CN111247119B

CN111247119B - Amidine and guanidine derivatives, preparation method and application thereof in medicines

Info

Publication number: CN111247119B
Application number: CN201980005190.7A
Authority: CN
Inventors: 李桂英; 蔡家强; 游泽金; 韩润丰; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-01-19
Filing date: 2019-01-04
Publication date: 2023-02-03
Anticipated expiration: 2039-01-04
Also published as: CN111247119A; WO2019141095A1

Abstract

The compound shown in the formula (I), a pharmaceutical composition, a pharmaceutical preparation and the application of the compound in preparing medicines for preventing or treating diseases related to IDO activity or IDO mediated immunosuppression.

Description

Amidine and guanidine derivatives, preparation method and medical application thereof

Technical Field

The invention relates to novel amidine and guanidine derivatives as IDO inhibitors, a preparation method thereof, a pharmaceutical composition containing the compounds and application thereof in medicines.

Background

Due to unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (surgery, radiotherapy and chemotherapy) clinically adopted at present cannot completely remove or completely kill tumor cells, and the tumor cells can escape from the monitoring of the immune system of the body through various ways, so that the tumor metastasis or relapse is caused. Tumor immunotherapy is the process of enhancing the anti-tumor immunity of the tumor microenvironment by mobilizing the immune system of the body (such as inhibiting the IDO-mediated tumor immune escape mechanism), thereby controlling and killing tumor cells. Due to the characteristics of safety, effectiveness, low adverse reaction and the like, the traditional Chinese medicine composition becomes a new therapy for treating tumors after operations, radiotherapy and chemotherapy.

IDO is currently one of the most potential small molecule drug targets for tumor immunotherapy entering the clinical research phase. In 1969 IDO was first found intracellularly by the Hayaishi group (Hayaishi O. Et al, science,1969, 164, 389-396), a heme-containing monomeric enzyme whose cDNA-encoded protein consists of 403 amino acids, has a molecular weight of 45kDa, is a rate-limiting enzyme that catalyzes the catabolism of tryptophan via the kynurenine pathway, is widely distributed in tissues other than the liver of humans and other mammals (e.g., rabbits, mice), and is the only rate-limiting enzyme other than the liver that catalyzes the catabolism of tryptophan. The IDO of various cells in a tumor microenvironment is highly expressed, so that tryptophan metabolism is exhausted, and the kynurenine level is increased, thereby blocking the activation of T cells, inducing the T cell apoptosis mediated by oxygen free radicals, enhancing the immunosuppression effect mediated by regulatory T cells (Tregs) and promoting the tumor to escape from the immune monitoring of an organism.

Besides tumors, IDO is associated with the occurrence of diseases such as depression, senile dementia, cataract, etc. In addition, IDO is also implicated in neurological and psychiatric disorders such as mood disorders and other chronic diseases caused by activation of IDO leading to tryptophan degradation, such as viral infections (e.g., AIDS), autoimmune diseases, bacterial infections such as lyme disease and streptococcal infections, and the like. Therefore, inhibition of IDO activity has great therapeutic value.

The IDO small molecule inhibitor Epacadostat developed by Incyte corporation is currently used in combination with the PD-1 antibody keytruda or the PD-L1 antibody avelumab in clinical phase I/II trials to treat a variety of cancers, such as advanced or metastatic solid tumors, relapsed glioblastoma, and the like. The IDO small molecule inhibitor BMS-986205 of Bristol-Myers Squibb is currently used in combination with Nivolumab in a clinical phase III trial to treat a variety of cancers, such as advanced renal cell carcinoma, untreated metastatic or unresectable melanoma; treatment of advanced malignancies in combination with Nivolumab and LAG-3 antibody relatlimab in a clinical phase I/II trial. NewLink Genetics is also conducting a number of clinical trials of indoximod (NLG-8189) in combination with other drugs, for example in phase II/III trials in the treatment of metastatic melanoma in combination with the PD-1 antibody keytruda or Nivolumab. Published patent applications for IDO inhibitors include WO2016073770, WO2016073734, WO2016073738 and the like. However, no IDO inhibitors are currently on the market. In order to achieve better therapeutic effects and better meet market demands, development of new IDO inhibitors with high efficiency and low toxicity is urgently needed.

Disclosure of Invention

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

wherein:

n =0 or 1;

R ¹ is selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, or 9-10 membered arylheterocyclo; said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, 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; said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, 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 、-NR ⁷ R ⁸ ；

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

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

R ⁶ Is selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, -CH ₂ -C ₆ -C ₁₄ Aryl, -CH ₂ -5-14 membered heteroaryl, C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclo; said C ₆ -C ₁₄ Aryl, 5-14 membered heteroAryl, -CH ₂ -C ₆ -C ₁₄ Aryl, -CH ₂ -5-14 membered heteroaryl, C ₃ -C ₇ The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, -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 、-NR ⁷ R ⁸ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Haloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, -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 、-NR ⁷ R ⁸ (ii) a Preferably R ⁶ Is selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, -CH ₂ -C ₆ -C ₁₄ Aryl, -CH ₂ -5-14 membered heteroaryl, C ₃ -C ₇ Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclyi; said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, C ₃ -C ₇ The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, -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 、-NR ⁷ R ⁸ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Haloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, -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 、-NR ⁷ R ⁸ ；

R ⁷ 、R ⁸ And R ⁹ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, 4-7 membered heterocyclic group, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl are optionally substituted with the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ 、CO ₂ H, or R ⁷ 、R ⁸ And together with the N atom to which they are attached form a 4-7 membered heterocyclyl; when a plurality of R ⁷ When both are present, each R ⁷ May be the same or different; when a plurality of R ⁸ When both are present, each R ⁸ May be the same or different; when a plurality of R ⁹ When both are present, each R ⁹ May be the same or different;

R ¹⁰ is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl, 4-7 membered heterocyclic group, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl and 4-7 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ 、CO ₂ H, or R ⁹ 、R ¹⁰ And together with the N and C or S atoms to which they are attached form a 4-7 membered heterocyclyl; when multiple R ¹⁰ When present simultaneously, each R ¹⁰ May be the same or different;

x is NR ¹¹ Or CHNO ₂ ；

R ¹¹ Selected from hydrogen, OH, CN, NH ₂ 、NHMe、NMe ₂ 、-SO ₂ R ¹² 、-C(O)R ¹³ ，

R ¹² Is selected from C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ A cycloalkyl group; said C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl is optionally substituted with the following substituents: OH, OC ₁ -C ₆ Alkyl, NH ₂ 、NHMe、NMe ₂ 4-7 membered heterocyclyl;

R ¹³ is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 4-7 membered heterocyclyl.

In some embodiments of the invention, the compound has the structure of formula II, III, IV or V:

wherein R is ¹ 、R ⁵ 、R ⁶ And X is as defined above for formula I;

wherein R is ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ And X is as defined above for formula I; preferably, R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ An alkyl group;

wherein R is ¹ 、R ⁴ 、R ⁵ 、R ⁶ And X is as defined above for formula I; preferably, R ⁴ Is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ ；

Wherein R is ¹ P ring, R ⁵ 、R ⁶ And X is as defined above for formula I.

In some embodiments of the invention, the compound has the structure of formula II-1, II-2, III-1, III-2, IV-1, IV-2, V-1, or V-2:

wherein R is ¹ 、R ⁵ 、R ⁶ And X is as defined above for formula I;

wherein R is ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ And X is as defined above for formula I; preferably, R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl, aryl, heteroaryl, and heteroaryl,C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ An alkyl group;

wherein R is ¹ 、R ⁴ 、R ⁵ 、R ⁶ And X is as defined above for formula I; preferably, R ⁴ Is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ ；

Wherein R is ¹ P ring, R ⁵ 、R ⁶ And X is as defined above for formula I.

In some preferred embodiments of the invention, R ¹ Is selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, 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; said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₆ Alkyl radical, 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 radical, 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 、-NR ⁷ R ⁸ ；R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ As defined above.

In a more preferred embodiment of the invention, R ¹ Is selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 9-10 membered benzoheterocyclyl; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkoxy, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, C ₁ -C ₄ 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 ₁₁ Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Hydroxyalkyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Alkoxy, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, C ₁ -C ₄ 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 、-NR ⁷ R ⁸ ；R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ As defined above.

In a more preferred embodiment of the invention, R ¹ Is selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: halogen, C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Hydroxyalkyl, -C (O) NR ⁷ R ⁸ (ii) a Said C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with the following substituents: OH, -NR ⁷ R ⁸ ；R ⁷ 、R ⁸ As defined above.

In a more preferred embodiment of the invention, R ¹ Selected from phenyl, quinolyl and pyridineA pyridyl group indazolyl group,

The phenyl, the quinolyl, the pyridyl, the indazolyl,

May be optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, -C (O) NH (CH) ₃ )、-C(O)N(CH ₃ ) ₂ 、-OCH ₂ CH ₂ OH、-OCH ₂ CH ₂ NH(CH ₃ )、-OCH ₂ CH ₂ N(CH ₃ ) ₂ 。

In a preferred embodiment of the invention, R ¹ Selected from phenyl, quinolyl and pyridyl, wherein the phenyl, quinolyl and pyridyl can be optionally substituted by the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy.

In a preferred embodiment of the invention, R ¹ Selected from phenyl, p-methoxyphenyl, quinolyl, pyridyl,

In a preferred embodiment of the invention, n =1.

In a preferred embodiment of the invention, n =0.

In a preferred embodiment of the invention, R ² And R ³ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical，C ₁ -C ₄ Hydroxyalkyl radical of said C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Hydroxyalkyl groups may be optionally substituted with the following substituents: OH, halogen, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ Hydroxyalkyl, or R ² 、R ³ And together with the C atom to which they are attached form a P ring selected from C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl.

In a more preferred embodiment of the invention, R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl or R ² 、R ³ And together with the C atom to which they are attached form a P ring selected from C ₃ -C ₅ A cycloalkyl group.

In a more preferred embodiment of the invention, R ² And R ³ Each independently selected from hydrogen, methyl, ethyl, propyl, or R ² 、R ³ And together with the C atom to which they are attached form a P ring selected from cyclopropane, cyclobutane or cyclopentane.

In a more preferred embodiment of the invention, R ² And R ³ Each independently selected from hydrogen, methyl, ethyl, propyl; preferably, R ² And R ³ Each independently selected from hydrogen, methyl.

In some preferred embodiments of the invention, R ⁴ And R ⁵ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy radical, C ₂ -C ₄ Hydroxyalkyl radical, C ₂ -C ₄ alkyl-OC ₂ -C ₄ Alkyl radical, said C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy radical, C ₂ -C ₄ Hydroxyalkyl radical, C ₂ -C ₄ alkyl-OC ₂ -C ₄ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₄ Haloalkyl, CN, CO ₂ H、-NR ⁷ R ⁸ 、C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ ；R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ As defined above.

In a more preferred embodiment of the invention, R ⁴ And R ⁵ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Hydroxyalkyl of said C ₁ -C ₄ Alkyl groups may be optionally substituted with the following substituents: halogen, -NR ⁷ R ⁸ ，R ⁷ 、R ⁸ As defined above.

In a more preferred embodiment of the invention, R ⁴ And R ⁵ Each independently selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, -CH ₂ CH ₂ NH(CH ₃ )、-CH ₂ CH ₂ N(CH ₃ ) ₂ 。

In a more preferred embodiment of the invention, R ⁴ And R ⁵ Each independently selected from hydrogen, methyl, ethyl, propyl; preferably, R ⁴ And R ⁵ Each is hydrogen.

In some preferred embodiments of the invention, R ⁶ Is selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ Aryl, -CH ₂ -5-10 membered heteroaryl, C ₃ -C ₇ Cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ Aryl, -CH ₂ -5-10 membered heteroaryl, C ₃ -C ₇ The cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl can be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Hydroxyalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl, -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 、-NR ⁷ R ⁸ 、C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; said C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Hydroxyalkyl radical, OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H、C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Hydroxyalkyl, C ₁ -C ₄ Haloalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl, -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 、-NR ⁷ R ⁸ ；R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ As defined above.

In a more preferred embodiment of the invention, R ⁶ Selected from C optionally substituted by a substituent ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ Aryl, -CH ₂ -5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl, said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl cocoa, optionally substituted with the following substituents: OH, halogen, CN, NO ₂ 、CO ₂ H、C ₁ -C ₄ Alkyl radical, C ₃ -C ₅ Cycloalkyl, C ₁ -C ₄ Alkoxy radical, C ₂ -C ₄ Hydroxyalkyl, -OC ₂ - ₄ alkyl-OH, -OC ₂ - ₄ alkyl-NR ⁷ R ⁸ 4-7 membered heterocyclyl, R ⁷ 、R ⁸ As defined above.

In a more preferred embodiment of the invention, R ⁶ Selected from phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridinyl, thiazolyl, pyrrolidinyl, 2, 3-dihydrobenzo [ b][1，4]Dioxinyl, said phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridinyl, thiazolyl, pyrrolidinyl, 2, 3-dihydrobenzo [ b ]][1，4]The dioxinyl group may be optionally substituted by the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CN, hydroxyethyl, hydroxypropyl, -OCH ₂ CH ₂ OH、-OCH ₂ CH ₂ NHCH ₃ 、-OCH ₂ CH ₂ N(CH ₃ ) ₂ Pyrrolidinyl, 3-hydroxypyrrolidinyl.

In a more preferred embodiment of the invention, R ⁶ Is phenyl, optionally substituted with fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or CN; preferably, R ⁶ Is phenyl, optionally substituted with fluoro, chloro, methoxy or CN.

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

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

In a more preferred embodiment of the invention, R ⁷ 、R ⁸ And R ⁹ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy radical, said C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy may be optionally substituted for NH by ₂ 、NHMe、NMe ₂ 。

In a more preferred embodiment of the invention, R ⁷ 、R ⁸ And R ⁹ Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.

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

In a more preferred embodiment of the invention, R ¹⁰ Is selected from C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₂ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₂ -C ₄ Hydroxyalkyl radical, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl, 4-6 membered heterocyclic group, said C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₂ -C ₄ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₂ -C ₄ Hydroxyalkyl radical, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl, 4-6 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH ₂ 、NHMe、NMe ₂ 、CO ₂ H, or R ⁹ 、R ¹⁰ And together with the N and C atoms to which they are attached form a 4-7 membered heterocyclyl.

In a more preferred embodiment of the invention, R ¹⁰ Is selected from C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy radical, said C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkoxy groups may be optionally substituted with the following substituents: NH ₂ 、NHMe、NMe ₂ 。

In a more preferred embodiment of the invention, R ¹⁰ Selected from methyl, ethyl, propyl, isopropyl.

In some preferred embodiments of the invention, X is NR ¹¹ Or CHNO ₂ (ii) a Preferably, X is NR ¹¹ ；

R ¹² Is selected from C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ A cycloalkyl group; said C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl groups may be optionally substituted with the following substituents: OH, OC ₁ -C ₄ Alkyl, NH ₂ 、NHMe、NMe ₂ 4-7 membered heterocyclyl;

R ¹³ is selected from C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, said C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₆ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 4-7 membered heterocyclyl;

in a preferred embodiment of the invention, X is selected from NR ¹¹ Or CHNO ₂ (ii) a Preferably, X is NR ¹¹ ；

R ¹² Is selected from C ₁ -C ₄ Alkyl radical, C ₃ -C ₅ A cycloalkyl group;

R ¹³ is selected from C ₁ -C ₄ Alkyl radical, C ₃ -C ₅ Cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl radical, said C ₁ -C ₄ Alkyl radical, C ₃ -C ₅ Cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C ₁ -C ₄ Haloalkyl, CN, C (O) NH ₂ 、NH ₂ 、NHMe、NMe ₂ 4-6 membered heterocyclyl.

In a more preferred embodiment of the invention, X is selected from NR ¹¹ Or CHNO ₂ Preferably, X is NR ¹¹ (ii) a Wherein R is ¹¹ Selected from CN, -SO ₂ R ¹² ；R ¹² Is selected from C ₁ -C ₄ Alkyl radical, C ₃ -C ₅ A cycloalkyl group.

In a more preferred embodiment, X is selected from NR ¹¹ Or CHNO ₂ Preferably, X is NR ¹¹ (ii) a Wherein R is ¹¹ Selected from CN, -SO ₂ R ¹² ；R ¹² Selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane; preferably, X is selected from NR ¹¹ Or CHNO ₂ More preferably, X is NR ¹¹ (ii) a Wherein R is ¹¹ Selected from CN, -SO ₂ Me、-SO ₂ Et、-SO ₂ Pr、-SO ₂ -i-Pr、-SO ₂ -cyclopropane, -SO ₂ -cyclobutane; further preferably, X is selected from N-SO ₂ Me、N-CN、CH-NO ₂ (ii) a Even more preferably, X is selected from N-SO ₂ Me、N-CN。

In an embodiment of the invention, the compounds of the invention are selected from, but not limited to:

preparation method

One aspect of the present invention provides a process for preparing a compound of the present invention, said process comprising:

synthesis of intermediate A

R ¹ As defined above for formula I.

The first step is as follows: compound A-1 in base and PhNTf ₂ Under the action of (1), or Tf ₂ And generating an enolization intermediate A-2 under the action of O and 2, 6-di-tert-butyl-4-methylpyridine.

The alkali is LiHMDS, LDA, naHMDS, KHMDS, ^t BuOK, naH or NaOH, etc., and solvent is THF, CH ₃ CN, DCM or DCE, etc., at-78 deg.C to 25 deg.C;

the second step is that: combining A-2 with R ¹ Boronic acids or esters are subjected to a coupling reaction (e.g. a Suzuki reaction) to yield intermediate a-3.

The catalyst used is Pd (PPh) ₃ ) ₄ Or Pd (dppf) Cl ₂ Etc., the base used is Cs ₂ CO ₃ 、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ Or K ₂ CO ₃ Etc., the solvent is Dioxane/H ₂ O、DMF/H ₂ O、DMSO/H ₂ O or CH ₃ CN/H ₂ O, etc. at the temperature of 60-120 ℃;

the third step: compound a-3 is reduced to intermediate a-4 under catalytic hydrogenation conditions.

The catalyst is Pd/C, ptO ₂ Or Pd (OH) ₂ C, etc., the solvent is MeOH or EtOH, etc., and the temperature is rt to 80 ℃;

the fourth step: and removing the Boc protecting group of the compound A-4 under the action of acid to obtain an intermediate A.

The acid used is a solution of HCl in Dioxane or TFA in DCM, etc., at a temperature of 0 ℃ to rt.

Synthesis of intermediate B

R ¹ As defined above for formula I, R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₃ -C ₆ Cycloalkyl radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ An alkyl group.

The first step is as follows: compound B-1 in base and PhNTf ₂ Under the action of (1), or (Tf) ₂ And generating an enolization intermediate B-2 under the action of O and 2, 6-di-tert-butyl-4-methylpyridine.

The reaction conditions were as described in the first step of the process for the preparation of intermediate a.

The second step: compounds B-2 and R ¹ Boronic acids or esters are subjected to a coupling reaction (e.g. a Suzuki reaction) to yield intermediate B-3.

The reaction conditions were as described in the second step of the process for the preparation of intermediate a.

The third step: compound B-3 is reduced to intermediate B-4 under catalytic hydrogenation conditions.

The reaction conditions were as described in the third step of the process for the preparation of intermediate a.

The fourth step: and performing alkylation reaction on the compound B-4 in the presence of alkali to generate an intermediate B-5.

The alkylating agent used is R ² -L ¹ And/or R ³ -L ¹ (L ¹ is-Cl, -Br, -I or-OMs, etc.), is subjected to one and/or two alkylations, the bases used are BuLi, liHMDS, LDA, ^t BuOK、NaH、Cs ₂ CO ₃ 、K ₂ CO ₃ Or NaOH, etc., and the solvent is THF or CH ₃ CN, DCM, DMF, DMSO, DCE or Acetone, etc., at-78 deg.C to rt;

the fifth step: the compound B-5 is hydrolyzed in the presence of alkali to obtain an intermediate B-6.

The base used is LiOH, naOH or KOH, etc., in MeOH/H ₂ O or EtOH/H ₂ O, etc. at a temperature of 0 to 80 ℃;

and a sixth step: compound B-6 undergoes Curtius rearrangement to produce intermediate B-7.

The base used is Et ₃ N, DIPEA, etc., DPPA, etc., as a reagent, and DPPA, etc., as a solvent ^t BuOH, toluene, DCM, ^t A mixed solvent of BuOH and toluene, etc., at a temperature of 40 to 110 ℃.

The seventh step: the compound B-7 is hydrolyzed under alkaline conditions to generate a product B.

The base is NaOH, liOH or KOH, etc., and the solvent is Dioxane/H ₂ O，MeOH/H ₂ O，EtOH/H ₂ O, etc., at a temperature of rt to 80 ℃.

Synthesis of intermediate C

R ¹ As defined above for formula I, R ⁴ Is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl radical, said C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ alkyl-OC ₁ -C ₆ Alkyl groups may be optionally substituted with the following substituents: OH, CN, -NR ⁷ R ⁸ 、-C(O)NR ⁷ R ⁸ 、-NR ⁹ C(O)R ¹⁰ 。

The first step is as follows: the compound A-4 reacts with R under the action of alkali ⁴ -L ¹ (L ¹ is-Cl, -Br, -I or-OMs, etc.), or with R ⁴ The OH is subjected to a Mitsunobu reaction to generate an intermediate C-1.

The base used for alkylation is BuLi, liHMDS, LDA, ^t BuOK、NaH、Cs ₂ CO ₃ 、K ₂ CO ₃ Or NaOH, etc., and the solvent is THF or CH ₃ CN, DCM, DMF, DMSO, DCE or Acetone, etc., at-78 deg.C to 60 deg.C; if the Mitsunobu reaction occurs, the reagent used is generally DIAD or DEAD, etc., and the solventTHF, DCM or DCE etc. at a temperature of 0 ℃ to 80 ℃;

the second step: and removing the Boc protecting group of the intermediate C-1 under the action of acid to generate an intermediate C.

The reaction conditions were as described in the fourth step of the process for the preparation of intermediate a.

Synthesis of intermediate D

R ¹ As defined above for formula I, ring P is C ₃ -C ₆ Cycloalkyl or 4-7 membered heterocyclyl.

The first step is as follows: compound R ¹ -L ² (L ² Cl, br, I or OTf, etc.) with D-1a or D-1b via a coupling reaction (e.g., a Suzuki reaction) to produce intermediate D-2.

The reaction conditions were as described in the second step of the process for the preparation of intermediate a. The second step is that: the compound D-2 generates an intermediate D-3 under reducing conditions.

The third step: the compound D-3 generates an intermediate D-4 under the action of acid.

The acid is HCl or H ₂ SO ₄ P-toluenesulfonic acid or methanesulfonic acid, and the like, and the solvent is THF, DCM, DCE, meOH, etOH, DMF, DMSO, CH ₃ CN, dioxane, acetone or Toluene and the like at the temperature of rt to 100 ℃;

the fourth step-A: the compound D-4 and the compound D-5 generate an intermediate D-6 under the alkaline condition.

The alkali used is LDA, n-BuLi, ^t BuOK, naOH, naH, liHMDS, naHMDS or KHMDS etc., and the solvent is THF, DCM, DCE, meOH, etOH, DMF, CH ₃ CN, dioxane or Toluene, etc., at-78 deg.C to rt;

the fourth step-B: the compound D-4 and amine are subjected to reductive amination to obtain an intermediate A

The amine source is ammonium chloride, ammonium acetate, NH ₃ In aqueous or MeOH, etc., the reducing agent being NaBH ₃ CN、NaBH ₄ 、NaBH(OAc) ₃ Etc., the solvent is THF, DCM, DCE, meOH, etOH, DMF, CH ₃ CN, dioxane or Toluene, etc., at a temperature of 0 ℃ to 80 ℃.

The fifth step: the compound D-6 is dehydrated to obtain an intermediate D-7.

The dehydrating agent is an acid, such as HCl, H ₂ SO ₄ Or TFA, or the like, or with Burgess dehydrating agent in the form of THF, DCM, DCE, meOH, etOH, DMF, CH ₃ CN, dioxane or Toluene, etc.

And a sixth step: the compound D-7 generates an intermediate D-8 under reducing conditions.

The seventh step: the compound D-8 is hydrolyzed under alkaline/acidic conditions to generate an intermediate D-9.

The acid is HCl or H ₂ SO ₄ P-toluenesulfonic acid or methanesulfonic acid, etc., the base is LiOH, naOH or KOH, etc., and the solvent is THF, DCM, DCE, meOH, etOH, DMF, DMSO, CH ₃ CN, dioxane or Toluene, etc., at rt to 100 ℃;

eighth step: compound D-9 undergoes Curtius rearrangement to yield intermediate D-10.

The reaction conditions were as described in the sixth step of the process for the preparation of intermediate B.

The ninth step: compound D-10 is hydrolyzed under basic conditions to intermediate D.

The reaction conditions were as described in the seventh step of the process for the preparation of intermediate B.

Synthesis of intermediate E

R ⁵ 、R ⁶ As defined above for formula I.

The compound E-1 and E-2 generate an intermediate E under the action of alkali. The base is LiHMDS, LDA, naHMDS, KHMDS, TEA, DIPEA, or mixtures thereof, ^t BuOK, naH or Cs ₂ CO ₃ And the like, the solvent is THF, DCM, DCE, DMF, DMSO, or a mixture thereof,CH ₃ CN, dioxane, meOH, etOH or Toluene, etc., at a temperature of-10 ℃ to 140 ℃.

Synthesis of intermediate F

R ⁵ 、R ⁶ 、R ¹² As defined above for formula I.

The compound F-1 and the compound E-2 generate an intermediate F under the action of alkali.

The reaction conditions were as described in the first step of the process for the preparation of intermediate E.

Synthesis of intermediate G

R ⁵ 、R ⁶ As defined above for formula I.

The compound G-1 and the compound E-2 generate an intermediate G under the action of alkali.

Synthesis of Compounds of formula II-formula V (method one)

R ¹ 、R ⁵ 、R ⁶ 、R ¹² As defined above for formula I, R ⁴ As defined above for intermediate C, R ² And R ³ As defined in the above intermediate B, the P ring is as defined in the above intermediate D, and X is N-CN, N-SO ₂ R ¹² Or CH-NO ₂ 。

The first step is as follows: reaction of intermediates A, B, C or D with intermediates E, F or G, respectively, under basic conditions produces compounds of formula II, formula III, formula IV, and formula V, respectively.

Specifically, intermediate A reacts with intermediates E, F and G respectively under alkaline conditions to generate the compound of formula II.

Specifically, intermediate B reacts with intermediates E, F, G, respectively, under basic conditions to produce the compound of formula III.

Specifically, intermediate C reacts with intermediates E, F, G, respectively, under basic conditions to produce the compound of formula IV.

Specifically, intermediate D reacts with intermediates E, F, G, respectively, under basic conditions to produce a compound of formula V.

Synthesis of Compounds of formula II-formula V (method two)

R ¹ 、R ⁵ 、R ⁶ 、R ¹² As defined above for formula I, R ⁴ As defined above for intermediate C, R ² And R ³ As defined above for intermediate B, the P ring is as defined above for intermediate D, and X is N-CN, N-SO ₂ R ¹² Or CH-NO ₂ And X' is PhO or MeS.

The first step is as follows: and reacting the intermediate A, B, C or D with the intermediate E-1, F-1 or G-1 respectively under alkaline conditions to generate the intermediate A ', B', C 'or D'.

Specifically, the intermediate A reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate the intermediate A'.

Specifically, the intermediate B reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate B'.

Specifically, the intermediate C reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate C'.

Specifically, the intermediate D reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate D'.

The second step: intermediate A ', B'C 'or D' with intermediate R ⁵ -NH-R ⁶ Respectively reacting under alkaline conditions to generate compounds of formula II, formula III, formula IV and formula V.

In particular, intermediate A' and intermediate R ⁵ -NH-R ⁶ Under alkaline conditions to produce the compound of formula II.

In particular, intermediate B' and intermediate R ⁵ -NH-R ⁶ Under alkaline conditions to produce the compound of formula III.

In particular, intermediate C' and intermediate R ⁵ -NH-R ⁶ Under alkaline conditions to produce the compound of formula IV.

In particular, intermediate D' and intermediate R ⁵ -NH-R ⁶ Under alkaline conditions to produce the compound of formula V.

Pharmaceutical compositions, formulations, methods of making pharmaceutical compositions, and methods of treatment

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical compositions are used to treat diseases associated with IDO activity or IDO-mediated immunosuppression.

Another aspect of the invention provides a method of making a pharmaceutical composition, the method comprising combining a compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, with one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical compositions are used to treat diseases associated with IDO activity or IDO-mediated immunosuppression.

Another aspect of the invention provides a pharmaceutical formulation comprising a compound of the invention, a stereoisomer, tautomer or mixture thereof of said compound, a pharmaceutically acceptable salt, polymorph, co-crystal or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of the invention.

Another aspect of the present invention provides a compound of the present invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a co-crystal, or a solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for use in the manufacture of a medicament for the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression.

Another aspect of the present invention provides a compound of the present invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, polymorph, cocrystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, for use in the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression.

Another aspect of the present invention provides a method for preventing or treating a disease associated with IDO activity or IDO-mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and optionally comprising administering to a subject in need thereof an additional agent for the treatment of a disease, such as cancer.

Another aspect of the present invention provides a method for the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and administering to a subject in need thereof a PD-1 antibody or a PD-L1 antibody.

The diseases related to IDO activity or IDO mediated immunosuppression comprise but are not limited to tumors, depression, senile dementia and the like.

Such tumors include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female reproductive tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.

In the present invention, the "subject in need thereof" includes mammals, such as bovines, equines, porcines, canines, felines, rodents, primates; such as a human.

Another aspect of the invention provides a formulation comprising a compound of the invention, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in modulating (e.g., reducing or inhibiting) the activity of an IDO in cells of a subject (e.g., a mammal, e.g., a bovine, an equine, a porcine, a canine, a feline, a rodent, a primate; e.g., a human).

Another aspect of the invention provides a compound of the invention, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in the preparation of a formulation for modulating (e.g., reducing or inhibiting) IDO activity in a cell (e.g., mammalian, e.g., bovine, equine, porcine, canine, feline, rodent, primate; e.g., human) of a subject.

Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in modulating (e.g., reducing or inhibiting) the activity of IDO in the cells of a subject (e.g., a mammal, e.g., a bovine, equine, porcine, canine, feline, rodent, primate, e.g., human).

Another aspect of the invention provides a method of modulating (e.g., reducing or inhibiting) the activity of IDO in a cell of a subject (e.g., a mammal, e.g., a bovine, an equine, a porcine, a canine, a feline, a rodent, a primate; e.g., a human), comprising administering to the cell an effective amount of a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound.

In some embodiments, the formulation is administered to a subject to modulate (e.g., reduce or inhibit) the activity of IDO in cells in the subject; alternatively, the formulation is administered to cells in vitro (e.g., cell lines or cells from an individual) to modulate (e.g., reduce or inhibit) the activity of IDO in the cells.

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to one of ordinary skill in the art. 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.

The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 6, e.g., 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), which may be optionally substituted with one or more (such as 1 to 3) suitable substituents such as halo (when 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 ring, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has, for example, 3 to 7 carbon atoms, for example, 3 to 6 carbon atoms. For example, as herein describedAs used, the term "C ₃ -C ₇ Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) having from 3 to 7 ring carbon atoms, which may be optionally substituted by one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

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

The term "alkoxy," as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. C ₁ -C ₆ Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-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. For example, as used herein, the term "C ₆ -C ₁₄ Aryl "means an aromatic group containing 6 to 14 carbon atoms, such as 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.).

As used herein, the term "arylheterocyclo" refers to a cyclic group formed by an aryl group and a heterocyclyl group sharing two adjacent carbon atoms with each other, with the point of attachment to the other group being on the aryl group. Wherein aryl or heterocyclyl is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclo" means a group containing a total of 9-12 ring atoms of the arylheterocyclo, 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 hereinThe term "heteroaryl" is used to indicate a monocyclic heteroaryl group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (a heteroaromatic ring meaning an aromatic ring system containing at least one heteroatom), which has, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 7, 8, 9 or 10 ring atoms, in the point of attachment to other groups on the heteroaromatic ring, and which comprises one or more heteroatoms (for example 1, 2,3,4 or 5) which may be identical or different (for example oxygen, nitrogen or sulfur), and which may, in each case, share two adjacent atoms with the aryl, heterocyclyl or cycloalkyl group with one another to form a cyclic group. 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 fused ring derivatives thereof, and ring derivatives are not limited to heteroaryloaryl, heteroarylheterocyclo, or heteroarylocycloalkyl, particularly 5-6 membered heteroaryloaryl, 5-6 membered heteroaryloahenyl, 5-6 membered heteroaryloaryl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryloaryl C ₄ - ₆ Cycloalkyl (in particular 5-6 membered heteroarylocyclobutyl, 5-6 membered heteroarylocyclopentyl, 5-6 membered heteroarylocyclohexyl), examples include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, indolyl, and the like,

And the like.

As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2,3,4,5, 6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1, 2,3, or 4) substituents selected from C (= O), O, S (= O) 2, and NR (R represents a hydrogen atom or a substituted or unsubstituted moietyRadicals such as, but not limited to, alkyl or cycloalkyl) whose point of attachment to other radicals is on the heterocycle. As used herein, the term "3-14 membered heterocyclyl" means a heterocyclyl group containing 3-14 ring atoms (including 3-7 membered heterocyclyl groups, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like) and fused ring derivatives thereof, and fused ring derivatives thereof include, but are not limited to, heterocyclylheterocyclylheterocyclylheteroaryl, heterocyclylfused heteroaryl, heterocyclylcycloalkyl, particularly 3-7 membered heterocyclylfused 3-7 membered heterocyclyl, 3-7 membered heterocyclylfused aryl, 3-7 membered heterocyclylfused heteroaryl, particularly 3-7 membered heterocyclylfused cycloalkyl, 3-7 membered heterocyclylfused phenyl, 3-7 membered heterocyclylfused 5-10 membered heteroaryl, 3-7 membered heterocyclylfused C ₄ - ₆ A cycloalkyl group, which is a cyclic alkyl group, examples include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopent-aziridinyl, pyrrolidinyl-cyclobutyl, and the like pyrrolidinyl-, pyrrolidinyl-piperidinyl-, pyrrolidinyl-piperazinyl-, pyrrolidinyl-morpholinyl-, piperidinyl-piperazinyl-, p-pyrrolidinyl-morpholinyl-, p-pyrrolidinyl-, piperidinyl-, p-morpholinyl-, and p-morpholinyl groups,

Or spiro derivatives, e.g. but not limited to

And the like.

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.

As used herein, the term "hydroxyalkyl" means that the hydrogen atom of an alkyl group is replaced by one or moreMore than one (e.g., 1, 2,3, or 4) hydroxy substitution, as used herein, the term "C ₁ - ₆ Hydroxyalkyl "means C ₁ -C ₆ The hydrogen atom of the alkyl group is substituted with one or more (e.g., 1, 2,3, or 4) hydroxyl groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.

The term "substituted" means that one or more (e.g., 1, 2,3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the present circumstances is not exceeded and the substitution results in 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", the substituent may be (1) unsubstituted or (2) substituted with one or more (e.g., 1, 2,3, or 4) substituents. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.

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

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

Unless indicated, as used herein, 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 (stable isotopic derivatives) which are identical to those of the invention except for oneOne 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 predominant in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen) ² H、 ³ H) (ii) a Isotopes of carbon (e.g. of ¹¹ C、 ¹³ C and ¹⁴ c) (ii) a Isotopes of chlorine (e.g. of chlorine) ³⁶ Cl); isotopes of fluorine (e.g. of fluorine) ¹⁸ F) (ii) a Isotopes of iodine (e.g. of iodine) ¹²³ I and ¹²⁵ i) (ii) a Isotopes of nitrogen (e.g. of ¹³ N and ¹⁵ n); isotopes of oxygen (e.g. of ¹⁵ O、 ¹⁷ O and ¹⁸ o); isotopes of phosphorus (e.g. of phosphorus) ³² P); and isotopes of sulfur (e.g. of 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 result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different 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, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:

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

Unless otherwise indicated, the compounds of the present invention are intended to exist in the form of stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization 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 more than one polymorph in any ratio. It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative 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, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. 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 present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, 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 present invention are known to those skilled in the art.

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

Pharmaceutically acceptable carriers that may be employed 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. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. 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 optionally contain minor amounts of wetting agents, emulsifying agents or pH buffering agents. 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 systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations 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 amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

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 dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg person, this may amount 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 aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

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

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

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) with a disease (e.g., a disease described herein) or normal individuals. "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, livestock 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, such as in particular water, methanol or ethanol, as structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

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

The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present 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. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E.B.Roche editions, american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing appropriate functional groups present in a compound of the invention with certain moieties known to those skilled in the art as "pro-moieties", for example as described in "Design of Prodrugs", h.

The invention also encompasses compounds of the invention containing a protecting group. In 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 concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, as described, for example, in Protective Groups in Organic Chemistry, ed.j.f.w.mcmoie, plenum Press,1973; and 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.

Wave line used herein

The bonds in the structural formulae are meant to indicate that the structure represents cis or trans isomers, or a mixture of cis and trans isomers in any proportion.

Advantageous effects of the invention

The compound of the present invention has high inhibitory activity on IDO in cells, and has excellent properties such as good pharmacokinetic properties and good safety.

Detailed Description

Examples

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

The abbreviations in the present invention have the following meanings:

the structure of the compound is determined by nuclear magnetic resonance spectrum ( ¹ H NMR) and/or Mass Spectrometry (MS). The reaction was monitored by silica gel Thin Layer Chromatography (TLC) (GF 254 is the stationary phase) or LCMS.

¹ H NMR spectrometer Bruker superconducting NMR spectrometer (model AVACE III HD 400 MHz).

LC/MS mass spectrometer: aglient 1260 Infinity/Aglient 6120 Quadrupole.

The microwave reaction was performed using a BiotageInitiator microwave reactor.

The column chromatography generally uses 200-300 mesh silica gel (Qingdao sea) as a carrier. Flash column chromatography was performed using a biotage technologies instrument.

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

Reagents used in this application were purchased from Acros Organics, aldrich Chemical Company, or Tereber Chemical, among others.

Example 1: n- (((4-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 2) and its cis-trans isomers

The first step is as follows: n- (4-chlorophenyl) -N' - (methylsulfonyl) thioiminomethyl ester 2c

Compound 2a (59 mg) and compound 2b (100 mg) were placed in a 50mL three-necked flask, and anhydrous THF (5 mL) was added, and 1.6mL of a 1.0M solution of LiHMDS in THF was added under nitrogen. LCMS monitors for complete substrate conversion and 0.5mL of saturated NH is 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 silica gel plate (PE: EA = 2: 1) to give compound 2c (55 mg). MS m/z (ESI): 279.0[ 2 ] M + H] ⁺ 。

The second step is that: 4- ((tert-Butoxycarbonyl) amino) cyclohex-1-en-1-yl trifluoromethanesulfonate 2e

2d (2.0g, 9.4mmol) was added into THF (20 mL), cooled to-70 ℃ under nitrogen protection, 20.0mL of 1.0M LiHMDS was added dropwise thereto at-60 to-70 ℃ and the reaction was incubated for 1h, and then PhNTf was added ₂ (3.7g, 10.0mmol) was slowly dropped at-60 to-70 ℃ and reacted at room temperature overnight. After the reaction is finished, saturated NH is used ₄ The reaction was quenched with Cl solution (50 mL), extracted with ethyl acetate, and the organic phases were combined and washed with anhydrous Na ₂ SO ₄ Drying, evaporating the solvent under reduced pressure, and separating by silica gel column chromatography (PE: EA = 99: 1-80: 20) to obtain compound 2e (2.4 g). MS m/z (ESI): 346.1[ m ] +H] ⁺ 。

The third step: synthesis of tert-butyl (2, 3,4, 5-tetrahydro- [1,1' -biphenyl ] -4-yl) carbamate 2f

2e (2.4g, 7.0mmol), phenylboronic acid (1.3g, 10mmol), potassium phosphate (3.0g, 14mmol) and Pd (dppf) Cl were added under nitrogen protection ₂ (57mg, 0.07mmol) was dissolved in dioxane (20 mL) and the reaction was stirred overnight with heating to 90 ℃. TLC (PE: EA = 5: 1) showed completion of the reaction, then cooled to room temperature, poured into water (50 mL), extracted with methyl tert-butyl ether, and combined organic phases and extracted with anhydrous Na ₂ SO ₄ Drying, evaporating the solvent under reduced pressure, and separating by silica gel column chromatography (PE: EA = 99: 1-80: 20) to obtain compound 2f (0.8 g). MS m/z (ESI): 274.2[ M ] +H] ⁺ 。

The fourth step: synthesis of tert-butyl (4-phenylcyclohexyl) carbamate (2 g)

2f (0.8g, 2.9mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (100 mg) was added thereto, the reaction was carried out overnight at room temperature under a hydrogen atmosphere, and the filtrate was filtered and concentrated under reduced pressure to dryness to give 2g (0.8 g) of the compound. MS m/z (E SI): 276.2[ m ] +H] ⁺ 。

The fifth step: synthesis of 4-phenylcyclohexylamine hydrochloride 2h

2g (0.8g, 2.9mmol) was added to a 4N HCl Dioxane solution (8 mL) and reacted at room temperature for 3 hours, and the reaction solution was concentrated to dryness to give a compound (2 h, 0.6 g). MS m/z (ESI): 176.1[ M ] +H] ⁺

And a sixth step: n- (((4-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 2)

Compound 2c (55 mg) and compound 2h in free form (47 mg) were placed in a 10mL microwave reaction tube, DMF (3 mL) was added and dissolved with stirring, DIPEA (200 mg) was added, and the reaction was carried out for 4h at 100 ℃ under microwave conditions. LC-MS monitors that the substrate is completely converted, after the reaction is finished, the substrate is poured into 50mL of water, extracted by EtOAc and subjected to anhydrous Na ₂ SO ₄ Drying, evaporation of the solvent under reduced pressure and purification by Prep-HPLC gave Compound 2 (50 mg). The compound 2 is separated again by Prep-HPLC to obtain cis-or trans-isomer, 2A (peak 1, 11mg, collection time 5.8-6.1 min); 2B (Peak 2,9mg, collection time 6.2-6.4 min). MS m/z (ESI): 406.1[ M ] +H] ⁺ 。

2A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.88(s，1H)，7.77(br，1H)，7.48-7.10(m，9H)，4.18(brs，1H)，2.93(s，3H)，2.65-2.58(m，1H)，1.98-1.52(m，8H).

2B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.78(s，1H)，7.45-7.09(m，10H)，3.80-3.71(m，1H)，2.89(s，3H)，2.53-2.50(m，1H)，2.07-2.04(m，2H)，1.85(d，J＝12.8Hz，2H)，1.62-1.33(m，4H).

Example 2:1- (4-chlorophenyl) -2-cyano-3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) guanidine (Compound 3)

The first step is as follows: 6-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline 3b

Pd (dppf) Cl is added under the protection of nitrogen ₂ (1000mg，1.4mmol)、3a(6.5g，29.0mmol)、B ₂ pin ₂ (9.6 g, 38.0mmol) and AcOK (8.5 g, 87.0mmol) were dissolved in dioxane (70 mL) solution and reacted at 80 ℃ for 4 hours, after the reaction was completed, the solution was cooled to room temperature, filtered and washed with EtOAc, the mother liquor was concentrated under reduced pressure, 100mL of EtOAc was added, the mixture was washed with water (20 mL of Tu 3), and the combined organic layers were washed with anhydrous Na ₂ SO ₄ Drying and isolation by silica gel column chromatography (PE: EA = 10: 1) gave the title compound 3b (6.0 g), MS m/z (ESI): 274.1[ 2 ] M + H] ⁺ 。

The second step is that: (4- (6-Fluoroquinolin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 3c

Pd (dppf) Cl was added under nitrogen protection ₂ (292mg, 0.4mmol), 3b (2.0g, 7.3mmol), 2e (2.5g, 7.3mmol) and K ₂ CO ₃ (2.0 g,14.6 mmol) was dissolved in dioxane/water (20 mL/0.2 mL) and reacted at 80 ℃ for 4 hours. Cooled to room temperature, filtered and washed with EtOAc, the mother liquor was concentrated under reduced pressure and then 50mL of EtOAc was added, after washing with water (10 mL. Sup.3), the organic layer was washed with anhydrous Na ₂ SO ₄ Drying and isolation by silica gel column chromatography (PE: EA = 10: 1) gave the title compound 3c (2.0 g), MS m/z (ESI): 343.2[ M ] +H] ⁺ 。

The third step: (4- (6-Fluoroquinolin-4-yl) cyclohexyl) carbamic acid tert-butyl ester 3d

To a solution of 3c (2.8g, 8.1mmol) in methanol (20 mL) was added wet palladium on carbon (280mg, 10%) at room temperature, and the mixture was reacted under 1atm hydrogen atmosphere for 16 hours. After the LC-MS detection reaction is finished, filtering to remove palladium carbon, and concentrating the mother liquor under reduced pressure to obtain a target compound 3d (2.3 g), wherein MS m/z (ESI): 345.2[ M ] +H] ⁺ 。

The fourth step: 4- (6-Fluoroquinolin-4-yl) cyclohexylamine 3e

A solution of 3d (2.3g, 6.6 mmol) in trifluoroacetic acid/dichloromethane (10 mL/10 mL) was stirred at room temperature for 4h and the reaction was checked for completion by LC-MS. Concentration to dryness under reduced pressure gave the hydrochloride salt of the target product 3e (2.5 g), MS m/z (ESI): 245.1[ deg. ] M + H] ⁺ 。

The fifth step: 1- (4-chlorophenyl) -2-cyano-3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) guanidine (Compound 3)

Compound 3e (100mg, 0.4mmol), 2c (1.8mg, 0.4mmol) and DIPEA (200mg, 1.6mmol) were dissolved in acetonitrile, reacted at 100 ℃ for 1h under microwave conditions, cooled to room temperature after completion of the reaction, the solvent was distilled off under reduced pressure, and separated by Prep-HPLC to give Compound 3 (25 mg), MS m/z (ESI): 422.1[ m ] +H] ⁺ 。

¹ H NMR(400MHz，DMSO-d ₆ )δ9.15(s，1H)，8.86-8.82(m，1H)，8.15-7.91(m，2H)，7.67(td，J＝8.8，2.7Hz，1H)，7.47(t，J＝4.6Hz，1H)，7.43-7.30(m，3H)，7.26-7.24(m，2H)，4.26-3.74(m，1H)，3.43-3.25(m，1H)，3.27(s，0H)，2.06-1.62(m，8H).

Example 3: n- (((3-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 4) and its cis-trans isomers

The first step is as follows: n- (3-chlorophenyl) -N' - (methylsulfonyl) thioimidodicarbonic acid methyl ester 4b

4a (248 mg) and 2b (353 mg) were placed in a 100mL three-necked flask5mL of anhydrous THF was added, the mixture was cooled to 0 ℃ and 5.0mL of a 1.0M solution of LiHMDS in THF was added under nitrogen. LCMS detection, adding 0.5mL saturated NH after substrate completely disappears ₄ The reaction was quenched with Cl, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (PE: EA = 3: 1-5: 1) to obtain compound 4b (420 mg). MS m/z (ESI): 279.0[ M ] +H] ⁺ 。

The second step: n- (((3-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 4)

Compound 4b (220 mg) and 2h in free form (118 mg) were placed in a 20mL microwave tube, DMF (5 mL) was added to dissolve completely, DIPEA (350 mg) was added, and the reaction was stirred at 100 ℃ for 4h under microwave conditions. Obvious product formation. After the reaction was complete, it was cooled to room temperature, poured into 50mL of water, extracted with EtOAc, and the organic phases were combined and washed with anhydrous Na ₂ SO ₄ Drying, filtering, evaporating under reduced pressure to remove solvent, and separating and purifying by Prep-HPLC to obtain compound 4 (180 mg), and separating compound 4 again to obtain cis-or trans-isomer, 4A (peak 1, 44mg, collection time 5.6-6.1 min); 4B (Peak 2, 34mg, collection time 6.2-6.9 min). MS m/z (ESI): 406.1[ 2 ] M + H] ⁺ 。

4A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.90(s，1H)，7.80(br，1H)，7.51(t，J＝2.0Hz，1H)，7.43-7.13(m，8H)，4.18(brs，J＝7.8Hz，1H)，2.94(s，3H)，2.67-2.55(m，1H)，1.99-1.83(m，2H)，1.80-1.55(m，6H).

4B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.80(s，1H)，7.64-6.93(m，10H)，3.78-3.73(m，1H)，2.90(s，3H)，2.53-2.50(m，1H)，2.07-2.04(m，2H)，1.85(d，J＝11.9Hz，2H)，1.67-1.34(m，4H).

Example 4: n- (((3-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (compound 5) and its cis and trans isomers

The first step is as follows: n- (((3-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (Compound 5)

Dissolving 3e (50mg, 0.2mmol), 4b (0.3 g) and DIPEA (40mg, 0.3mmol) in DMF (5 mL), reacting at 100 deg.C under microwave for 2h, cooling to room temperature after reaction, pouring the reaction solution into water (50 mL), extracting with ethyl acetate, combining organic phases, anhydrous Na ₂ SO ₄ Drying, evaporation of the solvent under reduced pressure and preparative silica gel plate separation (DCM: meOH = 10: 1) gave the cis-or trans-isomer. 5A (15 mg, relatively less polar isomer); 5B (10 mg, relatively polar larger isomer), MS m/z (ESI): 475.1[ 2 ] M + H] ⁺ 。

5A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.92(s，1H)，8.87-8.86(d，J＝4.4Hz，1H)，8.13-8.05(m，2H)，7.69(br，1H)，7.71-7.66(m，1H)，7.52(s，1H)，7.42-7.33(m，3H)，7.20-7.16(m，1H)，4.26(brs，1H)，3.53-3.47(m，1H)，2.96(s，3H)，1.98-1.66(m，8H)。

5B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.87-8.82(m，2H)，8.13-8.01(m，2H)，7.70-7.65(m，1H)，7.46-7.42(m，2H)，7.38-7.32(m，3H)，7.22-7.20(m，1H)，3.84-3.82(m，1H)，3.35-3.33(m，1H)，2.92(s，3H)，2.02-2.01(m，2H)，1.96-1.94(m，2H)，1.70-1.65(m，4H)。

Example 5: n- (((4-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (Compound 6) and its cis-trans isomers

The cis-or trans-isomer of compound 6 was synthesized according to the synthesis method of compound 5, using compound 2c instead of 4 b. 6A (6 mg, relatively less polar isomer); 6B (5 mg, relatively polar larger isomer). MS m/z (ESI): 475.1[ M ] +H] ⁺ 。

6A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.90(s，1H)，8.87-8.86(d，J＝4.4Hz，1H)，8.11-8.05(m，2H)，7.81(br，1H)，7.71-7.66(m，1H)，7.44-7.38(m，5H)，4.26(brs，1H)，3.53-3.47(m，1H)，2.94(s，3H)，1.98-1.95(m，4H)，1.84-1.66(m，4H)。

6B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.87-8.82(m，2H)，8.11-8.07(m，1H)，8.03-8.01(d，J＝9.6Hz，1H)，7.77-7.65(m，1H)，7.42-7.36(m，5H)，7.27-7.25(d，J＝8Hz，1H)，3.84(brs，1H)，3.38-3.35(m，1H)，2.91(s，3H)，2.13(brs，2H)，1.95(brs，2H)，1.73-1.64(m，4H)。

Example 6:1- (4-chlorophenyl) -2-cyano-3- (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) guanidine (Compound 7)

The first step is as follows: ethyl 2- (4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-en-1-yl) acetate 7b

Trifluoromethanesulfonic anhydride (11.9mL, 70.86mmol) was added to a solution of 2, 6-di-tert-butyl-4-methylpyridine (18.19g, 88.58mmol) in dichloromethane (200 mL) and after 30min of reaction, a solution of 7a (10.88g, 59.05mmol) in dichloromethane (50 mL) was added and the reaction was continued at room temperature for 10h, after completion of the reaction, water was added to quench the reaction, and the organic phase was quenched with anhydrous Na ₂ SO ₄ After drying, the solvent was evaporated under reduced pressure and separated by silica gel column chromatography (PE: EA = 99: 1-3: 1) to obtain 7b (15 g).

The second step is that: 2- (4- (2-methylpyridin-4-yl) cyclohex-3-en-1-yl) acetic acid ethyl ester 7d

Under the protection of nitrogen, 7b (1.50g, 4.75mmol), 7c (650mg, 4.75mmol) and K were mixed ₂ CO ₃ (1.31g, 9.50mmol) and Pd (dppf) Cl ₂ (350mg, 0.48mmol) was dissolved in 40mL dioxane and 10mL water and heated to 80 ℃ for reaction overnight. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel column chromatography (PE: EA = 65: 35-100: 0) to isolate intermediate 7d (1.5 g). MS m/z (ESI): 260.2[ M ] +H] ⁺ 。

The third step: 2- (4- (2-methylpyridin-4-yl) cyclohexyl) acetic acid ethyl ester 7e

7d (1.5g, 5.79mmol) was dissolved in 15mL of methanol, and the solution was added150mg Pd/C, reacted for 4h under hydrogen atmosphere, filtered and the filtrate concentrated to dryness under reduced pressure to give intermediate 7e (1.5 g). MS m/z (ESI): 262.2[ 2 ] M + H] ⁺ 。

The fourth step: 2- (4- (2-methylpyridin-4-yl) cyclohexyl) propanoic acid ethyl ester 7f

Dissolving 7e (1.5g, 5.79mmol) in anhydrous THF (15 mL) under nitrogen protection, cooling to-78 deg.C, slowly adding 8.1mL 1M THF solution of LiHMDS, raising the temperature to-50 deg.C, reacting for 4h, adding CH ₃ I (987mg, 6.95mmol) and stirring continued for 2h. After the reaction was completed, the reaction mixture was saturated with 15mL of NH ₄ Quenched with aqueous Cl, extracted with ethyl acetate, the organic phases combined and washed with anhydrous Na ₂ SO ₄ After drying and filtration, the filtrate was concentrated to dryness under reduced pressure and subjected to silica gel column chromatography (PE: EA = 100: 0-65: 35) to isolate intermediate 7f (1.0 g). MS m/z (ESI): 276.1[ 2 ] M + H] ⁺ .

The fifth step: 7g of 2- (4- (2-methylpyridin-4-yl) cyclohexyl) propionic acid

7f (1.0 g, 3.64mmol) was dissolved in methanol (10 mL) and water (2 mL), then NaOH (436mg, 10.9mmol) was added, heated to 70 ℃ and stirred overnight, after the reaction was completed, pH was adjusted to 3-4 with 2M hydrochloric acid, and concentrated under reduced pressure to dryness to give 7g (1.5 g) of crude product, which was used in the next reaction without further purification. MS m/z (ESI): 248.2[ 2 ] M + H] ⁺ .

And a sixth step: (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) carbamoyl azide 7h

7g (500 mg), DPPA (668mg, 2.43mmol) and DIPEA (391mg, 3.03mmol) were dissolved in toluene (10 mL) and t-butanol (10 mL), heated to 110 ℃ for 4h, cooled, added to 20mL of water, extracted with ethyl acetate, the organic phases combined and then treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration of the filtrate to dryness under reduced pressure gave intermediate 7h (200 mg) which was isolated by silica gel column chromatography (DCM: meOH = 100: 0-90: 10). MS m/z (ESI): 288.22 [2 ] M + H] ⁺ .

The seventh step: 1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethylamine hydrochloride 7i

Dissolving 7h (200mg, 0.697mmol) in dioxane (6 mL) and water (0.5 mL), adding NaOH (84mg, 2.09mmol), reacted at room temperature for 2H, then added with 4M HCl in dioxane to adjust the pH to 3-4, concentrated under reduced pressure to dryness to give crude intermediate 7i (180 mg) which was used in the next reaction without further purification. MS m/z (ESI): 219.1[ M ] +H] ⁺ 。

Eighth step: phenyl N- (4-chlorophenyl) -N' -cyanooxoiminophenyl ester 7k

Dissolving 2a (0.16g, 1.3mmol), N-cyanocarbodiimindiphenyl ester 7j (0.3g, 1.3mmol) and DIPEA (0.16g, 1.3mmol) in DMF (5 mL), reacting for 1.5h under microwave conditions at 120 ℃, cooling to room temperature after the reaction is finished, pouring the reaction liquid into water (50 mL), extracting with ethyl acetate, and extracting with anhydrous Na ₂ SO ₄ Drying and concentration of the organic phase to dryness gave crude intermediate 7k (0.3 g) which was used in the next step without further purification, MS m/z (ESI): 272.1[ mu ] M + H] ⁺ 。

The ninth step: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) guanidine (Compound 7)

7k (30mg, 0.11mmol), 7i (34mg, 0.13mmol) and DIPEA (43mg, 0.33mmol) were dissolved in DMF (5 mL) and heated to 90 ℃ for reaction overnight. After the reaction was completed, it was cooled, 10mL of water was added, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine and anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure to dryness, and separating by Prep-HPLC to obtain compound 7 (8 mg, collection time 9.8-10.2 min), MS m/z (ESI): 396.2[ M ] C + H] ⁺ 。

¹ H NMR(400MHz，CD ₃ OD)δ8.29-8.25(m，1H)，7.38-7.36(m，2H)，7.25-7.10(m，4H)，3.84-3.80(m，1H)，2.70-2.68(m，1H)，2.50(s，3H)，2.00-1.82(m，3H)，1.70-1.60(m，4H)，1.50-1.46(m，2H)，1.19(t，J＝3.2Hz，3H).

Example 7: n- (((4-chlorophenyl) amino) ((1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 8)

The first step is as follows: n- (((4-chlorophenyl) amino) ((1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 8)

2c (31mg, 0.11mmol), 7i (34mg, 0.13mmol) and DIPEA (43mg, 0.33mmol) were dissolved in DMF (5 mL) and the reaction was stirred at 90 ℃ overnight. After cooling, 10mL of water was added, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous Na ₂ SO ₄ Drying, filtration and concentration of the filtrate to dryness under reduced pressure, separation by Prep-HPLC gave compound 8 (6 mg, collection time 8.9-9.3 min), MS m/z (ESI): 449.1[ 2 ] M + H] ⁺ 。

¹ H NMR(400MHz，CD ₃ OD)δ8.28-8.25(m，1H)，7.40-7.24(m，4H)，7.18-7.10(m，2H)，3.84-3.81(m，1H)，3.02(s，3H)，2.70-2.68(m，1H)，2.49(s，3H)，1.98-1.93(m，3H)，1.74-1.50(m，6H)，1.13(brs，3H).

Example 8:1- (4-chlorophenyl) -2-cyano-3- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) guanidine (Compound 9)

The first step is as follows: 2- (4- (6-Fluoroquinolin-4-yl) cyclohex-3-en-1-yl) acetic acid ethyl ester 9a

Pd (dppf) Cl is added under the protection of nitrogen ₂ (500mg, 0.7mmol), 3b (4.0g, 14.0mmol), 7b (4.2g, 14.0mmol) and K ₂ CO ₃ (5.8g, 42.0 mmol) was dissolved in dioxane/water (40 mL/2 mL) and heated to 80 ℃ for reaction for 16h. After the reaction was completed, the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration, the mother liquor was concentrated under reduced pressure, 100mL of ethyl acetate was added, and the organic layer was washed with water and then with anhydrous Na ₂ SO ₄ Drying, evaporation of the solvent under reduced pressure and separation by silica gel column chromatography (PE: EA = 10: 1) gave the target compound 9a (2.0 g), MS m/z (ESI): 314.1[ 2 ] M + H] ⁺ 。

The second step: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) acetic acid ethyl ester 9b

To 9a (2.0 g,6.6 mmol) of methanol (20 mL) at room temperature was added) Adding wet palladium carbon (200mg, 10%) into the solution, reacting for 1693 h in hydrogen atmosphere, detecting by LC-MS, filtering to remove palladium carbon, concentrating the mother liquor under reduced pressure to dryness to obtain target compound 9b (1.5 g), MS m/z (ESI): 316.1[ 2 ] M + H] ⁺ 。

The third step: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) propanoic acid ethyl ester 9c

At-78 deg.C, 10mL of a THF solution of 1.0M LiHMDS was added to a solution of the compound 9b (1.5g, 4.9mmol) in anhydrous THF (10 mL), and the reaction was carried out at-78 deg.C for 1 hour, after which CH ₃ A solution of I (1.4g, 9.8mmol) in anhydrous THF was slowly added to the reaction system, and after the reaction was carried out at-78 ℃ for 2 hours, the temperature was slowly raised to room temperature to continue the reaction for 2 hours. TLC monitoring (PE: EA = 5: 1) reaction completed, saturated NH was added ₄ The reaction was quenched with Cl solution (10 mL), extracted with ethyl acetate, and the organic phases were combined and washed with anhydrous Na ₂ SO ₄ Drying, evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (PE: EA = 5: 1) gave the target compound 9c (500 mg), MS m/z (ESI): 330.2[ 2 ] M + H] ⁺ 。

The fourth step: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) propanoic acid 9d

NaOH (140mg, 3.5mmol) was added to H of Compound 9c (500mg, 1.6mmol) ₂ Adding O/MeOH (5 mL/1 mL) in the mixed solution, reacting at 50 ℃ for 2h, adding 1M hydrochloric acid to adjust the pH value to 1 after the reaction is finished, extracting with ethyl acetate, and then adding anhydrous Na ₂ SO ₄ Drying and concentration under reduced pressure gave crude intermediate 9d (400 mg) which was used in the next reaction without further purification, MS m/z (ESI): 302.2[ 2 ] M + H] ⁺ 。

The fifth step: (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) carbamoyl azide 9e

A toluene/t-butanol (2 mL/2 mL) solution of 9d (400mg, 1.3mmol), DPPA (536mg, 1.95mmol) and triethylamine (408mg, 4.0mmol) was reacted at 90 ℃ for 4h under nitrogen protection, after cooling to room temperature, the solvent was evaporated under reduced pressure, and the objective product 9e (350 mg), MS m/z (ESI) was obtained by silica gel column chromatography (PE: EA = 5: 2): 342.2[ M ] +H] ⁺ 。

And a sixth step: 1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethylamine 9f

Adding NaOAdding H (50mg, 1.2mmol) into a dioxane/water (5 mL/1 mL) mixed solution of a compound 9e (350mg, 0.9mmol), reacting at room temperature for 2H, adding 1M hydrochloric acid to adjust the pH to 1 after the reaction is finished, and removing the solvent by reduced pressure evaporation to obtain a crude product (400 mg) of 9f, wherein MS M/z (ESI): 273.2[ M ] +H] ⁺ 。

The seventh step: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) guanidine (Compound 9)

A solution of 9f (150 mg, crude), 7k (150mg, 0.5mmol) and DIPEA (200mg, 1.6 mmol) in DMF was reacted at 90 ℃ for 169h and the reaction was monitored by LC-MS for completion. Prep-HPLC separation gave target compound 9 (10 mg), MS m/z (ESI): 450.2[ 2 ] M + H] ⁺ 。

¹ H NMR(400MHz，CD ₃ OD)δ8.75(dd，J＝10.4，4.7Hz，1H)，8.07(dd，J＝9.3，5.6Hz，1H)，7.89(dd，J＝10.7，2.7Hz，1H)，7.62-7.56(m，1H)，7.55-7.46(m，1H)，7.39(dd，J＝8.7，1.4Hz，2H)，7.29-7.21(m，2H)，3.48-3.40(m，1H)，2.11-1.56(m，9H)，1.46-1.38(m，1H)，1.19-1.16(m，3H)。

Example 9: n- (((4-chlorophenyl) amino) ((1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 10)

A solution of compound 9f (150 mg, crude), 2c (100mg, 0.5mmol) and DIPEA (200mg, 1.6 mmol) in DMF was reacted at 90 ℃ for 169h, after monitoring the completion of the reaction by LC-MS, cooled to room temperature, and separated by Prep-HPLC to give the title compound 10 (15 mg), MS m/z (ESI): 503.2[ 2 ] M + H] ⁺ 。

¹ H NMR(400MHz，CD ₃ OD)δ8.77-8.72(m，1H)，8.07(dd，J＝9.2，5.6Hz，1H)，7.89(dt，J＝10.6，3.0Hz，1H)，7.59(ddd，J＝9.4，6.7，2.7Hz，2H)，7.48-7.27(m，5H)，3.46(d，J＝16.7Hz，1H)，2.97(s，3H)，2.12-1.76(m，8H)，1.66-1.64(m，1H)，1.44-1.43(m，1H)，1.26(d，J＝12.2Hz，3H).

Example 10: n- (((4-methoxyphenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 11) and its cis-trans isomer

The first step is as follows: n- (4-methoxyphenyl) -N' - (methylsulfonyl) thioaminimide acid methyl ester 11b

2b (165mg, 1.0 mmol) and 11a (123mg, 1.5 mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0 deg.C, and 2.0mL of a 1.0M THF solution of LiHMDS was added, after which the mixture was stirred at room temperature for 3h. After the reaction, saturated ammonium chloride solution was added to quench the reaction, etOAc extraction was performed, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 99: 1-55: 45) to obtain the objective compound 11b (110 mg). MS m/z (ESI): 275.0[ 2 ] M + H] ⁺ 。

The second step is that: n- (((4-methoxyphenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 11

DIPEA (122.48mg, 0.95mmol) was added to a solution of 11b (130mg, 0.27mmol) and 2h (83mg, 0.18mmol) in DMF (4 mL) at room temperature. The reaction was heated to 120 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, adding ethyl acetate (50 mL) for dilution, washing with water (10 mL of Tmax 3), drying an organic phase by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, separating and purifying by Prep-HPLC to obtain a compound 11 (70 mg), separating and purifying the compound 11 by the Prep-HPLC again to obtain cis-isomer or trans-isomer, 11A (peak 1, 25mg, collecting time 6.7-7.0 min); 11B (Peak 2, 16mg, collection time 7.3-7.5 min). MS m/z (ESI): 402.3[ 2 ] M + H] ⁺ 。

11A： ¹ H NMR(400MHz，CD ₃ OD)δ7.28-7.13(m，7H)，6.98-6.96(m，2H)，4.08-4.07(m，1H)，3.81(s，3H)，2.97(s，3H)，2.59-2.58(m，1H)，1.96-1.94(m，2H)，1.75-1.58(m，6H).

11B： ¹ H NMR(400MHz，CD ₃ OD)δ7.20-7.12(m，7H)，6.98-6.96(m，2H)，3.82-3.77(m，1H)，3.81(s，3H)，2.98(s，3H)，2.48-2.46(m，1H)，2.06-2.04(m，2H)，1.88-1.86(m，2H)，1.57-1.55(m，2H)，1.41-1.38(m，2H).

Example 11: n- (((4-chlorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide (compound 18) and its cis-trans isomers

The first step is as follows: (4 '-methoxy-2, 3,4, 5-tetrahydro- [1,1' -biphenyl ] -4-yl) carbamic acid tert-butyl ester 18b

Under the protection of nitrogen, 18a (310.11mg, 2mmol), 2e (727.02mg, 2.00mmol) and Pd (dppf) Cl were added ₂ ＊CH ₂ Cl ₂ (83.27mg, 100.00. Mu. Mol) and K ₂ CO ₃ (563.27mg, 4.00mmol) was placed in a reaction flask and Dioxane (10 mL) and H were added ₂ O (2 mL), heated to 90 ℃ for reaction, monitored by TLC (PE: EA = 10: 1) until complete conversion of starting material. After the reaction was complete, cool to room temperature, filter and wash with EtOAc, add 50mL of EtOAc to dilute, wash three times with water, and then dilute the organic layer with anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA = 95: 1-90: 10) to obtain the target product 18b (250 mg).

The second step is that: (4- (4-methoxyphenyl) cyclohexyl) carbamic acid tert-butyl ester 18c

18b (263mg, 0.82mmol) was dissolved in MeOH (10 mL) at room temperature, 10% Pd/C (100mg, 0.08mmol) was added, the reaction was carried out under hydrogen atmosphere (1 atm), and TLC monitoring (PE: EA = 10: 1) was carried out until complete conversion of the starting material. After the reaction was completed, the reaction mixture was filtered through celite and washed with methanol, and the solvent was distilled off under reduced pressure, and the obtained crude product was used in the next reaction without further purification.

The third step: 4- (4-methoxyphenyl) cyclohexylamine hydrochloride 18d

18c (263.16mg, 818.57. Mu. Mol) was dissolved in 3.0mL of 4N HCl in dioxane at room temperature, LC-MS monitored complete conversion of starting material after 2h reaction, solvent was distilled off under reduced pressure after the reaction was complete, and the crude product obtained was carried on to the next step without further purificationAnd (4) reacting. MS m/z (ESI): 206.2[ M ] +H] ^+.

The fourth step: n- (((4-chlorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide 18

18d (188.78mg, 765.23. Mu. Mol), 2c (217.68mg, 765.23. Mu. Mol) and DIPEA (302.75mg, 2.30mmol) were dissolved in 6.0mL DMF, heated to 100 ℃ for reaction and monitored by TLC (PE: EA = 5: 1) until complete conversion of the starting material. After the reaction was complete, it was cooled to room temperature, diluted with 50mL EtOAc, washed with water and the organic phase was washed with anhydrous Na ₂ SO ₄ Drying, filtering, concentrating under reduced pressure to dry, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of compound 18, 18A (peak 1, 45mg, collection time 9.2-9.6 min); 18B (Peak 2, 42mg, collection time 9.7-9.9 min). MS m/z (ESI): 436.1 2[ M ] +H] ^+.

18A： ¹ H NMR(400MHz，CD ₃ OD)δ7.42-7.39(m，4H)，7.19(d，J＝8.4Hz，2H)，6.87(d，J＝8.4Hz，2H)，4.11-4.13(m，1H)，3.79(s，3H)，3.01(s，3H)，2.63-2.57(m，1H)，2.06-2.00(m，2H)，1.86-1.73(m，6H).

18B： ¹ H NMR(400MHz，CD ₃ OD)δ7.41(d，J＝8.0Hz，2H)，7.34(d，J＝8.0Hz，2H)，7.16(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，2H)，3.82-3.78(m，1H)，3.78(s，3H)，3.00(s，3H)，2.48-2.51(m，1H)，2.11-2.16(m，2H)，1.91-1.94(m，2H)，1.67-1.58(m，2H)，1.51-1.46(m，2H).

Example 12: n- (((4-cyanophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 25) and its cis and trans isomers

The first step is as follows: n- (4-cyanophenyl) -N' - (methylsulfonyl) thioaminimide acid methyl ester 25b

25a (79.66mg, 674.31. Mu. Mol) and 2b (112mg, 561.93. Mu. Mol) were dissolved in dry THF (3 mL) under nitrogen, cooled to 0 ℃ and 2.5mL of LiHMDS (561.93. Mu. Mol) in THF were addedAfter that, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction was quenched by adding water, extracted with EA, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure after filtration and separated and purified by silica gel column chromatography (100% EA) to obtain compound 25b (150 mg). MS m/z (ESI): 270.0[ M ] +H] ⁺

The second step is that: n- (((4-cyanophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 25

25b (150mg, 556.91. Mu. Mol) and 2h (97.61mg, 556.91. Mu. Mol) were dissolved in DMF (4 mL), DIPEA (287.90mg, 2.23mmol) was added, and the mixture was heated to 100 ℃ under microwave conditions for reaction for 4h. LCMS detects that the raw materials are completely converted, the reaction solution is cooled to room temperature after the reaction is finished, the reaction solution is poured into water and extracted by EA, organic phases are combined and dried by anhydrous sodium sulfate, filtered, decompressed and concentrated to be dry, and separated and purified by Prep-HPLC to obtain the cis-isomer or the trans-isomer of 25. 25A (Peak 1, 15mg, collection time 9.8-10.2 min); 25B (Peak 2, 111mg, collection time 10.3-10.8 min). MS m/z (ESI): 397.2[ 2 ] M + H] ⁺

25A： ¹ H NMR(400MHz，DMSO-d ₆ )δ：9.12(s，1H)，7.90(d，J＝8.3Hz，1H)，7.79-7.77(m，2H)，7.63(d，J＝8.4Hz，2H)，7.34-7.18(m，5H)，4.24(brs，1H)，2.98(s，3H)，2.66-2.59(m，1H)，1.90(d，J＝12.8Hz，2H)，1.78-1.62(m，6H).

25B： ¹ H NMR(400MHz，DMSO-d ₆ )δ：9.02(s，1H)，7.81-7.77(m，2H)，7.56(d，J＝8.3Hz，2H)，7.42(brs，1H)，7.32-7.17(m，5H)，3.84-3.77(m，1H)，2.93(s，3H)，2.56-2.53(m，1H)，2.10-2.06(m，2H)，1.88-1.84(m，2H)，1.62-1.40(m，4H).

Example 13: n- (((4-chlorophenyl) amino) ((4- (2-methylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 35)

The first step is as follows: 2-methyl-4- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) pyridine 35c

Pd (dppf) Cl was added to a mixture of 35a (3.23g, 18.79mmol), compound 35b (5.0 g, 18.79mmol), potassium carbonate (7.78g, 56.36mmol), water (5 mL) and dioxane (50 mL) under nitrogen ₂ (692.30mg, 939.36. Mu. Mol). Then the reaction solution is heated to 90 ℃ for reaction for 16h. After completion of the reaction, the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration, and the filtrate was separated and purified by silica gel column chromatography (PE: EA = 5: 2) to obtain the objective product 35c (3.5 g).

The second step is that: 2-methyl-4- (1, 4-dioxaspiro [4.5] decan-8-yl) pyridine 35d

A solution of 35C (3.37g, 13.84mmol) and Pd/C (85.85mg, 1.38mmol) in methanol was reacted under a balloon of hydrogen pressure for 3 hours at room temperature. After the reaction was complete, it was filtered and washed with MeOH, and the filtrate was concentrated to dryness under reduced pressure to give 35d (3.1 g).

The third step: 4- (2-methylpyridin-4-yl) cyclohexanone 35e

To a solution of compound 35d (3.1g, 13.29mmol) in acetone was added 10mL of 6M hydrochloric acid at room temperature, and the reaction was stirred at room temperature for 5 hours. Then, the mixture was concentrated under reduced pressure to remove the solvent, water (10 mL) was added and the mixture was made basic with saturated sodium bicarbonate, extracted with EtOAc (10 mL. Sup.3), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to dryness to give the aimed product 35e (2.2 g).

The fourth step: 4- (2-methylpyridin-4-yl) cyclohexylamine 35f

At room temperature, reacting NH ₄ Cl (282.69mg, 5.28mmol) was added to a solution of compound 35e (500mg, 2.64mmol) in MeOH (2.5 mL) and the reaction stirred at room temperature for 2h. Then NaBH is added ₃ CN (121.48mg, 5.28mmol) was added to the reaction and stirring was continued at room temperature for 16h. After completion of the reaction, most of the solvent was removed by concentration under reduced pressure, water (10 mL) was added, etOAc extraction was performed (15 mL. Sup.3), organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure to dryness and isolated and purified by silica gel column chromatography (DCM: meOH = 100: 3) to obtain 35f (300 mg). MS m/z (ESI): 191.2[ M ] +H] ⁺ 。

The fifth step: n- (((4-chlorophenyl) amino) ((4- (2-methylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide 35

At room temperature, willDIPEA (135.84mg, 1.05mmol) was added to a solution of compound 2c (146.51mg, 525.53. Mu. Mol), 35f (100mg, 525.53. Mu. Mol) in acetonitrile (2 mL). Heating to 100 ℃ under the microwave condition for reaction for 1h. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the product was separated and purified by Prep-HPLC to obtain Compound 35 (18 mg, collection time 4.2-5.4 min). MS m/z (ESI): 421.1[ mu ] M + H] ⁺ 。

¹ H NMR(400MHz，DMSO-d ₆ )δ8.77(s，1H)，8.40-8.36(m，1H)，7.42-7.33(m，4H)，7.19-7.12(m，3H)，3.79-3.70(m，1H)，2.91(s，3H)，2.55-2.51(m，1H)，2.46(s，3H)，2.06-2.04(s，1H)，1.87-1.85(m，2H)，1.74-1.37(m，5H).

Example 14: n- (((4-chlorophenyl) amino) ((4- (4-methylpyridin-3-yl) cyclohexyl) amino) methylene) methanesulfonamide (compound 36) and its cis-trans isomers

The first step is as follows: (4- (4-methylpyridin-3-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 36b

36a (100mg, 730.23. Mu. Mol), 2e (327.82mg, 949.29. Mu. Mol), potassium carbonate (201.54mg, 1.46mmol) and Pd (dppf) Cl under nitrogen ₂ (534.53mg, 730.23. Mu. Mol) to the mixture was added dioxane (15 mL) and water (5 mL), and the mixture was heated to 80 ℃ for 10 hours. LCMS monitored complete conversion of starting material reaction. And after the reaction is finished, cooling to room temperature, filtering, adding water into filtrate for dilution, extracting by EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA = 3: 1) to obtain the compound 36b. MS m/z (ESI): 289.2[ 2 ] M + H] ⁺ 。

The second step is that: (4- (4-methylpyridin-3-yl) cyclohexyl) carbamic acid tert-butyl ester 36c

36b (80mg, 277.41. Mu. Mol) was dissolved in methanol (6 mL) at room temperature, pd/C (10 mg) was added, and the reaction was carried out for 10 hours under a hydrogen atmosphere (1 atm). LCMS monitored complete conversion of starting material reaction. Filtering after the reaction is finished, and concentrating the filtrate under reduced pressure to be dry to obtain a crude product of the target product 36c(79 mg), the crude product was used in the next reaction without further purification. MS m/z (ESI): 291.2[ M ] +H] ⁺ 。

The third step: 4- (4-methylpyridin-3-yl) cyclohexylamine hydrochloride 36d

36c (80mg, 275.48. Mu. Mol,) was dissolved in 3.0mL of a 4M HCl solution in dioxane, stirred at 25 ℃ for 1h and concentrated under reduced pressure to dryness to give crude product 36d (50 mg) which was used in the next reaction without further purification. MS m/z (ESI): 191.1[ M ] +H] ⁺ 。

The fourth step: n- (((4-chlorophenyl) amino) ((4- (4-methylpyridin-3-yl) cyclohexyl) amino) methylene) methanesulfonamide 36

36d (50mg, 176.41. Mu. Mol), 2c (61.47mg, 220.51. Mu. Mol) and DIPEA (57.00mg, 441.02. Mu. Mol) were dissolved in DMF (5 mL) and heated to 125 ℃ for 5h. LCMS monitored complete conversion of starting material. After the reaction is finished, cooling to room temperature, adding water for dilution, extracting with EA, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by Prep-HPLC to obtain the compound 36 cis-isomer or trans-isomer. 36A (Peak 1, 20mg, collection time 5.8-6.1 min); 36B (Peak 2, 15mg, collection time 6.1-6.5 min). MS m/z (ESI): 421.1[ 2 ] M + H] ⁺ 。

36A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.89(s，1H)，8.40(s，1H)，8.26(d，J＝5.2Hz，1H)，7.80(br，1H)，7.43-7.37(m，4H)，7.16(d，J＝4.8Hz，1H)，4.23-4.21(m，1H)，2.94(s，3H)，2.87-2.85(m，1H)，2.26(s，3H)，1.96-1.93(m，2H)，1.74-1.65(m，6H).

36B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.74(br，1H)，8.38(s，1H)，8.25(d，J＝4.8Hz，1H)，7.43-7.37(m，4H)，7.16-7.14(m，2H)，3.82-3.80(m，1H)，2.94(s，3H)，2.75-2.73(m，1H)，2.31(s，3H)，2.07-2.05(m，2H)，1.62-1.59(m，2H)，1.53-1.51(m，2H)，1.49-1.43(m，2H).

Example 15: n- (((4-chlorophenyl) amino) ((4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (compound 37) and its cis-trans isomer

The first step is as follows: (2, 6-Dimethylpyridin-4-yl) boronic acid 37b

Under the protection of nitrogen, 37a (100mg, 537.49. Mu. Mol), B ₂ pin ₂ (163.83mg，644.99μmol)、KOAc(158.00mg，1.61mmol)、Pd(dppf)Cl ₂ (39.34mg, 53.75. Mu. Mol) was placed in a reaction flask, dioxane (20 mL) was added, and the mixture was heated to 80 ℃ and stirred for 10 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the target product 37b (60 mg) was isolated and purified by silica gel column chromatography (PE: EA = 1: 2). MS m/z (ESI): 152.1[ 2 ] M + H] ⁺ 。

The second step is that: (4- (2, 6-dimethylpyridin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 37c

Under nitrogen protection, 37b (80mg, 529.91. Mu. Mol), 2e (182.99mg, 529.91. Mu. Mol), potassium carbonate (146.25mg, 1.06mmol) and Pd (dppf) Cl were added ₂ (58.18mg, 79.49. Mu. Mol) was placed in a reaction flask, and water (1.00 mL) and dioxane (5.00 mL) were added to the flask, which was heated to 90 ℃ and stirred for 10 hours. After the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure and separated and purified by silica gel column chromatography (PE: EA = 99: 1-55: 45) to obtain intermediate 37c (80 mg). MS m/z (ESI): 303.2[ M ] +H] ⁺ 。

The third step: tert-butyl (4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) carbamate 37d.

37c (80mg, 264.54. Mu. Mol) was dissolved in methanol (5 mL) at room temperature, palladium on carbon (10 mg) was added, and the mixture was stirred for 6 hours under a hydrogen atmosphere (1 atm). After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to dryness to give 37d of crude product (80 mg), which was used in the next reaction without further purification. MS m/z (ESI): 305.2[ M ] +H] ⁺ 。

The fourth step: synthesis of 4- (2, 6-dimethylpyridin-4-yl) cyclohexylamine hydrochloride 37e

37d (60mg, 197.09. Mu. Mol) was added to 4.0mL of a 4M HCl solution in dioxane, stirred at 25 ℃ for 1h, then concentrated under reduced pressure to dryness to give crude 37e (50 mg) as crude productUsed in the next reaction without further purification. MS m/z (ESI): 205.2[ M ] +H] ⁺ 。

The fifth step: n- (((4-chlorophenyl) amino) ((4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide 37

37e (50mg, 207.67. Mu. Mol), 2c (57.89mg, 207.67. Mu. Mol, FR) and DIPEA (53.68mg, 415.33. Mu. Mol) were dissolved in DMF (5 mL) and heated to 125 ℃ for reaction for 6h. After the reaction is finished, cooling to room temperature, adding water for dilution, extracting by EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to be dry, and separating and purifying cis-isomer or trans-isomer of the compound 37 by Prep-HPLC. 37A (Peak 1, 17mg, collection time 6.5-7.0 min); 37B (Peak 2, 15mg, collection time 7.1-7.4 min). MS m/z (ESI): 435.1[ 2 ] M + H] ⁺ 。

37A： ¹ H NMR(400MHz，CD ₃ OD)δ7.37-7.35(m，4H)，6.99(s，2H)，4.11-4.10(m，1H)，2.98(s，3H)，2.62-2.60(m，1H)，2.46(s，6H)，2.00-1.98(m，2H)，1.77-1.70(m，6H).

37B： ¹ H NMR(400MHz，CD ₃ OD)δ7.40-7.29(m，4H)，6.96(s，2H)，3.79-3.78(m，1H)，2.98(s，3H)，2.50-2.46(m，1H)，2.45(s，6H)，2.11-2.10(m，2H)，1.90-1.88(m，2H)，1.67-1.57(m，2H)，1.49-1.40(m，2H).

Example 16: n- (((4-chlorophenyl) amino) ((4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexyl) amino) methylene) methanesulfonamide (compound 42) and its cis-trans isomer

The first step is as follows: 2- (4-bromophenoxy) -N, N-dimethylethylamine 42c

42a (500mg, 2.89mmol) and potassium carbonate (997.07mg, 7.23mmol) were added to a 100mL one-neck flask, acetone (30 mL) was added, 42b (499.55mg, 3.47mmol) was added, stirring was carried out for 15min, and then heating to 60 ℃ for reaction. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: meOH = 20: 1) to obtain 42c (553 mg).

The second step is that: 2- (4- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) phenoxy) -N, N-dimethylethylamine 42d

42c (554mg, 2.27mmol), 35b (603.95mg, 2.27mmol) and Pd (dppf) Cl were added under nitrogen protection ₂ ·CH ₂ Cl ₂ (92.66mg, 113.47. Mu. Mol) and K ₂ CO ₃ (782.91mg, 5.67mmol) was placed in a reaction flask and dioxane (15 mL) and H were added ₂ O (3 mL), heated to 100 ℃ for reaction. LCMS monitoring until complete conversion of starting material. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and isolated and purified by silica gel column chromatography (DCM: meOH = 96: 4) to give 42d (688 mg).

The third step: 2- (4- (1, 4-dioxaspiro [4.5] decan-8-yl) phenoxy) -N, N-dimethylethylamine 42e

42d (720mg, 2.37mmol) was dissolved in MeOH (15 mL), pd/C (288.22mg, 2.37mmol) was added, and the reaction was heated to 30 ℃ under hydrogen atmosphere (1 atm), and LCMS was used to monitor until the conversion of the starting material was complete. After the reaction was completed, the reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure, whereby the obtained crude 42e (720 mg) was used in the next reaction without further purification.

The fourth step: 4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexanone 42f

42e (720mg, 2.36mmol) was dissolved in acetone (10 mL), and HCl (aq) (2.36mmol, 10mL) solution was added, stirred at room temperature, and LCMS was performed until the conversion of the starting material was completed. After completion of the reaction, the pH was adjusted to be alkaline with 6M NaOH (aq) solution, EA was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then separated and purified by silica gel column chromatography (DCM: meOH = 97: 3) to obtain compound 42f (379 mg)

The fifth step: 42g of 4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexylamine

42f (379mg, 1.45mmol) was dissolved in MeOH (10 mL) and NH was added ₄ AcO (335.32mg, 4.35mmol), heated to 60 ℃ and stirred for 2h. Then NaBH is added ₃ CN (182.25mg, 2.90mmol), stirring was continued for 6h, and LCMS detection indicated complete conversion of the starting material. After the reaction is finished, the mixture is cooled to room temperature, sodium bicarbonate solution is quenched and then extracted by DCM, organic phases are combined and anhydrous sulfur is usedThe sodium salt was dried, filtered and the filtrate was concentrated to dryness under reduced pressure to give 42g of crude product (153 mg) which was used in the next reaction without further purification.

And a sixth step: n- (((4-chlorophenyl) amino) ((4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexyl) amino) methylene) methanesulfonamide 42

42g (153.06mg, 571.67. Mu. Mol, FR), 2c (162.62mg, 571.67. Mu. Mol, FR) and DIPEA (226.17mg, 1.72mmol,98% purity) were dissolved in DMF (5 mL) under nitrogen protection, heated to 100 ℃ and reacted for 6h. After the reaction, the reaction mixture was cooled to room temperature, diluted with 50ml of LEtOAc and washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and purified by Prep-HPLC to obtain the cis-or trans-isomer of compound 42, 42A (peak 1) and 42B (peak 2). The 42A and 42B were again purified by Prep-HPLC to give high purity 42A (7 mg, collection time 5.0-5.8 min) and 42B (24 mg, collection time 6.1-6.4 min), respectively. MS m/z (ESI): 493.2[ M ] C + H] ⁺ 。

42A： ¹ H NMR(400MHz，CD ₃ OD)δ7.42-7.37(m，4H)，7.23(d，J＝8.0Hz，2H)，6.95(d，J＝8.8Hz，2H)，4.25-4.22(t，J＝4.8Hz，2H)，4.14-4.12(t，J＝2.8Hz，1H)，3.23-3.20(t，J＝5.2Hz，2H)，3.01(s，3H)，2.70(s，6H)，2.65-2.59(m，1H)，2.04-2.01(m，2H)，1.87-1.74(m，6H).

42B： ¹ H NMR(400MHz，CD ₃ OD)δ7.42(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，2H)，7.17(d，J＝8.4Hz，2H)，6.91(d，J＝8.8Hz，2H)，4.16-4.13(t，J＝5.2Hz，2H)，3.82-3.80(m，1H)，3.00(s，3H)，2.97-2.94(t，J＝5.2Hz，2H)，2.54-2.51(m，1H)，2.50(s，6H)，2.16-2.12(m，2H)，1.94-1.91(m，2H)，1.67-1.58(m，2H)，1.51-1.43(m，2H).

Example 17: n- (((4- (2-hydroxyethoxy) phenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 48) and its cis-trans isomers

The first step is as follows: n' -methylsulfonyl-N- (4-phenylcyclohexyl) thioiminocarboxylic acid methyl ester 48a

DIPEA (518.74mg, 4.01mmol) was added to a solution of compound 2h (175.87mg, 1.00mmol) and 2b (200mg, 1.00mmol) in acetonitrile (5 mL) at room temperature, then warmed to 90 ℃ for 16h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (DCM: MEOH = 100: 3) to obtain the objective compound 48a (200 mg).

The second step is that: n- (((4- (2-hydroxyethoxy) phenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 48

DIPEA (47.50mg, 367.56. Mu. Mol) was added to a solution of compounds 48b (28.15mg, 183.78. Mu. Mol) and 48a (60mg, 183.78. Mu. Mol) in acetonitrile (2 mL) at room temperature, and heated to 100 ℃ under microwave conditions for 2 hours. After the reaction is finished, cooling to room temperature, removing the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of the target compound 48. 48A (Peak 1, 10mg, collection time 8.6-9.0 min); 48B (Peak 2, 20mg, collection time 9.4-9.8 min). MS m/z (ESI): 432.3[ mu ] M + H] ⁺ 。

48A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.70(s，1H)，7.61(br，1H)，7.31(t，J＝7.5Hz，2H)，7.27-7.16(m，5H)，6.92(d，J＝8.8Hz，2H)，4.88(t，J＝5.5Hz，1H)，4.13-4.11(m，1H)，3.97(t，J＝5.0Hz，2H)，3.71(dd，J＝10.2，5.3Hz，2H)，2.88(s，3H)，2.62-2.60(m，1H)，1.99-1.88(m，2H)，1.79-1.55(m，6H).

48B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.61(s，1H)，7.32-7.14(m，7H)，6.94(d，J＝8.8Hz，2H)，4.88(t，J＝5.5Hz，1H)，3.98(t，J＝5.0Hz，2H)，3.72-3.69(m，3H)，2.86(s，3H)，2.49-2.41(m，1H)，2.02(brs，2H)，1.83(d，J＝11.8Hz，2H)，1.60-1.51(m，2H)，1.45-1.37(m，2H).

Example 18: n- (((4-methoxybenzyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 86) and its cis-trans isomers

The first step is as follows: N-4-methoxybenzyl-N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 86b

2b (200mg, 1.00mmol), 86a (165.18mg, 1.20mmol) and DIPEA (259.37mg, 2.01mmol) were dissolved in ethanol (20 mL), and the reaction was stirred at 75 ℃ for 10h. LCMS monitors complete conversion of starting material, after reaction is complete, cools to room temperature, removes solvent under reduced pressure and purifies by silica gel column chromatography (PE: EA = 1: 1) to afford the desired product 86b. MS m/z (ESI): 289.1[ 2 ] M + H] ⁺ 。

The second step is that: n- (((4-methoxybenzyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 86

86b (50mg, 173.38. Mu. Mol), 2h (30.39mg, 173.38. Mu. Mol) and DIPEA (44.81mg, 346.76. Mu. Mol) were dissolved in DMF (2.50 mL) and the reaction was stirred at 125 ℃ for 6h. And (3) monitoring complete conversion of the raw materials by LCMS, cooling to room temperature after the reaction is finished, adding water for dilution, then extracting by EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by Prep-HPLC to obtain the cis-isomer or trans-isomer of the compound 86. 86A (Peak 1, 25mg, collection time 9.7-9.9 min); 86B (Peak 2,7mg, collection time 9.9-10.1 min) two enantiomers. MS m/z (ESI): 416.2[ 2 ] M + H] ⁺ 。

86A： ¹ H NMR(400MHz，DMSO-d ₆ )δ7.50(br，1H)，7.25-7.15(m，7H)，6.93(d，J＝8.4Hz，2H)，6.90(br，1H)，4.33(d，J＝5.6Hz，2H)，3.75(s，3H)，3.57-3.55(m，1H)，2.76(s，3H)，2.51-2.50(m，1H)，1.98-1.96(m，2H)，1.84-1.82(m，2H)，1.56-1.50(m，2H)，1.44-1.36(m，2H).

86B： ¹ H NMR(400MHz，CD ₃ OD)δ7.33-7.20(m，4H)，7.20-7.13(m，3H)，6.89(d，J＝8.4Hz，2H)，4.41(s，2H)，3.91-3.90(m，1H)，3.75(s，3H)，2.85(s，3H)，2.55-2.53(m，1H)，1.92-1.89(m，2H)，1.71-1.60(m，6H).

Example 19: n- (((4-chlorophenyl) amino) ((4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (compound 87) and its cis-trans isomer

The first step is as follows: (2, 3-dimethylpyridin-4-yl) boronic acid 87b

87a (100mg, 537.49. Mu. Mol) and B ₂ pin ₂ (163.83mg, 644.99. Mu. Mol), KOAc (158.00mg, 1.61mmol) and Pd (dppf) Cl ₂ (39.34mg, 53.75. Mu. Mol) was placed in a reaction flask, dioxane (20 mL) was added, and the mixture was heated to 80 ℃ under nitrogen and stirred for 10h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, which was separated and purified by silica gel column chromatography (PE: EA = 1: 2) to obtain 87b (60 mg). MS m/z (ESI): 152.1[ 2 ] M + H] ⁺ 。

The second step: (4- (2, 3-dimethylpyridin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 87c

87b (80mg, 529.91. Mu. Mol), 2e (182.99mg, 529.91. Mu. Mol), potassium carbonate (146.25mg, 1.06mmol) and Pd (dppf) Cl ₂ (58.18mg, 79.49. Mu. Mol) was placed in a reaction flask, to which were added water (1.00 mL) and dioxane (5.00 mL), and the mixture was heated to 90 ℃ under nitrogen and stirred for 10h. After the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE: EA = 99: 1-55: 45) to obtain 87c (80 mg). MS m/z (ESI): 303.2[ M ] +H] ⁺ 。

The third step: (4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) carbamic acid tert-butyl ester 87d

87C (80mg, 264.54. Mu. Mol) was dissolved in methanol (5 mL) at room temperature, pd/C (10 mg) was added, and the mixture was stirred under hydrogen atmosphere (1 atm) for 6 hours. Then filtered and the filtrate concentrated under reduced pressure to dryness to give 87d of crude product (80 mg) which was used in the next reaction without further purification. MS m/z (ESI): 305.2[ 2 ] M + H] ⁺ 。

The fourth step: 4- (2, 3-dimethylpyridin-4-yl) cyclohexylamine hydrochloride 87e

87d (60mg, 197.09. Mu. Mol) was added to 4.0mL of a 4M HCl solution in dioxane, stirred at 25 ℃ for 1h, then removed under reduced pressureThe solvent was removed to give 87e as crude product (50 mg), which was used in the next reaction without further purification. MS m/z (ESI): 205.2[ 2 ] M + H] ⁺ 。

The fifth step: n- ((4-chlorophenyl) amino) ((4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) sulfonamide 87

87e (50mg, 207.67. Mu. Mol), 2c (57.89mg, 207.67. Mu. Mol, FR) and DIPEA (53.68mg, 415.33. Mu. Mol) were dissolved in DMF (5 mL) and heated to 125 ℃ for 6h. Cooling to room temperature after the reaction is finished, adding water for dilution, EA (ethyl acetate) for extraction, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to be dry, and separating and purifying cis-isomer or trans-isomer of the compound 87 by Prep-HPLC (peak 1, 20mg, collecting time 8.1-8.4 min); 87B (Peak 2, 15mg, collection time 8.6-8.9 min). MS m/z (ESI): 435.1[ M ] +H] ⁺ 。

87A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.88(s，1H)，8.21(d，J＝5.2Hz，1H)，7.77(br，1H)，7.43-7.37(m，4H)，7.03(d，J＝5.2Hz，1H)，4.21-4.20(m，1H)，2.93(s，3H)，2.93-2.91(m，1H)，2.44(s，3H)，2.23(s，3H)，1.94-1.93(m，2H)，1.76-1.74(m，2H)，1.61-1.54(m，4H).

87B： ¹ H NMR(400MHz，CD ₃ OD)δ8.13(d，J＝5.2Hz，1H)，7.38-7.35(m，2H)，7.32-7.29(m，2H)，7.15-7.09(m，1H)，3.83-3.82(m，1H)，2.97(s，3H)，2.91-2.86(m，1H)，2.49(s，3H)，2.28(s，3H)，2.14-2.13(m，2H)，1.84-1.83(m，2H)，1.58-1.53(m，2H)，1.53-1.48(m，2H).

Example 20: n- (((2-fluorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 88) and its cis-trans isomers

The first step is as follows: n- (2-fluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 88b

88a (148mg, 1.33mmol) and 2b (221.23mg, 1.11mmol) were dissolved in anhydrous THF (7 mL) under nitrogen,after cooling to-5 ℃, 1.66ml of 1.0m solution of LiHMDS in THF was added, reaction was quenched for 3h with saturated ammonium chloride, EA was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure, and the desired product 88b (150 mg) was obtained by separation and purification by silica gel column chromatography (PE: EA = 3: 1). MS m/z (ESI): 263.0[ mu ] M + H] ⁺ 。

The second step: n- (((2-fluorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 88

88b (50mg, 190.60. Mu. Mol), 2h (40.09mg, 228.72. Mu. Mol, FR) and DIPEA (49.27mg, 381.21. Mu. Mol) were dissolved in DMF (5 mL) and heated to 120 ℃ with stirring for 6h. After the reaction is finished, cooling to room temperature, adding water for dilution, EA (ethyl acetate) for extraction, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to be dry, and separating and purifying by Prep-HPLC (preparative-HPLC) to obtain cis-isomer or trans-isomer of the compound 88, namely 88A (peak 1, 10mg, collecting time 8.8-9.2 min); 88B (Peak 2, 20mg, collection time 9.4-9.6 min). MS m/z (ESI): 390.1[ M ] +H] ⁺ 。

88A： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.82(br，1H)，7.86(br，1H)，7.34-7.18(m，9H)，4.13-4.12(m，1H)，2.84(s，3H)，2.63-2.60(m，1H)，1.95-1.93(m，2H)，1.74-1.58(m，6H).

88B： ¹ H NMR(400MHz，DMSO-d ₆ )δ8.74(br，1H)，7.16-7.34(m，10H)，3.75-3.73(m，1H)，2.83(s，3H)，2.51-2.50(m，1H)，2.07-2.03(m，2H)，1.85-1.83(m，2H)，1.54-1.40(m，4H).

Example 21: n- (((2, 4-difluorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide (compound 89) and its cis-trans isomer

The first step is as follows: n- (2, 4-difluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 89b

89a (777.31mg, 6.02mmol) and 2b (1.0 g, 5.02mmol) were dissolved in THF (10 mL), cooled to 0 deg.C, liHMDS (5.02mmol, 21mL) was added slowly, and the mixture was allowed to warm to room temperature for 5h. After completion of the reaction, water was added to quench the reaction, and the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (PE: EA = 75: 25) to obtain 89b (578 mg).

The second step: n- (((2, 4-difluorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide 89

18d (168.42mg, 661.82. Mu. Mol) and 89b (214.81mg, 728.01. Mu. Mol) were dissolved in DMF (5.0 mL) at room temperature, followed by the addition of DIPEA (426 mg,3.3 mmol) and the reaction was allowed to warm to 100 ℃ for 27h. After completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc and washed with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and separated and purified by Prep-HPLC to obtain cis-or trans-isomer of compound 89, 89A (peak 1) and 89B (peak 2). The 89A and 89B were purified by Prep-HPLC to obtain 89A (50 mg, collection time 7.6-8.0 min) and 89B (43 mg, collection time 11.3-11.5 min) with high purity, respectively. MS m/z (ESI): 438.1[ m ] +H] ⁺ 。

89A： ¹ H NMR(400MHz，CDCl ₃ )δ8.73(br，1H)，7.41(br，1H)，7.03-6.96(m，4H)，6.84(d，J＝8.8Hz，2H)，4.64(br，1H)，4.13(br，1H)，3.79(s，3H)，3.05(s，3H)，2.56-2.50(m，1H)，1.91-1.87(m，2H)，1.78-1.64(m，6H).

89B： ¹ H NMR(400MHz，CDCl ₃ )δ8.68(br，1H)，7.33(br，1H)，7.09(d，J＝8.8Hz，2H)，7.01-6.95(m，2H)，6.85-6.82(m，2H)，4.28(br，1H)，3.83(br，1H)，3.78(s，3H)，3.06(s，3H)，2.42-2.36(m，1H)，2.14-2.11(m，2H)，1.92-1.89(m，2H)，1.60-1.51(m，2H)，1.26-1.17(m，2H).

The compounds of the invention (except compounds 5 and 6) were purified by HPLC using Aglient 1260, both at 25 ℃ and under the other separation conditions as shown in the following table:

biological evaluation

The following examples further illustrate the invention but are not intended to limit the scope of the invention.

Experimental example 1 measurement of IDO enzyme inhibitory Activity in Hela cells

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

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

The experimental method comprises the following steps:

and (3) cell culture: in vitro monolayer culture of tumor cells, wherein the culture conditions are as follows: hela cells, DMEM plus 10% fetal bovine serum, at 37 ℃ with 5% CO ₂ Cultured in an incubator. Digesting with pancreatin-EDTA for 2-3 times a week for passage. When the cells are in exponential growth phase, the cells are harvested, counted and plated. The cell concentration (10000 HeLa cells/well) was adjusted, and the cells were seeded in a 96-well plate at 70. Mu.L/well. The cover of the 96-well plate is marked and put into an incubator to be cultured for 24 hours. Test wells without added cells were set as negative controls.

Compound preparation: dissolving a compound to be detected by DMSO to prepare a mother solution, sucking a proper amount of the mother solution into the culture solution, mixing uniformly, and preparing the drug solution into a corresponding incubation concentration. Add 10. Mu.L of the prepared compound solution to each well and incubate the cells for an additional 1h.

IDO stimulation and substrate addition: mu.L of 500ng/mL IFN-. Gamma.IFN (Recombinant Human IFN-gamma Protein) (dissolved in complete medium) was added, together with 10. Mu.L of sterile 0.5mM L-tryptophan solution (dissolved in 20mM Hepes), and incubated for 48h.

And (3) detection: after completion of incubation, 25. Mu.L of the supernatant was transferred to 384-well plates, 5. Mu.L of NFK Green was added to each well, and incubated at 37 ℃ for 4h with a lid. Fluorescence is detected by a microplate reader, and Ex./Em. =400 +/-25 nm/510 +/-20 nm.

Data processing: compound inhibition (%) = (1-Savg/Cavg) × 100%; savg is the average value of the fluorescence readings of the compounds to be detected, cavg is the average value of the fluorescence readings of the negative control group, IC ₅₀ Calculated by GraphPad Prism software.

As a result:

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

Compound number	IC ₅₀ (nM)
		2	7.5
2A	9.1
		3	39.4
4A	21.2
		5A	15.7
6A	2.2
		6B	33.3
8	6.1
		9	9.4
10	4.3
		18A	0.88
25A	10.0
		36A	17.4
87A	5.5
		89A	7.0

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

Experimental example 2: hERG assay

Using Predictor ^TM The hERG Fluorescence Polarization Assay Kit (manufacturer: thermoFisher) was used to test the inhibition of compounds on the hERG potassium channel at a concentration of 10. Mu.M according to the Kit instructions, and the results are shown in Table 2.

TABLE 2 inhibition of hERG by the compounds

Compound (I)	Inhibition ratio (%) of 10. Mu.M
		2A	9.96±11.83
4A	38.05±8.64
		25A	19.33±2.80
89A	7.51±0.82

The results indicate that compounds 2A, 4A, 25A and 89A tested had no significant inhibition of hERG and had little potential to cause 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, of which the most important are CYP1A2, CYP2D6, and CYP3A4. In the inhibition assay for CYP450 enzymes, P450-Glo was used ^TM CYP1A2 Screening System、

CYP2D6Cyan Screening Kit and

CYP3A4Red Screening Kit, according to the Kit instructions, respectively measuring the inhibitory activity of the compound on CYP1A2, CYP2D6 and CYP3A4, wherein the test concentration is 1 mu M and 10 mu M. The test results are shown in Table 3.

TABLE 3 inhibition of CYP enzymes by Compounds

The results show that the compounds 2A, 4A, 25A, 87A and 89A have no obvious inhibition effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.

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

Claims

1. A compound of formula I, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound:

wherein:

n =0 or 1;

R ¹ is selected from C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl optionally substituted with the following substituents: halogen, C ₁ -C ₄ Alkyl or C ₁ -C ₄ An alkoxy group; said C ₁ -C ₄ Alkoxy is optionally substituted with the following substituents: -NR ⁷ R ⁸ ；

R ² And R ³ Each independently selected from hydrogen or C ₁ -C ₆ An alkyl group;

R ⁴ and R ⁵ Is hydrogen;

R ⁶ is selected from C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl or-CH ₂ -C ₆ -C ₁₄ An aryl group; said C ₆ -C ₁₄ Aryl, 5-14 membered heteroaryl, -CH ₂ -C ₆ -C ₁₄ Aryl groups may be optionally substituted with the following substituents: OH, halogen, CN or C ₁ -C ₆ An alkoxy group; saidC ₁ -C ₆ Alkoxy is optionally substituted with the following substituents: c ₁ -C ₆ A hydroxyalkyl group;

R ⁷ and R ⁸ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group;

x is NR ¹¹ ；

R ¹¹ Selected from CN or-SO ₂ R ¹² ，

R ¹² Is selected from C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ A cycloalkyl group.

2. The compound of claim 1, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ¹ Selected from phenyl, quinolinyl, pyridyl or indazolyl, said phenyl, quinolinyl, pyridyl, indazolyl being optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -OCH ₂ CH ₂ NH(CH ₃ ) or-OCH ₂ CH ₂ N(CH ₃ ) ₂ 。

3. The compound of claim 2, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ¹ Selected from phenyl, p-methoxyphenyl, quinolyl, pyridyl,

4. A compound according to any one of claims 1 to 3, a stereoisomer, a tautomer, or a salt thereofOr a mixture thereof, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein, R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group.

5. The compound of claim 4, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R ² And R ³ Each independently selected from hydrogen, methyl, ethyl, propyl.

6. The compound of claim 5, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R ² And R ³ Each independently selected from hydrogen and methyl.

7. The compound of any one of claims 1-3 or 5-6, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R is ⁶ Is selected from C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ An aryl group; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ Aryl groups may be optionally substituted with the following substituents: OH, halogen, CN or C ₁ -C ₄ An alkoxy group; said C ₁ -C ₄ Alkoxy is optionally substituted with the following substituents: c ₁ -C ₄ A hydroxyalkyl group.

8. The compound of claim 4, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ⁶ Is selected from C ₆ -C ₁₀ An aryl group,5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ An aryl group; said C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ Aryl groups may be optionally substituted with the following substituents: OH, halogen, CN or C ₁ -C ₄ An alkoxy group; said C ₁ -C ₄ Alkoxy is optionally substituted with the following substituents: c ₁ -C ₄ A hydroxyalkyl group.

9. The compound of claim 7, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R ⁶ Selected from phenyl and pyridyl, said phenyl, pyridyl being optionally substituted with the following substituents: fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, CN or-OCH ₂ CH ₂ OH。

10. The compound of claim 9, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ⁶ Is phenyl, optionally substituted with fluoro, chloro, methoxy or CN.

11. The compound of any one of claims 1-3, 5-6, or 8-10, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R is ⁷ And R ⁸ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl and C ₁ -C ₄ A haloalkyl group.

12. The compound of claim 4, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R ⁷ And R ⁸ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl and C ₁ -C ₄ A haloalkyl group.

13. The compound of claim 7, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R ⁷ And R ⁸ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl and C ₁ -C ₄ A haloalkyl group.

14. The compound of claim 11, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ⁷ And R ⁸ Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group.

15. The compound of claim 14, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ⁷ And R ⁸ Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.

16. The compound of claim 15, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, wherein R is ⁷ And R ⁸ Is methyl.

17. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein,

R ¹² is selected from C ₁ -C ₄ Alkyl and C ₃ -C ₆ A cycloalkyl group.

18. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein R is ¹¹ Selected from CN, -SO ₂ Me、-SO ₂ Et、-SO ₂ Pr or-SO ₂ -i-Pr。

19. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, wherein X is selected from N-SO ₂ Me and N-CN.

20. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, the compound having the structure of formula II:

wherein R is ¹ 、R ⁵ 、R ⁶ And X is as defined in any one of claims 1 to 3 or 7 to 19.

21. The compound of claim 20, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, said compound having the structure of II-1 or II-2:

22. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, the compound having the structure of formula III:

wherein R is ¹ 、R ² 、R ³ 、R ⁵ 、R ⁶ And X is as defined in any one of claims 1 to 19.

23. The compound of claim 22, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, said compound having the structure of formula III-1 or III-2:

24. The compound of any one of claims 1-3, 5-6, 8-10, or 12-16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, the compound having the structure of formula IV:

wherein R is ¹ 、R ⁴ 、R ⁵ 、R ⁶ And X is as defined in any one of claims 1 to 19.

25. The compound of claim 24, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt of said compound, or a stable isotopic derivative of said compound, said compound having the structure of formula IV-1 or IV-2:

26. The compound of any one of claims 1-25, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a mixture of thereof, wherein the compound is selected from the group consisting of:

27. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-26, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, stable isotopic derivative thereof, and one or more pharmaceutically acceptable carriers.

28. The pharmaceutical composition of claim 27, which is administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

29. A pharmaceutical formulation comprising a compound of any one of claims 1-26, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt of the compound, or a stable isotopic derivative of the compound, or the pharmaceutical composition of any one of claims 27 or 28.

30. Use of a compound of any one of claims 1-26, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, stable isotopic derivative thereof, or a pharmaceutical composition of any one of claims 27 or 28, or a pharmaceutical formulation of claim 29, in the manufacture of a medicament for the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression.

31. The use of claim 30, wherein the disease associated with IDO activity or IDO-mediated immunosuppression includes, but is not limited to, tumors, depression, senile dementia.

32. The use of claim 31, wherein the tumor includes, but is not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.