WO2019141095A1 - Amidine and guanidine derivative, preparation method therefor and medical use thereof - Google Patents

Abstract

A compound represented by formula (I), a pharmaceutical composition, a pharmaceutical formulation and use of the compound in the preparation of a medicament for preventing or treating diseases associated with IDO activity or IDO mediated immunosuppression.

Description

Terpenoids and anthraquinone derivatives, preparation methods thereof and their application in medicine Technical field

The present invention relates to novel terpenoids and anthraquinone derivatives as IDO inhibitors, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use in medicine.

Background technique

Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, and tumor cells can escape the offline immune system through various channels. Surveillance, thus leading to tumor metastasis or recurrence. Tumor immunotherapy is to control and kill tumor cells by modulating the immune system of the body to enhance the anti-tumor immunity of the tumor microenvironment (such as inhibiting IDO-mediated tumor immune escape mechanism). Because of its safety, effectiveness, and low adverse reactions, it has become a new treatment for cancer treatment after surgery, radiotherapy and chemotherapy.

IDO is one of the most promising small molecule drug targets for cancer immunotherapy currently entering clinical research. In 1969, the Hayaishi group (Hayaishi O. et al., Science, 1969, 164, 389–396) first discovered IDO in cells. It is a monomeric enzyme containing heme. The cDNA encoded protein is composed of 403 amino acids. It is 45kDa, the rate-limiting enzyme that catalyzes the catabolism of tryptophan by the kynurenine pathway. It is widely distributed in tissues other than the liver of humans and other mammals (such as rabbits and mice). It is the only catalyzed color ammonia outside the liver. The rate-limiting enzyme for acid catabolism. High expression of IDO in various cells in the tumor microenvironment leads to depletion of tryptophan metabolism and increased kynurenine levels, thereby blocking the activation of T cells, inducing oxygen free radical-mediated T cell apoptosis, and enhancing regulation. T cell (Treg) mediated immunosuppression promotes immune surveillance of tumor escape.

In addition to tumors, IDO is associated with the development of diseases such as depression, senile dementia, and cataracts. In addition, IDO is also involved in neurological and psychiatric disorders (such as mood disorders) and other chronic diseases caused by IDO activation leading to degradation of tryptophan, such as viral infections (such as AIDS), autoimmune diseases, bacterial infections such as Lyme disease and Streptococcal infection, etc. Therefore, inhibition of IDO activity has enormous therapeutic value.

The IDO small molecule inhibitor Epacadostat developed by Incyte is currently used in combination with the PD-1 antibody keytruda or the PD-L1 antibody avelumab in clinical I/II trials to treat a variety of cancers, such as advanced or metastatic solid tumors, relapsing gelatinous mothers. Cell tumors, etc. Bristol-Myers Squibb's IDO Small Molecule Inhibitor BMS-986205 is currently used in clinical phase III trials with Nivolumab for the treatment of a variety of cancers, such as advanced renal cell carcinoma, untreated metastatic or unresectable melanoma; In the phase I/II trial, Nivolumab and the LAG-3 antibody relatlimab were used in the treatment of advanced malignancies. NewLink Genetics is also conducting clinical trials of multiple indoximod (NLG-8189) in combination with other drugs, such as in the clinical phase II/III trial with PD-1 antibody keytruda or Nivolumab for the treatment of metastatic melanoma. Published IDO inhibitor patent applications include WO2016073770, WO2016073734, WO2016073738, and the like. However, there are currently no IDO inhibitors listed. In order to achieve better therapeutic effects and better meet market demand, it is urgent to develop new high-efficiency and low-toxic IDO inhibitors.

Summary of the invention

One 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, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotope derivative, metabolite or prodrug of the compound:

among them:

n=0 or 1;

R ^{1 is} selected from a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, or a 9-10 membered arylheterocyclyl group; said C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group The 9-10 membered arylheterocyclyl group may be optionally substituted by the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl. , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group; said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ ring Alkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered The cyclic group may be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ ;

R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC _1- C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl may be optionally substituted by OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 Heterocyclyl, the 4-7 membered heterocyclyl is optionally substituted by OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkane An oxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₆ hydroxyalkyl group, or R ² , R ³ and a C atom attached thereto form a P ring, said P ring being selected from C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclic group;

R ⁴ and R ⁵ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally The ground is substituted by 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 ring Alkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclyl; said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, -CH ₂ -C ₆ -C ₁₄ An aryl group, a -CH ₂ -5-14 membered heteroaryl group, a C ₃ -C ₇ cycloalkyl group, a 3-14 membered heterocyclic group, a 9-12 membered arylheterocyclyl group may be optionally substituted by the following substituents Substitution: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, 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 a heterocyclic group; said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ hydroxyalkyl group, -OC ₁ -C ₆ alkane The base-OC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl can be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Alkyl group, C ₁ -C ₆ haloalkyl, -OC ₁ -C ₆ alkyl group -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 ; 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 Heterocyclyl, 9-12 membered arylheterocyclyl; said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclic group The 9-12 membered arylheterocyclyl can be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl. , C ₁ -C ₆ alkoxy, 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 , a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group; said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or The 3-10 membered heterocyclyl can be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkane Oxyl, 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 are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C _1- C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, 4-7 membered heterocyclyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl and 4-7 membered heterocyclyl are optionally substituted by the following substituents : OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ together with the N atom to which they are attached form a 4-7 membered heterocyclic group; when a plurality of R ⁷ are present simultaneously , each R ⁷ may be the same or different; when a plurality of R ^{8 are} simultaneously present, each R ⁸ may be the same or different; when a plurality of R ^{9 are} simultaneously present, each R ⁹ may be the same or different;

R ^{10 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ alkyl-OC ₁ -C ₆ alkyl, 4-7 membered heterocyclic group, said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl and 4-7 membered heterocyclyl can be optionally substituted by OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ and the N and C or S atoms to which they are attached form a 4-7 membered heterocyclic group; when a plurality of R ¹⁰ are present simultaneously, each R ¹⁰ may be the same Or different

X is NR ¹¹ or CHNO ₂ ;

R ^{11 is} selected from the group consisting of 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, C ₃ -C ₆ cycloalkyl; said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl is optionally substituted by the following substituent: OH , OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group;

R ^{13 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- The OC ₁ -C ₆ alkyl group may be optionally substituted by the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 Heterocyclic group.

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

Wherein R ¹ , R ⁵ , R ⁶ and X are as defined above for formula I;

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X are as defined above for formula I; preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl;

Wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and X are as defined above for formula I; preferably, R ^{4 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C _{The 1-} C ₆ alkyl-OC ₁ -C ₆ alkyl group may be optionally substituted by 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 ¹ , P ring, R ⁵ , R ⁶ and X are as defined in the above 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 ¹ , R ⁵ , R ⁶ and X are as defined above for formula I;

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X are as defined above for formula I; preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl;

Wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and X are as defined above for formula I; preferably, R ^{4 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C _1- C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally substituted by 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 ¹ , P ring, R ⁵ , R ⁶ and X are as defined in the above 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 The 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 member The aryl or 3-10 membered heterocyclyl can be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C (O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ ; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are 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, The 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 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 ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy , C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl The or 3-10 membered heterocyclyl can be optionally substituted by OH, CN, halogen, CO ₂ H, C ₁ -C ₄ alkyl, 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, 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 are 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, The 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with a halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₄ alkoxy, C ₁ -C ₄ hydroxyalkyl, -C(O)NR ⁷ R ⁸ ; C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ The cycloalkyl group may be optionally substituted by the following substituents: OH, -NR ⁷ R ⁸ ; R ⁷ , R ⁸ are as defined above.

所述的苯基、喹啉基、吡啶基、吲唑基、

可任 选地被下述取代基取代：氟、氯、甲基、乙基、丙基、异丙基、正丁基、甲氧基、乙氧基、丙氧基、异丙氧基、-C(O)NH(CH ₃)、-C(O)N(CH ₃) ₂、-OCH ₂CH ₂OH、-OCH ₂CH ₂NH(CH ₃)、-OCH ₂CH ₂N(CH ₃) ₂。 In a more preferred embodiment of the invention, R ^{1 is} selected from the group consisting of phenyl, quinolyl, pyridyl, oxazolyl,

The phenyl group, quinolyl group, pyridyl group, carbazolyl group,

It may be optionally substituted by 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 is} selected from the group consisting of phenyl, quinolyl, pyridyl, and the phenyl, quinolyl, pyridyl group may be optionally substituted with the following substituents: fluorine, chlorine, Methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy.

In a preferred embodiment of the invention, R ^{1 is} selected from the group consisting of 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 are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ - C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, said C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl may be optionally substituted by OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group, which may be optionally substituted by the following substituents: OH, halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C _{a 4-} haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, or R ² , R ³ and a C atom attached thereto form a P ring, The P ring is selected from a C ₃ -C ₆ cycloalkyl group or a 4-7 membered heterocyclic group.

In a more preferred embodiment of the invention, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₄ alkyl or R ² , R ³ and the C atom to which they are attached form a P ring, said P The ring is selected from a C ₃ -C ₅ cycloalkyl group.

In a more preferred embodiment of the invention, R ² and R ³ are each independently selected from hydrogen, methyl, ethyl, propyl, or R ² , R ³ and the C atom to which they are attached form a P ring, The P ring is selected from cyclopropane, cyclobutane or cyclopentane.

In a more preferred embodiment of the invention, R ² and R ³ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; preferably, R ² and R ³ are each independently selected from hydrogen, methyl.

In some preferred embodiments of the invention, R ⁴ and R ⁵ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, C ₂ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkyl-OC ₂ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, C ₂ -C ₄ hydroxyalkyl, C ₂ -C ₄ alkyl- OC ₂ -C ₄ alkyl may be optionally substituted by 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 are as defined above.

In a more preferred embodiment of the invention, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, said C ₁ -C ₄ alkyl It is optionally substituted by the 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 are each independently selected from the group consisting of 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 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; preferably, R ⁴ and R ⁵ are each hydrogen.

In some preferred embodiments of the invention, R ^{6 is} selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ aryl, -CH ₂ -5-10 a heteroaryl group, a C ₃ -C ₇ cycloalkyl group, a 3-10 membered heterocyclic group, a 9-12 membered benzoheterocyclyl group; said C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -CH ₂ -C ₆ -C ₁₀ aryl, -CH ₂ -5-10 membered heteroaryl, C ₃ -C ₇ cycloalkyl, 3-10 membered heterocyclic, 9-12 membered benzoheterocyclyl Cocoa may be optionally substituted by the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, 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 a heteroaryl group or a 3-10 membered heterocyclic group; said C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₄ hydroxyalkyl group OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl can be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₄ alkyl, C _{3 -} C ₆ Cycloalkyl, C ₁ -C ₄ alkoxy, 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 are as defined above.

In a more preferred embodiment of the invention, R ^{6 is} selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -CH ₂ -C ₆ -C ₁₀ aryl optionally substituted by a substituent , -CH ₂ -5-10 membered heteroaryl, 3-10 membered heterocyclic group, 9-12 membered benzoheterocyclyl, said C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3 The -10 membered heterocyclyl, 9-12 membered benzoheterocyclylcocoa is optionally substituted with the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C _3- C ₅ cycloalkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ hydroxyalkyl, -OC _2-4 alkyl-OH, -OC _2-4 alkyl-NR ⁷ R ⁸ , 4-7 A heterocyclic group, R ⁷ and R ⁸ are as defined above.

In a more preferred embodiment of the invention, R ^{6 is} selected from the group consisting of phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2,3-dihydrobenzene And [b][1,4]dioxanyl, the phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2 , 3-dihydrobenzo[b][1,4]dioxenyl can be optionally substituted by the following substituents: fluoro, chloro, methyl, ethyl, propyl, isopropyl, Oxy, 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, which is optionally fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, C. Oxy, isopropoxy or CN substituted; preferably, R ⁶ is phenyl which is optionally substituted by fluorine, chlorine, methoxy or CN.

In some preferred embodiments of the invention, R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, 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 alkane a C ₂ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ hydroxyalkyl group, a C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl group and a 4-7 membered hetero The cyclic group may be optionally substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ and the N atom to which they are attached form a 4-7 membered impurity. Ring base.

In a more preferred embodiment of the invention, R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-6 membered heterocyclyl, said C ₁ -C ₄ alkane , C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ The alkyl, 4-6 membered heterocyclyl can be optionally substituted with OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ and the N to which they are attached The atoms together form a 4-7 membered heterocyclic group.

In a more preferred embodiment of the invention, R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, said C ₁ -C ₄ The alkyl, C ₂ -C ₄ alkoxy group can be optionally substituted with NH ₂ , NHMe, NMe _{2 with the} following substituents.

In a more preferred embodiment of the invention, R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl.

In some preferred embodiments of the invention, R ^{10 is} selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-7 membered heterocyclic group, said C ₁ -C ₄ alkyl group, C ₂ -C ₄ alkoxy group, 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 can be optionally substituted by the following substituents : OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ and the N and C or S atoms to which they are attached form a 4-7 membered heterocyclic group.

In a more preferred embodiment of the invention, R ^{10 is} selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-6 membered heterocyclyl, said C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C _2- C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-6 membered heterocyclic group Optionally substituted with OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ and the N and C atoms to which they are attached form a 4-7 membered heterocyclic ring base.

In a more preferred embodiment of the invention, R ^{10 is} selected from C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, said C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy It may be optionally substituted with the following substituents: NH ₂ , NHMe, NMe ₂ .

In a more preferred embodiment of the invention, R ^{10 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl.

In some preferred embodiments of the invention, X is NR ¹¹ or CHNO ₂ ; preferably, X is NR ¹¹ ;

R ^{11 is} selected from the group consisting of hydrogen, OH, CN, NH ₂ , NHMe, NMe ₂ , -SO ₂ R ¹² , -C(O)R ¹³ ,

R ^{12 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl; said C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by the following substituents: OH, OC ₁ -C ₄ alkyl, NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group;

R ^{13 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl may be optionally substituted by OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group;

In a preferred embodiment of the invention, X is selected from NR ¹¹ or CHNO ₂ ; preferably, X is NR ¹¹ ;

R ^{11 is} selected from the group consisting of hydrogen, OH, CN, NH ₂ , NHMe, NMe ₂ , -SO ₂ R ¹² , -C(O)R ¹³ ,

R ^{12 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl;

R ^{13 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₃ - C ₅ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl may be optionally substituted by OH, halogen, C ₁ -C ₄ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-6 membered heterocyclic group.

In a more preferred embodiment of the invention, X is selected from NR ¹¹ or CHNO ₂ , preferably X is NR ¹¹ ; wherein R ^{11 is} selected from CN, -SO ₂ R ¹² ; R ^{12 is} selected from C ₁ -C ₄ Alkyl, C ₃ -C ₅ cycloalkyl.

In a more preferred embodiment, X is selected from NR ¹¹ or CHNO ₂ , preferably X is NR ¹¹ ; wherein R ^{11 is} selected from CN, -SO ₂ R ¹² ; R ^{12 is} 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 ; wherein R ^{11 is} 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 ; Still more preferably, X is selected from the group consisting of N-SO ₂ Me, N-CN.

In an embodiment of the invention, the compound of the invention is selected from, but not limited to:

Preparation

One aspect of the invention provides a method of making a compound of the invention, the method comprising:

Synthesis of Intermediate A

R ^{1 is} as defined in the above formula I.

First step: Compound A-1 forms enolization intermediate A-2 under the action of a base and PhNTf ₂ or Tf ₂ O and 2,6-di-tert-butyl-4-methylpyridine.

The base used is LiHMDS, LDA, NaHMDS, KHMDS, ^t BuOK, NaH or NaOH, etc., the solvent is THF, CH ₃ CN, DCM or DCE, etc., the temperature is -78 ° C to 25 ° C;

The second step: the compound A-2 is reacted with an R ¹ -boric acid or a boronic ester by a coupling reaction (for example, Suzuki reaction) to form an intermediate A-3.

The catalyst used is Pd(PPh ₃ ) ₄ or Pd(dppf)Cl _{2 ,} etc., and 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., and the solvent is Dioxane. /H ₂ O, DMF / H ₂ O, DMSO / H ₂ O or CH ₃ CN / H ₂ O, etc., the temperature is 60 ° C to 120 ° C;

Third step: Compound A-3 is reduced to intermediate A-4 under catalytic hydrogenation conditions.

The catalyst used is Pd / C, PtO ₂ or Pd (OH) ₂ / C, etc., the solvent is MeOH or EtOH, etc., the temperature is rt to 80 ° C;

The fourth step: Compound A-4 removes the Boc protecting group under the action of an acid to obtain Intermediate A.

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

Synthesis of Intermediate B

R ^{1 is} as defined above for formula I, and R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ - C ₆ alkyl-OC ₁ -C ₆ alkyl.

First step: Compound B-1 forms enolization intermediate B-2 under the action of a base and PhNTf ₂ or Tf ₂ O and 2,6-di-tert-butyl-4-methylpyridine.

The reaction conditions are as described in the first step of the preparation method of Intermediate A.

Second step: Compound B-2 is reacted with R ¹ -boric acid or a boronic ester by a coupling reaction (for example, Suzuki reaction) to give intermediate B-3.

The reaction conditions are as described in the second step of the preparation method of Intermediate A.

Third step: Compound B-3 is reduced to intermediate B-4 under catalytic hydrogenation conditions.

The reaction conditions are as described in the third step of the preparation method of Intermediate A.

The fourth step: the alkylation of the compound B-4 in the presence of a base to form the 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.), undergoing one and/or two alkylation, the base used Is BuLi, LiHMDS, LDA, ^t BuOK, NaH, Cs ₂ CO ₃ , K ₂ CO ₃ or NaOH, etc., the solvent is THF, CH ₃ CN, DCM, DMF, DMSO, DCE or Acetone, etc., the temperature is -78 ° C to Rt;

Step 5: Compound B-5 is hydrolyzed in the presence of a base to give Intermediate B-6.

The base used is LiOH, NaOH or KOH, etc., the solvent is MeOH / H ₂ O or EtOH / H ₂ O, etc., the temperature is 0 to 80 ° C;

The sixth step: the Curtius rearrangement reaction of compound B-6 produces intermediate B-7.

The base used is Et ₃ N, DIPEA, etc., the reagent is DPPA or the like, and the solvent is ^t BuOH, toluene, DCM, a mixed solvent of ^t BuOH and toluene, and the like, and the temperature is 40 to 110 °C.

Step 7: Compound B-7 is hydrolyzed under basic conditions to form product B.

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

Synthesis of Intermediate C

R ^{1 is} as defined above for formula I, R ^{4 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally substituted by the following substituents: OH, CN, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ .

First step: Compound A-4 undergoes alkylation with R ⁴ -L ¹ (L ¹ is -Cl, -Br, -I or -OMs, etc.) under the action of a base, or Mitsunobu reaction with R ⁴ OH 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, CH ₃ CN, DCM, DMF, DMSO, DCE or Acetone, etc., temperature Is -78 ° C to 60 ° C; if Mitsunobu reaction occurs, the reagent used is generally DIAD or DEAD, etc., the solvent is THF, DCM or DCE, etc., the temperature is 0 ° C to 80 ° C;

The second step: intermediate C-1 removes the Boc protecting group to form intermediate C under the action of an acid.

The reaction conditions are as described in the fourth step of the preparation method of Intermediate A.

Synthesis of intermediate D

R ^{1 is} as defined above for formula I, and the P ring is a C ₃ -C ₆ cycloalkyl group or a 4-7 membered heterocyclic group.

First step: Compound R ¹ -L ² (L ² is Cl, Br, I or OTf, etc.) is coupled to D-1a or D-1b by a coupling reaction (for example, Suzuki reaction) to give intermediate D-2.

The reaction conditions are as described in the second step of the preparation method of Intermediate A. The second step: Compound D-2 produces intermediate D-3 under reducing conditions.

The reaction conditions are as described in the third step of the preparation method of Intermediate A.

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

The acid used is HCl, H ₂ SO ₄ , p-toluenesulfonic acid or methanesulfonic acid, etc., and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH ₃ CN, Dioxane, Acetone or Toluene, etc., temperature is rt To 100 ° C;

The fourth step-A: Compound D-4 and Compound D-5 form Intermediate D-6 under basic conditions.

The base used is LDA, n-BuLi, ^t BuOK, NaOH, NaH, LiHMDS, NaHMDS or KHMDS, and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH ₃ CN, Dioxane or Toluene, and the temperature is -78. °C to rt;

Step 4 - B: Reductive amination of compound D-4 with an amine can also give intermediate A

The amine source used is ammonium chloride, ammonium acetate, an aqueous solution of NH ₃ or a MeOH solution, and the reducing agent is NaBH ₃ CN, NaBH ₄ , NaBH(OAc) _{3 ,} etc., and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF. , CH ₃ CN, Dioxane or Toluene, etc., the temperature is 0 ° C to 80 ° C.

Step 5: Dehydration of compound D-6 gave intermediate D-7.

The dehydrating reagent used is an acid such as HCl, H ₂ SO ₄ or TFA, or the Burgess dehydrating agent, and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH ₃ CN, Dioxane or Toluene.

Step 6: Compound D-7 produces intermediate D-8 under reducing conditions.

The reaction conditions are as described in the third step of the preparation method of Intermediate A.

Step 7: Compound D-8 is hydrolyzed under basic/acidic conditions to give intermediate D-9.

The acid used is HCl, 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 a temperature of rt to 100 ° C;

Step 8: Compound D-9 is rearranged by Curtius to form intermediate D-10.

The reaction conditions are as described in the sixth step of the preparation method of Intermediate B.

Step 9: Compound D-10 is hydrolyzed to intermediate D under basic conditions.

The reaction conditions are as described in the seventh step of the preparation method of Intermediate B.

Synthesis of intermediate E

R ⁵ and R ^{6 are} as defined in the above formula I.

Compounds E-1 and E-2 form intermediate E under the action of a base. The base used is LiHMDS, LDA, NaHMDS, KHMDS, TEA, DIPEA, ^t BuOK, NaH or Cs ₂ CO _{3 ,} etc., and the solvent used is THF, DCM, DCE, DMF, DMSO, CH ₃ CN, Dioxane, MeOH, EtOH or Toluene. Etc., the temperature is -10 ° C to 140 ° C.

Synthesis of intermediate F

R ⁵ , R ⁶ and R ^{12 are} as defined in the above formula I.

Compound F-1 and Compound E-2 form Intermediate F under the action of a base.

The reaction conditions are as described in the first step of the preparation process of Intermediate E.

Synthesis of intermediate G

R ⁵ and R ^{6 are} as defined in the above formula I.

Compound G-1 and Compound E-2 form Intermediate G under the action of a base.

The reaction conditions are as described in the first step of the preparation process of Intermediate E.

Synthesis of a compound of formula II-form V (method 1)

R ¹ , R ⁵ , R ⁶ , R ^{12 are} as defined in the above formula I, R ^{4 is} as defined in the above intermediate C, R ² and R ^{3 are} as defined in the above intermediate B, and the P ring and the above intermediate D The definitions are the same, and X is N-CN, N-SO ₂ R ¹² or CH-NO ₂ .

First step: Intermediates A, B, C or D are reacted with intermediates E, F or G under basic conditions to form compounds of formula II, formula III, formula IV, and formula V, respectively.

Specifically, intermediate A is reacted with intermediates E, F, G, respectively, under basic conditions to form a compound of formula II.

Specifically, intermediate B is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula III.

Specifically, intermediate C is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula IV.

Specifically, intermediate D is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula V.

The reaction conditions are as described in the first step of the preparation process of Intermediate E.

Synthesis of compounds of formula II-form V (method 2)

R ¹ , R ⁵ , R ⁶ , R ^{12 are} as defined in the above formula I, R ^{4 is} as defined in the above intermediate C, R ² and R ^{3 are} as defined in the above intermediate B, and the P ring and the above intermediate D The definitions are the same, X is N-CN, N-SO ₂ R ¹² or CH-NO ₂ , and X' is PhO or MeS.

First step: Intermediates A, B, C or D are reacted with intermediate E-1, F-1 or G-1, respectively, under basic conditions to form intermediates A', B', C' or D'.

Specifically, intermediate A is reacted with intermediates E-1, F-1, and G-1 under basic conditions to form intermediate A'.

Specifically, the intermediate B is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form the intermediate B'.

Specifically, the intermediate C is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form an intermediate C'.

Specifically, the intermediate D is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form the intermediate D'.

The reaction conditions are as described in the first step of the preparation process of Intermediate E.

Step Two: Intermediate A ', B', C 'or D' Intermediate R ⁵ -NH-R ⁶ Formula II, Formula III, Formula IV, and a compound of Formula V were reacted under basic conditions.

In particular compounds, intermediates A 'Intermediate R ⁵ -NH-R ⁶ under basic conditions formula II.

Specifically, the intermediate B 'Intermediate R ⁵ -NH-R ⁶ of the compound of formula III under basic conditions.

Specifically, compound ^6, an intermediate C 'Intermediate R ⁵ -NH-R in the formula under basic conditions to IV.

Specifically, intermediate D 'Intermediate R ⁵ -NH-R ⁶ of the compound of formula V under basic conditions.

The reaction conditions are as described in the first step of the preparation process of Intermediate E.

Pharmaceutical composition, preparation, preparation method and treatment method of pharmaceutical composition

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound A eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical composition is for treating a disease associated with IDO activity or IDO mediated immunosuppression.

Another aspect of the invention provides a method of preparing a pharmaceutical composition, the method comprising administering a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, the compound being pharmaceutically Accepted salts, polymorphs, eutectics or solvates, or stable isotope derivatives, metabolites or prodrugs of the compounds, in combination with one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical composition is for treating a disease 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, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound a conjugate, a eutectic or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound , or a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, prepared for the prevention or treatment of IDO activity-related or IDO-mediated immunity Use in drugs that inhibit related diseases.

Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound , or a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in preventing or treating IDO activity-related or IDO-mediated immunosuppression Related diseases.

Another aspect of the invention provides a method of 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 invention, a stereoisomer of the compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, Or a pharmaceutical composition of the invention or a pharmaceutical preparation of the invention, and optionally comprising administering to an individual in need thereof other drugs for treating diseases such as cancer.

Another aspect of the invention provides a method of 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 invention, a stereoisomer of the compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, Or a pharmaceutical composition of the invention or a pharmaceutical preparation of the invention, and comprises administering a PD-1 antibody or a PD-L1 antibody to an individual in need thereof.

Diseases associated with IDO activity or IDO mediated immunosuppression according to the invention include, but are not limited to, tumors, depression, Alzheimer's disease and the like.

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, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, Testicular cancer, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, multiple myeloma, melanoma, glioma or sarcoma.

In the present invention, the "individuals in need thereof" include mammals such as bovine, equine, porcine, canine, feline, rodent, primate; for example, human .

Another aspect of the invention provides a formulation comprising a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound a eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, which is used to modulate (e.g., reduce or inhibit) an individual (e.g., a mammal, such as a bovine, a horse) The activity of IDO in cells of animals, porcines, canines, felines, rodents, primates; for example, humans.

Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound Or a use of a stable isotopic derivative, metabolite or prodrug of said compound for the preparation of a formulation for modulating (e.g., reducing or inhibiting) an individual cell (e.g., a mammal, such as a bovine, The activity of IDO in equines, porcines, canines, felines, rodents, primates; for example, humans.

Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound Or a stable isotope derivative, metabolite or prodrug of said compound for use in regulating (eg, reducing or inhibiting) an individual (eg, a mammal, such as a bovine, equine, porcine, dog) The activity of IDO in the cells of animals, felines, rodents, primates; for example, humans.

Another aspect of the invention provides a modulator (eg, reducing or inhibiting) an individual (eg, a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate) A method of the activity of an IDO in an animal; for example, a human cell comprising administering to said cell an effective amount of a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, said compound A pharmaceutically acceptable salt, polymorph, eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of the compound.

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

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled 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 invention.

The terms "including", "comprising", "having", "containing", or "comprising", as used herein, and other variants thereof, are inclusive or open, and not Exclude other unlisted elements or method steps.

As used herein, the term "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 6, such as from 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 from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which may be optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen ( At this time, the group is referred to as "haloalkyl" such as 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 ,} and the like.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridging systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.) , which is optionally substituted by 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 As used herein, the term "C ₃ -C ₇ cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 7 ring-forming carbon atoms (eg, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which may be optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

As used herein, the term "alkoxy" refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. Representative examples of C ₁ -C ₆ alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutyl Oxyl, tert-butoxy, pentyloxy, hexyloxy and the like.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C ₆ -C ₁₄ aryl" means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl. The aryl group may be optionally 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 "arylheterocyclyl" refers to a cyclic group formed by the aryl and heterocyclyl groups sharing two adjacent carbon atoms with each other, the point of attachment to other groups being on the aryl group. . Wherein aryl or heterocyclic is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclyl" means a group containing an arylheterocyclyl group of a total of 9 to 12 ring atoms, particularly phenyl and 5-8. a heterocyclic group, particularly a phenyl-5-6 membered heterocyclic group (9-10 membered benzoheterocyclyl), examples of which include, but are not limited to, carbazolyl,

等。 The term "heteroaryl" as used herein, refers to a monocyclic heteroaryl or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (heteroaromatic ring means an aromatic ring system containing at least one heteroatom). , the point of attachment to other groups on the heteroaryl ring, having, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5, 6, 7, 8, 9 or 10 ring atoms, and which contain one or more (eg 1, 2, 3, 4 or 5) heteroatoms (eg, oxygen, nitrogen or sulfur) which may be the same or different, and, in each case The aryl group, the heterocyclic group or the cycloalkyl group may be shared with two adjacent atoms to form a cyclic group. For example, as used herein, the term "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atoms (including a 5-6 membered heteroaryl group, examples of which include, but are not limited to, thienyl, Furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridine a pyridyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, and the like, and a cyclo- and derivative thereof, and a cyclo-derivative is not limited to a heteroaryl-heteroaryl group, a heteroaryl-aryl group, a heteroaryl group. And heterocyclyl, or heteroarylcycloalkyl, especially 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl phenyl, 5-6 membered heteroaryl And a 5-6 membered heterocyclic group, or a 5-6 membered heteroaryl and C _4-6 cycloalkyl group (especially a 5-6 membered heteroarylcyclobutyl group, a 5-6 membered heteroarylcyclopentylene group) a group, a 5-6 membered heteroarylcyclohexylene group, examples of which include, but are not limited to, anthracenyl, isodecyl, oxazolyl, benzimidazole, quinolyl, isoquinolyl,

Wait.

或螺环衍生物，例如但不限于

等。 The term "heterocyclyl," as used herein, refers to a monocyclic or polycyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more in the ring. (for example, 1, 2, 3 or 4) selected from C(=O), O, S, S(=O), S(=O)2 and NR (R represents a hydrogen atom or a substituent, for example However, it is not limited to a group of an alkyl group or a cycloalkyl group, and its point of attachment to other groups is on the hetero ring. The term "3-14 membered heterocyclyl" as used herein means a heterocyclic group containing 3 to 14 ring atoms (including a 3-7 membered heterocyclic group, examples of which include, but are not limited to, ethylene oxide) , aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholine a base, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a trithianyl group, and the like, and a cyclo- and derivative thereof, and a cyclic derivative includes, but not limited to, a heterocyclic heterocyclic group. , heterocyclyl-aryl, heterocyclylheteroaryl, heterocyclylcycloalkyl, especially 3-7 membered heterocyclyl 3-7 membered heterocyclic, 3-7 membered heterocyclyl Aryl, 3-7 membered heterocyclylheteroaryl, 3-7 membered heterocyclylcycloalkyl, especially 3-7 membered heterocyclylphenyl, 3-7 membered heterocyclyl 5- 10-membered heteroaryl, 3-7 membered heterocyclyl and C _4-6 cycloalkyl, examples of which include, but are not limited to, pyrrolidino-cyclopropyl, cyclopentyl-azacyclopropyl, pyrrolidinyl Cyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinyl Piperazinyl, morpholinyl and pyrrolidinyl, piperidinyl and morpholinyl,

Or a spiro derivative, such as but not limited to

Wait.

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

The term "hydroxyalkyl" as used herein means that the hydrogen atom of the alkyl group is substituted by one or more (eg, 1, 2, 3 or 4) hydroxyl groups, as used herein, the term "C _{1 -6} hydroxyalkyl" means that the hydrogen atom of the C ₁ -C ₆ alkyl group is substituted by one or more (for example, 1, 2, 3 or 4) hydroxyl groups. Examples thereof include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted with", the substituent may be unsubstituted (1) or (2) substituted with one or more (eg 1, 2, 3 or 4) substituents. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

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 otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

The present invention also encompasses all pharmaceutically acceptable isotopic compounds (stable isotope derivatives) which are identical to the compounds of the present invention except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature. The atomic substitution of the dominant atomic mass or mass number. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., ² H, ³ H); isotopes of carbon (e.g., ¹¹ C, ¹³ C, and ¹⁴ C); isotopes of chlorine (e.g. ³⁶ Cl); isotope of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O) ); an isotope of phosphorus (eg, ³² P); and an isotope of sulfur (eg, ³⁵ S).

The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers, which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, nitroso-oxime can be present in solution in the following tautomeric forms:

It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof. For example, hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

The compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.

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

The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, 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, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

The dosing regimen can be adjusted to provide the optimal 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 urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

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

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

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional 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 ( Edited by EBRoche, American Pharmaceutical Association). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

The wavy line "~~" is used herein to mean a bond in the structural formula which represents a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.

Advantageous effects of the invention

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

Detailed ways

Example

The invention is further described in the following examples, but the examples 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 was confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) and/or mass spectrometry (MS). The reaction was monitored by silica gel thin layer chromatography (TLC) (GF 254 as the stationary phase) or LCMS.

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

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

The microwave reaction was carried out using a Biotage Initiator microwave reactor.

Column chromatography generally uses 200 to 300 mesh silica gel (Qingdao Ocean) as a carrier. Flash column chromatography was performed using a Biotage Technologies instrument.

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

The reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.

Example 1: N-(((4-chlorophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide (Compound 2) and its cis-trans isomer

First step: N-(4-chlorophenyl)-N'-(methylsulfonyl)thioaminoimidate methyl ester 2c

Compound 2a (59 mg) and Compound 2b (100 mg) were placed in a 50 mL three-necked flask, and 5 mL of anhydrous THF was added, and 1.6 mL of 1.0 M LiHMDS in THF was added under nitrogen. LCMS was used to monitor the complete conversion of the substrate, and the reaction was quenched by the addition of 0.5 mL of saturated NH ₄ Cl, concentrated to dryness under reduced pressure, and dissolved in a small amount of DCM, purified by preparative silica gel (PE: EA = 2:1) to give compound 2c (55 mg) . MS m/z (ESI): 279.0 [M+H] ⁺ .

Second step: 4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yltrifluoromethanesulfonate 2e

2d (2.0g, 9.4mmol) was added to THF (20mL), cooled to -70 ° C under nitrogen atmosphere, 20.0mL of 1.0M LiHMDS was added dropwise at -60 ~ -70 ° C, and the incubation reaction was added for 1 h. Subsequently, PhNTf ₂ (3.7 g, 10.0 mmol) was slowly added dropwise thereto at -60 to -70 ° C, and allowed to react at room temperature overnight. After completion of the reaction with saturated NH ₄ Cl solution (50mL) The reaction was quenched, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous Na ₂ SO _4, the solvent was distilled off under reduced pressure and silica gel column chromatography (PE: EA = 99: 1-80:20) Compound 2e (2.4 g) was obtained. MS m/z (ESI): 346.1 [M+H] ⁺ .

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

2e (2.4 g, 7.0 mmol), phenylboronic acid (1.3 g, 10 mmol), potassium phosphate (3.0 g, 14 mmol) and Pd(dppf)Cl ₂ (57 mg, 0.07 mmol) were dissolved in dioxane under nitrogen ( The reaction was stirred overnight by heating to 90 ° C in 20 mL). TLC (PE: EA = 5:1) showed that the reaction was completed and then cooled to room temperature. The mixture was poured into water (50 mL), extracted with methyl tert-butyl ether, and the organic phase was combined and dried over anhydrous Na ₂ SO ₄ After removing the solvent by pressure evaporation, silica gel column chromatography (PE: EA=99:1 - 80:20) gave compound 2f (0.8 g). MS m / z (ESI): 274.2 [M + H] +.

The fourth step: the synthesis of (4-phenylcyclohexyl)carbamic acid tert-butyl ester 2g

2f (0.8 g, 2.9 mmol) was dissolved in methanol (10 mL), 10% palladium carbon (100 mg) was added, and the mixture was allowed to react overnight at room temperature under a hydrogen atmosphere, and the filtrate was concentrated under reduced pressure to dryness to give compound 2 g (0.8 g). . MS m/z (ESI): 276.2 [M+H] ⁺ .

Step 5: Synthesis of 4-phenylcyclohexylamine hydrochloride 2h

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

Step 6: N-(((4-Chlorophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide (Compound 2)

Compound 2c (55 mg) and the free state of compound 2h (47 mg) were placed in a 10 mL microwave reaction tube, dissolved in DMF (3 mL), and then DIPEA (200 mg) was added and reacted at 100 ° C for 4 h under microwave conditions. After LC-MS was monitored, the substrate was completely converted. After the reaction was completed, it was poured into 50 mL of water, extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ and evaporated. . Compound 2 was again separated by Prep-HPLC to give the cis or trans isomer, 2A (peak 1, 11 mg, collection time 5.8-6.1 min); 2B (peak 2, 9 mg, 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 = 12.8 Hz, 2H), 1.62-1.33 (m, 4H).

Example 2: 1-(4-Chlorophenyl)-2-cyano-3-(4-(6-fluoroquinolin-4-yl)cyclohexyl)anthracene (Compound 3)

First step: 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 3b

Pd(dppf)Cl ₂ (1000 mg, 1.4 mmol), 3a (6.5 g, 29.0 mmol), B ₂ pin ₂ (9.6 g, 38.0 mmol) and AcOK (8.5 g, 87.0 mmol) were dissolved in two under nitrogen. oxygen six ring (70 mL) solution was reacted at 80 ℃ 4h, after the reaction was cooled to room temperature, filtered and washed with EtOAc, and concentrated under reduced pressure and the mother liquor was added 100 mL EtOAc, washed with water (20mL * 3) the combined organic layer was dried over anhydrous Na ₂ sulfate SO _4, purified by silica gel column chromatography (PE: EA = 10: 1 ) to give the title compound isolated 3b (6.0g), MS m / z (ESI): 274.1 [m + H] +.

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

Pd(dppf)Cl ₂ (292 mg, 0.4 mmol), 3b (2.0 g, 7.3 mmol), 2e (2.5 g, 7.3 mmol) and K ₂ CO ₃ (2.0 g, 14.6 mmol) were dissolved in two under nitrogen. In hexacyclohexane/water (20 mL/0.2 mL), it was reacted at 80 ° C for 4 h. 50mL, drying and cooling to room temperature, filtered and washed with EtOAc and the mother liquor was concentrated under reduced pressure and EtOAc was added and washed with water (10mL * 3) The organic layer was dried over anhydrous Na ₂ SO _4, purified by silica gel column chromatography (PE: EA = 10: 1 ) isolated yield the title compound 3c (2.0g), 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 (2.8 g, 8.1 mmol) in MeOH (20 mL), EtOAc (EtOAc) After completion of the reaction by LC-MS, the palladium carbon was removed by filtration, and the residue was evaporated to dryness to give the title compound 3d (2.3 g), MS m/z (ESI): 345.2 [M+H] ⁺ .

Fourth step: 4-(6-fluoroquinolin-4-yl)cyclohexylamine 3e

A 3 d (2.3 g, 6.6 mmol) solution of trifluoroacetic acid / dichloromethane (10 mL / 10 mL) was stirred at room temperature for 4 h, and the reaction was completed by LC-MS. Concentration to dryness <RTI ID=0.0></RTI>^</RTI>^< RTI ID=0.0></RTI>

Step 5: 1-(4-Chlorophenyl)-2-cyano-3-(4-(6-fluoroquinolin-4-yl)cyclohexyl)anthracene (Compound 3)

Compound 3e (100 mg, 0.4 mmol), 2c (1.8 mg, 0.4 mmol) and DIPEA (200 mg, 1.6 mmol) were dissolved in acetonitrile and reacted at 100 ° C for 1 h under microwave conditions. After the reaction was completed, it was cooled to room temperature and evaporated under reduced pressure. Compound 3 (25 mg), MS m/z (ESI): 4221. [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 = 4.6 Hz, 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 isomer

First step: N-(3-chlorophenyl)-N'-(methylsulfonyl)thioaminoimidate methyl ester 4b

4a (248 mg) and 2b (353 mg) were placed in a 100 mL three-necked flask, 5 mL of anhydrous THF was added, cooled to 0 ° C, and 5.0 mL of a 1.0 M solution of LiHMDS in THF was added under nitrogen. After LCMS was detected, after the substrate was completely disappeared, the reaction was quenched by the addition of 0.5 mL of saturated NH ₄ Cl. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (PE: EA=3: 1-5:1) to give compound 4b (420 mg) . MS m/z (ESI): 279.0 [M+H] ⁺ .

Second step: N-(((3-chlorophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide (Compound 4)

Compound 4b (220 mg) and 2 h of free state (118 mg) were placed in a 20 mL microwave tube, DMF (5 mL) was added to dissolve completely, then DIPEA (350 mg) was added and the mixture was stirred at 100 ° C for 4 h under microwave conditions. There is a clear product formation. After the reaction was cooled to room temperature, poured into 50mL water, EtOAc. The combined organic phase was dried over anhydrous Na ₂ SO _4, filtered and the solvent was distilled off under reduced pressure, purification Prep-HPLC to give compound (180mg) 4, Compound 4 was again isolated to give the cis or trans isomer, 4A (peak 1, 44 mg, collection time 5.6-6.1 min); 4B (peak 2, 34 mg, collection time 6.2-6.9 min). MS m/z (ESI): 406.1 [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 = 7.8 Hz, 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 = 11.9 Hz, 2H), 1.67-1.34 (m, 4H).

Example 4: N-(((3-chlorophenyl)amino)((4(6-fluoroquinolin-4-yl)cyclohexyl)amino)methyl)methylsulfonamide (Compound 5) and its Anti-isomer

First step: N-(((3-chlorophenyl)amino)((4(6-fluoroquinolin-4-yl)cyclohexyl)amino)methyl)methylsulfonamide (Compound 5)

3e (50mg, 0.2mmol), 4b (0.3g) and DIPEA (40mg, 0.3mmol) were dissolved in DMF (5mL), reacted under microwave conditions at 100 ° C for 2h, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water (50mL), the dried extracted with ethyl acetate, the organic phases were combined, dried over anhydrous Na ₂ SO _4, the solvent was distilled off under reduced pressure, silica gel prep plate separation (DCM: MeOH = 10: 1 ) to give cis- or trans isomer. 5A (15 mg, relatively less polar isomer); 5B (10 mg, relatively more polar isomer), MS m/z (ESI): 475.1 [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)methylsulfonamide (Compound 6) and its Anti-isomer

Instead of 4b, compound 2c is used to synthesize the cis or trans isomer of compound 6 according to the synthesis of compound 5. 6A (6 mg, relatively polar isomer); 6B (5 mg, relatively polar 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 = 8 Hz, 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)anthracene (Compound 7)

First step: 2-(4-(((trifluoromethyl))sulfonyl)oxy)cyclohex-3-en-1-yl)acetate 7b

Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was added to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in dichloromethane (200 mL). 7a (10.88g, 59.05mmol) of dichloromethane (50mL) was added and the reaction was continued for 10h at room temperature. After the reaction was completed, the reaction was quenched with water. The organic phase was dried over anhydrous Na ₂ SO ₄ and evaporated. Column chromatography (PE: EA = 99: 1-3: 1) gave 7b (15 g).

The second step: 2-(4-(2-methylpyridin-4-yl)cyclohex-3-en-1-yl)acetate 7d

7b (1.50g, 4.75mmol), 7c (650mg, 4.75mmol), K ₂ CO ₃ (1.31g, 9.50mmol) and Pd(dppf)Cl ₂ (350mg, 0.48mmol) were dissolved in 40mL of dioxane under nitrogen protection. In a six ring and 10 mL water, the reaction was heated to 80 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. MS m/z (ESI): 260.2 [M+H] ⁺ .

The third step: 2-(4-(2-methylpyridin-4-yl)cyclohexyl)acetate 7e

7d (1.5g, 5.79mmol) was dissolved in 15 mL of methanol, 150 mg of Pd/C was added, and the mixture was reacted under a hydrogen atmosphere for 4 h, filtered, and the filtrate was concentrated to dryness to give Intermediate 7e (1.5 g). MS m/z (ESI): 262.2 [M+H] ⁺ .

The fourth step: ethyl 2-(4-(2-methylpyridin-4-yl)cyclohexyl)propanoate 7f

7e (1.5g, 5.79mmol) was dissolved in anhydrous THF (15mL) under nitrogen, cooled to -78 ° C, slowly added 8.1mL of 1M LiHMDS in THF solution, added to -50 ° C, after 4 h reaction CH ₃ I (987 mg, 6.95 mmol) was added at this temperature and stirring was continued for 2 h. After the reaction, the reaction solution saturated with 15mL quenched with aqueous NH ₄ Cl, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous Na ₂ SO _4, after filtration, the filtrate was concentrated to dryness under reduced pressure, purified by silica gel column chromatography ( PE: EA = 100: 0-65: 35) Intermediate 7f (1.0 g) was isolated. MS m/z (ESI): 276.1 [M+H] ⁺ .

Step 5: 2-(4-(2-methylpyridin-4-yl)cyclohexyl)propanoic acid 7g

7f (1.0g, 3.64mmol) was dissolved in methanol (10mL) and water (2mL), then added NaOH (436mg, 10.9mmol), heated to 70 ° C and stirred overnight, after the reaction was adjusted to pH 3 with 2M hydrochloric acid The mixture was concentrated to dryness to dryness (yield: 7g). MS m/z (ESI): 248.2 [M+H] ⁺ .

Step 6: (1-(4-(2-methylpyridin-4-yl)cyclohexyl)ethyl)carbamoyl azide 7h

7g (500mg), DPPA (668mg, 2.43mmol) and DIPEA (391mg, 3.03mmol) were dissolved in toluene (10mL) and tert-butanol (10mL), heated to 110 ° C for 4h, cooled, add 20mL of water, use extracted with ethyl acetate, the combined organic phase was dried over Na ₂ SO ₄ anhydrous, filtered and the filtrate was concentrated to dryness under reduced pressure, purified by silica gel column chromatography (DCM: 10 MeOH = 100: : 0-90) was isolated Intermediate 7h (200 mg). MS m/z (ESI): 288.2 [M+H] ⁺ .

Step 7: 1-(4-(2-Methylpyridin-4-yl)cyclohexyl)ethylamine hydrochloride 7i

7h (200mg, 0.697mmol) was dissolved in dioxane (6mL) and water (0.5mL), NaOH (84mg, 2.09mmol) was added, reacted at room temperature for 2h, then added 4M HCl in dioxane solution to adjust the pH The mixture was concentrated to dryness to EtOAc (EtOAc m. MS m/z (ESI): 219.1 [M+H] ⁺ .

Step 8: Phenyl N-(4-chlorophenyl)-N'-cyanooxyaminoimidate phenyl 7k

2a (0.16g, 1.3mmol), N-cyanocarbonylimine diphenyl ester 7j (0.3g, 1.3mmol) and DIPEA (0.16g, 1.3mmol) were dissolved in DMF (5mL) under microwave conditions 120 ℃ reaction 1.5h, cooled to room temperature after the completion of the reaction, the reaction mixture was poured into water (50mL) and ethyl acetate extraction, dried over anhydrous Na ₂ SO _4, the organic phase was concentrated to dryness to give intermediate 7k (0.3g) The crude product was used in the next step without further purification, MS m/z (ESI): 2721.[M+H] ⁺ .

Step 9: 1-(4-Chlorophenyl)-2-cyano-3-(1-(4-(2-methylpyridin-4-yl)cyclohexyl)ethyl)indole (Compound 7)

7k (30mg, 0.11mmol), 7i (34mg, 0.13mmol) and DIPEA (43mg, 0.33mmol) were dissolved in DMF (5mL) and heated to 90 ° C overnight. After the reaction was cooled and dried, was added 10mL of water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO _4, after filtration, the filtrate was concentrated to dryness under reduced pressure, separated Prep-HPLC to give compound 7 (8mg , collection time 9.8-10.2 min), MS m/z (ESI): 396.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.29-8.25 (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 = 3.2 Hz, 3H).

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

First step: N-(((4-chlorophenyl)amino)((1-(4-(2-methylpyridin-4-yl)cyclohexyl)ethyl)amino)methylene)methanesulfonamide (Compound 8)

2c (31 mg, 0.11 mmol), 7i (34 mg, 0.13 mmol), and DIPEA (43 mg, 0.33 mmol) were dissolved in DMF (5 mL). After cooling, 10mL of water was added, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous Na ₂ SO _4, filtered and the filtrate was concentrated to dryness under reduced pressure, separated Prep-HPLC to give Compound 8 (6mg, The collection time was 8.9-9.3 min), MS m/z (ESI): 449.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.28-8.25 (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)indole (Compound 9)

First step: 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1-yl)acetate 9a

Pd(dppf)Cl ₂ (500 mg, 0.7 mmol), 3b (4.0 g, 14.0 mmol), 7b (4.2 g, 14.0 mmol) and K ₂ CO ₃ (5.8 g, 42.0 mmol) were dissolved in two under nitrogen. In a hexacyclohexane/water (40 mL/2 mL), the mixture was heated to 80 ° C for 16 h. After cooling to room temperature the reaction was completed, insolubles were removed by filtration, the mother liquor was concentrated under reduced pressure was added 100mL of ethyl acetate, the organic layer was washed with water and dried over anhydrous Na ₂ SO _4, the solvent was distilled off under reduced pressure, purified by silica gel column chromatography ( PE: EA = 10:1) gave the title compound 9a (2.0 g), MS m/z (ESI): 314.1 [M+H] ⁺ .

Second step: 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate 9b

Wet palladium on carbon (200 mg, 10%) was added to a solution of 9a (2.0 g, 6.6 mmol) in methanol (20 mL) at room temperature, and reacted under a hydrogen atmosphere for 16 h. The reaction was completed by LC-MS. and concentrated to dryness under reduced pressure to obtain the title compound 9b (1.5g), MS m / z (ESI): 316.1 [m + H] +.

The third step: ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoate 9c

10 mL of a 1.0 M solution of LiHMDS in THF was added to a solution of compound 9b (1.5 g, 4.9 mmol) in anhydrous THF (10 mL), and then reacted at -78 ° C for 1 h, then CH ₃ I (1.4 g, 9.8 mmol) of anhydrous THF solution was slowly added to the reaction system, and the reaction was kept at -78 ° C for 2 h, and then slowly raised to room temperature to continue the reaction for 2 h. After completion of the reaction, the addition of saturated NH ₄ Cl solution (10 mL) to quench the reaction, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous Na ₂ SO _4, the solvent was distilled off under reduced pressure and was monitored by TLC (1 PE:: EA = 5 ) purification by column chromatography on silica gel (: EA = 5: PE 1 ) to give the title compound via 9c (500mg), MS m / z (ESI): 330.2 [m + H] +.

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

NaOH (140 mg, 3.5 mmol) was added to a mixed solution of compound 9c (500 mg, 1.6 mmol) in H ₂ O / MeOH (5 mL / 1 mL), and then reacted at 50 ° C for 2 h. After the reaction was completed, 1 M hydrochloric acid was added to adjust the pH. ~ 1, extracted with ethyl acetate and dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure a crude product (400 mg of) to give the intermediate 9d of the crude product without further purification was used directly in the next step, MS m / z (ESI) : 302.2 [M+H] ⁺ .

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

Under a nitrogen atmosphere, 9d (400mg, 1.3mmol), DPPA (536mg, 1.95mmol) and triethylamine (408mg, 4.0mmol) in toluene / tert-butanol (2mL / 2mL) solution was reacted at 90 ° C for 4h, to be cooled to room temperature and the solvent was distilled off under reduced pressure, purified by silica gel column chromatography (PE: EA = 5: 2 ) to give the target product 9e (350mg), MS m / z (ESI): 342.2 [m + H] +.

Step 6: 1-(4-(6-Fluoroquinolin-4-yl)cyclohexyl)ethylamine 9f

Add NaOH (50 mg, 1.2 mmol) to a mixed solution of compound 9e (350 mg, 0.9 mmol) in dioxane/water (5 mL / 1 mL), and react at room temperature for 2 h. After completion of the reaction, add 1 M hydrochloric acid to adjust the pH~ 1, except the crude product was distilled under reduced pressure (400 mg of) solvent to obtain the 9f, MS m / z (ESI) : 273.2 [m + H] +.

Step 7: 1-(4-Chlorophenyl)-2-cyano-3-(1-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)anthracene (Compound 9)

9f (150mg, crude), 7k (150mg, 0.5mmol) and DIPEA (200mg, 1.6mmol) in DMF was reacted at 90 ° C for 16 h, the reaction was monitored by LC-MS. Isolated Prep-HPLC to give the title compound 9 (10mg), MS m / z (ESI): 450.2 [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, 1.4 Hz, 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)

Compound 9f (150 mg, crude), 2c (100 mg, 0.5 mmol) and DIPEA (200 mg, 1.6 mmol) in DMF was reacted at 90 ° C for 16 h. After LC-MS was monitored, cooled to room temperature and separated by Prep-HPLC. title compound 10 (15mg), MS m / z (ESI): 503.2 [m + H] +.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.77 - 8.72 (m, 1H), 8.07 (dd, J = 9.2, 5.6 Hz, 1H), 7.89 (dt, J = 10.6, 3.0 Hz, 1H), 7.59 (ddd, J=9.4, 6.7, 2.7 Hz, 2H), 7.48–7.27 (m, 5H), 3.46 (d, J = 16.7 Hz, 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 = 12.2 Hz, 3H).

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

First step: methyl N-(4-methoxyphenyl)-N'-(methylsulfonyl)thiocarbimidate 11b

2b (165 mg, 1.0 mmol) and 11a (123 mg, 1.5 mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0 ° C, and then a solution of 2.0 mL of 1.0M LiHMDS in THF was added and stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. 55:45) The target compound 11b (110 mg) was obtained. MS m/z (ESI): 275.0 [M+H] ⁺ .

Second step: N-(((4-methoxyphenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide 11

DIPEA (122.48 mg, 0.95 mmol) was added to a solution of 11b (130 mg, 0.27 mmol) The reaction was heated to 120 ° C for 4 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with water (10 mL*3). (70 mg), Compound 11 was again purified by Prep-HPLC to give the cis or trans isomer, 11A (peak 1, 25 mg, collection time 6.7-7.0 min); 11B (peak 2, 16 mg, collection time 7.3-7.5 min) ). MS m / z (ESI): 402.3 [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 isomer

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

Under a nitrogen atmosphere, 18a (310.11 mg, 2 mmol), 2e (727.02 mg, 2.00 mmol), Pd(dppf)Cl ₂ *CH ₂ Cl ₂ (83.27 mg, 100.00 μmol) and K ₂ CO ₃ (563.27 mg, 4.00 mmol) The reaction mixture was placed in a reaction flask, and a mixed solvent of Dioxane (10 mL) and H ₂ O (2 mL) was added, and the mixture was heated to 90 ° C, and monitored by TLC (PE: EA = 10:1) until the starting material was completely converted. After the reaction was cooled to room temperature, filtered and washed with EtOAc, diluted with 50 mL EtOAc was added, the organic layer was washed with water three times and dried over anhydrous Na ₂ SO _4, after filtration, the filtrate was concentrated to dryness under reduced pressure, was purified by silica gel column chromatography ( PE: EA = 95: 1-90: 10) The desired product 18b (250 mg) was obtained.

Second step: (4-(4-methoxyphenyl)cyclohexyl)carbamic acid tert-butyl ester 18c

18b (263mg, 0.82mmol) was dissolved in MeOH (10mL), 10% Pd / C (100mg, 0.08mmol) was added and reacted under hydrogen atmosphere (1 atm), TLC monitoring (PE: EA=10:1) ) until the raw material is completely converted. After the reaction, the celite was filtered and washed with methanol, and the solvent was evaporated.

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

18c (263.16mg, 818.57μmol) was dissolved in 3.0mL 4N HCl in dioxane solution at room temperature. After 2h reaction, LC-MS monitored the complete conversion of the raw materials. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was obtained. Further purification was carried out directly to the next reaction. MS m/z (ESI): 206.2 [M+H] ^+.

Fourth step: N-(((4-chlorophenyl)amino)((4-(4-methoxyphenyl)cyclohexyl)amino)methylene)methanesulfonamide 18

18d (188.78mg, 765.23μmol), 2c (217.68mg, 765.23μmol) and DIPEA (302.75mg, 2.30mmol) were dissolved in 6.0mL DMF, heated to 100 ° C reaction, TLC monitoring (PE: EA = 5:1) ) until the raw material is completely converted. After the reaction was cooled to room temperature, diluted with 50mL EtOAc was added, washed with water, dried Na ₂ SO ₄ the organic phase was dried over anhydrous, filtered and concentrated to dryness under reduced pressure, Purification by Prep-HPLC to give the cis or trans compound of formula 18 iso Construct, 18A (peak 1, 45 mg, collection time 9.2-9.6 min); 18B (peak 2, 42 mg, collection time 9.7-9.9 min). MS m/z (ESI): 436.1 [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 = 8.8 Hz, 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-trans isomer

First step: methyl N-(4-cyanophenyl)-N'-(methylsulfonyl)thiocarbimidate 25b

Under a nitrogen atmosphere, 25a (79.66 mg, 674.31 μmol) and 2b (112 mg, 561.93 μmol) were dissolved in anhydrous THF (3 mL), cooled to 0 ° C, and then added with 2.5 mL of LiHMDS (561.93 μmol) in THF. Stir at room temperature for 3 h. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc)EtOAc. MS m/z (ESI): 270.0 [M+H] ⁺

Second step: N-(((4-cyanophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide 25

25b (150 mg, 556.91 μmol) and 2 h (97.61 mg, 556.91 μmol) were dissolved in DMF (4 mL), then DIPEA (287.90 mg, 2.23 mmol) was added and heated to 100 ° C for 4 h under microwave conditions. LCMS was used to detect the complete conversion of the starting materials. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was poured into water and extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and purified by Prep-HPLC. The cis or trans isomer of 25 is obtained. 25A (peak 1, 15 mg, collection time 9.8-10.2 min); 25B (peak 2, 111 mg, collection time 10.3-10.8 min). MS m/z (ESI): 397.2 [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 = 8.4 Hz, 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 = 12.8 Hz, 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)

First step: 2-methyl-4-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)pyridine 35c

Add to a mixture of 35a (3.23g, 18.79mmol), compound 35b (5.0g, 18.79mmol), potassium carbonate (7.78g, 56.36mmol) in water (5mL) and dioxane (50mL) under nitrogen. Pd(dppf)Cl ₂ (692.30 mg, 939.36 μmol). The reaction solution was then heated to 90 ° C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was separated and purified by silica gel column chromatography (PE: EA=5:2) to give the desired product 35c (3.5 g).

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

A solution of 35c (3.37 g, 13.84 mmol) and Pd/C (85.85 mg, 1.38 mmol) in methanol was reacted under a hydrogen pressure of a balloon for 3 hours at room temperature. After completion of the reaction, it was filtered and washed with EtOAc.

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

To a solution of the compound 35d (3.1 g, 13.29 mmol) in acetone was added 10 mL of 6M hydrochloric acid at room temperature, and the mixture was stirred at room temperature for 5 h. The solvent was then concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Target product 35e (2.2 g).

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

NH ₄ Cl (282.69 mg, 5.28 mmol) was added to a solution of compound 35e (500 mg, 2. NaBH ₃ CN (121.48 mg, 5.28 mmol) was then added to the reaction system and stirring was continued at room temperature for 16 h. After the reaction was completed, the residue was evaporated to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssssssss Separation and purification (DCM: MeOH = 100:3) gave 35f (300mg). MS m/z (ESI): 1921. [M+H] ⁺ .

Step 5: N-(((4-chlorophenyl)amino)((4-(2-methylpyridin-4-yl)cyclohexyl)amino)methylene)methanesulfonamide 35

DIPEA (135.84 mg, 1.05 mmol) was added to a solution of compound 2c (146.51 mg, 525.53 μmol), 35f (100 mg, 525.53 μmol) in acetonitrile (2 mL). The mixture was heated to 100 ° C under microwave conditions for 1 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure, and then purified and purified to afford compound 35 (18 mg, MS m/z (ESI): 421.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (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 Cis-trans isomer

First step: (4-(4-methylpyridin-3-yl)cyclohex-3-en-1-yl)carbamic acid tert-butyl ester 36b

Adding dioxane to a mixture of 36a (100mg, 730.23μmol), 2e (327.82mg, 949.29μmol), potassium carbonate (201.54mg, 1.46mmol) and Pd(dppf)Cl ₂ (534.53mg, 730.23μmol) under nitrogen protection Hexacyclic (15 mL) and water (5 mL) were heated to 80 ° C for 10 h. LCMS monitored the complete conversion of the starting material reaction. After the completion of the reaction, the mixture was cooled to room temperature. After filtration, the filtrate was diluted with water, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. Purification of compound 36b. MS m/z (ESI): 289.2 [M+H] ⁺ .

Second step: (4-(4-methylpyridin-3-yl)cyclohexyl)carbamic acid tert-butyl ester 36c

36b (80 mg, 277.41 μmol) was dissolved in methanol (6 mL) at room temperature, and Pd/C (10 mg) was added and reacted under a hydrogen atmosphere (1 atm) for 10 h. LCMS monitored the complete conversion of the starting material reaction. After the reaction was completed, the filtrate was evaporated. MS m/z (ESI): 29.21. [M+H] ⁺ .

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

36c (80 mg, 275.48 μmol,) was dissolved in 3.0 mL of 4M HCl in dioxane, and the mixture was stirred at 25 ° C for 1 h. Used directly in the next step. MS m/z (ESI): 191.1 [M+H] ⁺ .

Fourth step: N-(((4-chlorophenyl)amino)((4-(4-methylpyridin-3-yl)cyclohexyl)amino)methylene)methanesulfonamide 36

36d (50mg, 176.41μmol), 2c (61.47mg, 220.51μmol) and DIPEA (57.00mg, 441.02μmol) were dissolved in DMF (5mL) and heated to 125 ° C for 5h. LCMS monitored complete conversion of the starting material. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness under reduced pressure and purified by Prep-HPLC to give compound 36 cis or trans isomer. . 36A (peak 1, 20 mg, collection time 5.8-6.1 min); 36B (peak 2, 15 mg, collection time 6.1-6.5 min). MS m/z (ESI): 421.1 [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 = 4.8 Hz, 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 isomers

第一步：(2，6-二甲基吡啶-4-基)硼酸37b

First step: (2,6-dimethylpyridin-4-yl)boronic acid 37b

37a (100 mg, 537.49 μmol), B ₂ pin ₂ (163.83 mg, 644.99 μmol), KOAc (158.00 mg, 1.61 mmol), Pd(dppf)Cl ₂ (39.34 mg, 53.75 μmol) were placed in a reaction flask under a nitrogen atmosphere. Dioxane (20 mL) was added, and the mixture was heated to 80 ° C and stirred for 10 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness, and then purified to silica gel column chromatography (PE: EA = 1:2) to afford product 37b (60 mg). MS m/z (ESI): 1521. [M+H] ⁺ .

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

37b (80 mg, 529.91 μmol), 2e (182.99 mg, 529.91 μmol), potassium carbonate (146.25 mg, 1.06 mmol) and Pd(dppf)Cl ₂ (58.18 mg, 79.49 μmol) were placed in a reaction flask under nitrogen atmosphere. Water (1.00 mL) and dioxane (5.00 mL) were added, and the mixture was heated to 90 ° C and stirred for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc was evaporated. Isolated and purified intermediate 37c (80 mg). MS m/z (ESI): 303.2 [M+H] ⁺ .

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

37c (80 mg, 264.54 μmol) was dissolved in methanol (5 mL), and palladium carbon (10 mg) was added and stirred under a hydrogen atmosphere (1 atm) for 6 h. After completion of the reaction, the mixture was filtered, and then evaporated, evaporated, evaporated MS m/z (ESI): 305.2 [M+H] ⁺ .

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

</ RTI><RTIgt; The next step is to react. MS m/z (ESI): 205.2 [M+H] ⁺ .

Step 5: N-(((4-chlorophenyl)amino)((4-(2,6-dimethylpyridin-4-yl)cyclohexyl)amino)methylene)methanesulfonamide 37

37e (50 mg, 207.67 μmol), 2c (57.89 mg, 207.67 μmol, FR) and DIPEA (53.68 mg, 415.33 μmol) were dissolved in DMF (5 mL) and heated to 125 ° C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness under reduced pressure, and the cis or trans isomer of compound 37 was purified by Prep-HPLC. 37A (peak 1, 17 mg, collection time 6.5-7.0 min); 37B (peak 2, 15 mg, collection time 7.1-7.4 min). MS m/z (ESI): 435.1 [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) Sulfonamide (Compound 42) and its cis-trans isomer

First step: 2-(4-bromophenoxy)-N,N-dimethylethylamine 42c

42a (500mg, 2.89mmol) and potassium carbonate (997.07mg, 7.23mmol) were added to a 100mL single-mouth bottle, Acetone (30mL) was added, then 42b (499.55mg, 3.47mmol) was added, stirred for 15min and heated to 60 °C reaction. After completion of the reaction, the mixture was cooled to room temperature.

Second step: 2-(4-(1,4-Dioxaspiro[4.5]dec-7-ene-8-yl)phenoxy)-N,N-dimethylethylamine 42d

42c (554 mg, 2.27 mmol), 35b (603.95 mg, 2.27 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (92.66 mg, 113.47 μmol) and K ₂ CO ₃ (782.91 mg, 5.67 mmol) under nitrogen. Place in a reaction flask, add dioxane (15 mL) and H ₂ O (3 mL), and heat to 100 ° C to react. LCMS was monitored until complete conversion of the starting material. After completion of the reaction, the mixture was cooled to room temperature, and the filtrate was evaporated to dryness.

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

42d (720 mg, 2.37 mmol) was dissolved in MeOH (15 mL). EtOAc (EtOAc) After completion of the reaction, the mixture was filtered over EtOAc EtOAcjjjjjj

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

42e (720 mg, 2.36 mmol) was dissolved in EtOAc (10 mL). EtOAc (EtOAc) After the reaction, the pH was made basic with 6M NaOH (aq) solution, EA was extracted, and the organic phase was combined and dried over anhydrous sodium sulfate, filtered and purified by silica gel column chromatography (DCM: MeOH=97:3) (379mg)

Step 5: 4-(4-(2-(Dimethylamino)ethoxy)phenyl)cyclohexylamine 42g

The 42f (379mg, 1.45mmol) was dissolved in MeOH (10mL), was added _{NH 4 AcO (335.32mg, 4.35mmol)} , was heated to 60 deg.] C stirred for 2h. Was added _{NaBH 3 CN (182.25mg, 2.90mmol)} , stirring was continued for 6h, LCMS analysis showed complete conversion of starting material. After completion of the reaction, the mixture was cooled to room temperature. EtOAc (EtOAc m. Further purification was used directly for the next reaction.

Step 6: N-(((4-chlorophenyl)amino)((4-(4-(2-(dimethylamino)ethoxy)phenyl)cyclohexyl)amino)methylene) Sulfonamide 42

Under a nitrogen atmosphere, 42 g (153.06 mg, 571.67 μmol, FR), 2c (162.62 mg, 571.67 μmol, FR) and DIPEA (226.17 mg, 1.72 mmol, 98% purity) were dissolved in DMF (5 mL) and heated to 100 °C reaction for 6h. After the reaction was completed, it was cooled to room temperature, diluted with 50 mL of EtOAc and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated , 42A (peak 1) and 42B (peak 2). The above 42A and 42B were again purified by Prep-HPLC to obtain high purity 42A (7 mg, collection time 5.0-5.8 min) and 42B (24 mg, collection time 6.1-6.4 min). MS m / z (ESI): 493.2 [M + 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 = 4.8 Hz, 2H), 4.14 - 4.12 (t, J = 2.8 Hz, 1H), 3.23 - 3.20 (t, J = 5.2 Hz, 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 = 8.8 Hz, 2H), 4.16-4.13 (t, J = 5.2 Hz, 2H), 3.82-3.80 (m, 1H), 3.00 (s, 3H), 2.97-2.94 (t, J = 5.2 Hz, 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 isomer

First step: methyl N'-methylsulfonyl-N-(4-phenylcyclohexyl)thiocarbimidate 48a

DIPEA (518.74 mg, 4.01 mmol) was added to a solution of compound 2h (175.87 mg, 1.00 mmol) and 2b (200 mg, 1.00 mmol) in acetonitrile (5 mL) and then warmed to 90 ° C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated.

Second step: N-(((4-(2-hydroxyethoxy)phenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide 48

DIPEA (47.50 mg, 367.56 μmol) was added to a solution of compound 48b (28.15 mg, 183.78 μmol) and 48a (60 mg, 183.78 μmol) in acetonitrile (2 mL) at room temperature and heated to 100 ° C for 2 h under microwave conditions. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. and purified by Prep-HPLC to give the cis or trans isomer of the object compound 48. 48A (peak 1, 10 mg, collection time 8.6-9.0 min); 48B (peak 2, 20 mg, collection time 9.4-9.8 min). MS m/z (ESI): 432.3 [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 = 8.8 Hz, 2H), 4.88 (t, J = 5.5 Hz, 1H), 4.13-4.11 (m, 1H), 3.97 (t, J = 5.0 Hz, 2H), 3.71 (dd, J =10.2, 5.3 Hz, 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 = 5.5 Hz, 1H), 3.98 (t, J = 5.0 Hz, 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 = 11.8 Hz, 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 isomer

第一步：N-4-甲氧基苄基-N'-(甲基磺酰基)硫代氨基亚胺酸甲酯86b

First step: N-4-methoxybenzyl-N'-(methylsulfonyl) thioaminoimidate methyl ester 86b

2b (200 mg, 1.00 mmol), 86a (165.18 mg, 1.20 mmol) and DIPEA (259.37 mg, 2.01 mmol) were dissolved in ethanol (20 mL), and the mixture was heated to 75 ° C and stirred for 10 h. LCMS was used to monitor the complete conversion of the starting material. After the reaction was completed, it was cooled to room temperature, and the solvent was removed under reduced pressure and purified by silica gel column chromatography (PE: EA = 1:1) to give the desired product 86b. MS m/z (ESI): 289.1 [M+H] ⁺ .

Second step: N-(((4-methoxybenzyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide 86

86b (50 mg, 173.38 μmol,), 2 h (30.39 mg, 173.38 μmol), and DIPEA (44.81 mg, 346.76 μmol) were dissolved in DMF (2.50 mL), and heated to 125 ° C to stir the reaction for 6 h. LCMS was used to monitor the complete conversion of the starting materials. After the reaction was completed, it was cooled to room temperature, diluted with water, and then extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure and purified by Prep-HPLC. Cis or trans isomer. 86A (peak 1, 25 mg, collection time 9.7-9.9 min); 86B (peak 2, 7 mg, collection time 9.9-10.1 min) two enantiomers. MS m/z (ESI): 416.2 [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 = 5.6 Hz, 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 isomers

First step: (2,3-dimethylpyridin-4-yl)boronic acid 87b

87a (100 mg, 537.49 μmol), B ₂ pin ₂ (163.83 mg, 644.99 μmol), KOAc (158.00 mg, 1.61 mmol) and Pd(dppf)Cl ₂ (39.34 mg, 53.75 μmol) were placed in a reaction flask and added Dioxane (20 mL) was heated to 80 ° C under nitrogen for 10 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness, and purified by silica gel column chromatography (PE: EA = 1:2) to afford 87b (60 mg). MS m/z (ESI): 1521. [M+H] ⁺ .

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

87b (80 mg, 529.91 μmol), 2e (182.99 mg, 529.91 μmol), potassium carbonate (146.25 mg, 1.06 mmol) and Pd(dppf)Cl ₂ (58.18 mg, 79.49 μmol) were placed in a reaction flask, and water was added ( 1.00 mL) and dioxane (5.00 mL) were heated to 90 ° C under nitrogen for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc was evaporated. ) 87c (80mg). 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 (80 mg, 264.54 μmol) was dissolved in methanol (5 mL), Pd/C (10 mg) was added, and the mixture was stirred under hydrogen atmosphere (1 atm) for 6 h. After filtration, the filtrate was concentrated to dryness (EtOAc m. MS m/z (ESI): 305.2 [M+H] ⁺ .

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

87d (60 mg, 197.09 μmol) was added to a solution of EtOAc (4 mL, EtOAc, EtOAc. One step reaction. MS m/z (ESI): 205.2 [M+H] ⁺ .

Step 5: N-((4-chlorophenyl)amino)((4-(2,3-dimethylpyridin-4-yl)cyclohexyl)amino)methylene)sulfonamide 87

87e (50 mg, 207.67 μmol), 2c (57.89 mg, 207.67 μmol, FR) and DIPEA (53.68 mg, 415.33 μmol) were dissolved in DMF (5 mL) and heated to 125 ° C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 87A (peak 1, 20 mg, collection time 8.1-8.4 min); 87B (peak 2, 15 mg, 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 = 5.2 Hz, 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 isomer

First step: methyl N-(2-fluorophenyl)-N'-(methylsulfonyl)thiocarbimidate 88b

88a (148mg, 1.33mmol) and 2b (221.23mg, 1.11mmol) were dissolved in anhydrous THF (7mL) under nitrogen atmosphere, cooled to -5 ° C, then added 1.66mL 1.0M LiHMDS in THF solution, after 3h reaction The reaction was quenched by the addition of aq. EtOAc. EtOAc (EtOAc m. 88b (150 mg). MS m/z (ESI): 263.0 [M+H] ⁺ .

Second step: N-(((2-fluorophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide 88

88b (50 mg, 190.60 μmol), 2 h (40.09 mg, 228.72 μmol, FR) and DIPEA (49.27 mg, 381.21 μmol) were dissolved in DMF (5 mL) and heated to 120 ° C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjj , 88A (peak 1, 10 mg, collection time 8.8-9.2 min); 88B (peak 2, 20 mg, 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 Cis-trans isomer

First step: methyl N-(2,4-difluorophenyl)-N'-(methylsulfonyl)thiocarbimidate 89b

89a (777.31 mg, 6.02 mmol) and 2b (1.0 g, 5.02 mmol) were dissolved in THF (10 mL), cooled to 0 ° C, and slowly added to EtOAc (5.02 mmol, 21 mL). After completion of the reaction, the reaction was quenched with water, and the solvent was evaporated, evaporated, mjjjjjjjjjj

Second step: N-(((2,4-difluorophenyl)amino)((4-(4-methoxyphenyl)cyclohexyl)amino)methylene)methanesulfonamide 89

18d (168.42mg, 661.82μmol,) and 89b (214.81mg, 728.01μmol,) were dissolved in DMF (5.0mL) at room temperature, then DIPEA (426mg, 3.3mmol) was added, and the reaction was increased to 100 ° C for 27h. . After completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc EtOAc. EtOAc EtOAc. (peak 1) and 89B (peak 2). The above 89A and 89B were purified by Prep-HPLC to obtain high purity 89A (50 mg, collection time 7.6-8.0 min) and 89B (43 mg, collection time 11.3-11.5 min). 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 present invention (except compounds 5 and 6) were separated and purified by Agilent 1260 type HPLC, and the column temperatures were both 25 ° C. The other separation conditions are shown in the following table:

Biological evaluation

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

Experimental Example 1. Determination of IDO Enzyme Inhibitory Activity in HeLa Cells

The effect of the compound on intracellular IDO enzyme activity was determined by the NFK Green method.

Reagents: NFK Green fluorescent dye (NTRC); L-tryptophan (Sigma-Aldrich); Recombinant Human IFN-gamma Protein (R&D systems)

experimental method:

Cell culture: Tumor cells were cultured in vitro in a single layer. The culture conditions were: Hela cells, DMEM plus 10% fetal bovine serum, and cultured in an incubator containing 5% CO ₂ at 37 °C. Digestion treatment with trypsin-EDTA was performed 2-3 times a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and plated. The cell concentration (10,000 cells/well of HeLa cells) was adjusted, and the cells were seeded at 70 μL/well into the corresponding wells of a 96-well plate. Label the 96-well plate and place it in the incubator for 24 hours. A test well without cells was set as a negative control group.

Compound preparation: The test compound is dissolved in DMSO to prepare a mother liquid, and an appropriate amount of the mother liquid is aspirated into the culture solution to be mixed, and the drug solution is prepared into a corresponding incubation concentration. 10 μL of the prepared compound solution was added to each well, and the cells were further incubated for 1 h.

IDO stimulation and substrate addition: Add 10 μL of 500 ng/mL IFN-γ (Recombinant Human IFN-gamma Protein) (dissolved in complete medium) while adding 10 μL of sterile 0.5 mM L-tryptophan solution (dissolved in 20 mM) Hepes), incubated for 48 h.

Detection: After the incubation was completed, 25 μL of the supernatant was transferred to a 384-well plate, and 5 μL of NFK Green was added to each well, and incubated at 37 ° C for 4 hours. The fluorescence was measured by a microplate reader, Ex./Em.=400±25 nm/510±20 nm.

Data processing: Compound inhibition rate (%) = (1-Savg / Cavg) × 100%; Savg average fluorescence reading for the test compound, Cavg is the average fluorescence reading the negative control group, IC ₅₀ is calculated by the GraphPad Prism software.

result:

Table 1. Inhibition of IDO Enzyme Activity in Hela Cells by Compounds of the Invention IC 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 experiment

Using Predictor ^TM hERG Fluorescence Polarization Assay Kit (manufacturer: ThermoFisher), according to the kit instructions, the test compound to inhibit hERG potassium ion channel test concentrations of 10 M, the test results in Table 2.

Table 2 Results of inhibition test of compound on hERG

Compound 10μM inhibition rate (%) 2A 9.96±11.83 4A 38.05±8.64 25A 19.33±2.80 89A 7.51±0.82

The results showed that the tested compounds 2A, 4A, 25A and 89A had no significant inhibitory effect on hERG and were less likely to cause prolongation of the QT interval in the heart.

Experimental Example 3: CYP enzyme inhibition test

CYP2D6Cyan Screening Kit和

CYP3A4Red Screening Kit，按照试剂盒说明，分别测定化合物对CYP1A2、CYP2D6和CYP3A4的抑制活性，测试浓度为1μM和10μM。测试结果见表3。 CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, the most important of which are CYP1A2, CYP2D6 and CYP3A4. In the inhibition test of CYP450 enzyme, P450-Glo ^TM CYP1A2 Screening System,

CYP2D6Cyan Screening Kit and

The CYP3A4Red Screening Kit was assayed for inhibitory activity against CYP1A2, CYP2D6 and CYP3A4 according to the kit instructions at 1 μM and 10 μM. The test results are shown in Table 3.

Table 3 Results of inhibition test of compounds on CYP enzyme

The results showed that compounds 2A, 4A, 25A, 87A and 89A had no significant inhibitory effects on CYP1A2, CYP2D6, and CYP3A4 enzymes.

In addition to those described herein, various modifications of the invention are intended to come within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims (23)

a compound of formula I, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound Stable isotope derivative, metabolite or prodrug:

among them: n=0 or 1; R ^{1 is} selected from a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, or a 9-10 membered arylheterocyclyl group; said C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group The 9-10 membered arylheterocyclyl group is optionally substituted with the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C _6- C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic ring The group is optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ Alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -N R ⁷ R ⁸ ; R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC _1- C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl is optionally substituted by OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7-membered a cycloalkyl group, which is optionally substituted by the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₆ hydroxyalkyl group, or R ² , R ³ and a C atom attached thereto form a P ring, the P ring being selected from C ₃ -C ₆ a cycloalkyl group or a 4-7 membered heterocyclic group; R ⁴ and R ⁵ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl optionally Substituted by 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 ring Alkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclyl; said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, -CH ₂ -C ₆ -C ₁₄ An aryl group, a -CH ₂ -5-14 membered heteroaryl group, a C ₃ -C ₇ cycloalkyl group, a 3-14 membered heterocyclic group, a 9-12 membered arylheterocyclyl group may be optionally substituted by the following substituents Substitution: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, 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 a heterocyclic group; said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ hydroxyalkyl group, -OC ₁ -C ₆ alkane The base-OC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted by OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl Group, C ₁ -C ₆ haloalkyl, -OC ₁ -C ₆ alkyl group -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 ; 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 a cyclic group, a 9-12 membered arylheterocyclyl group; said C ₆ -C ₁₄ aryl group, 5-14 membered heteroaryl group, C ₃ -C ₇ cycloalkyl group, 3-14 membered heterocyclic group, The 9-12 membered arylheterocyclyl can be optionally substituted with OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, 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, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic , C ₁ -C ₆ hydroxyalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-1 The 0-membered heterocyclic group may be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , 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 are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C _1- C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, 4-7 membered heterocyclyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl and 4-7 membered heterocyclyl are optionally substituted by the following substituents : OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ together with the N atom to which they are attached form a 4-7 membered heterocyclic group; when a plurality of R ⁷ are present simultaneously , each R ⁷ may be the same or different; when a plurality of R ^{8 are} simultaneously present, each R ⁸ may be the same or different; when a plurality of R ^{9 are} simultaneously present, each R ⁹ may be the same or different; R ^{10 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ alkyl-OC ₁ -C ₆ alkyl, 4-7 membered heterocyclic group, said C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl group, C _{The 1-} C ₆ hydroxyalkyl group, the C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl group and the 4-7 membered heterocyclic group are optionally substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe , NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ and the N and C or S atoms to which they are attached form a 4-7 membered heterocyclic group; when a plurality of R ¹⁰ are present simultaneously, each R ¹⁰ may be the same or different; X is NR ¹¹ or CHNO ₂ ; R ^{11 is} selected from the group consisting of 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, C ₃ -C ₆ cycloalkyl; said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl is optionally substituted by the following substituent: OH , OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group; R ^{13 is} selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- OC ₁ -C ₆ alkyl is optionally substituted by OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7-membered Ring base. A compound according to claim 1, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, or stable isotope compound derivative, metabolite or prodrug thereof, wherein, R ¹ is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 9-10 membered benzo-heterocyclic group; said C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl optionally substituted by OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C _4- alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 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 ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic group; said C ₁ -C ₄ alkyl group, C ₁ - C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5 The -10 membered heteroaryl or 3-10 membered heterocyclic group is optionally substituted with the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₄ alkyl, 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, 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 are} as defined in formula I; Preferably, R ^{1 is} selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group or a 9-10 membered benzoheterocyclyl group; said C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group The benzyl or 9-10 membered benzoheterocyclyl can be optionally substituted with OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C ₃ -C ₆ naphthenic , C ₁ -C ₄ alkoxy, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 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 a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group; said C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, C ₃ -C ₆ Cycloalkyl, -OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 member The heterocyclic group may be optionally substituted by the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₄ alkyl, 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, 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 are} as defined in formula I; Preferably, R ^{1 is} selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group or a 9-10 membered benzoheterocyclyl group; said C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group The base or 9-10 membered benzoheterocyclyl is optionally substituted by a halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ hydroxyalkyl, -C(O)NR ⁷ R ⁸ ; said C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl optionally Substituted by the following substituents: OH, -NR ⁷ R ⁸ , R ⁷ , R ^{8 are} as defined in formula I; More preferably, R ^{1 is} selected from the group consisting of phenyl, quinolyl, pyridyl, oxazolyl,

The phenyl group, quinolyl group, pyridyl group, carbazolyl group,

Optionally substituted with the following substituents: fluoro, chloro, 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 ; More preferably, R ^{1 is} selected from the group consisting of phenyl, quinolyl, pyridyl, and the phenyl, quinolyl, pyridyl group may be optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl , propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy; More preferably, R ^{1 is} selected from the group consisting of phenyl, p-methoxyphenyl, quinolyl, pyridyl,

A compound according to claim 1 or 2, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, or a stable isotopic derivative, metabolite or prodrug of the compound, wherein R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, said C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C _3- C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl are optionally substituted by the following substituents: OH, halogen, CN, C(O a NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group optionally substituted by the following substituents: OH, halogen, CN, C ₁ -C ₄ alkane a C ₁ -C ₄ haloalkyl group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ hydroxyalkyl group, or R ² , R ³ and a C atom attached thereto Forming a P ring together, the P ring being selected from a C ₃ -C ₆ cycloalkyl group or a 4-7 membered heterocyclic group; Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, or R ² , R ³ and the C atom to which they are attached form a P ring, said P ring being selected from C ₃ -C ₅ cycloalkyl; More preferably, R ² and R ³ are each independently selected from hydrogen, methyl, ethyl, propyl, or R ² , R ³ and the C atom to which they are attached form a P ring, said P ring being selected from Cyclopropane, cyclobutane or cyclopentane; More preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; More preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen and methyl. A compound according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotope derivative, metabolite or prodrug of said compound, wherein R ⁴ and R ⁵ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, C _2- C ₄ hydroxyalkyl, C ₂ -C ₄ alkyl-OC ₂ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, C ₂ -C ₄ hydroxyalkane The C ₂ -C ₄ alkyl-OC ₂ -C ₄ alkyl group is optionally substituted by 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 are} as defined in formula I; Preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ hydroxyalkyl, and said C ₁ -C ₄ alkyl is optionally substituted by the following substituents Halogen, -NR ⁷ R ⁸ , R ⁷ , R ^{8 are} as defined in formula I; More preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, -CH ₂ CH ₂ NH(CH ₃ ), - CH ₂ CH ₂ N(CH ₃ ) ₂ ; More preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; More preferably, R ⁴ and R ⁵ are each hydrogen. A compound according to any one of claims 1 to 4, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R ^{6 is} selected from the group consisting of 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 cycloalkyl, 3-10 membered heterocyclic group The 9-12 membered benzoheterocyclyl group may be optionally substituted with the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, 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, C ₁ -C ₄ alkoxy , C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ hydroxyalkyl, OC ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl The base or 3-10 membered heterocyclyl is optionally substituted with OH, CN, halogen, CO ₂ H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ Alkoxy, 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 are} as defined in formula I; Preferably, 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, optionally substituted by a substituent a heteroaryl group, a 3-10 membered heterocyclic group, a 9-12 membered benzoheterocyclyl group, said C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, a 3-10 membered heterocyclic group, 9 The -12-membered benzoheterocyclyl can be optionally substituted by the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ hydroxyalkyl, -OC _2-4 alkyl OH, -OC _2-4 alkyl NR ⁷ R ⁸ , 4-7 membered heterocyclic group, R ⁷ , R ⁸ As defined by Formula I; More preferably, R ^{6 is} selected from the group consisting of phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2,3-dihydrobenzo[b][1 , 4] dioxolyl, the phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2,3-dihydrobenzene And [b][1,4]dioxenyl can 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 NH(CH ₃ ), -OCH ₂ CH ₂ N(CH ₃ ) ₂ , Pyrrolidinyl, 3-hydroxypyrrolidinyl; More preferably, R ⁶ is phenyl, which is optionally fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy Substituted by CN or CN; More preferably, R ⁶ is phenyl which is optionally substituted by fluorine, chlorine, methoxy or CN. A compound according to any one of claims 1 to 5, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound Or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl , C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-7 membered heterocyclic ring a C ₁ -C ₄ alkyl group, a C ₂ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ hydroxyalkyl group, a C ₁ -C ₄ alkyl-OC ₁ group The C ₄ alkyl group and the 4-7 membered heterocyclic group are optionally substituted by OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ and their attached thereto. The N atoms together form a 4-7 membered heterocyclic group; Preferably, R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ naphthenic a C ₂ -C ₄ hydroxyalkyl group, a C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl group, a 4-6 membered heterocyclic group, said C ₁ -C ₄ alkyl group, C ₁ -C ₄ Haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, 4-6 The heterocyclic group is optionally substituted by OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁷ , R ⁸ and the N atom to which they are attached form a 4-7 membered hetero Ring base Preferably, R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, said C ₁ -C ₄ alkyl, C ₂ -C _{The 4} alkoxy group may be optionally substituted with NH ₂ , NHMe, NMe ₂ by the following substituents; More preferably, R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl. A compound according to any one of claims 1 to 6, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R ^{10 is} selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, 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 , C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl and 4-7 membered heterocyclic ring The base is optionally substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ and the N and C or S atoms to which they are attached form 4-7 Metacyclic heterocyclic group; Preferably, R ^{10 is} selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, 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 group, C ₁ -C ₄ haloalkyl group, C ₂ -C ₄ alkoxy group a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ hydroxyalkyl group, a C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl group, a 4-6 membered heterocyclic group, optionally substituted by the following substituents : OH, CN, halogen, NH ₂ , NHMe, NMe ₂ , CO ₂ H, or R ⁹ , R ¹⁰ together with the N and C atoms to which they are attached form a 4-7 membered heterocyclic group; Preferably, R ^{10 is} selected from C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, said C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy may be optionally substituted by Base substitution: NH ₂ , NHMe, NMe ₂ ; More preferably, R ^{10 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl. A compound according to any one of claims 1 to 7, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotope derivative, metabolite or prodrug of said compound, wherein X is NR ¹¹ or CHNO ₂ ; R ^{11 is} selected from the group consisting of hydrogen, OH, CN, NH ₂ , NHMe, NMe ₂ , -SO ₂ R ¹² , -C(O)R ¹³ ; R ^{12 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl; said C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl is optionally substituted by the following substituent: OH , OC ₁ -C ₄ alkyl, NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group; R ^{13 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl is optionally substituted by OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-7 membered heterocyclic group; Preferably, X is selected from NR ¹¹ or CHNO ₂ ; R ^{11 is} selected from the group consisting of hydrogen, OH, CN, NH ₂ , NHMe, NMe ₂ , -SO ₂ R ¹² , -C(O)R ¹³ ; R ^{12 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl; R ^{13 is} selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl, said C ₁ -C ₄ alkyl, C ₃ - C ₅ cycloalkyl, C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl is optionally substituted by OH, halogen, C ₁ -C ₄ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , 4-6 membered heterocyclic group; More preferably, X is selected from NR ¹¹ or CHNO ₂ wherein R ^{11 is} selected from the group consisting of CN, -SO ₂ R ¹² ; R ^{12 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropane, cyclobutane; more preferably, X is selected from NR ¹¹ or CHNO ₂ , wherein R ^{11 is} selected from the group consisting of CN, -SO ₂ Me, -SO ₂ Et, -SO ₂ Pr, -SO ₂ -i-Pr, -SO ₂ -cyclopropane, -SO ₂ -cyclobutane; More preferably, X is selected from the group consisting of N-SO ₂ Me, N-CN, CH-NO ₂ ; More preferably, X is selected from the group consisting of N-SO ₂ Me, N-CN. A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, Or a stable isotope derivative, metabolite or prodrug of the compound having the structure of formula II:

Wherein R ¹ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8. A compound according to claim 9, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound of said compound A stable isotope derivative, metabolite or prodrug having a structure of II-1 or II-2:

Wherein R ¹ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8. A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, Or a stable isotope derivative, metabolite or prodrug of the compound having the structure of formula III:

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8; Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC _1- C ₆ alkyl. A compound according to claim 11, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound of said compound A stable isotope derivative, metabolite or prodrug having the structure of formula III-1 or III-2:

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8; Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl-OC _1- C ₆ alkyl. A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, Or a stable isotope derivative, metabolite or prodrug of the compound having the structure of formula IV:

Wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8; Preferably, R ^{4 is} selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, Said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl optionally substituted by 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 . A compound according to claim 13, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound of said compound A stable isotope derivative, metabolite or prodrug having the structure of Formula IV-1 or IV-2:

Wherein R ¹ , R ⁴ , R ⁵ , R ⁶ and X are as defined in any one of claims 1-8; Preferably, R ^{4 is} selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, Said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl optionally substituted by 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 . A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, Or a stable isotope derivative, metabolite or prodrug of the compound having the structure of formula V:

Wherein R ¹ , P ring, R ⁵ , R ⁶ and X are as defined in any one of claims 1-8. A compound according to claim 15, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound of said compound A stable isotope derivative, metabolite or prodrug having a structure of formula V-1 or V-2:

Wherein R ¹ , P ring, R ⁵ , R ⁶ and X are as defined in any one of claims 1-8. A compound according to any one of claims 1 to 16, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a metabolite or prodrug of said compound, said compound being selected from the group consisting of:

A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, Polymorphs, eutectics, solvates, stable isotope derivatives, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition of claim 18 which is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 17, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound a eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition according to any one of claims 18 or 19. A compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt, polymorph, eutectic or solvate thereof a stable isotope derivative, metabolite or prodrug, or the pharmaceutical composition according to any one of claims 18 or 19, or the pharmaceutical preparation according to claim 20 for use in the prevention or treatment of IDO activity or IDO Use in a drug that mediates an immunosuppression-related disease; Preferably, the diseases associated with IDO activity or IDO mediated immunosuppression include, but are not limited to, tumors, depression, Alzheimer's disease; More preferably, the tumor includes, but is not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrium Cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, 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. A compound according to any one of claims 1 to 17, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt, polymorph, eutectic or solvate thereof A stable isotope derivative, metabolite or prodrug, or a pharmaceutical composition according to any one of claims 18 or 19, or a pharmaceutical preparation according to claim 20 for use in preventing or treating IDO activity or IDO Mediated immune suppression related diseases; Preferably, the diseases associated with IDO activity or IDO mediated immunosuppression include, but are not limited to, tumors, depression, Alzheimer's disease; More preferably, the tumor includes, but is not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrium Cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, 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. A method of 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 according to any one of claims 1-17, or a stereoisomer thereof, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, polymorph, eutectic, solvate, stable isotope derivative, metabolite or prodrug thereof, or any one of claims 18 or 19. The pharmaceutical composition of claim 20, or the pharmaceutical preparation of claim 20, and optionally comprising administering to the individual in need thereof other drugs for treating diseases such as cancer; Preferably, the diseases associated with IDO activity or IDO mediated immunosuppression include, but are not limited to, tumors, depression, Alzheimer's disease; More preferably, the tumor includes, but is not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrium Cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, 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.