WO2019179362A1 - Amidine and guanidine derivatives, preparation method therefor and medical uses thereof - Google Patents

Abstract

Disclosed are amidine and guanidine derivatives of formulas (I-A) and (I-B), preparation method therefor, and medical uses thereof for preventing, relieving and/or treating immunosuppressive diseases or conditions. (I-A), (I-B)

Description

Terpenoids and anthraquinone derivatives, preparation methods thereof and their application in medicine Field of invention

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

Background of the invention

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 1967, the Hayaishi group (Hayaishi O. et al., Science, 1969, 164, 389-396) first discovered IDO in cells, which is a monomeric enzyme containing heme, whose cDNA-encoded protein consists of 403 amino acids. The molecular weight is 45kDa, which is 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), and is the only catalytic color outside the liver. The rate-limiting enzyme for catabolism of lysine. 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 Alzheimer's disease and cataract. In addition, IDO also involves neurological and psychiatric disorders (such as depression, mood disorders) and other diseases caused by abnormally high expression of IDO leading to tryptophan degradation, such as intrauterine fetal rejection, viral infections (such as AIDS), and Immune diseases, bacterial infections such as Lyme disease and streptococcal infections. 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 (NG-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.

IDO inhibitors have great potential to treat and prevent a variety of diseases, but there are currently no drugs that inhibit IDO. 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, their pharmaceutical compositions and related methods.

Summary of invention

One aspect of the present invention provides a safe and effective IDO inhibitor compound having a novel structure, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or Prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound. In some embodiments, the IDO inhibitor is a compound of Formula I-A:

among them:

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

X is NR ¹¹ or CHNO ₂ ;

m=0, 1 or 2;

n=0 or 1;

t=0, 1 or 2;

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

R ² and R 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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , a C ₃ -C ₆ cycloalkyl or a 4-7 membered heterocyclyl optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C _{a 6} alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₆ hydroxyalkyl group; or, R ² and R ³ are bonded to each other The linked C atoms together form a P ring selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group;

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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or a 4-7 membered heterocyclic group optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ hydroxyalkyl;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally The ground is substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C(O ) R ¹⁰ ;

R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclic group, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C (O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, -OC _{1 as described} herein. -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally Substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl group -OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C ( O) R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; or

R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclyl, -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH , halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic ring a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group, an -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl group, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, _{halogen, CO 2 H, C 1 -C} 6 -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₆ ring Group, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl group -OC ₁ -C ₆ alkyl, C ₁ -C ₆ ^{hydroxyalkyl, -C (O) R 10,} -C (O) OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;or

R ⁵ and R ⁶ are bonded to form a 5-14 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-14 membered heteroaryl group, 9-10 membered aryl group And the heterocyclic group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic as described herein , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic ring The group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C( O) R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

R ⁷ , R ⁸ and R 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 and 4-7 membered heterocyclic, 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 can be optionally one or more Substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic group together with the N atom to which they are attached;

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 group and 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 one or more of the following substituents: OH, CN, halogen , NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached;

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

R ^{12 is} selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by one or more of the following Base substitution: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic;

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 and C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- OC ₁ -C ₆ alkyl may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group;

requirement is:

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

(2) When n = 0, m = 1, t = 1, Q is N, X is NR ¹¹ , R ¹¹ is H, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

以及 (3) When n = 0, m = 2, t = 0, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

as well as

(4) When n = 0, m = 0, t = 2, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

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

among them:

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

X is NR ¹¹ or CHNO ₂ ;

m=0, 1 or 2;

t=0, 1 or 2;

R ^{5 is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, and C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, 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 optionally be one or more 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 or -NR ⁹ C(O)R ¹⁰ ;

R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclic group, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C (O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, -OC _{1 as described} herein. -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally Substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl group -OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C ( O) R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; or

R ⁵ and R ⁶ are bonded to form a 5-14 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-14 membered heteroaryl group, 9-10 membered aryl group And the heterocyclic group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic as described herein , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic ring The group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C( O) R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

R ⁷ , R ⁸ and R 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 and 4-7 membered heterocyclic, 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 can be optionally one or more Substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic group together with the N atom to which they are attached;

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 group and 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 one or more of the following substituents: OH, CN, halogen , NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached;

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

R ^{12 is} selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by one or more of the following Base substitution: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic;

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 and C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- OC ₁ -C ₆ alkyl may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula IA or IB of the invention, a stereoisomer, tautomer or mixture thereof, stable isotope derivatization of said compound And a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, and one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or Medicament, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention for the preparation of a disease for the prevention, alleviation and/or treatment of IDO activity Use in a medicament for a condition such as a tumor, depression or Alzheimer's disease.

Another aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention for use in preventing, alleviating and/or treating a disease associated with IDO activity Or a condition (eg, tumor, depression, or Alzheimer's disease).

Another aspect of the invention provides a method of preventing, ameliorating and/or treating a disease or condition associated with IDO activity, such as a tumor, depression or Alzheimer's disease, the method comprising administering to an individual in need thereof an effective dose A compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, the pharmacy of the compound An acceptable salt, eutectic, polymorph or solvate, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention, prepared for the prevention, alleviation and/or treatment due to immunosuppression Use in medicines for diseases or conditions such as tumors, viral infections or autoimmune diseases, and the like.

Another aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or Medicament, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention for use in preventing, alleviating and/or treating a result of immunosuppression A disease or condition (eg, a tumor, a viral infection, or an autoimmune disease, etc.).

Another aspect of the invention provides a method of preventing, ameliorating and/or treating a disease or condition (e.g., a tumor, a viral infection, an autoimmune disease, etc.) caused by immunosuppression, the method comprising administering to an individual in need thereof An effective amount of a compound of Formula IA or IB of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a process for the preparation of a compound of the invention.

Detailed description of the invention

Compound and preparation method

A first aspect of the invention relates to a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or a compound A pharmaceutically acceptable salt, eutectic, polymorph or solvate.

The compounds of the invention include a compound of formula I-A:

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

X is NR ¹¹ or CHNO ₂ ;

m=0, 1 or 2;

n=0 or 1;

t=0, 1 or 2;

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

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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , a C ₃ -C ₆ cycloalkyl or a 4-7 membered heterocyclyl optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C _{a 6} alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₆ hydroxyalkyl group; or, R ² and R ³ are bonded to each other The linked C atoms together form a P ring selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group;

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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or a 4-7 membered heterocyclic group optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ hydroxyalkyl;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally The ground is substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C(O ) R ¹⁰ ;

R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And heterocyclic group, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C (O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, -OC _{1 as described} herein. -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally Substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C (O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; or

R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclyl, -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH , halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic ring a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group, an -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl group, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, _{halogen, CO 2 H, C 1 -C} 6 -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₆ ring Group, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl group -OC ₁ -C ₆ alkyl, C ₁ -C ₆ ^{hydroxyalkyl, -C (O) R 10,} -C (O) OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;or

R ⁵ and R ⁶ are bonded to form a 5-14 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-14 membered heteroaryl group, 9-10 membered aryl group And the heterocyclic group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic as described herein , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic ring The group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C( O) R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

R ⁷ , R ⁸ and R 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 and 4-7 membered heterocyclic, 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 can be optionally one or more Substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic group together with the N atom to which they are attached;

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 group and 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 one or more of the following substituents: OH, CN, halogen , NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached;

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

R ^{12 is} selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by one or more of the following Base substitution: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic;

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 and C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- OC ₁ -C ₆ alkyl may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group;

requirement is:

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

(2) When n = 0, m = 1, t = 1, Q is N, X is NR ¹¹ , R ¹¹ is H, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

以及 (3) When n = 0, m = 2, t = 0, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

as well as

(4) When n = 0, m = 0, t = 2, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

In some embodiments of the invention, R ¹ , R ⁶ are each independently selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, and 9-10 membered arylheterocyclyl, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy Alkyl, -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; C ₁ -C as described herein ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₀ aryl group, The 5-10 membered heteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ Alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C( O) OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C( O) R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₆ alkyl, C _{1 as} described herein -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, The 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, - C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₀ aryl group, The 5-10 membered heteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ - C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, - C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ ,- C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkyl, as described herein, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl The base, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C _1- C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl , -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ .

其中环P′为苯基或5-7元杂芳基，所述苯基、吡啶基、喹啉基、异喹啉基、 苯并咪唑基和5-7元杂芳基可任选地被一个或多个下列取代基取代：OH、F、Cl、CN、NO ₂、CO ₂H、C ₁-C ₃烷基、C ₃-C ₆环烷基、C ₁-C ₃烷氧基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、-C(O)OR ⁷、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸、-NR ⁷R ⁸、-C(O)R ¹⁰、-SO ₂R ¹⁰、C ₆-C ₁₀芳基、5-10元杂芳基或3-10元杂环基；此处所述的C ₁-C ₃烷基、C ₁-C ₃烷氧基、C ₃-C ₆环烷基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、C ₆-C ₁₀芳基、5-10元杂芳基和3-10元杂环基可任选地被一个或多个下列取代基取代：OH、CN、卤素、CO ₂H、C ₁-C ₆烷基、C ₁-C ₆卤代烷基、C ₃-C ₆环烷基、C ₁-C ₆烷氧基、-OC ₁-C ₆烷基-OC ₁-C ₆烷基、C ₁-C ₆羟烷基、-C(O)R ¹⁰、-C(O)OR ⁷、-SO ₂R ¹⁰、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸或-NR ⁷R ⁸； In some preferred embodiments, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolinyl, benzimidazolyl, and

Wherein ring P' is phenyl or a 5-7 membered heteroaryl, said phenyl, pyridyl, quinolyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl optionally being Substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5- 10-membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C as described herein ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can optionally be one Or substituted with more than one of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy a group, -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 ^{1 0} , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O) OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O) R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C as described herein ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5- The 10-membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy;

Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, methyl, CN or methoxy;

Preferably, R ^{1 is} selected from the group consisting of phenyl, pyridyl and quinolyl, which may be optionally substituted by one or more of the following substituents: F, Cl, CN or methoxy base;

Preferably, R ^{1 is} selected from the group consisting of

Preferably, R ^{6 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following substituents: F, Cl, CN or methoxy;

Preferably, R ^{6 is} selected from:

其中环P″为5-6元杂环，所述5-6元杂环可任选地被一个或多个下列取代基取代：OH、F、Cl、CN、NO ₂、CO ₂H、C ₁-C ₃烷基、C ₃-C ₆环烷基、C ₁-C ₃烷氧基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、-C(O)OR ⁷、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸、-NR ⁷R ⁸、-C(O)R ¹⁰、-SO ₂R ¹⁰、C ₆-C ₁₀芳基、5-10元杂芳基或3-10元杂环基；此处所述的C ₁-C ₃烷基、C ₁-C ₃烷氧基、C ₃-C ₆环烷基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、 C ₁-C ₃羟烷基、C ₆-C ₁₀芳基、5-10元杂芳基和3-10元杂环基可任选地被一个或多个下列取代基取代：OH、CN、卤素、CO ₂H、C ₁-C ₆烷基、C ₁-C ₆卤代烷基、C ₃-C ₆环烷基、C ₁-C ₆烷氧基、-OC ₁-C ₆烷基-OC ₁-C ₆烷基、C ₁-C ₆羟烷基、-C(O)R ¹⁰、-C(O)OR ⁷、-SO ₂R ¹⁰、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸或-NR ⁷R ⁸； In other preferred embodiments, R ^{1 is} selected from

Wherein ring P" is a 5-6 membered heterocyclic ring, which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C _1- C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl , -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkane as described herein , C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C _{The 10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy 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 or -NR ⁷ R ⁸ ;

其中环P″为5-6元杂环，所述5-6元杂环可任选地被一个或多个下列取代基取代：OH、F、Cl、CN、NO ₂、CO ₂H、C ₁-C ₃烷基、C ₃-C ₆环烷基、C ₁-C ₃烷氧基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、-C(O)OR ⁷、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸、-NR ⁷R ⁸、-C(O)R ¹⁰、-SO ₂R ¹⁰、C ₆-C ₁₀芳基、5-10元杂芳基或3-10元杂环基；此处所述的C ₁-C ₃烷基、C ₁-C ₃烷氧基、C ₃-C ₆环烷基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、C ₆-C ₁₀芳基、5-10元杂芳基和3-10元杂环基可任选地被一个或多个下列取代基取代：OH、CN、卤素、CO ₂H、C ₁-C ₆烷基、C ₁-C ₆卤代烷基、C ₃-C ₆环烷基、C ₁-C ₆烷氧基、-OC ₁-C ₆烷基-OC ₁-C ₆烷基、C ₁-C ₆羟烷基、-C(O)R ¹⁰、-C(O)OR ⁷、-SO ₂R ¹⁰、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸或-NR ⁷R ⁸； Preferably, R ¹ is

Wherein ring P" is a 5-6 membered heterocyclic ring, which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C _1- C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl , -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkane as described herein , C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C _{The 10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy 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 or -NR ⁷ R ⁸ ;

其可任选地被一个或多个下列取代基取代：F、Cl、CN、甲基、CF ₃、CHF ₂或甲氧基； Preferably, R ^{1 is} selected from

It may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy;

Preferably, R ^{1 is} selected from

In other preferred embodiments, R ^{6 is} selected from the group consisting of -CH ₂ -(C ₆ -C ₁₄ aryl) and -CH ₂ -(5-14 membered heteroaryl), said -CH ₂ -(C ₆ -C ₁₄ aryl) and -CH ₂ -(5-14 membered heteroaryl) may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ - C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, - C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ ,- C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, as described herein, 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 The base, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C _1- C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl , -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -N R ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ^{6 is} selected from -CH ₂ -(C ₆ -C ₁₀ aryl) and -CH ₂ -(5-10 membered heteroaryl), said -CH ₂ -(C ₆ -C ₁₀ aryl) and -CH ₂ - (5-10 membered heteroaryl) optionally substituted with one or more of the following substituents: OH, _{halo, CN, NO 2, CO 2} H, C 1 -C 6 alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkane as described herein Oxy, 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 The heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O) R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ^{6 is} selected from -CH ₂ -phenyl and -CH ₂ -(5-6 membered heteroaryl), said -CH ₂ -phenyl and -CH ₂ -(5-6 membered heteroaryl) Optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ ,- NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ An aryl group, a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group; a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a C ₃ -C ₆ cycloalkyl group, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ ,- ^{_{SO 2 R 10, -C (O}} ) NR 7 R 8, -NR 9 C (O) R 10, -NR 9 SO 2 R 10, -SO 2 NR 7 R 8 -NR ⁷ R ^8;

Preferably, R ^{6 is} selected from -CH ₂ -phenyl and -CH ₂ -pyridyl, and the -CH ₂ -phenyl and -CH ₂ -pyridyl may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl- OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 A heterocyclic group; a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a C ₃ -C ₆ cycloalkyl group, an -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ group _; Alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH , CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkane --OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ⁶ is -CH ₂ - phenyl -CH ₂ - phenyl optionally substituted with one or more of the following substituents: OH, F, Cl, CN , NO 2, CO 2 H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkane Base, -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; C ₁ -C _{3 as} described herein Alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl may optionally be substituted with one or more of the following substituents: OH, CN, _{halogen, CO 2 H, C 1 -C} 6 alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ Hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ⁶ is -CH ₂ - phenyl -CH ₂ - phenyl optionally substituted with one or more of the following substituents: F, Cl, CN, methyl, CF _3, CHF ₂ or Methoxy

Preferably, R ⁶ is -CH ₂ -phenyl, the -CH ₂ -phenyl group may be optionally substituted by one or more of the following substituents: F or Cl;

Preferably, R ⁶ is

In some embodiments of the invention, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ alkyl-OC ₁ -C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH , halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ hydroxyalkyl;

R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or a 4-7 membered heterocyclic group optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ hydroxyalkyl;

R ² and R ³ are bonded to form a P ring together with the C atom to which they are attached, the P ring being selected from a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, S or N;

Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C _1- C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl;

Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl , isopropyl, C ₁ -C ₃ haloalkyl, methoxy, ethoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl; or R ² and R ^{3 are} attached to them The linked C atoms together form a P ring selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, more preferably selected from

More preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and -CH ₂ -cyclopropyl; or R ² and R ³ are bonded together with the C atom to which they are attached. P ring, the P ring is

In some embodiments of the invention, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, and C ₁ - C ₃ alkyl-OC ₁ -C ₃ alkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC _{The 1-} C ₃ alkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C(O)R ¹⁰ ;

Preferably, R ⁴ and R ⁵ are both hydrogen.

In other embodiments of the invention, R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl or 9-10 membered arylheterocyclyl group together with the N atom to which they are attached, said 5-10 membered heteroaryl, 9-10 membered heterocyclyl, and aryl may be optionally substituted with one or more of the following substituents: OH, _{halo, 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; C ₁ -C ₆ alkyl, C ₁ -C _{6 as} described herein 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 The heteroheteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O ) R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl or 9-10 membered arylheterocyclyl group together with the N atom to which they are attached, said 5-10 membered heteroaryl, 9- The 10-membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C( O) NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C as described herein _3- C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and The 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ ,- C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

其可任选地被一个或多个下列取代基取代：OH、F、Cl、CN、NO ₂、CO ₂H、C ₁-C ₃烷基、C ₃-C ₆环烷基、C ₁-C ₃烷氧基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、-C(O)OR ⁷、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸、-NR ⁷R ⁸、-C(O)R ¹⁰、-SO ₂R ¹⁰、C ₆-C ₁₀芳基、5-10元杂芳基或3-10元杂环基；此处所述的C ₁-C ₃烷基、C ₁-C ₃烷氧基、C ₃-C ₆环烷基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、C ₆-C ₁₀芳基、5-10元杂芳基 和3-10元杂环基可任选地被一个或多个下列取代基取代：OH、CN、卤素、CO ₂H、C ₁-C ₆烷基、C ₁-C ₆卤代烷基、C ₃-C ₆环烷基、C ₁-C ₆烷氧基、-OC ₁-C ₆烷基-OC ₁-C ₆烷基、C ₁-C ₆羟烷基、-C(O)R ¹⁰、-C(O)OR ⁷、-SO ₂R ¹⁰、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸或-NR ⁷R ⁸； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl as described herein , -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

其可任选地被一个或多个下列取代基取代：F、Cl、CN、甲基、CF ₃、CHF ₂或甲氧基； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy;

其可任选地被一个或多个下列取代基取代：F或Cl； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F or Cl;

Preferably, R ⁵ and R ⁶ are formed together with the N atom to which they are attached

In such embodiments, R ^{4 is} selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, and C ₁ -C ₃ alkyl-OC ₁ - C ₃ alkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl Optionally substituted with one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C ( O) R ¹⁰ ;

Preferably, R ⁴ is hydrogen.

In some embodiments of the invention, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ alkyl-OC ₁ -C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH , halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ hydroxyalkyl;

R ² and R ³ are bonded to form a P ring together with the C atom to which they are attached, the P ring being selected from a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, S or N;

Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C _1- C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl;

Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl , isopropyl, C ₁ -C ₃ haloalkyl, methoxy, ethoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl; or R ² and R ^{3 are} attached to them The linked C atoms together form a P ring selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, more preferably selected from

并且 More preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and -CH ₂ -cyclopropyl; or R ² and R ³ are bonded together with the C atom to which they are attached. P ring, the P ring is

and

R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₄ aryl group, 5-14 The heteroheteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₆ alkyl, C ₁ -C _{6 as} described herein 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 The heteroheteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O ^{) R 10, -C (O)} OR 7, -SO 2 R 10, -C (O) NR 7 R 8 ^{-NR 9 C (O) R 10} , -NR 9 SO 2 R 10, -SO 2 NR 7 R 8 or -NR ⁷ R ^8;

Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy;

Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, methyl, CN or methoxy;

R ^{5 is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, and C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, 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 optionally be one or more 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 or -NR ⁹ C(O)R ¹⁰ ;

R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-10 membered heteroaryl group, 9-10 membered aromatic The arylheterocyclyl can be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ ring as described herein 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 and 3-10 membered The cyclic group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

Preferably, R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl or 9-10 membered arylheterocyclyl group together with the N atom to which they are attached, said 5-10 membered heteroaryl, 9- The 10-membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C( O) NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C as described herein _3- C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and The 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ ,- C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

其可任选地被一个或多个下列取代基取代：OH、F、Cl、CN、NO ₂、CO ₂H、C ₁-C ₃烷基、C ₃-C ₆环烷基、C ₁-C ₃烷氧基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、-C(O)OR ⁷、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸、-NR ⁷R ⁸、-C(O)R ¹⁰、-SO ₂R ¹⁰、C ₆-C ₁₀芳基、5-10元杂芳基或3-10元杂环基；此处所述的C ₁-C ₃烷基、C ₁-C ₃烷氧基、C ₃-C ₆环烷基、-OC ₁-C ₃烷基-OC ₁-C ₃烷基、C ₁-C ₃羟烷基、C ₆-C ₁₀芳基、5-10元杂芳基和3-10元杂环基可任选地被一个或多个下列取代基取代：OH、CN、卤素、CO ₂H、C ₁-C ₆烷基、C ₁-C ₆卤代烷基、C ₃-C ₆环烷基、C ₁-C ₆烷氧基、-OC ₁-C ₆烷基-OC ₁-C ₆烷基、C ₁-C ₆羟烷基、-C(O)R ¹⁰、-C(O)OR ⁷、-SO ₂R ¹⁰、-C(O)NR ⁷R ⁸、-NR ⁹C(O)R ¹⁰、-NR ⁹SO ₂R ¹⁰、-SO ₂NR ⁷R ⁸或-NR ⁷R ⁸； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl as described herein , -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;

其可任选地被一个或多 个下列取代基取代：F、Cl、CN、甲基、CF ₃、CHF ₂或甲氧基； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy;

其可任选地被一个或多个下列取代基取代：F或Cl； Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F or Cl;

Preferably, R ⁵ and R ⁶ are formed together with the N atom to which they are attached

In some embodiments of the invention, R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C _3- C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₃ alkyl , C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclic ring The group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form together with the N atom to which they are attached 4-7 membered heterocyclic group.

In some embodiments of the invention, R ^{10 is} selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C _3- C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl can be optionally substituted by one or more of the following Substituent substitution: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached .

In some embodiments of the invention, R ^{11 is} selected from the group consisting of CN and -SO ₂ R ¹² .

In some embodiments of the invention, R ^{12 is} selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl Optionally substituted with one or more of the following substituents: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclyl;

Preferably, R ^{12 is} selected from C ₁ -C ₃ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl may be optionally one or more Substituted by the following substituents: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic;

Preferably, R ¹² is methyl and C ₃ -C ₆ cycloalkyl;

Preferably, R ¹² is a methyl group.

In some embodiments of the invention, R ^{13 is} selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, and C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl group, said C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₃ hydroxyalkyl group The C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group.

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

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

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

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

In some embodiments of the invention, the compound of Formula I-A has the structure of Formula II:

Wherein R ¹ , R ⁶ and X are as defined above for formula IA.

In some embodiments of the invention, the compound of Formula I-A has the structure of Formula III:

Wherein R ¹ , R ⁶ , X and R ² are as defined above for formula IA; preferably, R ² is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or -CH ₂ - ( C ₃ -C ₆ cycloalkyl); preferably, R ² is H, methyl, ethyl, cyclopropyl or -CH ₂ -cyclopropyl;

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

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

Wherein R ¹ , R ⁵ , R ⁶ , X, m and t are as defined above for formula IA.

In some embodiments, m=1.

In some embodiments, t=1.

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

In some embodiments, R ¹ is phenyl, which may be optionally substituted by one or more C ₁ -C ₆ alkoxy groups, preferably C ₁ -C ₃ alkoxy groups, more preferably methoxy groups ;

Preferably, R ¹ is

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

Preferably, R ⁶ is

In some embodiments, R ⁵ is hydrogen.

In some embodiments, X is NR ¹¹ , wherein R ¹¹ is —SO ₂ R ¹² ; and wherein R ¹² is C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, more preferably methyl.

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

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

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

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

The method includes the following steps:

First step: Compound II-1 is substituted or coupled with R ¹ -Br or R ¹ -I in the presence of a base to form compound II-2.

The base which can be used in the substitution reaction is ^t BuONa, ^t BuOK, ^t BuOLi, Cs ₂ CO ₃ , LiHMDS, LDA, NaHMDS, KHMDS, K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ or K ₂ CO _{3 ,} etc. The solvent that can be used is toluene, xylene, THF, DME, dioxane, DMF, DMSO or NMP, and the like, and the temperature is from 60 ° C to 140 ° C;

The catalysts which can be used in the coupling reaction (for example, Buchwald-Hartwig reaction) are Pd(OAc) ₂ , Pd ₂ (dba) ₃ , Pd(dba) ₂ , PdCl ₂ , Pd(PPh ₃ ) ₄ , Pd(dppf)Cl. ₂ , Pd (dppf) Cl ₂ *DCM, Pd (acac) ₂ or Pd (allyl) _2, etc., the ligands that can be used are PPh ₃ , XPhos, SPhos, RuPhos, XantPhos, Dppf, BINOL, BINAP or Pcy _3, etc. The base which can be used is ^t BuONa, ^t BuOK, ^t BuOLi, Cs ₂ CO ₃ , LiHMDS, LDA, NaHMDS, KHMDS, K ₃ PO ₄ , Na ₂ CO ₃ , AcOK, NaHCO ₃ or K ₂ CO _{3 ,} etc. The solvent to be used is toluene, xylene, THF, DME, dioxane, DMF, DMSO or NMP, and the like, and the temperature is from 60 ° C to 140 ° C.

The second step:

Method A: Compound II-2 is deprotected in the presence of an acid to give compound II-3.

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

Method B: Prolonging the reaction time (for example, >10 h) under the reaction conditions of the first step, and directly forming a compound II-3 by substituting or coupling reaction of the compound II-1 with R ¹ -Br or R ¹ -I in the presence of a base .

Third step: Compound II-3 is reacted with compound II-4 or II-5 under basic conditions to form a compound of formula II.

The base which can be used is LiHMDS, LDA, NaHMDS, KHMDS, TEA, DIPEA, ^t BuOK, NaH or Cs ₂ CO ₃ and the like. The solvent which can be used is THF, DCM, DCE, DMF, DMSO, CH ₃ CN, 1,4-dioxane or toluene, and the like, and the temperature is from rt to 140 °C.

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

among them:

R ¹ , R ⁶ , X and R ² are as defined above for formula IA;

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

The method includes the following steps:

First step: Compound III-1 is reacted with Compound III-2 in the presence of a base to form Compound III-3.

The base may be LDA, n-BuLi, ^t BuOK, ^t BuONa, ^t BuOLi, NaOH, KOH, NaH, Cs ₂ CO ₃ , LiHMDS, NaHMDS or KHMDS. The solvent that can be used is THF, DCM, DCE, MeOH, EtOH, DMF, CH ₃ CN, 1,4-dioxane or toluene, and the like, and the temperature is from 0 ° C to 120 ° C;

Second step: Compound III-3 is reduced by hydrogenation to give compound III-4.

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

Third step: Compound III-4 is reacted with R ¹ -Br or R ¹ -I in the presence of a base by a substitution or coupling reaction (for example, Buchwald-Hartwig reaction) to give compound III-5.

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

Step 4: Compound III-5 is hydrolyzed under basic or acidic conditions to give compound III-6.

For acidic conditions, the acid which can be used is HCl, H ₂ SO ₄ , TFA, trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid; for basic conditions, the base which can be used is LiOH, NaOH or KOH, etc. . The solvent which can be used is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH ₃ CN, 1,4-dioxane, toluene or a mixed solvent of the above solvent and water, etc., and the temperature is rt to 100 °C.

Step 5: Compound III-6 is rearranged by Curtius to give compound III-7.

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

Step 6: Compound III-7 produces III-8 under acidic or basic conditions.

For acidic conditions, the acid which can be used is HCl, HBr, TFA, H ₂ SO ₄ , HOAc, trifluoromethanesulfonic acid and the like; for basic conditions, the base which can be used is LiOH, NaOH or KOH. The solvent which can be used is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH ₃ CN, 1,4-dioxane, toluene or a mixed solvent of the above solvent and water, etc., and the temperature is rt to 120 °C.

Step 7: Compound III-8 is reacted with II-4 or II-5 under basic conditions to form a compound of formula III.

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

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

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

The method includes the following steps:

First step: Compound IV-1 is reacted with R ¹ -Br or R ¹ -I in the presence of a base by a substitution or coupling reaction (for example, Buchwald-Hartwig reaction) to give compound IV-2.

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

Second step: Compound IV-2 is deprotected in the presence of an acid to give compound IV-3.

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

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

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

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

among them:

R ¹ , R ⁶ and X are as defined above for formula IB;

R ^{a is} selected from the group consisting of benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and Cbz;

The method includes the following steps:

First step: Compound V-1 is reacted with a trifluoromethanesulfonylating reagent in the presence of a base to form compound V-2.

For example, the base is LiHMDS, LDA, NaHMDS, KHMDS, ^t BuOK, NaH or NaOH, etc., and the trifluoromethanesulfonylating reagent is PhNTf ₂ . Alternatively, the base is 2,6-di-tert-butyl-4-methylpyridine and the trifluoromethanesulfonylating reagent is Tf ₂ O. The solvent that can be used is THF, CH ₃ CN, DCM or DCE, etc., at a temperature of -78 ° C to 60 ° C;

The second step: Compound V-2 is reacted with R ¹ -boric acid or R ¹ -borate by a coupling reaction (for example, Suzuki reaction) to give compound V-3.

The catalyst which can be used is Pd(PPh ₃ ) ₄ Pd(dppf)Cl ₂ *DCM, or Pd(dppf)Cl _{2 ,} etc., and the bases which can be used are Cs ₂ CO ₃ , K ₃ PO ₄ , Na ₂ CO ₃ , AcOK. , NaHCO ₃ or K ₂ CO _{3 ,} etc., the solvent that can be used is 1,4-dioxane, DMF, DMSO, CH ₃ CN, or the like, or a mixed solvent of the above solvent and water, the temperature is 60 ° C to 120 ° C;

Third step: Compound V-3 is reduced to compound V-4 under catalytic hydrogenation conditions.

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

Fourth step: Compound V-4 is reacted with compound II-4 or II-5 under basic conditions to form a compound of formula V.

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

Pharmaceutical composition, preparation method and treatment method

A third aspect of the invention provides a pharmaceutical composition comprising a compound of the formula IA or IB of the invention, a stereoisomer, a tautomer or a mixture thereof, the pharmaceutically acceptable compound Accepted salts, eutectics, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compounds, and one or more pharmaceutically acceptable carriers.

A fourth aspect of the invention provides a process for the preparation of a pharmaceutical composition of the invention, which comprises a compound of formula IA or IB of the invention, a stereoisomer, tautomer of said compound or a mixture, a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound with one or more pharmaceutically acceptable Accepted carrier combinations.

A fifth aspect of the invention provides a pharmaceutical preparation comprising a compound of the formula IA or IB of the invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative of the compound A metabolite or prodrug, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition of the invention.

A sixth aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or former of said compound A pharmaceutical composition, a pharmaceutically acceptable salt, a eutectic, a polymorph or a solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in the prevention, amelioration and/or treatment of Use in drugs for diseases or conditions associated with IDO activity, such as tumors, depression, or Alzheimer's disease.

A seventh aspect of the invention provides a compound of formula IA or IB of the invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or former of said compound Medicament, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in prevention, alleviation and/or treatment A disease or condition associated with IDO activity (eg, tumor, depression, or Alzheimer's disease).

An eighth aspect of the invention provides a method of preventing, ameliorating and/or treating a disease or condition associated with IDO activity, such as a tumor, depression or Alzheimer's disease, the method comprising administering to an individual in need thereof an effective dose A compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, the pharmacy of the compound An acceptable salt, eutectic, polymorph or solvate, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and optionally, associated with prevention, alleviation and/or treatment of IDO activity A combination of other agents for a disease or condition (eg, tumor, depression, or Alzheimer's disease).

A ninth aspect of the invention provides a method of preventing, ameliorating and/or treating a disease or condition associated with IDO activity, such as a tumor, depression or Alzheimer's disease, the method comprising administering to an individual in need thereof an effective dose A compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, a pharmaceutically acceptable compound An acceptable salt, eutectic, polymorph or solvate, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and in combination with a PD-1, PDL-1 antibody.

The diseases or conditions associated with IDO activity described herein include, but are not limited to, tumors, depression, Alzheimer's disease, and the like.

The present invention also provides a compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, the pharmaceutical composition of the invention or the pharmaceutical formulation of the invention is prepared for prevention, alleviation and/or treatment due to immunosuppression Use in a medicament for a disease or condition caused by a disease, such as a tumor, a viral infection, or an autoimmune disease.

The present invention also provides a compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in prevention, alleviation and/or treatment due to immunosuppression A disease or condition caused (eg, a tumor, a viral infection, or an autoimmune disease, etc.).

The invention also provides a method of preventing, ameliorating and/or treating a disease or condition (eg, a tumor, a viral infection, an autoimmune disease, etc.) caused by immunosuppression, the method comprising administering an effective dose to an individual in need thereof A compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, the pharmacy of the compound An acceptable salt, eutectic, polymorph or solvate, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and optionally including prevention, amelioration and/or treatment due to immunosuppression A combination of other agents for a disease or condition (eg, a tumor, a viral infection, or an autoimmune disease, etc.).

The invention also provides a method of preventing, ameliorating and/or treating a disease or condition (eg, a tumor, a viral infection, an autoimmune disease, etc.) caused by immunosuppression, the method comprising administering an effective dose to an individual in need thereof A compound of the formula IA or IB of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, the pharmacy of the compound An acceptable salt, eutectic, polymorph or solvate, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and in combination with a PD-1, PDL-1 antibody.

The diseases or conditions caused by immunosuppression according to the present invention include, but are not limited to, tumors, viral infections, autoimmune diseases and the like.

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 are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (this when the group is referred to as "haloalkyl", for example _{CF 3, C 2 F 5,} CHF 2, CH 2 F, CH 2 CF 3, CH 2 Cl or -CH ₂ CH ₂ CF _3, etc.).

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (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.), It is optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 7 carbon atoms, for example 3 to 6 carbon atoms. For example, as used herein The term "C ₃ -C ₇ cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 7 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl) A group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as a methyl substituted cyclopropyl group.

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

The term "alkoxy" as used herein, refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom, preferably a C ₁ -C ₆ alkoxy group or a C ₁ -C ₃ alkoxy group. . 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.

例如，如本文中所使用，术语“C ₆-C ₁₄芳基”意指含有6至14个碳原子的芳族基团，优选为C ₆-C ₁₀芳基，优选为苯基或萘基。芳基可任选地被一个或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO ₂、C ₁-C ₆烷基等)取代。 As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system, and in each case may share two with the cycloalkyl group. Adjacent atoms form a cyclic group, and the point of attachment may be on the aryl group or on the cycloalkyl group. E.g,

For example, as used herein, the term "C ₆ -C ₁₄ aryl" means an aromatic group containing from 6 to 14 carbon atoms, preferably a C ₆ -C ₁₀ aryl group, preferably a phenyl or naphthyl group. . 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 "hydroxyalkyl" means an alkyl hydrogen atom is substituted with one or more hydroxyl groups, for example C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₃ hydroxyalkyl group. Examples thereof include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.

The term "arylheterocyclyl" as used herein, refers to a cyclic group formed by the aryl and heterocyclyl groups sharing two adjacent carbon atoms with each other, the point of attachment of which is on the aryl or heterocyclic group. Wherein an aryl or heterocyclic group is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclyl" means a group containing an arylheterocyclyl group of 9 to 12 ring atoms, particularly phenyl and 5-8 members. 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 group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (heteroaromatic ring means an aromatic ring system containing at least one hetero atom), Having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 7, 8, 9 or 10 ring atoms, and comprising at least one which may be the same or different Heteroatoms (such as oxygen, nitrogen or sulfur), and in each case may share two adjacent atoms with an aryl group, a heterocyclic group or a cycloalkyl group to form a hydrazine group, the point of attachment is On the heteroaryl ring or on other rings. For example, as used herein, the term "5-10 membered heteroaryl" means a heteroaryl group containing from 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, etc., and a cyclo- and derivative thereof, and a cyclo-derivative is not limited to a heteroaryl-heteroaryl group, a heteroaryl-aryl group, or a heteroaryl group. And a heterocyclic or heteroaryl-cycloalkyl group, especially a 5-6 membered heteroaryl and 5-6 membered heteroaryl group, a 5-6 membered heteroaryl phenyl group, a 5-6 membered heteroaryl group. a 5-6 membered heterocyclic group, or a 5-6 membered heteroaryl-C ₄ -C 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.

The term "heterocyclyl," as used herein, refers to a monocyclic or polycyclic group having 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more (in the ring) For example, 1, 2, 3 or 4) are selected from C(=O), O, S, S(=O), S(=O) ₂ and NR (R represents a hydrogen atom or a substituent, for example but It is not limited to a group of an alkyl group or a cycloalkyl group. The term "3-14 membered heterocyclyl" as used herein, means a heterocyclic group containing from 3 to 14 ring atoms, including a 3-10 or 4-7 membered heterocyclic group, examples of which include, but are not limited to, Ethylene oxide, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidine a group, a morpholinyl group, 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 including, but not limited to, a heterocyclic ring Heterocyclyl, heterocyclylcycloalkyl, especially 3-7 membered heterocyclyl 3-7 membered heterocyclic, 3-7 membered heterocyclylcycloalkyl, 3-7 membered heterocyclic ring And a C ₄ -C ₆ cycloalkyl group, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentyloxaziridine, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl , pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, piperidinylmorpholinyl; and bridge or spiro derivative, such as but not limited to:

等。

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 "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 or (2) substituted. 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 invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass or mass which is dominant in nature. A number of atomic substitutions. 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 a mixture of two or more different structural forms in a fast equilibrium, commonly referred to as tautomers. 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, when administered 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 acid addition salts and base addition salts thereof, such as hexafluorophosphate, meglumine salts 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 the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, 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 the body or to the body The above compounds can be converted to the compounds 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 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.

Herein, the bond in the structural formula represented by the wavy line "~~" is intended to mean a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.

表示的结构式中的键意在表示，该结构表示单键或双键。 This article uses

The bond in the structural formula represented is intended to represent a single bond or a double bond.

As used herein, "room temperature" means 15-30 °C.

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 drug-forming properties (e.g., good pharmacokinetic properties, good safety, and/or less side effects).

detailed description

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 this application have the following meanings:

The structure of the compound was confirmed by ( ¹ H NMR) and/or mass spectrometry (MS). The reaction was monitored by thin layer chromatography (TLC) or LC/MS.

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

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

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

The compound can be isolated and purified by chromatography on silica gel, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC), and flash column chromatography (Flash column chromatography).

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

Flash column chromatography was performed using a Biotage flash column chromatograph.

Prep-HPLC was performed on an Agilent 1260 chromatograph.

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.

Intermediate Int-1: methyl N-(4-chlorophenyl)-N'-(methylsulfonyl)thiocarbimidate

The compound Int-1a (59 mg) and the compound Int-1b (100 mg) were placed in a 50 mL three-necked flask under a nitrogen atmosphere, and 5 mL of anhydrous THF was added thereto, and 1.6 mL of a 1.0 M LiHMDS solution in THF was slowly added. After LCMS was used to complete the conversion of the substrate, the reaction was quenched by the addition of 0.5 mL of a saturated NH ₄ Cl solution, concentrated to dryness, and then dissolved in a small amount of DCM, and purified by preparative TLC (PE: EA = 2:1). Int-1 (55 mg).

MS m/z (ESI): 279.0 [M+H] ⁺ .

Intermediate Int-2: Methyl N-(4-cyanophenyl)-N'-(methylsulfonyl)thiocarbimidate

40 mL of a 1.0 M solution of LiHMDS in THF was added to a solution of Int-1b (2.0 g, 10.03 mmol) and Int-2a (1.19 g, 10.03 mmol) in anhydrous THF (20 mL) at -30 ° C. After reacting for 2 hours, the mixture was allowed to react to room temperature for 16 hours. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The target product Int-2 (1.2 g) was obtained.

MS m/z (ESI): 2721. [M+H] ⁺ .

Intermediate Int-3: methyl N-(4-chloro-2-fluorophenyl)-N'-(methylsulfonyl)thiocarbimidate

30 mL of a 1.0 M solution of LiHMDS in THF was added to a solution of Int-1b (1.5 g, 7.23 mmol) and Int-3a (1.10 g, 7.53 mmol) in THF (20 mL) at -30 ° C. After the hour, the reaction was allowed to rise to room temperature for 16 hours. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc) 1-3: 1) The objective product Int-3 (1.0 g) was obtained.

MS m/z (ESI): 297.0 [M+H] ⁺ .

Intermediate Int-4: Methyl N-4-chlorobenzyl-N'-(methylsulfonyl)thiocarbimidate

Int-4a (708 mg, 5.0 mmol), Int-1b (997 mg, 5.0 mmol) and DIPEA (1.29 g, 10.0 mmol) were dissolved in DMF (10 mL) under nitrogen and heated to 100 ° C for 4 h. After cooling to room temperature, it was diluted with EtOAc and washed with EtOAc. EtOAc EtOAc. ).

MS m / z (ESI): 293.0 [M + H] +.

Intermediate Int-5: methyl N-(4-chloro-3-fluorophenyl)-N'-(methylsulfonyl)thiocarbimidate

Int-1b (199mg, 1.0mmol) and Int-5a (218mg, 1.5mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0 ° C, then added 2.0mL 1.0M LiHMDS in THF, added to room temperature Stir for 3 hours. After the reaction was completed, the reaction was quenched with EtOAc EtOAc (EtOAc m. The target product Int-5 (160 mg) was isolated and purified.

MS m/z (ESI): 297.0 [M+H] ⁺ .

Intermediate Int-6: Phenyl N-(4-chlorophenyl)-N'-cyanocarbamoyl imide

4-Chloroaniline (0.16 g, 1.3 mmol), Int-6a (0.3 g, 1.3 mmol), and DIPEA (0.16 g, 1.3 mmol) were dissolved in DMF (5 mL) and reacted at 120 ° C for 1.5 h under microwave conditions. after the reaction was cooled to room temperature, the reaction mixture was poured into water (50mL), extracted EtOAc, the combined organic phase was dried over anhydrous Na ₂ SO _4, the organic phase was concentrated to dryness under reduced pressure to afford intermediate Int-6 (0.3g The crude product was used in the next step without further purification.

MS m/z (ESI): 27.21. [M+H] ⁺ .

Intermediate Int-7: methyl N-(5-chloropyridin-2-yl)-N'-(methylsulfonyl)thiocarbimidate

Int-7a (262.37 mg, 2.0 mmol) was dissolved in 3.0 mL of dry THF under a nitrogen atmosphere, cooled to 0 ° C, and 5.0 mL of 1.0 M LiHMDS in THF was slowly added, followed by Int-1b (419.61 mg, 2.00 mmol) The THF solution (7.0 mL) was added to the mixture at 0 ° C for 4 h. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM. The organic phase was combined and dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated.

MS m/z (ESI): 280.0 [M+H] ⁺ .

Example 1: N-(((4-chlorophenyl)amino)((1-(4-methoxyphenyl)piperidin-4-yl)amino)methylene)methanesulfonamide (Compound 1)

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

Compound 1a (117 mg, 0.5 mmol), 1b (100 mg, 0.5 mmol), Pd ₂ (dba) ₃ (23 mg, 0.025 mmol), RuPhos (23 mg, 0.05 mmol) and ^t BuONa (96 mg, 1.0 mmol) The mixture was placed in a 50 mL three-necked flask, followed by the addition of 4.0 mL of toluene, and the mixture was heated to 100 ° C. The reaction was completed by TLC until complete conversion of the starting material, then cooled to room temperature, filtered and washed with EtOAc. :EA = 5:1), the title compound 1c (100 mg) was obtained.

MS m/z (ESI): 307.3 [M+H] ⁺ .

Second step: 1-(4-methoxyphenyl)piperidin-4-amine (1d)

1c was dissolved in 5.0 mL of 4N HCl in dioxane, and the mixture was reacted at room temperature for 1 hr. The crude product was dissolved in 10.0 mL of DCM, washed with saturated NaHCO ₃ solution. The aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous Na ₂ SO _4, filtered and the solvent was distilled off under reduced pressure. The crude product obtained was used directly in the next reaction.

MS m/z (ESI): 207.1 [M+H] ⁺ .

Third step: N-(((4-chlorophenyl)amino)((1-(4-methoxyphenyl)piperidin-4-yl)amino)methylene)methanesulfonamide (1)

1d (62mg, 0.3mmol), Int-1 (92mg, 0.33mmol) and DIPEA (78mg, 0.6mmol) were dissolved in 3.0mL DMF, heated to 100 ° C reaction until the starting material was completely converted, cooled to room temperature, diluted with EtOAc The organic phase was washed with anhydrous Na ₂ SO ₄ , filtered, evaporated, evaporated, evaporated.

MS m/z (ESI): 437.1 [M+H] ⁺ .

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

Examples 2 to 11: Preparation of Compounds 2 to 11

First step: Intermediates 2A to 11A

Using the synthesis method similar to the first step of Example 1, the first intermediates 2A to 11A of the compounds 2 to 11 were obtained.

Step 2: Intermediates 2B to 11B

Using the synthesis method similar to the second step of Example 1, the second intermediates 2B to 11B of the compounds 2 to 11 were prepared from the corresponding 2A to 11A.

Step 3: Compound 2 to 11

Using a synthetic method similar to the third step of Example 1, the crude product was isolated and purified by Prep-HPLC to give Compounds 2 to 11.

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

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

Under a nitrogen atmosphere, 1a (527 mg, 2.25 mmol), 2a (482.67 mg, 2.25 mmol), Pd ₂ (dba) ₃ (103.12 mg, 112.61 μmol), RuPhos (105.09 mg, 225.23 μmol) and ^t BuONa (649.33 mg, 6.76 mmol) was placed in a 50 mL three-necked flask, followed by the addition of 5.0 mL of toluene, and heated to 100 ° C for 16 h. After completion of the reaction, it was cooled to room temperature, diluted with ethyl acetate (20 mL), and purified by silica gel column chromatography (DCM: MeOH = 20:3) to afford title compound 2c (300 mg).

Second step: N-(((4-chlorophenyl)amino)(((1-(4-methoxyphenyl)piperidin-4-yl)methyl)amino)methylene)methanesulfonamide (12)

DIPEA (46.36 mg, 358.71 μmol) was added to a solution of Int-1 (50 mg, 179.35 μmol) and 2c (39.46 mg, 179.35 μmol) in DMF (2 mL) at room temperature and heated to 95 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed with water (20 mL*3), and then evaporated.

MS m/z (ESI): 4521. [M+H] ⁺ .

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

Examples 13 to 25: Preparation of Compounds 13 to 25

First step: Intermediate 16A-20A

Intermediates 16A to 20A were obtained by a synthetic method similar to the first step of Example 1.

Step 2: Intermediates 13B to 25B

Using the synthetic procedure similar to the first step of Example 12, intermediates 13B to 15B of compounds 13 to 15, intermediates 24B and 25B of compounds 24 and 25 were respectively 4-fluoroiodobenzene, 4-chloro-3-fluoroiodo Benzene, 5-bromo-2-methoxypyridine, 4-bromo-2-fluoro-1-methoxybenzene, 1-bromo-2-fluoro-4-methoxybenzene are obtained by reacting with 2a. Using the synthetic procedure analogous to the second step of Compound 1, the second intermediate of compounds 16-20, 16B-20B, was prepared from the corresponding 16A-20A.

Step 3: Compound 13 to 25

Compounds 13 to 25 were obtained by a synthetic method similar to the second step of Example 12, and the final product was purified by Prep-HPLC.

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

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

3a (817 mg, 3.82 mmol) was dissolved in THF (9 mL), DMF (47 mg, 0.38 mmol) and Et ₃ N (1.16 g, 11.45 mmol), and then (Boc) ₂ O (1.00 g, 4.58 mmol) , reaction at room temperature for 4 h. After the reaction was completed, it was quenched with water and extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate, and filtered, and then filtered and purified by silica gel column chromatography (PE/EA system, 7% EA) to give compound 3b (360 mg, yield 30%).

MS m/z (ESI): 314.0 [M+H] ⁺ .

Second step: 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-2H-benzo[b][1,4]oxazine-4(3H) - tert-butyl carboxylate (3c)

3b (360 mg, 1.15 mmol), 2a (247 mg, 1.15 mmol), Pd ₂ (dba) ₃ (110 mg, 0.12 mmol), RuPhos (56 mg, 0.12 mmol) and ^t BuONa (277 mg, 2.88 mmol) were placed under nitrogen. To a 50 mL single-mouth bottle, toluene (8 mL) was added and heated to 90 ° C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and the reaction system was poured into water and extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate, and filtered and then filtered and purified by silica gel column chromatography (PE/EA system, 10% EA) to afford compound 3c (460 mg, yield 93%).

MS m/z (ESI): 448.3 [M+H] ⁺ .

The third step: (1-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)piperidin-4-yl)methanamine hydrochloride (3d)

3c (460 mg) was dissolved in dioxane (3 mL), then 10.0 mL of 4M HCl in dioxane solution was added and the mixture was monitored by TLC until complete conversion of starting material. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give Compound 3d.

MS m/z (ESI): 248.2 [M+H] ⁺ .

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

3d and compound Int-1 (340 mg, 1.22 mmol) were dissolved in DMF (5 mL) and stirred to dissolve completely, then DIPEA (1.00 g) was added and heated to 80 ° C and stirred for 15 h. After completion of the reaction, the mixture was cooled to room temperature, and the reaction system was poured into saturated brine and extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate.

ESI-MS (m/z): 477.8 [M+H] ⁺ .

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

Example 27: N-(((4-chlorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)amino)methylene)) Sulfonamide (Compound 27)

First step: 2-(1-benzylpiperidin-4-ylidene)propionic acid ethyl ester (4c)

4b (8.58g, 36.00mmol) was dissolved in 50mL THF, cooled to 0 ° C, slowly added NaH (827.63mg, 36.00mmol), after 30min reaction, 4a (5.68g, 30mmol) was added, and the reaction was heated to 70 ° C . After 24 h, the reaction was quenched, cooled to room temperature, and the solvent was evaporated to dryness.

MS m / z (ESI): 274.2 [M + H] +.

Step 2: Ethyl 2-(piperidin-4-yl)propanoate (4d)

4c (3.5 g, 12.80 mmol) was dissolved in anhydrous methanol (40 mL), 680 mg of 10% Pd/C was added, and the mixture was reacted under a hydrogen atmosphere (1 atm), and the mixture was monitored by TLC until the starting material was completely converted. After completion of the reaction, the mixture was filtered over EtOAc EtOAcjjjjjjjjjjj

MS m/z (ESI): 186.1 [M+H] ⁺ .

The third step: ethyl 2-(1-(4-methoxyphenyl)piperidin-4-yl)propanoate (4e)

4d (800mg, 4.3mmol), 4-iodoanisole (843mg, 3.6mmol), Pd ₂ (dba) ₃ (164mg, 0.18mmol), RuPhos (168mg, 0.36mmol) and ^t BuONa (692mg) under nitrogen protection , 7.2 mmol) was placed in a 50 mL three-necked flask, followed by the addition of 15.0 mL of toluene, heated to 100 ° C, and monitored by TLC until complete conversion of the starting material. After completion of the reaction, the mixture was cooled to room temperature, filtered and washed with EtOAc EtOAc.

MS m/z (ESI): 29.2 [M+H] ⁺ .

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

4e (800mg, 2.75mmol) was dissolved in methanol (15mL) and water (5mL), then NaOH (275mg, 6.86mmol) was added, heated to 50 ° C and stirred overnight, after the reaction was completed, the pH was adjusted to 3-4 with 1M hydrochloric acid. The residue was concentrated to dryness to dryness crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssss In the next step.

MS m/z (ESI): 264.2 [M+H] ⁺ .

Step 5: (1-(1-(4-Methoxyphenyl)piperidin-4-yl)ethyl)carbamoyl azide (4g)

The 4f (527mg, 2.0mmol), DPPA (1.46g, 6.0mmol) and Et ₃ N (606mg, 6.0mmol) was dissolved in toluene (10 mL), the reaction was heated to 100 deg.] C, TLC monitored until complete conversion of starting material, the reaction After cooling to room temperature, the solvent was evaporated under reduced pressure.

MS m/z (ESI): 304.2 [M+H] ⁺ .

Step 6: 1-(1-(4-Methoxyphenyl)piperidin-4-yl)ethylamine (4h)

4g (303mg, 1.0mmol) was dissolved in MeOH (20mL), NaOH (1.6g, 40.0mmol) aqueous solution (5.0mL) was added, and it was reacted at room temperature for 2 hours, then heated to 95 ° C for 96h, and then cooled to room temperature after completion of the reaction. The pH was adjusted to 3-4 with 1N HCl. The solvent was evaporated under reduced pressure. EtOAc (EtOAc m.) Used directly in the next step.

MS m/z (ESI): 235.3 (M-HCl-1).

Step 7: N-(((4-chlorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)amino)methylene) Sulfonamide

4h (234mg, 1.0mmol), Int-1 (352mg, 1.2mmol) and DIPEA (645mg, 5.0mmol) were dissolved in 10.0mL DMF, heated to 100 ° C for 21h, after the reaction was cooled to room temperature, diluted with EtOAc The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, evaporated, evaporated.

MS m/z (ESI): 464.9 [M+H] ⁺ .

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

Example 28: 1-(4-Chlorophenyl)-2-cyano-3-(1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)indole (Compound 28 )

4h (40mg, 0.15mmol), Int-6 (48mg, 0.18mmol) and DIPEA (39mg, 0.30mmol) were dissolved in 3.0mL DMF, heated to 100 ° C reaction until the starting material was completely converted, after the reaction was completed, cooled to room temperature. dried diluted with EtOAc and washed with water was added the organic layer was dried over anhydrous Na ₂ SO _4, filtered and the solvent was distilled off under reduced pressure, purification by Prep-HPLC to give target compound 28 (15mg).

MS m/z (ESI): 4121. [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.38 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.99-6.96 (m, 2H), 6.85-6.81 (m) , 2H), 3.88-3.85 (m, 1H), 3.74 (s, 3H), 3.53-3.49 (m, 2H), 2.61-2.54 (m, 2H), 1.88-1.81 (m, 2H), 1.57-1.46 (m, 3H), 1.23 (d, J = 6.8 Hz, 3H).

Example 29: N-(((4-Chloro-2-fluorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)amino) Methyl)methanesulfonamide (compound 29)

4h (70mg, 0.30mmol), Int-3 (106mg, 0.36mmol) and DIPEA (116mg, 0.90mmol) were dissolved in 3.0mL DMF, heated to 100 ° C reaction until the starting material was completely converted, after the reaction was completed, cooled to room temperature, dried diluted with EtOAc and washed with water was added the organic layer was dried over anhydrous Na ₂ SO _4, filtered and the solvent was distilled off under reduced pressure, purification by Prep-HPLC to give target compound 29 (23mg).

MS m/z (ESI): 483.1 [M+H] ⁺ .

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

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

There is one chiral center in compound 29 and thus has the (S)-isomer and the (R)-isomer. Two isomers can be obtained by chiral separation. Specifically, compound 29 was separated by a chiral column under the separation conditions described below to give compound 29A (peak 1, RT = 5.25 min) and compound 29B (peak 2, RT = 6.63 min).

Instrument: Shimadzu LC-20AT; column: CHIRALCEL OZ-H (OZH0CD-VF004) (0.46 cm ID × 15 cm L); column temperature: 35 ° C; detection wavelength: UV 254 nm; flow rate: 1.0 mL / min; mobile phase: N-hexane/ethanol = 50%: 50%.

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

Compound 29B: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.81 (br, 1H), 8.53 (br, 0.5H), 7.53 (s, 1H), 7.35-7.29 (m, 2.5H), 6.89 ( d, J=9.2 Hz, 2H), 6.82-6.79 (m, 2H), 3.82-3.77 (m, 1H), 3.68 (s, 3H), 3.56 (br, 2H), 2.80 (br, 3H), 2.58 -2.50 (m, 2H), 1.85-1.71 (m, 2H), 1.55-1.33 (m, 3H), 1.23-1.05 (m, 3H).

Example 32: N-(((4-chloro-3-fluorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)amino) Methyl)methanesulfonamide (compound 30)

4h (19mg, 0.08mmol), Int-5 (29mg, 0.96mmol) and DIPEA (52mg, 0.40mmol) were dissolved in 3.0mL DMF, heated to 100 ° C reaction until the starting material was completely converted, after the reaction was completed, cooled to room temperature, diluted with EtOAc and washed with water was added, the organic layer was dried over anhydrous Na ₂ SO _4, filtered and the solvent was distilled off under reduced pressure, purification by Prep-HPLC to give the title compound 30 (5mg).

MS m/z (ESI): 483.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.46 (m, 1H), 7.36 (br, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.03-6.98 (m, 2H), 6.88 -6.84 (m, 2H), 3.90-3.83 (m, 1H), 3.77 (s, 3H), 3.58-3.55 (m, 2H), 3.00 (s, 3H), 2.66-2.62 (m, 2H), 1.95 -1.87 (m, 2H), 1.57-1.52 (m, 3H), 1.35-1.27 (m, 3H).

Example 33: N-(((5-chloropyridin-2-yl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)ethyl)amino)methylene Methanesulfonamide (Compound 31)

Compound 4h (146 mg, 0.5 mmol, 80% Purity), Int-7 (155 mg, 0.5 mmol, 90% Purity) and DIPEA (330 mg, 2.5 mmol) were dissolved in DMF (5.0 mL). The reaction was carried out at 100 ° C for 22 h. After the reaction was completed, the mixture was cooled to EtOAc. The organic phase was combined and dried over anhydrous sodium sulfate (MgSO4)

MS m/z (ESI): 466.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (d, J = 8.4 Hz, 1H), 9.88 (s, 1H), 9.32 (d, J = 2.0 Hz, 1H), 7.95-7.92 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 3.97 -3.89 (m, 1H), 3.67 (s, 3H), 3.58-3.52 (m, 2H), 2.97 (s, 3H), 2.57-2.50 (m, 2H), 1.81-1.69 (m, 2H), 1.61 -1.53 (m, 1H), 1.44-1.33 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H).

Example 34: N-(((4-Chlorophenyl)amino)((1-(1-(6-methoxypyridin-3-yl)piperidin-4-yl)ethyl)amino) Methylene Methanesulfonamide (compound 32)

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

4d (205mg, 1.0mmol, 90% Purity), 5a (287mg, 1.2mmol), Pd ₂ (dba) ₃ (46mg, 0.05mmol), Ruphos (47mg, 0.1mmol) and sodium tert-butoxide (under nitrogen) 196 mg, 2.00 mmol) was dissolved in toluene (5.0 mL) and heated to 100 ° C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature, filtered over Celite, and evaporated to dryness.

Second step: 2-(1-(6-methoxypyridin-3-yl)piperidin-4-yl)propanoic acid (5c)

5b (150 mg, 0.5 mmol, 95% Purity) was dissolved in methanol (5.0 mL), NaOH (52 mg, 1.28 mmol) in water (2.0 mL) was added and the mixture was warmed to 50 ° C and was monitored by TLC (PE: EA) =5:1) until the starting material is completely converted. After completion of the reaction, the mixture was cooled to room temperature, and the pH was adjusted to 3-4 with 1N HCl. The obtained crude product was filtered with EtOAc EtOAc EtOAc.

MS m/z (ESI): 265.2 [M+H] ⁺ .

Third step: (1-(1-(6-methoxypyridin-3-yl)piperidin-4-yl)ethyl)carbamoyl azide (5d)

5c (147 mg, 0.5 mmol, 95% Purity), triethylamine (155 mg, 1.50 mmol), and DPPA (372 mg, 1.50 mmol) were dissolved in toluene (5.0 mL) under nitrogen and heated to 80 ° C for 1 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. The crude product was dissolved in EtOAc (EtOAc: EtOAc:EtOAc:

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

5d (95mg, 0.3mmol) was dissolved in methanol (10mL), NaOH (25mg, 0.6mmol) in water (2mL) was added, and it was reacted at room temperature and monitored by TLC (PE:EA=5:1) until the starting material is complete Conversion. Then a solution of NaOH (464 mg, 11.6 mmol) in water (2 mL) was added and the mixture was warmed to 95 ° C for 96 h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, This crude product was used in the next reaction without further purification.

MS m/z (ESI): 236.2 [M+H] ⁺ .

Step 5: N-(((4-chlorophenyl)amino)((1-(1-(6-methoxypyridin-3-yl)piperidin-4-yl)ethyl)amino)) Methanesulfonamide (32)

The crude product of 5e obtained in the previous step and int-1 (82 mg, 0.28 mmol) were dissolved in DMF (5.0 mL), and DIPEA (258 mg, 1.96 mmol) was added and reacted at 100 ° C for 9 h. The reaction mixture was cooled to rt. The organic phase was combined and dried over anhydrous sodium sulfate.

MS m/z (ESI): 466.1 [M+H] ⁺ .

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

Example 35: N-(((4-chlorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)propyl)amino)methylene)) Sulfonamide (Compound 36)

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

6b (4.63g, 18.00mmol) was dissolved in 50mL THF, cooled to 0 ° C, slowly added NaH (689.70mg, 18.00mmol), after 30min reaction, add 6a (3.57g, 15mmol), add to the temperature of 80 ° C 15h. After the reaction was completed, the mixture was cooled to EtOAc. The organic phase was combined, dried over anhydrous sodium sulfate and evaporated.

The second step: ethyl 2-(piperidin-4-yl)butanoate (6d)

6c (3.3 g, 9.96 mmol) was dissolved in MeOH (50 mL), EtOAc (EtOAc) (EtOAc) 1) Until the starting material is completely converted. After the reaction, the mixture was filtered over EtOAc EtOAc EtOAcjjjjjjj

MS m/z (ESI): 200.2 [M+H] ⁺ .

The third step: ethyl 2-(1-(4-methoxyphenyl)piperidin-4-yl)butanoate (6e)

6d (221 mg, 1.0 mmol, 90% Purity), 1a (286 mg, 1.20 mmol), Pd ₂ (dba) ₃ (46 mg, 0.05 mmol), Ruphos (48 mg, 0.1 mmol) and sodium tert-butoxide (196 mg, 2.00) Methyl) was placed in a 100 mL round bottom flask, toluene (5.0 mL) was added under nitrogen and heated to 100 ° C for 1 h. After the completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated.

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

6e (100 mg, 0.29 mmol, 90% Purity) was dissolved in water (2.0 mL), and a solution of NaOH (120 mg, 2.95 mmol) in methanol (5 mL) was added and heated to 90 ° C for 17 h. After completion of the reaction, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCI, and the solvent was evaporated to dryness. The obtained crude product was dissolved in a mixed solvent (50 mL) of DCM:MeOH = 5:1. Filtration and evaporation of the solvent <RTI ID=0.0>

MS m/z (ESI): 278.2 [M+H] ⁺ .

Step 5: (1-(1-(4-Methoxyphenyl)piperidin-4-yl)propyl)carbamoyl azide (6g)

The crude product of 6f in the previous step, DPPA (191 mg, 0.77 mmol) and triethylamine (79 mg, 0.77 mmol) were dissolved in toluene (5.0 mL) under nitrogen and then heated to 80 ° C for 1 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness, mjjjjjjjj

MS m/z (ESI): 318.2 [M+H] ⁺ .

Step 6: 1-(1-(4-Methoxyphenyl)piperidin-4-yl)propan-1-amine hydrochloride (6h)

6g (60mg, 0.17mmol, 90% Purity) was dissolved in methanol (10.0mL), NaOH (20mg, 0.51mmol) in water (2.0mL) was added, reacted at room temperature for 30min, then added NaOH (253.09mg, 6.20mmol) A solution of water (2.0 mL) was then heated to 120 ° C for 96 h. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was adjusted to 3-4 with 1N HCl.

MS m/z (ESI): 249.3 [M+H] ⁺ .

Step 7: N-(((4-Chlorophenyl)amino)((1-(1-(4-methoxyphenyl)piperidin-4-yl)propyl)amino)methylene) Sulfonamide (36)

The crude product obtained in the previous step and the mixture of Int-1 (35 mg, 0.12 mmol) and DIPEA (95 mg, 0.72 mmol) were dissolved in DMF (5.0 mL), and heated to 100 ° C for 16 h. After the reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc.

MS m/z (ESI): 479.1 [M+H] ⁺ .

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

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

Compound 4h (146 mg, 0.5 mmol, 80% Purity), Int-7 (163 mg, 0.5 mmol, 90% Purity) and DIPEA (330 mg, 2.5 mmol) were dissolved in DMF (5.0 mL). Heat to 100 ° C for 16 h. After the reaction was completed, the mixture was cooled to EtOAc. The organic phase was combined and dried over anhydrous sodium sulfate.

MS m/z (ESI): 479.1 [M+H] ⁺ .

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

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

First step: ethyl 2-(1-phenylpiperidin-4-yl)propanoate (7b)

7a (250 mg, 1.2 mmol), 4d (206 mg, 1 mmol, 90% Purity), Pd ₂ (dba) ₃ (46 mg, 0.05 mmol), Ruphos (48 mg, 0.1 mmol) and sodium tert-butoxide (under nitrogen) 196.12 mg, 2.00 mmol) was dissolved in toluene (5.0 mL) and heated to 100 ° C for 2.5 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness, mjjjjjjj

MS m/z (ESI): 262.2 [M+H] ⁺ .

Step 2: 2-(1-Phenylpiperidin-4-yl)propionic acid (7c)

7b (240mg, 0.9mmol) was dissolved in methanol (10.0mL), NaOH (112mg, 2.75mmol) in water (2.0mL) was added, heated to 50 ° C reaction, TLC (PE: EA = 5:1) monitoring Until the raw materials are completely converted. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated to dryness. The obtained crude product was dissolved in a mixed solvent of DCM:MeOH = 5:1, filtered, and then evaporated. Dry solvent gave the crude product of 7c, which was taken to the next step without further purification.

MS m/z (ESI): 2321. [M+H] ⁺ .

The third step: (1-(1-phenylpiperidin-4-yl)ethyl)carbamoyl azide (7d)

The crude product of 7c obtained in the previous step, DPPA (744 mg, 3.0 mmol) and triethylamine (309 mg, 3.0 mmol) were dissolved in toluene (10.0 mL) under nitrogen atmosphere and heated to 80 ° C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated to dryness, mjjjjjjj

MS m / z (ESI): 274.1 [M + H] +.

The fourth step: 1-(1-phenylpiperidin-4-yl)ethylamine hydrochloride (7e)

7d (222mg, 0.73mmol, 90% Purity) was dissolved in methanol (10.0mL), a solution of NaOH (89.60mg, 2.20mmol) in water (1.0mL) was added, and reacted for 1h at room temperature, then added NaOH (1.18g, 28.97mmol) A solution of water (1.0 mL) was heated to 95 ° C for 40 h. TLC (PE: EA = 5:1) was monitored until complete conversion of the starting material. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated to dryness under vacuo. The obtained crude product was dissolved in a mixed solvent of DCM: MeOH = 5:1, and filtered, and then evaporated to dryness to give the crude product of 7e.

MS m/z (ESI): 205.2 [M+H] ⁺ .

Step 5: N-(((4-Chlorophenyl)amino)((1-(1-phenylpiperidin-4-yl)ethyl)amino)methylene)methanesulfonamide (40)

The crude product of 7e obtained in the previous step, Int-1 (352 mg, 1.20 mmol) and DIPEA (528 mg, 4.00 mmol) were dissolved in DMF (10.0 mL) under nitrogen and then heated to 95 ° C for 15 h. After the reaction was completed, the mixture was cooled to EtOAc. The combined organic phases were dried over anhydrous sodium sulfate and filtered and evaporated, evaporated

MS m/z (ESI): 435.1 [M+H] ⁺ .

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

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

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

LiHMDS (1.0 M, 11.00 mL) was dissolved in 10 mL anhydrous THF and cooled to -78. A solution of 8a (2.38 g, 10.0 mmol) in THF (10 mL) was added slowly, and the mixture was reacted at -78 ° C for 30 min. A solution of 8b (4.01 g, 11.00 mmol) in THF (10 mL) was then slowly added and the mixture was stirred and maintained at -78 C for 2 h. The coolant was then removed and the reaction was slowly warmed to room temperature and allowed to react for 2 h. After completion of the reaction, the reaction was quenched with EtOAc EtOAc. The organic phase was combined and dried over anhydrous sodium sulfate.

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

8d (1.44g, 9.3mmol), 8c (3.25g, 8.45mmol), Pd(dppf)Cl ₂ *CH ₂ Cl ₂ (352mg, 0.42mmol) and potassium carbonate (2.38g, 16.9mmol) Place in a 100 mL reaction flask, add DMF (20 mL) and water (5 mL), then warm to 90 ° C for 2 h. After the reaction was completed, the mixture was cooled to EtOAc. The filtrate was washed with water, and the organic layer was dried (MgSO4)

MS m/z (ESI): 324.1 [M+H] ⁺ .

The third step: 4-(4-methoxyphenyl) piperidine (8f)

8e (700 mg, 2.16 mmol) was dissolved in methanol (30 mL), 10% Pd / C (115.18 mg, 108.23 μmol) was added and reacted under a hydrogen atmosphere (1 atm) and monitored by TLC until the starting material was completely converted. After the reaction was over, the mixture was filtered over Celite and washed with MeOH. The solvent was evaporated to dryness crystals crystals crystals crystals

MS m / z (ESI): 192.2 [M + H] +.

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

8f (60 mg, 0.30 mmol), Int-1 (88 mg, 0.30 mmol) and DIPEA (196 mg, 1.49 mmol) were dissolved in DMF (5.0 mL) and heated to 100 ° C for 8 h. The reaction mixture was cooled to rt. The organic phase was combined and dried over anhydrous sodium sulfate (MgSO4)

MS m/z (ESI): 4221. [M+H] ⁺ .

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

Separation and purification method:

In the present invention, except for the compound 32, which was separated and purified by Waters type HPLC, the other compounds 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 invention is further described and illustrated in the following examples, which are not intended to limit the scope of the invention.

Experimental Example 1. Determination of the inhibitory effect of compounds on IDO enzymes 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 program:

Hela cells were cultured in complete medium (DMEM containing 10% fetal bovine serum) (37 ° C, incubator with 5% CO ₂ ). 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 (10000 cells/well) was adjusted, and the cells were seeded in a 96-well plate at a dose of 70 μL/well, and cultured in an incubator for 24 hours.

The test compound is made into a mother liquid in DMSO, and an appropriate amount of the mother liquid is aspirated into the complete medium to be mixed, and the solution of the test compound is prepared at a corresponding concentration. 10 μL of the test compound solution was added to each well and incubated for 1 h. A well with only DMSO was set as a negative control group.

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

After the incubation was completed, 25 μL of the supernatant was transferred to a 384-well plate, 5 μL of NFK Green was added to each well, and the plate was sealed and incubated at 37 ° C for 4 h. 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 of the test compound, Cavg 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) 4 5.5 12 8.1 13 29.4 15 10.1 16 8.4 17 10.8 18 6.2 19 14.5 20 13.3 twenty three 23.3 twenty four 17.0 25 14.2 27 3.6 29 4.8 29A 1.5 30 3.9 32 8.0 36 9.6 40 15.3 41 10.9

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

Experimental Example 2: hERG test

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

Table 2. Results of inhibition test of compounds on hERG

Compound IC ₅₀ (μM) 15 >10 29A >10 32 >10 40 >10 41 >10

The results indicate that the compounds of the present invention (e.g., Compounds 15, 29A, 32, 40, and 41) have no significant inhibitory effect on hERG, resulting in a small likelihood of prolonged QT interval in the heart.

Experimental Example 3: CYP enzyme inhibition test

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.

CYP2D6 Cyan Screening Kit和

CYP3A4 Red 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。测试结果见表3A。 In the test for the inhibition of CYP450 enzyme by fluorescence, the P450-Glo ^TM CYP1A2 Screening System,

CYP2D6 Cyan Screening Kit and

For the CYP3A4 Red Screening Kit, the inhibitory activities of the compounds against CYP1A2, CYP2D6 and CYP3A4 were determined according to the kit instructions. The test results are shown in Table 3A.

Table 3A. Results of inhibition test of compounds on CYP enzyme

The inhibitory effect of Compound 29A on CYP3A4 was determined by LC-MS. The specific test is as follows:

Reagents and controls:

CYP3A4 probe substrate is selected from testosterone and midazolam. The positive inhibitor is ketoconazole. The incubation medium is mixed human liver microsome (HLM).

experiment method:

A mixture of probe substrate (50 μl), PBS (49 μl), test compound 29A or positive control compound ketoconazole (1 μl) and HLM (50 μl) was pre-incubated (at 37 ° C) for 5 min, then NADPH (50 μl) was added. ) and incubated for another 30 minutes. Among them, the incubation concentration of HLM was 0.1 mg/ml, the concentration of testosterone was 50 μM, and the concentration of midazolam was 2 μM. After the reaction time, 600 μl of internal standard ice acetonitrile was added to the testosterone reaction incubation solution to terminate the reaction, and 800 μl of internal standard ice acetonitrile was added to the reaction solution of midazolam to terminate the reaction. All samples were vortexed and centrifuged to obtain a supernatant for testing.

test methods:

LC-MS/MS: Mass spectrometry using Sciex API 5500. The liquid chromatography was performed using a Waters ACQUITY UPLC I-CLASS system. The column was Hypersil GOLD C ₁₈ (2.1 mm x 50 mm, 1.9 μm). Mobile phase: phase A was water + 0.1% formic acid, phase B was acetonitrile; flow rate was 0.4 ml/min, column temperature was 40 °C. The ion source is the ESI source positive ion mode and the scanning mode is multiple reaction monitoring (MRM).

In the vehicle group (DMSO) as the negative control, the main metabolite concentration determination at a different compound concentrations of substrate to produce a probe to determine the compound of CYP3A4 half maximal inhibitory concentration (IC _50).

Table 3B. Inhibition of CYP3A4 by Compound 29A

Compound 29A showed no significant inhibition of CYP3A4 (IC ₅₀ >10 μM).

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

Experimental Example 4: Pharmacokinetics (PK) Study in Rats

The compounds of the present invention were administered to the SPF male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics.

All animals were fasted for 10-14 hours prior to dosing and returned to food 4 hours after dosing. The doses of IV and PO were 1 mg/kg and 5 mg/kg, respectively, the medium of IV was 5% DMSO: 5% Solutol: 90% physiological saline, and the solvent of PO was 0.5% MC (sodium methylcellulose). Blood was collected before IV administration (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration, before PO administration (0 h) and after administration 0.25, 0.5, Blood was collected at 1, 2, 4, 6, 8 and 24 h, blood was anticoagulated with EDTA.K ₂ , and plasma samples were obtained by centrifugation within 30 min after blood collection and stored at -80 ° C for testing. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS. Mass spectrometry using Sciex API 5500, liquid chromatography using Waters ACQUITY I-CLASS system; chromatography column using Hypersil GOLD C ₁₈ (2.1 mm × 50 mm, 1.9 μm); mobile phase: phase A was 0.1% aqueous formic acid, phase B was acetonitrile; The flow rate is 0.5 ml/min, the column temperature is 40 ° C; the ion source is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM). The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The results are shown in Table 4 below:

Table 4. Pharmacokinetic parameters of the compound

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

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 (40)

a compound of formula IA, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutically acceptable compound of said compound Salt, eutectic, polymorph or solvate:

R ^{1 is} selected from the group consisting of C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclyl, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9 The -10 membered arylheterocyclyl can be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O )NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _{3 as} described herein -C ₆ cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3 The -10 membered heterocyclic group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C (O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; X is NR ¹¹ or CHNO ₂ ; m=0, 1 or 2; n=0 or 1; t=0, 1 or 2; Q is CH, N, COH, CF, CMe, CNH ₂ , CNHMe or CNMe ₂ ; 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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , a C ₃ -C ₆ cycloalkyl or a 4-7 membered heterocyclyl optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C _{a 6} alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₆ hydroxyalkyl group; 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 and 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 one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or a 4-7 membered heterocyclic group optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ hydroxyalkyl; R ² and R ³ are bonded to form a P ring together with the C atom to which they are attached, the P ring being selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group; R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl and C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl may be optionally The ground is substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C(O ) R ¹⁰ ; R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclic group, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C (O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, -OC _{1 as described} herein. -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally Substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C (O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; or R ^{6 is} selected from C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclyl, -CH ₂ -(C ₆ -C ₁₄ aryl), -CH ₂ -( 5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl and 3-14 membered heterocyclic group, said C ₆ -C ₁₄ aryl, 5-14 membered heteroaryl, 9-10 membered aryl And a heterocyclyl, -CH ₂ -(5-14 membered heteroaryl), C ₃ -C ₇ cycloalkyl, 3-14 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH , halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic ring a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group, an -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl group, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, _{halogen, CO 2 H, C 1 -C} 6 -alkyl, C ₁ -C ₆ -haloalkyl, C ₃ -C ₆ ring Group, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl group -OC ₁ -C ₆ alkyl, C ₁ -C ₆ ^{hydroxyalkyl, -C (O) R 10,} -C (O) OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ;or R ⁵ and R ⁶ are bonded to form a 5-14 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-14 membered heteroaryl group, 9-10 membered aryl group And the heterocyclic group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ naphthenic as described herein , -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic ring The group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C( O) R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; R ⁷ , R ⁸ and R 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 and 4-7 membered heterocyclic, 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 can be optionally one or more Substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic group together with the N atom to which they are attached; 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 group and 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 one or more of the following substituents: OH, CN, halogen , NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached; R ^{11 is} selected from the group consisting of hydrogen, OH, CN, -SO ₂ R ¹² and -C(O)R ¹³ ; R ^{12 is} selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by one or more of the following Base substitution: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic; 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 and C ₁ -C ₆ alkyl-OC ₁ - C ₆ alkyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkyl- OC ₁ -C ₆ alkyl may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group; requirement is: (1) When m=1, n=1 and t=1, Q is not CH; (2) When n = 0, m = 1, t = 1, Q is N, X is NR ¹¹ , R ¹¹ is H, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

(3) When n = 0, m = 2, t = 0, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

as well as (4) When n = 0, m = 0, t = 2, Q is N, X is NR ¹¹ , R ¹¹ is CN, R ⁴ is H, R ⁵ is H and R ⁶ is a C ₆ aryl group as defined above When R ^{1 is} not

A compound of formula IA according to claim 1, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₄ aryl group, a 5-14 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₄ aryl group, 5-14 The heteroheteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₆ alkyl, C ₁ -C _{6 as} described herein 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 The heteroheteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O ^{) R 10, -C (O)} OR 7, -SO 2 R 10, -C (O) NR 7 R 8 ^{-NR 9 C (O) R 10} , -NR 9 SO 2 R 10, -SO 2 NR 7 R 8 or -NR ⁷ R ^8; Preferably, R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₀ aryl group, The 5-10 membered heteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ Alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C( O) OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C( O) R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₆ alkyl, C _{1 as} described herein -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, The 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, - C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ¹ and R ⁶ are each independently selected from a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, and a 9-10 membered arylheterocyclyl group, said C ₆ -C ₁₀ aryl group, The 5-10 membered heteroaryl, 9-10 membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ - C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, - C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ ,- C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkyl, as described herein, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl The base, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C _1- C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl , -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ . A compound of formula IA according to claim 1 or 2, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and

Wherein ring P' is phenyl or 5-7 membered heteroaryl, said phenyl, pyridyl, quinolyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl optionally being Substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5- 10-membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C as described herein ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can optionally be one Or substituted with more than one of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy a group, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O) OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O) R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C as described herein ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5- The 10-membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy; Preferably, R ¹ and R ⁶ are each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, The isoquinolyl, benzimidazolyl and pyridoimidazolyl groups may be optionally substituted by one or more of the following substituents: F, Cl, methyl, CN or methoxy. A compound of formula IA according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{1 is} selected from the group consisting of phenyl, pyridyl and quinolyl, which may be optionally substituted by one or more of the following substituents: F, Cl, CN or methoxy; Preferably, R ^{1 is} selected from the group consisting of

A compound of formula IA according to any one of claims 1 to 4, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{6 is} selected from the group consisting of phenyl and pyridyl, which may be optionally substituted by one or more of the following substituents: F, Cl, CN or methoxy; Preferably, R ^{6 is} selected from:

A compound of formula IA according to claim 1 or 2, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{1 is} selected from

Wherein ring P" is a 5-6 membered heterocyclic ring, which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C _1- C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl , -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkane as described herein , C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C _{The 10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy 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 or -NR ⁷ R ⁸ ; Preferably, R ¹ is

Wherein ring P" is a 5-6 membered heterocyclic ring, which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C _1- C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl , -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkane as described herein , C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C _{The 10} aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy 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 or -NR ⁷ R ⁸ ; Preferably, R ^{1 is} selected from

It may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy; Preferably, R ^{1 is} selected from

A compound of formula IA according to claim 1, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{6 is} selected from -CH ₂ -(C ₆ -C ₁₄ aryl) and -CH ₂ -(5-14 membered heteroaryl), the -CH ₂ -(C ₆ -C ₁₄ aryl) and -CH _2- (5-14 membered heteroaryl) may be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C (O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, as described herein, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl And a 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ^{6 is} selected from -CH ₂ -(C ₆ -C ₁₀ aryl) and -CH ₂ -(5-10 membered heteroaryl), said -CH ₂ -(C ₆ -C ₁₀ aryl) and -CH ₂ - (5-10 membered heteroaryl) optionally substituted with one or more of the following substituents: OH, _{halo, CN, NO 2, CO 2} H, C 1 -C 6 alkyl, C _3- C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkane as described herein Oxy, 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 The heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O) R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ^{6 is} selected from -CH ₂ -phenyl and -CH ₂ -(5-6 membered heteroaryl), said -CH ₂ -phenyl and -CH ₂ -(5-6 membered heteroaryl) Optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ ,- NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ An aryl group, a 5-10 membered heteroaryl group or a 3-10 membered heterocyclic group; a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a C ₃ -C ₆ cycloalkyl group, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ ,- ^{_{SO 2 R 10, -C (O}} ) NR 7 R 8, -NR 9 C (O) R 10, -NR 9 SO 2 R 10, -SO 2 NR 7 R 8 -NR ⁷ R ^8; Preferably, R ^{6 is} selected from -CH ₂ -phenyl and -CH ₂ -pyridyl, and the -CH ₂ -phenyl and -CH ₂ -pyridyl may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl- OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 A heterocyclic group; a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a C ₃ -C ₆ cycloalkyl group, an -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ group _; Alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH , CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkane --OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ⁶ is -CH ₂ - phenyl -CH ₂ - phenyl optionally substituted with one or more of the following substituents: OH, F, Cl, CN , NO 2, CO 2 H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkane Base, -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; C ₁ -C _{3 as} described herein Alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl may optionally be substituted with one or more of the following substituents: OH, CN, _{halogen, CO 2 H, C 1 -C} 6 alkyl , C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ Hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ⁶ is -CH ₂ - phenyl -CH ₂ - phenyl optionally substituted with one or more of the following substituents: F, Cl, CN, methyl, CF _3, CHF ₂ or Methoxy Preferably, R ⁶ is -CH ₂ -phenyl, the -CH ₂ -phenyl group may be optionally substituted by one or more of the following substituents: F or Cl; Preferably, R ⁶ is

A compound of formula IA according to any one of claims 1 to 7, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , a C ₃ -C ₆ cycloalkyl or a 4-7 membered heterocyclyl optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C _{a 6} alkyl group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group, and a C ₁ -C ₆ hydroxyalkyl group; R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or a 4-7 membered heterocyclic group optionally substituted by one or more of the following substituents: OH, halogen, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₆ hydroxyalkyl; R ² and R ³ are bonded to form a P ring together with the C atom to which they are attached, the P ring being selected from a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, S or N; Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ , C ₃ -C ₆ cycloalkyl or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C _1- C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl; Preferably, R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkyl-OC _1- C ₃ alkyl and C ₁ -C ₃ hydroxyalkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ alkane The base-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl group may be optionally substituted by one or more of the following substituents: OH, halogen, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclyl, which may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl , isopropyl, C ₁ -C ₃ haloalkyl, methoxy, ethoxy, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ hydroxyalkyl; or R ² and R ^{3 are} attached to them The linked C atoms together form a P ring selected from the group consisting of a C ₃ -C ₆ cycloalkyl group and a 4-7 membered heterocyclic group containing O, more preferably selected from

More preferably, R ² and R ³ are each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and -CH ₂ -cyclopropyl; or R ² and R ³ are bonded together with the C atom to which they are attached. P ring, the P ring is

A compound of formula IA according to any one of claims 1 to 8, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, and C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, the C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy group, C ₁ -C ₃ hydroxyalkyl group, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl group may be optionally selected The ground is substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, CO ₂ H, -NR ⁷ R ⁸ , C(O)NR ⁷ R ⁸ or -NR ⁹ C(O ) R ¹⁰ ; Preferably, R ⁴ and R ⁵ are both hydrogen. A compound of formula IA according to claim 1, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl group or a 9-10 membered arylheterocyclic group together with the N atom to which they are attached, said 5-10 membered heteroaryl group, 9-10 membered aromatic The arylheterocyclyl can be optionally substituted by one or more of the following substituents: OH, halogen, CN, NO ₂ , CO ₂ H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ ring as described herein 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 and 3-10 membered The cyclic group may be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl , C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ⁵ and R ⁶ are bonded to form a 5-10 membered heteroaryl or 9-10 membered arylheterocyclyl group together with the N atom to which they are attached, said 5-10 membered heteroaryl, 9- The 10-membered arylheterocyclyl can be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C( O) NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C as described herein _3- C ₆ cycloalkyl, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and The 3-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ ,- C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: OH, F, Cl, CN, NO ₂ , CO ₂ H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ - C ₃ alkoxy, -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, -C(O)OR ⁷ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -C(O)R ¹⁰ , -SO ₂ R ¹⁰ , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl as described herein , -OC ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ hydroxyalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclic group Optionally substituted with one or more of the following substituents: OH, CN, halogen, CO ₂ H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, -OC ₁ -C ₆ alkyl-OC ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, -C(O)R ¹⁰ , -C(O)OR ⁷ , -SO ₂ R ¹⁰ , -C(O)NR ⁷ R ⁸ , -NR ⁹ C(O)R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ , -SO ₂ NR ⁷ R ⁸ or -NR ⁷ R ⁸ ; Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F, Cl, CN, methyl, CF ₃ , CHF ₂ or methoxy; Preferably, R ⁵ and R ⁶ are bonded to form together with the N atom to which they are attached

It may be optionally substituted by one or more of the following substituents: F or Cl; Preferably, R ⁵ and R ⁶ are formed together with the N atom to which they are attached

A compound of formula IA according to claim 10, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{4 is} selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, and C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl may optionally be one or more 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 or -NR ⁹ C(O)R ¹⁰ ; Preferably, R ⁴ is hydrogen. A compound of the formula IA according to any one of claims 1 to 11, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C _1- C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy , C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl can be optionally one or more Substituted by the following substituents: OH, CN, halogen, NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic group together with the N atom to which they are attached. A compound of formula IA according to any one of claims 1 to 12, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{10 is} selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ - C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclic group, said C ₁ -C ₃ alkyl group, C ₁ -C ₃ alkoxy group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl-OC ₁ -C ₃ alkyl and 4-7 membered heterocyclyl can be optionally substituted by one or more of the following substituents: OH, CN, halogen , NH ₂ , NHMe, NMe ₂ or CO ₂ H; or, R ⁹ and R ¹⁰ are bonded to form a 4-7 membered heterocyclic group together with the N and C or S atoms to which they are attached. A compound of formula IA according to any one of claims 1 to 13, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{11 is} selected from the group consisting of CN and -SO ₂ R ¹² . A compound of the formula IA according to any one of claims 1 to 14, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{12 is} selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl may be optionally substituted by one or more of the following Base substitution: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic; Preferably, R ^{12 is} selected from C ₁ -C ₃ alkyl and C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl may be optionally one or more Substituted by the following substituents: OH, OC ₁ -C ₆ alkyl, NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic; Preferably, R ¹² is methyl or C ₃ -C ₆ cycloalkyl; Preferably, R ¹² is a methyl group. A compound of formula IA according to any one of claims 1 to 15, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ^{13 is} selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl and C ₁ -C ₃ alkyl-OC ₁ - C ₃ alkyl, said C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkyl- OC ₁ -C ₃ alkyl may be optionally substituted by one or more of the following substituents: OH, halogen, C ₁ -C ₆ haloalkyl, CN, C(O)NH ₂ , NH ₂ , NHMe, NMe ₂ or 4-7 membered heterocyclic group. A compound of formula IA according to any one of claims 1 to 16, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: m = 0 or 1, preferably, m = 1. A compound of formula IA according to any one of claims 1 to 17, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: n=0 or 1. A compound of formula IA according to any one of claims 1 to 18, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: t = 0 or 1, preferably, t = 1. A compound of formula IA according to any one of claims 1 to 19, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: Q is CH or N; Preferably, Q is N. A compound of the formula IA according to any one of claims 1 to 9 and 12 to 20, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative of the compound , a metabolite or prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, wherein said compound has the structure of formula II:

Wherein R ¹ , R ⁶ and X are as defined in any one of claims 1 to 9 and 12 to 20. A compound of the formula IA according to any one of claims 1 to 9 and 12 to 20, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative of the compound a metabolite or prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, wherein said compound has the structure of formula III:

Wherein R ¹ , R ⁶ , X and R ^{2 are} as defined in any one of claims 1 to 9 and 12 to 20; Preferably, R ² is H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or -CH ₂ -(C ₃ -C ₆ cycloalkyl); Preferably, R ² is H, methyl, ethyl, cyclopropyl or -CH ₂ -cyclopropyl. A compound of formula IA according to claim 22, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or said A pharmaceutically acceptable salt, eutectic, polymorph or solvate of a compound, wherein the compound has the structure of Formula IV:

a compound of formula IB, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutically acceptable compound of said compound Salt, eutectic, polymorph or solvate:

Wherein R ¹ , R ⁵ , R ⁶ , X, m and t are as defined in any one of claims 1-7, 9-10, 12-17 and 19. A compound of the formula IB according to claim 24, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound wherein m = 1. A compound of the formula IB according to claim 24 or 25, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, or A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein t=1. A compound of the formula IB according to any one of claims 24 to 26, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or A prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein the compound has the structure of Formula V:

A compound of the formula IB according to any one of claims 24 to 27, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ¹ is phenyl, which may be optionally substituted by one or more C ₁ -C ₆ alkoxy groups, preferably C ₁ -C ₃ alkoxy groups, more preferably methoxy groups; Preferably, R ¹ is

A compound of the formula IB according to any one of claims 24 to 28, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: R ⁶ is phenyl, which may be optionally substituted by one or more halogens, preferably F or Cl, more preferably Cl; Preferably, R ⁶ is

A compound of the formula IB according to any one of claims 24 to 29, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrugs of said compound, or a pharmaceutically acceptable salt thereof, eutectic, polymorph or solvate thereof, wherein R ⁵ is hydrogen. A compound of the formula IB according to any one of claims 24 to 30, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or a prodrug, or a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, wherein: X is NR ¹¹ , Wherein R ¹¹ is -SO ₂ R ¹² ; and wherein R ¹² is C ₁ -C ₆ alkyl, preferably C ₁ -C ₃ alkyl, more preferably methyl. A compound according to claim 1 or 24, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutically acceptable compound An acceptable salt, eutectic, polymorph or solvate wherein the compound is selected from the group consisting of:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound, A eutectic, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of the compound, and one or more pharmaceutically acceptable carriers. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound, a total of a crystal, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition according to claim 33, and one or more pharmaceutically acceptable a. The compound according to any one of claims 1 to 32, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical formulation according to claim 34, prepared for prevention, Use in a medicament for alleviating and/or treating a disease or condition associated with IDO activity, Preferably, the disease or condition associated with IDO activity is selected from the group consisting of a tumor, depression, and Alzheimer's disease. The use according to claim 35, wherein the medicament further comprises other agents for preventing, alleviating and/or treating a disease or condition associated with IDO activity. The compound according to any one of claims 1 to 32, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical formulation according to claim 34, prepared for prevention, Use in a medicament for alleviating and/or treating a disease or condition caused by immunosuppression, Preferably, the disease or condition caused by immunosuppression is selected from the group consisting of a tumor, a viral infection, and an autoimmune disease. The use according to claim 37, wherein the medicament further comprises other agents for preventing, alleviating and/or treating a disease or condition caused by immunosuppression. The compound according to any one of claims 1 to 32, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical preparation according to claim 34, for use in prevention, Amelioration and/or treatment of a disease or condition caused by immunosuppression (eg, a tumor, a viral infection, or an autoimmune disease). A method of preventing, alleviating and/or treating a disease or condition caused by immunosuppression, the method comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 32, Stereoisomers, tautomers or mixtures thereof of the compounds, stable isotopic derivatives, metabolites or prodrugs of said compounds, pharmaceutically acceptable salts, eutectics, polymorphs of said compounds Or a solvate, the pharmaceutical composition of claim 33, or the pharmaceutical formulation of claim 34, and optionally comprising a disease or condition (such as a tumor) caused by preventing, alleviating and/or treating due to immunosuppression A combination of other drugs, viral infections or autoimmune diseases, preferably, in combination with PD-1, PDL-1 antibodies.