CN117185987A

CN117185987A - Amidine and guanidine derivatives, preparation method and medical application thereof

Info

Publication number: CN117185987A
Application number: CN202311144219.4A
Authority: CN
Inventors: 李桂英; 韩润丰; 游泽金; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-03-19
Filing date: 2019-03-15
Publication date: 2023-12-08
Also published as: CN111630048A; CN111630048B; WO2019179362A1

Abstract

The application discloses amidine and guanidine derivatives shown in formulas I-A and I-B, a preparation method and medical application thereof, which are used for preventing, relieving and/or treating diseases or symptoms caused by immunosuppression.

Description

Amidine and guanidine derivatives, preparation method and medical application thereof

The application relates to amidine and guanidine derivatives, a preparation method thereof and application thereof in medicine, which are classified as 201980009183.4, 2019, 3, 15 and the like.

Technical Field

The application relates to novel amidine and guanidine derivatives, a preparation method thereof, a pharmaceutical composition containing the compound and medical application thereof.

Background

Because of unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (operation, radiotherapy and chemotherapy) adopted clinically at present cannot completely remove or completely kill tumor cells, and the tumor cells can escape from monitoring of an organism immune system through various ways, so that tumor metastasis or recurrence is caused. Tumor immunotherapy is the control and killing of tumor cells by modulating the immune system of the body to enhance the antitumor immunity of the tumor microenvironment (e.g., to inhibit IDO-mediated tumor immune escape mechanisms). Because of the characteristics of safety, effectiveness, low adverse reaction and the like, the traditional Chinese medicine composition becomes a new therapy for treating tumors after surgery, radiotherapy and chemotherapy.

IDO is one of the most potential drug targets for tumor immunotherapy that is currently entering the clinical research stage. IDO was first found in cells by the Hayaishi group in 1967 (Hayaishi o. Et al, science,1969,164,389-396), a heme-containing monomeric enzyme whose cDNA-encoded protein consists of 403 amino acids and has a molecular weight of 45kDa, a rate-limiting enzyme that catalyzes the catabolism of tryptophan via the kynurenine pathway, and is widely distributed in tissues other than the liver in humans and other mammals (e.g., rabbits, mice), the only rate-limiting enzyme that catalyzes the catabolism of tryptophan other than the liver. IDO high expression of various cells in tumor microenvironment leads to tryptophan metabolic exhaustion and kynurenine level elevation, so that activation of T cells is blocked, apoptosis of T cells mediated by oxygen free radicals is induced, immune suppression mediated by regulatory T cells (Treg) is enhanced, and tumors are promoted to escape from immune monitoring of an organism.

IDO is associated with the occurrence of diseases such as senile dementia and cataract, in addition to tumors. IDO is also implicated in neurological and psychiatric disorders (e.g., depression, mood disorders) as well as other diseases caused by degradation of tryptophan due to abnormally high expression of IDO, such as intrauterine pediatric rejection, viral infections (e.g., AIDS), autoimmune diseases, bacterial infections such as lyme disease and streptococcal infections, and the like. Thus, inhibition of IDO activity is of great therapeutic value.

IDO small molecule inhibitors epacoaddostat developed by Incyte corporation are currently used in clinical phase I/II trials in combination with PD-1 antibody keyruda or PD-L1 antibody avelumab to treat a variety of cancers, such as advanced or metastatic solid tumors, recurrent glioblastoma, and the like. The IDO small molecule inhibitor BMS-986205 from Bristol-Myers Squibb company is currently used in clinical phase III trials in combination with Nivolumab to treat a variety of cancers, such as advanced renal cell carcinoma, untreated metastatic or unresectable melanoma; advanced malignancy was treated in a clinical phase I/II trial in combination with Nivolumab and LAG-3 antibody relatimab. NewLink Genetics is also conducting a number of clinical trials of indoximod (NG-8189) in combination with other drugs, for example in clinical phase II/III trials in combination with the PD-1 antibody keytrua or Nivolumab for the treatment of metastatic melanoma. Published IDO inhibitor patent applications include WO2016073770, WO2016073734, WO2016073738, and the like.

IDO inhibitors have great potential for the treatment and prevention of a variety of diseases, but no drug inhibiting IDO is currently marketed. In order to achieve better therapeutic effects and better meet the market demands, there is a need to develop new high-efficiency low-toxicity IDO inhibitors, pharmaceutical compositions thereof and related methods.

Summary of The Invention

An aspect of the present invention provides a safe and effective IDO inhibitor compound having a novel structure, a stereoisomer, tautomer, or mixture thereof, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound. In some embodiments, the IDO inhibitor is a compound represented by formula I-a:

wherein:

R ¹ selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

X is NR ¹¹ Or CHNO ₂ ；

m=0, 1 or 2;

n=0 or 1;

t=0, 1 or 2;

q is CH, N, COH, CF, CMe, CNH ₂ CNMe or CNMe ₂ ；

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and C ₁ -C ₆ Hydroxyalkyl group, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 、C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl or C ₁ -C ₆ A hydroxyalkyl group; alternatively, R ² And R is ³ Are linked to form, together with the C atom to which they are attached, a P ring selected from C ₃ -C ₆ Cycloalkyl and 4-7 membered heterocyclyl; or alternatively

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and C ₁ -C ₆ Hydroxyalkyl group, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl or C ₁ -C ₆ A hydroxyalkyl group;

R ⁴ and R is ⁵ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ or-NR ⁹ C(O)R ¹⁰ ；

R ⁶ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl and 3-14 membered heterocyclyl, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

R ⁶ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl and 3-14 membered heterocyclyl, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, may be optionally substituted with one or more of the following substituents: OH, halogen,CN、NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-14 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

R ⁷ 、R ⁸ And R is ⁹ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following substituents: OH, CN, halogen,NH ₂ 、NHMe、NMe ₂ Or CO ₂ H is formed; alternatively, R ⁷ And R is ⁸ To form together with the N atom to which they are attached a 4-7 membered heterocyclic group;

R ¹⁰ selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ Or CO ₂ H is formed; alternatively, R ⁹ And R is ¹⁰ Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl;

R ¹¹ selected from hydrogen, OH, CN, -SO ₂ R ¹² and-C (O) R ¹³ ；

R ¹² Selected from C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC ₁ -C ₆ Alkyl, NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl;

R ¹³ selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents:OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl;

the conditions are as follows:

(1) When m=1, n=1 and t=1, Q is not CH;

(2) When n=0, m=1, t=1, q is N, and X is NR ¹¹ ，R ¹¹ Is H, R ⁴ Is H, R ⁵ Is H and R ⁶ For C as defined above ₆ In the case of aryl radicals, R ¹ Not be of

(3) When n=0, m=2, t=0, q is N, and X is NR ¹¹ ，R ¹¹ Is CN, R ⁴ Is H, R ⁵ Is H and R ⁶ For C as defined above ₆ In the case of aryl radicals, R ¹ Not be ofAnd

(4) When n=0, m=0, t=2, q is N, X is NR ¹¹ ，R ¹¹ Is CN, R ⁴ Is H, R ⁵ Is H and R ⁶ For C as defined above ₆ In the case of aryl radicals, R ¹ Not be of

In other embodiments, the IDO inhibitor is a compound of formula I-B:

wherein:

X is NR ¹¹ Or CHNO ₂ ；

m=0, 1 or 2;

t=0, 1 or 2;

R ⁵ selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ or-NR ⁹ C(O)R ¹⁰ ；

R ⁷ 、R ⁸ And R is ⁹ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ Or CO ₂ H is formed; alternatively, R ⁷ And R is ⁸ To form together with the N atom to which they are attached a 4-7 membered heterocyclic group;

R ¹¹ selected from hydrogen, OH, CN, -SO ₂ R ¹² and-C (O) R ¹³ ；

R ¹² Selected from C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC ₁ -C ₆ Alkyl, NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl; and

R ¹³ selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclic group.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, and one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides the use of a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition associated with IDO activity, such as a tumor, depression, or senile dementia.

Another aspect of the invention provides a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the invention for use in the prevention, alleviation and/or treatment of a disease or condition associated with IDO activity (e.g., tumor, depression, or senile dementia).

Another aspect of the present invention provides a method for preventing, alleviating and/or treating a disease or condition associated with IDO activity (e.g., tumor, depression or senile dementia), comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a pharmaceutical composition of the present invention.

Another aspect of the invention provides the use of a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.).

Another aspect of the invention provides a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the invention for use in preventing, alleviating and/or treating a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.).

Another aspect of the present invention provides a method of preventing, alleviating and/or treating a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the present invention.

In another aspect, the invention provides a process for the preparation of the compounds of the invention.

Detailed Description

Compounds and methods of preparation

A first aspect of the invention relates to a compound of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound.

The compounds of the present invention include compounds of formula I-A:

X is NR ¹¹ Or CHNO ₂ ；

m=0, 1 or 2;

n=0 or 1;

t=0, 1 or 2;

q is CH, N, COH, CF, CMe, CNH ₂ CNHMe or CNMe ₂ ；

R ⁶ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl and 3-14 membered heterocyclyl, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

R ¹¹ selected from hydrogen, OH, CN, -SO ₂ R ¹² and-C (O) R ¹³ ；

R ¹³ selected from C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl;

the conditions are as follows:

(1) When m=1, n=1 and t=1, Q is not CH;

(4) When (when)n=0, m=0, t=2, q is N, X is NR ¹¹ ，R ¹¹ Is CN, R ⁴ Is H, R ⁵ Is H and R ⁶ For C as defined above ₆ In the case of aryl radicals, R ¹ Not be of

In some embodiments of the invention, R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ 。

In some preferred embodiments, R ¹ 、R ⁶ Each independently selected from phenyl groupsPyridyl, quinolinyl, isoquinolinyl, benzimidazolyl andwherein ring P' is phenyl or 5-7 membered heteroaryl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ 、R ⁶ Each independently selected from phenyl,Pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ 、R ⁶ Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridylThe methylimidazole group may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

preferably, R ¹ 、R ⁶ Each independently selected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl optionally being substituted with one or more of the following substituents: F. cl, methyl, CN or methoxy;

Preferably, R ¹ Selected from phenyl, pyridinyl and quinolinyl, which phenyl, pyridinyl and quinolinyl may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;

preferably, R ¹ Selected from:/>

preferably, R ⁶ Selected from phenyl and pyridinyl, which may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;

preferably, R ⁶ Selected from:

in other preferred embodiments, R ¹ Selected from the group consisting ofWherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ Is thatWherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ Selected from the group consisting of Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

preferably, R ¹ Selected from the group consisting of/>

In other preferred embodiments, R ⁶ Selected from-CH ₂ -(C ₆ -C ₁₄ Aryl) and-CH ₂ - (5-14 membered heteroaryl), said-CH ₂ -(C ₆ -C ₁₄ Aryl) and-CH ₂ -(5-14 membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁶ Selected from-CH ₂ -(C ₆ -C ₁₀ Aryl) and-CH ₂ - (5-to 10-membered heteroaryl), said-CH ₂ -(C ₆ -C ₁₀ Aryl) and-CH ₂ - (5-to 10-membered heteroaryl) optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁶ Selected from-CH ₂ -phenyl and-CH ₂ - (5-6 membered heteroaryl), said-CH ₂ -phenyl and-CH ₂ - (5-6 membered heteroaryl) optionally substituted by one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁶ Selected from-CH ₂ -phenyl and-CH ₂ -pyridinyl, said-CH ₂ -phenyl and-CH ₂ -pyridyl optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 memberedHeteroaryl or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁶ is-CH ₂ -phenyl, said-CH ₂ -phenyl optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-1The 0 membered heteroaryl and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁶ is-CH ₂ -phenyl, said-CH ₂ -phenyl optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

preferably, R ⁶ is-CH ₂ -phenyl, said-CH ₂ -phenyl optionally substituted with one or more of the following substituents: f or Cl;

preferably, R ⁶ Is that

In some embodiments of the invention, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 、C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclic groupsThe 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ² And R is ³ Are linked to form, together with the C atom to which they are attached, a P ring selected from C ₃ -C ₆ Cycloalkyl and 4-7 membered heterocyclyl comprising O, S or N;

preferably, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 、C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ A hydroxyalkyl group;

preferably, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, F, cl, CN methyl, ethyl, n-propyl, isopropyl, C ₁ -C ₃ Haloalkyl, methoxy, ethoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ A hydroxyalkyl group; or R is ² And R is ³ Are linked to form, together with the C atom to which they are attached, a P ring selected from C ₃ -C ₆ Cycloalkyl and 4-7 membered heterocyclyl containing O, more preferably selected from

More preferably, R ² And R is ³ Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH ₂ -cyclopropyl; alternatively, R ² And R is ³ Are linked to form together with the C atom to which they are attachedForming a P ring, wherein the P ring is

In some embodiments of the invention, R ⁴ And R is ⁵ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ or-NR ⁹ C(O)R ¹⁰ ；

Preferably, R ⁴ And R is ⁵ Are all hydrogen.

In other embodiments of the invention, R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl may optionally be substituted with oneOr a plurality of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁵ And R is ⁶ Are linked to form together with the N atom to which they are attachedWhich may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁵ And R is ⁶ Are linked to form together with the N atom to which they are attachedWhich may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy; />

Preferably, R ⁵ And R is ⁶ Are linked to form together with the N atom to which they are attachedWhich may be optionally substituted with one or more of the following substituents: f or Cl;

preferably, R ⁵ And R is ⁶ Together with the N atom to which they are attached form

In such embodiments, R ⁴ Selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ or-NR ⁹ C(O)R ¹⁰ ；

Preferably, R ⁴ Is hydrogen.

In some embodiments of the invention, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 、C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₆ A hydroxyalkyl group; or alternatively

More preferably, R ² And R is ³ Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH ₂ -cyclopropyl; alternatively, R ² And R is ³ Are linked together with the C atom to which they are attached to form a P ring, which isAnd is also provided with

R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ¹ 、R ⁶ Each independently of the otherSelected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl optionally being substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

R ⁵ selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ or-NR ⁹ C(O)R ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the Or,

R ⁵ and R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, -C (O) OR ⁷ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-C(O)R ¹⁰ 、-SO ₂ R ¹⁰ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; here, what is shownThe C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, -C (O) R ¹⁰ 、-C(O)OR ⁷ 、-SO ₂ R ¹⁰ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 、-NR ⁹ SO ₂ R ¹⁰ 、-SO ₂ NR ⁷ R ⁸ or-NR ⁷ R ⁸ ；

Preferably, R ⁵ And R is ⁶ Are linked to form together with the N atom to which they are attachedWhich may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

In some embodiments of the invention, R ⁷ 、R ⁸ And R is ⁹ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ Or CO ₂ H is formed; alternatively, R ⁷ And R is ⁸ And are linked to form, together with the N atom to which they are attached, a 4-7 membered heterocyclic group.

In some embodiments of the invention, R ¹⁰ Selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and 4-7 membered heterocyclyl groups may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ Or CO ₂ H is formed; alternatively, R ⁹ And R is ¹⁰ And are linked to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclic group.

In some embodiments of the invention, R ¹¹ Selected from CN and-SO ₂ R ¹² 。

In some embodiments of the invention, R ¹² Selected from C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC ₁ -C ₆ Alkyl, NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl;

preferably, R ¹² Selected from C ₁ -C ₃ Alkyl and C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC ₁ -C ₆ Alkyl, NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl;

preferably, R ¹² Is methyl and C ₃ -C ₆ Cycloalkyl;

preferably, R ¹² Is methyl.

In some embodiments of the invention, R ¹³ Selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclic group.

In some embodiments of the invention, m=0 or 1, preferably m=1.

In some embodiments of the invention, n=0 or 1.

In some embodiments of the invention, t=0 or 1, preferably t=1.

In some embodiments of the invention, Q is CH or N; preferably, Q is N.

In some embodiments of the invention, the compound of formula I-a has the structure of formula II:

wherein R is ¹ 、R ⁶ And X is as defined above for formula I-A.

In some embodiments of the invention, the compound of formula I-a has the structure of formula III:

wherein R is ¹ 、R ⁶ X and R ² As defined above for formula I-a; preferably, R ² H, C of a shape of H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl or-CH ₂ -(C ₃ -C ₆ Cycloalkyl); preferably, R ² Is H, methyl, ethyl, cyclopropyl or-CH ₂ -cyclopropyl;

more particularly, the compound of formula III has the structure of formula IV:

the compounds of the present invention also include compounds of formula I-B:

wherein R is ¹ 、R ⁵ 、R ⁶ X, m and t are as defined above for formula I-A.

In some embodiments, m=1.

In some embodiments, t=1.

In some embodiments, the compound of formula I-B has the structure of formula V:

in some embodiments, R ¹ Is phenyl, which phenyl may optionally be substituted with one or more C ₁ -C ₆ Alkoxy, preferably C ₁ -C ₃ Alkoxy, more preferably methoxy;

preferably, R ¹ Is that

In some embodiments, R ⁶ Is phenyl, which phenyl may be optionally substituted with one or more halogens, preferably F or Cl, more preferably Cl;

preferably, R ⁶ Is that

In some embodiments, R ⁵ Is hydrogen.

In some embodiments, X is NR ¹¹ Wherein R is ¹¹ is-SO ₂ R ¹² The method comprises the steps of carrying out a first treatment on the surface of the And wherein R is ¹² Is C ₁ -C ₆ Alkyl, preferably C ₁ -C ₃ Alkyl groups, more preferably methyl groups.

In some embodiments of the invention, the compounds of the invention are selected from, but are not limited to:

/>

in a second aspect the invention provides a process for the preparation of a compound of the invention.

In some embodiments, the present invention provides a method of preparing a compound of formula II:

wherein R is ¹ 、R ⁶ And X is as defined above for formula I-A;

the method comprises the following steps:

the first step: compounds II-1 and R ¹ -Br or R ¹ -I is substituted or coupled in the presence of a base to form compound II-2.

The bases which can be used in the substitution reaction are ^t BuONa、 ^t BuOK、 ^t BuOLi、Cs ₂ CO ₃ 、LiHMDS、LDA、NaHMDS、KHMDS、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ Or K ₂ CO ₃ And the like, and the solvents that can be used are toluene, xylene, THF, DME, dioxane, DMF, DMSO, NMP, or the like, at a temperature of 60 ℃ to 140 ℃;

the catalyst which can be used in the coupling reaction (e.g., buchwald-Hartwig reaction) is Pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(dba) ₂ 、PdCl ₂ 、Pd(PPh ₃ ) ₄ 、Pd(dppf)Cl ₂ 、Pd(dppf)Cl ₂ *DCM、Pd(acac) ₂ Or Pd (all) ₂ Etc., the ligand that can be used is PPh ₃ XPhos, SPhos, ruPhos, xantPhos, dppf, BINOL, BINAP or Pcy ₃ Etc., the base that can be used is ^t BuONa、 ^t BuOK、 ^t BuOLi、Cs ₂ CO ₃ 、LiHMDS、LDA、NaHMDS、KHMDS、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ Or K ₂ CO ₃ And the like, toluene, xylene, THF, DME, dioxane, DMF, DMSO, NMP, or the like can be used at a temperature of 60 ℃ to 140 ℃.

And a second step of:

method A: the compound II-2 is deprotected in the presence of an acid to form a compound II-3.

The acid may be a solution of 1, 4-dioxane of HCl or a solution of TFA in DCM, etc., at a temperature of 0 ℃ to rt.

Method B: extending the reaction time under the reaction conditions of the first step (e.g>10h) Compounds II-1 and R ¹ -Br or R ¹ -I directly forms compound II-3 by substitution or coupling reactions in the presence of a base.

And a third step of: the compound II-3 reacts with the compound II-4 or II-5 under basic conditions to produce the compound of formula II.

The alkali which can be used is LiHMDS, LDA, naHMDS, KHMDS, TEA, DIPEA, ^t BuOK, naH or Cs ₂ CO ₃ Etc. The solvent which can be used is THF, DCM, DCE, DMF, DMSO, CH ₃ CN, 1, 4-dioxane, toluene, etc., at a temperature of rt to 140 ℃.

In some embodiments, the invention provides a method of preparing a compound of formula III:

wherein:

R ¹ 、R ⁶ x and R ² As defined above for formula I-a;

R' is selected from benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl and Cbz; r' "is selected from Me, et and ^t Bu；

the method comprises the following steps:

the first step: the compound III-1 and the compound III-2 react in the presence of a base to generate a compound III-3.

The base can be LDA, n-BuLi, ^t BuOK、 ^t BuONa、 ^t BuOLi、NaOH、KOH、NaH、Cs ₂ CO ₃ LiHMDS, naHMDS or KHMDS, etc. The solvent which can be used is THF, DCM, DCE, meOH, etOH, DMF, CH ₃ CN, 1, 4-dioxane or toluene, etc. at 0-120 deg.c;

and a second step of: the compound III-3 is reduced by hydrogenation to form the compound III-4.

The catalyst which can be used is Pd/C, ptO ₂ Or Pd (OH) ₂ for/C, etc., meOH or EtOH, etc., can be used at a temperature of rt to 80 ℃.

And a third step of: compounds III-4 and R ¹ -Br or R ¹ -I is substituted or coupled in the presence of a base (e.g. Buchwald-Hartwig reaction) to form compound III-5.

The reaction conditions are as described in the first step of the process for the preparation of the compound of formula II.

Fourth step: the compound III-5 is hydrolyzed under alkaline or acidic conditions to form the compound III-6.

For acidic conditions, the acids that can be used are HCl, H ₂ SO ₄ TFA, trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid, and the like; for alkaline conditions, bases that can be used are LiOH, naOH, KOH, or the like. The solvent which can be used is THF, DCM, DCE, meOH, etOH, DMF, DMSO, CH ₃ CN, 1, 4-dioxane, toluene or a mixed solvent of the above solvents and water, etc., at a temperature of rt to 100 ℃.

Fifth step: the compound III-6 is rearranged by Curtius to generate a compound III-7.

The base which can be used is Et ₃ N, DIPEA, etc., the reagents that can be used are DPPA, etc., and the solvents that can be used are ^t BuOH, toluene, DCM, ^t Mixed solvents of BuOH and toluene, etc., at a temperature of rt to 110 ℃.

Sixth step: compound III-7 produces III-8 under acidic or basic conditions.

For acidic conditions, the acid that can be used is HCl, HBr, TFA, H ₂ SO ₄ HOAc, trifluoromethanesulfonic acid, etc.; for alkaline conditions, bases that can be used are LiOH, naOH, KOH, or the like. The solvent which can be used is THF, DCM, DCE, meOH, etOH, DMF, DMSO, CH ₃ CN, 1, 4-dioxane, toluene or a mixed solvent of the above solvents and water, etc., at a temperature of rt to 120 ℃.

Seventh step: the compound III-8 reacts with II-4 or II-5 under basic conditions to form the compound of formula III.

The reaction conditions are as described in the third step of the process for the preparation of the compound of formula II.

In some embodiments, the present invention provides a method of preparing a compound of formula IV:

wherein R is ¹ 、R ⁶ And X is as defined above for formula I-A;

the method comprises the following steps:

The first step: compounds IV-1 and R ¹ -Br or R ¹ -I is substituted or coupled in the presence of a base (e.g. Buchwald-Hartwig reaction) to form compound IV-2.

And a second step of: the compound IV-2 is deprotected in the presence of an acid to form compound IV-3.

The reaction conditions are as described in the second step of the process for the preparation of the compound of formula II.

And a third step of: the compound IV-3 is reacted with II-4 or II-5 under basic conditions to form the compound of formula IV.

In some embodiments, the invention provides a method of preparing a compound of formula V:

wherein:

R ¹ 、R ⁶ and X is as defined above for formula I-B;

R ^a selected from benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl and Cbz;

the method comprises the following steps:

the first step: the compound V-1 is reacted with a trifluoromethanesulfonyl reagent in the presence of a base to yield the compound V-2.

For example, the base is LiHMDS, LDA, naHMDS, KHMDS, ^t BuOK, naH or NaOH, etc., the trifluoromethanesulfonyl reagent is PhNTf ₂ . Alternatively, the base is 2, 6-di-tert-butyl-4-methylpyridine and the trifluoromethanesulfonyl reagent is Tf ₂ O. Solvents which can be used are THF, CH ₃ CN, DCM, DCE, etc., at-78deg.C to 60deg.C;

and a second step of: compounds V-2 and R ¹ -boric acid or R ¹ Formation of borates by coupling reactions, e.g. Suzuki reactionsCompound V-3.

The catalyst which can be used is Pd (PPh) ₃ ) ₄ Pd(dppf)Cl ₂ * DCM, or Pd (dppf) Cl ₂ Etc., the alkali that can be used is Cs ₂ CO ₃ 、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ Or K ₂ CO ₃ Etc., the solvents which can be used are 1, 4-dioxane, DMF, DMSO, CH ₃ CN, etc., or a mixed solvent of the above solvent and water, at a temperature of 60 ℃ to 120 ℃;

and a third step of: compound V-3 is reduced to compound V-4 under catalytic hydrogenation conditions.

The reaction conditions are as described in the second step of the process for the preparation of the compound of formula III;

fourth step: the compound V-4 is reacted with the compound II-4 or II-5 under basic conditions to produce the compound of formula V.

Pharmaceutical composition, preparation method and treatment method

A third aspect of the invention provides a pharmaceutical composition comprising a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, and one or more pharmaceutically acceptable carriers.

A fourth aspect of the invention provides a process for preparing a pharmaceutical composition of the invention, which comprises combining a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, with one or more pharmaceutically acceptable carriers.

A fifth aspect of the invention provides a pharmaceutical formulation comprising a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the invention.

In a sixth aspect, the invention provides the use of a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition associated with IDO activity, such as tumour, depression or senile dementia.

A seventh aspect of the invention provides a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in the prevention, alleviation and/or treatment of a disease or condition associated with IDO activity (e.g. tumour, depression or senile dementia).

An eighth aspect of the present invention provides a method for preventing, alleviating and/or treating a disease or condition associated with IDO activity (e.g., tumor, depression or senile dementia), comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and optionally including in combination with other agents for preventing, alleviating and/or treating a disease or condition associated with IDO activity (e.g., tumor, depression or senile dementia).

A ninth aspect of the invention provides a method for preventing, alleviating and/or treating a disease or condition associated with IDO activity (e.g. tumor, depression or senile dementia), said method comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and comprising the use in combination with a PD-1, PDL-1 antibody.

The diseases or conditions related to IDO activity described herein include, but are not limited to, tumors, depression, senile dementia, and the like.

The invention also provides the use of a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition caused by immunosuppression (e.g. a tumour, viral infection or autoimmune disease, etc.).

The invention also provides a compound of formula I-a or I-B of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in the prevention, alleviation and/or treatment of a disease or condition caused by immunosuppression (e.g. a tumour, viral infection or autoimmune disease, etc.).

The present invention also provides methods of preventing, alleviating and/or treating a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.), comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, stereoisomers, tautomers, or mixtures thereof, stable isotope derivatives, metabolites, or prodrugs of the compound, pharmaceutically acceptable salts, co-crystals, polymorphs, or solvates of the compound, the pharmaceutical compositions of the present invention, or the pharmaceutical formulations of the present invention, and optionally including in combination with other agents that prevent, alleviate and/or treat a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.).

The present invention also provides a method of preventing, alleviating and/or treating a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, and including use in combination with a PD-1, PDL-1 antibody.

Diseases or conditions caused by immunosuppression as described herein include, but are not limited to, for example, tumors, viral infections, autoimmune diseases, and the like.

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 6, for example 1 to 4 carbon atoms. For example, as used herein, the term "C ₁ -C ₆ Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as" haloalkyl ", e.g., CF) ₃ 、C ₂ F ₅ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.).

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclic [ 1.1.1:1: ]Amyl, bicyclo [2.2.1]Heptyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 7 carbon atoms, for example 3 to 6 carbon atoms. For example, as used herein, the term "C ₃ -C ₇ Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 7 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), optionally substituted with one or more (such as 1 to 3) suitable substituents, e.g., methyl substituted cyclopropyl.

As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.

As used herein, the term "alkoxy" means an alkyl group, preferably C, as defined above, attached to the parent molecular moiety through an oxygen atom ₁ -C ₆ Alkoxy or C ₁ -C ₃ An alkoxy group. C (C) ₁ -C ₆ Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system, and in each case may share two adjacent atoms with cycloalkyl groups to form a cyclic group, the point of attachment may be on the aryl or on the cycloalkyl. For example, the number of the cells to be processed, For example, as used herein, the term "C ₆ -C ₁₄ Aryl "means an aromatic group containing 6 to 14 carbon atoms, preferably C ₆ -C ₁₀ Aryl is preferably phenyl or naphthyl. Aryl groups may optionally be substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO) ₂ 、C ₁ -C ₆ Alkyl, etc.) substitution.

As used herein, the term "hydroxyalkyl" means that the hydrogen atom of an alkyl group is substituted with one or more hydroxyl groups, e.g., C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₃ Hydroxyalkyl groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl, among others.

As used herein, the term "aryl-heterocyclyl" refers to a cyclic group formed by aryl and heterocyclyl sharing two adjacent carbon atoms with each other, the point of attachment being on the aryl or heterocyclyl, wherein aryl or heterocyclyl are as defined herein. For example, as used herein, the term "9-12 membered arylalkylheterocyclyl" means a radical of an arylalkylheterocyclyl containing 9-12 ring atoms, particularly a phenyl 5-8 membered heterocyclyl, particularly a phenyl 5-6 membered heterocyclyl (9-10 membered benzoheterocyclyl), examples of which include, but are not limited to: indazolyl group,

As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (heteroaromatic ring refers to an aromatic ring system containing at least one heteroatom) having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 7, 8, 9 or 10 ring atoms, and which contains at least one heteroatom (e.g., oxygen, nitrogen or sulfur) which may be the same or different, and which in each case may share two adjacent atoms with each other with an aryl, heterocyclyl or cycloalkyl group forming a fused ring group, the point of attachment of which is on the heteroaromatic ring or on another ring. For example, as used herein, the term "5-10 membered heteroaryl" means heteroaryl containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, examples of which include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and the fused ring derivatives thereof, and the fused ring derivatives are not limited to heteroaryl-heteroaryl, heteroaryl-aryl, heteroaryl-heterocyclyl, or heteroaryl-cycloalkyl, particularly 5-6 membered heteroaryl-5-6 membered heteroaryl, 5-6 membered heteroaryl-phenyl, 5-6 membered heteroaryl-5-6 membered heterocyclyl, or 5-6 membered heteroaryl-C ₄ -C ₆ Cycloalkyl (especially 5-6 membered heteroaryl-cyclobutyl, 5-6 membered heteroaryl-cyclopentyl, 5-6 membered heteroaryl-cyclohexyl), examples include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.

As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having 2, 3, 4, 5, 6, 7, 8, 9, in the ringCarbon atoms and one or more (e.g. 1, 2, 3 or 4) are selected from C (=o), O, S, S (=o), S (=o) ₂ And NR (R represents a hydrogen atom or a substituent such as, but not limited to, an alkyl or cycloalkyl group). As used herein, the term "3-14 membered heterocyclyl" means heterocyclyl containing 3-14 ring atoms, including 3-10 or 4-7 membered heterocyclyl, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like; and their fused ring derivatives including, but not limited to, heterocyclyl-heterocyclylheterocyclyl, heterocyclyl-heterocyclylcycloalkyl, in particular 3-7 membered heterocyclyl-3-7 membered heterocyclyl, 3-7 membered heterocyclyl-cycloalkyl, 3-7 membered heterocyclyl-C ₄ -C ₆ Cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl; and bridge or spiro derivatives such as, but not limited to:

etc.

As used herein, the term "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.

The term "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted with … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.

If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopic compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g ² H、 ³ H) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of carbon (e.g ¹¹ C、 ¹³ C, C is a metal alloy ¹⁴ C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g ³⁶ Cl); isotopes of fluorine (e.g ¹⁸ F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g ¹²³ I, I ¹²⁵ I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g ¹³ N is N ¹⁵ N); isotopes of oxygen (e.g ¹⁵ O、 ¹⁷ O and O ¹⁸ O); isotopes of phosphorus (e.g ³² P) is as follows; isotopes of sulfur (e.g ³⁵ S)。

The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the application may exist as a mixture of two or more different structural forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:

it is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

Unless otherwise indicated, the compounds of the present application are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present application may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs. It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts, meglumine salts and the like. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.

For these routes of administration, the compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

The term "effective dose" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

The compounds of the invention may be present in the pharmaceutical composition in an amount or in an amount of from about 0.01mg to about 1000mg, suitably from 0.1 to 500mg, preferably from 0.5 to 300mg, more preferably from 1 to 150mg, particularly preferably from 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such disorder or condition, or one or more symptoms of such disorder or condition to which such term applies.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, and which, when administered into or onto the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T. Higuchi and V. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The bonds in the structural formulae indicated herein by wavy lines "-" are intended to represent either cis or trans isomers, or a mixture of cis and trans isomers in any ratio.

As used hereinThe bond in the represented structural formula is intended to represent a single bond or a double bond.

As used herein, "room temperature" refers to 15-30deg.C.

Advantageous effects of the application

The compounds of the present application have high inhibitory activity against IDO in cells, and have excellent properties such as good drug formation (e.g., good pharmacokinetic properties, good safety and/or fewer side effects).

Detailed Description

Examples

The application is further described below in connection with examples, which are not intended to limit the scope of the application.

Abbreviations in the present application have the following meanings:

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the structure of the compound passes through ¹ H NMR) and/or Mass Spectrometry (MS). The reaction was monitored by Thin Layer Chromatography (TLC) or LC/MS.

¹ H NMR spectrometer Bruker superconducting Nuclear magnetic resonance spectrometer (model AVACE III HD MHz).

LC/MS mass spectrometer: aglient 1260 Infinicity/Aglient 6120 Quadrapol.

Thin layer chromatography using silica gel GF 254 as stationary phase.

The compounds can be separated and purified by chromatography silica gel plate, silica gel column chromatography, preparative high performance liquid chromatograph (Prep-HPLC) and Flash column chromatography.

Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as a stationary phase.

Flash column chromatography using a Biotage Flash column chromatograph.

Prep-HPLC was performed using an Agilent 1260 chromatograph.

In the following examples, the reaction temperature was room temperature (15℃to 30 ℃) unless otherwise specified.

The reagents used in the present application are available from Acros Organics, aldrich Chemical Company or tertbe chemistry, among others.

Intermediate Int-1: n- (4-chlorophenyl) -N' - (methylsulfonyl) thioamino iminoacid methyl ester

Compound Int-1a (59 mg) and compound Int-1b (100 mg) were placed in 50mL three-necked bottles under nitrogen, 5mL of anhydrous THF was added, and a 1.6mL 1.0M LiHMDS solution in THF was slowly added. LCMS monitors after complete substrate conversion, 0.5mL of saturated NH was added ₄ The reaction was quenched with Cl, concentrated to dryness under reduced pressure, dissolved with a small amount of DCM, and purified by preparative TLC (PE: ea=2:1) to give intermediate Int-1 (55 mg).

MS m/z(ESI)：279.0[M+H] ⁺ 。

Intermediate Int-2: n- (4-cyanophenyl) -N' - (methylsulfonyl) thioamino iminoacid methyl ester

40mL of 1.0M LiHMDS in THF was added to a solution of Int-1b (2.0 g,10.03 mmol) and Int-2a (1.19 g,10.03 mmol) in anhydrous THF (20 mL) at-30deg.C, and the mixture was allowed to react at-30deg.C for 2 hours and then allowed to warm to room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL), 30mL of water was added, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (PE: ea=5:2) to give the target product Int-2 (1.2 g).

MS m/z(ESI)：270.1[M+H] ⁺ 。

Intermediate Int-3: n- (4-chloro-2-fluorophenyl) -N' - (methylsulfonyl) thioamino iminoacid methyl ester

30mL of 1.0M LiHMDS in THF was added to a solution of Int-1b (1.5 g,7.23 mmol) and Int-3a (1.10 g,7.53 mmol) in THF (20 mL) at-30deg.C, and the mixture was allowed to react at-30deg.C for 2 hours and then allowed to warm to room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL), 30mL of water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE: ea=5:1-3:1) to give the objective product Int-3 (1.0 g).

MS m/z(ESI)：297.0[M+H] ⁺ 。

Intermediate Int-4: N-4-chlorobenzyl-N' - (methylsulfonyl) thioamino iminoacid methyl ester

Int-4a (708 mg,5.0 mmol), int-1b (997 mg,5.0 mmol) and DIPEA (1.29 g,10.0 mmol) were dissolved in DMF (10 mL) under nitrogen, heated to 100deg.C for 4h, cooled to room temperature after the reaction, diluted with EtOAc and washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography over silica gel (PE: EA=5:1-3:1) to give Int-4 (1.1 g).

MS m/z(ESI)：293.0[M+H] ⁺ 。

Intermediate Int-5: n- (4-chloro-3-fluorophenyl) -N' - (methylsulfonyl) thioamino iminoacid methyl ester

Int-1b (199mg, 1.0 mmol) and Int-5a (218 mg,1.5 mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0℃and then a 2.0mL 1.0M LiHMDS THF solution was added thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction and extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA: pe=1:99-45:55) to give the objective product Int-5 (160 mg).

MS m/z(ESI)：297.0[M+H] ⁺ 。

Intermediate Int-6: phenyl N- (4-chlorophenyl) -N' -cyanocarbamoylimidoic acid ester

4-chloroaniline (0.16 g,1.3 mmol), int-6a (0.3 g,1.3 mmol) and DIPEA (0.16 g,1.3 mmol) were dissolved in DMF (5 mL), reacted at 120℃for 1.5h under microwave conditions, cooled to room temperature after completion of the reaction, the reaction solution was poured into water (50 mL), extracted with EtOAc, the organic phases combined and dried over anhydrous Na ₂ SO ₄ The organic phase was dried and concentrated to dryness under reduced pressure to give crude intermediate Int-6 (0.3 g) which was used in the next reaction without further purification.

MS m/z(ESI)：272.1[M+H] ⁺ 。

Intermediate Int-7: n- (5-chloropyridin-2-yl) -N' - (methylsulfonyl) thioamino iminoacid methyl ester

Int-7a (262.37 mg,2.0 mmol) was dissolved in 3.0mL of dry THF under nitrogen, cooled to 0deg.C, a solution of 5.0mL 1.0M LiHMDS in THF was slowly added followed by Int-1b (419.61 mg,2.00 mmol) in THF (7.0 mL) and the addition was completed at 0deg.C for 4h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (PE: ea=9:1-2:1) to give Int-7 (330 mg).

MS m/z(ESI)：280.0[M+H] ⁺ 。

Example 1: n- (((4-chlorophenyl) amino) ((1- (4-methoxyphenyl) piperidin-4-yl) amino) methylene) methanesulfonamide (compound 1)

The first step: (1- (4-methoxyphenyl) piperidin-4-yl) carbamic acid tert-butyl ester (1 c)

Under nitrogen, compound 1a (117 mg,0.5 mmol), 1b (100 mg,0.5 mmol) and Pd were reacted under nitrogen ₂ (dba) ₃ (23 mg,0.025 mmol), ruPhos (23 mg,0.05 mmol) and ^t BuONa (96 mg,1.0 mmol) was placed in a 50mL three-neck flask, followed by 4.0mL toluene, heating to 100 ℃ and reaction, TLC monitored complete conversion of starting material, then cooled to room temperature, filtered and washed with EtOAc, and after evaporation of the solvent under reduced pressure, purified by preparative TLC (PE: ea=5:1) to give the title compound 1c (100 mg).

MS m/z(ESI)：307.3[M+H] ⁺ 。

And a second step of: 1- (4-methoxyphenyl) piperidin-4-amine (1 d)

1c was dissolved in 5.0mL of 4N HCl in dioxane, and after reacting at room temperature for 1h, the solvent was distilled off under reduced pressure to give crude product (60 mg) of Compound 1 d. The crude product was dissolved in 10.0mL DCM with saturated NaHCO ₃ And (5) washing with a solution. The aqueous phase was extracted with DCM and the organic phases were combined and taken up with anhydrous Na ₂ SO ₄ Drying, filtering and evaporating the solvent under reduced pressure. The crude product obtained was used directly in the next reaction.

MS m/z(ESI)：207.1[M+H] ⁺ 。

And a third step of: n- (((4-chlorophenyl) amino) ((1- (4-methoxyphenyl) piperidin-4-yl) amino) methylene) methanesulfonamide (1)

1d (62 mg,0.3 mmol), int-1 (92 mg,0.33 mmol) and DIPEA (78 mg,0.6 mmol) were dissolved in 3.0mL DMF and heated to 100deg.C until complete conversion of the starting material, cooled to room temperature, diluted with EtOAc and washed with water and the organic phase was taken up in anhydrous Na ₂ SO ₄ Drying, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target compound 1 (45 mg).

MS m/z(ESI)：437.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,1H),7.40(d,J＝8.8Hz,2H),7.35(d,J＝8.8Hz,2H),7.25(d,J＝7.2Hz,1H),6.90(d,J＝8.8Hz,2H),6.81(d,J＝9.2Hz,2H),3.88-3.81(m,1H),3.67(s,3H),3.47-3.43(m,2H),2.89(s,3H),2.77-2.72(m，2H)，2.00-1.91(m，2H)，1.65-1.57(m，2H)。

Examples 2 to 11: preparation of Compounds 2 to 11

The first step: intermediates 2A to 11A

The first-step intermediates 2A to 11A of the compounds 2 to 11 were obtained by a synthesis method similar to that of the first step of example 1.

And a second step of: intermediates 2B to 11B

The second step intermediates 2B to 11B of compounds 2 to 11 were prepared from the corresponding 2A to 11A using a synthesis method similar to that of the second step of example 1.

And a third step of: compounds 2 to 11

Using a synthesis procedure similar to the third step of example 1, the crude product was purified by Prep-HPLC to afford compounds 2 to 11.

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Example 12: n- (((4-chlorophenyl) amino) (((1- (4-methoxyphenyl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (compound 12)

The first step: (1- (4-methoxyphenyl) piperidin-4-yl) methylamine (2 c)

Under nitrogen, 1a (227 mg,2.25 mmol), 2a (482.67 mg,2.25 mmol) and Pd were reacted with each other ₂ (dba) ₃ (103.12 mg, 112.61. Mu. Mol), ruPhos (105.09 mg, 225.23. Mu. Mol) and ^t BuONa (649.33 mg,6.76 mmol) was placed in a 50mL three-necked flask, followed by 5.0mL toluene and heating to 100deg.C for 16h. After the reaction was completed, cooled to room temperature, diluted with ethyl acetate (20 mL), and purified by silica gel column chromatography (DCM: meoh=20:3) to give the objective compound 2c (300 mg).

And a second step of: n- (((4-chlorophenyl) amino) (((1- (4-methoxyphenyl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (12)

DIPEA (46.36 mg, 358.71. Mu. Mol) was added to a solution of Int-1 (50 mg, 179.35. Mu. Mol) and 2c (39.46 mg, 179.35. Mu. Mol) in DMF (2 mL) at room temperature and heated to 95℃for reaction for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with 5mL of ethyl acetate, washed with clean water (20 ml×3), and the organic layer was dried and concentrated to obtain a crude product, which was separated and purified by Prep-HPLC to obtain the target compound 12 (40 mg).

MS m/z(ESI)：451.2[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(s,1H),7.41-7.31(m,5H),6.90-6.87(m,2H),6.82-6.79(m,2H),3.67(s,3H),3.53-3.50(m,2H),3.25-3.23(m,2H),2.88(s,3H),2.58-2.50(m,2H),1.77-1.68(m,3H),1.36-1.28(m,2H)。

Examples 13 to 25: preparation of Compounds 13 to 25

The first step: intermediates 16A-20A

The intermediates 16A to 20A were obtained using a synthesis similar to the first step of example 1.

And a second step of: intermediates 13B to 25B

By a method similar to the first step of example 12, intermediates 13B to 15B of compounds 13 to 15, and intermediates 24B and 25B of compounds 24 and 25 were each obtained by reacting 4-fluoroiodobenzene, 4-chloro-3-fluoroiodobenzene, 5-bromo-2-methoxypyridine, 4-bromo-2-fluoro-1-methoxybenzene, 1-bromo-2-fluoro-4-methoxybenzene with 2 a. The second step intermediates 16B-20B of compounds 16-20 were prepared from the corresponding 16A-20A using a similar synthetic procedure to that of the second step of compound 1.

And a third step of: compounds 13 to 25

Compounds 13 to 25 were prepared using a synthesis similar to the second step of example 12 and the final product was isolated and purified by Prep-HPLC.

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Example 26: n- (((4-chlorophenyl) amino) (((1- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (compound 26)

The first step: 6-bromo-2H-benzo [ b ] [1,4] oxazine-4 (3H) -carboxylic acid tert-butyl ester (3 b)

3a (817 mg,3.82 mmol) was dissolved in THF (9 mL) and DMAP (47 mg,0.38 mmol) and Et were added ₃ N (1.16 g,11.45 mmol) and further (Boc) ₂ O (1.00 g,4.58 mmol) was reacted at room temperature for 4h. After the reaction, water is added for quenching, and EA is used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was purified by silica gel column chromatography (PE/EA system, 7% EA) to give compound 3b (360 mg, yield 30%).

MS m/z(ESI):314.0[M+H] ⁺ 。

And a second step of: 6- (4- (((tert-Butoxycarbonyl) amino) methyl) piperidin-1-yl) -2H-benzo [ b ] [1,4] oxazine-4 (3H) -carboxylic acid tert-butyl ester (3 c)

3b (360 mg,1.15 mmol), 2a (247 mg,1.15 mmol), pd under nitrogen ₂ (dba) ₃ (110 mg,0.12 mmol), ruPhos (56 mg,0.12 mmol) and ^t BuONa (277 mg,2.88 mmol) was placed in a 50mL single-necked flask, toluene (8 mL) was added, and the mixture was heated to 90℃for 6h. After the reaction, the reaction mixture was cooled to room temperature, poured into water, and extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was purified by silica gel column chromatography (PE/EA system, 10% EA) to give compound 3c (460 mg, yield 93%).

MS m/z(ESI):448.3[M+H] ⁺ .

And a third step of: (1- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) piperidin-4-yl) methylamine hydrochloride (3 d)

3c (460 mg) was dissolved in dioxane (3 mL) and 10.0mL 4M HCl in dioxane was added and TLC monitored until complete conversion of the starting material. After the reaction, concentrating under reduced pressure to dryness to obtain hydrochloride of the compound 3 d.

MS m/z(ESI):248.2[M+H] ⁺ .

Fourth step: n- (((4-chlorophenyl) amino) (((1- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (26)

3d and Compound Int-1 (340 mg,1.22 mmol) were dissolved in DMF (5 mL) and stirred to complete dissolution followed by DIPEA (1.00 g) and heated to 80deg.C and stirred for 15h. After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into saturated brine, and extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was separated and purified by Prep-HPLC to give compound 26 (140 mg, yield 28%).

ESI-MS(m/z):477.8[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ:8.74(s,1H),7.41-7.31(m,5H),6.48(d,J＝8.4Hz,1H),6.16(d,J＝2.4Hz,1H),6.09(dd,J＝8.8,J＝2.8Hz,1H),5.56(s,1H),4.02(t,J＝4.4Hz,2H),3.42(d,J＝12.0Hz,2H),3.24-3.21(m,4H),2.88(s,3H),2.52-2.47(m,2H),1.74-1.65(m,3H),1.33-1.27(m,2H)。

Example 27: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 27)

The first step: 2- (1-Benzylpiperidin-4-ylidene) propionic acid ethyl ester (4 c)

4b (8.58 g,36.00 mmol) was dissolved in 50mL THF, cooled to 0deg.C, naH (827.63 mg,36.00 mmol) was slowly added, and after 30min the reaction was completed, 4a (5.68 g,30 mmol) was added and heated to 70deg.C. After 24h, the reaction was stopped, cooled to room temperature, the solvent was evaporated under reduced pressure and purified by column chromatography on silica gel (PE: ea=19:1-9:1) to give 4c (3.5 g).

MS m/z(ESI)：274.2[M+H] ⁺ 。

And a second step of: 2- (piperidin-4-yl) propionic acid ethyl ester (4 d)

4C (3.5 g,12.80 mmol) was dissolved in anhydrous methanol (40 mL), 680mg of 10% Pd/C was added and reacted under hydrogen atmosphere (1 atm), monitored by TLC until complete conversion of starting material. After the reaction was completed, it was filtered through celite and washed with DCM: meoh=10:1 mixed solvent, and the filtrate was concentrated to dryness under reduced pressure to give a crude product (2.34 g) of 4d, which was used in the next reaction without further purification.

MS m/z(ESI)：186.1[M+H] ⁺ 。

And a third step of: 2- (1- (4-methoxyphenyl) piperidin-4-yl) propionic acid ethyl ester (4 e)

4d (800 mg,4.3 mmol), 4-iodoanisole (843 mg,3.6 mmol), pd under nitrogen ₂ (dba) ₃ (164 mg,0.18 mmol), ruPhos (168 mg,0.36 mmol) and ^t BuONa (692 mg,7.2 mmol) was placed in a 50mL three-necked flask, followed by 15.0mL toluene, heating to 100deg.C and reaction, TLC monitored for complete conversion of starting material. After the reaction was cooled to room temperature, filtered and washed with EtOAc, the solvent was evaporated under reduced pressure and purified by preparative TLC (PE: ea=19:1-9:1) to give the target compound 4e (750 mg).

MS m/z(ESI)：292.2[M+H] ⁺ 。

Fourth step: 2- (1- (4-methoxyphenyl) piperidin-4-yl) propionic acid (4 f)

4e (800 mg,2.75 mmol) was dissolved in methanol (15 mL) and water (5 mL), then NaOH (275 mg,6.86 mmol) was added, heated to 50 ℃ and stirred overnight, after the reaction was completed, pH was adjusted to 3-4 with 1M hydrochloric acid, concentrated to dryness under reduced pressure to give crude 4f, which was dissolved in DCM: meoh=5:1 solution and slurried, filtered and the filtrate concentrated to dryness under reduced pressure, and the obtained 4f (680 mg) was used in the next reaction without further purification.

MS m/z(ESI)：264.2[M+H] ⁺ 。

Fifth step: (1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) carbamoyl azide (4 g)

4f (227 mg,2.0 mmol), DPPA (1.46 g,6.0 mmol) and Et ₃ N (606 mg,6.0 mmol) was dissolved in toluene (10 mL), heated to 100deg.C, monitored by TLC until complete conversion of starting material, cooled to room temperature after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was separated by column chromatography on silica gel (methanol/dichloromethane=0-10%) to give 4g (220 mg).

MS m/z(ESI)：304.2[M+H] ⁺ 。

Sixth step: 1- (1- (4-methoxyphenyl) piperidin-4-yl) ethylamine (4 h)

4g (303 mg,1.0 mmol) was dissolved in MeOH (20 mL), naOH (1.6 g,40.0 mmol) in water (5.0 mL) was added, the mixture was reacted at room temperature for 2 hours, then heated to 95℃and reacted for 96 hours, after the completion of the reaction, the mixture was cooled to room temperature, and the pH was adjusted to 3-4 with 1N HCl. The solvent was distilled off under reduced pressure, and the crude product was slurried once with a solution of DCM: meoh=10:1 and 5:1, respectively, and the solvent was filtered off and distilled off under reduced pressure to give crude hydrochloride (220 mg) for 4h, which was directly used in the next reaction.

MS m/z(ESI)：235.3(M-HCl+1)。

Seventh step: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide

4h (234 mg,1.0 mmol), int-1 (352 mg,1.2 mmol) and DIPEA (640 mg,5.0 mmol) were dissolved in 10.0mL DMF, heated to 100deg.C and reacted for 21h, cooled to room temperature after the reaction was completed, diluted with EtOAc and washed with water and the organic layer was taken up with anhydrous Na ₂ SO ₄ Drying, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target compound 27 (30 mg).

MS m/z(ESI)：464.9[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ7.39-7.28(m,4H),6.99-6.95(m,2H),6.85-6.81(m,2H),3.94-3.90(m,1H),3.73(s,3H),3.49-3.47(m,2H),2.96(s,3H),2.61-2.58(m,2H),1.94-1.85(m,2H),1.57-1.47(m,3H),1.27-1.18(m,3H)。

Example 28:1- (4-chlorophenyl) -2-cyano-3- (1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) guanidine (compound 28)

4h (40 mg,0.15 mmol), int-6 (48 mg,0.18 mmol) and DIPEA (39 mg,0.30 mmol) were dissolved in 3.0mL DMF and heated to 100deg.C until complete conversion of the starting material, cooled to room temperature after completion of the reaction, diluted with EtOAc and washed with water and the organic layer with anhydrous Na ₂ SO ₄ Drying, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target compound 28 (15 mg).

MS m/z(ESI)：412.0[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ7.38(d,J＝8.8Hz,2H),7.23(d,J＝8.4Hz,2H),6.99-6.96(m,2H),6.85-6.81(m,2H),3.88-3.85(m,1H),3.74(s,3H),3.53-3.49(m,2H),2.61-2.54(m,2H),1.88-1.81(m,2H),1.57-1.46(m,3H),1.23(d,J＝6.8Hz,3H)。

Example 29: n- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 29)

4h (70 mg,0.30 mmol), int-3 (106 mg,0.36 mmol) and DIPEA (116 mg,0.90 mmol) were dissolved in 3.0mL DMF and heated to 100deg.C for complete conversion of starting material, cooled to room temperature after completion of the reaction, diluted with EtOAc and washed with water and the organic layer with anhydrous Na ₂ SO ₄ Drying, filtration, and evaporation of the solvent under reduced pressure gave the title compound 29 (23 mg) as isolated and purified by Prep-HPLC.

MS m/z(ESI)：483.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.83(br,1H),8.52(br,0.5H),7.53(s,1H),7.37-7.28(m,2.5H),6.89(d,J＝9.2Hz,2H),6.80(d,J＝8.8Hz,2H),3.82-3.76(m,1H),3.67(s,3H),3.59-3.52(m,2H),2.78(br,3H),2.52-2.49(m,2H),1.85-1.71(m,2H),1.53-1.38(m,3H),1.23-1.05(m,3H)。

Examples 30 and 31: (S) -N- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide and (R) -N- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide

Compound 29 has one chiral center and thus has both the (S) -isomer and the (R) -isomer. Both isomers can be obtained by chiral separation. Specifically, compound 29 was isolated by chiral column under the isolation conditions described below, yielding compound 29A (peak 1, rt=5.25 min) and compound 29B (peak 2, rt=6.63 min).

Instrument: shimadzu LC-20AT; chromatographic column: CHIRALCEL OZ-H (OZH CD-VF 004) (0.46 cm I.D..times.15 cm L); column temperature: 35 ℃; detection wavelength: UV 254nm; flow rate: 1.0mL/min; mobile phase: n-hexane/ethanol=50%: 50%.

Compound 29A: ¹ H NMR(DMSO-d ₆ ,400MHz)δ8.82(br,1H),8.53(br,0.5H),7.54(s,1H),7.38–7.27(m,2.5H),6.89(d,J＝9.2Hz,2H),6.80(d,J＝8.8Hz,2H),3.82-3.77(m,1H),3.67(s,3H),3.55(br,2H),2.79(br,3H),2.58-2.50(m,2H),1.85-1.71(m,2H),1.54-1.36(m,3H),1.23-1.06(m,3H).

compound 29B: ¹ H NMR(DMSO-d ₆ ,400MHz)δ8.81(br,1H),8.53(br,0.5H),7.53(s,1H),7.35-7.29(m,2.5H),6.89(d,J＝9.2Hz,2H),6.82-6.79(m,2H),3.82-3.77(m,1H),3.68(s,3H),3.56(br,2H),2.80(br,3H),2.58-2.50(m,2H),1.85-1.71(m,2H),1.55-1.33(m,3H),1.23-1.05(m,3H).

example 32: n- (((4-chloro-3-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 30)

4h (19 mg,0.08 mmol), int-5 (29 mg,0.96 mmol) and DIPEA (52 mg,0.40 mmol) were dissolved in 3.0mL DMF and heatedThe reaction was carried out at 100℃until complete conversion of the starting material, cooled to room temperature after completion of the reaction, diluted with EtOAc and washed with water, and the organic layer was taken up in anhydrous Na ₂ SO ₄ Drying, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target compound 30 (5 mg).

MS m/z(ESI)：483.1[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ7.50-7.46(m,1H),7.36(br,1H),7.19(d,J＝7.6Hz,1H),7.03-6.98(m,2H),6.88-6.84(m,2H),3.90-3.83(m,1H),3.77(s,3H),3.58-3.55(m,2H),3.00(s,3H),2.66-2.62(m,2H),1.95-1.87(m,2H),1.57-1.52(m,3H),1.35-1.27(m,3H)。

Example 33: n- (((5-chloropyridin-2-yl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 31)

Compounds 4h (146 mg,0.5mmol,80% purity), int-7 (155 mg,0.5mmol,90% purity) and DIPEA (330 mg,2.5 mmol) were dissolved in DMF (5.0 mL) under nitrogen and heated to 100deg.C for 22h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the title compound 31 (50 mg).

MS m/z(ESI)：466.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.05(d,J＝8.4Hz,1H),9.88(s,1H),9.32(d,J＝2.0Hz,1H),7.95-7.92(dd,J＝8.8Hz,J＝2.4Hz,1H),7.16(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,2H),6.79(d,J＝8.8Hz,2H),3.97-3.89(m,1H),3.67(s,3H),3.58-3.52(m,2H),2.97(s,3H),2.57-2.50(m,2H),1.81-1.69(m,2H),1.61-1.53(m,1H),1.44-1.33(m,2H),1.19(d,J＝6.8Hz,3H)。

Example 34: n- (((4-chlorophenyl) amino) ((1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 32)

First step ethyl 2- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) propionate (5 b)

4d (205 mg,1.0mmol,90% purity), 5a (287 mg,1.2 mmol), pd under nitrogen ₂ (dba) ₃ (46 mg,0.05 mmol), ruphos (47 mg,0.1 mmol) and sodium tert-butoxide (196 mg,2.00 mmol) were dissolved in toluene (5.0 mL) and heated to 100deg.C for 2h. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the filtrate was evaporated to dryness under reduced pressure to give 5b (150 mg) by preparative TLC separation and purification (PE: ea=10:1).

And a second step of: 2- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) propionic acid (5 c)

5b (150 mg,0.5mmol,95% purity) was dissolved in methanol (5.0 mL), a solution of NaOH (52 mg,1.28 mmol) in water (2.0 mL) was added, the reaction was heated to 50deg.C and monitored by TLC (PE: EA=5:1) until complete conversion of the starting material. After the reaction, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated under reduced pressure. The crude product obtained was slurried with DCM: meoh=5:1 and filtered, the filtrate was evaporated to dryness under reduced pressure to give the crude product which was used in the next reaction without further purification.

MS m/z(ESI)：265.2[M+H] ⁺ 。

And a third step of: (1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) carbamoyl azide (5 d)

5c (147 mg,0.5mmol,95% purity), triethylamine (155 mg,1.50 mmol) and DPPA (372 mg,1.50 mmol) were dissolved in toluene (5.0 mL) under nitrogen and heated to 80℃for 1h. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was dissolved in DCM and purified by preparative TLC (PE: ea=4:1, containing 5% DCM) to give product 5d (95 mg).

Fourth step: 1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethylamine hydrochloride (5 e)

5d (95 mg,0.3 mmol) was dissolved in methanol (10 mL), a solution of NaOH (25 mg,0.6 mmol) in water (2 mL) was added and the reaction was monitored by TLC (PE: EA=5:1) until complete conversion of the starting material. A solution of NaOH (460 mg,11.6 mmol) in water (2 mL) was then added and the reaction was heated to 95℃for 96h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated under reduced pressure to give a crude product of 5 e. The crude product was used in the next reaction without further purification.

MS m/z(ESI)：236.2[M+H] ⁺ 。

Fifth step: n- (((4-chlorophenyl) amino) ((1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (32)

The crude product of 5e from the previous step and Int-1 (82 mg,0.28 mmol) were dissolved in DMF (5.0 mL), DIPEA (258 mg,1.96 mmol) was added and reacted at 100℃for 9h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the title compound 32 (60 mg).

MS m/z(ESI)：466.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(br,1H),7.78(s,1H),7.45-7.36(m,5H),7.18(br,1H),6.69(d,J＝8.8Hz,1H),3.87-3.80(m,1H),3.76(s,3H),3.61-3.55(m,2H),2.87(s,3H),2.58-2.50(m,2H),1.82-1.72(m,2H),1.56-1.49(m,1H),1.40-1.32(m,2H),1.16(br,3H)。

Example 35: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) amino) methylene) methanesulfonamide (compound 36)

The first step: 4- (1-ethoxy-1-oxobutane-2-ylidene) piperidine-1-carboxylic acid benzyl ester (6 c)

6b (4.63 g,18.00 mmol) was dissolved in 50mL THF, cooled to 0deg.C, naH (689.70 mg,18.00 mmol) was slowly added, after 30min of reaction 6a (3.57 g,15 mmol) was added and the addition was completed to 80deg.C for 15h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by separation and purification by silica gel column chromatography (PE: ea=19:1-9:1) to give 6c (3.3 g).

And a second step of: 2- (piperidin-4-yl) butanoic acid ethyl ester (6 d)

6C (3.3 g,9.96 mmol) was dissolved in methanol (50 mL) at room temperature, 10% Pd/C (604 mg,0.57 mmol) was slowly added and the reaction was monitored by TLC under hydrogen atmosphere (PE: EA=5:1) until complete conversion of the starting material was achieved. After the reaction was completed, the mixture was filtered through celite and washed with MeOH, and the filtrate was evaporated to dryness under reduced pressure to give a crude product (1.90 g) of 6d, which was used directly in the next reaction without further purification.

MS m/z(ESI)：200.2[M+H] ⁺ 。

And a third step of: ethyl 2- (1- (4-methoxyphenyl) piperidin-4-yl) butyrate (6 e)

6d (221 mg,1.0mmol,90% purity), 1a (284 mg,1.20 mmol), pd ₂ (dba) ₃ (46 mg,0.05 mmol), ruphos (48 mg,0.1 mmol) and sodium tert-butoxide (196 mg,2.00 mmol) were placed in a 100mL round-bottomed flask, toluene (5.0 mL) was added under nitrogen, and the mixture was heated to 100℃for 1h. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the mixture was purified by preparative TLC (PE: ea=10:1) to give 6e (100 mg).

Fourth step: 2- (1- (4-methoxyphenyl) piperidin-4-yl) butyric acid (6 f)

6e (100 mg,0.29mmol,90% purity) was dissolved in water (2.0 mL), a solution of NaOH (120 mg,2.95 mmol) in methanol (5 mL) was added and the mixture was heated to 90℃and reacted for 17h. After the reaction, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCL, and the solvent was evaporated under reduced pressure. The resulting crude product was slurried in a mixed solvent (50 mL) of DCM: meoh=5:1. Filtration and then evaporation of the solvent under reduced pressure gave the crude product of 6f, which was used directly in the next reaction without further purification.

MS m/z(ESI)：278.2[M+H] ⁺ 。

Fifth step: (1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) carbamoyl azide (6 g)

The crude 6f from the previous step, DPPA (191 mg,0.77 mmol) and triethylamine (79 mg,0.77 mmol) were dissolved in toluene (5.0 mL) under nitrogen and heated to 80deg.C for 1h. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the mixture was purified by preparative TLC (PE: ea=5:1) to give 6g (60 mg).

MS m/z(ESI)：318.2[M+H] ⁺ 。

Sixth step: 1- (1- (4-methoxyphenyl) piperidin-4-yl) propan-1-amine hydrochloride (6 h)

6g (60 mg,0.17mmol,90% purity) was dissolved in methanol (10.0 mL), a solution of NaOH (20 mg,0.51 mmol) in water (2.0 mL) was added, and after 30min at room temperature, a solution of NaOH (253.09 mg,6.20 mmol) in water (2.0 mL) was added, followed by heating to 120℃for 96h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, the solvent was evaporated under reduced pressure, and the obtained crude product was directly subjected to the next reaction without further purification.

MS m/z(ESI)：249.3[M+H] ⁺ 。

Seventh step: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) amino) methylene) methanesulfonamide (36)

The crude product from the previous step, int-1 (35 mg,0.12 mmol) and DIPEA (95 mg,0.72 mmol) were dissolved in DMF (5.0 mL) under nitrogen and heated to 100deg.C for 16h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc, washed with water, and then the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the target compound 36 (15 mg) was obtained by separation and purification by preparative HPLC.

MS m/z(ESI)：479.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.78(br,1H),7.38-7.20(brs,5H),6.88(d,J＝9.2Hz,2H),6.79(d,J＝9.2Hz,2H),3.78-3.72(m,1H),3.67(s,3H),3.55(t,J＝10.2Hz,2H),2.86(s,3H),2.56-2.50(m,2H),1.78-1.70(m,2H),1.55(br,2H),1.41(br,3H),0.92(br,3H)。

Example 36: n- (((4-chlorobenzyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 38)

Compounds 4h (146 mg,0.5mmol,80% purity)), int-7 (163 mg,0.5mmol,90% purity)) and DIPEA (330 mg,2.5 mmol) were dissolved in DMF (5.0 mL) under nitrogen and heated to 100deg.C for 16h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the title compound 38 (50 mg).

MS m/z(ESI)：479.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ7.60(br,1H),7.42(d,J＝8.4Hz,2H),7.31(d,J＝7.2Hz,2H),7.00(br,1H),6.87(d,J＝8.8Hz,2H),6.79(d,J＝8.8Hz,2H),4.38(s,2H),3.67(s,3H),3.63(br,1H),3.52-3.48(m,2H),2.72(s,3H),2.50-2.42(m,2H),1.68-1.62(m,2H),1.45-1.23(m,3H),1.10(br,3H)。

Example 37: n- (((4-chlorophenyl) amino) ((1- (1-phenylpiperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 40)

The first step: 2- (1-Phenylpiperidin-4-yl) propionic acid ethyl ester (7 b)

7a (250 mg,1.2 mmol), 4d (206 mg,1mmol,90% purity), pd under nitrogen ₂ (dba) ₃ (46 mg,0.05 mmol), ruphos (48 mg,0.1 mmol) and sodium tert-butoxide (196.12 mg,2.00 mmol) were dissolved in toluene (5.0 mL) and heated to 100deg.C for 2.5h. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the mixture was purified by preparative TLC (PE: ea=10:1) to give 7b (240 mg).

MS m/z(ESI)：262.2[M+H] ⁺ 。

And a second step of: 2- (1-Phenylpiperidin-4-yl) propionic acid (7 c)

7b (240 mg,0.9 mmol) was dissolved in methanol (10.0 mL), a solution of NaOH (112 mg,2.75 mmol) in water (2.0 mL) was added, heated to 50deg.C and reacted, and TLC (PE: EA=5:1) monitored until complete conversion of starting material. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, the solvent was evaporated to dryness under reduced pressure, the resulting crude product was dissolved in DCM: meoh=5:1 mixed solvent to be slurried, filtered, and then the solvent was evaporated to dryness under reduced pressure to give a crude product of 7c, which was directly subjected to the next reaction without further purification.

MS m/z(ESI)：234.1[M+H] ⁺ 。

And a third step of: (1- (1-phenylpiperidin-4-yl) ethyl) carbamoyl azide (7 d)

The crude product of 7c from the previous step, DPPA (744 mg,3.0 mmol) and triethylamine (309 mg,3.0 mmol) were dissolved in toluene (10.0 mL) under nitrogen and heated to 80deg.C for 1h. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the mixture was purified by preparative TLC (PE: ea=5:1, 5% dcm) to give 7d (200 mg).

MS m/z(ESI)：274.1[M+H] ⁺ 。

Fourth step: 1- (1-Phenylpiperidin-4-yl) ethylamine hydrochloride (7 e)

7d (222 mg,0.73mmol,90% purity) was dissolved in methanol (10.0 mL), a solution of NaOH (89.60 mg,2.20 mmol) in water (1.0 mL) was added, and after 1h reaction at room temperature, a solution of NaOH (1.18 g,28.97 mmol) in water (1.0 mL) was added and the mixture was heated to 95℃for 40h reaction. TLC (PE: ea=5:1) was monitored until complete conversion of starting material. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated under reduced pressure. The resulting crude product was dissolved in DCM: meoh=5:1 mixed solvent, slurried, filtered, and then the solvent was evaporated under reduced pressure to give 7e as crude product, which was carried forward without further purification.

MS m/z(ESI)：205.2[M+H] ⁺ 。

Fifth step: n- (((4-chlorophenyl) amino) ((1- (1-phenylpiperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (40)

The crude product of 7e from the previous step, int-1 (352 mg,1.20 mmol) and DIPEA (528 mg,4.00 mmol) were dissolved in DMF (10.0 mL) under nitrogen and heated to 95℃for 15h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the title compound 40 (180 mg).

MS m/z(ESI)：435.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),7.39-7.32(m,4H),7.20(t,J＝7.6Hz,3H),6.97-6.92(m,2H),6.77-6.73(m,1H),3.87-3.82(m,1H),3.77-3.72(m,2H),2.86(s,3H),2.65-2.59(m,2H),1.81-1.72(m,2H),1.61-1.55(m,1H),1.37-1.30(m,2H),1.16(br,3H)。

Example 38: n- (4-chlorophenyl) -4- (4-methoxyphenyl) -N' - (methylsulfonyl) piperidine-1-carboxamidine (Compound 41)

The first step: 4- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid benzyl ester (8 c)

LiHMDS (1.0M, 11.00 mL) was dissolved in 10mL anhydrous THF and cooled to-78deg.C. A solution of 8a (2.38 g,10.0 mmol) in THF (10 mL) was slowly added and reacted at-78deg.C for 30min. Then a solution of 8b (4.01 g,11.00 mmol) in THF (10 mL) was slowly added and the reaction was maintained at-78C for 2h after the addition. The cooling liquid was then removed, and the reaction system was slowly warmed to room temperature and reacted for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and then separated and purified by silica gel column chromatography (PE: ea=19:1-4:1) to give 8c (3.45 g).

And a second step of: 4- (4-methoxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid benzyl ester (8 e)

8d (1.44 g,9.3 mmol), 8c (3.25 g,8.45 mmol), pd (dppf) Cl under nitrogen ₂ *CH ₂ Cl ₂ (352 mg,0.42 mmol) and potassium carbonate (2.38 g,16.9 mmol) were placed in a 100mL reaction flask, DMF (20 mL) and water (5 mL) were added, and then heated to 90℃for 2h. After the reaction, the mixture was cooled to room temperature, and was purified by celiteThe earth was filtered and washed with EtOAc. The filtrate was washed with water, and the organic phase was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and separated and purified by silica gel column chromatography (PE: ea=19:1-9:1) to give 8e (700 mg).

MS m/z(ESI)：324.1[M+H] ⁺ 。

And a third step of: 4- (4-methoxyphenyl) piperidine (8 f)

8e (700 mg,2.16 mmol) was dissolved in methanol (30 mL), 10% Pd/C (115.18 mg, 108.23. Mu. Mol) was added and reacted under hydrogen atmosphere (1 atm) and monitored by TLC until complete conversion of the starting material. After the reaction was completed, the mixture was filtered through celite and washed with MeOH. The solvent was evaporated under reduced pressure to give crude 8f (400 mg), which was used in the next reaction without further purification.

MS m/z(ESI)：192.2[M+H] ⁺ 。

Fourth step: n- (4-chlorophenyl) -4- (4-methoxyphenyl) -N' - (methylsulfonyl) piperidine-1-carboxamidine (41)

8f (60 mg,0.30 mmol), int-1 (88 mg,0.30 mmol) and DIPEA (196 mg,1.49 mmol) were dissolved in DMF (5.0 mL) under nitrogen and heated to 100deg.C for 8h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the title compound 41 (40 mg).

MS m/z(ESI)：422.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(s,1H),7.40-7.37(m,2H),7.18-7.13(m,4H),6.86-6.83(m,2H),3.96-3.91(m,2H),3.71(s,3H),2.99-2.93(m,2H),2.87(s,3H),2.71-2.65(s,1H),1.74-1.68(m,2H),1.58-1.48(m,2H)。

The separation and purification method comprises the following steps:

except that the compound 32 is separated and purified by Waters type HPLC, the other compounds are separated and purified by Aglient 1260 type HPLC, the column temperature is 25 ℃, and other separation conditions are shown in the following table:

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biological evaluation

The following examples further describe and illustrate the invention, but are not meant to limit the scope of the invention.

Experimental example 1 measurement of the inhibitory Effect of Compounds on IDO enzyme in Hela cells

The effect of compounds on intracellular IDO enzyme activity was determined using NFK Green method.

Reagent: NFK Green fluorescent dye (NTRC); l-tryptophan (Sigma-Aldrich); recombinant Human IFN-gamma Protein (R & D systems)

Experimental protocol:

culturing Hela cells in complete medium (DMEM containing 10% foetal calf serum) (37 deg.C, 5% CO) ₂ Is provided). Digestion treatment with pancreatin-EDTA was carried out for passage 2-3 times a week. When cells are in exponential growth phase, cells are harvested, counted and plated. The cell concentration (10000 cells/well) was adjusted, and cells were inoculated into a 96-well plate in an amount of 70. Mu.L/well, and placed in an incubator to be cultured for 24 hours.

Preparing a mother solution of the compound to be tested by using DMSO, sucking a proper amount of mother solution into a complete culture medium, and uniformly mixing to prepare a compound solution to be tested with corresponding concentration. mu.L of the test compound solution was added to each well and incubated for 1 hour. Wells with DMSO alone were set as negative controls.

mu.L of 500ng/mL IFN-. Gamma. (Recombinant Human IFN-gamma.protein) (dissolved in complete medium) and 10. Mu.L of sterile 0.5mM L-tryptophan solution (dissolved in 20mM Hepes) were added and incubation continued for 48h.

After incubation was completed, 25 μl of supernatant was transferred to 384 well plates, 5 μl NFK Green was added to each well, the plates were closed and incubated for 4h at 37 ℃. The fluorescence is detected by an enzyme-labeled instrument, ex./ Em. =400.+ -. 25 nm/510.+ -. 20nm.

And (3) data processing: compound inhibition (%) = (1-Savg/Cavg) ×100%; savg is the mean value of the fluorescence readings of the compound to be tested, the mean value of the fluorescence readings of the Cavg negative control group, and IC ₅₀ Calculated by GraphPad Prism software.

Results:

TABLE 1 inhibition of IDO enzyme Activity by Hela cells by Compounds of the invention IC ₅₀

Numbering of compounds	IC ₅₀ (nM)
		4	5.5
12	8.1
		13	29.4
15	10.1
		16	8.4
17	10.8
		18	6.2
19	14.5
		20	13.3
23	23.3
		24	17.0
25	14.2
		27	3.6
29	4.8
		29A	1.5
30	3.9
		32	8.0
36	9.6
		40	15.3
41	10.9

As can be seen from Table 1, the compounds of the present invention have a remarkable inhibitory effect on the IDO enzyme in Hela cells.

Experimental example 2: hERG assay

By predictors ^TM hERG Fluorescence Polarization Assay Kit (manufacturer: thermoFisher), the inhibition of hERG potassium ion channel by the test compound (at a concentration of 10. Mu.M) was demonstrated by the kit, and the test results are shown in Table 2.

TABLE 2 inhibition assay results of hERG by Compounds

Compounds of formula (I)	IC ₅₀ (μM)
		15	>10
29A	>10
		32	>10
40	>10
		41	>10

The results indicate that the compounds of the invention (e.g., compounds 15, 29A, 32, 40 and 41) have no significant inhibitory effect on hERG, resulting in a low probability of prolongation of cardiac QT interval.

Experimental example 3: CYP enzyme inhibition assay

CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, the most predominant of which are CYP1A2, CYP2D6 and CYP3A4.

In assays for testing inhibition of CYP450 enzymes by fluorescence, P450-Glo is used ^TM CYP1A2 Screening System、CYP2D6 Cyan Screening Kit and +.>The inhibitory activity of the compounds on CYP1A2, CYP2D6 and CYP3A4 was measured separately according to the kit instructions. The test results are shown in Table 3A.

TABLE 3 inhibition test results of compounds on CYP enzymes

The inhibition of CYP3A4 by compound 29A was determined by LC-MS method, and the specific test is as follows:

reagent and reference substance:

the CYP3A4 probe substrate adopts testosterone and midazolam, the positive inhibitor adopts ketoconazole, and the incubation medium is mixed Human Liver Microsome (HLM)

The test method comprises the following steps:

after pre-incubation (at 37 ℃) for 5min of a mixture of probe substrate (50 μl), PBS (49 μl), test compound 29A or positive control compound ketoconazole (1 μl) and HLM (50 μl), NADPH (50 μl) was added and incubated for a further 30min. Wherein, the incubation concentration of HLM is 0.1mg/ml, the incubation concentration of testosterone is 50 mu M, and the incubation concentration of midazolam is 2 mu M. After the corresponding time of the reaction, 600. Mu.l of glacial acetonitrile containing the internal standard was added to the testosterone reaction incubation to terminate the reaction, and 800. Mu.l of glacial acetonitrile containing the internal standard was added to the midazolam reaction incubation to terminate the reaction. All samples were vortexed and centrifuged to obtain the supernatant to be tested.

The measuring method comprises the following steps:

LC-MS/MS: mass spectrometry used Sciex API 5500. Liquid chromatography employed the Waters ACQUITY UPLC I-CLASS system. The chromatographic column is Hypersil GOLD C ₁₈ (2.1 mm. Times.50 mm,1.9 μm). Mobile phase: phase A is water+0.1% formic acid, and phase B is acetonitrile; the flow rate was 0.4ml/min and the column temperature was 40 ℃. The ion source is ESI source positive ion mode, and the scanning mode is multi-reaction monitoring (MRM).

The concentration of the primary metabolite produced by the probe substrate at various concentrations of the compound was determined using the vehicle group (DMSO) as a negative control to determine the half Inhibitory Concentration (IC) of the compound on CYP3A4 ₅₀ )。

TABLE 3 inhibition of CYP3A4 by Compound 29A

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Compound 29A had no significant inhibition of CYP3A4 (IC ₅₀ >10μM)。

The results indicate that the compounds of the invention (e.g., compounds 4, 12, 13, 15, 19, 25, 27, 29A, 30 and 32) have no significant inhibitory effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.

Experimental example 4: pharmacokinetic (PK) studies in rats

SPF-grade male SD rats were given Intravenous (IV) and intragastric (PO), respectively, to examine pharmacokinetic properties.

All animals were fasted for 10-14 hours prior to dosing and had resumed dosing 4 hours after dosing. The dosage of IV and PO is 1mg/kg and 5mg/kg, respectively, the solvent of IV is 5% DMSO, 5% Solutol, 90% physiological saline, and the solvent of PO is 0.5% MC (sodium methylcellulose). Blood was collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours before IV dosing and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after PO dosing and blood was collected at time points of 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after PO dosing using edta.k ₂ Anticoagulation, and centrifuging within 30min after blood sampling to obtain plasma sample, and storing at-80deg.C for testing. Plasma samples were subjected to LC-MS/MS analysis after treatment with precipitated proteins. Mass spectrometry using Sciex API 5500Liquid chromatography uses the Waters ACQUITY I-CLASS system; the chromatographic column uses Hypersil GOLD C ₁₈ (2.1 mm. Times.50 mm,1.9 μm); mobile phase: phase A is 0.1% formic acid aqueous solution, and phase B is acetonitrile; the flow rate is 0.5ml/min, and the column temperature is 40 ℃; the ion source is ESI source positive ion mode, and the scanning mode is multi-reaction monitoring (MRM). Pharmacokinetic parameters were calculated using the non-compartmental model using WinNonlin 6.3 software and the results are shown in table 4 below:

TABLE 4 pharmacokinetic parameters of the compounds

The results indicate that the compounds of the application (e.g., compounds 1, 12, 15, 18 and 29A) have good PK properties in SD rats.

Various modifications of the application, in addition to those described herein, are intended to fall within the scope of the appended claims in light of the foregoing description. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims

1. A compound of formula I-a, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound:

R ¹ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

x is NR ¹¹ Or CHNO ₂ ；

m=0, 1 or 2;

n=0 or 1;

t=0, 1 or 2;

q is CH, N, COH, CF, CMe, CNH ₂ CNHMe or CNMe ₂ ；

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and C ₁ -C ₆ Hydroxyalkyl group, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 、C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one Or a plurality of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl or C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and C ₁ -C ₆ Hydroxyalkyl group, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl or C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ² And R is ³ Are linked to form, together with the C atom to which they are attached, a P ring selected from C ₃ -C ₆ Cycloalkyl and 4-7 membered heterocyclyl;

R ⁴ and R is ⁵ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, said C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H；

R ⁶ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl and 3-14 membered heterocyclyl, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ⁶ Selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ -(C ₆ -C ₁₄ Aryl) -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl and 3-14 membered heterocyclyl, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl-heterocyclo, -CH ₂ - (5-14 membered heteroaryl), C ₃ -C ₇ Cycloalkyl, 3-a 14 membered heterocyclyl group optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-14 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can optionally be substitutedOne or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

R ¹¹ selected from hydrogen, OH, CN, -SO ₂ R ¹² and-C (O) R ¹³ ；

the conditions are as follows:

(1) When m=1, n=1 and t=1, Q is not CH;

2. A compound of formula I-a according to claim 1, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ 、R ⁶ Each independently selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl and 9-10 membered aryl-heterocyclo, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 9-10 membered aryl-heterocyclo may optionally be substituted with one or moreThe following substituents were substituted: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl groups.

3. A compound of formula I-a according to claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹ 、R ⁶ Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl andwherein ring P' is phenyl or 5-7 membered heteroaryl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ 、R ⁶ Each independently selected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ HaloalkanesRadical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ 、R ⁶ Each independently selected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl optionally being substituted with one or more of the following substituents: F. cl, CN, methyl, CF ₃ 、CHF ₂ Or methoxy;

preferably, R ¹ 、R ⁶ Each independently selected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl, said phenyl, pyridinyl, quinolinyl, isoquinolinyl, benzimidazolyl, and pyridoimidazolyl optionally being substituted with one or more of the following substituents: F. cl, methyl, CN or methoxy.

4. A compound of formula I-a according to any one of claims 1 to 3, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹ Selected from phenyl, pyridinyl and quinolinyl, which phenyl, pyridinyl and quinolinyl may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;

preferably, R ¹ Selected from:

5. a compound of formula I-a according to any one of claims 1 to 4, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:

R ⁶ selected from phenyl and pyridinyl, which may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;

preferably, R ⁶ Selected from:

6. a compound of formula I-a according to claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹ selected from the group consisting ofWherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, OH,CN, halogen and CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ Is thatWherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring optionally being substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ¹ Selected from the group consisting of

7. A compound of formula I-a according to claim 1, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ⁶ selected from-CH ₂ -(C ₆ -C ₁₄ Aryl) and-CH ₂ - (5-14 membered heteroaryl), said-CH ₂ -(C ₆ -C ₁₄ Aryl) and-CH ₂ - (5-to 14-membered heteroaryl) optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁶ Selected from-CH ₂ -(C ₆ -C ₁₀ Aryl) and-CH ₂ - (5-to 10-membered heteroaryl), said-CH ₂ -(C ₆ -C ₁₀ Aryl) and-CH ₂ - (5-to 10-membered heteroaryl) optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁶ Selected from-CH ₂ -phenyl and-CH ₂ - (5-6 membered heteroaryl), said-CH ₂ -phenyl and-CH ₂ - (5-6 membered heteroaryl) optionally substituted by one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

Preferably, R ⁶ Selected from-CH ₂ -phenyl and-CH ₂ -pyridinyl, said-CH ₂ -phenyl and-CH ₂ -pyridyl optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁶ is-CH ₂ -phenyl, said-CH ₂ -phenyl optionally substituted with one or more of the followingGroup substitution: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁶ Is that

8. A compound of formula I-a according to any one of claims 1 to 7, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ² and R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₆ A hydroxyalkyl group; or alternatively

R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₆ A hydroxyalkyl group; or alternatively

preferably, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, halogen, CN, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ A hydroxyalkyl group;

preferably, R ² And R is ³ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl and C ₁ -C ₃ Hydroxyalkyl group, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl optionally being substituted with one or more of the following substituents: OH, F, cl, CN methyl, ethyl, n-propyl, isopropyl, C ₁ -C ₃ Haloalkyl, methoxy, ethoxy, C ₃ -C ₆ Cycloalkyl and C ₁ -C ₃ A hydroxyalkyl group; or R is ² And R is ³ To form a P ring together with the C atom to which they are attached,the P ring is selected from C ₃ -C ₆ Cycloalkyl and 4-7 membered heterocyclyl containing O, more preferably selected from

More preferably, R ² And R is ³ Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH ₂ -cyclopropyl; alternatively, R ² And R is ³ Are linked together with the C atom to which they are attached to form a P ring, which is

9. A compound of formula I-a according to any one of claims 1 to 8, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ⁴ And R is ⁵ Each independently selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN;

preferably, R ⁴ And R is ⁵ Are all hydrogen.

10. A compound of formula I-a according to claim 1, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ⁵ and R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁵ And R is ⁶ And are linked to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylalkylheterocyclyl, which 5-10 membered heteroaryl, 9-10 membered arylalkylheterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, C ₁ -C ₆ A hydroxyalkyl group;

preferably, R ⁵ And R is ⁶ Are linked to form together with the N atom to which they are attachedWhich may be optionally substituted with one or more of the following substituents: OH, F, cl, CN, NO ₂ 、CO ₂ H、C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; c as described herein ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, C ₁ -C ₃ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl group、C ₁ -C ₆ A hydroxyalkyl group;

11. A compound of formula I-a according to claim 10, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ⁴ selected from hydrogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H；

Preferably, R ⁴ Is hydrogen。

12. A compound of formula I-a according to any one of claims 1 to 11, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹¹ selected from CN and-SO ₂ R ¹² 。

13. A compound of formula I-a according to any one of claims 1 to 12, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

preferably, R ¹² Is methyl or C ₃ -C ₆ Cycloalkyl;

preferably, R ¹² Is methyl.

14. A compound of formula I-a according to any one of claims 1 to 13, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:

R ¹³ selected from C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ -C ₃ Alkyl, said C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ Hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ The alkyl group may be optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ Or a 4-7 membered heterocyclic group.

15. A compound of formula I-a according to any one of claims 1 to 9 and 12 to 14, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula II:

Wherein R is ¹ 、R ⁶ And X is as defined in any one of claims 1 to 9 and 12 to 14.

16. A compound of formula I-a according to any one of claims 1 to 9 and 12 to 14, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula III:

wherein R is ¹ 、R ⁶ X and R ² As defined in any one of claims 1 to 9 and 12 to 14;

preferably, R ² H, C of a shape of H, C ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl or-CH ₂ -(C ₃ -C ₆ Cycloalkyl);

preferably, R ² Is H, methyl, ethyl, cyclopropyl or-CH ₂ -cyclopropyl.

17. A compound of formula I-a according to claim 16, a stereoisomer, tautomer, or mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula IV:

18. a stereoisomer, tautomer, or mixture thereof of a compound, a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound is selected from the group consisting of:

/>

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, and one or more pharmaceutically acceptable carriers.

20. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 18, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition according to claim 19, and one or more pharmaceutically acceptable carriers.

21. Use of a compound according to any one of claims 1 to 18, a stereoisomer, a tautomer, or a mixture of same, a stable isotopic derivative, a metabolite, or a prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a pharmaceutical composition according to claim 19, or a pharmaceutical formulation according to claim 20, in the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease or condition associated with IDO activity,

Preferably, the disease or disorder associated with IDO activity is selected from the group consisting of tumors, depression and senile dementia.

22. The use of claim 21, wherein the medicament further comprises an additional agent for preventing, alleviating and/or treating a disease or disorder associated with IDO activity.

23. Use of a compound according to any one of claims 1 to 18, a stereoisomer, a tautomer or a mixture of same, a stable isotopic derivative, a metabolite or a prodrug of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate of said compound, or a pharmaceutical composition according to claim 19, or a pharmaceutical formulation according to claim 20, for the manufacture of a medicament for the prophylaxis, alleviation and/or treatment of a disease or condition caused by immunosuppression,

preferably, the disease or condition caused by immunosuppression is selected from the group consisting of a tumor, a viral infection, an autoimmune disease.

24. The use according to claim 23, wherein the medicament further comprises an additional agent for preventing, alleviating and/or treating a disease or condition caused by immunosuppression.