, turn to the synthesis of compound 16c, in which copper bromide is replaced by copper chloride to obtain compound 20b. ¹ H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 2H).

Starting with compound 20b, turn to the synthesis of compound 12 to obtain compound 20. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95-8.88 (m, 1H), 8.83-8.76 (m, 1H), 8.32-8.23 ( m, 1H), 7.90 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.68-7.64 (m, 1H), 7.61-7.58 (m, 1H), 7.56-7.41 (m, 7H) , 7.21-7.14 (m, 1H), 6.79-6.66 (m, 1H), 5.70 (s, 2H), 5.13-5.01 (m, 2H), 3.83-3.70 (m, 4H), 3.61 (t, J= 6.5 Hz, 1H), 3.51-3.47 (m, 1H), 3.44-3.41 (m, 1H), 2.86 (s, 1H), 2.53-2.52 (m, 2H), 2.16-2.00 (m, 3H), 1.73 -1.63 (m, 1H); MS (ESI): m/z 838.3 (M+H) ⁺ .

Example 21:

At 25°C, N-bromosuccinimide (6.28 g, 35.3 mmol) was added in portions to a solution of acetonitrile (30 ml) with dissolved 5-chloro-2-methylaniline (2.00 g, 14.1 mmol). The resulting reaction solution was stirred at the same temperature for 16 hours. The reaction was quenched with water (100 ml) and the aqueous phase was extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give dark red solid 21a (4.00 g, yield: 94.6%). ^1H NMR (500 MHz, Chloroform-d) δ 7.27 (s, 1H), 4.25 (s, 2H), 2.18 (s, 3H).

At 25°C and a nitrogen atmosphere, tert-butyl nitrite (3.91 g, 33.4 mmol) was slowly added dropwise to an ethanol (30 mL) solution of dissolved compound 21a (4.00 g, 13.4 mmol). The reaction solution was stirred for 2 hours at 50°C. The reaction solution was concentrated after cooling. The resulting residue was separated by silica gel column chromatography to obtain a white solid 21b (2.1 g, yield: 55.3%). ^1H NMR (500 MHz, Chloroform-d) δ 7.41 (s, 2H), 2.29 (s, 3H).

Starting with compound 21b, with reference to the synthesis of compound 12, compound 21 is obtained. ¹ H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=2.0 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H ), 8.31 8.29 (m, 1H), 7.84 (s, 1H), 7.72-7.63 (m, 2H), 7.53 (s, 1H), 7.48-7.39 (m, 5H), 7.33-7.25 (m, 2H) , 7.13 (d, J=7.0 Hz, 1H), 6.82 (s, 1H), 5.70 (s, 2H), 5.14-5.04 (m, 2H), 3.93 (d, J=14.5 Hz, 1H), 3.85 ( d, J=14.5 Hz, 1H), 3.80-3.73 (m, 2H), 3.67-3.54 (m, 3H), 3.14 (t, J=5.5 Hz, 1H), 2.54-2.53 (m, 2H), 2.38 (s, 3H), 2.12-2.04 (m, 3H), 1.72-1.64 (m, 1H); MS (ESI): m/z 818.8 (M+H) ⁺ .

Example 22:

Starting with INT-7 and glycine tert-butyl ether, compound 22 is prepared by reversing the reductive amination of INT-1j and the Boe deprotection step of compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.34-8.32 (m, 1H), 7.87 (s, 1H), 7.71 (d, J=8.5 Hz, 1H ), 7.67 (s, 1H), 7.56-7.46 (m, 9H), 7.17 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 5.73 (s, 2H), 5.11 (s, 2H) , 3.93 (s, 2H), 3.90-3.82 (m, 2H), 3.71-3.67 (m, 1H), 3.18 (s, 2H), 2.73-2.61 (m, 2H), 2.17-2.09 (m, 3H) , 1.75-1.69 (m, 1H); MS (ESI): m/z 774.7 (M+H) ⁺ .

Example 23:

Starting with compound INT-7 and isopropylserine, compound 23 is prepared with reference to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J=1.9 Hz, 1H), 8.83 (d, J=1.9 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.74-7.68 (m, 2H), 7.55-7.43 (m, 9H), 7.17 (d, J=7.0 Hz , 1H), 6.85 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.86-4.80 (m, 1H), 3.81-3.72 (m, 3H), 3.66-3.60 (m, 2H ), 3.54 (d, J=5.0 Hz, 2H), 3.19 (t, J=5.0 Hz, 1H), 2.56-2.54 (m, 2H), 2.14-2.07 (m, 3H), 1.74-1.65 (m, 1H), 1.11 (d, J=6.0 Hz, 3H), 1.08 (d, J=6.5 Hz, 3H); MS (ESI): m/z 846.7 (M+H) ⁺ .

Example 24:

Starting with INT-7 and ethanolamine, compound 24 is prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.71 (d, J=9.5Hz, 2H), 7.54 (t, J=7.5 Hz, 1H), 7.52-7.43 (m, 8H ), 7.17 (d, J=7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.09 (s, 2H), 3.79 (d, J=13.5 Hz, 1H), 3.77-3.73 (m, 3H), 3.66-3.61 (m, 1H), 3.47 (t, J=5.5 Hz, 2H), 2.59 (t, J=5.5 Hz, 2H), 2.57-2.54 (m, 2H), 2.15- 2.06 (m, 3H), 1.72-1.66 (m, 1H); MS (ESI): m/z 760.6 (M+H) ⁺ .

Example 25:

Starting with compound INT-7 and proline tert-butyl ester, compound 25 is prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 8.82 (d , J=2.0 Hz, 1H), 8.35-8.33 (m, 1H), 7.88 (s, 1H), 7.72-7.68 (m, 2H), 7.55-7.44 (m, 9H), 7.17 (d, J=7.0 Hz, 1H), 6.82 (s, 1H), 5.72 (s, 2H), 5.14-5.06 (m, 2H), 3.98 (d, J=14.0 Hz, 1H), 3.82 (d, J=14.0 Hz, 1H ), 3.77 (d, J=7.5 Hz, 2H), 3.65-3.62 (m, 1H), 3.05-3.02 (m, 1H), 2.56-2.54 (m, 2H), 2.15-2.03 (m, 5H), 1.90-1.84 (m, 1H), 1.81-1.65 (m, 4H); MS (ESI): m/z 814.8 (M+H) ⁺ .

Example 26:

Starting with compound INT-1j, compound 26b is prepared by reversing a reductive amination in the synthesis of compound INT-1j and a boron esterification step in the synthesis of compound INT-1. MS (ESI): m/z 744.6 (M+H) ⁺ .

Starting with compound 26b and compound INT-3, compound 26 is prepared with reference to the synthesis of compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz, 1H), 8.80 (d, J= 2.0 Hz, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72-7.68 (m, 2H), 7.57-7.43 (m, 9H), 7.17 (d, J=7.0 Hz, 1H), 6.80 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 3.82-3.69 (m, 6H), 3.66-3.58 (m, 2H), 2.55 (d, J=6.0 Hz, 2H) , 2.28 (s, 3H), 2.14-2.07 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m/z 818.8 (M+H) ⁺ .

Example 27:

Starting with INT-7, compound 27a is prepared by reversing the Boe deprotection step during the synthesis of compound 1. MS (ESI): m/z 715.5 (M+H) ⁺ .

At 25°C, (11)-3-hydroxypyrrolidine hydrochloride (21 mg, 0.14 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). mmol). The resulting reaction solution was stirred for 1 hour at the same temperature, and then sodium triacetate borohydride (58 mg, 0.27 mmol) was added. The reaction solution was further stirred for 16 hours at 25°C. After adding water (20 ml) to the reaction solution, it was extracted with ethyl acetate (15 ml × 2). The organic phase was concentrated and the residue was separated by preparative high performance liquid chromatography to obtain a white solid 27 (10 mg, yield: 22.6%). ¹ N NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 7.85 (s, 1H ), 7.71-7.65 (m, 2H), 7.52-7.40 (m, 9H), 7.15 (d, J=6.9 Hz, 1H), 6.80 (s, 1H), 5.69 (s, 2H), 5.07 (s, 2H), 3.77 (d, J=12.5 Hz, 1H), 3.74 (d, J=12.5 Hz, 1H), 3.62-3.56 (m, 3H), 2.92-2.86 (m, 1H), 2.69-2.61 (m , 2H), 2.54-2.52 (m, 4H), 2.11-2.05 (m, 3H), 1.95-1.90 (m, 2H), 1.70-1.64 (m, 1H); MS (ESI): m/z 814.8 (M+H) ⁺ .

Example 28:

Starting with compound INT-7a, compound INT-6 and serine isopropyl ether, compound 28 is prepared with reference to the synthesis of compound INT-7 and compound 23. ¹ H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J=2.0 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.30-8.28 (m, 1H), 7.88 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.68 (s, 1H ), 7.56-7.47 (m, 4H), 7.46 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.17 (d, J=7.1 Hz, 1H), 7.09 (d, J=1.6 Hz , 1H), 7.08-7.04 (m, 1H), 6.84 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.87-4.81 (m, 1H), 4.78 (t, J=5.8 Hz, 1H), 3.83 (s, 3H), 3.77 (d, J=14.7 Hz, 1H), 3.75-3.73 (m, 1H), 3.66-3.60 (m, 2H), 3.54 (t, J=5.6 Hz , 2H), 3.30-3.28 (m, 1H), 3.19 (t, J=5.3 Hz, 1H), 2.56 (d, J=6.0 Hz, 2H), 2.16-2.05 (m, 3H), 1.75-1.64 ( m, 1H), 1.11 (d, J=6.2 Hz, 3H), 1.09 (d, J=6.2 Hz, 3H); MS (ESI): m/z 876.2 (M+H) ⁺ .

Example 29:

Starting with compound INT-10, compound INT-2, compound INT-7a and ethanolamine, compound 29 is prepared with reference to the synthesis of compound INT-3, compound INT-7 and compound 23. ¹ H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.33-8.31 (m, 1H), 7.85 (s, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.72 (s, 1H), 7.69-7.65 (m, 1H), 7.60-7.54 (m, 2H), 7.52-7.47 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.18 (d, J=7.0 Hz, 1H), 6.87 (s, 1H), 5.72 (s, 2H), 5.11 (s, 2H), 3.92 (s, 3H) , 3.80 (s, 2H), 3.72 (d, J=4.0 Hz, 2H), 3.66-3.62 (m, 1H), 3.48 (t, J=5.5 Hz, 2H), 2.64 (t, J=5.5 Hz, 2H), 2.56 (d, J=6.0 Hz, 2H), 2.14-2.07 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m/z 791.6 (M+H) ⁺ .

Example 30:

Starting with compound INT-8 and L-serine O-tert-butyl ether tert-butyl ester, compound 30 was prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H) , 7.78 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.56-7.44 (m, 9H), 7.17 (d, J=7.0 Hz, 1H), 6.72 (s, 1H), 5.75 ( s, 2H), 3.89 (d, J=14.5 Hz, 1H), 3.83-3.75 (m, 3H), 3.68-3.63 (m, 2H), 3.61 (s, 3H), 3.60-3.57 (m, 1H) , 3.14 (t, J=5.5 Hz, 1H), 2.57 (d, J=6.5 Hz, 2H), 2.16-2.07 (m, 3H), 1.74-1.67 (m, 1H); MS (ESI): m/z 702.5 (M+H) ⁺ .

Example 31:

Starting with compounds INT-8 and (R)-(-)-4-amino-3-hydroxybutyric acid, compound 31 is prepared with reference to the synthesis of compound 27. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.43 (m, 7H), 7.17 (d, J=7.0 Hz, 1H ), 6.69 (s, 1H), 5.74 (s, 2H), 3.94-3.90 (m, 1H), 3.80-3.77 (m, 2H), 3.69-3.68 (m, 2H), 3.65-3.63 (m, 1H ), 3.60 (s, 3H), 2.57-2.53 (m, 4H), 2.45-2.39 (m, 1H), 2.28-2.22 (m, 1H), 2.13-2.05 (m, 3H), 1.75-1.65 (m , 1H); MS (ESI): m/z 716.7 (M+H) ⁺ .

Example 32:

Starting with compound INT-8 and glycine tert-butyl ether, compound 32 is prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J=9.0 Hz , 1H), 7.67 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.42 (m, 7H), 7.17 (d, J=7.0 Hz, 1H), 6.70 (s, 1H), 5.74 ( s, 2H), 3.80-3.72 (m, 4H), 3.65-3.62 (m, 1H), 3.60 (s, 3H), 3.07 (s, 2H), 2.55-2.53 (m, 2H), 2.14-2.07 ( m, 3H), 1.72-1.66 (m, 1H); MS (ESI): m/z 672.6 (M+H) ⁺ .

Example 33:

Starting with compound INT-8 and compound INT-11, compound 33a is prepared with reference to the synthesis of compound INT-5. MS (ESI): m/z 826.7 (M+H) ⁺ .

At 25°C, dissolved lithium hydroxide (10 mg, 0.42 mmol) was added to a mixed solution of methanol and water (9 mL, v/v = 8/1) with compound 33a (90 mg, 0.11 mmol). The reaction solution was stirred for 1 hour at the same temperature. The reaction solution was concentrated and then diluted with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (10 ml x 2). The combined organic phase was concentrated. The residue was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (4 ml, v/v=3/1) and the reaction was continued for 2 hours at 25°C. After concentrating the reaction solution, the residue was separated by preparative high-performance liquid chromatography to obtain a white solid 33 (10.3 mg, yield: 23.5%). ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.43 (m, 6H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83-3.74 (m, 2H), 3.67- 3.62 (m, 1H), 3.58 (s, 3H), 3.56-3.48 (m, 2H), 2.95-2.88 (m, 1H), 2.68-2.64 (m, 2H), 2.59-2.54 (m, 2H), 2.54-2.51 (m, 1H), 2.15-2.06 (m, 3H), 1.98-1.90 (m, 2H), 1.74-1.66 (m, 1H); MS (ESI): m/z 712.7 (M+H) ⁺ .

Example 34:

Starting with (R)-1-Boc-3-hydroxypyrrolidine, compound 34a is prepared by synthesizing compound INT-11 with reference to compound INT-11.

Starting with compound 34a and compound INT-8, compound 34 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H) , 7.68 (s, 1H), 7.55-7.43 (m, 8H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 3.81-3.73 (m, 2H), 3.66-3.61 (m, 1H), 3.58 (s, 3H), 3.56-3.47 (m, 2H), 2.92-2.86 (m, 1H), 2.69- 2.62 (m, 2H ), 2.56-2.53 (m, 2H), 2.49-2.46 (m, 1H), 2.14-2.07 (m, 3H), 1.96-1.90 (m, 2H), 1.74-1.66 (m, 1H); MS (ESI): m/z 712.7 (M+H) ⁺ .

Example 35:

Starting from N-Boc-(R)-3-piperidine formate, compound 35a was prepared according to the synthesis of compound INT-11.

Starting with compound 35a and compound INT-8, compound 35 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H) , 7.68 (s, 1H), 7.55-7.42 (m, 8H), 7.39 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.80 - 3.73 (m, 2H), 3.65-3.61 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H), 2.78-2.72 (m, 1H), 2.59-2.53 (m, 3H), 2.44-2.40 (m, 1H), 2.24-2.18 (m, 1H), 2.13-2.04 (m, 4H), 1.79-1.73 (m, 1H), 1.72-1.67 (m, 1H), 1.64-1.59 (m , 1H), 1.50-1.42 (m, 1H), 1.40-1.33 (m, 1H); MS (ESI): m/z 726.7 (M+H) ⁺ .

Example 36:

Starting with N-Boc-(S)-3-piperidine formate, compound 36a was prepared according to the synthesis of compound INT-11.

Starting with compound 36a and compound INT-8, compound 36 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H) , 7.68 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.43 (m, 6H), 7.39 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.68 (s, 1H ), 5.73 (s, 2H), 3.83-3.74 (m, 2H), 3.66-3.63 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H), 2.77-2.73 (m, 1H), 2.56 (m, 3H), 2.45-2.39 (m, 1H), 2.23-2.16 (m, 1H), 2.15-2.04 (m, 4H), 1.79-.73 (m, 1H), 1.72-1.66 (m, 1H), 1.64-1.59 (m, 1H), 1.50-1.42 (m, 1H), 1.41-1.33 (m, 1H); MS (ESI): m/z 726.7 (M+H) ⁺ .

Example 37:

Starting with methyl 4-piperidinoate and compound INT-8, compound 37 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.78-7.76 (m, 1H) , 7.67 (s, 1H), 7.53-7.46 (m, 7H), 7.35 (s, 1H), 7.32 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.81-3.73 (m, 2H), 3.65-3.62 (m, 1H), 3.58 (s, 3H), 3.52-3.50 (m, 2H), 2.80-2.77 (m, 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m, 1H), 2.13-2.08 (m, 3H), 2.02-1.98 (m, 4H), 1.78-1.74 (m, 2H), 1.72-1.67 (m , 1H), 1.56-1.52 (m, 2H); MS (ESI): m/z 726.7 (M+H) ⁺ .

Example 38:

Starting with butane nitrogen hydrochloride 3-methyl formate and compound INT-8, compound 38 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.55-7.44 (m, 8H), 7.27 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.72 (s , 2H), 3.84-3.77 (m, 2H), 3.68-3.63 (m, 1H), 3.58 (s, 3H), 3.47 (s, 2H), 3.42-3.38 (m, 2H), 3.23-3.17 (m , 3H), 2.58 (d, J=6.0 Hz, 2H), 2.16-2.06 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m/z 698.7 (M+H) ⁺ .

Example 39:

Starting with methyl bicycloate hydrochloride and compound INT-8, compound 39 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H ), 7.69 (s, 1H), 7.55-7.50 (m, 2H), 7.48-7.41 (m, 7H), 7.17 (d, J=7.0 Hz, 1H), 6.70 (s, 1H), 5.74 (s, 2H), 3.83 - 3.75 (m, 2H), 3.68 (s, 2H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 2.57 (d, J=6.0 Hz, 2H), 2.40 (d , J=6.5 Hz, 2H), 2.15-2.06 (m, 4H), 1.88 (d, J=11.0 Hz, 2H), 1.80 (d, J=11.0 Hz, 2H), 1.74-1.67 (m, 1H) , 1.43-1.37 (m, 1H), 1.32-1.22 (m, 2H), 0.94-0.84 (m, 2H); MS (ESI): m/z 754.8 (M+H) ⁺ .

Example 40:

Starting with trans-4-aminocyclohexanoate methyl ester hydrochloride and compound INT-8, compound 40 is prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.79 (d, J =8.5 Hz, 1H), 7.67 (s, 1H), 7.56-7.51 (m, 3H), 7.50-7.45 (m, 6H), 7.18 (d, J=7.0 Hz, 1H), 6.78 (s, 1H) , 5.76 (s, 2H), 3.95 (s, 2H), 3.88-3.80 (m, 2H), 3.69-3.65 (m, 1H), 3.64 (s, 3H), 2.81 (s, 1H), 2.62 (d , J=6.5 Hz, 2H), 2.18-2.09 (m, 4H), 2.04 (d, J=11.0 Hz, 2H), 1.94 (d, J=11.0 Hz, 2H), 1.75-1.67 (m, 1H) , 1.37-1.22 (m, 4H); MS (ESI): m/z 740.7 (M+H) ⁺ .

Example 41:

Starting with methyl cis-4-aminocyclohexanoate hydrochloride and compound INT-8, compound 41 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.56-7.51 (m, 3H), 7.50-7.45 (m, 6H), 7.18 (d, J=7.0 Hz, 1H), 6.76 (s, 1H), 5.76 (s, 2H), 3.92-3.78 (m, 4H), 3.69-3.66 (m, 1H), 3.63 (s, 3H), 2.87-2.83 (m, 1H), 2.61 (d, J=6.0 Hz, 2H ), 2.46-2.44 (m, 1H), 2.15-2.07 (m, 3H), 2.00-1.92 (m, 2H), 1.81-1.67 (m, 3H), 1.53-1.44 (m, 4H); MS (ESI): m/z 740.7 (M+H) ⁺ .

Example 42:

Starting with trans-4-hydroxyl-L-proline methyl ester hydrochloride and compound INT-8, compound 42 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.43 (m, 7H), 7.17 (d, J=7.0 Hz, 1H), 6.69 (d, J=7.0 Hz, 1H), 5.74 (s, 2H), 4.21-4.15 (m, 1H), 3.87-3.82 (m, 1H), 3.80-3.76 (m, 2H), 3.67-3.62 (m , 2H), 3.6-3.57 (m, 3H), 3.50-3.45 (m, 1H), 3.21-3.19 (m, 1H), 2.58-2.53 (m, 3H), 2.13-2.07 (m, 3H), 2.02 -1.90 (m, 1H), 1.81-1.75 (m, 1H), 1.73-1.67 (m, 1H); MS (ESI): m/z 728.7 (M+H) ⁺ .

Example 43:

Starting with L-proline methyl ester hydrochloride and compound INT-8, compound 43 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.55-7.43 (m, 10H), 7.17 (d, J=7.0 Hz, 1H), 6.70 (s, 1H), 5.75 (s, 2H), 3.93 ( d, J=14.0 Hz, 1H), 3.84 - 3.77 (m, 3H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 3.37 - 3.33 (m, 1H), 3.10 - 3.04 (m, 1H), 2.59-2.52 (m, 3H), 2.14-2.05 (m, 4H), 1.90-1.83 (m, 1H), 1.80-1.74 (m, 1H), 1.73 - 1.66 (m, 2H); MS (ESI): m/z 712.7 (M+H) ⁺ .

Example 44:

Starting with compound INT-8 and 4-aminomethyl benzoate hydrochloride, compound 44a was prepared with reference to the synthesis of compound INT-5. MS (ESI): m/z 862.7 (M+H) ⁺ .

Starting with compound 44a, compound 44b is prepared by reversing the reductive amination step in the synthesis of compound INT-1j. MS (ESI): m/z 876.8 (M+H) ⁺ .

Starting with compound 44b, compound 44 is prepared with reference to the last two steps of the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 7H), 7.40 (d, J=7.5 Hz, 2H), 7.17 ( d, J=7.0 Hz, 1H), 6.68 (s, 1H), 5.74 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 - 3.53 (m, 2H) , 3.57 (s, 3H), 3.45 (s, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.07 (m, 6H), 1.72 - 1.66 (m, 1H); MS (ESI): m/z 762.7 (M+H) ⁺ .

Example 45:

Starting with INT-8 and methyl p-aminophenylacetate, compound 45 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.17 (d, J=7.0 Hz, 1H), 7.02 (d, J=8.0 Hz , 2H), 6.92 (s, 1H), 6.75 (s, 1H), 6.55 (d, J=8.0 Hz, 2H), 5.72 (s, 2H), 4.41 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.61 (m, 4H), 3.35 (s, 2H), 2.98 (s, 3H), 2.58 - 2.53 (m, 2H), 2.14 - 2.06 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m/z 762.7 (M+H) ⁺ .

Example 46:

Starting with the compound INT-8 and methyl p-aminobenzoate, compound 46 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.64 - 7.60 (m, 5H), 7.59-7.50 (m, 3H), 7.50-7.46 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.87 (s, 1H), 6.85-6.81 (m, 1H), 6.68-6.63 (m, 2H), 5.72 (s, 2H), 4.53 (s, 2H), 4.25 (s, 2H), 3.91 -3.85 (m, 1H), 3.68 (s, 3H), 3.09 (s, 3H), 2.57 - 2.53 (m, 2H), 2.23 - 2.14 (m, 3H), 1.83-1.77 (m, 1H); MS (ESI): m/z 748.7 (M+H) ⁺ .

Example 47:

Starting with compound INT-8 and methyl bicycloate hydrochloride, compound 47 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J=8.5 Hz, 1H ), 7.67 (s, 1H), 7.53 - 7.40 (m, 8H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H) , 3.78 - 3.71 (m, 2H), 3.64 - 3.60 (m, 1H), 3.55 (s, 3H), 3.35 - 3.31 (m, 2H), 2.53 - 2.51 (m, 2H), 2.13-2.07 (m, 4H), 2.07 (s, 3H), 2.01-1.96 (m, 1H), 1.85 - 1.76 (m, 4H), 1.71-1.65 (m, 1H), 1.46 - 1.39 (m, 1H), 1.28 - 1.17 ( m, 3H), 0.82 - 0.73 (m, 2H); MS (ESI): m/z 768.4 (M+H) ⁺ .

Example 48:

Starting with 4-bromo-2-methylbenzaldehyde, compound 48a was prepared by reversing the boron esterification synthesis step of compound INT-7a. ¹ H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.60 (s, 1H), 2.61 (s, 3H), 1.29 (s, 12H).

Starting with compound 48a and 1,3-dibromo-2-chlorobenzene, compound 48b was prepared according to the synthesis of compound INT-3a. ¹ H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.48 - 7.34 (m, 4H), 2.66 (s, 3H).

Starting with compound 48b, compound INT-2, compound INT-8c and compound INT-11, compound 48 is prepared by reference to the synthesis of compound INT-3, compound INT-8 and compound 33. ¹ H NMR (500 MHz, DMSO-d6 ) δ 7.88 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.38 (m, 5H), 7.35 (s, 1H), 7.30 -7.23 (m, 2H), 7.14 (d, J=7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.74 - 3.67 (m, 2H), 3.65 - 3.61 (m, 1H), 3.56 (s , 3H), 3.52 - 3.48 (m, 2H), 2.92 - 2.85 (m, 1H), 2.64 - 2.61 (m, 2H), 2.59 - 2.56 (m, 2H), 2.34 (s, 3H), 2.11 - 2.05 (m, 3H), 1.94 - 1.89 (m, 2H), 1.71 - 1.66 (m, 1H); MS (ESI): m/z 726.2 (M+H) ⁺ .

Example 49:

Starting with 4-bromo-2-chlorobenzaldehyde, compound 49 was prepared according to the synthesis of compound 48. ¹ H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.77 (d, J=8.5 Hz, 1H ), 7.69 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.57 - 7.45 (m, 5H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.90 - 3.80 (m, 2H), 3.70 - 3.61 (m, 1H), 3.58 (s, 3H), 3.56 - 3.49 (m, 2H), 2.96-2.86 (m, 1H), 2.69-2.63 (m, 2H), 2.61 -2.56 (m, 2H), 2.53 -2.50 (m, 2H), 2.17-2.06 (m , 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.66 (m, 1H); MS (ESI): m/z 746.6 (M+H) ⁺ .

Example 50:

Starting with 4-bromo-3-chlorobenzaldehyde, compound 50 was prepared according to the synthesis of compound 48. ¹ H NMR (500 MHz, DMSO-J6) δ 7.80 (s, 1H), 7.76 (d, J=8.5 Hz, 1H ), 7.66 (s, 1H), 7.57 - 7.47 (m, 4H), 7.39 - 7.38 (m, 3H), 7.34 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.80 - 3.72 (m, 2H), 3.63 - 3.60 (m, 1H), 3.56 (s, 3H), 3.53 - 3.47 (m, 2H), 2.90 - 2.83 (m, 1H), 2.65 - 2.59 (m, 2H), 2.55-2.51 (m, 2H), 2.47-2.45 (m, 2H), 2.14-2.03 (m, 3H), 1.95 - 1.87 (m, 2H), 1.72 - 1.63 (m, 1H); MS (ESI): m/z 746.5 (M+H) ⁺ .

Example 51:

Starting with 4-bromo-2-(trifluoromethoxy)benzaldehyde, compound 51 was prepared according to the synthesis of compound 48. ¹ H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.82 - 7.73 (m, 2H ), 7.69 (s, 1H), 7.61 - 7.50 (m, 5H), 7.51 - 7.48 (m, 1H), 7.38 (s, 1H), 7.19 (d, J=7.0 Hz, 1H), 6.69 (s, 1H), 5.75 (s, 2H), 3.88-3.80 (m, 2H), 3.65 (t, J=6.5 Hz, 1H), 3.59 (s, 3H), 3.57 - 3.49 (m, 2H), 2.85 - 2.75 (m, 1H), 2.70 - 2.60 (m, 2H), 2.60 - 2.55 (m, 2H), 2.56 - 2.53 (m, 1H), 2.50 - 2.43 (m, 1H), 2.18 - 2.08 (m, 3H) , 1.98 - 1.85 (m, 2H), 1.77 - 1.67 (m, 1H); MS (ESI): m/z 796.7 (M+H) ⁺ .

Example 52:

Starting with compound INT-9 and compound INT-11, compound 52 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.68 (s, 1H), 7.57 - 7.47 (m, 4H), 7.42 (d, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.72 (m, 2H) , 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 - 3.50 (m, 2H), 2.95 - 2.87 (m, 1H), 2.70 - 2.62 (m, 2H), 2.60 - 2.54 (m, 2H), 2.53 - 2.51 (m, 2H), 2.17 - 2.04 (m, 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.65 (m, 1H); MS (ESI): m/z 742.2 (M+H) ⁺ .

Example 53:

Starting with compound INT-9 and L-serine O-tert-butyl ether tert-butyl ester, compound 53 was prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H) , 7.78 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.48 (m, 5H), 7.42 (d, J=1.1 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.10 (s, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.73 (s, 1H), 5.74 (s, 2H), 3.88 (d, J=14.6 Hz, 1H), 3.84 ( s, 3H), 3.81 - 3.74 (m, 3H), 3.68 - 3.63 (m, 2H), 3.61 (s, 3H), 3.60 -3.57 (m, 1H), 3.14 (t, J=5.4 Hz, 1H) , 2.62 - 2.57 (m, 2H), 2.18 - 2.04 (m, 3H), 1.76 -1.66 (m, 1H); MS (ESI): m/z 732.6 (M+H) ⁺ .

Example 54:

Starting with compound INT-9 and methyl bicycloate hydrochloride, compound 54 was prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-J6) δ 7.91 (s, 1H), 7.77 (d, J=8.6 Hz, 1H ), 7.67 (s, 1H), 7.57 - 7.45 (m, 5H), 7.45 - 7.39 (m, 2H), 7.17 (d, J=7.0 Hz, 1H), 7.09 (d, J=1.6 Hz, 1H) , 7.06 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.73 (m, 2H), 3.66 - 3.62 (m, 3H ), 3.60 (s, 3H), 2.59 - 2.54 (m, 2H), 2.37 - 2.33 (m, 2H), 2.18 - 2.05 (m, 4H), 1.90 - 1.84 (m, 2H), 1.82 - 1.76 (m , 2H), 1.72 - 1.68 (m, 1H), 1.42 - 1.32 (m, 1H), 1.32 -1.20 (m, 3H), 0.95 - 0.82 (m, 2H); MS (ESI): m/z 784.7 (M+H) ⁺ .

Example 55:

Starting with compound INT-9 and methyl bicycloate hydrochloride, compound 55 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.42 (d,J=7.7Hz, 1H), 7.38 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.09 (d,J=1.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.79 - 3.71 (m, 2H) , 3.66 - 3.62 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.58 - 2.56 (m, 2H), 2.15 - 2.06 (m, 9H), 1.89 - 1.80 (m, 4H) , 1.74 - 1.66 (m, 1H), 1.51 - 1.42 (m, 1H), 1.33 - 1.23 (m, 2H), 0.88 - 0.76 (m, 2H); MS (ESI): m/z 798.7 (M+H) ⁺ .

Example 56:

Starting with trans-4-aminocyclohexanoate methyl ester hydrochloride and compound INT-9, compound 56 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.42 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.05-7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75-3.68 (m,2H), 3.65-3.59 (m, 3H), 3.58 (s, 3H), 2.56 - 2.52 (m, 2H), 2.32-2.24 (m, 1H), 2.14-2.03 (m, 4H), 1.92 - 1.80 (m, 4H), 1.72- 1.63 (m, 1H), 130

- 1.18 (m, 2H), 1.05 -0.95 (m, 2H); MS (ESI): m/z 770.7 (M+H) ⁺ .

Example 57:

Starting with trans-4-aminocyclohexanoate methyl ester hydrochloride and compound INT-9, compound 57 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.44 (s, 2H), 2.56 - 2.52 (m, 2H), 2.39 - 2.31 (m, 1H), 2.14 - 2.10 (m, 7H), 1.95 - 1.86 (m, 2H), 1.81 - 1.74 (m, 2H), 1.71 - 1.65 (m, 1H), 1.31 - 1.23 (m, 4H); MS (ESI): m/z 784.8 (M+H) ⁺ .

Example 58:

Starting with compound INT-9 and compound INT-2, compound 58 is prepared with reference to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.53 - 7.44 (m, 4H), 7.41 (s, 1H), 7.40 (d,J=8.0Hz, 1H), 7.15 (d, J =7.0 Hz, 1H), 7.06 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.76 - 3.68 (m, 2H), 3.66 - 3.59 (m, 4H), 3.58 (s, 3H), 2.56 - 2.52 (m, 2H), 2.47 - 2.42 (m, 2H), 2.14 - 2.03 (m, 6H), 1.70 - 1.60 (m, 2H); MS (ESI): m/z 741.8 (M+H) ⁺ .

Example 59:

Starting with methyl cis-4-aminocyclohexanoate hydrochloride and compound INT-9, compound 59 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.45 (m, 4H), 7.43 (s, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.75-3.67 (m, 2H) , 3.62 - 3.60 (m, 3H), 3.58 (s, 3H), 2.55 - 2.52 (m, 3H), 2.31 - 2.25 (m, 1H), 2.13 - 2.04 (m, 3H), 1.87 - 1.79 (m, 2H), 1.72 - 1.63 (m, 1H), 1.57 - 1.48 (m, 2H), 1.46 - 1.37 (m, 4H); MS (ESI): m/z 770.7 (M+H) ⁺ .

Example 60:

Starting with methyl cis-4-aminocyclohexanoate hydrochloride and compound INT-9, compound 60 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H) , 3.64 - 3.60 (m, 1H), 3.56 (s, 2H), 3.42 - 3.35 (m, 3H), 2.57 - 2.52 (m, 2H), 2.45 -2.40 (m, 1H), 2.38-2.31 (m, 1H), 2.14-2.07 (m, 3H), 2.06 (s, 3H), 2.01 - 1.93 (m, 2H), 1.72 - 1.63 (m, 1H), 1.60 - 1.52 (m, 2H), 1.50 - 1.37 ( m, 4H); MS (ESI): m/z 784.7 (M+H) ⁺ .

Example 61:

Starting with compound INT-11 and compound INT-12, compound 61 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s,1H), 7.75 (d, J=8.5 Hz, 1H), 7.53 -7.48 (m, 2H), 7.48-7.43 (m, 4H), 7.41-7.36 (m, 2H), 7.35 (s,1H), 7.15 (d, J=7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.21 - 4.16 (m, 1H), 3.70 - 3.45 (m, 4H), 3.56 (s, 3H), 2.92 - 2.85 (m, 1H), 2.72 - 2.66 (m, 1H), 2.64 - 2.57 (m, 3H), 2.45 - 2.40 (m, 3H), 2.36 - 2.32 (m, 1H), 2.02 - 1.96 (m, 1H), 1.95 - 1.88 (m, 2H) , 1.58 - 1.52 (m, 1H); MS (ESI): m/z 685.8 (M+H) ⁺ .

Example 62:

Starting with compound INT-12 and compound 35a, compound 62 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J=8.5 Hz, 1H) , 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.37 (m, 3H), 7.17 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s , 2H), 4.24-4.19 (m, 1H), 3.66 - 3.58 (m, 2H), 3.57 (s, 3H), 3.41 (s, 2H), 2.80 - 2.72 (m, 1H), 2.73 - 2.67 (m , 1H), 2.64 - 2.55 (m, 2H), 2.46 - 2.43 (m, 1H), 2.42 - 2.38 (m, 1H), 2.37 - 2.34 (m, 1H), 2.22 -2.12 (m, 1H), 2.08 - 1.98 (m, 2H), 1.80 - 1.71 (m, 1H), 1.65 - 1.53 (m, 2H), 1.50 - 1.42 (m, 1H), 1.40 - 1.31 (m, 1H); MS (ESI): m/z 699.7 (M+H) ⁺ .

Example 63:

Starting with compound INT-12 and methyl bicycloate hydrochloride, compound 63 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.76 (d, J=8.5 Hz, 1H ), 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.38 (m, 3H), 7.17 (d,J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 ( s, 2H), 4.24 - 4.18 (m, 1H), 3.64 (d, J=13.0 Hz, 1H), 3.60 - 3.56 (m, 6H), 2.73 - 2.67 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.42 (m, 1H), 2.37 - 2.34 (m, 1H), 2.31 (d, J=6.5 Hz, 2H), 2.12 - 2.06 (m, 1H), 2.04 - 1.98 (m, 1H) , 1.89 - 1.84 (m, 2H), 1.82 - 1.77 (m, 2H), 1.59-1.52 (m, 1H), 1.39-1.32 (m, 1H), 1.31-1.21 (m, 2H), 0.93 - 0.83 ( m, 2H); MS (ESI): m/z 727.5 (M+H) ⁺ .

Example 64:

Starting with (S)-3-hydroxypyrrolidine hydrochloride and compound INT-3a, compound 64a was prepared with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m/z 586.4 (M+H) ⁺ .

Starting with compound 64a and compound INT-11, compound 64 was prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.75 (d, J=8.5 Hz, 1H ), 7.52 - 7.47 (m, 2H), 7.47 - 7.42 (m, 4H), 7.39 (s, 1H), 7.37 (d,J=8.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.22 - 4.15 (m, 1H), 3.64 - 3.57 (m, 2H), 3.56 (s, 3H), 3.52 - 3.45 (m, 2H), 2.90 - 2.82 (m, 1H), 2.70 - 2.56 (m, 4H), 2.45 - 2.38 (m, 3H), 2.35 - 2.30 (m, 1H), 2.02 - 1.95 (m, 1H) , 1.94 - 1.86 (m, 2H), 1.62 - 1.50 (m, 1H); MS (ESI): m/z 685.5 (M+H) ⁺ .

Example 65:

Starting with 3-hydroxyazetane hydrochloride, compound 65 was prepared according to the synthesis of compound 64. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 4H), 7.38 - 7.33 (m, ZN), 7.17 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H ), 5.34 - 5.26 (m, 1H), 4.23 -4.19 (m, 1H), 3.61 (s, 2H), 3.58 (s, 3H), 3.56-3.46 (m, 6H), 2.94-2.88 (m, 1H ), 2.82 -2.78 (m, 2H), 2.67-2.64 (m, 2H), 1.97-1.91 (m, 2H); MS (ESI): m/z 671.6 (M+H) ⁺ .

Example 66:

Starting with N-acetylethylenediamine and compound INT-3a, compound 66a was prepared with reference to the synthesis of compound INT-3. MS (ESI): m/z 481.2 (M+H) ⁺ .

Starting with compound 66a, compound INT-8c and compound INT-11, compound 66 is prepared with reference to the synthesis of compound INT-8 and compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.82 - 7.77 (m, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.40 (m, 6H), 7.35 (s, 1H), 7.15 (d, J =7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.73 (s, 2H), 3.56 (s, 3H), 3.52 - 3.47 (m, 2H), 3.16 -3.12 (m, 2H), 2.93 - 2.84 (m, 1H), 2.67 - 2.61 (m, 2H), 2.57 (t, J=6.5 Hz, 2H), 2.45 -2.42 (m, 2H), 1.96 - 1.87 (m, 2H) , 1.77 (s, 3H); MS (ESI): m/z 700.2 (M+H) ⁺ .

Example 67:

Starting with (R)-5-hydroxymethyl-2-pyrrolidone and compound INT-3a, compound 67a was prepared with reference to the synthesis of compound INT-2 and compound INT-3. MS (ESI): m/z 493.2 (M+H) ⁺ .

Starting with compound 67a, compound INT-8c and compound INT-11, compound 67 is prepared with reference to the synthesis of compound INT-8 and compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.39 (m, 6H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.77 - 3.71 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.52 - 3.48 (m, 2H), 2.91 - 2.83 (m, 1H), 2.66 - 2.60 (m, 2H), 2.55 - 2.51 (m, 2H), 2.47 - 2.45 (m, 2H), 2.15 - 2.04 (m, 3H), 1.95 - 1.88 (m, 2H), 1.72 - 1.64 (m, 1H); MS (ESI): m/z 712.6 (M+H) ⁺ .

Example 68:

Under ice bath conditions, methanesulfonic anhydride (135 mg, 0.77 mmol) and triethylamine (102 mg, 1.01 mmol) were added sequentially to dichloromethane (3 mL) dissolved in M-tert-butoxycarbonyl-1,2-ethylenediamine (99 mg, 0.62 mmol); The reaction solution was stirred under the same conditions for 1 hour. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with brine (30 ml), dried with anhydrous sodium sulfate. The filtrate was concentrated to give a white solid 68a (160 mg, yield: 86.6%).

A solution of compound 68a (160 mg, 0.67 mmol) dissolved in hydrochloric acid (4 M solution in 1,4-dioxane, 1.7 ml) was added to dichloromethane (2 ml). The reaction solution was stirred at 20°C for 16 hours. The reaction solution was concentrated to obtain a yellow oily substance 68b (90 mg, yield: 76.8%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 3H), 7.36 (t, J=6.0 Hz, 1H), 3.27 - 3.16 (m, 2H), 2.94 (s, 3H), 2.92 - 2.84 (m, 2H).

Starting with compound 68b, compound 68 is prepared with reference to the synthesis of compound 64. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.53 -7.48 ( m, 2H), 7.47 - 7.43 (m, 4H), 7.43-7.40 (m, 2H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.74 (s, 2H), 3.56 (s, 3H), 3.54 - 3.52 (m, 2H), 3.05 (t, J=6.5 Hz, 2H), 2.92 - 2.89 (m, 1H), 2.88 (s, 3H), 2.67 -2.60 (m, 4H), 2.47 - 2.45 (m, 2H), 1.95 - 1.87 (m, 2H); MS (ESI): m/z 736.9 (M+H) ⁺ .

Example 69:

Starting with compound INT-11, compound INT-Za and compound INT-8c, compound 69a is prepared with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m/z 628.5 (M+H) ⁺ .

Starting with compound 69a and (R)-3-hydroxypyrrolidine hydrochloride, compound 69 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J= 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.50 - 7.45 (m, 4H), 7.40 (d, J=8.0 Hz, 2H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.20 - 4.15 (m, 1H), 3.66 - 3.59 (m, 2H), 3.58 (s, 3H), 3.53 (d, J= 14.5 Hz, 1H), 3.48 (d, J=14.5 Hz, 1H), 2.96-2.91 (m, 1H), 2.74 (t, J=8.5 Hz, 1H), 2.66 - 2.62 (m, 2H), 2.61 - 2.58 (m, 1H), 2.42 - 2.32 (m, 4H), 2.01 - 1.94 (m, 3H), 1.56 - 1.49 (m, 1H); MS (ESI): m/z 685.3 (M+H) ⁺ .

Example 70:

Starting with compound INT-11, 4-bromo-2-methoxybenzaldehyde and compound INT-8c, compound 70a was prepared with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m/z 658.4 (M+H) ⁺ .

Starting with compound 70a and compound INT-2, compound 70 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d,J=8.5Hz, 1H) , 7.63 (s, 1H), 7.53-7.44 (m, 4H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.62 - 3.59 (m, 4H), 3.58 - 3.56 ( m, 4H), 2.95 - 2.89 (m, 1H), 2.77 - 2.71 (m, 1H), 2.70 - 2.65 (m, 1H), 2.58 - 2.52 (m, 2H), 2.47 - 2.43 (m, 2H), 2.11 - 2.02 (m, 3H), 1.98 - 1.92 (m, 2H), 1.67 - 1.60 (m, 1H); MS (ESI): m/z 742.7 (M+H) ⁺ .

Example 71:

Starting with compound 70a and (R)-3-hydroxypyrrolidine hydrochloride, compound 71 was prepared according to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.52 - 7.44 (m, 4H), 7.36 (d, J=7.5Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 - 7.07 ( m, 1H), 7.06-7.02 (m, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 4.18-4.11 (m, 1H), 3.80 (s, 3H), 3.61 - 3.59 (m, 2H), 3.56 (s, 3H), 3.53 - 3.46 (m, 2H), 2.95 - 2.87 (m, 1H), 2.78 - 2.71 (m, 1H), 2.69 - 2.64 (m, 1H), 2.64 - 2.53 ( m, 4H), 2.41 - 2.35 (m, 1H), 2.34 - 2.29 (m, 1H), 1.99 - 1.92 (m, 3H), 1.55 - 1.48 (m, 1H); MS (ESI): m/z 715.8 (M+H) ⁺ .

Example 72:

To a solution of acetonitrile (6 ml) with methyl 4-(bromomethyl)-3-chlorobenzoate (200 mg, 0.76 mmol) and 4-bromoindazole (150 mg, 0.76 mmol) was added dissolved potassium carbonate (231 mg, 1. 67 mmol). The reaction solution was stirred at 65°C for 10 hours. The reaction solution was cooled to room temperature. The filtrate was then concentrated and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 - 100/30) to obtain a white solid 72a (150 mg, yield: 52.1%). MS (ESI): m/z 379.2 (M+H) ⁺ .

At -65°C in dichloromethane (10 ml), a solution of compound 72a (150 mg, 0.40 mmol) of diisobutylaluminum hydride (1.5 M solution in toluene, 0.79 ml) was slowly added dropwise. The resulting reaction solution was stirred for half an hour at the same temperature. The reaction solution was then quenched with methanol (2 ml), warmed to room temperature and stirred thoroughly for 2 hours after adding sodium potassium tartrate (10% w/w aqueous solution, 10 ml). Dichloromethane (20 ml) was added to the mixture thus obtained. The organic phase was further washed with brine (30 ml), dried with anhydrous sodium sulfate. The filtrate was concentrated to give a colorless oily substance 72b (130 mg, yield: 93.6%). MS (ESI): m/z 351.1 (M+H) ⁺ .

Dess-Martin oxidizer (157 mg, 0.37 mmol) was added to a solution of dichloromethane (6 mL) with dissolved compound 72b (130 mg, 0.37 mmol). The reaction solution was stirred for 1 hour at 25°C. Saturated sodium bicarbonate solution (20 ml) and dichloromethane (20 ml) were added to the reaction solution, and the thus obtained organic phase was further washed with saturated brine (30 ml), and dried with anhydrous sodium sulfate. The filtrate was concentrated and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 - 100/30) to obtain a colorless oily substance 72 s (120 mg, yield: 92.8%). MS (ESI): m/z 349.1 (M+H) ⁺ .

Starting with compound 72 c, L-serine O-tert-butyl ester and compound INT-3, compound 72 was prepared with reference to the synthesis of compound INT-1 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.75 (d,J=8.5 Hz, 1H), 7.69 (s, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.52 - 7.44 (m, 8H), 7.29 - 7.25 ( m, 1H), 7.18 (d, J=7.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.77 (s, 2H), 3.90 (d, J=14.0 Hz, 1H), 3.81 - 3.76 (m, 3H), 3.65 - 3.63 (m, 1H), 3.62 - 3.56 (m, 2H), 3.09 (t, J=5.5 Hz, 1H), 2.57 - 2.54 (m, 2H), 2.13 - 2.07 ( m, 3H), 1.74 - 1.67 (m, 1H); MS (ESI): m/z 672.5 (M+H) ⁺ .

Example 73:

Dissolved azobis(isobutyronitrile) (9.4 mg, 0.17 mmol). The reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 - 100/25) to obtain a white solid 73a (204 mg, yield: 34.0%).

Starting with compound 73a, 4-bromondazole, L-serine O-tert-butyl ester and compound INT-3, compound 73 was prepared according to the synthesis of compound INT-1 and compound 1. ¹ H NMR (500 MHz, DMSO-d6 ) δ 8.18 8.16 (m, 2H), 7.87 (s, 1H), 7.77(d, J=8.6 Hz, 1H), 7.66 (s, 1H), 7.52-7.49 (m, 1H), 7.48 - 7.25 (m , 5H), 7.13 (d, J=7.0 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.68 (s, 2H), 3.96-3.92 (m, 1H) , 3.78 (d, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.69-3.61 (m, 2H), 3.60 - 3.51 (m, 2H), 3.14-3.08 (m, 1H), 2.56 (d , J=6.4 Hz, 2H), 2.12- 2.06 (m, 3H), 1.73 - 1.65 (m, 1H); MS (ESI): m/z 668.7 (M+H) ⁺ .

Example 74:

To a solution of dichloromethane (10 ml) with 6-hydroxymethyl methyl nicotinate (470 mg, 2.81 mmol) was added dissolved thionyl chloride (1.67 g, 14.1 mmol). The reaction solution was stirred for 3 hours at 25°C. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether=0/100 - 40/100) to obtain a white solid 74a (420 mg, yield: 80.5%). MS (ESI): m/z 186.0 (M+H) ⁺ .

Starting with compound 74a, compound 74 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.77 - 7.69 (m, 2H), 7.67 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.48 -7.44 (m, 6H), 7.15 (d, J=7.0 Hz, 1H ), 7.05 (d, J=8.0 Hz, 1H), 5.77 (s, 2H), 3.91 (d, J=13.5 Hz, 1H), 3.82 - 3.73 (m, 3H), 3.66 - 3.60 (m, 1H) , 3.60 - 3.53 (m, 2H), 3.09 (t, J=5.5 Hz, 1H), 2.55 (d, J=6.0 Hz, 2H), 2.16 - 2.03 (m, 3H), 1.78 - 1.61 (m, 1H ); MS (ESI): m/z 639.5 (M+H) ⁺ .

Example 75:

Dissolved copper cyanide (322 mg, 3.59 mmol) was added to a solution of N,Ndimethylformamide (5 ml) with compound INT-13 (550 mg, 1.80 mmol). The reaction solution was stirred for 16 hours at 120°C and a nitrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 - 100/30) to obtain a white solid 75a (210 mg, yield: 57.0%).

From compound 75a, compound 75 was obtained as a result of the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.84-7.82 (m, 2H), 7.67 (s, 1H), 7.54 - 7.50 (m, 2H), 7.50 - 7.42 (m, 6H), 7.18 (d, J=6.9 Hz, 1H), 6.92 (s, 1H), 5.82 (s, 2H), 3.85 (d, J=14.9 Hz , 1H), 3.80 - 3.73 (m, 3H), 3.71 (s, 3H), 3.64-3.60 (m, 2H), 3.60 - 3.54 (m, 1H), 3.15-3.11 (m, 1H), 2.55 - 2.54 (m, 2H), 2.13 - 2.06 (m, 3H), 1.71 - 1.67 (m, 1H); MS (ESI): m/z 693.2 (M+H) ⁺ .

Example 76:

Under ice bath conditions, a solution of concentrated sulfuric acid (0.5 ml) with pre-dissolved potassium nitrate (56.1 mg, 0.55 mmol). Then the reaction solution was stirred under the same conditions for half an hour. Ice water was added to the reaction solution, so the precipitated solid was washed with ice water and dried to obtain a white solid 76a (115 mg, yield: 92.0%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.29 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.64 (s, 3H).

Starting with compound 76a, compound 76 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-c/6) 5 8.29 (s, 1H), 7.96 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.51-7.49 (m, 3H), 7.47 - 7.43 (m, 4H), 7.19 (d, J=7.0 Hz , 1H), 6.13 (s, 1H), 6.11 (s, 1H), 3.87 (d,J=15.4Hz, 1H), 3.81 - 3.72 (m, 3H), 3.67 - 3.57 (m, 3H), 3.51 ( s, 3H), 3.15-3.12 (m, 1H), 2.56 - 2.52 (m, 2H), 2.14 - 2.08 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m/z 713.8 (M+H) ⁺ .

Example 77:

Dissolved N-chlorosuccinimide (467 mg, 3.50 mmol) was added to concentrated sulfuric acid (3 mL) containing INT-13b (300 mg, 1.66 mmol). The reaction solution was stirred at 25°C for 2 hours. Ice water (25 ml) and ethyl acetate (25 ml) were added to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate (30 ml) and brine (30 ml) and dried with anhydrous sodium sulfate. The filtrate was concentrated to give yellow solid 77a (360 mg, yield: 86.8%). ¹ H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.45 (s, 3H); MS (ESI): m/z 249.7 (M+H) ⁺ .

Starting with compound 77a, compound 77 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMS-d6) δ 7.86 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 2H), 7.48 - 7.43 (m, 6H), 7.17 (d, J=7.0 Hz, 1H), 5.81 (s, 2H), 3.95 (d , J=14.5 Hz, 1H), 3.82-3.79 (m, 3H), 3.77 (s, 3H), 3.66 - 3.59 (m, 3H), 3.20 (t, J=5.1 Hz, 1H), 2.57 - 2.58 ( m, 2H), 2.13 - 2.07 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m/z 736.7 (M+H) ⁺ .

Example 78:

Under ice bath conditions in concentrated sulfuric acid (2 mL) with methyl 3-chloro-4-methyl benzoate (500 mg, 2.71 mmol), dissolved N-iodosuccinimide (731 mg, 3.25 mmol) was added. The reaction solution was stirred for 2 hours at 25°C. Ice water (50 ml) and ethyl acetate (50 ml) were added to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate (50 ml) and brine (50 ml) and dried with anhydrous sodium sulfate. The filtrate was concentrated and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 - 100/15) to obtain a white solid 78a (820 mg, yield: 97.5%).

Under a nitrogen atmosphere and at 100°C in methanol (5 ml) a solution of compound 78a (1.00 g, 3.22 mmol), copper iodide (61.3 mg, 0.32 mmol), 1,10-phenanthroline ( 116 mg, 0.64 mmol) and cesium carbonate (2.10 g, 6.44 mmol) were stirred for 24 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in methanol (5 ml) and thionyl chloride (1.4 ml) was added. The reaction solution thus obtained was stirred for 2 hours at 60°C. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate (50 ml) and brine (50 ml), dried with anhydrous sodium sulfate. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0-100/5) to give a white solid 78b (480 mg, yield: 69.4%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J=1.6 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.31 (s, 3H).

Starting with compound 78b, compound 78 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.52 - 7.48 (m, 2H), 7.46 - 7.43 (m, 5H), 7.14-7.11 (m, 3H), 5.67 (s, 2H), 3.94 (d, J= 14.2 Hz, 1H), 3.81 - 3.78 (m, 2H), 3.77 (s, 3H), 3.65 - 3.61 (m, 4H), 3.15 - 3.09 (m, 1H), 2.57 - 2.55 (d, J=6.0 Hz , 2H), 2.13 - 2.07 (m, 3H), 1.73 - 1.66 (m, 1H); MS (ESI): m/z 702.7 (M+H) ⁺ .

Example 79:

Starting with compound 78a, compound 79a is prepared according to the method for the synthesis of compound 75a.

Starting with compound 79a, compound 79 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.90 - 7.85 ( m, 2H), 7.83 (s, 1H), 7.67 (s, 1H), 7.58 - 7.54 (m, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.48 - 7.42 (m, 5H), 7.18 (d, J=7.1 Hz, 1H), 5.82 (s, 2H), 3.95 (d, J=14.8 Hz, 1H), 3.81 -3.74 (m, 3H), 3.65-3.62 (m, 1H), 3.61- 3.56 (m, 2H), 3.12 (t,J=5.3 Hz, 1H), 2.56 (d, J=6.1 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m/z 697.5 (M+H) ⁺ .

Example 80:

To chloroform (35 ml) was added a solution of 2-hydroxy-6-methylnicotinic acid (1.00 g, 6.53 mmol), dissolved iodomethane (3.24 g, 22.9 mmol) and silver carbonate (1.81 g, 6.55 mmol). The reaction solution was stirred at 65°C for 16 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a colorless oily substance 80a (390 mg, yield: 33.0%). ¹ H NMR (500 MHz, Chloroform-d) δ 8.06 (d, J=7.7 Hz, 1H), 6.77 (d, J=1.1 Hz, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 2.48 (s, 3H); MS (ESI): m/z 182.0 (M+H) ⁺ .

A solution of compound 80a (363 mg, 2.00 mmol) of N-chlorosuccinimide (321 mg, 2.40 mmol) was added in acetonitrile (10 ml). The reaction solution was stirred at 70°C for 10 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 - 100/20) to obtain a colorless oily substance 80b (420 mg, yield: 97.2%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.51 (s, 3H).

Starting with compound 80b, compound 80 is prepared with reference to the synthesis of compound 73. ¹ H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.84 (s, 1H), 7.79 (d, J=8.4Hz, 1H), 7.67 (s, 1H), 7.53-7.51 (m, 1H), 7.48-7.44(m, 7H), 7.14 (d,J=7.0 Hz, 1H), 5.82 (s, 2H), 3.79 - 3.76 (m, 2H), 3.66 - 3.55 (m, 5H), 3.38 (s, 3H), 3.13 -3.08 (m, 1H), 2.58 -2.54 (m, 2H), 2.13-2.08 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m/z 703.2 (M+H) ⁺ .

Example 81:

Starting with 3-methoxy-4-methylbenzoic acid, compound 81a was prepared according to the synthesis of compound 80b. ¹ H NMR (500 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H).

In a dichloromethane (8 ml) solution of compound 81a (300 mg, 1.50 mmol), oxalyl chloride (345 mg, 2.72 mmol) was dissolved and 1 drop of N,N-dimethylformamide was added. The reaction solution was stirred at a temperature of 25°C for 3 hours, then the reaction solution was concentrated. The residue thus obtained was redissolved in dichloromethane (3 ml), then the solution was added to dichloromethane (8 ml), solution with 4-bromondazole (265 mg, 1.35 mmol), 4-dimethylaminopyridine (18.3 mg, 0.15 mmol) and triethylamine (302 mg, 2.99 mmol) dissolves. The reaction solution was stirred for 16 hours at 25°C. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=100/0 -100/20) to obtain a white solid 81b (410 mg, yield: 72.2%).

Starting with compound 81b, compound 81c is prepared with reference to the synthesis of compound 73a.

Potassium carbonate (72 mg) was dissolved in N'N-dimethylformamide (2 ml) with compound 81c (120 mg, 0.26 mmol) and O-isopropyl-L-serine tert-butyl ester (171 mg, 0.78 mmol). , 0.52 mmol). The reaction solution was added and stirred for 1 hour at 25°C. Add ethyl acetate (20 ml) and water (20 ml) to the reaction solution. The organic phase was further washed with brine (20 ml), dried with anhydrous sodium sulfate. The residue was separated on a silica gel thin layer chromatography plate (petroleum ether/ethyl acetate, v/v=4/1) to give a white solid 81d (70 mg, yield: 45.0%). MS (ESI): m/z 594.4 (M+H) ⁺ .

Starting with compound 81d, compound 81e is prepared by reversing the boron esterification step of the INT-1 synthesis process. MS (ESI): m/z 642.8 (M+H) ⁺ .

At 90°C and a nitrogen atmosphere, a solution in 1,4-dioxane (4 ml) with compound 81e (35 mg, 0.038 mmol), compound INT-3 (18.9 mg, 0.038 mmol), Pd(dppf)C12 (2 .8 mg, 0.0038 mmol) and potassium fluoride (6.7 mg, 0.11 mmol) were stirred for 16 hours. The reaction solution was concentrated and the residue was separated on a silica gel thin layer chromatography plate (dichloromethane/methanol, v/v=20/1) to obtain a colorless oily substance 81f (20 mg, yield: 36.7%). MS (ESI): m/z 928.2 (M+H) ⁺ .

Starting with compound 81f, compound 81 is prepared by reversing the last step in the synthesis of compound 1 to remove the Boc protecting group. ¹ H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J=8.0 Hz, 1H), 8.27 (s, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 - 7.53 (m, 1H), 7.52 - 7.49 (m, 3H), 7.47 -7.40 (m, 5H), 3.79 (s, 3H), 3.76 - 3.74 (m, 2H), 3.62 - 3.59 (m, 3H), 3.50 - 3.48 (m, 2H), 3.12-3.11 (m, 1H), 2.53 - 2.52 (m, 2H), 2.10 - 2.06 (m, 3H), 1.69 - 1.65 (m , 1H); MS (ESI): m/z 716.0 (M+H) ⁺ .

Example 82:

Starting with compound 80b, compound 82a is prepared by reference to the bromination step of compound 73a, the substitution step of compound 72a, and the ester hydrolysis and acid-amine condensation steps during the synthesis of compound INT-11d. MS (ESI): m/z 595.4 (M+H) ⁺ .

Starting with compound 82a and compound INT-3, compound 82 is prepared with reference to the last two steps of the synthesis process of compound 81. ¹ H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J=7.0 Hz, 1H), 8.23 ( s, 1H), 7.88 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.45 (m, 7H), 7.15 (d, J=7.0 Hz, 1H ), 5.93 (s, 2H), 4.28 - 4.26 (m, 1H), 3.85 - 3.75 (m, 3H), 3.67 - 3.60 (m, 2H), 3.39 (s, 3H), 2.59 (d, J=6.2 Hz, 2H), 2.14-2.07 (m, 3H), 1.72-1.69 (m, 1H); MS (ESI): m/z 717.2 (M+H) ⁺ .

Example 83:

At 80°C a solution of acetonitrile (20 ml) with 4-bromoindazole (500 mg, 2.54 mmol) and 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate (4.49 g, 12.7 mmol) was dissolved. Stirred for 15 hours. Ethyl acetate (100 ml) was added to the reaction solution, then the solution was washed with water (100 ml) and brine (100 ml), and dried with anhydrous sodium sulfate. The residue was separated by silica gel column chromatography to give white solid 83a (231 mg, yield: 42.3%). MS (ESI): m/z 215.1 (M+H) ⁺ .

Starting with compound 83a, L-serine O-tert-butyl ester and compound INT-3, compound 83 was prepared according to the synthesis of compound INT-8 and compound 1. ¹ H NMR (500 MHz, DMSO-d6) δ 7.84 7.79 (m, 1H), 7.66 (s, 1H), 7.62 - 7.58 (m, 1H), 7.52 - 7.43 (m, 8H), 7.17 (d, J=7.0 Hz, 1H), 6.84 (s, 1H), 5.62 (s, 2H), 3.91 - 3.79 (m, 4H), 3.67 (s, 3H), 3.65 - 3.56 (m, 3H), 3.17 - 3.15 (m, 1H), 2.60 - 2.55 (m, 2H), 2.14 - 2.09 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m/z 720.6 (M+H) ⁺ .

Example 84:

At 25°C, a solution of N'N-dimethylformamide (3 ml) with dissolved 4-bromoindazole (200 mg, 1.02 mmol), N-chlorosuccinimide (149 mg, 1.12 mmol) was stirred for 15 hours. Ethyl acetate (50 ml) was added to the reaction solution, then the solution was washed with water (50 ml) and dried with brine (50 ml), anhydrous sodium sulfate. The residue was separated by silica gel column chromatography to give a white solid 84a (122 mg, yield: 51.9%). MS (ESI): m/z 231.3 (M+H) ⁺ .

Starting with compound 84a, compound 84 is prepared with reference to the synthesis of compound 83. ¹ H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.59 - 7.55 ( m, 1H), 7.50 - 7.47 (m, 2H), 7.45 - 7.39 (m, 6H), 7.11 (d, J=7.0 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 5.75 - 5.68 (m, 1H), 5.70 (s, 1H), 3.89 - 3.86 (m, 1H), 3.79-3.75 (m, 3H), 3.65 (s, 3H), 3.62-3.59 (m, 3H), 3.14-3.12 (m, 1H), 2.54 (d, J=6.0 Hz, 2H), 2.11 2.06 (m, 3H), 1.70 - 1.65 (m, 1H); MS (ESI): m/z 736.5 (M+H) ⁺ .

Example 85:

Starting with compounds INT-8 and 5-aminoethyltetrazole, compound 85 was prepared according to the synthesis of compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.55 - 7.38 (m, 9H), 7.14 (d, J=7.0 Hz, 1H), 6.71 (s, 1H), 5.72 (s, 2H), 3.95 - 3.91 (m, 2H), 3.79 - 3.71 (m, 4H), 3.65 - 3.62 (m, 1H), 3.57 (s, 3H), 2.55 (d, J=6.0 Hz, 2H), 2.15 - 2.04 (m, 3H), 1.72 - 1.61 (m, 1H ); MS (ESI): m/z 696.1 (M+H) ⁺ .

Example 86:

Starting with compound INT-1c, tert-butyl bromoacetate and 4-bromoindazole, compound 86a was prepared with reference to the synthesis of compound INT-1i. MS (ESI): m/z 479.4 (M+H) ⁺ .

Starting with compound 86a, compound INT-3 and ethanolamine, compound 86 was prepared with reference to the synthesis of compound INT-7 and compound 22. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.77 (d , J=8.5 Hz, 1H), 7.67 (s, 1H), 7.53-7.41 (m, 9H), 7.15 (d, J=6.9 Hz, 1H), 6.94 (s, 1H), 5.70 (s, 2H) , 4.26 (s, 2H), 4.01 (s, 2H), 3.81 - 3.72 (m, 2H), 3.67 - 3.58 (m, 3H), 2.86 (t, J=5.4 Hz, 2H), 2.57 - 2.50 (m , 2H), 2.13 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m/z 702.4 (M+H) ⁺ .

Example 87:

Starting with (R)-3-hydroxypyrrolidine hydrochloride, 4-bromo-2-methoxybenzaldehyde and compound INT-8c, compound 87a was prepared with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m/z 616.4 (M+H) ⁺ .

Starting with compound 87a and compound INT-11, compound 87 was prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H ), 7.55 - 7.47 (m, 4H), 7.39 (d, J=7.5 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 4.23 - 4.17 (m, 1H), 3.82 (s, 3H), 3.64 - 3.56 (m, 5H), 3.55 - 3.47 (m, 2H), 2.88 - 2.82 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 3H), 2.47 - 2.43 (m, 2H), 2.41 - 2.36 (m , 2H), 2.05 - 1.97 (m, 1H), 1.95 - 1.89 (m, 2H), 1.58 - 1.52 (m, 1H); MS (ESI): m/z 715.7 (M+H) ⁺ .

Example 88:

Starting with ethanolamine, 4-bromo-2-methoxybenzaldehyde and compound INT-8 c, compound 88a was prepared with reference to the synthesis of compound INT-3 and compound INT-8. MS (ESI): m/z 690.4 (M+H) ⁺ .

Starting with compound 88a and compound INT-11, compound 88 was prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J=8.5 Hz, 1H ), 7.55 - 7.47 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.11 (s, 1H), 7.09 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.84 (s, 3H), 3.79 (d, J=3.5 Hz, 2H), 3.58 (s, 3H), 3.56 - 3.47 (m, 4H), 2.94 - 2.85 (m, 1H), 2.70 - 2.62 (m, 4H), 2.50 - 2.48 (m, 2H), 1.96 - 1.90 (m, 2H); MS (ESI): m/z 689.6 (M+H) ⁺ .

Example 89:

Starting with compound 76a, compound 89a is prepared with reference to the synthesis of compound 73. MS (ESI): m/z 925.5 (M+H) ⁺ .

Zinc powder (32 mg, 0.49 mmol) was added to a solution of acetic acid (3 ml) with dissolved compound 89a (150 mg, 0.16 mmol). The reaction solution was stirred at 70°C for half an hour. The reaction solution was concentrated and the residue was separated by preparative thin layer chromatography (dichloromethane/methanol, v/v.=20/1) to obtain a yellow oily substance 89b (30 mg, yield: 20.7%). MS (ESI): m/z 895.9 (M+H) ⁺ .

Starting with compound 89b, compound 89 is prepared by reversing the final Boc deprotection step during the synthesis of compound 1. ¹ HNMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.84(d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.54 - 7.42 (m, 8H), 7.14 (d, J=6.9 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.55 (s, 2H ), 5.00 - 4.95 (m, 1H), 3.84 - 3.73 (m, 4H), 3.63 (s, 3H), 3.60 - 3.51 (m, 3H), 3.04 - 3.02 (m, 1H), 2.56 - 2.52 (m , 2H), 2.13 - 2.06 (m, 3H), 1.73-1.66 (m, 1H); MS (ESI): m/z 683.1 (M+H) ⁺ .

Example 90:

Starting with 1,3-dibromo-2-toluene, 4-bromo-2-methoxybenzaldehyde, compound INT-2 and compound INT-8c, compound 90a was prepared with reference to the synthesis of compound INT-3 and compound INT-8. MS (ESI): m/z 723.5 (M+H) ⁺ .

Starting with compound 90a and compound INT-11, compound 90 is prepared with reference to the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.73 (d, J=8.5 Hz, 1H) , 7.66 (s, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.43 - 7.36 (m, 3H), 7.34 - 7.30 (m, 2H), 7.10 (d, J=7.0 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 3.84 (s, 3H), 3.82 - 3.77 (m, 2H), 3.70 - 3.65 (m, 1H), 3.58 (s, 3H), 3.53 (d, J=9.0 Hz, 2H), 2.95 - 2.88 (m, 1H), 2.68 - 2.62 (m, 4H), 2.53 - 2.52 (m , 2H), 2.16 - 2.08 (m, 3H), 2.00 (s, 3H), 1.97 - 1.91 (m, 2H), 1.75 - 1.68 (m, 1H); MS (ESI): m/z 722.3 (M+H) ⁺ .

Example 91:

Starting with compound INT-10, compound INT-2, compound INT-8c and methyl bicycloate hydrochloride, compound 91 was prepared with reference to the synthesis of compound INT-3, compound INT-8 and compound 44. ¹ H NMR (500 MHz, DMSO- d6) δ 7.88 (s, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 -7.64 (m, 2H), 7.59 - 7.49 (m, 3H ), 7.43 - 7.32 (m, 2H), 7.18 (d, J=7.0 Hz, 1H), 6.71 (s, 1H), 5.74 (s, 2H), 3.94 (s, 3H), 3.91 - 3.77 (m, 2H), 3.73 - 3.67 (m, 1H), 3.59 (s, 3H), 3.41 - 3.35 (m, 2H), 2.72 - 2.65 (m, 1H), 2.53 - 2.52 (m, 1H), 2.19 - 2.01 ( m, 9H), 1.91 - 1.79 (m, 4H), 1.77 - 1.68 (m, 1H), 1.53 - 1.40 (m, 1H), 1.34 - 1.21 (m, 2H), 0.88 - 0.78 (m, 2H); MS (ESI): m/z 799.7 (M+H) ⁺ .

Example 92:

Starting with compound 76a, 4-bromondazole, compound INT-6, compound 92a is prepared with reference to the synthesis of compound 73a, compound 82a and compound INT-8. MS (ESI): m/z 754.5 (M+H) ⁺ .

Starting with compound 92a and trans-4-aminocyclohexanoate methyl chloride, compound 92 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.96 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.54-7.48 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H) , 7.09 (d, J =1.5 Hz, 1H), 7.08 -7.04 (m, 1H), 6.11-6.08 (m, ZN), 3.82 (s, 3H), 3.78 -3.72 (m, 2H), 3.66 - 3.62 (m, 1H), 3.51 - 3.49 (m, 2H), 3.48 (s, ZN), 2.57 (d, J=6.0 Hz, 2H), 2.46-2.36 (m, 2H), 2.13 (s, 3H), 2.11 - 2.07 (m, 3H), 1.94 - 1.89 (m, 2H), 1.82 - 1.77 (m, 2H), 1.72 - 1.65 (m, 1H), 1.32 - 1.26 (m, 4H); MS (ESI): m/z 795.7 (M+H) ⁺ .

Example 93:

Starting with trans-4-aminocyclobutanoate methyl ester hydrochloride and compound INT-9, compound 93 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.30 - 3.24 (m, 2H), 3.04 - 2.98 (m, 1H), 2.84 - 2.79 (m, 1H), 2.55 - 2.50 ( m, 2H), 2.20 - 2.12 (m, 2H), 2.12 - 2.03 (m, 5H), 1.91 (s, 3H), 1.70 - 1.64 (m, 1H); MS (ESI): m/z 756.6 (M+H) ⁺ .

Example 94:

Starting with (4-piperidine) methyl acetate and compound INT-9, compound 94 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.74 - 3.68 (m, 2H) , 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 2.76 - 2.69 (m, 2H), 2.56 - 2.51 (m, 2H), 2.14 - 2.03 (m, 5H), 1.96 - 1.87 (m, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.54 (m, 2H), 1.22 - 1.14 (m, 2H); MS (ESI): m/z 770.6 (M+H) ⁺ .

Example 95:

Starting with compound INT-9 and compound INT-14, compound 95 is prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.39 (d, J=7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.08 - 7.05 (m, 1H), 7.05 - 7.01 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.69 (m, 2H), 3.64 - 3.58 (m, 1H), 3.56 (s, 3H), 3.44 - 3.35 (m, 2H), 2.54 - 2.51 (m, 2H), 2.35 - 2.29 (m, 1H), 2.12 - 2.10 (m, 1H), 2.09 (s, 3H), 2.07 - 2.05 (m, 1H), 2.04 (d, J=7.0 Hz, 2H), 1.76 - 1.71 (m, 4H), 1.69-1.63 (m, 1H), 1.59-1.51 ( m, 1H), 1.29- 1.20 (m, 2H), 0.99 - 0.86 (m, 2H); MS (ESI): m/z 798.7 (M+H) ⁺ .

Example 96:

For the synthesis of compound 92, trans-4-aminocyclohexanoate methyl ester hydrochloride was replaced by methyl aminocyclohexanoate hydrochloride to give compound 96. ¹ H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.98 (s, 1H), 7.80 (d,J=8.5Hz, 1H), 7.66 (s, 1H), 7.56-7.48 (m, 4H), 7.44-7.43 (m, 1H), 7.19 (d,J=6.9 Hz, 1H), 7.13- 7.11 (m, 1H), 7.09-7.07(m, 1H), 6.13 -6.11 (m, 3H), 3.85 (s, 3H), 3.80-3.79 (m, 2H), 3.71 - 3.64 (m, 1H), 3.49 (s, 3H), 3.41 (s, 2H), 2.64 -2.62 (m, 2H), 2.59-2.51 (m, 2H), 2.14 (s, 3H), 2.13-2.07 (m, 4H), 1.89- 1.81 (m, 4H), 1.73-1.68 (m, 1H), 1.50-1.45 (m, 1H), 1.33-1.24 (m, 2H), 0.88 - 0.80 (m, 2H); MS (ESI): m/z 809.8 (M+H).

Example 97:

Starting with the compound 4-bromo-2-hydroxybenzaldehyde, compound 97a was prepared with reference to the boron esterification of compound INT-7a and the synthesis of compound INT-3a.

Starting with compound 97a, compound 97b was prepared with reference to the alkylation reaction step of compound INT-8a. ¹ H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.86 - 7.82 (m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.24 (d, J=1.4 Hz, 1H), 7.10 - 7.06 (m, 1H), 4.23 (q, J=7.0 Hz, 2H), 1.38 (t, J= 7.0 Hz, 3H).

Starting with compound 97b, compound INT-2, compound INT-8c and methyl bicycloate hydrochloride, compound 97 was prepared according to the synthesis of compound 48. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 ( d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.55 - 7.44 (m, 4H), 7.39 (d, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J =7.0 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 7.04-7.00 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.08 (q, J=6.9 Hz , 2H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.55 - 2.53 (m, 2H), 2.13 - 2.03 (m , 9H), 1.86 - 1.75 (m, 4H), 1.72- 1.66 (m, 1H), 1.46- 1.40 (m, 1H), 1.33 (t, J=6.9 Hz, 3H), 1.27-1.21 (m, 2H ), 0.84 - 0.75 (m, 2H); MS (ESI): m/z 812.8 (M+H). Example 98:

For the synthesis of compound 97, iodoethane was replaced by 2-iodopropane to obtain compound 98. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J=1.1 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 7.01 -6.97 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.70 - 4.62 (m, 1H), 3.74 - 3.66 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.52 (m, 2H), 2.13 - 2.03 (m, 9H), 1.89 - 1.78 (m, 4H), 1.71 - 1.65 (m, 1H), 1.48 - 1.39 (m, 1H), 1.29 - 1.26 (m, 6H), 1.26 - 1.20 (m, 2H), 0.86 - 0.74 (m, 2H); MS (ESI): m/z 826.7 (M+H).

Example 99:

Starting with (R)-N-Boc-3-tetrahydropyrroleacetic acid, compound 99a was prepared according to the synthesis of compound INT-14. ¹ H NMR (500 MHz, DMSO-d6) δ 9.27 - 8.91 (m, 2H), 3.59 (s, 3H), 3.32 - 3.26 (m, 1H), 3.23 - 3.15 (m, 1H), 3.13 - 3.02 ( m, 1H), 2.80 - 2.71 (m, 1H), 2.55 - 2.49 (m, 3H), 2.10 - 2.02 (m, 1H), 1.55 - 1.48 (m, 1H).

Starting with compound 99a and compound INT-9, compound 99 was prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J=8.5 Hz, 1H ), 7.66 (s, 1H), 7.54 - 7.45 (m, 4H), 7.40 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.68 - 2.62 (m, 1H), 2.55 - 2.51 (m, 2H), 2.47 - 2.42 (m, 2H), 2.40 - 2.34 (m, 1H), 2.28 - 2.23 (m, 2H), 2.15 -2.05 (m, 4H), 1.97 - 1.89 (m, 1H), 1.72 -1.64 (m, 1H), 1.37 - 1.29 (m, 1H) ; MS (ESI): m/z 756.7 (M+H).

Example 100:

Starting with compound INT-9 and methyl bicycloate hydrochloride, compound 100a is prepared with reference to the synthesis of compound INT-5 and the Boc deprotection step in the last step of the synthesis of compound 1. MS (ESI): m/z 798.7 (M+H).

In N,N-dimethylformamide (2 ml) with compound 100a (40 mg, 0.050 mmol) dissolve formaldehyde (34% aqueous solution, 0.10 ml), acetic acid (6.0 mg, 0.10 mmol) and triacetate borohydride sodium (42 mg, 0.20 ml), mmol). The reaction solution was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate and concentrated to give brown oil 100b (35 mg, yield: 84.5%). MS (ESI): m/z 826.7 (M+H).

Starting with compound 100b, compound 100 is prepared with reference to the ester hydrolysis step in the synthesis of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J=8.5 Hz, 1H) , 7.55 - 7.45 (m, 5H), 7.44 (d, J=7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.03 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.74 - 3.68 (m, 1H), 3.56 (s, 3H), 3.53 - 3.49 ( m, 2H), 3.36 (s, 2H), 2.44 - 2.39 (m, 1H), 2.36 - 2.30 (m, 1H), 2.17 (s, 3H), 2.11 -2.05 (m, 9H), 1.87 - 1.78 ( m, 4H), 1.70 - 1.64 (m, 1H), 1.48 - 1.40 (m, 1H), 1.32 -1.21 (m, 2H), 0.86 - 0.76 (m, 2H); MS (ESI): m/z 812.7 (M+H).

Example 101:

Starting with compound INT-16 and methyl bicycloate hydrochloride, compound 101 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.78 (d, J=8.5 Hz, 1H ), 7.65 (s, 1H), 7.57 - 7.49 (m, 4H), 7.38 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.69 (s, 1H), 5.73 (s, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.61 - 3.59 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.53 - 2.51 (m, 2H), 2.13 - 2.03 (m, 6H), 2.09 (s, 3H), 1.88 - 1.78 (m, 4H), 1.70 - 1.62 (m, 1H), 1.49 - 1.41 (m, 1H) , 1.32 - 1.22 (m, 2H), 0.87 - 0.76 (m, 2H); MS (ESI): m/z 816.3 (M+H).

Example 102:

Starting with compound INT-15b, compound 102a is prepared with reference to the synthesis of compound INT-3. MS (ESI): m/z 553.6 (M+H).

Starting with compound 102a, compound INT-8c and methyl bicycloate hydrochloride, compound 102 was prepared according to the synthesis of compound INT-8 and compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.78 ( d,J=8.5Hz, 1H), 7.63 (s, 1H), 7.56-7.48 (m, 4H), 7.38 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.77 (s, 2H ), 6.70 (s, 1H), 5.73 (s, 2H), 3.82 (s, 6H), 3.76 - 3.70 (m, 2H), 3.60 - 3.56 (m, 4H), 3.36 (s, 2H), 2.53 - 2.52 (m, 2H), 2.13 - 2.04 (m, 9H), 1.89 - 1.79 (m, 4H), 1.70 - 1.61 (m, 1H), 1.50 - 1.42 (m, 1H), 1.32 - 1.23 (m, 2H ), 0.87 - 0.77 (m, 2H); MS (ESI): m/z 828.5 (M+H).

Example 103:

At 25°C, a solution of dimethyl sulfoxide (5 ml) with dissolved L-proline (132 mg, 1.14 mmol), sodium hydroxide (46 mg, 1.14 mmol) was stirred for 1 hour. Compound INT-13 (350 mg, 1.14 mmol), sodium methanesulfinate (1.17 g, 11.4 mmol) and copper iodide (218 mg, 1.14 mmol) were then added. The resulting reaction solution was replaced with nitrogen 3 times and stirred for 2 hours under a nitrogen atmosphere and at a temperature of 120°C. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with brine (100 ml), dried with anhydrous sodium sulfate and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v.=1/1) to give a white solid 103a (232 mg, yield: 94.5%). ¹ H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.07 (s, 3H), 2.74 (s , 3H); MS (ESI): m/z 259.1 (M+H).

Starting with compound 103a, compound 103 is prepared with reference to the synthesis of compound 92. ¹ H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.96 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.56-7.47 (m, 4H), 7.40 (d, J=7.6 Hz, 1H), 7.18 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 7.06-7.02 (m, 1H), 6.3 l(s, 1H), 6.14 (s, 2H), 3.82 (s, 3H), 3.76 - 3.67 (m, 2H), 3.64 - 3.59 (m , 1H), 3.48 (s, 2H), 3.47 (s, 3H), 3.21 (s, 3H), 2.56 - 2.52 (m, 2H), 2.39 - 2.33 (m, 1H), 2.11 (s, 3H), 2.11 - 2.07 (m, 3H), 2.07 - 2.04 (m, 1H), 1.94 - 1.87 (m, 2H), 1.82 - 1.76 (m, 2H), 1.71 - 1.64 (m, 1H), 1.32 - 1.23 (m , 4H); MS (ESI): m/z 828.2 (M+H).

Example 104:

Starting with compound INT-9 and cis-3-aminocyclobutanedicarboxylate hydrochloride, compound 104 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.66 (s, 1H),7.52 - 7.47 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H ), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.26 (s, 2H), 2.82 - 2.75 (m, 1H), 2.67 - 2.60 (m, 1H), 2.57 - 2.52 (m, 2H ), 2.23 - 2.17 (m, 2H), 2.14-2.04 (m, 3H), 1.94-1.87 (m, 2H), 1.92 (s, 3H), 1.71 - 1.64 (m, 1H); MS (ESI): m/z 755.9 (M+H).

Example 105:

Starting with compound INT-9 and 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride, compound 105 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s , 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.38 (s, 1H) , 7.15 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.05-7.02 (m, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.81 ( s, 3H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.56 - 2.52 (m, 2H), 2.14 - 2.04 ( m, 3H), 1.99 (s, 3H), 1.75 - 1.66 (m, 7H), 1.60 - 1.49 (m, 6H); MS (ESI): m/z 810.2 (M+H).

Example 106:

Starting with compounds INT-9 and 6-aminosirenone [3.3]heptane-2-methylcarboxylate hydrochloride, compound 106 was prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.15 (d ,J=7.0Hz, 1H), 7.08-7.06 (m, 1H), 7.05-7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.21 (s, 2H), 2.93 - 2.86 (m, 1H), 2.74 - 2.68 (m, 1H), 2.55 - 2.52 (m, 2H), 2.20 - 1.98 (m, 9H), 1.88 (s, 3H), 1.80 - 1.74 (m, 1H), 1.72 - 1.65 (m, 2H); MS (ESI): m/z 796.2 (M+H).

Example 107:

Starting with compound 75a, compound 107 was prepared with reference to the synthesis of compound 92. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (s , 1H), 7.65 (s, 1H), 7.53 - 7.46 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.07 (d, J= 1.5 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.90 (s, 1H), 5.80 (s, 2H), 3.81 (s, 3H), 3.71 (d, J=3.0 Hz, 2H), 3.69 ( s, 3H), 3.63 - 3.60 (m, 1H), 3.47 (s, 2H), 2.54-2.52 (m, 2H), 2.39-2.36 (m, 1H), 2.12-2.06 (m, 4H), 2.10 ( s, 3H), 1.93 - 1.88 (m, 2H), 1.81 - 1.76 (m, 2H), 1.70 - 1.66 (m, 1H), 1.30 - 1.25 (m, 4H); MS (ESI): m/z 775.3 (M+H).

Example 108:

For the synthesis of compound 107, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with compound INT-14 to give compound 108. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.83 (d, J= 8.5 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.54 - 7.46 (m, 4H), 7.42 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.92 (s, 1H), 5.80 (s, 2H), 3.87 - 3.78 (m, 2H), 3.83 (s, 3H ), 3.71 - 3.66 (m, 1H), 3.70 (s, 3H), 3.51 - 3.45 (m, 2H), 2.54-2.52 (m, 2H), 2.14-2.04 (m, 8H), 1.78- 1.68 (m , 5H), 1.59 - 1.53 (m, 1H), 1.31 - 1.21 (m, 2H), 0.98-0.90 (m, 2H); MS (ESI): m/z 789.1 (M+H).

Example 109:

Starting from CIS-(N-BOC-4-aminocyclohexyl)acetic acid, compound 109a was prepared according to the synthesis of compound INT-14. ¹ H NMR (500 MHz, DMSO-d6) δ 7.95 (brs, 3H), 3.57 (s, 3H), 3.18 - 3.08 (m, 1H), 2.27 (d, J=7.5 Hz, 2H), 1.95 - 1.86 (m, 1H), 1.69-1.56 (m, 4H), 1.54-1.38 (m, 4H).

Starting with compound 109a and compound INT-9, compound 109 is prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J=8.5 Hz, 1H) , 7.65 (s, 1H), 7.54 - 7.46 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.71 (d, J=3.0 Hz, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.43 (s, 2H), 2.56 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.21 - 2.16 (m, 2H), 2.13 -2.04(m,3H), 2.07 (s, 3H), 1.98 1.91 (m, 1H), 1.72-1.66 (m, 1H), 1.61-1.53 (m, 2H), 1.51 - 1.39 (m, 6H); MS (ESI): m/z 798.3 (M+H).

Example 110:

Under ice bath conditions, boron tribromide (1 m dichloromethane solution, 3.95 mL) was added dropwise to 10 mL dichloromethane solution (500 mg, 1.32 mmol) dissolved in INT-8b (500 mg, 1.32 mmol) . The reaction solution was stirred for 1 hour under the same conditions. Ice water (30 ml) was added to the reaction solution to cool, and the resulting mixture was further stirred for half an hour. The aqueous phase was extracted (50 ml x 2) with dichloromethane. The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give compound 110a as a white solid (370 mg, yield: 76.8%). MS (ESI): m/z 365.2 (M+H).

Starting with compound 110a, compound 110b is prepared with reference to the alkylation reaction step of compound INT-8a. ¹ H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.13 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.48 - 7.24 (m, 2H), 6.80 (s , 1H), 5.78 (s, 2H), 4.55 - 4.32 (m, 1H), 1.19 (d, J=6.0 Hz, 6H).

Starting with compound 110b, compound INT-6 and methyl bicycloate hydrochloride, compound 110 was prepared according to the synthesis of compound INT-8 and compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.74 ( d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.54 - 7.45 (m, 4H), 7.43 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J =7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.41 (s, 1H), 5.72 (s, 2H), 4.20 - 4.12 (m, 1H), 3.86 - 3.82 (m, 2H), 3.84 (s, 3H), 3.71 - 3.66 (m, 1H), 3.33 (s, 2H), 2.73 - 2.63 (m, 2H), 2.14 2.06 (m, 9H), 1.87- 1.77 (m, 4H), 1.72-1.68 (m, 1H), 1.48- 1.39 (m, 1H), 1.30- 1.22 (m, 2H), 1.05 (d, J=6.0 Hz, 6H), 0.86 - 0.76 ( m, 2H); MS (ESI): m/z 826.3 (M+H).

Example 111:

Starting with 2-fluoro-5-hydroxybenzoic acid, compound 111a was prepared according to the synthesis of compound INT-1c and compound INT-8b. MS (ESI): m/z 363.1 (M+H).

Starting with compound 111a, compound INT-2 and methyl bicycloate hydrochloride, compound 111 was prepared according to the synthesis of compound INT-8 and compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.79 ( d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.49 (m, 2H), 7.48 - 7.42 (m, 6H), 7.18 -7.12 (m, 2H), 6.88 (d, J= 6.0 Hz, 1H), 5.69 (s, 2H), 3.80 - 3.72 (m, 2H), 3.66 - 3.60 (m, 1H), 3.65 (s, 3H), 3.36 (s, 2H), 2.56 - 2.53 (m , 2H), 2.14 - 2.07 (m, 6H), 2.09 (s, 3H), 1.89 - 1.78 (m, 4H), 1.73 - 1.66 (m, 1H), 1.50 - 1.40 (m, 1H), 1.31 - 1.22 (m, 2H), 0.85 - 0.76 (m, 2H); MS (ESI): m/z 752.3 (M+H).

Example 112:

Starting with 5-hydroxy-2-methylbenzoic acid, compound 112a was prepared according to the synthesis of compound INT-1c and compound INT-8b. MS (ESI): m/z 359.2 (M+H).

Starting with compound 112a, compound INT-6 and methyl bicycloate hydrochloride, compound 112 was prepared with reference to the synthesis of compound INT-8 and compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 ( d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.46 (m, 4H), 7.44 (d, J=7.5 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J=7.5 Hz, 1H), 6.60 (s, 1H), 5.66 (s, 2H), 3.88 - 3.82 (m, 2H), 3.85 (s, 3H), 3.72 - 3.67 (m, 1H), 3.57 (s, 3H), 3.43 - 3.40 (m, 2H), 2.67 (d, J=6.0 Hz, 2H), 2.25 (s, 3H), 2.18 2.04 (m, 9H) , 1.89 - 1.80 (m, 4H), 1.76 - 1.68 (m, 1H), 1.55 - 1.45 (m, 1H), 1.32 - 1.23 (m, 2H), 0.86 - 0.75 (m, 2H); MS (ESI): m/z 778.4 (M+H).

Example 113:

Starting with INT-16 and trans-4-aminocyclobutanoate methyl chloride, compound 113 was prepared according to the synthesis of compound 101. ¹ H NMR(500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.76 (d, J= 8.5 Hz, 1H), 7.62 (s, 1H), 7.56 -7.45 (m, 4H), 7.34 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.02-6.93 (m, 2H), 6.68 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.83 - 3.72 (m, 2H), 3.62- 3.58 (m. 1H), 3.57 (s, 3H), 3.27 - 3.25 ( m, 2H), 3.06 - 2.97 (m, 1H), 2.87 - 2.78 (m, 1H), 2.56 - 2.52 (m, 2H), 2.22 -2.15 (m, 2H), 2.14 - 1.99 (m, 5H), 1.92 (s, 3H), 1.69 - 1.60 (m, 1H); MS (ESI): m/z 774.2 (M+H).

Example 114:

Starting with compound INT-16 and trans-4-aminocyclohexanoate methyl chloride, compound 114 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J= 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.98 -6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.60 - 3.56 (m,l H), 3.57 (s, 3H), 3.45 (brs , 2H), 2.52 - 2.50 (m, 2H), 2.40 - 2.35 (m, 1H), 2.12 -2.03 (m, 7H), 1.94 - 1.87 (m, 2H), 1.81 - 1.75 (m, 2H), 1.69 - 1.60 (m, 1H), 1.32 -1.23 (m, 4H); MS (ESI): m/z 802.2 (M+H).

Example 115:

Starting with compound INT-16 and compound 109a, compound 115 is prepared with reference to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J=8.5 Hz, 1H) , 7.63 (s, 1H), 7.55 - 7.45 (m, 4H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.67 (s, 1H ), 5.71 (s, 2H), 3.86 (s, 3H), 3.78 -3.69 (m, 2H), 3.60 - 3.58 (m, 1H), 3.57 (s, 3H), 3.45 (s, 2H), 2.53 - 2.50 (m, 2H), 2.36 -2.31 (m, 1H), 2.09 (s, 3H), 2.07-2.02 (m, 5H), 1.78- 1.70 (m, 4H), 1.68- 1.60 (m, 1H), 1.59 - 1.50 (m, 1H), 1.31 - 1.18 (m, 2H), 0.98 - 0.86 (m, 2H); MS (ESI): m/z 816.2 (M+H).

Example 116:

Starting from the compound INT-16 and 4-aminobicyclo[2.2.2]octane-1-carbamate methyl ester hydrochloride, compound 116 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.97 -7.88 (m, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.55-7.47 (m, 4H), 7.38 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.98-6.94 (m, 2H), 6.66 (s, 1H), 5.70 (s, 2H), 3.85 (s, 3H), 3.77 - 3.69 (m, 2H), 3.65 - 3.59 (m, 1H) , 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.54 (m, 2H), 2.14-2.03 (m, 3H), 1.99 (s, 3H), 1.76- 1.69 (m, 6H), 1.67 -1.61 (m, 1H), 1.58 - 1.52 (m, 6H); MS (ESI): m/z 828.1 (M+H).

Example 117:

Starting with 4-bromo-6-chloroindazole, compound 117 was prepared according to the synthesis of compound INT-8 and compound 30. ¹ H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.93 (s, 1H ), 7.66 (s, 1H), 7.55-7.44 (m, 8H), 7.24 (s, 1H), 6.78 (s, 1H), 5.74 (brs, 2H), 3.91 - 3.85 (m, 1H), 3.79 - 3.76 (m, 2H), 3.69 - 3.57 (m, 7H), 3.15 - 3.08 (m, 1H), 2.57 - 2.55 (m, 2H), 2.15 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H ); MS (ESI): m/z 736.0 (M+H).

Example 118:

Starting with compound 118a, compound 118b was prepared with reference to the synthesis of compound INT-14.

Starting with compound 118b and compound INT-9, compound 118 was prepared with reference to the synthesis of compound 44.

¹ H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.45 (m, 4H), 7.40 (d , J=7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.65 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H ), 2.56 - 2.52 (m, 2H), 2.14-2.03 (m, 10H), 1.80- 1.73 (m, 2H), 1.72- 1.65 (m, 3H), 1.58 - 1.53 (m, 1H), 1.44 - 1.36 (m, 1H), 0.97 - 0.86 (m, 2H), 0.83 - 0.75 (m, 2H); MS (ESI): m/z 812.2 (M+H).

Example 119:

Under nitrogen atmosphere, tert-butyl-3-oxocyclobutylcarbamate (1.0 g, 5.4 mmol) and ethoxyformylmethylenetriphenylphosphine (2.1 g, 5.9 mmol) were dissolved in toluene (15 mmol). ml) the solution was stirred at 110°C for 6 hours. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction solution, and the aqueous phase was further extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain compound 119a (1.1 g, yield: 79.8%) as a white solid. MS (ESI): m/z 256.3 (M+H).

Under a hydrogen atmosphere, a solution of compound 119a (1.1 g, 4.3 mmol), palladium (10% w/w adsorbed on activated carbon, 150 mg) in methanol (15 ml) was stirred at 25°C overnight. The reaction solution was filtered and the filtrate was concentrated to obtain a white solid 119b (1.1 g, yield: 99.8%). MS (ESI): m/z 258.3 (M+H).

To a solution of compound 119b (1.1 g, 4.3 mmol) in dichloromethane (15 ml) was added hydrochloric acid (4 M in 1,4-dioxane, 5.4 ml), the resulting reaction mixture was stirred at room temperature for 2 hours . The reaction solution was concentrated to give 119 s as a colorless oil (0.83 g, yield: 99.5%).

Starting with compound 119 c and compound INT-9, compound 119 was prepared with reference to the synthesis of compound 44 (based on NMR, the compound should be a mixture of cis and trans isomers in a 6:4 ratio). ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s,1H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.55-7.47 (m, 4H), 7.42 (d , J=7.0 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.06 (dd, J =7.5, 1.5 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 ( s, 3H), 3.25 (s, 2H), 3.03 - 2.95 (m, 0.4H), 2.74 - 2.69 (m, 0.6H), 2.58 - 2.54 (m, 2H), 2.43 - 2.35 (m, 1H), 2.31 - 2.27 (m, 1.2H), 2.23 - 2.06 (m, 5H), 2.04 - 1.97 (m, 0.8H), 1.91 (s, 3H), 1.80 - 1.73 (m, 0.8H), 1.72 - 1.64 ( m, 1H), 1.51 - 1.41 (m, 1.2H); MS (ESI): m/z 770.0 (M+H).

Example 120:

Starting from trans-4-(Boc-amino)cyclohexylformaldehyde, compound 120b was prepared according to the synthesis of compound 119a and compound 119c. MS (ESI): m/z 198.6 (M+H).

Starting with compound 120b and compound INT-9, compound 120 is prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J=8.5 Hz, 1H) , 7.66 (s, 1H), 7.56 - 7.47 (m, 4H), 7.42 (d, J=7.7 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.10 ( s, 1H), 7.09-7.05 (m, 1H), 6.77 - 6.71 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 5.72 - 5.66 (m, 1H), 3.84 (s, 3H), 3.82 - 3.73 (m, 2H), 3.68 - 3.63 (m, 1H), 3.59 (s, 3H), 3.53 - 3.42 (m, 2H), 2.61 - 2.56 (m, 2H), 2.44 - 2.36 ( m, 1H), 2.17-2.06 (m, 7H), 1.86-1.75 (m, 4H), 1.75-1.66 (m, 1H), 1.40-1.27 (m, 2H), 1.18 - 1.08 (m, 2H); MS (ESI): m/z 810.2 (M+H).

Example 121:

Starting with compound 120a, compound 121 is prepared with reference to the synthesis of compound 119. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.41 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.08 (d, J=1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.46 (brs, 2H), 2.57-2.54 (m, 2H), 2.38-2.30 (m, 1H), 2.18 (t, J=7.5 Hz, 2H), 2.15-2.05 (m, 6H), 1.81 1.65 (m, 5H), 1.38 (t, J=7.5 Hz, 2H), 1.29-1.17 (m, 2H), 1.17-1.08 (m, 1H), 0.92 - 0.82 (m, 2H); MS (ESI): m/z 812.2 (M+H).

Examples 122 and 123:

Starting with compound INT-9, cyclopropylamine and methyl 4-oxocyclohexanoate, compound 122 and compound 123 were prepared with reference to the synthesis of compound 44.

Compound 122: ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.55-7.45 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 7.31 (s, 1H), 7.17 (d, J=7.0Hz, 1H), 7.09-7.07 (m, 1H), 7.07-7.03 (m, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 3.73 - 3.72 (m, 2H), 3.68 (s, 2H), 3.65 - 3.60 (m, 1H), 3.59 (s, 3H ), 2.56 - 2.53 (m, 2H), 2.46 - 2.42 (m, 1H), 2.14-2.03 (m, 5H), 1.93 - 1.87 (m, 2H), 1.83 -1.78 (m, 2H), 1.72 - 1.67 (m, 1H), 1.38 - 1.30 (m, 2H), 1.26 - 1.20 (m, 2H), 0.40 -0.35 (m, 2H), 0.26 - 0.17 (m, 2H); MS (ESI): m/z 810.2 (M+H).

Compound 123: ¹ H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.45 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.15 (d, J=7.0Hz, 1H), 7.07-7.06 (m, 1H), 7.05-7.02 (m, 1H), 6.63 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.70 (m, 2H), 3.68 - 3.66 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H ), 2.55 - 2.52 (m, 2H), 2.45 - 2.42 (m, 1H), 2.13 -2.03 (m, 5H), 1.70 - 1.65 (m, 1H), 1.60 -1.55 (m, 2H), 1.47 - 1.40 (m, 2H), 1.31 - 1.25 (m, 4H), 0.37 - 0.32 (m, 2H), 0.22 - 0.17 (m, 2H); MS (ESI): m/z 810.2 (M+H). Example 124:

For the synthesis of compound 110, isopropyl iodide was replaced with iodoethane to give compound 124. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (s, 1H ), 7.55 - 7.47 (m, 4H), 7.42 (d, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.09 (d, J=1.6 Hz , 1H), 7.08 -7.05 (m, 1H), 6.59 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.78 (q, J=7.0 Hz, 2H), 3.75 - 3.71 ( m, 2H), 3.65 -3.61 (m, 1H), 3.36 (brs, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.03 (m, 6H), 2.08 (s, 3H), 1.89 1.80 (m , 4H), 1.72 1.66 (m, 1H), 1.50 1.42 (m, 1H), 1.29 1.24 (m, 2H), 1.18 (t, J=7.0 Hz, 3H), 0.85 - 0.79 (m, 2H); MS (ESI): m/z 812.2 (M+H).

Example 125:

Starting with compound INT-9, trans-4-aminocyclohexanoate methyl ester hydrochloride and benzaldehyde, compound 125 was prepared according to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.74 ( d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.43 (m, 4H), 7.44 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.30 - 7.23 (m , 4H), 7.22-7.13 (m, 2H), 7.08 - 7.06 (m, 1H), 7.05-7.02 (m, 1H), 6.62 (s, 1H), 5.68 (s, 2H), 3.81 (s, 3H ), 3.77 - 3.70 (m, 2H), 3.66 - 3.61 (m, 1H), 3.57 (s, 2H), 3.54 (s, 3H), 3.51 (s, 2H), 2.59 - 2.54 (m, 2H), 2.41 - 2.36 (m, 1H), 2.14 - 2.04 (m, 4H), 1.94 - 1.87 (m, 2H), 1.84 - 1.79 (m, 2H), 1.71 - 1.65 (m, 1H), 1.41 - 1.32 (m , 2H), 1.20 - 1.11 (m, 2H); MS (ESI): m/z 860.1 (M+H).

Example 126:

Starting with compound INT-9, trans-4-aminocyclohexanoate methyl chloride and cyclopropyl formaldehyde, compound 126 was prepared with reference to the synthesis of compound 44. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.55 - 7.46 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.10 -7.08 (m, 1H), 7.08-7.03 (m, 1H), 6.67 (s, 1H), 5.72 (s, 3H), 3.83 (s, 3H), 3.76 - 7.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 (s, 2H), 2.56 -2.53 (m, 2H), 2.32 (d, J=6.0 Hz, 2H), 2.15 - 2.05 (m, 4H), 1.93 - 1.88 (m, 2H), 1.80 - 1.73 (m, 2H), 1.72 - 1.66 (m, 1H), 1.30 - 1.21 (m, 5H), 0.75 - 0.69 (m, 1H) , 0.37 -0.31 (m, 2H), 0.03 - 0.00 (m, 2H); MS (ESI): m/z 824.1 (M+H).

Example 127:

For the synthesis of compound 110, isopropyl iodide was replaced by 2-bromoacetamide to obtain compound 127. ¹ H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J=1.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.51 -7.47 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.37 (s, 1H), 7.34 (s , 1H), 7.15 (d,J=7.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.79 (s, 1H), 5.68 (s, 2H) , 4.28 (s, 2H), 3.81 (s, 3H), 3.72 (d, J=3.0 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.43 (s, 2H), 2.58 -2.55 (m, 2H ), 2.15 - 2.09 (m, 6H), 2.08 (s, 3H), 1.83 - 1.76 (m, 4H), 1.69 - 1.66 (m, 1H), 1.46 - 1.43 (m, 1H), 1.26 - 1.22 (m , 2H), 0.83 - 0.78 (m, 2H); MS (ESI): m/z 841.2 (M+H).

Example 128:

For the synthesis of compound 110, isopropyl iodide was replaced by tert-butyl2-bromoacetate to obtain compound 128. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.73 (d, J=8.5 Hz, 1H) , 7.67 (s, 1H), 7.51 - 7.46 (m, 4H), 7.42 -7.37 (m, 2H), 7.14 (d, J=7.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.79 (s, 1H), 5.65 (s, 2H), 4.09 (brs, 2H), 3.81 (s, 3H), 3.73-3.69 (m, 2H), 3.63-3.60 ( m, 1H), 3.41 (s, 2H), 2.54 - 2.52 (m, 2H), 2.33 - 2.28 (m, 1H), 2.20 (s, 3H), 2.12 -2.05 (m, 5H), 1.86 1.80 (m , 4H), 1.71 1.66 (m, 1H), 1.59 1.50 (m, 1H), 1.29 1.23 (m, 2H), 0.87 - 0.80 (m, 2H); MS (ESI): m/z 843.2 (M+H).

Example 129

Starting with compound INT-9 and trans-4-aminocyclohexanoate methyl chloride, compound 129a was prepared according to the synthesis of compound 44 (except for the last de-Boc step). MS (ESI): m/z 883.6 (M+H).

Starting with compound 129a and methanesulfonamide, compound 129 was prepared according to the acid-amine condensation conditions of the synthesis of compound 82a and the de-Boc conditions of compound 1 in the last step. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.56-7.47 (m, 4H), 7.44 (d , J=7.5 Hz, 1H), 7.41 (s, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.70 (s , 1H), 5.73 (s, 2H), 3.85 (s, 3H), 3.84 - 3.79 (m, 2H), 3.71 - 3.65 (m, 1H), 3.59 (s, 3H), 3.53 (s, 2H), 3.05 (s, 3H), 2.65 (d, J=6.0 Hz, 2H), 2.46-2.40 (m, 1H), 2.15 (s, 3H), 2.14-2.05 (m, 4H), 1.88- 1.78 (m, 4H), 1.75 - 1.68 (m, 1H), 1.35 - 1.22 (m, 4H); MS (ESI): m/z 861.3 (M+H).

Example 130:

Starting with compound INT-16 and compound 118b, compound 130 is prepared with reference to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.75 (d, J=8.5 Hz, 2H) , 7.63 (s, 1H), 7.54 - 7.48 (m, 4H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.67 (s, 1H ), 5.71 (s, 2H), 3.85 (s, 3H), 3.76 -3.70 (m, 2H), 3.60 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.53 - 2.50 (m, 2H), 2.11 - 2.02 (m, 10H), 1.79 - 1.74 (m, 2H), 1.71 - 1.66 (m, 2H), 1.65 - 1.60 (m, 1H), 1.58 -1.51 (m, 1H ), 1.44 - 1.36 (m, 1H), 0.95 - 0.87 (m, 2H), 0.83 - 0.74 (m, 2H); MS (ESI): m/z 830.1 (M+H).

Example 131:

Starting with compound INT-16 and compound 121a, compound 131 is prepared with reference to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J=8.5 Hz, 1H) , 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.66 (s, 1H ), 5.71 (s, 2H), 3.85 (s, 3H), 3.77 -3.69 (m, 2H), 3.62 - 3.59 (m, 1H), 3.56 (s, 3H), 3.44 (s, 2H), 2.55 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.19 - 2.14 (m, 2H), 2.09 (s, 3H), 2.07 - 2.02 (m, 3H), 1.77 - 1.69 (m, 4H), 1.66 - 1.60 (m, 1H), 1.39 - 1.33 (m, 2H), 1.24 - 1.17 (m, 2H), 1.13 - 1.08 (m, 1H), 0.89 - 0.82 (m, 2H); MS (ESI): m/z 830.1 (M+H).

Example 132:

Starting with compound INT-16 and compound 120b, compound 132 is prepared with reference to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J=8.5 Hz, 1H) , 7.63 (s, 1H), 7.54 - 7.47 (m, 4H), 7.37 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.76 - 6.69 (m , 1H), 6.67 (s, 1H), 5.71 (s, 2H), 5.69 - 5.64 (m, 1H), 3.86 (s, 3H), 3.77 - 3.71 (m, 2H), 3.61 - 3.58 (m, 1H ), 3.57 (s, 3H), 3.46 (s, 2H), 2.52 - 2.50 (m, 2H), 2.14 - 2.02 (m, 8H), 1.84 - 1.74 (m, 4H), 1.69 - 1.60 (m, 1H ), 1.34-1.24 (m, 2H), 1.16-1.07 (m, 2H); MS (ESI): m/z 828.1 (M+H).

Example 133:

For the synthesis of compound 91, the hemostatic methyl ester hydrochloride was replaced with methyl ester 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride to give compound 133. lH NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.58 - 7.49 (m, ZN), 7.40 (s, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.69 (s, 1H), 5.72 (s, 2H), 3.92 (s, 3H), 3.76 - 3.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.43 (s, 2H), 2.60 - 2.54 (m, 2H), 2.16 - 2.07 (m, 3H), 2.01 (s, 3H) , 1.77- 1.65 (m, 7H), 1.61- 1.54 (m, 6H); MS (ESI): m/z 811.1 (M+H).

Example 134:

For the synthesis of compound 110, isopropyl iodide was replaced by (S)-5-bromomethyl-2-pyrrolidone to give compound 134. ¹ H NMR (500 MHz, DMSO-d6) δ7.89 (s, 1H), 7.78 - 7.73 (m , 2H), 7.66 (s, 1H), 7.52 - 7.46 (m, 4H), 7.40 (d, J=7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=7.0 Hz, 1H) , 7.07 (s, 1H), 7.04 (d,J=7.5 Hz, 1H), 6.72 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.80 - 3.76 (m, 1H), 3.75 - 3.72 (m, 1H), 3.72 - 3.70 (m, 2H), 3.66 - 3.60 (m, 2H), 3.40 - 3.35 (m, 2H), 2.57 - 2.52 (m, 2H), 2.17 (d, J =11.0 Hz, 1H), 2.12 - 2.08 (m, 6H), 2.08 (s, 3H), 2.06 - 2.04 (m, 1H), 1.87 - 1.75 (m, 5H), 1.70 - 1.64 (m, 1H), 1.47 - 1.40 (m, 1H), 1.30 - 1.20 (m, 3H), 0.85 - 0.77 (m, 2H); MS (ESI): m/z 881.2 (M+H).

Example 135:

Starting with compound 80b, 4-bromondazole and compound INT-15, compound 135a was prepared with reference to the synthesis of compound 73a and compound INT-16. MS (ESI): m/z 661.4 (M+H).

Starting with compound 135a and 4-aminobicyclo[2.2.2]octane-1-methylcarboxylate hydrochloride, compound 135 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.57 - 7.43 (m, 4H), 7.12 (d, J=7.0 Hz, 1H), 6.96 (s , 1H), 6.94 (d, J=8.5 Hz, 1H), 5.78 (s, 2H), 3.85 (s, 3H), 3.74 - 3.73 (m, 2H), 3.58 -3.56 (m, 3H), 3.37 ( s, 3H), 2.51-2.50 (m, 2H), 2.10 - 2.03 (m, 3H), 1.99 (s, 3H), 1.70 -1.67 (m, 6H), 1.64 - 1.62 (m, 1H), 1.54 - 1.51 (m, 6H); MS (ESI): m/z 829.2 (M+H)/

Example 136:

Starting with compound INT-16 and 3-aminobicyclo[1.1.1]pentane-1-carbamate hydrochloride, compound 136 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H ), 7.75 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.46 (m, 4H), 7.33 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.00 -6.94 (m, 2H), 6.67 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.57 (s, 3H), 3.56 - 3.52 (m , 1H), 3.40 (s, 2H), 2.55 - 2.52 (m, 2H), 2.10 - 2.03 (m, 6H), 1.89 (s, 6H), 1.68 - 1.60 (m, 1H); MS (ESI): m/z 786.0 (M+H).

Example 137:

Starting with compound INT-10, compound INT-2, compound 80b and 4-bromondazole, compound 137a was prepared with reference to the synthesis of compound INT-3, compound 73a and compound 16. MS (ESI): m/z 644.3 (M+ H).

Starting with compound 137a and 4-aminobicyclo[2.2.2]octane-1-methylcarboxylate hydrochloride, compound 137 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.83 - 7.80 (m, 3H ), 7.70 - 7.65 (m, ZN), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.47 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.14 (d, J= 7.0 Hz, 1H), 5.80 (s, 2H), 3.92 (s, 3H), 3.73 - 3.71 (m, 2H), 3.65 - 3.63 (m, 1H), 3.39 (s, 3H), 3.36 (brs, 2H ), 2.56 (d, J=6.0 Hz, 2H), 2.14-2.07 (m, 3H), 2.00 (s, 3H), 1.72-1.68 (m, 7H), 1.56-1.52 (m, 6H); MS (ESI): m/z 812.1 (M+H).

Example 138:

For the synthesis of compound 107, compound INT-6 was replaced by compound INT-15 to give compound 138. ¹ H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.84 (d, J=8.6 Hz, 1H ), 7.71 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 4H), 7.18 (d, J=7.0 Hz, 1H), 6.99 - 6.97 (m, 2H), 6.92 (s, 1H), 5.82 (s, 2H), 3.87 (s, 3H), 3.76 - 3.73 (m, 2H), 3.71 (s, 3H), 3.62 - 3.58 (m, 1H), 3.49 (s, 2H), 2.60 -2.55 (m, 2H), 2.45-2.35 (m, 1H), 2.12(s, 3H), 2.10-2.04 (m, 3H), 1.94-1.92 (m, 2H), 1.81 -1.79 (m, 2H) , 1.69 - 1.62 (m, 1H), 1.34-1.23 (m, 5H); MS (ESI): m/z 793.0 (M+H).

Example 139:

For the synthesis of compound 138, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to give compound 139. ¹ H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, J=7.1 Hz, 1H), 6.99 - 6.95 ( m, 2H), 6.91 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, J=4.2 Hz, 2H), 3.69 (s, 3H), 3.58 -3.56 (m , 1H), 3.26 (brs, 2H), 3.03 - 3.01 (m, 1H), 2.80 - 2.76 (m, 1H), 2.51 - 2.48 (m, 2H), 2.20 - 2.15 (m, 2H), 2.09 - 2.02 (m, 5H), 1.92 (s, 3H), 1.66 - 1.62 (m, 1H); MS (ESI): m/z 765.1 (M+H).

Example 140:

For the synthesis of compound 138, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with 4-aminobicyclo[2.2.2]octane-1-carboxylate methyl ester hydrochloride to give compound 140. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (s , 1H), 7.84 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.56 - 7.49 (m, 4H), 7.18 (d, J=7.0 Hz, 1H) , 7.00 - 6.97 (m, 2H), 6.91 (s, 1H), 5.81 (s, 2H), 3.87 (s, ZN), 3.75 (d, J=4.5 Hz, 2H), 3.70 (s, 3H), 3.62 - 3.56 (m, 1H), 3.45 (s, 2H), 2.54 - 2.52 (m, 2H), 2.09 - 2.05 (m, 3H), 2.02 (s, 3H), 1.75 - 1.72 (m, 6H), 1.68 - 1.63 (m, 1H), 1.59 - 1.56 (m, 6H); MS (ESI): m/z 819.0 (M+H).

Example 141:

For the synthesis of compound 138, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with compound INT-14 to give compound 141. ¹ H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 4H), 7.17 (d, J=7.0 Hz, 1H), 6.97 - 6.95 (m, 2H), 6.90 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, J=4.1 Hz, 2H), 3.69 (s, 3H), 3.58 - 3.55 (m, 1H), 3.46 (s, 2H), 2.52 - 2.49 (m, 2H), 2.36 - 2.33 (m, 1H), 2.10 (s, 3H), 2.08-2.01 (m, 5H), 1.77- 1.70 (m, 4H), 1.66 - 1.61 (m, 1H), 1.58 -1.52 (m, 1H), 1.29 - 1.22 (m, 2H), 0.96 - 0.89 (m, 2H); MS (ESI): m/z 807.1 (M+H).

Example 142:

For the synthesis of compound 92, compound INT-6 was replaced by compound INT-15 to give compound 142. ¹ H NMR (500 MHz, DMSO-d6) 5 8.17 (s, 1H), 7.99 (s, 1H), 7.78 (d , J=8.5 Hz, 1H), 7.64 (s, 1H), 7.57 - 7.46 (m, 4H), 7.17 (d, J=7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.10 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.73 (d, J=4.5 Hz, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H), 3.48 (s, 3H ), 2.53 - 2.51 (m, 2H), 2.43 - 2.37 (m, 1H), 2.13 (s, 3H), 2.11 - 2.01 (m, 4H), 1.95 - 1.86 (m, 2H), 1.84 - 1.75 (m , 2H), 1.68 - 1.59 (m, 1H), 1.33 - 1.23 (m, 4H); MS (ESI): m/z 813.3 (M+H).

Example 143:

For the synthesis of compound 142, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to give compound 143. ¹ H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.99 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, J=6.5 Hz, 1H), 7.00 - 6.96 ( m, 2H), 6.12 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77-3.70 (m, 2H), 3.59-3.55 (m, 1H), 3.48 (s, 3H) , 3.32 - 3.30 (m, 2H), 3.09 - 3.02 (m, 1H), 2.87 - 2.78 (m, 1H), 2.52 - 2.48 (m, 2H), 2.21 - 2.16 (m, 2H), 2.12 - 2.02 ( m, 5H), 1.95 (s, 3H), 1.67 - 1.60 (m, 1H); MS (ESI): m/z 785.3 (M+H).

Example 144:

For the synthesis of compound 142, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with compound INT-14 to give compound 144. ¹ H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.98 (s, 1H) , 7.78 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 (d, J=6.5 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H), 3.48 (s, 3H), 2.54 - 2.50 (m, 2H), 2.36 - 2.33 (m, 1H), 2.13 (s, 3H), 2.10-2.02 (m, 5H), 1.78- 1.70 (m, 4H), 1.67 1.64 (m , 1H), 1.57 - 1.52 (m, 1H), 1.32 - 1.21 (m, 2H), 0.98-0.88 (m, 2H); MS (ESI): m/z 827.1 (M+H).

Example 145:

For the synthesis of compound 142, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with 4-aminobicyclo[2.2.2]octane-1-carboxylate methyl ester hydrochloride to give compound 145. ¹ H NMR (500 MHz, DMSO-d6) δ 8.18( s, 1H), 7.98 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.47 (m, 4H), 7.17 (d, J=7.0 Hz, 1H ), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.08 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.48 (s, 3H), 3.45 (s, 2H), 2.54 - 2.50 (m, 2H), 2.10 - 2.04 (m, 3H), 2.03 (s, 3H), 1.74 - 1.69 (m, 6H), 1.68 - 1.62 (m, 1H), 1.60 - 1.55 (s, 6H); MS (ESI): m/z 839.1 (M+H).

Example 146:

Copper iodide (156 mg, 0.82 mmol) was added to a solution of compound INT-13 (50 mg, 0.16 mmol) and methylfluorosulfonyldifluoroacetate (314 mg, 1.6 mmol) in N,N-dimethylformamide (2 ml). the resulting mixture was stirred at 150°C for 4 hours. After filtering the reaction solution, a mixture of ethyl acetate and water (100 ml, v/v=1/1) was added to the filtrate. The resulting organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 146a as a white solid (40 mg, yield: 98.7%). ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.27 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H); MS (ESI): m/z 249.0 (M+H).

From compound 146a, regarding the synthesis of compound 92, in which trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced by compound INT-14, compound 146 was obtained. ¹ H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.46 (m, 4H), 7.40 (d, J=7.7 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 7.07 (d,J=1.6 Hz, 1H), 7.04 (dd, J=7.5, 1.6 Hz, 1H), 6.32 (s, 1H), 5.82 (s, 2H), 3.82 (s, 3H), 3.71 (d, J=3.0 Hz, 2H), 3.65 -3.59 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 -2.06 (m, 6H), 2.02 (d,J=7.1Hz, 2H), 1.76- 1.67 (m, 5H), 1.58-1.51 (m, 1H), 1.29 -1.21 (m, 2H), 0.97 - 0.87 (m, 2H); MS (ESI): m/z 832.2 (M+H).

Example 147:

For the synthesis of compound 146, compound INT-6 was replaced by compound INT-15 to give compound 147. ¹ H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.70 (s, 1H), 7.68 - 7.61 (m, 2H), 7.57 - 7.47 (m, 4H), 7.17 (d, J=7.0 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.33 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.62 - 3.54 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.50 (m, 2H), 2.36 - 2.31 (m, 1H), 2.10 (s, 3H), 2.09-2.01 (m, 5H), 1.77 - 1.69 (m, 4H), 1.67-1.61 (m, 1H), 1.59 - 1.52 (m, 1H), 1.31 - 1.24 (m, 2H), 0.97 - 0.88 (m, 2H); MS (ESI): m/z 850.1 (M+H).

Example 148:

For the synthesis of compound 147, compound INT-14 was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to give compound 148. ¹ H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.70 (s, 1H) , 7.69 - 7.61 (m, 2H), 7.57 - 7.46 (m, 4H), 7.17 (d, J=7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.33 (s, 1H), 5.82 (s , 2H), 3.86 (s, 3H), 3.78 - 3.68 (m, 2H), 3.61 - 3.55 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.56 - 2.50 (m, 2H ), 2.39 - 2.33 (m, 1H), 2.10 (s, 3H), 2.09-2.02 (m, 4H), 1.94- 1.87 (m, 2H), 1.82 - 1.74 (m, 2H), 1.68 - 1.60 (m , 1H), 1.34 - 1.24 (m, 4H); MS (ESI): m/z 836.1 (M+H).

Example 149:

For the synthesis of compound 147, compound INT-14 was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to give compound 149. ¹ H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.69 - 7.62 (m, 3H), 7.57 - 7.47 (m, 4H), 7.17 (d, J=6.9 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.34 (s, 1H), 5.83 (s, 2H), 3.86 (s , 3H), 3.79 - 3.70 (m, 2H), 3.61 - 3.54 (m, 1H), 3.46 (s, 3H), 3.29 (s, 2H), 3.06 - 2.97 (m, 1H), 2.83 - 2.75 (m , 1H), 2.56 - 2.52 (m, 2H), 2.19 - 2.14 (m, 2H), 2.11 - 2.01 (m, 5H), 1.91 (s, 3H), 1.68 - 1.61 (m, 1H); MS (ESI): m/z 808.1 (M+H).

Example 150:

For the synthesis of compound 147, compound INT-14 was replaced with 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride to give compound 150. ¹ H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H ), 7.72 (s, 1H), 7.67 - 7.61 (m, 2H), 7.58 - 7.47 (m, 4H), 7.17 (d, J=7.0 Hz, 1H), 7.05 - 6.94 (m, 2H), 6.32 ( s, 1H), 5.82 (s, 2H), 3.86 (s, ZN), 3.78 - 3.70 (m, 2H), 3.61 - 3.55 (m, 1H), 3.46 (s, 3H), 3.44 (s, 2H) , 2.60 - 2.54 (m, 2H), 2.10 - 2.02 (m, 3H), 1.99 (s, 3H), 1.74 - 1.68 (m, 6H), 1.66 - 1.62 (m, 1H), 1.59 - 1.53 (m, 6H); MS (ESI): m/z 862.1 (M+H).

Example 151:

Regarding the synthesis of compound 137, compound 151 was prepared by replacing methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride with methyl trans-4-aminocyclohexanecarboxylate hydrochloride. ¹ H NMR (500 MHz, DMSO-d6) δ 7.83 - 7.78 (m, 3H), 7.72 - 7.63 (m, 3H), 7.54 (t, J=7.5 Hz, 1H), 7.50 -7.45 (m, 2H) , 7.30 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.0 Hz, 1H), 5.80 (s, 2H), 3.90 (s, 3H), 3.70 (d, J=3.5 Hz, 2H) , 3.65 - 3.60 (m, 1H), 3.39 (s, 2H), 3.37 (s, 3H), 2.55 -2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 - 2.05 (m, 4H) , 2.08 (s, 3H), 1.93 - 1.87 (m, 2H), 1.78 - 1.73 (m, 2H), 1.71 - 1.66 (m, 1H), 1.29 - 1.23 (m, 4H); MS (ESI): m/z 786.0 (M+H).

Example 152:

For the synthesis of compound 91, methyl hemostatic acid hydrochloride was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to give compound 152. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.59 - 7.49 (m, 3H), 7.38 (s, 1H), 7.32 (d, J=7.4 Hz , 1H), 7.18 (d, J=7.0 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.92 (s, 3H), 3.76 - 3.70 (m, 2H), 3.66 -3.61 ( m, 1H), 3.59 (s, 3H), 3.46 (s, 2H), 2.56 - 2.55 (m, 2H), 2.42 - 2.35 (m, 1H), 2.16 - 2.06 (m, 4H), 2.12 (s, 3H), 1.96 - 1.88 (m, 2H), 1.83 - 1.76 (m, 2H), 1.74 - 1.66 (m, 1H), 1.34 - 1.23 (m, 4H); MS (ESI): m/z 784.8 (M+H).

Example 153:

For the synthesis of compound 57, compound INT-2 was replaced by compound INT-17 to give compound 153. ¹ H NMR (500 MHz, DMSO-d6) 5 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 1H ), 7.54 - 7.48 (m, 4H), 7.41 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.19-7.14 (m, 2H), 7.10 (brs, 1H), 7.07-7.03 ( m, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.76 - 3.66 (m, 2H), 3.58 (s, 3H), 3.46 (s, 2H), 3.41 - 3.36 (m, 1H), 2.61 - 2.58 (m, 2H), 2.16 - 2.05 (m, 3H), 2.13 (s, 3H), 1.95 - 1.89 (m, 2H), 1.83 - 1.74 (m, 4H) , 1.63 - 1.54 (m, 1H), 1.36 - 1.23 (m, 6H); MS (ESI): m/z 799.1 (M+H).

Example 154:

At -78°C, lithium diisopropylamide (2.0 M in tetrahydrofuran, 2.6 ml) was added to a solution of 1-chloro-2-bromo-4-fluorobenzene (1.0 g, 4.8 mmol) in tetrahydrofuran (6 ml); The resulting reaction solution was stirred at the same temperature for 1 hour. N,N-dimethylformamide (1.7 g, 24 mmol) was then added to the reaction solution, and the resulting mixture was further stirred at -78°C for 1 hour. The reaction was quenched with aqueous ammonium chloride (40 ml, 5% w/w) and the aqueous phase was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether=10/1) to give a white solid 154a (830 mg, yield: 73.2%). MS (ESI): m/z 237.1 (M+H).

Compound 154a (830 mg, 3.5 mmol), hydrazine hydrate (2.0 ml, analytical purity 85%) in ethylene glycol dimethyl ether (5 ml) was stirred at 90°C for 3 hours. After cooling the reaction mixture, ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, the organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether=10/1) to give compound 154b as a pale yellow solid (725 mg, yield: 89.6%). MS (ESI): m/z 231.0 (M+H).

Starting with compound 154b, compound 154 was prepared with reference to the synthesis of compound INT-9 and compound 30. ¹ H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=9.0 Hz, 1H), 7.71 (s, 1H ), 7.65 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.48 (s, 1H), 7.43 - 7.39 (m, 2H), 7.07 - 7.02 ( m, 2H), 6.75 (s, 1H), 5.73 (s, 2H), 3.88 - 3.84 (m, 1H), 3.82 (s, 3H), 3.79 - 3.73 (m, 3H), 3.65 - 3.64 (m, 1H), 3.62 (s, 3H), 3.60 - 3.55 (m, 2H), 3.13 3.11 (m, 1H), 2.59 - 2.54 (m, 2H), 2.11 2.06 (m, 3H), 1.71 - 1.65 (m, 1H); MS (ESI): m/z 765.9 (M+H).

Example 155:

4-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) in acetonitrile (10 ml) and N-chlorosuccinimide (843 mg, 6.3 mmol) were added portionwise. The reaction solution was stirred under reflux for 2 hours. After cooling the reaction solution, 5% aqueous potassium carbonate solution (50 ml) was added and the resulting aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (eluent: petroleum ether) to give compound 155a as a white solid (1.0 g, yield: 84.6%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.21 (t, J=2.0 Hz, 1H), 7.09 (dd, J=10.0, 2.0 Hz, 1H), 4.04 (brs, 2H).

At room temperature, a solution of compound 155a (1.0 g, 4.5 mmol) in aqueous sulfuric acid (25% w/w) was stirred for half an hour, then cooled to -5°C and then dissolved sodium nitrite (369 mg, 5 .4 mmol) in water (5 ml). The reaction solution was further stirred at -5°C for 1 hour and at the same temperature a mixed solution of ethyl acetate and water (50 ml, v/v=3/2) dissolved in potassium iodide (1.5 g, 8.9 d), mmol) was slowly added dropwise. The resulting reaction solution was reacted at room temperature for 1 hour.

After separation of the reaction solution, the aqueous phase was further extracted with ethyl acetate (30 ml x 2), the combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (eluent: petroleum ether) to give compound 155b (800 mg, yield: 53.6%) as a colorless oil. ¹ H NMR (500 MHz, Chloroform-d) δ 7.45 (t, J=2.0 Hz, 1H), 7.13 (dd, J=7.0, 2.0 Hz, 1H).

Under nitrogen atmosphere and at 80°C, a mixed solution of 1,4-dioxane and water (11 ml, v/v=10/1) with compound 155b (1.0 g, 3.0 mmol), vinyl borate pinacol ether (1.4 g, 9.0 mmol)), a mixture of Pd(dppf)C12 (109 mg, 0.15 mmol) and sodium bicarbonate (504 mg, 6.0 mmol) was stirred for 16 hours. The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance 155 s (550 mg, yield: 58.7%).

At room temperature, periodate (1.4 g, 6.6 mmol). The reaction solution was stirred at the same temperature for 2 hours. Water (30 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (30 ml x 2). The combined organic phase was washed with brine (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, v/v=10/1) to obtain a colorless oily substance 155d (400 mg, yield: 76.3%). ¹ H NMR (500 MHz, Chloroform-J) δ 10.40 (brs, 1H), 7.48 (d, J=1.5 Hz, 1H), 7.33 - 7.29 (m, 1H).

Starting with compound 155d, compound 155 is prepared with reference to the synthesis of compound INT-16 and compound 101. ¹ H NMR (500 MHz, DMSO-d6) 5 7.93 (s, 1H), 7.76 (d,J=8.5 Hz, 1H) , 7.63 (s, 1H), 7.55 -7.48 (m, 4H), 7.36 (s, 1H), 7.19-7.17 (m, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.11-7.09 (m , 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.85 - 3.83 (m, 2H), 3.62 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.51 (m, 2H), 2.11-2.04 (m, 8H), 1.86-1.77 (m, 4H), 1.67-1.61 (m, 1H), 1.48-1.39 (m, 1H ), 1.27-1.19 (m, 3H), 0.85-0.75 (m, 2H); MS (ESI): m/z 832.2 (M+H).

Example 156:

Sodium methoxide (1.8 g, 33.5 mmol) was added to a solution in tetrahydrofuran (40 ml) with dissolved methyl 4,6-dichloronicotinate (4.6 g, 22.3 mmol). The resulting reaction solution was stirred at 50°C for 16 hours. Water (100 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (100 ml x 2). The combined organic phase was brine (150 ml), washed, dried with anhydrous sodium sulfate, filtered, concentrated. The residue was separated by silica gel column chromatography to give a white solid 156a (2.8 g, yield: 62.2%). MS (ESI): m/z 202.1 (M+H).

Starting with compound 156a, compound 156b was prepared with reference to the synthesis of compound 72c. MS (ESI): m/z 172.1 (M+H).

Starting with compound 156b, compound 156 was prepared with reference to the synthesis of compound INT-10 and compound 133. ¹ H NMR (500 MHz, DMSO-d6) δ 8.24 (d,J=1.7 Hz, 1H), 7.94 (s, 1H ), 7.78 (d, J=8.5Hz, 1H), 7.68 (s, 1H), 7.61-7.48 (m, 5H), 7.40 (s, 1H), 7.18 (d, J=7.0 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.88 (s, 3H), 3.86 (s, 2H), 3.65 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 2.66 - 2.56 (m, 2H), 2.15 - 2.05 (m, 3H), 2.00 (s, 3H), 1.77 - 1.67 (m, 7H), 1.61 - 1.52 (m, 6H); MS (ESI): m/z 811.1 (M+H).

Example 157:

Starting with compound INT-15a, compound 157a was prepared with reference to the synthesis of compound INT-le. MS (ESI): m/z 276.8 (M+H).

Starting with compound 157a, compound 157c was prepared with reference to the synthesis of 155c. ¹ H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.31 (d, J=1.5 Hz, 1H), 6.19 (d, J=1.5 Hz, 1H), 4.11 - 4.07 (m, 2H ), 3.96 - 3.92 (m, 2H), 3.90 (s, 3H).

At 0°C, sodium borohydride (29 mg, 0.77 mmol) was added to a solution in tetrahydrofuran (20 ml) with dissolved compound 157c (400 mg, 1.53 mmol). The reaction solution was then stirred at room temperature for half an hour. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, and the solution was extracted with ethyl acetate (20 ml x 2). The combined organic phase was brine (50 mL), washed, dried with anhydrous sodium sulfate, filtered and concentrated to give yellow solid 157d (400 mg, yield: 99.2%). MS (ESI): m/z 263.3 (M+H).

Starting with compound 157d, compound 157e is prepared according to the synthesis of compound INT-8c and compound INT-li. MS (ESI): m/z 445.5 (M+H).

Starting with compound 157e, compound 157 is prepared with reference to the synthesis of compound 133. ¹ H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.56 - 7.49 (m, 3H), 7.30 (d, J=7.5 Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.58 (s, 1H), 5.76 (s, 2H), 3.90 (s, 3H), 3.70 (d,J=3.5 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.60 (s, 3H), 3.45 (s, 2H), 2.54 (d, J=6.0 Hz, 2H), 2.14-2.05 (m, 3H), 1.89 (s, 3H), 1.74-1.69 (m, 6H), 1.69-1.64 (m, 1H ), 1.62-1.57 (m, 6H); MS (ESI): m/z 829.3 (M+H).

Example 158:

Starting with 1-chloro-2-fluoro-4-bromobenzene, compound 158 was prepared according to the synthesis of compound 154. ¹ H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.66 (s, 1H) , 7.56 - 7.49 (m, 4H), 7.45 - 7.39 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 7.05 (dd, J=7.6 , 1.6 Hz, 1H), 6.04 - 6.00 (m, 3H), 3.81 (s, 3H), 3.73 - 3.69 (m, 2H), 3.66 - 3.56 (m, 3H), 3.45 - 3.41 (m, 2H), 3.38 (s, 3H), 3.25 - 3.22 (m, 1H), 2.55 - 2.50 (m, 2H), 2.11 2.05 (m, 3H), 1.71 - 1.65 (m, 1H); MS (ESI): m/z 766.0 (M+H).

Example 159:

Regarding the synthesis of compound 116, compound 159 was obtained by replacing the formaldehyde used in the reductive amination step with acetaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.54-7.47 (m, 4H), 7.15 (d, J=7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.64 (s, 1H), 5.70 (s, 2H), 3.86 (s, 3H), 3.77 - 3.71 (m , 2H), 3.62 - 3.57 (m, 1H), 3.60 (s, 3H), 3.56 (s, 2H), 2.57 - 2.50 (m, 4H), 2.10 - 2.03 (m, 3H), 1.72 - 1.66 (m , 6H), 1.65-1.61 (m, 1H), 1.56 - 1.51 (m, 6H), 0.78 (t, J=7.0 Hz, 3H); MS (ESI): m/z 842.1 (M+H).

Example 160:

At 60°C, a solution of thionyl chloride (2 ml) with dissolved 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (150 mg, 0.49 mmol) was stirred for 2 hours. After concentrating the reaction solution, the residue was dissolved in acetonitrile (3 ml) and trimethylsilylated diazomethane (2Mb n-hexane, 0.24 ml) was added. The resulting reaction solution was stirred at room temperature for 2 hours. Triethylamine (0.13 ml), silver trifluoroacetate (154 mg, 0.70 mmol) and methanol (1 ml) were then added to the above solution at 0°C. The resulting reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered. The filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain a white solid 160a (50 mg, yield: 32.4%). ¹ H NMR (500 MHz, DMSO-d6) δ 7.37 - 7.26 (m, 5H), 6.87 (s, 1H), 4.92 (s, 2H), 3.53 (s, ZN), 2.05 (s, 2H), 1.75 - 1.66 (m, 6H), 1.55 - 1.42 (m, 6H); MS (ESI): m/z 332.4 (M+H).

At room temperature and under a hydrogen atmosphere, a solution of methanol (3 ml) with dissolved compound 160a (100 mg, 0.30 mmol) and palladium hydroxide (10% w/w, adsorbed on activated carbon, 20 mg) was stirred for 1 hour . The reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, the residue was dissolved in dichloromethane (2 ml) and hydrochloric acid (4Mb ethyl acetate, 0.15 ml) was added dropwise. The resulting reaction solution was stirred for half an hour at room temperature. The reaction solution was concentrated to a solid residue and washed with ethyl acetate to obtain a white solid 160b (60 mg, yield: 85.1%). MS (ESI): m/z 198.5 (M+H).

Starting with compound INT-16 and compound 160b, compound 160 is prepared with reference to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.76 (d, J=8.5 Hz, 1H) , 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.40 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.98 - 6.95 (m, 2H), 6.67 (s, 1H ), 5.72 (s, 2H), 3.87 (s, 3H), 3.79 -3.71 (m, 2H), 3.65 - 3.59 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H), 2.60 - 2.54 (m, 2H), 2.14 - 2.03 (m, 3H), 1.99 (s, 3H), 1.96 (s, 2H), 1.76 - 1.69 (m, 1H), 1.60 - 1.46 (m, 12H); MS (ESI): m/z 842.3 (M+H).

Example 161:

Regarding the synthesis of compound 116, compound 161 was prepared by replacing 2-chloro-1,3-dibromobenzene with 2-methyl-1,3-dibromobenzene. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (d,J=1.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.47 (m, 1H ), 7.40 - 7.36 (m, 2H), 7.35 - 7.31 (m, 2H), 7.09 (d, J=7.0 Hz, 1H), 6.93 - 6.88 (m, 2H), 6.65 (s, 1H), 5.72 ( s, 2H), 3.87 (s, 3H), 3.78 - 3.71 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.42 (s, 2H), 2.56 - 2.53 (m, 2H), 2.13 - 2.06 (m, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.76 - 1.68 (m, 6H), 1.69 - 1.63 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m/z 808.1 (M+H).

Example 162:

Starting with INT-16 and trans-4-aminocyclohexanol, compound 162 was prepared according to the synthesis of compound 101. ¹ H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J=1.0 Hz, 1H), 7.76 ( d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.54 -7.48 (m, 4H), 7.35 (s, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.98 - 6.94 (m , 2H), 6.67 (s, 1H), 5.71 (s, 2H), 4.43 (d, J=4.5 Hz, 1H), 3.85 (s, 3H), 3.77 - 3.70 (m, 2H), 3.62 - 3.60 ( m, 1H), 3.56 (s, 3H), 3.42 (s, 2H), 3.35 - 3.32 (m, 1H), 2.55 - 2.52 (m, 1H), 2.36 - 2.33 (m, 1H), 2.10-2.04( m, 6H), 1.84-1.78 (m, 2H), 1.72-1.67 (m, 2H), 1.65-1.59 (m, 1H), 1.31 - 1.20 (m, 2H), 1.14-1.06 (m, 2H); MS (ESI): m/z 774.1 (M+H).

Example 163:

Regarding the synthesis of compound 135, compound 163 was prepared by replacing methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride with methyl trans-4-aminocyclohexanecarboxylate hydrochloride. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 - 7.83 (m, 1H), 7.81 - 7.75 (m, 1H), 7.71 - 7.61 (m, 2H), 7.55 - 7.44 (m, 4H), 7.15 - 7.09 (m, 1H), 6.99 - 6.92 (m, 2H), 5.83 - 5.76 (m, 2H), 3.88 - 3.83 (m, 3H), 3.76 - 3.70 (m, 2H), 3.59 - 3.54 (m, 1H ), 3.40 - 3.38 (m, 2H), 3.37 - 3.36 (m, 3H), 2.51 - 2.50 (m, 2H), 2.35 - 2.30 (m, 1H), 2.10 - 2.03 (m, 6H), 1.90 - 1.81 (m, 3H), 1.76 - 1.69 (m, 2H), 1.68 - 1.61 (m, 1H), 1.24 - 1.16 (m, 4H); MS (ESI): m/z 803.1 (M+H).

Example 164:

Regarding the synthesis of compound 133, compound 164 was prepared by replacing 2-chloro-1,3-dibromobenzene with 2-methyl-1,3-dibromobenzene. ¹ H NMR (500 MHz, DMSO-d6) δ 7.81 - 7.77 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.50 -7.44 (m, 2H), 7.40 - 7.35 (m, 2H), 7.34 - 7.30 (m, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H), 6.65 (s, 1H), 5.70 ( s, 2H), 3.88 (s, 3H), 3.75 - 3.68 (m, 2H), 3.66 -3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.54 (d, J= 6.0 Hz, 2H), 2.15-2.05 (m, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.75 - 1.69 (m, 6H), 1.69 - 1.65 (m, 1H), 1.59 - 1.52 (m, 6H); MS (ESI): m/z 791.0 (M+H).

Example 165:

At -78°C and under a nitrogen atmosphere, diisobutylaluminum hydride (1Mb toluene, 30.6 ml) was slowly added dropwise to a solution in tetrahydrofuran (40 ml) with dissolved 5-bromo-3-fluoro-2-pyridinecarbonitrile (4.1 g , 20.4 mmol). The reaction solution was then stirred at the same temperature for 2 hours. Then, water (50 ml) was added to the reaction solution, and the solution was filtered through diatomaceous earth. The resulting filtrate was extracted with ethyl acetate (50 ml x 2). The combined organic phase was brine (100 ml), washed, dried with anhydrous sodium sulfate, filtered, concentrated. The residue was separated by silica gel column chromatography to give a white solid 165a (2.7 g, yield: 64.9%). MS (ESI): m/z 204.0 (M+H).

Starting with compound 165a, compound 165b is prepared with reference to the synthesis of compound 156a. MS (ESI): m/z 216.3 (M+H).

Starting with compound 165b and 3-bromo-2-methylphenol, compound 165 was prepared with reference to the synthesis of compound INT-10 and compound 133. ¹ H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.83 ( s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.52 - 7.48 (m, 1H), 7.46 - 7.43 (m, 1H), 7.42 - 7.38 (m, 2H) , 7.37 - 7.33 (m, 1H), 7.19 (s, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.66 (s, 1H), 5.72 (s, 2H), 3.92 (s, 3H), 3.78 - 3.69 (m, 2H), 3.67 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 - 3.38 (m, 2H), 2.55 (d, J=6.0 Hz, 2H), 2.15 - 2.06 ( m, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.77 - 1.71 (m, 6H), 1.71 -1.65 (m, 1H), 1.61 - 1.54 (m, 6H); MS (ESI): m/z 791.0 (M+H).

Example 166:

Regarding the synthesis of compound 135, compound 166 was prepared by replacing 2-chloro-1,3-dibromobenzene with 2-methyl-1,3-dibromobenzene. ¹ H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J=1.0 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.50 - 7.46 (m, 1H), 7.41 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 7.09 - 7.05 (m, 1H), 6.95 - 6.89 (m, 2H), 5.82 (s, 2H), 3.88 (s, 3H), 3.80 - 3.72 (m, 2H), 3.65 - 3.55 (m, 1H), 3.38 (s, 3H), 3.35 - 3.30 (m, 2H), 2.54 - 2.50 (m, 2H), 2.13 - 2.05 (m, 3H), 2.02 (s, 6H), 1.76 - 1.70 (m, 6H), 1.69 - 1.64 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m/z 809.1 (M+H).

Example 167:

For the synthesis of compound 133, compound INT-2 was replaced by compound 67a to give compound 167. ¹ H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.57 - 7.49 (m, 4H), 7.39 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.69 (s, 1H) , 5.72 (s, 2H), 3.87 (s, 3H), 3.78 - 3.71 (m, 2H), 3.59 - 3.53 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H), 2.54 - 2.53 (m, 2H), 2.11 - 2.04 (m, 3H), 2.00 (s, 3H), 1.75 - 1.70 (m, 6H), 1.67 - 1.63 (m, 1H), 1.60 - 1.54 (m, 6H); MS (ESI): m/z 828.1 (M+H).

Example 168:

For the synthesis of compound 133, compound INT-2 was replaced by compound INT-18 to give compound 168. ¹ H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.78 (d, J=8.7 Hz, 1H ), 7.55 - 7.50 (m, 4H), 7.39 (s, 1H), 7.19 -7.11 (m, 2H), 7.01-6.97 (m, 2H), 6.69 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.75-3.70 (m, 2H), 3.58 (s, 3H), 3.42 (s, 2H), 3.36 - 3.35 (m, 1H), 2.53 - 2.52 (m, 2H), 2.12 - 2.07 (m, 2H), 2.00 (s, 3H), 1.76 - 1.70 (m, 8H), 1.58 - 1.54 (m, 7H), 1.34 - 1.27 (m, 1H); MS (ESI): m/z 842.1 (M+H).

Example 169:

Regarding the synthesis of compound 137, compound 169 was prepared by replacing 2-chloro-1,3-dibromobenzene with 2-methyl-1,3-dibromobenzene. ¹ H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J=7.5 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.73 - 7.69 (m, 2H), 7.51 - 7.44 (m, 2H) , 7.42 - 7.37 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.81 (s, 2H), 3.90 (s, 3H), 3.75 - 3.67 (m, 2H), 3.66 - 3.59 (m, 1H), 3.37 (s, 3H), 3.35 (s, 2H), 2.58 - 2.54 (m, 2H), 2.14 - 2.06 (m, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.75 - 1.66 (m, 7H), 1.61 - 1.44 (m, 6H); MS (ESI): m/z 792.2 (M+H).

Example 170:

At 0°C, a solution of water (50 ml) with dissolved sodium nitrite (10 g, 147 mmol) was slowly added dropwise to a mixed solution of acetonitrile and water (250 ml, v/v=3/2) with 2-amino Pre-dissolved - 5-bromo-3-methoxypyrazine (2 g, 9.8 mmol) and hydroiodic acid (57 wt.%, 50 ml). The reaction solution was heated to 50°C with stirring and reacted under the same conditions for 16 hours. The reaction solution was neutralized with 20% aqueous sodium hydroxide and extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with saturated sodium thiosulfate and brine (150 ml each), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to give a brown solid 170a (1.55 g, yield: 50.2%).

Under a nitrogen atmosphere and at -40°C, isopropyl magnesium chloride-lithium chloride (1.3 M in tetrahydrofuran solution, 1.83 ml) was slowly added dropwise to the tetrahydrofuran solution (10 ml) with dissolved compound 170a (500 mg, 1. 6 mmol). The reaction solution was further stirred under the same conditions for half an hour, then heated to 15°C, and then N,N-dimethylformamide (1.2 ml) was slowly added. The resulting reaction solution was further stirred for 2 hours at 15°C. The reaction solution was neutralized with citric acid and extracted with ethyl acetate (50 ml x 2). The combined organic phase was brine (100 ml), washed, dried with anhydrous sodium sulfate, filtered, concentrated. The residue was separated by silica gel column chromatography to give a light yellow solid 170b (300 mg, yield: 87.1%). MS (ESI): m/z 217.0 (M+H).

Starting with compound 165b and 3-bromo-2-methylphenol, compound 170 was prepared with reference to the synthesis of compound INT-10 and compound 133. ¹ H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.81 ( s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J=7.4 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.44 - 7.37 (m , 3H), 7.09 (d, J=7.0 Hz, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.95 (s, 3H), 3.87 (s, 2H), 3.63 - 3.60 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.57 (m, 2H), 2.11 (s, 3H), 2.10 - 2.02 (m, 3H), 1.99 (s, 3H), 1.73 - 1.67 (m, 7H), 1.58 - 1.53 (m, 6H); MS (ESI): m/z 792.1 (M+H).

Example 171:

Starting with compound INT-16, trans-4-aminocyclohexanoate methyl chloride and tert-butyldimethylsiloxylacetaldehyde, compound 171 was prepared with reference to the synthesis of compound 125. ¹ H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.80 ( d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.60 - 7.50 (m, 5H), 7.17 (d, J=7.1 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.69 (s , 1H), 5.73 (s, 2H), 3.89 (s, 3H), 3.85 - 3.80 (m, 2H), 3.78 -3.47 (m, 5H), 3.60 (s, 3H), 2.56-2.53 (m, 2H ), 2.16-2.04 (m, 5H), 1.94-1.87 (m, 2H), 1.81-1.65 (m, 4H), 1.63 - 1.53 (m, 1H), 1.31-1.20 (m, 4H); MS (ESI): m/z 832.0 (M+H).

Example 172:

For the synthesis of compound 135, compound INT-2 was replaced by compound INT-18 to give compound 172. ¹ H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.81 (d, J=8.5 Hz, 1H ), 7.71 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 -7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 5.81 (s, 2H), 3.88 (s, 3H), 3.76 - 3.69 (m, 2H), 3.38 (s, 3H), 3.36 - 3.29 (m, 3H), 2.57 - 2.53 (m, 2H), 2.15 - 2.05 (m, 2H), 2.00 (s, 3H), 1.79 - 1.68 (m, 8H), 1.60 - 1.52 (m, 7H), 1.35 - 1.28 (m, 1H); MS (ESI): m/z 843.1 (M+H).

Example 173:

At 0°C, concentrated sulfuric acid (1 ml) with dissolved potassium nitrate (55 mg, 0.54 mmol) was added dropwise to concentrated sulfuric acid (2 ml) with pre-dissolved methyl 3-chloro-4-methylbenzoate (100 mg , 0.54 mmol). The reaction solution was stirred under the same conditions for half an hour. The reaction solution was then poured into ice water and extracted with ethyl acetate (15 ml x 2). The combined organic phase was washed with brine (30 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=10/1, v/v) to obtain a colorless oily substance 173a (100 mg, yield: 80.4%). ¹ H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.93 (s, 1H), 3.83 (s, 3H), 2.44 (s, 3H).

Starting with compound 173a and trans-4-aminocyclohexanoate methyl chloride, compound 173 c was prepared with reference to the synthesis of compound 72 c and reductive amination of compound 44. MS (ESI): m/z 549.0 (M+H).

Add zinc powder (44 mg, 0.67 mmol) to a solution of acetic acid (4 ml) dissolved in compound 173c (74 mg, 0.13 mmol); the resulting reaction solution is heated and stirred at 60°C for 2 hours.

After concentrating the reaction solution, ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml) were added; the organic phase was dried over anhydrous sodium sulfate, and after concentration, compound 173d.MS (ESI): m/z 519.0 (M+H) was obtained.

Starting with compound 173d, compound INT-18, and compound INT-2, compound 173 is prepared by reference to the Suzuki reaction of compound INT-7, the reductive amination reaction of compound INT-3b, and the ester hydrolysis reaction of compound 33. ¹ H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.64 (s, 1H), 7.55 - 7.46 (m, 4H), 7.15 (d, J=7.0 Hz, 1H ), 7.04 (s, 1H), 6.98 - 6.96 (m, 2H), 6.23 (s, 1H), 5.60 (s, 2H), 5.38 (s, 2H), 3.86 (s, 3H), 3.73 (d, J=4.3 Hz, 2H), 3.58 - 3.56 (m, 1H), 3.42 (s, 2H), 2.53 - 2.50 (m, 2H), 2.34-2.30 (m, 1H), 2.23 (brs, 1H), 2.10 -1.95 (m, 3H), 2.03 (s, 3H), 1.92 - 1.86 (m, 2H), 1.77-1.71 (m, 2H), 1.66-1.61 (m, 1H), 1.32-1.18 (m, 4H) ; MS (ESI): m/z 787.8 (M+H).

Example test

Detection of biological activity of PD-1/PD-L1 signaling inhibition at the cellular level

This detection method is used to evaluate the biological activity at the cellular level of the compounds of the present invention. Experimental principle

This detection method uses a luciferase reporter gene method to detect the biological activity of a compound in inhibiting PD-1/PD-L1 signal at the cellular level. PD-1/NFAT reporter - Jurkat cells stably express human PD-1 and express a luciferase reporter gene regulated by the NFAT element; TCR Activator/PD-L1 CHO cells stably express human PD-L1 and TCR activator elements. When the two cell lines were co-cultured, PD-1/PD-L1 binding inhibited the TCR signaling pathway, thereby inhibiting the expression of the downstream luciferase reporter gene controlled by NFAT. When an antibody or PD-1/PD-L1 inhibitor is added, this inhibitory effect is reversed and luciferase is expressed so that the effect of the PD-1/PD-L1 inhibitor on luciferase activity can be detected. Experimental materials and equipment

PD-1/NFAT - Reporter - Jurkat cell (cat. no. 60535) and TCR activator / PD-L1 - CHO cell (cat. no. 60536) were purchased from BPS Bioscience Company; PD-L1 antibody (Atezolizumab, cat. no. A2004) was purchased from Selleck Company. Luciferase detection reagent (ONE-Glo™ Luciferase Assay System, cat. #E6120) was purchased from Promega Company; A multifunctional microplate detector (model SpectraMax i3x) was purchased from the Company's Molecular Devices. Basic experimental procedures

PD-1/NFAT-Reporter-Jurkat and TCR/PD-L1 activator-CHO cells were cultured according to a routine cell culture protocol.

TCR/PD-L1 activator - CHO cells were collected and seeded into a 96-well culture plate at 35,000 cells/well in a medium volume of 100 μl and incubated overnight at 37°C. The next day, the medium was removed, compound was added and incubated for 30 minutes, while vehicle control (dimethyl sulfoxide, DMSO, final concentration 0.1%) and PD-L1 antibody (atezolizumab, final concentration about 10 nM) were positive controls were installed. PD-1/NFAT-reporter-Jurkat cells were then added. After culture for 6 h, luciferase activity was determined according to the instructions for the luciferase detection reagent.

Using the PD-L1 antibody as a positive control, the degree of inhibition of PD-1/PD-L1 binding to the test compound (%) = (chemiluminescence value in compound-treated wells/average chemiluminescence value in solvent control-1 wells)/ (Average chemiluminescence value in the well with PD-L1 antibody/average chemiluminescence value in the control well with solvent - 1) × 100%.

According to the above detection method, the compounds of the present invention were evaluated for their biological activity at the cellular level, and the activity results are shown in the following table.

From the above results, it can be seen that the compounds of the present invention can effectively inhibit PD-1/PD-L1 and have good PD-1/PD-L1 inhibitory activity.

Claims (69)

1. A compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof: wherein L ₁ is selected from: -CR ^A R ^B - and -C(O)-; L ₂ , L ₃ , selected from: -(CR ^C R ^D ) _p , -(CR ^C R ^D ) _p -NR ^z -(CR ^C R ^D ) _q -, -(CR ^C R ^D ) _p -O- (CR ^C R ^D ) _q - and -C(O)-; W ₁ , W ₂ are each independently CR ^L or N; R ¹ is each independently hydrogen or -NR ^a R ^b , or -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene (3-6-membered heterocycloalkyl containing one nitrogen atom) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, -C(O)OR ^a and -C(O)NR ^a R ^b ; R ² represents hydrogen, halogen, nitro, cyano, -NR ^a R ^b , -SO ₂ R ^a , -S(O)R ^a , C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl; R ³ and R ⁴ are each independently hydrogen or halogen; R ⁵ independently represents hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl; Cy represents a benzene ring or a six-membered heteroaryl substituted with 0, 1, 2 or 3 R ⁶ , and the six-membered heteroaryl may optionally contain 1 or 2 nitrogen atoms; wherein R ⁶ represents hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or -O(C ₁ -C ₆ alkyl) substituted with 0, 1, 2 or 3 halogens, -O(C ₀ - C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene)(3-6-membered heterocycloalkyl); wherein R ^L represents: hydrogen, -O(C ₁ -C ₆ alkyl), -O(C ₃ -C ₆ cycloalkyl), halogen or cyano; T represents: -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)-(C ₃ -C ₁₂ cycloalkyl) or -(C ₀ -C ₆ alkylene)-(3-12 membered heterocycle , containing at least one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , cyano C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C(O)R ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O) OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b ; A represents: -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)-(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₆ alkylene)-(3-12 membered heterocycle containing at least one nitrogen atom), -(C ₀ -C ₆ alkylene)-(C ₆ -C ₁₀ aryl) or -(C ₀ -C ₆ alkylene)-(5-10-membered heteroaryl containing at least at least one nitrogen atom) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , cyanoC ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl), C ₃ - C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C(O)R ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O)OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C (O)R ^b ; wherein R ^A , R ^B each independently represents: hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkylene)(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₃ alkylene)(3 -12-membered heterocycle), halogen (C ₁ -C ₆ alkyl) or halogen, or R ^A and R ^B together with the carbon atom to which they are attached form a 3-6 membered ring; R ^C , R ^D each independently represents: hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkylene)(C ₃ -C ₁₂ cycloalkyl), -(C ₀ -C ₃ alkylene)(3-12 -membered heterocycle), halogen (C ₁ -C ₆ alkyl) or halogen, or R ^C and R ^D together with the carbon atom to which they are attached form a 3-6 membered ring; R ^a , R ^b are each independently: hydrogen, C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)OH, -(C ₀ -C ₃ alkylene)( C ₃ -C ₁₂ cycloalkyl), or -(C ₀ -C ₃ alkylene) (3-12 membered heterocycle); R ^z represents hydrogen, C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)OH, -(C ₀ -C ₃ alkylene)(C ₃ -C ₁₂ cycloalkyl ), -(C ₀ -C ₃ alkylene)(C ₆ -C ₁₀ aryl), or halogen(C ₁ -C ₆ alkyl); wherein m, o are each independently 0, 1 or 2; And wherein p, q are each independently 0, 1, 2 or 3. 2. The compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein the compound of Formula (I) has the following structure of Formula (II): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o are as defined in paragraph 1; wherein r is 0, 1, 2 or 3. 3. The compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein the compound of Formula (I) has the following structure of Formula (III): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o are as defined in paragraph 1; wherein W ₃ represents CR ^M or N; wherein ^RM represents: hydrogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or halogen; wherein r is 0, 1 or 2. 4. The compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein the compound of Formula (I) has the structure of Formula (IV): wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ₁ , L ₂ , L ₃ , T, A, W ₁ , W ₂ , m, o are as defined in paragraph 1; wherein W ₄ represents CR ^N or N; wherein R ^N represents: hydrogen, C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or halogen; where r means 0, 1 or 2. 5. Connection according to any one of paragraphs. 1-4, wherein L ₁ is selected from -CR ^A R ^B - and, wherein R ^A and R ^B are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and halogen(C ₁ -C ₆ alkyl), preferably hydrogen. 6. Connection according to any one of paragraphs. 1-4, where L ₂ and L ₃ are each independently selected from -CR ^C R ^D - and -CR ^C R ^D -NR ^z - (CR ^C R ^D ) _q -, wherein q is selected from 0, 1 or 2 and wherein ^RC , ^RD are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and halogen(C ₁ -C ₆ alkyl), preferably hydrogen; R ^z is each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl) and -(C ₀ -C ₃ alkylene)C ₃ -C ₁₂ cycloalkyl. 7. A compound of Formula (I) according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt or isomer thereof, wherein W ₁ and W ₂ are each independently CH or N. 8. Connection according to any one of paragraphs. 3, 5 or 6, where W ₃ represents CH or N. 9. Connection according to any one of paragraphs. 4-6, where W ₄ represents CH or N. 10. Connection according to any one of paragraphs. 1-9, where T represents -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)-(C ₃ -C ₁₂ cycloalkyl) or -(C ₀ -C ₆ alkylene)-(3- A 12-membered heterocycle containing at least one heteroatom selected from the group consisting of a nitrogen atom and an oxygen atom) substituted with 0, 1, 2 or 3 substituents, and where the substituents are selected from: cyano, oxo, halogen, C ₁ - C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , cyanoC ₁ -C ₆ alkyl, halogen(C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C (O)R ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O)OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b , with R ^a and R ^b each independently represents hydrogen, C ₁ -C ₆ alkyl or halogen (C ₁ -C ₆ alkyl); And A represents: -(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkylene)-(C ₃ -C ₁₂ cycloalkyl) or -(C ₀ -C ₆ alkylene)-(3-12 membered heterocycle , containing at least one nitrogen atom) substituted with 0, 1, 2 or 3 substituents; and wherein the substituents are selected from: cyano, oxo, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₆ alkylene)OR ^a , cyanoC ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl), C ₃ -C ₈ cycloalkyl, -(C ₀ -C ₆ alkylene)C(O)R ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O) OR ^a , -(C ₀ -C ₆ alkylene)NR ^a R ^b , -C(O)NR ^a R ^b , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b , wherein R ^a and R ^b are each independently hydrogen or C ₁ -C ₆ alkyl. 11. A compound according to claim 10, where T represents a C ₁ -C ₆ alkyl, a C ₃ -C ₁₂ cycloalkyl or a 3-12 membered heterocycle containing at least one heteroatom selected from the group consisting of a nitrogen atom and a oxygen, substituted with 0, 1 or 2 substituents, where the substituents are selected from: cyano, oxo, -OR ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C( O)OR ^a , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b , where R ^a and R ^b are each independently hydrogen, C ₁ - C ₆ alkyl or halogen (C ₁ -C ₆ alkyl), and A represents: -(C ₁ -C ₆ alkyl), C ₃ -C ₁₂ cycloalkyl or 3-12 membered heterocycle containing at least one nitrogen atom, substituted with 0, 1 or 2 substituents; wherein the substituents are selected from: cyano, oxo, OR ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a , -(C ₀ -C ₆ alkenyl)C(O)OR ^a , -NR ^a SO ₂ R ^b , -C(O)NR ^a SO ₂ R ^b and -NR ^a C(O)R ^b , wherein R ^a and R ^b are each independently hydrogen or C ₁ -C ₆ alkyl. 12. The connection according to claim 11, where T is: , , optionally substituted with 0, 1 or 2 substituents, the substituents being selected from C ₁ -C ₆ alkyl, -OR ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a and -(C ₀ -C ₆ alkenyl) C(O)OR ^a where R ^a is hydrogen or C ₁ -C ₆ alkyl, preferably hydrogen where α is 1, 2 or 3, and A represents: , , optionally substituted with 0, 1 or 2 substituents, the substituents being selected from C ₁ -C ₆ alkyl, -OR ^a , -(C ₀ -C ₆ alkylene)C(O)OR ^a and -(C ₀ -C ₆ alkenyl) C(O)OR ^a where R ^a is hydrogen or C ₁ -C ₆ alkyl, preferably hydrogen, where α is 1, 2 or 3, where α is 1, 2, 3 or 4. 13. The compound according to claim 12, where T represents the following groups: and A represents the following groups: . 14. The connection according to claim 11, where T, A each independently represents optionally substituted with 0, 1 or 2 substituents, the substituents being selected from: C ₁ -C ₆ alkyl, -OR ^a and halogen, where R ^e , R ^{a are} each independently hydrogen or C ₁ -C ₆ alkyl; where α represents 1, 2, 3 or 4. 15. The connection according to claim 14, where T, A each independently represents where R ^e represents hydrogen or C ₁ -C ₆ alkyl, where α represents 1, 2, 3 or 4. 16. The connection according to claim 11, where T, A each independently represents: . 17. Connection according to any one of paragraphs. 1-16, where R ¹ represents -O(C ₁ -C ₆ alkyl), -O(C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene)( 3-6 membered heterocycloalkyl containing one nitrogen atom) substituted with 0, 1, 2 or 3 substituents, where the substituents are selected from: cyano and oxo. 18. Connection according to any one of paragraphs. 1-16, where R ² represents hydrogen, halogen, nitro, cyano, -SO ₂ ^Ra , C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl; where R ^a represents hydrogen, C ₁ -C ₆ alkyl or halogen (C ₁ -C ₆ alkyl). 19. Connection according to any one of paragraphs. 1-16, where R ³ , R ⁴ each independently represent hydrogen or halogen. 20. Connection according to any one of paragraphs. 1-16, where R ⁵ represents hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, halogen (C ₁ -C ₆ alkyl) or C ₃ -C ₆ cycloalkyl. 21. Connection according to any one of paragraphs. 1-16, where R ⁶ represents hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or -O(C ₁ -C ₆ alkyl) substituted with 0, 1, 2 or 3 halogens, -O (C ₀ -C ₆ alkylene)(C ₃ -C ₆ cycloalkyl) or -O(C ₀ -C ₆ alkylene)(3-6-membered heterocycloalkyl). 22. Connection according to any one of paragraphs. 1-21, where R ^L represents hydrogen or halogen. 23. Connection according to any one of paragraphs. 1-21, wherein ^RM , ^RN are each preferably independently hydrogen. 24. A compound selected from the group consisting of: 25. A pharmaceutical composition for the prevention or treatment of a disease or condition that responds to inhibition of PD-L1 binding to PD-1, containing a compound according to any one of paragraphs. 1-24 and optionally a pharmaceutically acceptable carrier. 26. Use of a compound according to any one of paragraphs. 1-24 or the pharmaceutical composition of claim 25 for the manufacture of a medicament for the prevention or treatment of a disease or condition that responds to inhibition of PD-L1 binding to PD-1. 27. Use according to claim 26, wherein the disease or condition is selected from tumors, cancer, viral infections, diseases associated with inflammation, and autoimmune diseases. 28. A method of treating a disease or condition that responds to inhibition of PD-L1 binding to PD-1, comprising administering a compound according to any one of claims. 1-24, or the pharmaceutical composition according to claim 25 to a mammal in need thereof. 29. A method of inhibiting the binding of PD-L1 to PD-1, including exposure to a compound according to any one of claims. 1-24 or the pharmaceutical composition according to claim 25 for PD-L1 and/or PD-1.