WO2019120256A1 - Five-membered heteroaryl ring derivative, pharmaceutical composition containing same, and application thereof - Google Patents

Abstract

The present invention discloses a five-membered heteroaryl ring derivative (I), and an isomer, a solvate, a crystalline form of the solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable salt thereof. The five-membered heteroaryl ring derivative of the present invention has good IDO inhibitory effect, and can effectively treat, alleviate, and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, and autoimmune diseases.

Description

Five-membered heteroaryl ring derivative, its pharmaceutical composition and application

This application claims priority from Chinese Patent Application No. CN201711404528.5, filed on Dec. 22, 2017. The present application claims priority to Chinese Patent Application No. CN201810102631.2, filed on Feb. 1, 2018. The present application claims priority to Chinese Patent Application No. CN201810148831.1, filed on Feb. 13, 2018. The present application claims priority to Chinese Patent Application No. CN201810182186.5, filed on March 6, 2018. The present application claims priority from Chinese Patent Application No. CN201810325713.3, filed on Apr. 12, 2018. The present application claims priority to Chinese Patent Application No. CN201810062990.X filed on Jan. 23, 2018. The present application claims priority to Chinese Patent Application No. CN201810103001.7, filed on Feb. 1, 2018. The present application claims priority to Chinese Patent Application No. CN201810256091.3, filed on March 27, 2018. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The present invention relates to a five-membered heteroaryl ring derivative, a pharmaceutical composition thereof and use thereof.

Background technique

Indoleamine 2,3-dioxygenase (IDO) is an immunomodulatory enzyme produced by some alternative activated macrophages and other immunoregulatory cells (also used by many tumors as a strategy to destroy immunity) in humans. The middle is encoded by the IDO gene. Its role is to break down the essential L-tryptophan to kynurenine. The depletion of tryptophan and its metabolites lead to a strong inhibition of the immune response, causing the cessation of T cell growth, blocking the activation of T cells, inducing T cell apoptosis and increasing the production of regulatory T cells. The metabolic pathway from tryptophan to kynurenine has now been established as a key regulatory pathway for innate and adaptive immunity.

A large number of preclinical studies have shown that this immune tolerance pathway is activated in tumor immunity, autoimmunity, infection, transplant rejection, and allergies. The increased activity of cancer cell IDO is now considered to be an important factor in the proliferation and metastasis of cancer. Studies have shown that IDO inactivates tumor-specific cytotoxic T lymphocytes or can no longer attack cancer cells in patients. In fact, many human cancers, such as prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, and gastric cancer, Ovarian cancer, brain cancer, lung cancer, etc., all overexpress human IDO. Inhibition of IDO can reverse the inhibition of tumor immune function, resulting in an effective anti-tumor immune response. Because IDO inhibitors can activate T cells to enhance the body's immune function, IDO inhibitors have therapeutic effects on many diseases, including tumor resistance and rejection, chronic infections, HIV infection and AIDS, autoimmune diseases or conditions, such as Rheumatoid arthritis, immune tolerance and prevention of fetal rejection in the uterus. Inhibitors of IDO can also be used to treat neurological or neuropsychiatric disorders or disorders such as depression (Protula et al, 2005, Blood, 106: 238290; Munn et al, 1998, Science 281: 11913).

A large number of preclinical and clinical studies have shown that inhibition of IDO and its pathways can enhance the body's immunity and significantly improve the anti-tumor efficacy of various chemotherapeutic drugs and the efficacy of other immunosuppressive diseases (CJDAustin and LMRendina) , Drug Discovery Today 2014, 1-9). IDO-/- mouse knockout is feasible and the mice are healthy, which means that IDO inhibition may not cause serious toxicity by the mechanism of action.

IDO small molecule inhibitors currently under development to treat and prevent the above-mentioned IDO-related diseases, for example, PCT Patent Application WO 99/29310 discloses a method of altering T cell-mediated immunity, including by administering a certain amount of 1-methyl DL. Tryptophan or p-(3 benzofuranyl)-DL-alanine alters the extracellular concentration of local tryptophan and tryptophan metabolites (Munn, 1999). Compounds capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) are disclosed in WO2004/0234623; U.S. Patent Application No. 2004/0234623 discloses the treatment of cancer by administering an IDO inhibitor in combination with other treatments or The method of infecting patients.

In view of the large number of experimental data indicating that IDO inhibitors have good treatment and prevention for immunosuppression, tumor suppression, chronic infection, viral infection including HIV infection, autoimmune diseases or disorders and intrauterine fetal rejection, it is best to adopt A method of inhibiting IDO activity to inhibit inhibition of tryptophan. When a malignant tumor or a virus such as HIV inhibits T cells, an IDO inhibitor can be used to enhance the activity of T cells. In addition, IDO chemistry has been well studied and its x-ray crystal structure has also been resolved, which has helped to better use structure-based drug design and structural optimization of drugs. IDO is currently a very attractive target for therapeutic intervention.

Summary of the invention

The technical problem to be solved by the present invention is to provide a novel five-membered heteroaryl ring derivative, a pharmaceutical composition thereof and use thereof. The five-membered heteroaryl ring derivative of the present invention has a good IDO inhibitory action, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, and autoimmune diseases.

Although the activity of the compound represented by the formula (I) disclosed in the present invention is manifested by inhibition of IDO, its mechanism of inhibiting IDO activity has not been thoroughly studied, and it is not excluded that it has inhibition of TDO (tryptophan 2, 3 - the possibility of dioxygenase activity. Thus, all references to "IDO inhibitors" in the present invention may include the following meanings: IDO inhibitors, TDO inhibitors, or dual inhibitors of IDO and TDO.

The present invention provides a five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;

Wherein Cy is a pyrrole ring or an imidazole ring; when Cy is a pyrrole ring, X is NR, Y is CR ₁ , Z is CR ₂ , or X is CR ₁ , Y is NR, Z is CR ₂ '; When it is an imidazole ring, X is NR, Y is CR ₁ , and Z is N;

A is

{E.g

{E.g

{E.g

{E.g

R is independently H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S( O) ₂ R _a , C _1-6 alkyl {for example C _1-3 alkyl, for example methyl, ethyl, n-propyl or isopropyl, also for example methyl or isopropyl}, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl {eg C _3-5 cycloalkyl, again such as cyclopropyl, cyclobutyl or cyclopentyl, again such as cyclopropyl}, 3 -8 membered heterocycloalkyl, C _6-10 aryl or 5-6 membered heteroaryl; said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 The cycloalkyl or 3-8 membered heterocycloalkyl group is unsubstituted or optionally substituted at one position by one or more groups selected from the group consisting of: hydrazine, halogen, hydroxy {when it is substituted for C _{1- In the case of 6} alkyl, the substituted C _1-6 alkyl group may be 2-hydroxyethyl}, fluorenyl, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} alkylamino, -C _1-6 alkylene-OH, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C(O)NH( C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _1-6 alkyl, -S(O) _0-2 -C _1-6 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S(O) ₂ -N (C _1-6 alkyl ) _2, C _3-8 cycloalkyl, and 3-8 membered heterocycloalkyl of one or more; R _a is independently H, C _1-6 alkyl, C _3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, or 3-8 membered heterocycloalkyl C _1-6 alkyl;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD ₃ ) or 2-deuteropropene- 2-based {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium, halogen {e.g., fluorine, chlorine, bromine or iodine, again such as bromine}, cyano, amido, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said phenyl or 5-6 membered heteroaryl is unsubstituted or optionally substituted with 1 to 3 groups at any position, Said group is one or more of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy and halogenated C _1-3 alkoxy;

R ₂ 'is independently hydrogen, deuterium, halogen {eg fluorine, chlorine, bromine or iodine, again such as iodine} or C _1-3 alkyl {eg methyl, ethyl, n-propyl or isopropyl, for example methyl};

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen, deuterium, halogen {e.g., fluorine, chlorine, bromine or iodine, further such as fluorine}, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy or halogen C _{1- 3} alkoxy.

In some embodiments, in the crystalline form of the five-membered heteroaryl ring derivative (I) solvate or the five-membered heteroaryl ring derivative (I) solvate, the definition of the solvate can be as follows An undescribed group can be as described in any of the above schemes:

The solvate may be a hydrate and/or a methanolate, and may also be a hydrate or a water-methanol compound.

In the hydrate, the molar ratio of the water to the five-membered heteroaryl ring derivative (I) may be from 1.0 to 1.5.

In the methanolate, the molar ratio of the methanol to the five-membered heteroaromatic ring derivative (I) may be from 1.0 to 1.5.

In the water/methanol compound, the molar ratio of the water to the five-membered heteroaromatic ring derivative (I) may be from 1.0 to 1.5, and the methanol and the five-membered heteroaryl ring are The molar ratio of the derivative (I) may be from 1.0 to 1.5. The molar ratio of the water to the five-membered heteroaryl ring derivative (I) may be 1.0, and the molar ratio of the methanol to the five-membered heteroaryl ring derivative (I) may be 1.0.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

(E.g

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

When Cy is a pyrrole ring, X is NR, Y is CR ₁ , and Z is CR ₂ , the five-membered heteroaryl ring derivative (I) is as

Shown.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

When Cy is a pyrrole ring, X is CR ₁ , Y is NR, and Z is CR ₂ ', the five-membered heteroaryl ring derivative (I) is as

Shown.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

When Cy is an imidazole ring, X is NR, Y is CR ₁ , and Z is N, the five-membered heteroaryl ring derivative (I) is as

Shown.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Said

for

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is an imidazole ring.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R is independently H.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R is independently C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or alternatively substituted with one or more hydroxy groups Anywhere.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ }.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ }.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{1 is} independently methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ }.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{1 is} independently hydrogen, methyl, ethyl, propyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ }.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{1 is} independently t-butyl.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{2 is} independently hydrogen, deuterium, halogen or cyano.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{2 is} independently hydrogen, deuterium or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{2 is} independently hydrogen or deuterium.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R ₂ 'is independently hydrogen, deuterium or C _1-3 alkyl.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{3 is} independently

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{3 is} independently

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{5 is} independently hydrogen or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

R _{5 is} independently hydrogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium, halogen or cyano;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring;

A is

R is independently H;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium, halogen or cyano;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring;

A is

R is independently H;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium or halogen;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring;

A is

R is independently H;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium or halogen;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring, X is NR, Y is CR ₁ , and Z is CR ₂ ;

A is

R is independently H;

R _{1 is} independently methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen or deuterium;

R _{3 is} independently

R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is a pyrrole ring, X is CR ₁ , Y is NR, and Z is CR ₂ ';

A is

R is independently H;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 'is} independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Cy is an imidazole ring;

A is

R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

R is independently C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or alternatively substituted with one or more hydroxy groups Any position;

R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ };

R _{2 is} independently hydrogen, deuterium, halogen or cyano;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen or halogen.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

A is

R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

R _{1 is} independently t-butyl;

R _{2 is} independently hydrogen, deuterium, halogen or cyano;

R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

R _{3 is} independently

R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

R _{5 is} independently hydrogen or halogen.

In some embodiments, Cy is a pyrrole ring, X is NH, Y is CR ₁ and Z is CR ₂ .

In some embodiments, Cy is a pyrrole ring, X is CR ₁ , Y is NH, and Z is CR ₂ .

In some embodiments, R ₁ is methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD ₃ ) or 2-deutero-2-yl {-CD(CH ₃ ) ₂ } .

In some embodiments, R ₁ is t-butyl.

In some embodiments, R ₁ is trifluoromethyl or difluoromethyl.

In some embodiments, A is

The present invention provides a five-membered heteroaryl ring derivative (II), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;

Among them, A is

Z is N or CR ₂ ;

R is H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S(O) ₂ R _a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl or 5 a 6-membered heteroaryl group; the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group is unsubstituted or Optionally substituted at any position by one or more groups selected from the group consisting of: hydrazine, halogen, hydroxy, thiol, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, -C _1-6 alkylene-OH, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C(O NH(C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _1-6 Alkyl, -S(O) _0-2 -C _1-6 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S(O) One or more of _2- N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl; R _a is H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, or 3-8 Heterocycloalkyl C _1-6 alkyl;

R ₁ is methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ), 2-deutero-2-yl {-CD(CH ₃ ) ₂ }; , R ₁ is a trifluoromethyl group, or a difluoromethyl group;

R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted or optionally substituted with 1 to 3 groups at any position, the group being an anthracene, a halogen, an amino group, a cyano group, C One or more of _1-3 alkyl, C _1-3 alkoxy and halogenated C _1-3 alkoxy;

R ₃ is

R ₄ is methyl, cyano, methoxy, ethoxy, trifluoromethoxy, or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

The combination including any of the Z, R, R ₁ , R ₃ and A embodiments as described in the formula (I) is included in the scope of the structural formula shown in the formula (II) of the present invention.

All of the embodiments described below by the formula (II) are included in the scope of the structural formula shown in the formula (II) of the present invention.

In some embodiments of formula (II), said Z is N.

In some embodiments of formula (II), said Z is CR ₂ .

In some embodiments of formula (II), said R is H.

In some embodiments of formula (II), R is a substituted or unsubstituted methyl group.

In some embodiments of formula (II), R is a substituted or unsubstituted ethyl group.

In some embodiments of formula (II), R is substituted or unsubstituted isopropyl.

In some embodiments of formula (II), R is a substituted or unsubstituted cyclopropyl group.

In some embodiments of formula (II), R is a substituted or unsubstituted tert-butyl group.

In some embodiments of formula (II), wherein said methyl, ethyl, isopropyl, cyclopropyl or t-butyl is unsubstituted or optionally substituted with one hydroxy group. position.

The five-membered heteroaryl ring derivative (III), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:

Among them, A is

Or, A is

Or, A is

R ₁ is methyl, ethyl or isopropyl; or, R ₁ is propyl, trifluoromethyl, difluoromethyl; or R ₁ is deuterated methyl (-CD ₃ ); or, R ₁ Is 2-deutero-2-yl {-CD(CH ₃ ) ₂ }; or, R ₁ is a tert-butyl group;

R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

R ₃ is

R ₄ is methyl, methoxy, cyano or trifluoromethoxy; or R ₄ is ethoxy or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

Combinations including any of the R ₁ , R ₂ , R ₃ and A embodiments as described in formula (I) are included within the scope of the structural formulas of the invention as shown in formula (III).

All of the embodiments described below according to formula (III) are included in the scope of the structural formula shown in formula (III) of the present invention.

In some embodiments of formula (III), the A is

Wherein R ₄ and R ₅ are as defined above.

In some embodiments of formula (III), the A is

Wherein R ₄ and R ₅ are as defined above.

In some embodiments of formula (III), the A is

Wherein R ₄ and R ₅ are as defined above.

In some embodiments of formula (III), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (III), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (III), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (III), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (III), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (III), R ₁ is methyl.

In some embodiments of formula (III), R ₁ is ethyl.

In some embodiments of formula (III), R ₁ is isopropyl.

In some embodiments of formula (III), R ₁ is t-butyl.

In some embodiments of formula (III), said R ₂ is hydrogen.

In some embodiments of formula (III), said R ₂ is deuterium.

In some embodiments of formula (III), said R ₂ is chloro.

In some embodiments of formula (III), said R ₂ is bromine.

In some embodiments of formula (III), said R ₂ is iodine.

In some embodiments of formula (III), said R ₂ is cyano.

In some embodiments of formula (III), said R ₂ is methyl.

In some embodiments of formula (III), said R ₄ is methyl.

In some embodiments of formula (III), R ₄ is methoxy.

In some embodiments of formula (III), said R ₄ is difluoromethoxy.

In some embodiments of formula (III), said R ₄ is trifluoromethoxy.

In some embodiments of formula (III), R ₄ is cyano.

In certain embodiments of formula (III), said R ₅ is hydrogen.

In certain embodiments of formula (III), said R ₅ is fluoro.

In certain embodiments of formula (III), said R ₅ is chloro.

In certain embodiments of formula (III), said R ₅ is bromo.

In some embodiments of formula (III), R ₅ is cyano.

In some embodiments of formula (III), R ₅ is amino.

In some embodiments of formula (III), said R ₅ is methyl.

In some embodiments of formula (III), said R ₅ is methoxy.

In some embodiments of formula (III), R ₅ is trifluoromethoxy.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, R, R ₁ and R ₂ are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, R and R ₁ are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, Z, R, R ₁ and R3 are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:

Wherein, A, R ₁ and R ₂ are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, R ₁ , R ₂ and R ₃ are as defined above.

The present invention provides a five-membered heteroaryl ring derivative (IV), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;

Among them, A is

R is H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S(O) ₂ R _a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, or a 5-6 membered heteroaryl group; said C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, or 3-8 membered heterocycloalkyl group Substituted or selectively 1 to 3 are selected from the group consisting of: hydrazine, halogen, hydroxy, decyl, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, - C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-6 alkyl), -C(O)N (C _{1 -6} alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _1-6 alkyl, -S(O) _0-2 -C _1-6 alkyl, - S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S(O) ₂ -N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl And a substituent of a 3-8 membered heterocycloalkyl group at any position; R _a is H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 An aryl group, a 5-6 membered heteroaryl group, a C _3-8 cycloalkyl C _1-6 alkyl group, or a 3-8 membered heterocycloalkyl C _1-6 alkyl group;

R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, deuterated methyl, or 2-deutero-2-yl;

R ₂ 'is hydrogen, deuterium, halogen, or C _1-3 alkyl;

R ₃ is

R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

Combinations including any of R, R ₁ , R ₂ ', R ₃ and A embodiments as described in formula (I) are included in the scope of the structural formulas of the invention as shown in formula (IV).

All of the embodiments described below by the formula (IV) are included in the scope of the structural formula shown in the formula (IV) of the present invention.

In some embodiments of formula (IV), said R is H.

In some embodiments of formula (IV), R is a substituted or unsubstituted methyl group.

In some embodiments of formula (IV), R is a substituted or unsubstituted ethyl group.

In some embodiments of formula (IV), R is substituted or unsubstituted isopropyl.

In some embodiments of formula (IV), R is a substituted or unsubstituted cyclopropyl group.

In some embodiments of formula (IV), R is a substituted or unsubstituted tert-butyl group.

In some embodiments of formula (IV), wherein said methyl, ethyl, isopropyl, cyclopropyl or t-butyl group is unsubstituted or optionally substituted with 1 hydroxy group. position.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:

Among them, A is

R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD ₃ ), or 2-deutero-2-yl {- CD(CH ₃ ) ₂ }; or, R ₁ is a tert-butyl group;

R ₂ 'is hydrogen, deuterium, halogen, or C _1-3 alkyl;

R ₃ is

R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

Combinations including any of R, R ₁ , R ₂ ', R ₃ and A embodiments as described in formula (I) are included in the scope of the structural formula shown in formula (V) of the present invention.

All of the embodiments described below by the formula (V) are included in the scope of the structural formula shown in the formula (V) of the present invention.

In some embodiments of formula (V), the A is

Wherein R ₄ and R ₅ are as defined above.

In some embodiments of formula (V), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (V), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (V), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (V), the A is

Among them, the definition of R ₄ is as described above.

In some embodiments of formula (V), R ₁ is methyl.

In some embodiments of formula (V), R ₁ is isopropyl.

In some embodiments of formula (V), R ₁ is deuterated methyl.

In some embodiments of formula (V), R ₁ is 2-deutero-2-yl.

In some embodiments of formula (V), said R ₂ 'is hydrogen.

In some embodiments of formula (V), said R ₂ 'is deuterium.

In some embodiments of formula (V), said R ₂ 'is chloro.

In some embodiments of formula (V), said R ₂ 'is bromine.

In some embodiments of formula (V), said R ₂ 'is iodine.

In some embodiments of formula (V), said R ₂ 'is methyl.

In certain embodiments of formula (V), said R ₄ is methyl.

In some embodiments of formula (V), said R ₄ is methoxy.

In some embodiments of formula (V), said R ₄ is difluoromethoxy.

In some embodiments of formula (V), said R ₄ is trifluoromethoxy.

In some embodiments of formula (V), said R ₄ is cyano.

In certain embodiments of formula (V), said R ₅ is hydrogen.

In certain embodiments of formula (V), said R ₅ is fluoro.

In certain embodiments of formula (V), said R ₅ is chloro.

In certain embodiments of formula (V), said R ₅ is bromo.

In some embodiments of formula (V), R ₅ is cyano.

In certain embodiments of formula (V), said R ₅ is amino.

In certain embodiments of formula (V), said R ₅ is methyl.

In some embodiments of formula (V), said R ₅ is methoxy.

In certain embodiments of formula (V), said R ₅ is trifluoromethoxy.

The pyrrole derivative (I), an isomer thereof, a solvate, a crystal form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably have a structural formula:

Wherein, A, R, R ₁ and R ₂ ' are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, R, R ₁ , R ₂ ' and R ₃ are as defined above.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:

Wherein, the definitions of A, R ₁ and R ₂ ' are as described above.

The following preferred schemes are included in the definition of the compound as shown in formula (V-1):

In some preferred embodiments, A is

In some preferred embodiments, R ₁ is methyl, isopropyl, deuterated methyl or 2-deutero-2-yl.

In some preferred embodiments, R ₂ 'is H or D.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably having a structural formula for:

Wherein, A, R ₁ , R ₂ ' and R ₃ are as defined above.

The following preferred schemes are included in the definition of a compound as shown in formula (V-2) or (V-3):

In some preferred embodiments, A is

In some preferred embodiments, R ₁ is methyl, isopropyl, deuterated methyl or 2-deutero-2-yl.

In some preferred embodiments, R ₂ 'is H or D.

In some preferred embodiments, R ₃ is

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Among them, A is

Or, A is

Or, A is

R ₁ is methyl, ethyl or isopropyl; or, R ₁ is propyl, trifluoromethyl, difluoromethyl; or R ₁ is deuterated methyl (-CD ₃ );

R ₂ is hydrogen, deuterium, halogen, cyano, amino, acyl, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or a 5-6 membered heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl , C _1-3 alkoxy, halo or a C _1-3 alkoxy group substituted at any position;

R ₃ is

R ₄ is methyl, methoxy, cyano or trifluoromethoxy; or R ₄ is ethoxy or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Among them, A is

Or, A is

Or, A is

R ₁ is methyl, ethyl or isopropyl; or, R ₁ is propyl, trifluoromethyl, difluoromethyl; or R ₁ is deuterated methyl (-CD ₃ ); or, R ₁ Is 2-deutero-2-yl (-CD(CH ₃ ) ₂ );

R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

R ₃ is

R ₄ is methyl, methoxy, cyano or trifluoromethoxy; or R ₄ is ethoxy or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Among them, A is

Or, A is

Or, A is

R ₁ is methyl, ethyl or isopropyl; or, R ₁ is propyl; or, R ₁ is deuterated methyl (-CD ₃ ); or R ₁ is 2-deutero-2-yl (-CD(CH ₃ ) ₂ ); or, R ₁ is a tert-butyl group;

R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

R ₃ is

R ₄ is methyl, methoxy, cyano or trifluoromethoxy; or R ₄ is ethoxy or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

In some embodiments, the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:

Among them, A is

Or, A is

R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD ₃ ), or 2-deutero-2-yl {- CD(CH ₃ ) ₂ };

R ₂ 'is hydrogen, deuterium, halogen, or C _1-3 alkyl;

R ₃ is

R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt Heteroaromatic ring derivative (I) {The "five-membered heteroaryl ring derivative (I)" herein refers not only to the "five-membered heteroaryl ring derivative (I)" in the above sentence, but also to the above "its". Unless otherwise stated, the full text is the same as any of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt The heteroaromatic ring derivative (I) is preferably one of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, the five The heteroaromatic ring derivative (I) may be any of the following structures:

The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, the five The heteroaromatic ring derivative (I) may be any of the following structures:

The solvate of the five-membered heteroaryl ring derivative (I) is any of the following structures:

The solvate of the five-membered heteroaryl ring derivative (I) may be the following compound:

The unit cell parameters are: a=18.3907(5), α=90°; b=7.1972(2), β=95.737(1)°; c=19.6381(5)°, γ=90°; space group, P2 /n;

or,

The unit cell parameters are: a=10.7762(18), α=105.536(7)°; b=12.762(2), β=91.288(8)°; c=12.914(2), γ=90.951(10)° ; space group, P-1.

The solvate of the five-membered heteroaryl ring derivative (I) may be the following compound:

Its parameters are:

or,

Its parameters are:

The present invention also provides the five-membered heteroaryl ring derivative (II), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt. The preparation method is any one of the following methods.

Method 1: in a solvent, a compound I-b and a compound X-1 are subjected to a condensation reaction under the action of a base;

Wherein, A, Z, R, R ₁ and R ₃ are as defined above.

In the method shown in the reaction formula 1, the conditions and steps of the condensation reaction may be the conditions and steps of the condensation reaction conventional in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably dichloromethane or N. N-dimethylformamide; the solvent is preferably used in an amount of 5 to 20 mL / mmol of the compound Ib; the base is preferably N, N-diisopropylethylamine, N-methylmorpholine or triethylamine; The molar ratio of the base to the compound Ib is preferably 1:1 to 5:1; to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine, the 4-dimethylaminopyridine and the 4-dimethylaminopyridine may be added to the reaction system. The molar ratio of the compound Ib is preferably from 0.05:1 to 0.2:1. The condensing agent in the condensation reaction is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'-diisopropylcarbodiimide (DIC), more preferably EDCI, the molar ratio of the condensing agent to the compound Ib is preferably 1:1 to 3:1; the temperature of the reaction is preferably 0 to 30 ° C The reaction can be detected by TLC, generally as the end point of the reaction when the compound Ib disappears, preferably 0.5 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, preferably including the following steps: After quenching with ice water, the reaction system is diluted with a solvent, the organic phase is separated, the organic phase is dried, the organic solvent is removed under reduced pressure, and the residue is purified by a conventional purification method, for example, silica gel column chromatography, flash column chromatography or prep-HPLC. . The steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.

The preparation method of the compound I-b can be a conventional method for such a reaction in the art, and preferably includes the following steps: deprotecting the compound I-a in a solvent;

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R, R ₁ and Z are as defined above.

In the method of Reaction Scheme 2, the deprotection of Compound I-a can be carried out under acidic or basic conditions. The acidic conditions are preferably a hydrochloric acid/alcohol system or a hydrogen chloride/alcohol system, preferably methanol or ethanol. In the alkaline condition: the solvent may be a solvent commonly used in such reactions in the art, preferably ethanol, methanol, tetrahydrofuran, water, or a mixed solvent of any two to four kinds of ethanol, methanol, tetrahydrofuran and water, more preferably ethanol. / Water mixed solvent, wherein the volume ratio of ethanol to water is preferably 1:0.5 to 2:1. The amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL/mmol of the compound I-a. The base is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, and the molar ratio of the base to the compound Ia is preferably from 2:1 to 10:1, and the base is usually used. An aqueous solution of a base is prepared by first dissolving in water in a mixture solvent. The temperature of the deprotection reaction is preferably 20 to 100 ° C, more preferably 60 to 100 ° C, still more preferably 80 to 100 ° C. The progress of the reaction can be detected by TLC, and is generally the end point of the reaction when the compound I-a disappears, preferably 10 minutes to 2 hours. After the completion of the reaction, the product may be further purified by post-treatment, preferably including the following steps: after removing the organic solvent under reduced pressure, the residue is sufficiently acidified, the obtained solid is filtered, and the filter cake is dried in vacuo to give compound I-b.

Method 2: performing amine transesterification of compound I-a and compound X-1 under the action of trimethylaluminum in a solvent;

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R, R ₁ and Z are as defined above.

In the method shown in Reaction Scheme 3, the conditions and steps of the condensation reaction may be the conditions and steps of the conventional amine transesterification reaction in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably toluene, The solvent is preferably used in an amount of 5 to 20 mL/mmol of compound Ia; the molar ratio of trimethylaluminum to compound X-1 is preferably 2:1 to 3:1. The molar ratio of the compound X-1 to the compound Ia is preferably 1:1 to 3:1; the temperature of the reaction is preferably room temperature to solvent reflux; the temperature of the reaction is more preferably 90 to 110 ° C; the reaction can be passed The TLC is detected, generally as the end point of the reaction when the compound Ia disappears, preferably 1 to 24 hours; after the end of the reaction, the product may be further purified by post-treatment, the purification method includes silica gel column chromatography, flash column layer Purification by precipitation or prep-HPLC. The steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.

Compound I-a can be synthesized by the methods shown in Reaction Schemes 4 to 8, and Compound 1-b can also be synthesized by the method shown in Reaction Scheme 6:

Wherein, Pg is a carboxy protecting group, preferably a C ₁ - ₆ alkyl, more preferably methyl or ethyl; A and R ₁ are defined as described above in.

In the method shown in Reaction Scheme 4, the following conditions are preferred: Step 1: Solvent (preferably tetrahydrofuran), Compound I-a-2 is reacted with Y-3 in the presence of a base (preferably sodium hydrogen) to give Compound 1-a-3. Step 2: In a solvent (preferably ethanol), the compound I-a-3 and ammonium acetate are heated under reflux and stirred for 2 to 4 hours, and after workup, the compound I-a (H/NH) is obtained.

Wherein, Pg is a carboxy protecting group, preferably a C ₁ - ₆ alkyl, more preferably methyl or ethyl; R ₁ (D) is a deuterated or 2- deutero-2-yl, A, and The definition of R ₁ is as described above.

In the method shown in Reaction Scheme 5, the following conditions are preferred: Step 1: Compound I-a-3 and ammonium acetate are heated under reflux in deuterated methanol for 2 to 4 hours, and post-treated to give compound I-a (D/D). Step 2: I-a (D/D) was stirred at room temperature for 1 to 3 hours in a trifluoroacetic acid / dichloromethane system to afford compound I-a (H/D).

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A and R ₁ are as defined above.

In the method shown in Reaction Scheme 6, the following conditions are preferred: Step 1: Solvent (preferably tetrahydrofuran), Compound Ia (H/NH) or Ib (H/NH) is reacted with N-bromosuccinimide to obtain a compound. Ia (Br) or Ib (Br), or reacted with N-iodosuccinimide to give compound Ia (I) or Ib (I). Step 2: Condition (1), the compound obtained in Step 1 and cuprous cyanide are reacted in N,N-dicarboximide to obtain Compound Ia(CN) or Ib(CN); or Condition (2), Step 1 The obtained compound is reacted with a deuterated carboxylic acid/triethylamine/tetratriphenylphosphine palladium system or a heavy water/cerium carbonate/tetratriphenylphosphine palladium system in a deuterated dimethyl sulfoxide solution to obtain a compound Ia(D) or Ib. (D).

Wherein, Pg is a carboxy protecting group, preferably a C ₁ - ₆ alkyl, more preferably methyl or ethyl; A and R ₁ are defined as described above in.

In the method shown in Reaction Scheme 7, the following conditions are preferred: Step 1: Compound I-a-2 and pyridine are reacted with Dess-Martin oxidizing agent to obtain Compound I-a-4 in a solvent (preferably dichloromethane). Step 2: The reaction of the solvent (preferably acetic acid), 1-a-4, ammonium acetate and Y-4 under microwave heating gives compound I-a (N/NH).

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl or ethyl group; L is a bromine, iodine, boric acid or boronic acid ester; R is a C _1-6 alkyl group; The definitions of A and R ₁ are as described above.

In the method shown in Reaction Scheme 8, when L is bromine or iodine, the following conditions are preferred: in the solvent (preferably N,N-dimethylformamide), and the compound Ia(NH) and RL are under basic conditions (preferably) Sodium hydrogen) is stirred at room temperature for 1 to 6 hours, and after work-up, compound Ia is obtained.

In the method shown in Reaction Scheme 8, when L is a boric acid or a boric acid ester, the following conditions are preferred, in a solvent (preferably 1,2-dichloroethane), and the compound Ia(NH) and RL are under basic conditions (preferably) Sodium carbonate) is reacted with copper acetate and 2,2-bipyridine under microwave heating (temperature preferably 100 to 120 ° C) for 2 to 6 hours, and after treatment, compound Ia is obtained.

The present invention also provides the five-membered heteroaryl ring derivative (IV), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt. The preparation method is any one of the following methods.

Method 1: in a solvent, a compound II-b and a compound X-1 are subjected to a condensation reaction under the action of a base;

Wherein, A, R ₁ , R ₂ and R ₃ are as defined above.

In the method of the reaction formula 9, the conditions and steps of the condensation reaction may be the conditions and steps of the condensation reaction conventional in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably dichloromethane or N. N-dimethylformamide; the solvent is preferably used in an amount of 5 to 20 mL/mmol of compound II-b; the base is preferably N,N-diisopropylethylamine, N-methylmorpholine or triethylamine The molar ratio of the base to the compound II-b is preferably 1:1 to 5:1; to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine may also be added to the reaction system, the 4-di The molar ratio of methylaminopyridine to compound II-b is preferably from 0.05:1 to 0.2:1. The condensing agent in the condensation reaction is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'-diisopropylcarbodiimide (DIC), more preferably EDCI, the molar ratio of the condensing agent to the compound II-b is preferably 1:1 to 3:1; the temperature of the reaction is preferably 0 to 30 ° C; the reaction can be detected by TLC, generally as the end of the reaction when the compound II-b disappears, preferably 0.5 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, preferably including The following steps: the reaction system is quenched with ice water, diluted with a solvent, the organic phase is separated, the organic phase is dried, the organic solvent is removed under reduced pressure, and the residue is purified by conventional purification means, for example, silica gel column chromatography, flash column chromatography or Prep-HPLC purification. The steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.

The preparation method of the compound II-b can be a conventional method of such a reaction in the art, and preferably comprises the steps of: deprotecting the compound II-a in a solvent;

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R ₁ and R ₂ are as defined above.

In the method shown in Reaction Scheme 10, the deprotection of the compound II-a can be carried out under acidic or basic conditions. The acidic conditions are preferably a hydrochloric acid/alcohol system, a hydrogen chloride/alcohol system or a trifluoroacetic acid/dichloromethane system, preferably methanol or ethanol. In the alkaline condition: the solvent may be a solvent commonly used in such reactions in the art, preferably ethanol, methanol, tetrahydrofuran, water, or a mixed solvent of any two to four kinds of ethanol, methanol, tetrahydrofuran and water, more preferably ethanol. / Water mixed solvent, wherein the volume ratio of ethanol to water is preferably 1:0.5 to 2:1. The amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL/mmol of the compound II-a. The base is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, and the molar ratio of the base to the compound II-a is preferably from 2:1 to 10:1, usually under normal conditions. An aqueous solution of a base is prepared by dissolving a base in water in a solvent of the mixture. The temperature of the deprotection reaction is preferably 20 to 100 ° C, more preferably 60 to 100 ° C, still more preferably 80 to 100 ° C. The progress of the reaction can be detected by TLC, and is generally used as the end point of the reaction when the compound II-a disappears, preferably 10 minutes to 2 hours. After the completion of the reaction, the product may be further purified by post-treatment, preferably including the following steps: after removing the organic solvent under reduced pressure, the residue is sufficiently acidified, the obtained solid is filtered, and the filter cake is dried in vacuo to obtain compound II- b.

Method 2: performing amine transesterification of compound II-a and compound X-1 under the action of trimethylaluminum in a solvent;

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R ₁ , R ₂ and R ₃ are as defined above.

In the method shown in Reaction Scheme 11, the conditions and steps of the condensation reaction may be the conditions and steps of the conventional amine transesterification reaction in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably toluene, The solvent is preferably used in an amount of 5 to 20 mL/mmol of compound II-a; the molar ratio of trimethylaluminum to compound X-1 is preferably 2:1 to 3:1. The molar ratio of the compound X-1 to the compound II-a is preferably 1:1 to 3:1; the temperature of the reaction is preferably room temperature to solvent reflux; the temperature of the reaction is more preferably 90 to 110 ° C; The product can be detected by TLC, generally as the end point of the reaction when the compound II-a disappears, preferably 1 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, the purification method includes silica gel column chromatography. , Flash column chromatography or prep-HPLC purification. The steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.

In the first or second method, in the compound II-a, when R is H and R ₂ is H, it can be synthesized by the method shown in Reaction Scheme 12 or 14; the R is H, R ₂ is halogen, or D It can be synthesized by the method shown in Reaction Scheme 15; when R is a methyl group or an ethyl group, and R ₂ is H, it can be synthesized by the method shown in Reaction Scheme 16. In the compound II-b, when R is H and R ₂ is halogen or D, it can be synthesized by the method shown in Reaction Scheme 14.

Wherein, Pg is a carboxy protecting group, preferably a C ₁ - ₆ alkyl, more preferably methyl or ethyl; defined as above A, R and R ₁ are the.

In the method shown in Reaction Scheme 12, the following conditions are preferably employed, in which a compound II-a-3 and a compound Y-5 or Y-6 are obtained by a suzuki coupling reaction in a solvent (preferably a mixed solvent of dioxane and water). Compound II-a (H/H), the suzuki coupling reaction conditions are conventional conditions in the art, wherein the catalyst is preferably tetrakistriphenylphosphine palladium.

Compound II-a-3 can be synthesized by the method shown in Reaction Scheme 13:

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and R ₁ is a methyl group, an ethyl group, a propyl group or an isopropyl group.

In the method shown in Reaction Scheme 13, the following conditions are preferred, Step 1: Solvent (preferably tetrahydrofuran), Compound II-a-1 in the presence of a base (preferably sodium ethoxide and diisopropylethylamine) and Y-7 The reaction gives the compound II-a-2. Step 2: In a solvent (preferably a mixed solvent of methyl tert-butyl ether and dichloromethane), the compound II-a-2 is reacted with hydrobromic acid to give a compound II-a-3 after workup.

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl, ethyl or t-butyl group; R ₁ is hydrogen, methyl, deuterated methyl, ethyl or isopropyl .

In the method shown in Reaction Scheme 14, the following conditions are preferred, in a solvent (preferably tetrahydrofuran and/or dimethyl sulfoxide), and compound Y-8 is in the presence of a base (preferably potassium t-butoxide or sodium hydrogen) and compound 1- A-5 is closed, and after treatment, compound Ia (H/H) is obtained.

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl group or an ethyl group; and A and R ₁ are as defined above.

In the method shown in Reaction Scheme 15, the following conditions are preferred, Step 1: Solvent (preferably tetrahydrofuran), Compound II-a (H) or II-b (H) is reacted with N-bromosuccinimide to obtain a compound. II-a (Br) or II-b (Br), or reacted with N-iodosuccinimide to give compound II-a (I) or II-b (I), or with N-chlorobutane The imide reaction gives compound II-a (Cl) or II-b (Cl). Step 2: Compound II-a (Br or I) or II-b (Br or I) obtained in the previous step in deuterated dimethyl sulfoxide solution and deuterated formic acid / triethylamine / tetratriphenylphosphine palladium system Or heavy water / cesium carbonate / tetratriphenylphosphine palladium system reaction to give compound II-a (D) or II-b (D).

Wherein Pg is a carboxy protecting group, preferably a C _1-6 alkyl group, more preferably a methyl or ethyl group; and X is iodine or bromine;

In the method shown in Reaction Scheme 16, the compound II-a (H/H) is subjected to a nucleophilic substitution reaction under a base to obtain a compound II-a (H) in a solvent (preferably acetone). The conditions of the nucleophilic substitution reaction are conventional conditions in the art, and the base is preferably potassium carbonate or cesium carbonate.

Method 3: in the solvent, under the action of a base, the compound IV (Br) or IV (I) is deuterated to obtain the compound IV (D);

Wherein R ₁ is methyl, ethyl, propyl or isopropyl; and A and R ₃ are as defined above.

In the method shown in the reaction formula 17, the conditions and steps of the deuteration reaction may be the conditions and steps of the deuteration reaction conventional in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably deuterated two Sulfuric acid, the solvent is preferably used in an amount of 10 to 50 mL / mmol of compound IV (Br) or VI (I); the reaction is preferably the following reaction system: deuterated formic acid / triethylamine / tetratriphenylphosphine palladium system or Heavy water / cesium carbonate / tetratriphenylphosphine palladium system; the reaction temperature is preferably 100 ~ 130 ° C; the reaction can be detected by TLC, generally as the end of the reaction when the compound IV (Br) or IV (I) disappears Preferably, after 1 to 24 hours; after the end of the reaction, the product may be further purified by post-treatment, which comprises silica gel column chromatography, flash column chromatography or prep-HPLC purification. The steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.

The pharmaceutically acceptable salt of the five-membered heteroaryl ring derivative (I) can be synthesized by a general chemical method.

In general, the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising the above-mentioned five-membered heteroaryl ring derivative (I), and isomer thereof Form, solvate, crystalline form of the solvate, prodrug, stable isotope derivative or pharmaceutically acceptable salt.

In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.

In the pharmaceutical composition, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.

The pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment. Preferred are liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) and the like.

In order to shape the pharmaceutical composition in the form of a tablet, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; wetting agents such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Such as pure talc, stearate, boric acid powder and polyethylene glycol. It is also possible to use a usual coating material to prepare a sugar-coated tablet, a gelatin film tablet, a casing tablet, a film-coated tablet, a two-layer film tablet, and a multilayer tablet.

In order to shape the pharmaceutical composition in the form of a pill, any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.

In order to shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .

In order to prepare a pharmaceutical composition in the form of an injection, the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood. Any of the commonly used carriers in the art can also be used in the preparation of the injection. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. In addition, usual solubilizers, buffers, analgesics, and the like can be added.

In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.

In the present invention, the administration method of the pharmaceutical composition is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.

The present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition in the preparation of a guanamine 2,3-dioxygenase inhibitor (IDO1 inhibitor). The indoleamine 2,3-dioxygenase inhibitor (IDO1 inhibitor) refers to inhibition of IDO1 activity or expression (including abnormal activity or overexpression of IDO1, and abnormal activity of IDO pathway), and reverses IDO1 - a compound that mediates immunosuppression. The IDO1 inhibitor can inhibit IDO1.

The present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition in the preparation of a medicament.

The present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition for the preparation of a medicament for stimulating T cell proliferation.

The present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the pharmaceutical composition is formulated to treat, alleviate and/or prevent "viral or other infections (eg, skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (" For example: the application of drugs such as rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).

The five-membered heteroaryl ring derivative and/or pharmaceutically acceptable salt of the formula (I) as described in any of the embodiments described in the present invention, or the pharmaceutical composition is prepared for treatment and amelioration And/or use in a medicament for preventing a disease associated with IDO1, the use comprising administering to the individual (e.g., a patient) a therapeutically effective amount of a compound or pharmaceutical composition of the invention. The IDO1 mediated related disease means that any disease, condition or disorder can be treated, alleviated and/or prevented with an IDO1 inhibitor. Particularly mentioned diseases caused by IDO1 mediated immunosuppression, including but not limited to: viruses or other infections (eg, skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.) ), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).

The present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition for the preparation of a medicament for the treatment, amelioration and/or prevention of a related disease mediated by indoleamine 2,3-dioxygenase. The use comprises administering to the individual (e.g., a patient) a therapeutically effective amount of a compound or pharmaceutical composition of the invention. The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a combination thereof Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease. The 2,3-dioxygenase-mediated related disease refers to a disease caused by 2,3-dioxygenase-mediated immunosuppression, which may include: a virus or other infection (eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).

The invention also provides a method of treating, ameliorating and/or preventing a related disease mediated by indoleamine 2,3-dioxygenase, comprising administering to a subject a therapeutically required amount of said five-membered heteroaryl ring Derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition. The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a combination thereof Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease. The 2,3-dioxygenase-mediated related disease refers to a disease caused by 2,3-dioxygenase-mediated immunosuppression, which may include: a virus or other infection (eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).

The invention also provides a method of treating, ameliorating and/or preventing a viral or other infection, cancer, or autoimmune disease comprising administering to a subject a therapeutically required amount of the five-membered heteroaryl ring derivative (I) a form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, an isomer, a solvate thereof, a solvate, or the pharmaceutical composition. The five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a combination thereof Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease.

The other kind of therapeutic agent for treating cancer may be a single-administered therapeutic dosage form with the five-membered heteroaryl ring derivative (I) or a therapeutic dosage form administered sequentially.

The other types of therapeutic agents and/or therapeutic methods for treating cancer may include, but are not limited to, tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, Hormone and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (eg, specific kinase inhibitors), immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiotherapy One or more.

The tubulin inhibitor may be selected from, but not limited to, a vinblastine series (eg, vinblastine, vincristine, vinorelbine, vindesine), a taxane (docetaxel, paclitaxel), and a One or more of eribulin sulfonate.

The alkylating agent may be selected from one or more of the group consisting of nitrogen mustard, ethyleneimine derivative, methanesulfonate, nitrosourea, and triazene.

The topozyme I/II inhibitor may be selected from, but not limited to, one or more of irinotecan, topotecan, doxorubicin, and dexrazoxane.

The platinum compound may be selected from, but not limited to, cisplatin and/or carboplatin.

The anti-metabolites may be selected from, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, for example: methotrexate, 5-fluorouracil, fluorouridine, arabinose One or more of cytidine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin, and gemcitabine.

The immunotherapeutic agent can be selected from, but not limited to, anti-tumor vaccines (eg, synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cytokine treatments (eg, IL2 and GM- One or more of CSF), chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulator, tumor microenvironmental modulator, and anti-angiogenic factor. The immunostimulatory antibodies can include, but are not limited to, 1) protein antagonists that inhibit T cell activity (eg, immunological checkpoint inhibitors): CTLA4 (eg, ipilimumab and tremelimumab), PD-1 (eg, pembrolizumab and nivolumab) ), PD-L1 (eg, durvalumab, avelumab, and atezolizumab), PD-L2, LAG3, TIM1, TIM3, TIM4, CD73, Galectin9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA , one or more of 2B4, CD48, GARP, PD1H, and LAIR1; 2) Protein agonists that stimulate T cell activity: B7-1, B7-2, CD28, ICOS, ICOS-L, GITR, GITRL, CD70 One or more of DR3, CD28H, GITR, OX40, OX40L, 4-1BB (CD137), CD27 and CD40. 3) Receptor antagonists acting on NK cells: KIR (eg, Iirilumab); 4) Receptor antagonists that inhibit or deplete macrophages or monocytes: CSF-1R.

The signal transduction pathway inhibitor (STI) may be selected from, but not limited to, a BCR/ABL kinase inhibitor, an epidermal growth factor receptor inhibitor, a her-2/neu receptor inhibitor, an AKT family kinase inhibitor, PI3K Signal pathway inhibitors, and cell cycle checkpoint inhibitors.

The angiogenesis inhibitor can be selected from, but not limited to, one or more of a VEGF/VEGFR signaling pathway inhibitor, a Src family kinase inhibitor, a Src signaling pathway inhibitor, and a c-Fes kinase inhibitor.

The viral infection may include: from influenza, hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) ), infections caused by viruses such as poliovirus, varicella-zoster virus, coxsackie virus, or human immunodeficiency virus (HIV).

The cancer can include a solid tumor or a liquid tumor.

In some embodiments, the solid tumor can include, but is not limited to, the eye, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovaries (including those from Stromal cells produced by epithelial cells, germ cells and interstitial cells), bladder, testis, spinal cord, kidney (including adenocarcinoma, nephroblastoma), mouth, lips, throat, oral cavity (including squamous cell carcinoma), nasal cavity, Small intestine, colon, rectum, parathyroid gland, gallbladder, bile duct, cervix, heart, inferior gland, bronchus, liver, ureter, vagina, anus, larynx, thyroid (including thyroid cancer and medullary carcinoma), esophagus, nasopharynx Pituitary, salivary gland, adrenal gland, intraepithelial neoplasia of the head and neck (including Bowen's disease and Paget's disease), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, osteosarcoma), skin (including melanoma, Related tumors such as Kaposi's sarcoma, basocellular carcinoma and squamous cell carcinoma.

In some embodiments, the liquid tumor can include, but is not limited to, lymphoid tissue (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytes). Lymphoma, T-cell and B-cell chronic lymphocytic leukemia), chronic lymphocytic leukemia, myeloid leukemia and AIDS-related leukemia and other related tumors.

The autoimmune diseases may include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, knot Pontic vasculitis, nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membrane proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, malignancy) Anemia (including anemia, hyperthyroidism, etc.), liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection (eg One or more of AIDS, malaria, etc.

The present invention also provides a crystalline form, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable form of the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate or a solvate thereof. Or a method of inhibiting tryptophan degradation in a pharmaceutical composition comprising the steps of inhibiting degradation of tryptophan in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I) The system is a tissue, mammal or cell tissue that expresses IDO.

Said mammal, preferably a human.

In the present invention, when the bonding to a substituent is shown to intersect the bonding of two atoms in the linking ring, then such a substituent may be bonded to any bondable ring atom on the ring.

In the present invention, unless otherwise indicated, the term "substituted at one position by one or more groups" means that any one or more of the hydrogen atoms of one or more atoms specified on the group are represented by the specified group. Substituted, provided that the normal valence of the specified atom is not exceeded, the substitutions are all reasonable substitutions that are common in the art. In the present invention, "substituted at one position by one or more groups" is preferably "substituted at any position by 1 to 4 groups", more preferably "substituted at any position by 1 to 3 groups"; for example: Substitution at any position by 1 to 3 groups means that one, two or three identical or different substituents may be reasonably substituted at any position.

Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings:

The term "alkyl" refers to a saturated straight or branched hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6, from 1 to 5, from 1-4, from 1-3, or 1 to 2 carbon atoms, representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl , hexyl, heptyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, and various isomers thereof. The term "alkylene" refers to an alkyl group which may be attached as a linking bond to two other groups, which may be either straight-chain or branched.

The term "cycloalkyl" refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds). A 3-10 membered monocycloalkyl group is preferred, and a 3-8 membered monocycloalkyl group is more preferred, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, Cyclododecyl, cyclohexenyl. The cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.

The term "heterocycloalkyl" refers to a 3-20 membered non-aromatic cyclic group consisting of a carbon atom and a saturated or partially unsaturated (containing 1 or 2 double bonds) consisting of a hetero atom selected from nitrogen, oxygen or sulfur. The cyclic group may be a monocyclic or bicyclic group. In the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and a nitrogen, carbon or sulfur atom in the heterocycloalkyl group. It can optionally be oxidized. The nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt. The "heterocycloalkyl group" is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group. For example: aziridine, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like. The heterocycloalkyl group can be attached to the parent molecule through any ring atom on the ring. The above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.

The term "alkoxy" refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group. Thus, "alkoxy" includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.

The term "cycloalkylalkyl" refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group. Thus, "cycloalkylalkyl" embraces the definitions of alkyl and cycloalkyl as described above.

The term "heterocycloalkylalkyl" refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl as described above.

The term "aryl" refers to any stable 6-20 membered monocyclic or polycyclic aromatic group, preferably a _C6-10 aryl group; for example: phenyl, naphthyl, and the like. The aryl group is unsubstituted or alternatively selected from 1 to 3 selected from the group consisting of hydrazine, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, cyano, hydroxy, The substituent of the amino group, the halogenated C _1-4 alkyl group, or the halogenated C _1-4 alkoxy group is substituted at any position.

The term "heteroaryl" refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A bicyclic structure, preferably a 5-6 membered heteroaryl group. In the present invention, the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1 , 2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl and the like. The heteroaryl group is unsubstituted or alternatively selected from 1 to 3 selected from the group consisting of hydrazine, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, cyano, hydroxy The substituent of the amino group, the halogenated C _1-4 alkyl group or the halogenated C _1-4 alkoxy group is substituted at any position.

The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond. The term "_C2-4" alkenyl refers to an alkenyl group having 2 to 4 carbon atoms, and the term " _C2-6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl and propenyl. , butenyl, 2-methylbutenyl and cyclohexenyl.

The term "alkynyl" refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond. The term "C _2-6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "haloalkyl" refers to an alkyl group optionally substituted by halogen. Thus, "haloalkyl" embraces the definitions of the above halo and alkyl.

The term "haloalkoxy" refers to an alkoxy group optionally substituted by halogen. Thus, "haloalkoxy" includes the definitions of the above halo and alkoxy.

The term "amido" refers to -C(O)N(R) ₂ wherein R is hydrogen or C _1-6 alkyl.

The term "ester group" refers to -C(O)OR, wherein R is hydrogen or _C1-6 alkyl.

The term "cyano" refers to -CN.

The term "amino" refers to -NH ₂ . The term "alkylamino" means that at least one hydrogen atom on the amino group is substituted by an alkyl group, including but not limited to: -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₂ CH ₃ ) ₂ .

The term "solvate" means a substance which is formed by the compound I with a suitable solvent. The solvent is preferably water and/or an organic solvent.

The isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms. A substituted derivative or an isotopically substituted derivative obtained by substituting an oxygen atom of any of Formula I with 1-3 oxygen atoms.

By "prodrug" is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.

"Pharmaceutically acceptable salts" as described herein are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-sulfonate, mandelate, pyruvate, stearin Acid salt, ascorbate, salicylate. When the compound of the present invention contains an acidic group, the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.

As used herein, "isomer" means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention. In the present invention, a compound of the formula I or a salt thereof, in stereoisomeric form (for example, which contains one or more asymmetric carbon atoms), is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted. The scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. The invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers. The invention includes all combinations and subsets of stereoisomers of all the specific groups defined above. The invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.

The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.

The reagents and starting materials used in the present invention are commercially available.

Detailed ways

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The structures of all compounds of the invention can be identified by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS).

^{The 1} H NMR chemical shift (δ) was recorded in PPM (10 ^-6 ). ¹ H NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), deuterated dimethyl sulfoxide (DMSO-d ₆ ) or deuterated formic acid (DCOOD), tetramethylsilane (TMS) as internal Standard.

Low resolution mass spectrometry (MS) was determined by an Agilent 1200 HPLC/6120 mass spectrometer with an ESI source using XBridge C18, 4.6 x 50 mm, 3.5 μm, gradient elution conditions: 80-5% solvent A ₁ and 20-95 % solvent B ₁ (1.8 minutes), then 95% solvent B ₁ and 5% solvent A ₁ (more than 3 minutes), the percentage being the volume percentage of a solvent to the total solvent volume. Solvent A ₁ : an aqueous solution of 0.01% trifluoroacetic acid (TFA); solvent B ₁ : a solution of 0.01% trifluoroacetic acid in acetonitrile; the percentage is the volume fraction of the solute in the solution. Gradient elution conditions 2: 80-5% solvent A ₂ and 20-95% solvent B ₂ (1.5 minutes), then 95% solvent B ₂ and 5% solvent A ₂ (more than 2 minutes), the percentage is a certain solvent Volume percent of total solvent volume. Solvent A ₂ : 10 mM aqueous solution of ammonium hydrogencarbonate; solvent B ₂ : acetonitrile.

All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, thin layer silica gel plates, and rapid separation machines.

High performance liquid chromatography (prep-HPLC) was carried out using Shimadzu LC-20 preparative liquid chromatography at a detection wavelength of 214 nm & 254 nm; flow rate: 9.0 mL / min. The column is: waters xbridge Pre C18, 10 μm, 19 mm x 260 mm. Elution conditions (basic conditions): Solvent A: 10 mM aqueous solution of ammonium hydrogencarbonate; solvent B: acetonitrile.

Silica gel column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.

The thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.

Rapid separator (Flash column chromatography) (flash system / Cheetah ^TM) using Agela Technologies MP200, supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.

All compounds of the present invention can be analyzed by ultra performance liquid chromatography (UPLC) using a Waters ACQUITY Hclass platform: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7μm, mobile phase A: acetonitrile, mobile phase B: 5 mm aqueous potassium dihydrogen phosphate solution (pH adjusted to 2.5 with phosphoric acid). Gradient elution time 15 min, flow rate: 0.4 mL/min, detection wavelength: 214 nm & 254 nm; column temperature: 40 ° C; injection volume 1 μL; gradient elution conditions are as follows:

Time (minutes)	Flow rate phase A (%)	Flow rate phase B (%)
0.00	10	90
5.00	40	60
7.00	90	10
13.00	90	10
13.10	10	90
15.00	10	90

The configuration of the compound of the present invention can be confirmed by single crystal diffraction experiments, and the diffraction intensity data is collected by a Bruker SMART APEX-II diffractometer for single crystal diffraction, CuKα radiation, graphite monochromator, single conduit diameter Φ=0.50 mm, compound crystal and CCD. Detector distance d=60.3mm, tube pressure 40kV, tube flow 30mA, scanning method:

Scan, collect the total number of diffraction points, the number of independent diffraction points, and observe the number of points (|F| ² ≥ 2σ|F| ² ). The direct structure (Shelxs97) is used to analyze the crystal structure to obtain all non-hydrogen atom positions. The least squares method is used to correct the structural parameters and discriminate the atom types. The geometric calculation method and the difference Fourier method are used to obtain the positions of all hydrogen atoms, and finally the stereo configuration of the compounds is determined. .

Example 1: 3-(Difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid

Step 1: Ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (2.8 g, 17.93 mmol) was suspended in tetrahydrofuran (30 mL). EtOAc (1. %), stirring for 30 minutes, adding methyl iodide (3.8 g, 26.9 mmol) dropwise, stirring at ambient temperature for 16 hours, then adding sodium hydrogen (1.1 g, 26.9 mmol, 60%), stirring for 30 minutes, adding methyl iodide dropwise (3.8g, 26.9mmol), the mixture was stirred at 25 ° C for additional 16 hours, then added with water (20 mL). Concentrated by filtration, the crude product was purified by silica gel column chromatography ( silica gel eluting with triethylamine) (8% methanol / dichloromethane) to give 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid Ethyl ester (280 mg, yield: 9%) was an off-white solid. [M+H] ⁺ 171.2, ¹ H NMR (400MHz, CDCl ₃ ): δ 8.24 (br.s, 1H), 7.55 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.77 ( s, 3H), 1.35 (t, J = 7.2 Hz, 3H).

Step 2: 3-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (250 mg, 1.47 mmol), potassium carbonate (609 mg, 4.41 mmol) and ethyl difluorobromoacetate (596 mg, 2.94 mmol) It was suspended in N,N-dimethylformamide (5 mL), and the mixture was stirred at 55 ° C for 16 hours, diluted with ethyl acetate (100 mL), washed with water (x3) and brine, dried over anhydrous sodium sulfate Concentrated by filtration and purified by prep-TLC (petrole ether / ethyl acetate = 4 / 1) to give ethyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylate (116 mg , Yield: 36%) as a pale yellow solid. [M+H] ⁺ 221.2, ¹ H NMR (400MHz, CDCl ₃ ): δ 7.75 (s, 1H), 7.17, 6.99, 6.81 (3s, 1H, -CHF ₂ ), 4.29 (q, J = 7.2 Hz , 2H), 3.81 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

Step 3: Ethyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylate (110 mg, 0.50 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) Tetrahydrofuran (2.0 mL) and water (1.0 mL) were stirred at 50 ° C for 2 hours, then methanol (1.0 mL) was added, and the mixture was stirred at room temperature overnight, and most of the organic solvent was evaporated to dryness. Ethyl ester (5 mL×3), EtOAcjjjjjjjjjjj %) is a white solid. [M+H] ⁺ 193.0.

Example 2: Synthesis of Compound 1a/1b

Step 1: -78 ° C, 1,4-dioxaspiro[4.5]decane-8-one (6.0 g, 38.4 mmol), N-phenylbis(trifluoromethanesulfonimide) under nitrogen atmosphere. (16.5 g, 46.1 mmol) of methyl tert-butyl ether (95 mL) was added dropwise to a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.0 M, 23 mL). hour. The reaction was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc /1) Purification gave Compound 1.1 (10.8 g, yield: 97%) as a yellow oil.

Step 2: Compound 1.1 (8.0 g, 27.8 mmol), bispinacol borate (9.17 g, 36.1 mmol), potassium acetate (8.18 g, 83.3 mmol), sodium bromide (1.14 g, 11.1 mmol) and _{Pd (dppf) Cl 2 (1.0g} , 1.4mmol) in 1,4-dioxane (100 mL) was stirred at reflux overnight. The reaction system was cooled to room temperature, and the solvent was evaporated,jjjjjjjjjjjjj .

Step 3: Compound 1.2 (3.22 g, 12.1 mmol), 4-chloro-6-fluoroquinoline (2.1 g, 13.8 mol), potassium carbonate (3.85 g, 27.3 mmol) and Pd (PPh ₃ ). ₄ (0.22 g, 0.19 mmol) of water / 1,4-dioxane (50 mL, 4 / 1) mixture was stirred under reflux overnight, then the mixture was concentrated and extracted with ethyl acetate (60 mL × 3) The organic layer was dried over anhydrous sodium sulfate (MgSO4)

Step 4: To a solution of compound 1.3 (2.0 g, 7.02 mmol) in isopropanol (30 mL) was added Pd / C (200 mg, 10%), under a hydrogen atmosphere (hydrogen balloon) at 55 ° C Stir overnight. Then, the reaction system was filtered through Celite to remove Pd/C, and the filtrate was concentrated under reduced pressure to give Compound 1.4 (1.9 g, yield: 90%) as a yellow oil. m/z: [M+H] ⁺ 288.0.

Step 5: A mixture of compound 1.4 (2.0 g, 6.. <RTI ID=0.0></RTI> </RTI> <RTIgt; The reaction system was then concentrated under reduced pressure. The residue was purified from ethyl acetate (EtOAc) (EtOAc) The residue was purified by flash column chromatography (EtOAc:EtOAc:EtOAc

Step 6: Mixing compound 1.5 (750 mg, 3.09 mmol) and p-methylbenzenesulfonylmethyl isocyanide (784 mg, 4.02 mmol) in ethylene glycol dimethyl ether (20 mL) and ethanol (2 mL) under ice bath. Potassium tert-butoxide (943 mg, 7.73 mmol) was added to the solution. The reaction system was stirred at room temperature overnight, then quenched with EtOAc EtOAc (EtOAc) The organic layer was washed with brine, filtered and evaporated. The residue was purified by flash column chromatography ( petroleum ether / ethyl acetate = 3 / 1) to afford compound 1.6a (263 mg, less polar, single stereo configuration) and 1.6b (300 mg, more polar, single solid Configuration), all of them are colorless oils.

Step 7: To a solution of the compound 1.6a (263 mg, 1.04 mmol) in tetrahydrofuran (10 mL) was added dropwise to a solution of lithium tetrahydroaluminum in tetrahydrofuran (0.85 mL, 2.5 M), and the mixture was stirred at 0 ° C. hour. Then, water (0.3 mL), 15% aqueous sodium hydroxide solution (0.3 mL), water (1.0 mL) was added dropwise, filtered, and the filter cake was rinsed with tetrahydrofuran. The obtained filtrate was dried over anhydrous sodium sulfate and evaporated. m/z: [M+H] ⁺ 259.0.

Substituting 4-chloro-6-fluoroquinoline in step 3 with 4-bromo-2,6-lutidine or 4-bromo-2-methylpyridine by the method of synthesizing compound 1a, in step 6 The resulting cis and trans isomers were not separated into a single stereo configuration, and finally compounds 2 and 3 were obtained, both of which were cis-trans isomer mixtures:

Example 5: Synthesis of Compound 4

Step 1: Dissolve bromoacetone (2.0 g, 14.7 mmol), ethyl cyanoacetate (1.66 g, 14.7 mmol), sodium ethoxide (1 g, 14.7 mmol) and diisopropylethylamine (1.89 g, 14.7 mmol) The reaction solution was stirred at room temperature overnight in anhydrous tetrahydrofuran (40 mL). The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate. The organic phase was separated and the organic phase dried with anhydrous sodium The residue was purified by flash column chromatography eluting elut elut elut elut elut

Step 2: Compound 4.1 (1.2 g, 7.09 mmol) was dissolved in a mixed solvent of methyl tert-butyl ether (3 mL) and dichloromethane (2 mL), and the solution was slowly added dropwise to hydrobromic acid at 5 ° C ( In a 33%, 12 mL) solution of acetic acid, the resulting mixture was stirred at this temperature for 15 minutes. TLC (petroleum ether / ethyl acetate = 4 / 1) was found to be complete. The reaction solution was extracted with dichloromethane, and the organic layer was separated and evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] ⁺ 233.0.

Step 3: Compound 4.2 (200 mg, 0.86 mmol), (2-methoxypyridin-3-yl)boronic acid (263 mg, 1.72 mmol), potassium carbonate (356 mg, 2.58 mmol), tetratriphenylphosphine palladium (92.4 A suspension of mg, 0.08 mmol) of 1,4 dioxane (3 mL) and water (1 mL) was subjected to microwave reaction at 120 ° C for 1 hour. The reaction solution was then filtered, and the filtrate was extracted with ethyl acetate. The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] ⁺ 261.0.

Step 4: A solution of compound 4.3 (200 mg, 0.77 mmol) and aqueous sodium hydroxide (4M, 3 mL) in ethanol (3 mL) was stirred at 100 ° C for 6 hr. The mixture was extracted with EtOAc (2M). The residue was purified by flash column chromatography (60% ethyl acetate / petroleum ether) to afford 4-(2-methoxypyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Comp. , 53 mg, yield: 30%) as a yellow oil. m/z: [M+H] ⁺ 233.2.

Example 6: Synthesis of Compound 5

Substituting the (2-methoxypyridin-3-yl)boronic acid in Step 3 with 2-fluoro-6-methylpyridine-5-boronic acid to give 4-(6-fluoro-2-) Methylpyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Compound 5). m/z: [M+H] ⁺ 235.2.

Example 7: Synthesis of Compound 6

Substituting the (2-methoxypyridin-3-yl)boronic acid in Step 3 with the 6-methoxypyridine-2-boronic acid pinacol ester to obtain 4-(6-methoxyl) by the synthesis of Compound 4. Pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Compound 6). m/z: [M+H] ⁺ 233.2.

Example 8: Synthesis of Compound 7

Replace the bromoacetone in step 1 with 1-bromo-3-methyl-2-butanone by the synthesis of compound 4, and replace the (2-methoxypyridin-3-yl)boronic acid in step 3 with 6 -Methoxypyridine-2-boronic acid pinacol ester gives 5-isopropyl-4-(6-methoxypyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 7).

Example 9: Synthesis of Compound 8

Substituting the bromoacetone in step 1 with 1-bromo-3-methyl-2-butanone to give 5-isopropyl-4-(2-methoxypyridin-3-yl) by the synthesis of compound 4.3 -1H-pyrrole-3-carboxylic acid ethyl ester (Compound 8). m/z: [M+H] ⁺ 289.2.

Example 10: Synthesis of Compound 9

Step 1: To a solution of Compound 4.3 (0.7 g, 2.68 mmol) in EtOAc (10 mL), EtOAc (EtOAc (EtOAc) Then, the reaction system was cooled to room temperature, and concentrated under reduced pressure to give Compound 9.1 (700 mg, yield: 95%) as a yellow liquid. m/z: [M+H] ⁺ 275.2.

Step 2: To a solution of the compound 9.1 (300 mg, 1.09 mmol) in MeOH (5 mL), EtOAc (EtOAc, EtOAc. Add methyl tert-butyl ether and aqueous sodium hydroxide solution (1M) to the mixture, and add hydrochloric acid (2M) to the aqueous phase to adjust the pH<1. The aqueous phase is extracted with ethyl acetate. The organic phase is combined with saturated brine. After washing, the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to afford 4-(2-methoxypyridin-3-yl)-1,5-dimethyl-1H-pyrrole-3-carboxylic acid (compound 9, 120 mg, yield: 89%) was a brown solid. m/z: [M+H] ⁺ 247.2.

Example 11: Synthesis of Compound 10

Step 1: To a solution of compound 4.3 (1 g, 3.84 mmol) and cyclopropylboronic acid (0.66 g, 7.68 mmol) in 1,2-dichloroethane (10 mL), EtOAc (0.73 g, 3. Sodium carbonate (0.81 g, 7.68 mmol), 2,2-bipyridine (0.6 g, 3.84 mmol), the reaction system was replaced with nitrogen three times, then stirred at 100 ° C for 16 hours, then the reaction system was cooled to room temperature, filtered The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj m/z: [M+H] ⁺ 301.2.

Step 2: To a solution of the compound 10.1 (150 mg, 0.55 mmol) in MeOH (5 mL), EtOAc (EtOAc, EtOAc. Add methyl tert-butyl ether and aqueous sodium hydroxide solution (1M) to the mixture, and add hydrochloric acid (2M) to the aqueous phase to adjust the pH<1. The aqueous phase is extracted with ethyl acetate. The organic phase is combined with saturated brine. After washing, the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated toield of <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Compound 10, 50 mg, yield: 33%) was obtained as a brown solid. m/z: [M+H] ⁺ 273.2.

Example 12: Synthesis of Compound 11

Step 1: N,N'-carbonyldiimidazole (5.3 g, 0.03) was added to a mixed solution of 2-methoxynicotinic acid (5.0 g, 0.03 mol) in tetrahydrofuran (16 mL) and acetonitrile (80 mL). (mmol), the reaction system was stirred at room temperature for 0.5 hours. Then, a monomethyl malonate potassium salt (10.2 g, 0.06 mol), triethylamine (9.9 g, 0.09 mol) and magnesium chloride (13.9 g, 0.14 mol) were added to the reaction mixture, and the resulting mixture was stirred at room temperature 2 hour. The reaction solution was concentrated to dryness, then quenched with hydrochloric acid (1M) and pH = 7-8. The mixture was extracted with EtOAc (EtOAc m. The residue was purified by flash column chromatography (EtOAcjjjjjj

Step 2: Add sodium hydrogen (60%, 286 mg, 7.17 mmol) to a solution of compound 11.1 (1.0 g, 4.78 mmol) in tetrahydrofuran (15 mL) under ice-cooling. Stir for 0.5 hours. Then, 1-bromo-3-methyl-2-butanone (1.18 g, 7.17 mmol) was added to the reaction mixture, and the reaction mixture was heated to reflux for 0.5 hr. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride and the mixture was evaporated. The organic phases were combined and washed with brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,363363363363363363363363363363363363363363363363363363 It is a yellow oil.

Step 3: Under a nitrogen atmosphere, compound 11.2 (400 mg, 1.36 mmol) and ammonium acetate (315 mg, 4.09 mol) were added to ethanol (15 mL) and refluxed for 3 hours, then the reaction mixture was concentrated and ethyl acetate was added to the residue, then Wash with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate.

Step 4: A solution of compound 11.3 (350 mg, 1.27 mmol) and aqueous sodium hydroxide (4M, 2.5 mL, 10.0 mmol) After the reaction system was cooled to room temperature, water (40 mL) was added to the reaction mixture, and the organic solvent was evaporated. The residue was adjusted to pH 5-6 with hydrochloric acid (1M), stirred for 30 min, filtered, and then filtered and dried under vacuum at 50 ° C to give 5-isopropyl-2-(2-methoxypyridin-3-yl) -1H-pyrrole-3-carboxylic acid (Compound 11, 340 mg, Yield: 100%) was a yellow solid. m/z: [M+H] ⁺ 261.0.

Example 13: Synthesis of Compound 13

Replace the 2-methoxynicotinic acid in step 1 with 6-difluoromethoxypyridine-2-carboxylic acid, 1-bromo-3-methyl-2- in step 2 by the synthesis of compound 11. The butanone was replaced with bromoacetone to give 2-(6-(difluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Compound 13). m/z: [M+H] ⁺ 269.2.

Example 14: Synthesis of Compound 14

Replace the 2-methoxynicotinic acid in step 1 with 3-methoxypyrazine-2-carboxylic acid, 1-bromo-3-methyl-2-butyl in step 2 by the synthesis of compound 11. The ketone was replaced with bromoacetone to give 2-(3-methoxypyrazin-2-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Compound 14). m/z: [M+H] ⁺ 234.2.

Example 15: Synthesis of Compound 15

Substituting the 2-methoxynicotinic acid in step 1 with 4-methoxypyrimidine-5-carboxylic acid, 1-bromo-3-methyl-2-butanone in step 2 by the synthesis of compound 11.3 Replace with bromoacetone to give methyl 2-(4-methoxypyrimidin-5-yl)-5-methyl-1H-pyrrole-3-carboxylate (Compound 15). m/z: [M+H] ⁺ 248.2.

Example 16: Synthesis of Compound 16

Replace the 2-methoxynicotinic acid in step 1 with 3-methylpyrazine-2-carboxylic acid, 1-bromo-3-methyl-2-butanone in step 2 by the synthesis of compound 11. Replace with bromoacetone to give 5-methyl-2-(3-methylpyrazin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 16).

Example 17: Synthesis of Compound 17

2-Chloro-3-methyl-2-butanone in Step 2 was replaced with bromoacetone by the synthesis of Compound 11 to give 2-(2-methoxypyridin-3-yl)-5-methyl- 1H-pyrrole-3-carboxylic acid (compound 17). m/z: [M+H] ⁺ 233.2.

Example 18: Synthesis of Compound 18

N-bromosuccinimide (109 mg, 0.61 mmol) was added to a solution of Compound 11 (160 mg, 0.61 mmol) in THF (5 mL), and the mixture was stirred at 0 ° C for 2 hours. It was then stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture, followed by ethyl acetate (5 mL×3). The organic phases were combined and washed with brine. The organic phase was then separated and concentrated to dryness to give a crude material. The crude product was purified by flash column chromatography ( petroleum ether / ethyl acetate = 4/1 to 1 / 1) to give 4-bromo-5-isopropyl-2-(2-methoxypyridin-3-yl)-1H Pyrrole-3-carboxylic acid (Compound 18, 120 mg, yield: 58%) was an off-white solid. m/z: [M+H] ⁺ 339.0.

Example 19: Synthesis of Compound 19

By the synthesis method of the compound 11, the 2-methoxynicotinic acid in the step 1 was replaced with 2-methylnicotinic acid, and the 1-bromo-3-methyl-2-butanone in the step 2 was replaced with the bromoacetone. 5-Methyl-2-(2-methylpyridin-3-yl)-1H-pyrrole-3-carboxylic acid (Compound 19). m/z: [M+H] ⁺ 217.2.

Example 20: Synthesis of Compound 20

Replace the 2-methoxynicotinic acid in step 1 with 2-trifluoromethylnicotinic acid by the synthesis of compound 11, and replace the 1-bromo-3-methyl-2-butanone in step 2 with bromine. Acetone gave 5-methyl-2-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (Compound 20). m/z: [M+H] ⁺ 271.2.

Example 21: Synthesis of Compound 21

Substituting the 2-methoxynicotinic acid in step 1 with 2-chloro-6-trifluoromethoxypyridine by the synthesis of compound 11.3, 1-bromo-3-methyl-2-butyl in step 2. The ketone was replaced with bromoacetone to give methyl 2-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylate (Compound 21). m/z: [M+H] ⁺ 335.0; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (br.s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.29 (d, J) = 8.4 Hz, 1H), 6.46-6.42 (m, 1H), 3.74 (s, 3H), 2.32 (d, J = 0.8 Hz, 3H).

Example 22: Synthesis of Compound 22

Substituting the 2-methoxynicotinic acid in step 1 with 2-chloro-6-trifluoromethoxypyridine to give 2-(6-chloro-2-(trifluoromethoxy) by the synthesis of compound 11.3 Methyl pyridin-3-yl)-5-isopropyl-1H-pyrrole-3-carboxylate (Compound 22). m/z: [M+H] ⁺ 363.0.

Example 23: Synthesis of Compound 23

Ammonium formate (28 mg, 443 mmol) and palladium on carbon (7 mg, 10%) were added to a solution of Compound 21 (74 mg, 221 mmol) in MeOH (5 mL), and then the mixture was stirred three times with hydrogen and stirred at 55 ° C for 16 hours. The resulting mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was dissolved with EtOAc (EtOAc) (EtOAc)EtOAc. Methyl-1H-pyrrole-3-carboxylate (Compound 23, 58 mg, Yield: 91%) was obtained as a white solid. m/z: [M+H] ⁺ 301.2.

Example 24: Synthesis of Compound 24

Using the synthesis of compound 23, using compound 22 as a starting material to give 5-isopropyl-2-(2-(trifluoromethoxy)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid Ester (Compound 24). m/z: [M+H] ⁺ 329.2.

Example 25: Synthesis of Compound 25

Substituting the 2-methoxynicotinic acid in step 1 with 2-(difluoromethoxy)nicotinic acid, 1-bromo-3-methyl-2-butanone in step 2 by the synthesis of compound 11.3 Replace with bromoacetone to give methyl 2-(2-(difluoromethoxy)pyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylate (Compound 25). m/z: [M+H] ⁺ 283.2.

Example 26: Synthesis of Compound 26

2-(2-(difluoromethoxy)pyridin-3-yl is obtained by substituting the 2-methoxynicotinic acid in step 1 with 2-(difluoromethoxy)nicotinic acid by the synthesis of compound 11.3. -5-Isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Compound 26). m/z: [M+H] ⁺ 311.1.

Example 27: Synthesis of Compound 27

The 2-methoxynicotinic acid in step 1 was replaced with 2-bromonicotinic acid by the synthesis of compound 11.3, and the 1-bromo-3-methyl-2-butanone in step 2 was replaced with bromoacetone to obtain 2 Methyl (2-bromopyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylate (Compound 27).

Example 28: Synthesis of Compound 28

Compound 27 (300 mg, 1.01 mmol) and cuprous cyanide (273 mg, 3.03 mol) were added to N,N-dimethylformamide (9 mL) under nitrogen, and the reaction was stirred at 120 ° C under microwave conditions. hour. The reaction solution was then cooled to room temperature, ethyl acetate and water were added, filtered and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash column chromatography ( petroleum ether / ethyl acetate = 4/1 to 1 / 1) to give 2-(2-cyanopyridin-3-yl)-5-methyl-1H-pyrrole-3- Methyl carboxylate (Compound 28, 74 mg, Yield: 30%) was obtained as a white solid. m/z: [M+H] ⁺ 242.2.

Example 29: Synthesis of Compound 30

Step 1: Methyl 2-(6-chloro-2-(trifluoromethoxy)nicotinyl)-4-oxopentanoate (under the synthesis of compound 11.2, 2 in step 1 under nitrogen protection) - methoxynicotinic acid is replaced by 6-chloro-2-(trifluoromethoxy)nicotinic acid, and 1-bromo-3-methyl-2-butanone in step 2 is replaced by bromoacetone) (250 mg, 0.7 mmol) was dissolved in deuterated methanol (5 mL) and stirred at 100 ° C for 2 hours. The reaction system was cooled to room temperature, ammonium acetate (82 mg, 1.1 mmol) was added and stirred at 100 ° C for 16 hours. The mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc) (EtOAc) =2/1) Purified 2-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-4-deutero-5-deuteromethyl-1H-pyrrole-3-carboxylic acid Methyl ester (Compound 29, 80 mg, yield: 33%) was obtained as a white solid. _{^{1 H NMR (400MHz, CDCl 3}} ): δ8.40 (br.s., 1H), 8.06 (d, J = 8.0Hz, 1H), 7.28 (d, J = 8.4Hz, 1H), 3.74 (s, 3H).

Step 2: The compound 23 is reacted with compound 23 to give 4-deutero-5-deuteromethyl-2-(2-(trifluoromethoxy)pyridin-3-yl)-1H-pyrrole- Methyl 3-carboxylate (Compound 30). m/z: [M+H] ⁺ 305.1, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.38 (br.s., 1H), 8.27 (d, J = 4.8 Hz, 1H), 8.09 (d) , J = 7.2 Hz, 1H), 7.29-7.24 (m, 1H), 3.73 (s, 3H).

Example 30: Synthesis of Compound 31

4-Chloro-5-indole A was obtained by the synthesis of compound 30 using methyl 2-(6-chloro-2-(methoxy)nicotinoyl)-4-oxopentanoate as a starting material. Methyl 2-(2-methoxypyridin-3-yl)-1H-pyrrole-3-carboxylate (Compound 31). m/z: [M+H] ⁺ 251.2.

Example 31: Synthesis of Compound 32

Substituting the 2-methoxynicotinic acid in step 1 with 3-(trifluoromethoxy)pyridine-2-carboxylic acid, 1-bromo-3-methyl- in step 2, using the synthesis of compound 11.3 The 2-butanone was replaced with bromoacetone to give methyl 5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylate (Compound 32). m/z: [M+H] ⁺ 301.1.

Example 32: Synthesis of Compound 34

Step 1: N-bromosuccinimide (125 mg, 699 μmol) was added portionwise to a solution of compound 23 (200 mg, 666 μmol) in tetrahydrofuran (5 mL), and the reaction was stirred at 0 ° C for 10 min. . The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Purification of methyl 4-bromo-5-methyl-2-(2-(trifluoromethoxy)pyridin-3-yl)-1H-pyrrole-3-carboxylate (compound) with ethyl acetate = 4/1) 33,147 mg, yield: 58%) as a white solid. m/z: [M+H] ⁺ 379.0, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.47 (br.s, 1H), 8.30 (dd, J = 2.0, 4.8 Hz, 1H), 7.84 (dd , J = 2.0, 7.6 Hz, 1H), 7.28-7.24 (m, 1H), 3.70 (s, 3H), 2.32 (s, 3H).

Step 2: To a solution of compound 33 (147 mg, 388 μmol) in deuterated dimethyl sulfoxide (2 mL) was added succinic acid (93 mg, 1.9 mmol), triethylamine (236 mg, 2.3 mmol) and THF. Phenylphosphine palladium (45 mg, 2.3 μmol), the reaction system was replaced with nitrogen three times and stirred at 110 ° C for 4 hours. After filtration with celite, the mixture was washed with EtOAc (EtOAc (EtOAc)EtOAc. Ester = 4/1) purified to give methyl 4-deutero-5-methyl-2-(2-(trifluoromethoxy)pyridin-3-yl)-1H-pyrrole-3-carboxylate (compound 34 , 65 mg, yield: 56%) as a white solid. m/z: [M+H] ⁺ 302.2, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.40 (br.s, 1H), 8.27 (dd, J = 2.0, 4.8 Hz, 1H), 8.08 (dd , J = 2.0, 7.6 Hz, 1H), 7.30-7.24 (m, 1H), 3.73 (s, 3H), 2.32 (s, 3H).

Example 33: Synthesis of Compound 35

Substituting compound 23 in step 1 with compound 24 to obtain 4-deutero-5-isopropyl-2-(2-(trifluoromethoxy)pyridin-3-yl)-1H by the synthesis of compound 34 Methyl pyrrole-3-carboxylate (Compound 35). m/z: [M+H] ⁺ 330.2, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.48 (br.s, 1H), 8.26 (dd, J = 2.0, 4.8 Hz, 1H), 8.15 (dd , J = 1.6, 7.6 Hz, 1H), 7.30-7.25 (m, 1H), 3.74 (s, 3H), 3.01-2.88 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H).

Example 34: Synthesis of Compound 36

Substituting compound 23 in step 1 with compound 25 to obtain 2-(2-(difluoromethoxy)pyridin-3-yl)-4-deutero-5-methyl-1H- by the synthesis of compound 34 Methyl pyrrole-3-carboxylate (Compound 36). m/z: [M+H] ⁺ 284.2, ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.51 (s, 1H), 8.24 (dd, J = 1.6, 4.8 Hz, 1H), 7.88 (dd , J=1.6, 7.6 Hz, 1H), 7.82, 7.64, 7.46 (3s, 1H, -OCHF ₂ ), 7.32 (dd, J=4.8, 7.4 Hz, 1H), 3.54 (s, 3H), 2.20 (s , 3H).

Example 35: Synthesis of Compound 37

By the synthesis of compound 29, using compound 11.2 as a starting material to give 4-deutero-5-(2-deutero-2-yl)-2-(2-methoxypyridin-3-yl)- Methyl 1H-pyrrole-3-carboxylate (Compound 37). m/z: [M+H] ⁺ 277.2.

Example 36: Synthesis of Compound 38

Substituting the 2-methoxynicotinic acid in step 1 with 3-methoxy-1-methyl-1H-pyrrole-4-carboxylic acid by the synthesis of compound 11, 1-bromo-3 in step 2 -Methyl-2-butanone was replaced with bromoacetone to give 2-(3-methoxy-1-methyl-1H-pyrrol-4-yl)-5-methyl-1H-pyrrole-3-carboxylic acid ( Compound 38). m/z: [M+H] ⁺ 236.2.

Example 37: Synthesis of Compound 39

Substituting the 2-methoxynicotinic acid in Step 1 with 3-methoxy-1-methyl-1H-pyrrole-4-carboxylic acid by the synthesis of Compound 11 to give 5-isopropyl-2-( 3-methoxy-1-methyl-1H-pyrrol-4-yl)-1H-pyrrole-3-carboxylic acid (Compound 39). m/z: [M+H] ⁺ 264.2.

Example 38: Synthesis of Compound 40

Substituting compound 23 in step 1 with compound 11 to obtain 4-deutero-5-isopropyl-2-(2-methoxypyridin-3-yl)-1H-pyrrole-3 by the synthesis of compound 34 - carboxylic acid (compound 40). m/z: [M+H] ⁺ 262.2.

Example 39: Synthesis of Compound 41

Substituting the 2-methoxynicotinic acid in step 1 with 3-(trifluoromethoxy)pyridine-2-carboxylic acid by the synthesis of compound 11 to give 5-isopropyl-2-(3-(3) Fluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 41). m/z: [M+H] ⁺ 315.2.

Example 40: Synthesis of Compound 43

Step 1: Compound 31 (260 mg, 1.04 mmol) was added to a mixed solution of trifluoroacetic acid (2 mL) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, ethyl acetate and aq. The organic phase was concentrated, and the residue was purified tojjjjjjjjjj

Step 2: Compound 42 (50 mg, 0.20 mmol) was added to a mixed solution of ethanol (1 mL) and aqueous sodium hydroxide (4M, 1 mL). The reaction was then quenched with hydrochloric acid (1 M) to adjust pH = 6-7. The solid was precipitated, filtered, and the filter cake was dried in vacuo to give 2-(2-methoxypyridin-3-yl)-5-deuteromethyl-1H-pyrrole-3-carboxylic acid (Comp. Yield: 9%) is an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.07-8.08 (m, 1H), 7.72-7.75 (m, 1H), 6.95-6.98 (m, 1H), 6.27 (s, 1H), 3.91 (s) , 3H).

Example 41: Synthesis of Compound 44

Substituting the 2-methoxynicotinic acid in step 1 with 3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid by the synthesis of compound 11.3, in step 2 1-Bromo-3-methyl-2-butanone was replaced with bromoacetone to give 2-(3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl)-5-methyl Methyl-1H-pyrrole-3-carboxylate (Compound 44). m/z: [M+H] ⁺ 286.2.

Example 42: Synthesis of Compound 45

Substituting the 2-methoxynicotinic acid in step 1 with 3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid to give 5-isopropyl group by the synthesis of compound 11.3 Methyl 2-(3-(difluoromethoxy)-1-methyl-1H-pyrazol-4-yl)-1H-pyrrole-3-carboxylate (Compound 45). m/z: [M+H] ⁺ 300.2.

Example 43: Synthesis of Compounds 47 and 48

Step 1: Methyl 4-oxo-2-(3-(trifluoromethoxy)pyridine-2-formyl)pentanoate (under the synthesis of compound 11.2, 2 in step 1 under nitrogen protection) - methoxynicotinic acid is replaced by 3-(trifluoromethoxy)pyridine-2-carboxylic acid, and 1-bromo-3-methyl-2-butanone in step 2 is replaced by bromoacetone) (200 mg, 0.63 mmol) was dissolved in deuterated methanol (5 mL) and stirred at 100 ° C for 2 hours. The reaction system was cooled to room temperature, ammonium acetate (96 mg, 1.25 mmol) was added, and the mixture was stirred at 100 ° C for 16 hours. Then it was cooled to room temperature and concentrated under reduced pressure to give compound 46 (190 mg, yield: 100%) as yellow oil.

Step 2: A mixed solution of the compound 46 (160 mg, 0.53 mmol) in ethanol (3 mL) and aqueous sodium hydroxide (3 mL, 4M) was stirred under reflux for 2 hr. The reaction system was cooled to room temperature and quenched with hydrochloric acid (1M) to adjust pH = 6-7. The precipitated solid was filtered, and the filter cake was dried under vacuum at 50 ° C to give 5-demethylmethyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid ( Compound 47, 106 mg, yield: 70%) was obtained as white solid. m/z: [M+H] ⁺ 290.2.

Step 3: N-bromosuccinimide (17.6 mg, 0.09 mmol) was added portionwise to a solution of compound 47 (22 mg, 0.07 mmol) in tetrahydrofuran (3 mL). Stir for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. 2-(3-(Trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 48, 28 mg, yield: 100%) as a white solid. m/z: [M+H] ⁺ 368.0.

Example 44: Synthesis of Compound 51

Step 1: Methyl 2-(6-chloro-3-(trifluoromethoxy)pyridine-2-formyl)-5-methyl-4-oxohexanoate (using compound 11.2) In the synthesis method, the 2-methoxynicotinic acid in step 1 is replaced by 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid (50 mg, 0.13 mmol) dissolved in deuterated methanol ( 2 mL) and stirred at 100 ° C for 2 hours. The reaction system was cooled to room temperature, ammonium acetate (20 mg, 0.26 mmol) was added and stirred at 100 ° C for 16 hours. The reaction system was cooled to room temperature and then evaporated to dryness.

Step 2: To a solution of the compound 49 (47 mg, 0.13 mmol) in methanol (5 mL), EtOAc (40 mg, 0.64 mmol) and palladium carbon (30 mg, 10%). The mixture was stirred under heating for 6 hours. The resulting mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was dissolved with EtOAc (EtOAc) (EtOAc)

Step 3: A solution of compound 50 (30 mg, EtOAc) (EtOAc) The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered, and then evaporated. Pyrrole-3-carboxylic acid (Compound 51, crude, 50 mg) was obtained as a yellow oil. m/z: [M+H] ⁺ 316.2.

Example 45: Synthesis of Compound 53

Step 1: Methyl 5-(tert-butyl)-2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylate (using compound 11 Synthetic method, replacing 2-methoxynicotinic acid in step 1 with 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid, 1-bromo-3-methyl- in step 2 2-butanone was replaced by 1-bromo-3,3-dimethylbutan-2-one (48 mg, 0.13 mmol), ammonium formate (33 mg, 0.52 mmol) and palladium on carbon (10 mg, 10%) were added to methanol. In (5 mL), the reaction system was replaced with hydrogen three times, and then refluxed under a hydrogen atmosphere for 1 hour. The reaction solution was cooled to room temperature, filtered over Celite, and evaporated. Ethyl acetate and water were added to the residue, and the organic layer was evaporated.

Step 2: A mixed solution of Compound 52 (46 mg, 0.13 mmol) in methanol (4 mL) The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered, and then evaporated. The acid (Compound 53, 30 mg, Yield: 71%) was obtained as a yellow oil. m/z: [M+H] ⁺ 329.2.

Example 46: Synthesis of Compound 56

Step 1: To the methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (using compound under ice bath) A method for synthesizing 11 by replacing 2-methoxynicotinic acid in step 1 with 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid) (35 mg, 0.1 mmol) of N, N To the solution of dimethylformamide (2 mL) was added sodium hydrogen (8 mg, 0.2 mmol, 60%), and the mixture was stirred for 15 min. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was stirred with EtOAc EtOAc. %) is a yellow oil.

Steps 2 & 3: Using the synthesis of compound 53 and reacting with compound 54 to give 1,5-dimethyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 56) is a yellow oil. m/z: [M+H] ⁺ 349.0.

Example 47: Synthesis of Compound 57

Using the synthesis of compound 56, the methyl iodide in step 1 was replaced with 2-iodopropane to give 1-isopropyl-5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl. -1H-pyrrole-3-carboxylic acid (compound 57). m/z: [M+H] ⁺ 377.2.

Example 48: Synthesis of Compound 61

Step 1: To a solution of methyl 3-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-3-pyruvate (150 mg, 0.50 mmol) and pyridine (119 mg, 1.50) Dess-Martin oxidant (321 mg, 0.76 mmol) was slowly added to a solution of dichloromethane (8 mL). After the addition, the reaction was stirred at room temperature for 3 hours, then a saturated aqueous solution of sodium thiosulfate (2 mL) and Saturated aqueous sodium hydrogencarbonate (2 mL) was stirred at room temperature for 1 hour. The reaction system was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] ⁺ 312.0.

Step 2: Compound 58 (80 mg, 0.26 mmol), EtOAc (EtOAc (EtOAc,EtOAc) The residue was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] ⁺ 378.2.

Step 3: A mixture of compound 59 (50 mg, 0.13 mmol), palladium carbon (20 mg) and ammonium formate (33 mg, 0.52 mmol) in methanol (10 mL) was replaced with hydrogen three times, then the reaction was stirred under a hydrogen atmosphere for one hour. . The reaction system was cooled to room temperature, and the palladium carbon was removed by filtration over Celite, and then the filtrate was concentrated to afford compound 60 (45 mg, crude) as white solid. m/z: [M+H] ⁺ 344.2.

Step 4: A solution of compound 60 (45 mg, EtOAc) (EtOAc) The organic solvent was concentrated under reduced pressure, and the aqueous phase was adjusted to pH 4 to 5 with hydrochloric acid (1M), and solid was precipitated, and filtered under reduced pressure to give 2-(t-butyl)-5-(3-(trifluoromethoxy)pyridine. 2-yl)-1H-imidazole-4-carboxylic acid (Compound 61, 20 mg, two-step yield: 44%) as a white solid. m/z: [M+H] ⁺ 330.2.

Example 49: Synthesis of Compound 62

Substituting the pivalaldehyde in step 2 with acetaldehyde by the synthesis method of compound 61 to obtain 2-methyl-5-(3-(trifluoromethoxy)pyridin-2-yl)-1H-imidazole-4- Carboxylic acid (compound 62). m/z: [M+H] ⁺ 288.2.

Example 50: Synthesis of Compound 65

Step 1: Drying to methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (170 mg, 0.51 mmol) Cyclopropylboronic acid (131 mg, 1.52 mmol), copper acetate (139 mg, 0.77 mmol), 2,2-bipyridine (120 mg, 0.77 mmol) and sodium carbonate were added sequentially to 1,2-dichloroethane (10 mL). 162 mg, 1.52 mmol), the reaction system was replaced with nitrogen three times, and then heated to 120 ° C for 3 hours. The reaction was cooled to room temperature, and the mixture was evaporated. The residue was purified by flash column chromatography chromatography eluting elut elut elut elut elut

Steps 2 & 3: Using the synthesis of compound 53 and reacting with compound 63 to give 1-cyclopropyl-5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3 - carboxylic acid (compound 65). m/z: [M+H] ⁺ 327.2.

Example 51: Synthesis of Compound 68

Step 1: To a solution of methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (280 mg, Sodium hydrogen (67.2 mg, 1.68 mmol, 60%) was added to a solution of 0.84 mmol) of N,N-dimethylformamide (5 mL). The reaction system was stirred at 0 ° C for 30 minutes and then added to the above reaction system ( 2-Bromoethoxy)(tert-butyl)dimethylsilane (402 mg, 1.68 mmol). The reaction system was further stirred at room temperature overnight, and the mixture was evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut

Steps 2 & 3: Using the synthesis of compound 53 and reacting with compound 66 to give 1-(2-hydroxyethyl)-5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H Pyrrole-3-carboxylic acid (compound 68). m/z: [M+H] ⁺ 331.2.

Example 52: Synthesis of Compound 73

Step 1: Methyl 5-(tert-butyl)-2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylate under ice-bath conditions (1 g, 2.7 mmol) of N,N-dimethylformamide (10 mL) was added portionwise sodium hydrogen (160 mg, 4.0 mmol), and the mixture was stirred for 0.5 hr. After the addition of the reaction mixture, the reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate. Concentrated Compound 69 (1.1 g, yield: 98%) was obtained as a pale creamy liquid.

Step 2: To a solution of compound 69 (300 mg, 0.72 mmol) in 1,4-dioxane (3mL), water (1. 5mL), potassium hydride (VI) dihydrate (118mg, 0.36mmol) N-methyl-N-oxidized morpholine (253 mg, 2.16 mmol). After stirring at room temperature for 3 hours, sodium periodate (766 mg, 3.6 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with aq. EtOAc EtOAc (EtOAc)EtOAc. /1 to 5/1) Purification gave Compound 70 (82 mg, yield: 28%) as a pale creamy liquid.

Step 3: To a solution of compound 70 (80 mg, 0.19 mmol) elute The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated.

Steps 4 & 5: Using the synthesis of compound 53 and reacting with compound 71 to give 5-tert-butyl-1-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)pyridin-2-yl)- 1H-pyrrole-3-carboxylic acid (compound 73).

Example 53: Synthesis of Compound 74

Synthesis of 1-deuterated methyl-p-toluenesulfonylmethyl isocyanide: to m-phenylbenzenesulfonylmethyl isocyanide (3.0 g, 15.4 mmol) in dichloromethane under ice-cooling (under nitrogen) Benzyltriethylammonium chloride (700 mg, 3.07 mmol) and deuterated iodomethane (1.85 mL, 30.7 mmol) were added to the solution, respectively, and then aqueous sodium hydroxide (30%, 30 mL) was added dropwise. The reaction was stirred at 0 ° C for 3 hr then EtOAc (EtOAc) (EtOAc) The product was isolated by flash column chromatography (peel ether / ethyl acetate = 4 / 1) to give 1-de-methyl-p-toluenesulfonylmethyl isonitrile (2.6 g, yield: 78%) as a brown liquid.

Step 1: 2-methoxy-3-pyridine aldehyde (1.0 g, 7.29 mmol) and ethoxycarbonylmethylenetriphenylphosphine (2.4 g, 7.29 mmol) were dissolved in tetrahydrofuran (20 mL). Stir at room temperature overnight. The reaction mixture was then concentrated, and the residue was purified mjjjjjjjjj

Step 2: To a solution of the compound 74.1 (500 mg, 2.41 mmol) and 1-decylmethyl-p-toluenesulfonylmethylisonitrile (1.0 g, 4.82 mmol) in THF (20 mL) 7.23 mmol), the reaction system was stirred at room temperature for 3 hours. After the reaction was quenched with water, EtOAc (EtOAc)EtOAc. Ethyl (2-methoxypyridin-3-yl)-5-deuteromethyl-1H-pyrrole-3-carboxylate (Compound 74, 0.1 g, yield: 16%) m/z: [M+H] ⁺ 264.2.

Example 54: Synthesis of Compound 75

N-iodosuccinimide (244 mg, 1.90 mmol) was slowly added to a solution of compound 4 (210 mg, 0.90 mmol) in tetrahydrofuran (8 mL). The reaction system was slowly warmed to room temperature and stirred for 2 hours. TLC (petrole ether / ethyl acetate = 4 / 1) was followed to afford the reaction. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Purification by (alkali method) 2-iodo-4-(2-methoxypyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Compound 75, 220 mg, yield: 68%) It is a brown solid.

Example 55: Synthesis of Compound 76

Step 1: To a solution of 2-bromo-6-methoxypyridine (1 g, 5.3 mmol) and tert-butyl acrylate (3.4 g, 26.6 mmol) in tetrahydrofuran (40 mL), palladium acetate (118 g, 0.53 mmol) Triethylamine (2.68 g, 2.65 mmol) and tris(2-methylphenyl)phosphorate (322 mg, 1.06 mmol) were reacted three times with nitrogen, and then the reaction was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj Dry over sodium sulfate and concentrate under reduced pressure. The residue was purified by flash column chromatography (EtOAc:EtOAc: m/z: [M+H] ⁺ 236.2.

Step 2: Sodium hydrogen (60%, 688 mg, 17.2 mmol) was added portionwise to a solution of TosMIC (1.49 g, 7.7 mmol) in N, N-dimethylformamide (3 mL). After the addition, the reaction system was further stirred for 0.5 hours, and then Compound 76.1 (1 g, 4.3 mmol) was added to the reaction system. The reaction system was stirred to room temperature and stirred for 2 hours. The reaction was quenched with water (50 mL)EtOAcEtOAc The organic phase was combined, washed with brine brine and evaporated The residue was purified by flash column chromatography chromatography eluting elut elut elut elut elut m/z: [M+H] ⁺ 275.2.

Step 3: To a solution of compound 76.2 (530 mg, 1. <RTI ID=0.0></RTI><RTIgt; The organic solvent was then concentrated under reduced pressure to dryness crystals crystals crystals crystals m/z: [M+H] ⁺ 219.0.

Example 56: Synthesis of Compound 77

Step 1: To a solution of methyl 3-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-3-oxopropanoate (2.2 g, 7.39 mmol) in tetrahydrofuran Sodium borohydride (84 mg, 2.22 mmol) was added portionwise in a mixture of 10 mL) and methanol (10 mL). The mixture was stirred at 0 ° C for 30 min then quenched with water (10 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford Compound 77.1 (2.2 g, yield: 99%). m/z: [M+H] ⁺ 300.0.

Step 2: To a solution of the compound 77.1 (2.2 g, 7.34 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (1.4 g, 7.34 mmol), and the reaction was refluxed at 150 ° C for 10 hours. The organic layer was washed with EtOAc (EtOAc) (EtOAc) Purification (petroleum ether / ethyl acetate = 4 / 1) afforded compound 77.2 (400 mg, yield: 19%) as pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.90 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 16.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.52 ( d, J = 16.4 Hz, 1H), 3.84 (s, 3H).

Step 3: Compound 77.2 (320 mg, 1.14 mmol) and 1-methyl-p-toluenesulfonylmethylisonitrile (356 mg, 1.70 mmol) were dissolved in tetrahydrofuran (5 mL). 1.70mmol), the final mixture was heated to 50 ° C for 2 hours, cooled to room temperature, hydrochloric acid (1M) was added to adjust the pH = 6, ethyl acetate (20mL × 2) was extracted, the combined organic phase was washed with saturated brine, anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj m/z: [M+H] ⁺ 335.0, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.46 (br.s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.39 (d, J) = 2.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.67 (s, 3H), 2.11 (s, 3H).

Step 4: Compound 77.3 (190 mg, 0.57 mmol) was dissolved in MeOH (5 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc After stirring for 48 hours, the reaction solution was filtered through Celite, and then filtered and washed with ethyl acetate, and the filtrate was concentrated to give 5-methyl-4-(2-(trifluoromethoxy)pyridin-3-yl)- Methyl 1H-pyrrole-3-carboxylate (Compound 77, 130 mg, Yield: 76%) was an off white solid. m/z: [M+H] ⁺ 301.2.

Example 57: Synthesis of Compound 78A+78B

Step 1: To a compound 78.1 at room temperature (3-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-3-oxoprop in step 1 using the synthesis of compound 77.2 Replacement of methyl ester with methyl 3-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-3-oxopropanoate) (155 mg, 0.9 mmol) and 1-methyl- Potassium tert-butoxide (155 mg, 1.4 mmol) was added to a solution of toluenesulfonylmethyl isocyanide (290 mg, 1.4 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 50 ° C for 30 min under nitrogen atmosphere and then cooled to room temperature. The mixture was extracted with ethyl acetate (3×10 mL). The mixture of the compound 78.2A and 78.2B (204 mg, yield: 65%) was obtained as a yellow solid. m/z: [M+H] ⁺ 335.0.

Step 2: To a solution of the mixture of compound 78.2A and 78.2B (204 mg, 0.6 mmol) in methanol (10 mL), EtOAc (EtOAc (EtOAc) It was replaced three times and stirred at 66 ° C for 16 hours. It was filtered through Celite and washed with methanol (3×5 mL). It was dissolved in ethyl acetate (10 mL), EtOAc (EtOAc m. -1H-pyrrole-3-carboxylic acid methyl ester (Compound 78A) and 2-methyl-4-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid A A mixture of the ester (Compound 78B) (150 mg, yield: 82%) was obtained as a yellow oil. m/z: [M+H] ⁺ 301.2.

Example 58: Synthesis of Compound 79

Using the synthesis method of 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Example 53, substituting deuterated methyl iodide with 2-iodopropane to obtain 1-isopropyl-p-toluenesulfonylmethyl isocyanide .

Substituting the 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Step 3 with 1-isopropyl-p-toluenesulfonylmethyl isocyanide to give 5-isopropyl- in the synthesis of Compound 77 Methyl 4-(2-(trifluoromethoxy)pyridin-3-yl)-1H-pyrrole-3-carboxylate (Compound 79).

Example 59: Synthesis of Compound 80

Using the synthesis method of 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Example 53, the deuterated methyl iodide was replaced with ethyl iodide to give 1-ethyl-p-toluenesulfonylmethyl isocyanide.

Substituting the 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Step 2 with 1-ethyl-p-toluenesulfonylmethyl isocyanide to give 5-ethyl-4- Ethyl (2-methoxypyridin-3-yl)-1H-pyrrole-3-carboxylate (Compound 80).

Example 60: Synthesis of Compound 1-1

Compound 11 (150 mg, 0.57 mmol), Compound 1a (163 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol), N , a solution of N-diisopropylethylamine (223 mg, 1.73 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol) in N,N-dimethylformamide (5 mL) The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. HPLC (alkaline method, elution gradient: mobile phase B: 20 to 75% (v/v%)) to afford compound 1-1 (single stereo configuration, 89.6 mg, yield: 31%) as a white solid. UPLC RT=6.901 min; m/z: [M+H] ⁺ 501.0; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (d, J = 4.8 Hz, 1H), 8.07-8.11 (m, 2H) ), 7.91 (dd, J = 10.4, 2.8 Hz, 1H), 7.74 (dd, J = 7.2, 2.0 Hz, 1H), 7.55 - 7.63 (m, 2H), 6.98 - 7.01 (m, 1H), 6.26 ( s, 1H), 3.94 (s, 3H), 3.35-3.46 (m, 3H), 2.93-2.96 (m, 1H), 2.05-2.10 (m, 1H), 1.79-1.89 (m, 8H), 1.31 ( d, J = 6.8 Hz, 6H).

Example 61: Synthesis of Compound 1-2

In the synthesis of Compound 1-1, Compound 11 was replaced with Compound 17 to give Compound 1-2 (single stereo configuration). UPLC RT=6.096 min; m/z: [M+H] ⁺ 473.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.76 (d, J = 4.0 Hz, 1H), 8.07-8.10 (m, 2H) ), 7.87-7.91 (m, 1H), 7.72-7.74 (m, 1H), 7.55-7.61 (m, 2H), 6.97-7.00 (m, 1H), 6.21 (s, 1H), 3.94 (s, 3H) ), 3.44 - 3.47 (m, 2H), 3.33 - 3.52 (m, 1H), 2.28 (s, 3H), 2.01-2.11 (m, 1H), 1.75-1.91 (m, 8H).

Example 62: Synthesis of Compound 1-3

Substitution of Compound 11 with Compound 18 to give Compound 1-3 (single stereo configuration) by the synthesis of Compound 1-1. UPLC RT=7.271 min; m/z: [M+H] ⁺ 579.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.76 (d, J = 4.0 Hz, 1H), 8.07-8.10 (m, 2H) ), 7.87-7.91 (m, 1H), 7.72-7.74 (m, 1H), 7.55-7.61 (m, 2H), 6.97-7.00 (m, 1H), 6.21 (s, 1H), 3.94 (s, 3H) ), 3.44 - 3.47 (m, 2H), 3.33 - 3.52 (m, 1H), 2.28 (s, 3H), 2.01-2.11 (m, 1H), 1.75-1.91 (m, 8H).

Example 63: Synthesis of Compound 1-4

A suspension of compound 1-3 (29 mg, 0.05 mmol) and cuprous cyanide (9.0 mg, 0.01 mmol) in N,N-dimethylformamide (5 mL) was subjected to microwave reaction at 120 ° C for 2 hours, then the reaction was carried out. The system was cooled to room temperature, water (15 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Purification by prep-HPLC (basic method, elution gradient: mobile phase B: 20 to 75% (v/v%)) gave Compound 1-4 (4.4 mg, yield: 34%) as white solid. UPLC RT=6.577min; m/z: [M+H] ⁺ 526.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.7 (s, 1H), 8.82 (d, J = 4.4 Hz, 1H) , 8.16-8.18 (m, 1H), 8.07-8.11 (m, 1H), 7.94 (dd, J = 10.4, 2.4 Hz, 1H), 7.64 - 7.73 (m, 3H), 7.46 (d, J = 4.4 Hz) , 1H), 7.04-7.07 (m, 1H), 3.84 (s, 3H), 3.26-3.30 (m, 3H), 3.12-3.15 (m, 1H), 1.87-1.88 (m, 1H), 1.61-1.72 (m, 8H), 1.32 (d, J = 6.8 Hz, 6H).

Example 64: Synthesis of Compound 1-5

Substitution of compound 11 with compound 13 by the synthesis of compound 1-1 gives compound 1-5 (single stereo configuration). UPLC RT = 7.361 min; [M+H] ⁺ 509.3; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.23 (s, 1H), 8.84 (d, J = 4.4 Hz, 1H), 8.07-8. (m, 4H), 7.96-7.99 (m, 1H), 7.80-7.84 (m, 1H), 7.65-7.70 (m, 1H), 7.49 (d, J = 4.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 3.38-3.42 (m, 3H), 2.29 (s, 3H), 2.00-2.10 (m, 1H), 1.62-1.88 (m, 8H).

Example 65: Synthesis of Compound 1-6

Compound 11 is replaced with compound 14 by the synthesis of compound 1-1 to give compound 1-6 (single stereo configuration). UPLC RT = 6.633 min; [M+H] ⁺ 474.3; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.76 (s, d, J = 4.0 Hz, 1H), 8.12 - 8.05 (m, 3H), 7.80-7.75 (m, 1H), 7.57-7.56 (m, 2H), 6.46 (s, 1H), 4.07 (s, 3H), 3.56 (d, J = 8.0 Hz, 2H), 3.34 (m, 1H) , 2.32 (s, 3H), 2.10-2.20 (m, 1H), 1.39-1.81 (m, 8H).

Example 66: Synthesis of Compound 1-7

A solution of compound 1a (67.1 mg, 0.26 mmol) and trimethylaluminum (1.6 M in toluene, 0.4 mL, 0.65 mmol) in toluene (3 mL) was stirred at 90 ° C for 2 hr. The reaction system was then cooled to room temperature, and compound 15 (32.1 mg, 0.13 mmol) was added, and the obtained suspension was stirred at 90 ° C for 16 hours. The reaction mixture was quenched with water and then evaporated and evaporated. The residue was purified by prep-HPLC ( EtOAc (EtOAc:EtOAc:EtOAc) UPLC RT = 5.076 min; [M+H] ⁺ 474.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (s, d, J = 4.0 Hz, 1H), 8.44 (s, 1H), 8.11 8.09 (m, 1H), 7.90-7.80 (m, 2H), 7.63-7.56 (m, 2H), 6.38 (s, 1H), 3.67-3.64 (m, 5H), 3.37-3.32 (m, 1H), 2.28 (s, 3H), 1.90-1.79 (m, 9H).

Example 67: Synthesis of Compound 1-8

Compound 11 is replaced with compound 16 by the synthesis of compound 1-1 to give compound 1-8 (single stereo configuration). UPLC RT = 5.216 min; [M+H] ⁺ 458.1; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75-8.73 (d, J = 8.0 Hz, 1H), 8.45-8.41 (m, 2H), 8.08-8.05(m,1H), 7.89-7.86(m,1H), 7.62-7.53(m,2H), 6.34(s,1H), 3.48-3.45(m,2H), 3.36(m,1H), 2.50 (s, 3H), 2.30 (s, 3H), 2.13 - 2.05 (m, 1H), 1.88-1.76 (m, 8H).

Example 68: Synthesis of Compound 1-9

Substitution of Compound 11 with Compound 19 by the synthesis of Compound 1-1 gave Compound 1-9 (single stereo configuration). UPLC RT = 4.324 min; [M+H] ⁺ 457.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (d, J = 4.8 Hz, 1H), 8.35-8.37 (m, 1H), 8.04 8.08 (m, 1H), 7.89 (m, 1H), 7.52-7.71 (m, 3H), 7.26-7.29 (m, 1H), 6.29 (s, 1H), 3.41-3.44 (m, 2H), 3.33 3.34 (m, 1H), 2.42 (s, 3H), 2.27 (s, 3H), 2.03-2.04 (m, 1H), 1.75-1.86 (m, 8H).

Example 69: Synthesis of Compound 1-10

Compound 11 is replaced with compound 20 by the synthesis of compound 1-1 to give compound 1-10 (single stereo configuration). UPLC RT = 6.437 min; [M+H] ⁺ 511.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.08-8.04 ( m,1H), 7.93-7.85 (m, 2H), 7.71-7.51 (m, 3H), 6.30 (s, 1H), 3.41-3.37 (m, 2H), 3.33 (m, 1H), 2.27 (s, 3H), 2.07-2.02 (m, 1H), 1.87-1.70 (m, 8H).

Example 70: Synthesis of Compound 1-11

Compound 1a (50 mg, 0.19 mmol) was dissolved in toluene (5 mL), and then a solution of trimethylaluminum in toluene (0.4 mL, 1.6 M) was added and stirred at 110 ° C for 1 hour. Under a nitrogen atmosphere, the reaction system was cooled to room temperature, then compound 23 (48 mg, 0.16 mmol) was added and stirred at 110 ° C for 4 hours. Then, the reaction was quenched by dropwise addition of EtOAc (EtOAc) (EtOAc). The residue was purified by prep-HPLC ( EtOAc (EtOAc:EtOAc) UPLC RT=6.921 min; m/z: [M+H] ⁺ 527.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 (d, J = 4.6 Hz, 1H), 8.24 - 8.15 (m, 1H) ), 8.11-8.00 (m, 1H), 7.93-7.77 (m, 2H), 7.63-7.50 (m, 2H), 7.37-7.28 (m, 1H), 6.26 (s, 1H), 3.44 (d, J) = 7.8 Hz, 2H), 3.39-3.33 (m, 1H), 2.28 (s, 3H), 2.15-2.05 (m, 1H), 1.93-1.71 (m, 8H).

Example 71: Synthesis of Compound 1-12

Substitution of compound 23 with compound 24 affords compound 1-12 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 7.413min; [M + H] + 555.2; 1 H NMR (400MHz, CD 3 OD): δ8.73 (d, J = 4.8Hz, 1H), 8.20 (dd, J = 4.8,2.0Hz, 1H), 8.06 (dd, J=9.6, 5.6 Hz, 1H), 7.92-7.85 (m, 2H), 7.63-7.51 (m, 2H), 7.33 (dd, J=7.2, 4.8 Hz, 1H), 6.31 (s, 1H), 3.49-3.40 (m, 2H), 3.35 (br.s, 1H), 3.00-2.88 (m, 1H), 2.10 (br.s, 1H), 1.92-1.71 (m, 8H) , 1.29 (d, J = 7.2 Hz, 6H).

Example 72: Synthesis of Compound 1-13

Substitution of compound 23 with compound 25 affords compound 1-13 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 6.682 min; [M+H] ⁺ 509.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (s, d, J = 4.0 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.83-7.81 (m, 2H), 7.58-7.21 (m, 3H), 7.19-7.18 (m, 1H), 6.24 (s, 1H), 3.44-3.31 (m, 3H), 2.28 (s, 3H), 2.09 (m, 1H), 1.85-1.77 (m, 8H).

Example 73: Synthesis of Compound 1-14

Substitution of compound 23 with compound 26 affords compound 1-14 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 7.332 min; [M+H] ⁺ 537.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (s, d, J = 4.0 Hz, 1H), 8.13 - 8.04 (m, 2H), 7.88-7.83(m,2H), 7.65-7.22(m,3H), 7.20-7.19(m,1H), 6.29(s,1H),3.44-3.31(m,3H),2.97-2.91(m,1H ), 2.10 (m, 1H), 1.85-1.76 (m, 8H), 1.30-1.13 (m, 6H).

Example 74: Synthesis of Compound 1-15

Substitution of compound 23 with compound 28 affords compound 1-15 (single stereo configuration) by the synthesis of compound 1-11. [M+H] ⁺ 468.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (d, J = 4.4 Hz, 1H), 8.42-8.50 (m, 2H), 8.06-8.10 (m, 1H) , 7.88-7.91 (m, 1H), 7.57-7.62 (m, 2H), 7.47-7.50 (m, 1H), 6.42 (s, 1H), 3.59 (d, J = 8.0 Hz, 2H), 3.38-3.40 (m, 1H), 2.53 (s, 3H), 2.02-2.03 (m, 1H), 1.83-1.95 (m, 8H).

Example 75: Synthesis of Compound 1-16

Substitution of compound 23 with compound 30 affords compound 1-16 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 6.921 min; [M+H] ⁺ 531.2; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (d, J = 3.6 Hz, 1H), 8.26-8.13 (m, 1H), 8.12 8.01 (m, 1H), 7.94-7.87 (m, 1H), 7.86-7.76 (m, 1H), 7.64-7.49 (m, 2H), 7.40-7.28 (m, 1H), 3.52-3.40 (m, 2H) ), 3.40-3.33 (m, 1H), 2.16-2.04 (m, 1H), 1.97-1.67 (m, 8H).

Example 76: Synthesis of Compound 1-17

Substitution of compound 23 with compound 31 affords compound 1-17 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 5.309 min; [M+H] ⁺ 477.3.

Example 77: Synthesis of Compound 1-18

Substitution of compound 23 with compound 32 affords compound 1-18 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 6.698 min; [M+H] ⁺ 527.1; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75 (d, J = 4.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H) , 8.09-8.05 (m, 1H), 7.89-7.80 (m, 2H), 7.61-7.54 (m, 2H), 7.46-7.43 (m, 1H), 6.32 (s, 1H), 3.51-3.48 (m, 2H), 3.96 (s, 1H), 2.30 (s, 3H), 2.10 (s, 1H), 1.92-1.77 (m, 8H).

Example 78: Synthesis of Compound 1-19

Substitution of compound 23 with compound 34 affords compound 1-19 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 6.920 min; [M+H] ⁺ 528.2.

Example 79: Synthesis of Compound 1-20

Substitution of compound 23 with compound 35 affords compound 1-20 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 7.444 min; [M+H] ⁺ 556.2.

Example 80: Synthesis of Compound 1-21

Compound 23 is replaced with compound 36 by the synthesis of compound 1-11 to give compound 1-21 (single stereo configuration). UPLC RT = 6.736 min; [M+H] ⁺ 510.2.

Example 81: Synthesis of Compound 1-22

Compound 23 is replaced with compound 37 by the synthesis of compound 1-11 to give compound 1-22 (single stereo configuration). [M+H] ⁺ 503.2.

Example 82: Synthesis of Compound 1-23

Compound 11 is replaced with compound 40 by the synthesis of compound 1-1 to give compound 1-23 (single stereo configuration). UPLC RT = 7.000 min; [M+H] ⁺ 502.2.

Example 83: Synthesis of Compound 1-24

Compound 11 is replaced with compound 41 by the synthesis of compound 1-1 to give compound 1-24 (single stereo configuration). UPLC RT = 7.285 min; [M+H] ⁺ 555.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.66-8.63 (m, 1H), 8.48-8.47 (m, 1H), 8.00-7.80 (m) , 1H), 7.78-7.73 (m, 2H), 7.47-7.46 (m, 2H), 7.38-7.35 (m, 1H), 6.29 (s, 1H), 3.42-3.21 (m, 3H), 2.90-2.85 (m, 1H), 2.10-2.03 (m, 1H), 2.01-1.68 (m, 8H), 1.23-1.05 (m, 6H).

Example 84: Synthesis of Compound 1-25

Compound 11 is replaced with compound 43 by the synthesis of compound 1-1 to give compound 1-25 (single stereo configuration). UPLC RT = 6.114 min; [M+H] ⁺ 476.2.

Example 85: Synthesis of Compound 1-26

Compound 11 is replaced with compound 47 by the synthesis of compound 1-1 to give compound 1-26 (single stereo configuration). UPLC RT = 6.690 min; [M+H] ⁺ 530.2.

Example 86: Synthesis of Compound 1-27

Compound 11 is replaced with compound 48 by the synthesis of compound 1-1 to give compound 1-27 (single stereo configuration). [M+H] ⁺ 608.2.

Example 87: Synthesis of Compound 1-28

To a mixture of compound 1-27 (18 mg, 0.03 mmol) and tetrakistriphenylphosphine palladium (17 mg, 0.015 mmol) in deuterated dimethyl sulfoxide (3 mL) was added triethylamine (36 mg, 0.35 mmol). And deuterated formic acid (13.6 mg, 0.29 mmol). The reaction system was stirred at 110 ° C for 3 hours. After the reaction mixture was cooled to room temperature, water (10 mL) The combined organic layers were washed with EtOAc EtOAc. The residue was purified by prep-HPLC (EtOAc, EtOAc (EtOAc: EtOAc) UPLC RT = 6.682 min; [M+H] ⁺ 531.1.

Example 88: Synthesis of Compounds 1-29 and 1-30

Step 1 : To a solution of compound 1-24 (130 mg, 0.23 mmol) in THF (10 mL). The reaction system was stirred at 0 ° C for 1 hour, then concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl ether/ethyl acetate=3/1) to afford compound 1-29 (65 mg, yield: 45%) It is a white solid. [M+H] ⁺ 633.2.

Step 2: To a mixture of compound 1-29 (40 mg, 0.06 mmol) and tetrakistriphenylphosphine palladium (36 mg, 0.03 mmol) in deuterated dimethyl sulfoxide (3 mL) was added triethylamine (73 mg). , 0.72 mmol) and deuterated formic acid (28 mg, 0.6 mmol). The reaction system was subjected to microwave reaction at 110 ° C for 3 hours, and the reaction mixture was cooled to room temperature, then water (10 mL) The combined organic layers were washed with EtOAc EtOAc. The residue was purified by prep-HPLC (basic method, mobile phase B: 20 to 70% (v/v%)) to afford compound 1-30 (10.0 mg, yield: 30%) as white solid. UPLC RT = 7.263 min; [M+H] ⁺ 556.2.

Example 89: Synthesis of Compound 1-31

Compound 11 is replaced with compound 51 by the synthesis of compound 1-1 to give compound 1-31 (single stereo configuration). UPLC RT = 7.270 min; [M+H] ⁺ 556.2.

Example 90: Synthesis of Compound 1-32

Compound 11 is replaced with compound 53 by the synthesis of compound 1-1 to give compound 1-32 (single stereo configuration). UPLC RT=7.363 min; [M+H] ⁺ 569.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75-8.74 (m, 1H), 8.58-8.57 (m, 1H), 8.07-8.06 (m, 1H), 7.89-7.82 (m, 2H), 7.59-7.54 (m, 2H), 7.49-7.46 (m, 1H), 6.40 (s, 1H), 3.51-3.13 (m, 3H), 2.09-1.76 ( m, 9H), 1.5 (s, 9H).

Example 91: Synthesis of Compound 1-33

Compound 11 is replaced with compound 56 by the synthesis of compound 1-1 to give compound 1-33 (single stereo configuration). UPLC RT=6.915 min; [M+H] ⁺ 541.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.78 - 8.72 (m, 1H), 8.53 - 8.52 (m, 1H), 8.07-8.04 (m, 1H), 7.88-7.84 (m, 2H), 7.81-7.52 (m, 3H), 6.37 (s, 1H), 3.42-3.30 (m, 3H), 2.31 (s, 3H), 2.01-1.74 (m, 9H).

Example 92: Synthesis of Compound 1-34

Compound 11 is replaced with compound 57 by the synthesis of compound 1-1 to give compound 1-34 (single stereo configuration). UPLC RT = 7.371 min; [M+H] ⁺ 569.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.72 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.06 (dd, J = 5.6, 9.2 Hz, 1H), 7.90-7.80 (m, 2H), 7.62-7.46 (m, 3H), 6.37 (s, 1H), 4.23-4.10 (m, 1H), 3.41 3.32 (m, 3H), 2.42 (s, 3H), 2.07-1.98 (m, 1H), 1.88-1.66 (m, 8H), 1.37 (t, J = 6.8 Hz, 6H).

Example 93: Synthesis of Compound 1-35

Compound 11 is replaced with compound 65 by the synthesis of compound 1-1 to give compound 1-35 (single stereo configuration). UPLC RT = 7.167 min; [M+H] ⁺ 567.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 - 8.72 (d, J = 4.0 Hz, 1H), 8.62 - 8.60 (d, J = 8.0 Hz) , 1H), 8.08-8.04 (m, 1H), 7.87-7.83 (m, 2H), 7.60-7.51 (m, 3H), 6.34 (s, 1H), 3.42-3.39 (m, 2H), 3.33-3.32 (m, 1H), 3.20-3.15 (m, 1H), 2.39 (s, 3H), 2.03-2.01 (m, 1H), 1.78-1.71 (m, 8H), 0.75-0.70 (m, 2H), 0.49 (m, 1H), 0.37 (m, 1H).

Example 94: Synthesis of Compound 1-36

Substitution of compound 11 with compound 68 affords compound 1-36 (single stereo configuration) by the synthesis of compound 1-1. UPLC RT = 6.284 min; [M+H] ⁺ 571.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 - 8.72 (d, J = 4.0 Hz, 1H), 8.61 - 8.59 (d, J = 8.0 Hz) , 1H), 8.08-8.8.04 (m, 1H), 7.88-7.82 (m, 2H), 7.58-7.52 (m, 3H), 6.37 (s, 1H), 4.60 (m, 2H), 3.61-3.58 (m, 2H), 3.48-3.13 (m, 3H), 2.36 (s, 3H), 2.05 (m, 1H), 1.85-1.74 (m, 8H).

Example 95: Synthesis of Compound 1-37

Compound 11 is replaced with compound 73 by the synthesis of compound 1-1 to give compound 1-37 (single stereo configuration). UPLC RT = 7.013 min; [M+H] ⁺ 613.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.81 - 8.80 (m, 1H), 8.61 - 8.60 (m, 1H), 8.10 - 8.06 (m, 1H), 7.97-7.94 (m, 2H), 7.84-7.80 (m, 1H), 7.78-7.64 (m, 1H), 7.55-7.42 (m, 1H), 6.42 (s, 1H), 4.81-4.78 ( m, 1H), 4.48-4.46 (m, 1H), 3.81-3.80 (m, 1H), 3.27-3.21 (m, 2H), 3.01 (s, 1H), 1.95 (s, 1H), 1.71-1.63 ( m, 8H), 1.39 (s, 9H).

Example 96: Synthesis of Compound 2-1

Substitution of compound 23 with compound 38 affords compound 2-1 (single stereo configuration) by the synthesis of compound 1-11. [M+H] ⁺ 476.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.79 (d, J = 4.8 Hz, 1H), 8.08-8.11 (m, 1H), 8.00 (s, 1H), 7.89 -7.92 (m, 1H), 7.58-7.64 (m, 2H), 6.17 (s, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.51 (d, J = 7.6 Hz, 2H), 3.36-3.39 (m, 1H), 2.25 (s, 3H), 2.08-2.15 (m, 1H), 1.82-1.92 (m, 8H).

Example 97: Synthesis of Compound 2-2

Substitution of compound 23 with compound 39 affords compound 2-2 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT=7.090 min; [M+H] ⁺ 504.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.79 (d, J = 4.8 Hz, 1H), 8.07-8.11 (m, 1H), 7.98 ( s, 1H), 7.89-7.92 (m, 1H), 7.59-7.64 (m, 2H), 6.24 (s, 1H), 3.98 (s, 3H), 3.77 (s, 3H), 3.51 (d, J = 8.0 Hz, 2H), 3.37-3.39 (m, 1H), 2.91-2.95 (m, 1H), 2.08-2.15 (m, 1H), 1.81-1.92 (m, 8H), 1.29 (d, J = 6.8 Hz) , 6H).

Example 98: Synthesis of Compound 2-3

Substitution of compound 23 with compound 44 affords compound 2-3 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT=6.693min; [M+H] ⁺ 512.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.78 (d, J = 4.8 Hz, 1H), 8.11 - 8.08 (m, 1H), 7.91 7.87 (m, 1H), 7.82 (s, 1H), 7.64 - 7.58 (m, 2H), 7.16, 6.98, 6.79 (3s, 1H), 6.21 (s, 1H), 3.81 (s, 3H), 3.48 ( d, J = 8.0 Hz, 2H), 3.36 (overlapping with solvent, 1H), 2.25 (s, 3H), 2.11-2.03 (m, 1H), 1.88-1.80 (m, 8H).

Example 99: Synthesis of Compound 2-4

Substitution of compound 23 with compound 45 affords compound 2-4 (single stereo configuration) by the synthesis of compound 1-11. UPLC RT = 7.265 min; [M+H] ⁺ 540.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 9.6, 5.6 Hz, 1H), 7.89 (dd, J = 10.4, 2.4 Hz, 1H), 7.81 (s, 1H), 7.63 - 7.57 (m, 2H), 7.16, 6.97, 6.79 (3s, 1H, -CHF ₂ ), 6.27 ( s, 1H), 3.81 (s, 3H), 3.51-3.48 (m, 2H), 3.38 (br.s, 1H), 2.98-2.87 (m, 1H), 2.11 (br.s, 1H), 1.91 1.80 (m, 8H), 1.28 (d, J = 6.8 Hz, 6H).

Example 100: Synthesis of Compound 3-1

By the synthesis of the compound 1-1, the compound 11 was replaced with the compound 61 to give the compound 3-1 (single stereo configuration). UPLC RT = 7.183min; [M+H] ⁺ 570.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.76-8.77 (d, J = 4.8 Hz, 1H), 8.62 - 8.63 (d, J = 4.0 Hz) , 1H), 8.07-8.11 (m, 1H), 7.88-7.92 (m, 2H), 7.57-7.63 (m, 3H), 3.37-3.56 (m, 3H), 2.10-2.20 (m, 1H), 1.78 -1.98 (m, 8H), 1.45 (s, 9H).

Example 101: Synthesis of Compound 3-2

Compound 11 is replaced with compound 62 by the synthesis of compound 1-1 to give compound 3-2 (single stereo configuration). UPLC RT = 5.158 min; [M+H] ⁺ 528.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77-8.78 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.07-8.11 (m,1H), 7.89-7.92 (m, 2H), 7.57-7.64 (m, 3H), 3.53-3.64 (m, 2H), 3.37-3.40 (m, 1H), 2.47 (s, 3H), 2.08 -2.19 (m, 1H), 1.77-1.95 (m, 8H).

Example 102: Synthesis of Compound 4-1

Compound 4 (53.4 mg, 0.23 mmol), Compound 1a (59.4 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67.1 mg, 0.35 mmol , N,N-diisopropylethylamine (118 mg, 0.92 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in N,N-dimethylformamide (3 mL) After the reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Purification by prep-HPLC (basic method, elution gradient: mobile phase B: 70 to 35% (v/v%)) gave compound 4-1 (single stereo configuration, 9 mg, yield: 8%) as a white solid . UPLC RT=5.891 min; m/z: [M+H] ⁺ 473.4, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.64 (d, J = 4.0 Hz, 1H), 7.97 - 7.95 (m, 2H) ), 7.76–7.74 (m, 1H), 7.46–7.41 (m, 3H), 7.09 (s, 1H), 6.91–6.88 (m, 1H), 3.76 (s, 3H), 3.29–3.27 (m, 3H) ), 1.97 (s, 3H), 1.81 - 1.60 (m, 9H).

Example 103: Synthesis of Compound 4-2

Substitution of Compound 4 with Compound 5 by the synthesis of Compound 4-1 gave Compound 4-2 (single stereo configuration). UPLC RT=6.090 min; m/z: [M+H] ⁺ 475.4, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.76 - 8.75 (m, 1H), 8.11 - 8.07 (m, 1H), 7.90 –7.89(m,1H), 7.72–7.70(m,1H), 7.69–7.68(m,1H),7.54–7.53(m,1H),7.32(s,1H),6.93–6.90(m,1H) , 3.42–3.34 (m, 3H), 2.28 (s, 3H), 2.05 (s, 3H), 1.81–1.60 (m, 9H).

Example 104: Synthesis of Compound 4-3

Substitution of Compound 4 with Compound 6 by the synthesis of Compound 4-1 gave Compound 4-3 (single stereo configuration). UPLC RT=5.709min; m/z: [M+H] ⁺ 473.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.78–8.77 (m, 1H), 8.11-8.07 (m, 1H), 7.88 –7.85(m,1H), 7.75–7.71(m,1H), 7.54–7.53(m,2H), 7.26(s,1H),7.01–6.99(m,1H),6.72–6.70(m,1H) , 3.91 (s, 3H), 3.55 - 3.52 (m, 2H), 3.35 - 3.33 (m, 1H), 2.25 (s, 3H), 2.07 - 1.73 (m, 9H).

Example 105: Synthesis of Compound 4-4

Substitution of Compound 4 with Compound 7 by the synthesis of Compound 4-1 gave Compound 4-4 (single stereo configuration). UPLC RT=6.738min; m/z: [M+H] ⁺ 501.3, ¹ H NMR (400MHz, CD ₃ OD): δ 8.78 (d, J = 4.8 Hz, 1H), 8.07–8.11 (m, 1H) ), 7.85–7.88 (m, 1H), 7.70–7.74 (m, 1H), 7.60–7.62 (m, 1H), 7.53 (d, J=4.8 Hz, 1H), 7.30 (s, 1H), 6.97 ( d, J = 7.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.49 (d, J = 7.6 Hz, 2H), 3.32 - 3.34 (m, 1H), 3.13–3.17 (m, 1H), 1.92–1.98 (m, 1H), 1.65–1.83 (m, 8H), 1.26 (d, J = 7.2 Hz, 6H).

Example 106: Synthesis of Compound 4-5

Compound 1-4 (single stereo configuration) was obtained by substituting compound 4 for compound 75 by the synthesis of compound 4-1. UPLC RT = 6.346 min; m/z: [M+H] ⁺ 599.4.

Example 107: Synthesis of Compound 4-6

Compound 4-5 (30 mg, 0.05 mmol), trimethylcyclotriboroxane (38 mg, 0.15 mmol) and potassium carbonate (21 mg, 015 mmol) were mixed and suspended in 1,4-dioxane (3 mL) and water. To a mixed solution of (1 mL), tetrakistriphenylphosphine palladium (6.0 mg, 0.005 mmol) was added. The reaction mixture was replaced with nitrogen three times, and then subjected to microwave reaction at 120 ° C for 0.5 hour. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (basic method, elution gradient: mobile phase B: 80-35 % (v/v%)) was purified to give compound 4-6 (1.4 mg, yield: 6%) as a white solid. UPLC RT=5.902min; m/z: [M+H] ⁺ 487.4, ¹ HNMR (400MHz, CD ₃ OD): δ 8.99 (d, J = 5.2 Hz, 1H), 8.21-8.25 (m, 1H) , 8.15–8.18 (m, 1H), 8.06–8.07 (m, 1H), 7.89–7.91 (m, 2H), 7.55–7.58 (m, 1H), 7.00–7.03 (m, 1H), 3.89 (s, 3H), 3.50 - 3.54 (m, 1H), 3.40 (d, J = 7.6 Hz, 2H), 2.41 (s, 3H), 2.05 (s, 3H), 1.60 - 1.85 (m, 9H).

Example 108: Synthesis of Compounds 4-7 and 4-8

Step 1: N-bromosuccinimide (41 mg, 0.23 mmol) was added portionwise to a solution of compound 4-1 (100 mg, 0.23 mmol) in tetrahydrofuran (10 mL). Stir for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. /ethyl acetate = 3/1) Compound 4-7 (80 mg, yield: 63%) was obtained as white solid. m/z: [M+H] ⁺ 551.0.

Step 2: To a solution of compound 4-7 (80 mg, 0.17 mmol) in deuterated dimethyl sulfoxide (5 mL) was added EtOAc (1 mL), tetratriphenylphosphine palladium (39 mg, 0.03 mmol)铯 (166 mg, 0.51 mmol), the reaction was replaced with nitrogen three times and stirred at 130 ° C for 5 hours. After filtration with celite, EtOAc (3 mL, EtOAc) was evaporated. Degradation: Mobile phase B: 80 to 35% (v/v%)) Purified to give compound 4-8 (6.5 mg, yield: 10%) as a pink solid. UPLC RT=5.972min; m/z: [M+H] ⁺ 474.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.76 (d, J = 4.8 Hz, 1H), 8.07–8.11 (m, 2H) ), 7.87–7.90 (m, 1H), 7.53–7.63 (m, 3H), 7.00–7.03 (m, 1H), 3.87 (s, 3H), 3.52–3.42 (m, 3H), 2.09 (s, 3H) ), 1.90–1.98 (m, 1H), 1.73–1.89 (m, 8H).

Example 109: Synthesis of Compound 4-9

Compound 4 was replaced with compound 76 by the synthesis of compound 4-1 to give compound 4-9 (single stereo configuration). UPLC RT=5.268min; m/z: [M+H] ⁺ 459.0, ¹ H NMR (400MHz, CD ₃ OD): δ 8.79 (d, J = 2.0 Hz, 1H), 8.08–8.11 (m, 1H) ), 7.87–7.90 (m, 1H), 7.71–7.75 (m, 1H), 7.57–7.61 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.28–7.30 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.62 (d, J = 8.0 Hz, 2H), 3.32 - 3.33 (m, 1H), 2.11 - 2.28 (m, 1H), 1.76 –1.98 (m, 8H).

Example 110: Synthesis of Compound 4-10

Compound 1a (201 mg, 0.78 mmol) was dissolved in toluene (5 mL) under nitrogen, and then a solution of trimethylaluminum in toluene (1.3 mL, 1.6 M) was added and stirred at 110 ° C for 2 hours. Under a nitrogen atmosphere, the reaction system was cooled to room temperature, then compound 8 (150 mg, 0.52 mmol) was added and stirred at 110 ° C for 4 hours. Then, the reaction was quenched by dropwise addition of 10 ml of methanol, filtered over Celite and washed with dichloromethane/methanol mixture (10/1, 5mL×3). The residue was purified by prep-HPLC ( EtOAc (EtOAc:EtOAc) UPLC RT=6.924min; m/z: [M+H] ⁺ 501.2, ¹ H NMR (400MHz, CD ₃ OD): 8.77–8.75 (d, J=8.0Hz, 1H), 8.11–8.09 (m, 2H) ), 7.80–7.75 (m, 1H), 7.57–7.54 (m, 3H), 7.24 (s, 1H), 7.02–7.00 (m, 1H), 3.82 (s, 3H), 3.34–3.32 (m, 3H) ), 2.80–2.73 (m, 1H), 1.90–1.70 (m, 9H), 1.30–1.19 (m, 6H).

Example 111: Synthesis of Compound 4-11

Substitution of compound 12 with compound 77 affords compound 4-11 (single stereo configuration) by the synthesis of compound 4-10. UPLC RT=6.797 min; m/z: [M+H] ⁺ 527.2, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75 (d, J = 4.8 Hz, 1H), 8.18 (dd, J = 4.8) , 1.6 Hz, 1H), 8.08 (dd, J = 9.2, 5.6 Hz, 1H), 7.88 (dd, J = 10.4, 2.4 Hz, 1H), 7.78 (dd, J = 7.6, 1.6 Hz, 1H), 7.60 (dt, J = 8.6, 2.8 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.34 (dd, J = 7.6, 4.8 Hz, 1H), 7.25 (s, 1H), 3.42 (d, J = 7.6 Hz, 2H), 3.36 (br.s, 1H), 2.13 (s, 3H), 2.05 (br.s, 1H), 1.87 - 1.77 (m, 8H).

Example 112: Synthesis of Compounds 4-12 and 4-13

By the synthesis of compound 4-10, compound 12 was replaced with a mixture of compounds 78A and 78B to give a mixture of compounds 4-12 and 4-13, followed by prep-HPLC (base method, elution gradient: mobile phase B: 45). ~65% (v/v%)) isolated compound 4-12 (single stereo configuration, peak time: 15.6 to 16.4 minutes) and compound 4-13 (single stereo configuration, peak time: 16.5 to 17.0 minutes) ), all white solids. m/z: [M+H] ⁺ 527.2, 4-12: UPLC RT = 6.494 min; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (d, J = 4.8 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.09 - 8.03 (m, 1H), 7.86 (dd, J = 2.8, 10.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.27 (s, 1H), 3.42 (d, J = 7.6 Hz, 2H), 3.38 - 3.32 (m, 1H), 2.13 (s, 3H), 2.07–1.98 (m, 1H), 1.88–1.69 (m, 8H); 4-13: UPLC RT = 6.506 min; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75 (d) , J = 4.4 Hz, 1H), 8.50 (d, J = 4.4 Hz, 1H), 8.11 - 8.02 (m, 1H), 7.87 (dd, J = 2.4, 10.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.39 - 7.31 (m, 1H), 7.00 (s, 1H), 3.50 (d, J = 8.0 Hz, 2H), 3.42 - 3.33 (m, 1H) ), 2.46 (s, 3H), 2.11 - 2.00 (m, 1H), 1.91 - 1.69 (m, 8H).

Example 113: Synthesis of Compound 4-14

Substitution of compound 8 with compound 74 affords compound 4-14 (single stereo configuration) using the synthesis of compound 4-10. UPLC RT=5.917min; m/z: [M+H] ⁺ 476.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.75–8.76 (d, J=4.0Hz, 1H), 8.07–8.10 (m) , 2H), 7.86–7.90 (m, 1H), 7.53–7.63 (m, 3H), 7.20 (s, 1H), 7.00–7.03 (m, 1H), 3.37 (s, 3H), 3.33–3.41 (m) , 3H), 1.90–1.98 (m, 1H), 1.72–1.83 (m, 8H).

Example 114: Synthesis of Compounds 4-15 and 4-16

Step 1 : N-bromosuccinimide (19 mg, 0.11 mmol) was added portionwise to a solution of compound 4-14 (50 mg, 0.11 mmol) in THF (5 mL). Stir under 10 minutes. The reaction was quenched with EtOAc (EtOAc)EtOAc. /Methanol = 10/1) Compound 4-15 (42 mg, yield: 72%) was obtained as white solid. m/z: [M+H] ⁺ 554.2.

Step 2: Compound 4-15 (42 mg, 0.08 mmol), deuterated acid (36.8 mg, 0.8 mmol), tetratriphenylphosphine palladium (46.2 mg, 0.04 mmol) and triethylamine (97.1 mg, 0.96 mmol) The mixture was stirred at 110 ° C for 5 hours in deuterated dimethyl sulfoxide (3 mL). The reaction mixture was poured into water, EtOAc (EtOAc m. (20 mg, yield: 52%) was obtained as a yellow solid. UPLC RT = 5.914 min; m/z: [M+H] ⁺ 477.4.

Example 115: Synthesis of Compound 4-17

Substitution of compound 4 with compound 79 affords compound 4-17 (single stereo configuration) by the synthesis of compound 4-10. UPLC RT = 7.292min; m/z: [M+H] ⁺ 555.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.74 - 8.76 (d, J = 4.0 Hz, 1H), 8.19 - 8.21 (m , 1H), 8.06–8.10 (m, 1H), 7.86–7.89 (m, 1H), 7.76–7.78 (m, 1H), 7.57–7.62 (m, 1H), 7.53–7.54 (d, J=4.0 Hz) , 1H), 7.33–7.36 (m, 1H), 7.29 (s, 1H), 3.35–3.43 (m, 3H), 2.76–2.83 (m, 1H), 2.00–2.08 (m, 1H), 1.76–1.99 (m, 8H), 1.15–1.30 (m, 6H).

Example 116: Synthesis of Compound 4-18

Substitution of compound 8 with compound 80 affords compound 4-18 (single stereo configuration) by the synthesis of compound 4-10. UPLC RT=6.319min; m/z: [M+H] ⁺ 487.2, ¹ H NMR (400MHz, CD ₃ OD): δ 8.77-8.65 (m, 1H), 8.14-8.00 (m, 2H), 7.90 -7.77(m,1H), 7.63-7.41(m,3H), 7.21(s,1H), 7.04-6.91(m,1H),3.84(s,3H),3.44-3.34(m,3H),2.48 - 2.36 (m, 2H), 2.09-1.84 (m, 1H), 1.83-1.61 (m, 8H), 1.15-1.02 (m, 3H).

Example 117: Synthesis of compound 4-19

Potassium carbonate (60 mg, 0.42 mmol) and 2-iodopropane (51 mg, 0.3 mmol) were added to a solution of compound 4-1 (100 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL). The system was heated to 70 ° C and stirred for 24 hours, then the reaction system was cooled to room temperature and quenched with water. The obtained mixture was extracted with EtOAc. EtOAc (EtOAc m. -35% (v/v%)) was purified to give compound 4-19 (2.3 mg, yield: 2%) as white solid. UPLC RT=6.876min; m/z: [M+H] ⁺ 515.3, ¹ H NMR (400MHz, CD ₃ OD): δ 8.74 - 8.73 (d, 1H), 8.08-8.05 (m, 2H), 7.88 -7.85(m,1H), 7.61-7.55(m,1H),7.53-7.51(m,2H),7.35(s,1H),7.05-6.98(m,1H),4.44-4.37(m,1H) , 3.84(s,3H), 3.61(s,3H), 3.39-3.30(m,3H),2.21-2.27(m,1H),2.06(s,3H),2.03-2.00(m,1H),1.81 -1.60 (m, 7H), 1.1-0.8 (m, 4H).

Example 118: Synthesis of Compound 4-20

Compound 10 (50 mg, 0.18 mmol), Compound 1a (55.1 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.4 mg, 0.27 mmol) , a solution of N,N-diisopropylethylamine (105 mg, 0.73 mmol) and 4-dimethylaminopyridine (12 mg, 0.05 mmol) in dichloromethane (3 mL) Diluted with dichloromethane (10 mL), washed with water (25 mL) and brine. 70 to 35% (v/v%)) purification gave compound 4-20 (single stereo configuration, 29 mg, yield: 31%) as a white solid. UPLC RT=6.881 min; m/z: [M+H] ⁺ 513.3, ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 - 8.73 (d, 1H), 8.07-8.05 (m, 2H), 7.87 -7.84 (m, 1H), 7.61-7.55 (m, 1H), 7.53-7.50 (m, 2H), 7.19 (s, 1H), 7.00-6.97 (m, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 3.39-3.30 (m, 3H), 2.15 (s, 3H), 1.91 (s, 1H), 1.81-1.69 (m, 7H), 1.06-0.94 (m, 4H).

Example 119: Synthesis of compounds 5-1A and 5-1B

By the synthesis method of the compound 4-1, the compound 1a was replaced with the compound 2 to obtain the compound 5-1 (cis-trans isomer mixture), and the compound 5-1 was subjected to prep-HPLC (basic conditions, elution gradient: mobile phase B). : 65 to 30% (v/v%)) Compound 5-1A (peak time: 11.6-12.0 minutes, single stereo configuration) and 5-1B (peak time: 11.1-11.6 minutes, single stereostructure) were isolated. type). m/z: [M+H] ⁺ 433.1; 5-1A: UPLC RT = 4.158 min; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.07 - 8.09 (m, 1H), 7.54 - 7.57 (m, 1H), 7.18(s,1H), 6.99–7.03(m,3H), 3.30–3.32(m,2H),2.52–2.58(m,1H),2.46(s,6H),2.08(s,3H) , 1.56–1.81 (m, 9H).

Example 120: Synthesis of Compounds 6-1A and 6-1B

Compound 6-1 is reacted with compound 4-1 to obtain compound 6-1 (cis-trans isomer mixture), and compound 6-1 is subjected to prep-HPLC (basic conditions, elution gradient: mobile phase B). : 30 to 70% (v/v%)) Compound 6-1A was isolated (peak time: 17.2-17.8 min, single stereo configuration) and 6-1B (peak time: 18.0-18.5 min, single stereostructure) type). m/z: [M+H] ⁺ 545.2; 6-1A: UPLC RT = 4.194 min; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.17 - 8.15 (d, J = 8.0 Hz, 1H), 7.97 –7.95 (d, J=8.0 Hz, 1H), 7.46–7.43 (m, 1H), 7.08–7.06 (s, 1H), 7.00–6.98 (d, J=8.0 Hz, 1H), 6.91–6.88 (m) , 1H), 3.77 (s, 3H), 3.00 - 2.97 (m, 2H), 2.39 (s, 3H), 2.36 - 2.32 (m, 1H), 2.01 (s, 3H), 1.74 - 1.71 (d, J = 12.0Hz, 2H), 1.59-1.56 ( d, J = 12.0Hz, 2H), 1.34-1.27 (m, 3H), 0.91-0.87 (m, 2H); 6-1B: UPLC RT = 4.429min; 1 H NMR (400 MHz, CD ₃ OD): δ 8.16 - 8.14 (d, J = 8.0 Hz, 1H), 7.95 - 7.93 (m, 1H), 7.44 - 7.42 (m, 1H), 7.09 (s, 1H) , 7.03–7.01 (d, J=8.0 Hz, 1H), 6.89–6.86 (m, 1H), 3.75 (s, 3H), 3.18 (s, 1H), 2.48–2.47 (m, 1H), 2.39 (s) , 3H), 2.00 (s, 3H), 1.46 - 1.44 (m, 10H).

Example 121: Synthesis of Compound 7-1

Compound 4-1 (single stereo configuration) was obtained by substituting compound 4 with compound 9 by the synthesis of compound 4-1. UPLC RT=6.278min; m/z: [M+H] ⁺ 487.3, ¹ H NMR (400MHz, CD ₃ OD): δ 8.74 - 8.73 (m, 1H), 8.08-8.04 (m, 2H), 7.87 -7.84 (m, 1H), 7.61-7.55 (m, 1H), 7.53-7.50 (m, 2H), 7.17 (s, 1H), 7.01-6.98 (m, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 3.39-3.30 (m, 3H), 2.03 (s, 3H), 1.90-1.69 (m, 9H).

Example 122: Synthesis of Compound 8-1

Compound 8-1 (single stereo configuration) was synthesized by the same synthesis method of Compound 1-1. UPLC RT = 7.813 min; [M+H] ⁺ 568.0; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75-8.76 (m, 1H), 8.07-8.09 (m, 1H), 7.87-7.90 (m) , 1H), 7.55-7.61 (m, 3H), 7.40-7.45 (m, 2H), 7.34-7.36 (m, 1H), 6.31 (s, 1H), 3.43-3.45 (m, 2H), 3.32-3.35 (m, 1H), 2.05-2.07 (m, 1H), 1.77-1.85 (m, 8H), 1.35 (s, 9H).

Example 123: Synthesis of Compound 8-2

Compound 8-2 (single stereo configuration) was synthesized by the same synthesis method of Compound 1-1. UPLC RT = 6.613 min; [M+H] ⁺ 486.0; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.44 - 8.45 (m, 1H), 7.96-8.00 (m, 1H), 7.75 - 7.80 (m) , 3H), 7.47-7.49 (m, 2H), 7.17-7.19 (m, 1H), 6.41 (s, 1H), 3.49-3.51 (m, 2H), 3.27-3.31 (m, 1H), 2.06-2.08 (m, 1H), 1.71-1.81 (m, 8H), 1.27 (s, 9H).

Example 124: Single crystal diffraction experiment of compounds 1-32 and 4-1

1. Single crystal culture: Compounds 1-32 (10 mg) and 4-1 (10 mg) were dissolved in anhydrous methanol (10 mL), respectively, and water (4 mL) was added, filtered, and the filtrate was added to two 100 mL single ports. In an Erlenmeyer flask, it was allowed to stand at 10-20 ° C for 20-30 days, and a single crystal was precipitated, and a single crystal was collected for single crystal diffraction test.

2. The test parameters are shown in the following table:

3. Test results: The configuration of compound 1-32 was determined by single crystal diffraction to be a cis configuration, and the chemical name was: 5-(tert-butyl)-N-((1s,4s)-4-(6- Fluoroquinolin-4-yl)cyclohexyl)methyl)-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide. The configuration of Compound 4-1 was determined by single crystal diffraction to be a cis configuration, and the chemical name was: N-(((1s, 4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl )-4-(2-Methoxypyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxamide.

According to the single crystal diffraction results of the compounds 1-32 and 4-1, the compounds of the present invention 1-1 to 1-37, 2-1 to 2-4, 3-1 to 3-2, 4-1 to 4-20 can be obtained. 7-1, 8-1~8-2 are all cis configurations, and the chemical names of some compounds are shown in the following table (named by Chemdraw software):

Biological test examples: Determination of IDO biological activity

Example 1: HeLa cell-based IDO inhibitory activity test (IC ₅₀ )

HeLa cell line source: ATCC, cultured in MEM/EBSS liquid medium, plus bovine fetal serum (10% FBS), penicillin-streptomycin (100,000 U/L), non-essential amino acids (0.1 mM), sodium pyruvate (Na-pyruvate) (1.0 mM). The cells were maintained at 37 ° C, 95% humidity and 5% carbon dioxide in the incubator. Co-incubation with gamma-interferon (IFNy) allows expression of IDO, which allows the metabolism of tryptophan to N-formyl kynurenine in the medium. The specific experimental methods are as follows:

HeLa cells were seeded in 96-well plates at 25,000 cells/well, each well containing 100 μl of medium, followed by IFNγ and specific concentrations of test compound (concentration range 10 μM to 1 nM, which is in conventional medium) The final volume of 200 μL) induced cells overnight to express human recombinant IDO. Next, incubate, transfer the supernatant (140 μL) to a 96-well plate, add 6.1N TCA (10 μL) and continue incubation at 50 ° C for 30 minutes to fully hydrolyze the N-formyl kynurenine produced by IDO. For kynurenine. The reaction solution was then centrifuged at 2500 rpm for 10 minutes to remove the solid precipitate, after which the supernatant was transferred to another 96-well plate at 100 μL/well, and 100 μL of 2% (w/v) 4-(N was added. , N-dimethylamino) benzaldehyde in acetic acid solution. Incubation at room temperature for 10 minutes, kynurenine producing a yellow solution can be recorded with a microplate reader (TECAN Infinite M1000 Pro) at 480 nm.

The percentage inhibition of each concentration of the test compound was determined by using 0.1% DMSO blank solution as a reference to evaluate the reduction of kynurenine in the test compound system. The data was determined by Graph Pad.

4 IC ₅₀ values were obtained by nonlinear regression.

The activity test results of the five-membered heteroaryl ring derivative of the present invention, IC ₅₀ values are shown in the following table:

Compound number	Hela cell IC 50 (nM)	Compound number	Hela cell IC 50 (nM)
1-1	0.56	1-36	0.62
1-3	11.1	1-37	0.85
1-4	58.4	2-1	37.8
1-5	1.18	2-2	2.61
1-6	1.50	2-3	1.68
1-8	3.38	2-4	0.82
1-9	39.5	3-1	1.85
1-10	48.1	3-2	4.17
1-11	0.39	4-1	0.63
1-12	0.82	4-2	57.8
1-13	0.58	4-3	0.69
1-14	0.27	4-4	13.0
1-15	38.6	4-5	3.37
1-16	0.37	4-6	8.47
1-17	3.16	4-8	1.21
1-18	0.33	4-9	1.84
1-19	0.61	4-10	40.0
1-20	0.99	4-11	0.42

1-21	1.35	4-12	1.00
1-22	8.17	4-13	2.36
1-23	0.81	4-14	0.95
1-24	0.80	4-16	1.14
1-25	0.64	4-17	15.1
1-26	0.44	4-18	4.35
1-28	0.51	4-19	2.87
1-31	0.31	4-20	0.55
1-32	1.12	6-1B	31.6
1-33	0.48	7-1	1.34
1-34	0.86	8-1	1.90
1-35	0.51	8-2	13.1
Ref.A	87.5	Ref.C	34.6
Ref.B	78.4	Ref.E	22.1

Example 2: Pharmacokinetic test

Drugs and reagents: The test compounds were prepared into solutions by the following solvents, and the other reagents were of analytical grade:

Test animals: male SPF grade SD rats (6 in each group) were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., all animals were fasted for 10-14 hours before administration, and returned to food 4 hours after administration. .

Dosage: Oral (PO) 10 mg/Kg, 10 mL/kg; intravenous (IV): 2.5 mg/Kg, 5 mL/Kg.

Pharmacokinetic test: The test compounds were administered to SD male rats by oral and intravenous administration respectively. Blood samples were collected by jugular vein puncture. Each sample was collected about 0.20 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows: Blood collection time in the intravenous administration group: before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after administration. Blood collection time in the oral administration group: before administration, 0.25 h after administration, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h. Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis. Plasma samples were analyzed by LC-MS/MS (API5500). The oral bioavailability average of the test samples was calculated using the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model based on the drug blood concentration data. %), area under the curve (AUC), half-life (t _1/2 ), and mean residence time (MRT). The results are as follows:

Example 3: Cytochrome oxidase P450 inhibition test

The inhibition of the CYP3A4 subtype by the compounds was evaluated by LC-MS/MS method. The method mixes the test compound with a solution of human liver microsomes containing the CYP model substrate, and is incubated together under the condition of adding NADPH, and the compound inhibits the inhibition of CYP3A4 by measuring the amount of the metabolite of the model substrate in the reaction solution. ₅₀ . The specific experimental methods are as follows:

The test compound was prepared in DMSO as a 10 mM stock solution, which was then diluted to 4 mM with an acetonitrile solution. At the same time, the corresponding reference inhibitor solution was prepared for the CYP subtype, for example, the reference inhibitor was Ketoconazole, and the two were separately prepared (8 μL inhibitor DMSO stock solution + 12 μL acetonitrile), and the sample prepared under the above conditions was 400X concentration. Subsequently, the above solution was diluted with a mixture of DMSO:acetonitrile (v/v: 40:60) in a 3-fold gradient to prepare a final test solution, and each test compound was set at 7 concentration points, and the initial test final concentration was 10 uM. The NADPH, CYP enzyme model substrate and human liver microsome solution were diluted to a suitable concentration with preheated potassium phosphate buffer (0.1 M, pH 7.4). The human liver microsome solution was purchased from BD Gentest (20 mg/mL, Corning, Cat. #452161).

400 μL of human liver microsome solution (0.2 mg/mL) was added to each well of the test compound in a 96-well plate, followed by the addition of 2 μl of the test compound prepared by the above gradient dilution to the final test sample; for the reference inhibitor corresponding to each well, 200 μL of human liver microsome solution (0.2 mg/mL) and 1 μL of the final test sample were added. Each well of the corresponding model substrate was dispensed into 15 μL into a 96-well plate, and the microsome solution was mixed, and then 30 μL of the test compound/reference inhibitor-human liver microsome mixture was transferred and transferred to the substrate-added solution. In a 96-well plate, mix and preheat for 5 minutes at 37 ° C, then start the reaction by adding 15 μL of 8 mM NADPH solution preheated at 37 °C. Each test was provided with a duplicate well control and a blank control with no test substance added. A 96-well plate containing a total volume of 60 μL of the reaction solution was incubated at 37 ° C. After the incubation, 120 μL of a cold acetonitrile solution containing an internal standard was added to each well to terminate the reaction, followed by a 96-well plate on a microplate shaker. Shake for 5 minutes (600 rpm / min), put into a centrifuge 6000 rpm, 4 degrees, away from 20 minutes. Then, 40 μL of the supernatant was transferred from each well to another 96-well plate, and 80 μL of ultrapure water was added to each well, and the mixture was placed in a shaker for 5 minutes (600 rpm/min), centrifuge 6,000 rpm, 4 degrees. , 20 minutes away. Then LC-MS/MS detection was performed. The inhibition rate was determined by comparing the amount of model substrate metabolites at each test concentration and without test substance addition. In GraphPad Prism 5.0 software, the logarithm of the test concentration was plotted on the abscissa and the inhibition rate was on the ordinate. linear regression (Sigmoidal (non-linear) dose -response model) analysis, the IC ₅₀ value of the test compound. The results are as follows:

Example 4: Cardiac Safety Assessment - hERG Test

This experiment uses a hHG cDNA to stably transfect and express a pHO hERG channel CHO cell line. The cells were cultured in a humidified incubator containing 5% CO ₂ at 37 ° C in medium (Ham's F12, 10% v/v FBS, 100 μg/mL hygromycin B, 100 μg/mL geneticin) (from Invitrogen) Cultivate. The cells were grown under the above conditions and reached a confluence of about 80-90%. The cells were treated with Detachin (Genlantis) for 3-5 minutes. The medium was titrated for 15-20 times at 37 ° C, and then the cells were resuspended in CHO-S-SFM II medium (serum-free medium, Invitrogen) buffered with HEPES (25 mM). Cells used in QPatch studies must meet the following criteria: under microscopy, most of the suspended cells should be single and isolated; the survival rate is greater than 95%; the cell density in the final suspension should be prior to application to the QPatch mixing chamber. In the range of 3-8 x 10 ⁶ cells/mL. Cells that meet the above criteria can be used for records within 4 hours of harvest.

The test compound was made into a 10 mM DMSO stock solution. Selecting six doses (30,10,3,1,0.3 and 0.1 uM) to obtain a curve fit and IC _50. The final DMSO concentration was 0.1% or less. The IC ₅₀ evaluation doses of the positive control cisapride were 3, 1, 0.3, 0.1, 0.03 and 0.01 μM, respectively. Electrophysiological recording internal solution composition: CaCl2 2 mM, MgCl2 1 mM, KCl 4 mM, NaCl 145 mM, Glucose 10 mM, HEPES 10 mM, pH 7.4 (NaOH), external solution composition: CaCl2 374 mM, MgCl2 1.75 mM, KCl 120 mM, HEPES 10 mM, EGTA 5 mM Na-ATP 4 mM, pH 7.25 (KOH) (all reagents used were from sigma).

Whole cell recording was performed using automated QPatch (Sophion Biosciences, Denmark). Cells were recorded for 120 seconds to assess current stability. The above voltage is then applied to the cells every 15 seconds throughout the process. Only stable cells with recorded parameters above the threshold are allowed to enter the drug testing procedure. All experiments were carried out at about 25 °C. An external solution containing 0.1% DMSO (vehicle) was applied to the cells to establish a baseline. After the current was allowed to stabilize for 3 minutes, the test compound was tested. The compound solution was added and the cells were kept in the test solution until the action of the compound reached a steady state for up to 4 minutes. For dose-measurement measurements, compounds are cumulatively applied to cells from low to high concentrations. The compound was rinsed with an external solution after testing.

The data was analyzed using Sophion Assay software (assay software V5.0), Microsoft Excel and Graphpad Prism 5.0 to obtain the compound IC ₅₀ . The results are as follows:

Compound number	hERG IC 50 (μM)
1-11	>30
1-12	>30
1-24	>30
1-32	>30
1-35	>30
Ref.A	4.37

Note that Ref. A (positive control) in the biological test example is the compound 14-1b disclosed in Chinese Patent Application CN201710644418X, chemical name: 5-methyl-N-(((1r, 4r or 1s, 4s)- 4-(2-methylpyridin-4-yl)cyclohexyl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-3-carboxamide;

Ref.B (positive control) is compound 13-13 disclosed in Chinese patent application CN201710644418X, chemical name: 5-methyl-N-(1-(4-phenylcyclohexyl)ethyl)-2-(pyridine- 3-yl)-1H-pyrrole-3-carboxamide;

Ref.C (positive control) is compound 6-11a disclosed in Chinese patent application CN201710644418X, chemical name: N-(((1r, 4r) or (1s, 4s)-4-phenylcyclohexyl)methyl)- 4-(pyridin-3-yl)-1H-pyrrole-3-carboxamide;

Ref.D (positive control) is compound 24-1b disclosed in Chinese patent application CN201710644418X, chemical name: N-(((1r, 4r) or (1s, 4s)-4-(6-fluoroquinoline-4- Cyclohexyl)methyl)-5-isopropyl-2-(2-(trifluoromethoxy)phenyl)-1H-pyrrole-3-carboxamide;

Ref. E (positive control) is Example 239 disclosed in Chinese Patent Application No. CN2015800603285, chemical name: N-((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl) Cyclohexyl)ethyl)-4-(5-methoxypyridin-2-yl)benzamide.

Claims (27)

1. a five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;

   

   Wherein Cy is a pyrrole ring or an imidazole ring; when Cy is a pyrrole ring, X is NR, Y is CR ₁ , Z is CR ₂ , or X is CR ₁ , Y is NR, Z is CR ₂ '; When it is an imidazole ring, X is NR, Y is CR ₁ , and Z is N;

   A is

   

   

   R is independently H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S( O) ₂ R _a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl Or a 5-6 membered heteroaryl group; said C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group Substituted or optionally substituted with one or more groups at any position selected from the group consisting of: hydrazine, halogen, hydroxy, fluorenyl, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 alkylamino, -C _1-6 alkylene-OH, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C (O) NH(C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _{1 -6} alkyl, -S(O) _0-2 -C _1-6 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S( O) one or more of ₂ -N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl; R _{a is} independently H, C _1-6 Alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, or 3-8 membered heterocycloalkyl C _1-6 alkyl;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 a heteroaryl group; the phenyl or 5-6 membered heteroaryl group being unsubstituted or optionally substituted at 1 to 3 groups at any position, the group being an anthracene, a halogen, an amino group, a cyano group, C One or more of _1-3 alkyl, C _1-3 alkoxy and halogenated C _1-3 alkoxy;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy or halo C _1-3 alkoxy.
2. The five-membered heteroaryl ring derivative (I) according to claim 1, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Characterized in that the solvate is a hydrate and/or a methanolate;

   And/or, when Cy is a pyrrole ring, X is NR, Y is CR ₁ , and Z is CR ₂ , the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And/or, when Cy is a pyrrole ring, X is CR ₁ , Y is NR, and Z is CR ₂ ', the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And/or, when Cy is an imidazole ring, X is NR, Y is CR ₁ , and Z is N, the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And / or, said

   

   for

   

   

   And/or when the A is

   

   When said

   

   for

   

   And/or when the A is

   

   When said

   

   for

   

   And/or when the A is

   

   When said

   

   for

   

   And/or when the A is

   

   When said

   

   for

   

   And/or, when the R is a C _1-6 alkyl group, the C _1-6 alkyl group is a C _1-3 alkyl group;

   And/or, when the R is a C _3-8 cycloalkyl group, the C _3-8 cycloalkyl group is a C _3-5 cycloalkyl group;

   And/or, when said R ₂ is halogen, said halogen is fluorine, chlorine, bromine or iodine;

   And/or, when said R ₂ 'is halogen, said halogen is fluorine, chlorine, bromine or iodine;

   And/or, when said R ₂ 'is a C _1-3 alkyl group, said C _1-3 alkyl group is methyl, ethyl, n-propyl or isopropyl;

   And/or, when said R ₅ is halogen, said halogen is fluorine, chlorine, bromine or iodine.
3. The five-membered heteroaryl ring derivative (I) according to claim 2, an isomer, a solvate thereof, a crystal form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, When the solvate is a hydrate, the molar ratio of the water to the five-membered heteroaryl ring derivative (I) is from 1.0 to 1.5;

   And/or, when the solvate is a methanolate, the molar ratio of the methanol to the five-membered heteroaryl ring derivative (I) is from 1.0 to 1.5;

   And/or, when the solvate is a water·methanol compound, the molar ratio of the water to the five-membered heteroaryl ring derivative (I) is from 1.0 to 1.5, and the methanol and The molar ratio of the five-membered heteroaryl ring derivative (I) is from 1.0 to 1.5;

   And/or, when Cy is a pyrrole ring, X is NR, Y is CR ₁ , and Z is CR ₂ , the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And/or, when Cy is a pyrrole ring, X is CR ₁ , Y is NR, and Z is CR ₂ ', the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And/or, when Cy is an imidazole ring, X is NR, Y is CR ₁ , and Z is N, the five-membered heteroaryl ring derivative (I) is as

   

   Shown

   And/or, when the R is a C _1-6 alkyl group, the C _1-6 alkyl group is a methyl group, an ethyl group, a n-propyl group or an isopropyl group;

   And/or, when R is a C _3-8 cycloalkyl group, the C _3-8 cycloalkyl group is a cyclopropyl group, a cyclobutyl group or a cyclopentyl group;

   And/or, when said R ₂ is halogen, said halogen is bromine;

   And/or, when said R ₂ 'is halogen, said halogen is iodine;

   And/or, when said R ₂ 'is a C _1-3 alkyl group, said C _1-3 alkyl group is a methyl group;

   And/or, when said R ₅ is halogen, said halogen is fluorine.
4. The five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable according to at least one of claims 1 to 3 An acceptable salt, characterized in that Cy is a pyrrole ring;

   And / or, A is

   

   And/or R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; said C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or alternatively one Or multiple hydroxyl substitutions at any position;

   And/or R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl or 2-deutero-2-yl;

   And/or R _{2 is} independently hydrogen, deuterium, halogen or cyano;

   And/or, R ₂ 'is independently hydrogen, deuterium or C _1-3 alkyl;

   And/or, R _{3 is} independently

   

   And/or R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   And/or R _{5 is} independently hydrogen or halogen.
5. The five-membered heteroaryl ring derivative (I) according to claim 4, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that A is

   

   

   And/or, R is independently H;

   And/or R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl or 2-deutero-2-yl;

   And/or, R _{2 is} independently hydrogen, deuterium or halogen;

   And/or, R _{3 is} independently

   

   And/or R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

   And/or, R _{5 is} independently hydrogen.
6. The five-membered heteroaryl ring derivative (I) according to claim 5, an isomer thereof, a solvate, a crystal form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that A is

   

   

   And/or R _{1 is} independently hydrogen, methyl, ethyl, propyl, deuterated methyl or 2-deutero-2-yl;

   And/or, R _{2 is} independently hydrogen or deuterium.
7. The five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable according to at least one of claims 1 to 3 An acceptable salt characterized in that Cy is an imidazole ring;

   And/or, R is independently C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or alternatively one or more Hydroxyl substitution at any position;

   And/or, R _{1 is} independently tert-butyl.
8. The five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable according to at least one of claims 1 to 3 An acceptable salt characterized in that it is any of the following:

   Option 1: A is

   

   R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium, halogen or cyano;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen or halogen;

   Scheme 2: Cy is a pyrrole ring;

   A is

   

   R is independently H;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium, halogen or cyano;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen or halogen;

   Scheme 3: Cy is a pyrrole ring;

   A is

   

   R is independently H;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium or halogen;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen;

   Scheme 4: Cy is a pyrrole ring;

   A is

   

   R is independently H;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium or halogen;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen;

   Scheme 5: Cy is a pyrrole ring, X is NR, Y is CR ₁ , and Z is CR ₂ ;

   A is

   

   R is independently H;

   R _{1 is} independently methyl, ethyl, propyl, isopropyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen or deuterium;

   R _{3 is} independently

   

   R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen;

   Scheme 6: Cy is a pyrrole ring, X is CR ₁ , Y is NR, and Z is CR ₂ ';

   A is

   

   R is independently H;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 'is} independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methoxy, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen;

   Scheme 7: Cy is an imidazole ring;

   A is

   

   R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl or 2-deutero-2-yl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen or halogen;

   Option 8: A is

   

   R is independently C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or alternatively substituted with one or more hydroxy groups Any position;

   R _{1 is} independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl or 2-deutero-2-yl;

   R _{2 is} independently hydrogen, deuterium, halogen or cyano;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen or halogen;

   Option 9: A is

   

   R is independently H, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;

   R _{1 is} independently t-butyl;

   R _{2 is} independently hydrogen, deuterium, halogen or cyano;

   R ₂ 'is independently hydrogen, deuterium, halogen or C _1-3 alkyl;

   R _{3 is} independently

   

   R _{4 is} independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;

   R _{5 is} independently hydrogen or halogen;

   Option 10: stated

   

   for

   

   A is

   

   

   R ₁ is methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, or deuterated methyl;

   R ₂ is hydrogen, deuterium, halogen, cyano, amino, acyl, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or a 5-6 membered heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl , C _1-3 alkoxy, halo or a C _1-3 alkoxy group substituted at any position;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 11: stated

   

   for

   

   A is

   

   

   

   R ₁ is methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, deuterated methyl, or 2-deutero-2-yl;

   R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 12: stated

   

   for

   

   A is

   

   

   R ₁ is methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl, or 2-deutero-2-yl;

   R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 13: stated

   

   for

   

   A is

   

   

   R ₁ is methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, isopropyl, tert-butyl, deuterated methyl, or 2-deutero-2-yl;

   R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C _1-3 alkyl, C _{1- a} substituent of a ₃ -alkoxy group or a halogenated C _1-3 alkoxy group at any position;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 14: stated

   

   for

   

   A is

   

   

   Z is N or CR ₂ ;

   R is H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S(O) ₂ R _a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl or 5 a 6-membered heteroaryl group; the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group is unsubstituted or Optionally substituted at any position by one or more groups selected from the group consisting of: hydrazine, halogen, hydroxy, thiol, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, -C _1-6 alkylene-OH, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C(O NH(C _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _1-6 Alkyl, -S(O) _0-2 -C _1-6 alkyl, -S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S(O) One or more of _2- N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl and 3-8 membered heterocycloalkyl; R _a is H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, 5-6 membered heteroaryl, C _3-8 cycloalkyl C _1-6 alkyl, or 3-8 Heterocycloalkyl C _1-6 alkyl;

   R ₁ is methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD ₃ ), 2-deutero-2-yl {-CD(CH ₃ ) ₂ }; , R ₁ is a trifluoromethyl group, or a difluoromethyl group;

   R ₂ is hydrogen, deuterium, halogen, cyano, amide, ester, C _1-3 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted or optionally substituted with 1 to 3 groups at any position, the group being an anthracene, a halogen, an amino group, a cyano group, C One or more of _1-3 alkyl, C _1-3 alkoxy and halogenated C _1-3 alkoxy;

   R ₃ is

   

   R ₄ is methyl, cyano, methoxy, ethoxy, trifluoromethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 15: stated

   

   for

   

   A is

   

   

   R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, deuterated methyl, or 2-deutero-2-yl;

   R ₂ is hydrogen, deuterium, halogen, or C _1-3 alkyl;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy;

   Option 16:

   

   for

   

   A is

   

   

   R is H, -C(O)N(R _a ) ₂ , -C(O)R _a , -C(O)OR _a , -S(O) ₂ N(R _a ) ₂ , -S(O) ₂ R _a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 aryl, or a 5-6 membered heteroaryl group; said C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, or 3-8 membered heterocycloalkyl group Substituted or selectively 1 to 3 are selected from the group consisting of: hydrazine, halogen, hydroxy, decyl, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino, - C(O)OH, -C(O)OC _1-6 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-6 alkyl), -C(O)N (C _{1 -6} alkyl) ₂ , -NH(CO)-C _1-6 alkyl, -C(O)-C _1-6 alkyl, -S(O) _0-2 -C _1-6 alkyl, - S(O) ₂ NH ₂ , -S(O) ₂ -NH(C _1-6 alkyl), -S(O) ₂ -N(C _1-6 alkyl) ₂ , C _3-8 cycloalkyl And a substituent of a 3-8 membered heterocycloalkyl group at any position; R _a is H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C _6-10 An aryl group, a 5-6 membered heteroaryl group, a C _3-8 cycloalkyl C _1-6 alkyl group, or a 3-8 membered heterocycloalkyl C _1-6 alkyl group;

   R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, deuterated methyl, or 2-deutero-2-yl;

   R ₂ is hydrogen, deuterium, halogen, or C _1-3 alkyl;

   R ₃ is

   

   R ₄ is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;

   R ₅ is hydrogen, deuterium, halogen, amino, cyano, C _1-3 alkyl, C _1-3 alkoxy, or halogenated C _1-3 alkoxy.
9. The five-membered heteroaryl ring derivative (I) according to claim 1, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that the five-membered heteroaryl ring derivative (I) is any of the following structures:

   

   

   
10. The five-membered heteroaryl ring derivative (I) according to claim 9, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that the five-membered heteroaryl ring derivative (I) is any of the following structures:

    

    

    

    And/or the solvate of the five-membered heteroaryl ring derivative (I) is any of the following structures:

    
11. The five-membered heteroaryl ring derivative (I) according to claim 10, an isomer thereof, a solvate, a crystal form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that the solvate of the five-membered heteroaryl ring derivative (I) is as follows:

    

    Its unit cell parameters are: a=18.3907(5), α=90°; b=7.1972(2), β=95.737(1)°; c=19.6381(5), γ=90°; space group, P2/ n;

    or,

    

    The unit cell parameters are: a=10.7762(18), α=105.536(7)°; b=12.762(2), β=91.288(8)°; c=12.914(2), γ=90.951(10)° ; space group, P-1.
12. The five-membered heteroaryl ring derivative (I) according to claim 11, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that the solvate of the five-membered heteroaryl ring derivative (I) is as follows:

    

    Its parameters are:

    

    

    or,

    

    Its parameters are:

    
13. The five-membered heteroaryl ring derivative (I) according to claim 1, an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, It is characterized in that the five-membered heteroaryl ring derivative (I) is any of the following structures:

    

    

    

    

    

    

    

    

    

    
14. A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient together with a pharmaceutically acceptable excipient;

    The active component comprises the five-membered heteroaryl ring derivative (I) according to at least one of claims 1 to 13, an isomer, a solvate thereof, a solvate crystal form, a prodrug, and a stable An isotope derivative or a pharmaceutically acceptable salt.
15. The pharmaceutical composition according to claim 14, wherein said active ingredient further comprises other therapeutic agents for cancer, viral infection or autoimmune diseases;

    And/or the pharmaceutically acceptable excipients include pharmaceutically acceptable carriers, diluents and/or excipients.
16. A five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotopic derivative according to at least one of claims 1 to 13 Or a pharmaceutically acceptable salt, or the use of the pharmaceutical composition according to claim 14 or 15 in the preparation of a guanamine 2,3-dioxygenase inhibitor.
17. A five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotopic derivative according to at least one of claims 1 to 13 Or a pharmaceutically acceptable salt, or the use of the pharmaceutical composition according to claim 14 or 15 in the preparation of a medicament.
18. The use according to claim 17 wherein said medicament is for stimulating T cell proliferation.
19. The use according to claim 17, wherein said medicament is for treating, alleviating and/or preventing a related disease mediated by indoleamine 2,3-dioxygenase, or said medicament For the treatment, amelioration and/or prevention of diseases such as viruses or other infections, cancers, or autoimmune diseases.
20. The use according to at least one of claims 17 to 19, characterized in that the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug a stable isotopic derivative or a pharmaceutically acceptable salt, or a combination of said pharmaceutical composition and one or more other therapeutic agents and/or methods of treatment for treating cancer; said other types of use Therapeutic agents and/or treatments for the treatment of cancer are tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, hormones and hormone analogues, signal transduction pathway inhibition One or more of agents, angiogenesis inhibitors, targeted therapies, immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiation therapy.
21. The use according to claim 19, wherein said guanamine 2,3-dioxygenase-mediated related diseases include: viruses or other infections, cancers, or autoimmune diseases.
22. The use according to claim 19 or 21, wherein the virus or other infection is a skin infection, a gastrointestinal infection, a genitourinary infection and/or a systemic infection; the cancer includes but is not limited to Bone cancer, liver cancer, esophageal cancer, rectal cancer, oral cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck One or more of cancer, lymphoma, leukemia and skin cancer; the autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic scleroderma, dermatomyositis , one or more of nodular vasculitis, nephropathy, endocrine-related diseases, liver disease, psoriasis, and autoimmune reactions due to infection; the virus infection is caused by influenza, hepatitis B virus, type C Hepatitis virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus, poliovirus, varicella-zoster virus, coxsackie virus, and human immunodeficiency virus A variety of infections.
23. A method of treating, ameliorating and/or preventing "a related disease mediated by indoleamine 2,3-dioxygenase" or "virus or other infection, cancer, or autoimmune disease", comprising administering to an individual A therapeutically required amount of the five-membered heteroaryl ring derivative (I) according to at least one of claims 1 to 13, an isomer, a solvate thereof, a solvate crystal form, a prodrug, and a stable An isotope derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 14 or 15.
24. The method according to claim 23, wherein the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable Accepted salts, or combinations of said pharmaceutical compositions with one or more other classes of therapeutic agents and/or methods of treatment for treating cancer; said other classes of therapeutic agents and/or treatments for treating cancer Methods are tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, hormones and hormone analogues, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies One or more of immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiation therapy.
25. The method of claim 23, wherein said guanamine 2,3-dioxygenase mediated related diseases comprise: a virus or other infection, cancer, or an autoimmune disease.
26. The method according to claim 23 or 25, wherein the virus or other infection is a skin infection, a gastrointestinal infection, a genitourinary infection, and/or a systemic infection; the cancer includes but is not limited to Bone cancer, liver cancer, esophageal cancer, rectal cancer, oral cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck One or more of cancer, lymphoma, leukemia and skin cancer; the autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic scleroderma, dermatomyositis , one or more of nodular vasculitis, nephropathy, endocrine-related diseases, liver disease, psoriasis, and autoimmune reactions due to infection; the virus infection is caused by influenza, hepatitis B virus, type C Hepatitis virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus, poliovirus, varicella-zoster virus, coxsackie virus, and human immunodeficiency virus A variety of infections.
27. A five-membered heteroaryl ring derivative (I) according to at least one of claims 1 to 13, an isomer, a solvate thereof, a solvate crystal form, a prodrug, a stable isotope derivative Or a pharmaceutically acceptable salt, or a method of inhibiting tryptophan degradation in a pharmaceutical composition according to claim 14 or 15.