CN111630048A - Amidine and guanidine derivatives, preparation method and application thereof in medicines - Google Patents

Amidine and guanidine derivatives, preparation method and application thereof in medicines Download PDF

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CN111630048A
CN111630048A CN201980009183.4A CN201980009183A CN111630048A CN 111630048 A CN111630048 A CN 111630048A CN 201980009183 A CN201980009183 A CN 201980009183A CN 111630048 A CN111630048 A CN 111630048A
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radical
alkyl
compound
cycloalkyl
hydroxyalkyl
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CN111630048B (en
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李桂英
韩润丰
游泽金
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

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

Description

Amidine and guanidine derivatives, preparation method and application thereof in medicines Technical Field
The invention relates to novel amidine and guanidine derivatives, a preparation method thereof, a pharmaceutical composition containing the amidine and guanidine derivatives and medical application thereof.
Background
Due to unlimited growth, infiltration and metastasis of malignant tumors, three conventional treatment methods (surgery, radiotherapy and chemotherapy) clinically adopted at present cannot completely remove or completely kill tumor cells, and the tumor cells can escape from the monitoring of the immune system of the body through various ways, so that the tumor metastasis or relapse is caused. Tumor immunotherapy is the process of enhancing the anti-tumor immunity of the tumor microenvironment (such as inhibiting IDO-mediated tumor immune escape mechanism) by mobilizing the body's immune system, thereby controlling and killing tumor cells. Due to the characteristics of safety, effectiveness, low adverse reaction and the like, the traditional Chinese medicine composition becomes a new therapy for treating tumors after operations, radiotherapy and chemotherapy.
IDO is currently one of the most potential small molecule drug targets for tumor immunotherapy entering the clinical research phase. In 1967 IDO was first found intracellularly by the Hayaishi group (Hayaishi O. et al, Science,1969,164, 389-396), a heme-containing monomeric enzyme whose cDNA-encoded protein consists of 403 amino acids, has a molecular weight of 45kDa, is a rate-limiting enzyme that catalyzes the catabolism of tryptophan via the kynurenine pathway, is widely distributed in tissues other than the liver of humans and other mammals (e.g., rabbits, mice), and is the only rate-limiting enzyme other than the liver that catalyzes the catabolism of tryptophan. High IDO expression of various cells in a tumor microenvironment leads to tryptophan metabolism exhaustion and kynurenine level increase, thereby blocking T cell activation, inducing oxygen free radical mediated T cell apoptosis, enhancing regulatory T cell (Treg) mediated immunosuppression and promoting tumor escape from immune surveillance of an organism.
Besides tumors, IDO is associated with the occurrence of diseases such as senile dementia and cataract. Furthermore, IDO is also implicated in neurological and psychiatric disorders (e.g., depression, mood disorders) and other diseases caused by tryptophan degradation due to abnormally high expression of IDO, such as intrauterine fetal rejection, viral infections (e.g., AIDS), autoimmune diseases, bacterial infections such as lyme disease and streptococcal infections, and the like. Therefore, inhibition of IDO activity has great therapeutic value.
The IDO small molecule inhibitor, Epacadostat, developed by Incyte, is currently used in combination with the PD-1 antibody, keytruda, or PD-L1 antibody, avelumab, in clinical phase I/II trials to treat a variety of cancers, such as advanced or metastatic solid tumors, recurrent glioblastoma, and the like. The IDO small molecule inhibitor BMS-986205 of Bristol-Myers Squibb, inc, is currently used in combination with Nivolumab in a phase III clinical trial to treat a variety of cancers, such as advanced renal cell carcinoma, untreated metastatic or unresectable melanoma; treatment of advanced malignancies in combination with Nivolumab and LAG-3 antibody relatlimab in a clinical phase I/II trial. NewLink Genetics is also conducting a number of clinical trials of indoximod (NG-8189) in combination with other drugs, for example in phase II/III trials for the treatment of metastatic melanoma in combination with the PD-1 antibody, keytruda or Nivolumab. Published patent applications for IDO inhibitors include WO2016073770, WO2016073734, WO2016073738 and the like.
IDO inhibitors have great potential for the treatment and prevention of a variety of diseases, but no drug that inhibits IDO is currently on the market. In order to achieve better therapeutic effects and better meet the market demand, there is a need to develop new IDO inhibitors with high potency and low toxicity, pharmaceutical compositions thereof and methods related thereto.
Summary of The Invention
An 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 of the compound, a stable isotope derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, a cocrystal, a polymorph, or a solvate of the compound. In some embodiments, the IDO inhibitor is a compound represented by formula I-a:
Figure PCTCN2019078301-APPB-000001
wherein:
R1is selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
X is NR11Or CHNO2；
m is 0, 1 or 2;
n is 0 or 1;
t is 0, 1 or 2;
q is CH, N, COH, CF, CMe, CNH2CNMe or CNMe2；
R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group; or, R2And R3Are linked so as to form, together with the C atom to which they are attached, a P ring selected fromFrom C3-C6Cycloalkyl and 4-7 membered heterocyclyl; or
R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group;
R4and R5Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl radicals),-CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
R5And R6Are linked so as to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or a 9-10 membered arylAnd heterocyclyl, said 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
R7、R8And R9Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclyl;
R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl;
R11selected from hydrogen, OH, CN, -SO2R12and-C (O) R13；
R12Is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
with the following conditions:
(1) when m is 1, n is 1 and t is 1, Q is not CH;
(2) when N is 0, m is 1, t is 1, Q is N, X is NR11，R11Is H, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000002
(3) When N is 0, m is 2, t is 0, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000003
And
(4) when N is 0, m is 0, t is 2, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000004
In other embodiments, the IDO inhibitor is a compound represented by formula I-B:
Figure PCTCN2019078301-APPB-000005
wherein:
R1is selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
X is NR11Or CHNO2；
m is 0, 1 or 2;
t is 0, 1 or 2;
R5selected from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
R5And R6Linked to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、 -NR9SO2R10、-SO2NR7R8or-NR7R8；
R7、R8And R9Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclyl;
R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl;
R11selected from hydrogen, OH, CN, -SO2R12and-C (O) R13；
R12Is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group; and
R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group.
Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I-a or I-B of the invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, and one or more pharmaceutically acceptable carriers.
Another aspect of the present invention provides a compound represented by formula I-a or I-B 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 salt, a co-crystal, a polymorph, or a solvate of the compound, or a use of a pharmaceutical composition of the present invention for the preparation of a medicament for the prevention, alleviation, and/or treatment of diseases or disorders associated with IDO activity (e.g., tumors, depression, or senile dementia).
Another aspect of the present invention provides a compound represented by formula I-a or I-B 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, co-crystal, polymorph, or solvate of the compound, or a pharmaceutical composition of the present invention, for use in the prevention, alleviation, and/or treatment of diseases or disorders associated with IDO activity (e.g., tumors, depression, or senile dementia).
Another aspect of the present invention provides a method for preventing, alleviating and/or treating a disease or disorder associated with IDO activity (e.g., tumor, depression or senile dementia), the method comprising administering to a subject in need thereof an effective dose of a compound of formula I-a or I-B of the present invention, a stereoisomer, a tautomer or a mixture thereof of the compound, a stable isotope derivative, a metabolite or a prodrug of the compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate of the compound, or a pharmaceutical composition of the present invention.
Another aspect of the present invention provides a compound represented by formula I-a or I-B 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 salt, a co-crystal, a polymorph, or a solvate of the compound, or a use of a pharmaceutical composition of the present invention in the preparation of a medicament for the prevention, alleviation, and/or treatment of diseases or disorders due to immunosuppression (e.g., tumors, viral infections, or autoimmune diseases, etc.).
Another aspect of the present invention provides a compound represented by formula I-a or I-B 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, a co-crystal, a polymorph, or a solvate of the compound, or a pharmaceutical composition of the present invention, for use in the prevention, alleviation, and/or treatment of diseases or disorders due to immunosuppression (e.g., tumors, viral infections, or autoimmune diseases, etc.).
Another aspect of the present invention provides a method for preventing, alleviating and/or treating a disease or disorder caused by immunosuppression (e.g., tumor, viral infection or autoimmune disease, etc.), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer or mixture thereof of the compound, a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a pharmaceutical composition of the present invention.
Another aspect of the invention provides a process for the preparation of the compounds of the invention.
Detailed Description
Compounds and methods of preparation
A first aspect of the invention relates to a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotope derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound.
The compounds of the present invention include compounds represented by formula I-A:
Figure PCTCN2019078301-APPB-000006
R1is selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylA heterocyclic group of general formula (I), said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
X is NR11Or CHNO2；
m is 0, 1 or 2;
n is 0 or 1;
t is 0, 1 or 2;
q is CH, N, COH, CF, CMe, CNH2CNHMe or CNMe2；
R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group; or, R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and 4-7 membered heterocyclyl; or
R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group;
R4and R5Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heteroarylA cyclic group; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
R5And R6Linked to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
R7、R8And R9Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclyl;
R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl;
R11selected from hydrogen, OH, CN, -SO2R12and-C (O) R13；
R12Is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
with the following conditions:
(1) when m is 1, n is 1 and t is 1, Q is not CH;
(2) when N is 0, m is 1, t is 1, Q is N, X is NR11，R11Is H, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000007
(3) When N is 0, m is 2, t is 0, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000008
And
(4) when N is 0, m is 0, t is 2, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
Figure PCTCN2019078301-APPB-000009
In some embodiments of the invention, R1、R6Each independently selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radicals、-OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1、R6Each independently selected from C6-C10Aryl, 5-10 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C10Aryl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-to 10-membered heteroAryl and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1、R6Each independently selected from C6-C10Aryl, 5-10 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C10Aryl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8。
In some preferred embodiments, R1、R6Each independently selected from the group consisting of phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and
Figure PCTCN2019078301-APPB-000010
wherein ring P' is phenyl or 5-7 membered heteroaryl, which phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen,CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, which may optionally be substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, which may optionally be substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, which may optionally be substituted with one or more of the following substituents: F. cl, methyl, CN or methoxy;
preferably, R1Selected from phenyl, pyridyl and quinolyl, which may be optionally substituted by one or more of the following substituents: F. cl, CN or methoxy;
preferably, R1Selected from:
Figure PCTCN2019078301-APPB-000011
Figure PCTCN2019078301-APPB-000012
preferably, R6Selected from phenyl and pyridyl, which may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;
preferably, R6Selected from:
Figure PCTCN2019078301-APPB-000013
in other preferred embodiments, R1Is selected from
Figure PCTCN2019078301-APPB-000014
Wherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1Is composed of
Figure PCTCN2019078301-APPB-000015
Wherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1Is selected from
Figure PCTCN2019078301-APPB-000016
Figure PCTCN2019078301-APPB-000017
Figure PCTCN2019078301-APPB-000018
Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R1Is selected from
Figure PCTCN2019078301-APPB-000019
In other preferred embodiments, R6Is selected from-CH2-(C6-C14Aryl) and-CH2- (5-14 membered heteroaryl), the-CH2-(C6-C14Aryl) and-CH2- (5-to 14-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R6Is selected from-CH2-(C6-C10Aryl) and-CH2- (5-to 10-membered heteroaryl), the-CH2-(C6-C10Aryl) and-CH2- (5-to 10-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: o isH. CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R6Is selected from-CH2-phenyl and-CH2- (5-6 membered heteroaryl), the-CH2-phenyl and-CH2- (5-to 6-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R6Is selected from-CH2-phenyl and-CH2-pyridyl, -said-CH2-phenyl and-CH2-the pyridyl group may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: f or Cl;
preferably, R6Is composed of
Figure PCTCN2019078301-APPB-000020
In some embodiments of the invention, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl and C1-C6A hydroxyalkyl group; or
R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical can beOptionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl and C1-C6A hydroxyalkyl group; or
R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and 4-7 membered heterocyclyl containing O, S or N;
preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group;
preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, C1-C3Haloalkyl, methoxy, ethoxy, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group; or R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and O-containing 4-7 membered heterocyclyl, more preferably selected from
Figure PCTCN2019078301-APPB-000021
More preferably, R2And R3Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH2-a cyclopropyl group; or, R2And R3Are linked together with the C atom to which they are attached to form a P ring which is
Figure PCTCN2019078301-APPB-000022
In some embodiments of the invention, R4And R5Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl group、CN、CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
Preferably, R4And R5Are all hydrogen.
In other embodiments of the present invention, R5And R6Are linked so as to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-10 membered heteroaryl, 9-10 membered arylheterocyclo being optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked so as to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-10 membered heteroaryl, 9-10 membered arylheterocyclo being optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000023
Which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000024
Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000025
Which may be optionally substituted with one or more of the following substituents: f or Cl;
preferably, R5And R6Together with the N atom to which they are attached form
Figure PCTCN2019078301-APPB-000026
In such embodiments, R4Selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
Preferably, R4Is hydrogen.
In some embodiments of the invention, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radicals、C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl and C1-C6A hydroxyalkyl group; or
R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and 4-7 membered heterocyclyl containing O, S or N;
preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group;
preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, C1-C3Haloalkyl, methoxy, ethoxy, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group; or R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and O-containing 4-7 membered heterocyclyl, more preferably selected from
Figure PCTCN2019078301-APPB-000027
More preferably, R2And R3Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH2-a cyclopropyl group; or, R2And R3Are linked together with the C atom to which they are attached to form a P ring which is
Figure PCTCN2019078301-APPB-000028
And is
R1、R6Each independently selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、 -C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, which may optionally be substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R1、R6Each independently selected from the group consisting of phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolinylIsoquinolinyl, benzimidazolyl and pyridoimidazolyl may be optionally substituted with one or more of the following substituents: F. cl, methyl, CN or methoxy;
R5selected from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10(ii) a Alternatively, the first and second electrodes may be,
R5and R6Are linked so as to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-10 membered heteroaryl, 9-10 membered arylheterocyclo being optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl may optionally be substituted by one or moreA plurality of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked so as to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-10 membered heteroaryl, 9-10 membered arylheterocyclo being optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000029
Which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
Preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000030
Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
preferably, R5And R6Are linked to form together with the N atom to which they are attached
Figure PCTCN2019078301-APPB-000031
Which may be optionally substituted with one or more of the following substituents: f or Cl;
preferably, R5And R6Together with the N atom to which they are attached form
Figure PCTCN2019078301-APPB-000032
In some embodiments of the invention, R7、R8And R9Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclic group, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclic groupOptionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclic group.
In some embodiments of the invention, R10Is selected from C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclic group, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl.
In some embodiments of the invention, R11Selected from CN and-SO2R12。
In some embodiments of the invention, R12Is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
preferably, R12Is selected from C1-C3Alkyl and C3-C6Cycloalkyl radical, said C1-C3Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
preferably, R12Is methyl and C3-C6A cycloalkyl group;
preferably, R12Is methyl.
In some embodiments of the invention, R13Is selected from C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group.
In some embodiments of the present invention, m is 0 or 1, preferably m is 1.
In some embodiments of the invention, n is 0 or 1.
In some embodiments of the present invention, t is 0 or 1, preferably t is 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:
Figure PCTCN2019078301-APPB-000033
wherein R is1、R6And X is as defined above for formula I-A.
In some embodiments of the invention, the compound of formula I-A has the structure of formula III:
Figure PCTCN2019078301-APPB-000034
wherein R is1、R6X and R2As defined above for formula I-A; preferably, R2Is H, C1-C3Alkyl radical, C3-C6Cycloalkyl or-CH2-(C3-C6Cycloalkyl groups); preferably, R2Is H, methyl, ethyl, cyclopropyl or-CH2-a cyclopropyl group;
more particularly, the compound of formula III has the structure of formula IV:
Figure PCTCN2019078301-APPB-000035
the compounds of the present invention also include compounds of formula I-B:
Figure PCTCN2019078301-APPB-000036
wherein R is1、R5、R6X, m and t are as defined above for formula I-A.
In some embodiments, m ═ 1.
In some embodiments, t ═ 1.
In some embodiments, the compound of formula I-B has the structure of formula V:
Figure PCTCN2019078301-APPB-000037
in some embodiments, R1Is phenyl, said phenyl optionally being substituted by one or more C1-C6Alkoxy, preferably C1-C3Alkoxy, more preferably methoxy;
preferably, R1Is composed of
Figure PCTCN2019078301-APPB-000038
In some embodiments, R6Is phenyl, which may optionally be substituted with one or more halogens, preferably F or Cl, more preferably Cl;
preferably, R6Is composed of
Figure PCTCN2019078301-APPB-000039
In some embodiments, R5Is hydrogen.
In some embodiments, X is NR11Wherein R is11is-SO2R12(ii) a And wherein R12Is C1-C6Alkyl, preferably C1-C3Alkyl, more preferably methyl.
In some embodiments of the invention, the compounds of the invention are selected from, but not limited to:
Figure PCTCN2019078301-APPB-000040
Figure PCTCN2019078301-APPB-000041
a second aspect of the invention provides a process for the preparation of a compound of the invention.
In some embodiments, the present invention provides a method of preparing a compound of formula II:
Figure PCTCN2019078301-APPB-000042
wherein R is1、R6And X is as defined above for formula I-A;
the method comprises the following steps:
the first step is as follows: compounds II-1 and R1-Br or R1The compound II-2 is generated by the substitution or coupling reaction of the compound I in the presence of alkali.
Bases which can be used in the substitution aretBuONa、tBuOK、tBuOLi、Cs2CO3、LiHMDS、LDA、NaHMDS、KHMDS、K3PO4、Na2CO3、AcOK、NaHCO3Or K2CO3Etc., and the solvent which can be used is toluene, xylene, THF, DME, dioxane, DMF, DMSO, NMP, etc., at a temperature of 60 ℃ to 140 ℃;
a catalyst which may be used in the coupling reaction (e.g.Buchwald-Hartwig reaction) is Pd (OAc)2、Pd2(dba)3、Pd(dba)2、PdCl2、Pd(PPh3)4、Pd(dppf)Cl2、Pd(dppf)Cl2*DCM、Pd(acac)2Or Pd (allyl)2Etc., the ligand which can be used is PPh3XPhos, SPhos, RuPhos, XantPhos, Dppf, BINOL, BINAP or Pcy3Etc., bases which can be used aretBuONa、tBuOK、tBuOLi、Cs2CO3、LiHMDS、LDA、NaHMDS、KHMDS、K3PO4、Na2CO3、AcOK、NaHCO3Or K2CO3And the like, and usable solvents are toluene, xylene, THF, DME, dioxane, DMF, DMSO, NMP, or the like, and the temperature is 60 ℃ to 140 ℃.
The second step is that:
the method A comprises the following steps: and removing the protecting group of the compound II-2 in the presence of acid to generate a compound II-3.
The acid can be HCl in 1, 4-dioxane or TFA in DCM, etc., at a temperature of 0 deg.C to rt.
The method B comprises the following steps: the reaction time is prolonged under the reaction conditions of the first step (e.g.>10h) Compounds II-1 and R1-Br or R1Directly generating a compound II-3 by substitution or coupling reaction in the presence of alkali.
The third step: the compound II-3 reacts with the compound II-4 or II-5 under alkaline conditions to generate the compound shown in the formula II.
Can be usedThe base is LiHMDS, LDA, NaHMDS, KHMDS, TEA, DIPEA, or mixtures thereof,tBuOK, NaH or Cs2CO3And the like. Solvents which can be used are THF, DCM, DCE, DMF, DMSO, CH3CN, 1, 4-dioxane or toluene at rt-140 deg.C.
In some embodiments, the present invention provides a method of preparing a compound of formula III:
Figure PCTCN2019078301-APPB-000043
wherein:
R1、R6x and R2As defined above for formula I-A;
r' is selected from benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl and Cbz; r' is selected from Me, Et andtBu；
the method comprises the following steps:
the first step is as follows: the compound III-1 reacts with the compound III-2 in the presence of a base to generate a compound III-3.
The alkali can be LDA, n-BuLi,tBuOK、tBuONa、tBuOLi、NaOH、KOH、NaH、Cs2CO3LiHMDS, NaHMDS or KHMDS, etc. Solvents which can be used are THF, DCM, DCE, MeOH, EtOH, DMF, CH3CN, 1, 4-dioxane or toluene at 0-120 deg.c;
the second step is that: the compound III-3 is reduced by hydrogenation to generate a compound III-4.
A catalyst which may be used is Pd/C, PtO2Or Pd (OH)2and/C, etc., MeOH, EtOH, etc., solvents which can be used are rt to 80 ℃.
The third step: compounds III-4 and R1-Br or R1-I is subjected to a substitution or coupling reaction (e.g., Buchwald-Hartwig reaction) in the presence of a base to produce compound III-5.
The reaction conditions are as described in the first step of the process for the preparation of the compound of formula II.
The fourth step: the compound III-5 is hydrolyzed under alkaline or acidic conditions to generate a compound III-6.
For acidic conditions, the acids that can be used are HCl, H2SO4TFA, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or the like; for the alkaline condition, usable bases are LiOH, NaOH, KOH, or the like. Solvents which can be used are THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH3CN, 1, 4-dioxane, toluene or the mixed solvent of the solvent and water, and the like, and the temperature is rt to 100 ℃.
The fifth step: compound III-6 undergoes Curtius rearrangement to give compound III-7.
A base which can be used is Et3N, DIPEA, DPPA and the like can be used as a reagent, and DPPA and the like can be used as a solventtBuOH, toluene, DCM,tA mixed solvent of BuOH and toluene, etc., at a temperature of rt to 110 ℃.
And a sixth step: the compound III-7 generates III-8 under acidic or basic conditions.
For acidic conditions, acids which can be used are HCl, HBr, TFA, H2SO4HOAc, trifluoromethanesulfonic acid, etc.; for the alkaline condition, usable bases are LiOH, NaOH, KOH, or the like. Solvents which can be used are THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH3CN, 1, 4-dioxane, toluene or the mixed solvent of the solvent and water, and the like, and the temperature is rt to 120 ℃.
The seventh step: the compound III-8 reacts with II-4 or II-5 under alkaline conditions to generate the compound shown in the formula III.
The reaction conditions are as described in the third step of the process for the preparation of the compound of formula II.
In some embodiments, the present invention provides a method of preparing a compound of formula IV:
Figure PCTCN2019078301-APPB-000044
wherein R is1、R6And X is as defined above for formula I-A;
the method comprises the following steps:
first step of: compounds IV-1 and R1-Br or R1-I is subjected to a substitution or coupling reaction (e.g., Buchwald-Hartwig reaction) in the presence of a base to produce compound IV-2.
The reaction conditions are as described in the first step of the process for the preparation of the compound of formula II.
The second step is that: and removing the protecting group of the compound IV-2 in the presence of acid to generate a compound IV-3.
The reaction conditions are as described in the second step of the process for the preparation of the compound of formula II.
The third step: the compound IV-3 reacts with II-4 or II-5 under alkaline conditions to generate the compound shown in the formula IV.
The reaction conditions are as described in the third step of the process for the preparation of the compound of formula II.
In some embodiments, the present invention provides a method of preparing a compound of formula V:
Figure PCTCN2019078301-APPB-000045
wherein:
R1、R6and X is as defined above for formula I-B;
Raselected from benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl and Cbz;
the method comprises the following steps:
the first step is as follows: and reacting the compound V-1 with a trifluoromethanesulfonylation reagent in the presence of a base to generate a compound V-2.
For example, the base is LiHMDS, LDA, NaHMDS, KHMDS,tBuOK, NaH or NaOH, etc., the trifluoromethanesulfonylation reagent is PhNTf2. Or the base is 2, 6-di-tert-butyl-4-methylpyridine, and the trifluoromethanesulfonylation reagent is Tf2And O. Solvents which can be used are THF, CH3CN, DCM or DCE, etc., at-78 deg.C to 60 deg.C;
the second step is that: compounds V-2 and R1-boronic acid or R1Boronic esters are subjected to a coupling reaction (e.g., a Suzuki reaction) to form compound V-3.
Can be usedThe catalyst is Pd (PPh)3)4Pd(dppf)Cl2DCM, or Pd (dppf) Cl2Etc., the base which can be used is Cs2CO3、K3PO4、Na2CO3、AcOK、NaHCO3Or K2CO3Etc., 1, 4-dioxane, DMF, DMSO, CH can be used as the solvent3CN, or a mixed solvent of the above solvent and water, at a temperature of 60 ℃ to 120 ℃;
the third step: the compound V-3 is reduced to the compound V-4 under catalytic hydrogenation conditions.
The reaction conditions are as described in the second step of the process for the preparation of the compound of formula III;
the fourth step: the compound V-4 reacts with the compound II-4 or II-5 under alkaline conditions to generate the compound shown in the formula V.
The reaction conditions are as described in the third step of the process for the preparation of the compound of formula II.
Pharmaceutical compositions, methods of preparation and methods of treatment
A third aspect of the invention provides a pharmaceutical composition comprising a compound of formula I-a or I-B of the invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, and one or more pharmaceutically acceptable carriers.
A fourth aspect of the invention provides a process for preparing a pharmaceutical composition of the invention, which process comprises combining a compound of the invention of formula I-a or I-B, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, with one or more pharmaceutically acceptable carriers.
A fifth aspect of the invention provides a pharmaceutical formulation comprising a compound of formula I-a or I-B of the invention, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, metabolite, or prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a pharmaceutical composition of the invention.
A sixth aspect of the invention provides a use of a compound of formula I-a or I-B of the invention, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for the prevention, alleviation, and/or treatment of a disease or disorder associated with IDO activity (e.g., a tumor, depression, or senile dementia).
A seventh aspect of the invention provides a compound of formula I-a or I-B of the invention, a stereoisomer, a tautomer, or a mixture thereof, a stable isotope derivative, metabolite, or prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, for use in the prevention, alleviation, and/or treatment of a disease or disorder associated with IDO activity (e.g., a tumor, depression, or senile dementia).
An eighth aspect of the present invention provides a method for preventing, alleviating and/or treating a disease or disorder associated with IDO activity (e.g. tumor, depression or senile dementia) comprising administering to a subject in need thereof an effective dose of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotope derivative, metabolite or prodrug of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and optionally comprising the combination with other agents for preventing, alleviating and/or treating a disease or disorder associated with IDO activity (e.g. tumor, depression or senile dementia).
A ninth aspect of the present invention provides a method for the prevention, alleviation and/or treatment of a disease or disorder associated with IDO activity (e.g. tumors, depression or senile dementia), which method comprises administering to a subject in need thereof an effective dose of a compound of formula I-a or I-B of the present invention, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph or a solvate of said compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, in combination with a PD-1, PDL-1 antibody.
The diseases or symptoms related to IDO activity in the invention include but are not limited to tumors, depression, senile dementia and the like.
The invention also provides a compound shown as the formula I-A or I-B, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, a pharmaceutically acceptable salt, a eutectic compound, a polymorph or a solvate of the compound, and application of the pharmaceutical composition or the pharmaceutical preparation in preparing medicines for preventing, relieving and/or treating diseases or symptoms (such as tumors, virus infection or autoimmune diseases and the like) caused by immunosuppression.
The invention also provides a compound shown as the formula I-A or I-B, a stereoisomer, a tautomer or a mixture thereof, a stable isotope derivative, a metabolite or a prodrug of the compound, a pharmaceutically acceptable salt, a eutectic compound, a polymorphic substance or a solvate of the compound, a pharmaceutical composition or a pharmaceutical preparation, which is used for preventing, relieving and/or treating diseases or symptoms caused by immunosuppression (such as tumors, viral infections or autoimmune diseases and the like).
The invention also provides methods of preventing, ameliorating and/or treating a disease or condition caused by immunosuppression (e.g., a tumor, viral infection, or autoimmune disease, etc.), the method comprising administering to a subject in need thereof an effective amount of a compound of formula I-A or I-B of the invention, stereoisomers, tautomers or mixtures thereof of said compounds, stable isotopic derivatives, metabolites or prodrugs of said compounds, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, and optionally including use in combination with other agents for the prevention, alleviation and/or treatment of diseases or conditions resulting from immunosuppression, such as tumors, viral infections or autoimmune diseases and the like.
The present invention also provides a method for preventing, alleviating and/or treating a disease or disorder caused by immunosuppression (e.g., tumor, viral infection or autoimmune disease, etc.), comprising administering to a subject in need thereof an effective amount of a compound of formula I-a or I-B of the present invention, a stereoisomer, tautomer or mixture thereof, a stable isotopic derivative, metabolite or prodrug of said compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of said compound, a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, in combination with a PD-1, PDL-1 antibody.
Diseases or conditions caused by immunosuppression according to the present invention include, but are not limited to, for example, tumors, viral infections, autoimmune diseases, and the like.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent 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 present invention.
As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 6, e.g., 1 to 4, carbon atoms. For example, as used herein, the term "C1-C6Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halo (when the group is referred to as" haloalkyl ", e.g., CF)3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl or-CH2CH2CF3Etc.).
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic ring, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 7 carbon atoms, for example 3 to 6 carbon atoms. For example, as used herein, the term "C3-C7Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) having from 3 to 7 ring carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.
As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.
The term "alkoxy" as used herein, means an alkyl group, preferably C, as defined above attached to the parent molecular moiety through an oxygen atom1-C6Alkoxy or C1-C3An alkoxy group. C1-C6Generation of alkoxyIllustrative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, and the like.
As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system, and in each case may share two adjacent atoms with one another with a cycloalkyl group to form a cyclic group, the point of attachment may be on the aryl group or on the cycloalkyl group. For example,
Figure PCTCN2019078301-APPB-000046
for example, as used herein, the term "C6-C14Aryl "means an aromatic radical containing from 6 to 14 carbon atoms, preferably C6-C10Aryl, preferably phenyl or naphthyl. Aryl groups may optionally be substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)2、C1-C6Alkyl, etc.).
As used herein, the term "hydroxyalkyl" means that a hydrogen atom of an alkyl group is substituted with one or more hydroxyl groups, e.g., C1-C6Hydroxyalkyl or C1-C3A hydroxyalkyl group. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.
As used herein, the term "arylheterocyclo" refers to a cyclic group formed by an aryl group and a heterocyclyl group that share two adjacent carbon atoms with each other with the point of attachment being on the aryl or heterocyclyl group, wherein the aryl or heterocyclyl group is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclo" means a group of arylheterocyclo containing 9-12 ring atoms, particularly a phenyl-5-8 membered heterocyclyl, particularly a phenyl-5-6 membered heterocyclyl (9-10 membered benzoheterocyclyl), examples of which include, but are not limited to: indazolyl group,
Figure PCTCN2019078301-APPB-000047
Figure PCTCN2019078301-APPB-000048
As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (a heteroaromatic ring refers to an aromatic ring system containing at least one heteroatom), having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5,6, 7, 8, 9 or 10 ring atoms, and which contains at least one heteroatom which may be the same or different (e.g. oxygen, nitrogen or sulfur), and which in each case may share two adjacent atoms with the aryl, heterocyclyl or cycloalkyl group with one another to form a bicyclic group, the point of attachment of which is on the heteroaromatic ring or other ring. For example, as used herein, the term "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, examples thereof include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and fused ring derivatives thereof, the fused ring derivative is not limited to heteroaryloaryl, heteroaryloaryl group, heteroaryloaterocyclyl group or heteroaryloaycloalkyl group, in particular 5-6 membered heteroaryland 5-6 membered heteroaryl, 5-6 membered heteroarylacenyl, 5-6 membered heteroaryland 5-6 membered heterocyclyl, or 5-6 membered heteroarylacen C.4-C6Cycloalkyl (particularly 5-6 membered heteroarylocyclobutyl, 5-6 membered heteroarylocyclopentyl, 5-6 membered heteroarylocyclocyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, indolyl, dihydroindolyl, dihydro,
Figure PCTCN2019078301-APPB-000049
Figure PCTCN2019078301-APPB-000050
And the like.
As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having 2, 3,4, 5,6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) selected from C (═ O), O, S, S (═ O), S (═ O)2And NR (R represents a hydrogen atom or a substituent such as, but not limited to, an alkyl group or a cycloalkyl group). As used herein, the term "3-14 membered heterocyclyl" means a heterocyclyl group containing 3-14 ring atoms, including 3-10 or 4-7 membered heterocyclyl groups, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), and the like; and fused ring derivatives thereof including, but not limited to, heterocyclo-heterocyclyl, heterocyclo-cycloalkyl, particularly 3-7 membered heterocyclo-3-7 membered heterocyclyl, 3-7 membered heterocyclo-cycloalkyl, 3-7 membered heterocyclo-C4-C6Cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopenta-cyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl; and bridge or spiro derivatives such as, but not limited to:
Figure PCTCN2019078301-APPB-000051
Figure PCTCN2019078301-APPB-000052
and the like.
As used herein, the term "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted with … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.
If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, the term "one or more" means 1 or more than 1, such as 2, 3,4, 5 or 10, under reasonable conditions.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
The invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)2H、3H) (ii) a Isotopes of carbon (e.g. of11C、13C and14C) (ii) a Isotopes of chlorine (e.g. of chlorine)36Cl); isotopes of fluorine (e.g. of fluorine)18F) (ii) a Isotopes of iodine (e.g. of iodine)123I and125I) (ii) a Isotopes of nitrogen (e.g. of13N and15n); isotopes of oxygen (e.g. of15O、17O and18o); isotopes of phosphorus (e.g. of phosphorus)32P); and isotopes of sulfur (e.g. of35S)。
The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:
Figure PCTCN2019078301-APPB-000053
it is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio. It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate, meglumine salts and the like. For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
For these routes of administration, the compositions of the present invention may be administered in suitable dosage forms.
Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.
The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.
The compound of the invention may be present in the pharmaceutical composition in an amount or amount of from about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg, more preferably 1-150mg, especially 1-50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.
As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.
As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.
The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987(E.B.Roche editions, American Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.
The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.
The bonds in the structural formulae herein represented by the wavy lines "-" are intended to mean that the structure represents the cis or trans isomer, or a mixture of the cis and trans isomers in any proportion.
As used herein
Figure PCTCN2019078301-APPB-000054
The bond in the structural formula shown is intended to mean that the structure represents a single bond or a double bond.
As used herein, "room temperature" means 15-30 ℃.
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 fewer side effects).
Detailed Description
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The abbreviations in this application have the following meanings:
Figure PCTCN2019078301-APPB-000055
Figure PCTCN2019078301-APPB-000056
the structure of the compound is shown by (1H NMR) and/or Mass Spectrometry (MS). The reaction was monitored by Thin Layer Chromatography (TLC) or LC/MS.
1H NMR spectrometer Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).
LC/MS mass spectrometer: aglient 1260Infinity/Aglient 6120 Quadrupole.
The thin layer chromatography adopts silica gel GF 254 as a stationary phase.
The compound can be separated and purified by chromatography silica gel plate, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC), and Flash column chromatography (Flash column chromatography).
The column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as a stationary phase.
Flash column chromatography was performed using a Biotage Flash column chromatograph.
Prep-HPLC was performed using Agilent 1260 chromatography.
In the following examples, the reaction temperature was room temperature (15 ℃ C. to 30 ℃ C.), unless otherwise specified.
Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Tereber Chemical, among others.
Intermediate Int-1: n- (4-chlorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000057
Compound Int-1a (59mg) and compound Int-1b (100mg) were placed in a 50mL three-necked flask under nitrogen, anhydrous THF5mL was added, and 1.6mL of a 1.0M solution of LiHMDS in THF was added slowly. LCMS monitors for complete substrate conversion and 0.5mL saturated NH is added4The reaction was quenched with Cl solution, concentrated to dryness under reduced pressure and dissolved with a small amount of DCM and purified by preparative TLC separation (PE: EA ═ 2:1) to give intermediate Int-1(55 mg).
MS m/z(ESI)：279.0[M+H]+。
Intermediate Int-2: n- (4-cyanophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000058
40mL of a 1.0M THF solution of LiHMDS was added to a solution of Int-1b (2.0g,10.03mmol) and Int-2a (1.19g, 10.03mmol) in anhydrous THF (20mL) at-30 deg.C, and the reaction was allowed to proceed at-30 deg.C for 2 hours and then warmed to room temperature for 16 hours. The reaction was quenched with a saturated ammonium chloride solution (10mL), water was added to 30mL, extraction was performed with EtOAc, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE: EA ═ 5:2) to obtain Int-2(1.2g) as an objective product.
MS m/z(ESI)：270.1[M+H]+。
Intermediate Int-3: n- (4-chloro-2-fluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000059
30mL of a 1.0M THF solution of LiHMDS was added to a solution of Int-1b (1.5g,7.23mmol) and Int-3a (1.10g, 7.53mmol) in THF (20mL) at-30 deg.C, and the reaction was allowed to proceed at-30 deg.C for 2 hours and then warmed to room temperature for 16 hours. The reaction was quenched with a saturated ammonium chloride solution (10mL), water (30mL) was added, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE: EA ═ 5:1-3:1) to obtain the target product Int-3(1.0 g).
MS m/z(ESI)：297.0[M+H]+。
Intermediate Int-4: N-4-chlorobenzyl-N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000060
Int-4a (708mg, 5.0mmol), Int-1b (997mg, 5.0mmol) and DIPEA (1.29g, 10.0mmol) were dissolved in DMF (10mL) under nitrogen, heated to 100 ℃ for reaction for 4h, cooled to room temperature after the reaction was completed, diluted with EtOAc, washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE: EA ═ 5:1-3:1) to give Int-4(1.1 g).
MS m/z(ESI)：293.0[M+H]+。
Intermediate Int-5: n- (4-chloro-3-fluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000061
Int-1b (199mg, 1.0mmol) and Int-5a (218mg, 1.5mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0 deg.C, then 2.0mL of a 1.0M solution of LiHMDS in THF were added and stirred at room temperature for 3 hours after the addition was completed. After the reaction is finished, saturated ammonium chloride aqueous solution is added to quench the reaction, the reaction is extracted by ethyl acetate, the combined organic phase is dried by anhydrous sodium sulfate, and after decompression and concentration, the target product Int-5(160mg) is obtained by separation and purification through column chromatography (EA: PE: 1:99-45: 55).
MS m/z(ESI)：297.0[M+H]+。
Intermediate Int-6: phenyl N- (4-chlorophenyl) -N' -cyanocarbamimidoyl ester
Figure PCTCN2019078301-APPB-000062
Dissolving 4-chloroaniline (0.16g, 1.3mmol), Int-6a (0.3g, 1.3mmol) and DIPEA (0.16g, 1.3mmol) in DMF (5mL), reacting at 120 ℃ for 1.5h under microwave conditions, cooling to room temperature after reaction is finished, pouring the reaction solution into water (50mL), extracting with EtOAc, combining organic phases and using anhydrous Na2SO4Drying and concentration of the organic phase under reduced pressure to dryness gave the crude intermediate Int-6(0.3g), which was used in the next reaction without further purification.
MS m/z(ESI)：272.1[M+H]+。
Intermediate Int-7: n- (5-Chloropyridin-2-yl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester
Figure PCTCN2019078301-APPB-000063
Int-7a (262.37mg,2.0mmol) was dissolved in 3.0mL dry THF under nitrogen, cooled to 0 deg.C and 5.0mL 1.0M LiHMDS in THF was added slowly followed by Int-1b (419.61mg,2.00mmol) in THF (7.0mL) and the reaction was completed at 0 deg.C for 4 h. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 9:1-2:1) to give Int-7(330 mg).
MS m/z(ESI)：280.0[M+H]+。
Example 1: n- (((4-chlorophenyl) amino) ((1- (4-methoxyphenyl) piperidin-4-yl) amino) methylene) methanesulfonamide (Compound 1)
Figure PCTCN2019078301-APPB-000064
The first step is as follows: (1- (4-methoxyphenyl) piperidin-4-yl) carbamic acid tert-butyl ester (1c)
Under nitrogen protection, compound 1a (117mg, 0.5mmol), compound 1b (100mg, 0.5mmol) and Pd2(dba)3(23mg, 0.025mmol), RuPhos (23mg, 0.05mmol) andtBuONa (96mg, 1.0mmol) was placed in a 50mL three-necked flask, followed by addition of 4.0mL toluene, heating to 100 ℃ for reaction, TLC monitoring complete conversion of the starting material, then cooling to room temperature, filtration and washing with EtOAc, and purification by preparative TLC separation (PE: EA ═ 5:1) after evaporation of the solvent under reduced pressure to give the title compound 1c (100 mg).
MS m/z(ESI)：307.3[M+H]+。
The second step is that: 1- (4-methoxyphenyl) piperidin-4-amine (1d)
Dissolve 1c in 5.0mL of 4N HCl in dioxane, react at room temperature for 1h, and evaporate the solvent under reduced pressure to give the crude compound 1d (60 mg). The crude product was dissolved in 10.0mL DCM and saturated NaHCO3And (4) washing with the solution. The aqueous phase was extracted with DCM, the organic phases were combined and washed with anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure. The crude product was used directly in the next reaction.
MS m/z(ESI)：207.1[M+H]+。
The 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 ℃ to react until complete conversion of the starting material, cooled to room temperature, diluted with EtOAc and washed with water and the organic phase washed with anhydrous Na2SO4After drying, filtration and evaporation of the solvent under reduced pressure, the objective compound 1(45mg) was isolated and purified by Prep-HPLC.
MS m/z(ESI)：437.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.81(s,1H),7.40(d,J＝8.8Hz,2H),7.35(d,J＝8.8Hz,2H),7.25(d,J＝7.2Hz,1H),6.90(d,J＝8.8Hz,2H),6.81(d,J＝9.2Hz,2H),3.88-3.81(m,1H),3.67(s,3H), 3.47-3.43(m,2H),2.89(s,3H),2.77-2.72(m，2H)，2.00-1.91(m，2H)，1.65-1.57(m，2H)。
Examples 2 to 11: preparation of Compounds 2 to 11
The first step is as follows: intermediates 2A to 11A
Using a synthetic method similar to the first step of example 1, first step intermediates 2A to 11A of compounds 2 to 11 were obtained.
Figure PCTCN2019078301-APPB-000065
The second step is that: intermediates 2B to 11B
Second step intermediates 2B to 11B of compounds 2 to 11 were prepared from the corresponding 2A to 11A using a synthesis similar to the second step of example 1.
Figure PCTCN2019078301-APPB-000066
Figure PCTCN2019078301-APPB-000067
The third step: compounds 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.
Figure PCTCN2019078301-APPB-000068
Figure PCTCN2019078301-APPB-000069
Figure PCTCN2019078301-APPB-000070
Example 12: n- (((4-chlorophenyl) amino) ((((1- (4-methoxyphenyl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (Compound 12)
Figure PCTCN2019078301-APPB-000071
The first step is as follows: (1- (4-methoxyphenyl) piperidin-4-yl) methylamine (2c)
Under nitrogen protection, 1a (527mg,2.25mmol), 2a (482.67mg,2.25mmol) and Pd2(dba)3(103.12mg, 112.61. mu. mol), RuPhos (105.09mg, 225.23. mu. mol) andtBuONa (649.33mg,6.76mmol) was placed in a 50mL three-necked flask, followed by addition of 5.0mL of toluene and heating to 100 ℃ for 16 h. After completion of the reaction, it was cooled to room temperature, diluted with ethyl acetate (20mL), and isolated and purified by silica gel column chromatography (DCM: MeOH ═ 20:3) to give the objective compound 2c (300 mg).
The second step is that: n- (((4-chlorophenyl) amino) ((((1- (4-methoxyphenyl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (12)
DIPEA (46.36mg, 358.71. mu. mol) was added to a solution of Int-1(50mg, 179.35. mu. mol) and 2c (39.46mg, 179.35. mu. mol) in DMF (2mL) at room temperature and heated to 95 ℃ for 5 hours. After the reaction is finished, the reaction product is cooled to room temperature, diluted by ethyl acetate 5mL, washed by clean water (20mL x 3), the organic layer is dried and concentrated to obtain a crude product, and the crude product is separated and purified by Prep-HPLC to obtain the target compound 12(40 mg).
MS m/z(ESI)：451.2[M+H]+。
1H NMR(400MHz,DMSO-d6)8.73(s,1H),7.41-7.31(m,5H),6.90-6.87(m,2H),6.82-6.79(m,2H),3.67(s,3H),3.53-3.50(m,2H),3.25-3.23(m,2H),2.88(s,3H),2.58-2.50(m,2H),1.77-1.68(m,3H),1.36-1.28(m,2H)。
Examples 13 to 25: preparation of Compounds 13 to 25
The first step is as follows: intermediates 16A-20A
Intermediates 16A to 20A were obtained using a synthesis similar to the first step of example 1.
Figure PCTCN2019078301-APPB-000072
Figure PCTCN2019078301-APPB-000073
The second step is that: intermediates 13B to 25B
Intermediates 13B to 15B of compounds 13 to 15, and intermediates 24B and 25B of compounds 24 and 25 were obtained by reacting 4-fluoroiodobenzene, 4-chloro-3-fluoroiodobenzene, 5-bromo-2-methoxypyridine, 4-bromo-2-fluoro-1-methoxybenzene, 1-bromo-2-fluoro-4-methoxybenzene and 2a, respectively, using a synthesis method similar to the first step of example 12. Second step intermediates 16B-20B of compounds 16-20 were prepared from the corresponding 16A-20A using a synthetic procedure similar to the second step of compound 1.
Figure PCTCN2019078301-APPB-000074
Figure PCTCN2019078301-APPB-000075
The third step: compounds 13 to 25
Compounds 13 to 25 were prepared using a synthetic method similar to the second step of example 12, and the final products were isolated and purified by Prep-HPLC.
Figure PCTCN2019078301-APPB-000076
Figure PCTCN2019078301-APPB-000077
Figure PCTCN2019078301-APPB-000078
Example 26: n- (((4-chlorophenyl) amino) ((((1- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (Compound 26)
Figure PCTCN2019078301-APPB-000079
The first step is as follows: 6-bromo-2H-benzo [ b ] [1,4] oxazine-4 (3H) -carboxylic acid tert-butyl ester (3b)
3a (817mg, 3.82mmol) was dissolved in THF (9mL), DMAP (47mg, 0.38mmol) and Et were added3N (1.16g,11.45mmol) was added followed by (Boc)2O (1.00g,4.58mmol), reacted at room temperature for 4 h. After the reaction, water was added to quench and extract with EA. The organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, the filtrate was separated and purified by silica gel column chromatography (PE/EA system, 7% EA) to obtain compound 3b (360mg, yield 30%).
MS m/z(ESI):314.0[M+H]+。
The second step is that: 6- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -2H-benzo [ b ] [1,4] oxazine-4 (3H) -carboxylic acid tert-butyl ester (3c)
3b (360mg,1.15mmol)、2a(247mg，1.15mmol)、Pd2(dba)3(110mg, 0.12mmol), RuPhos (56mg, 0.12mmol) andtBuONa (277mg, 2.88mmol) was placed in a 50mL one-neck flask, toluene (8mL) was added, and the reaction was heated to 90 ℃ for 6 h. After the reaction, the reaction mixture was cooled to room temperature, poured into water, and extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, the filtrate was separated and purified by silica gel column chromatography (PE/EA system, 10% EA) to obtain compound 3c (460mg, 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) methylamine hydrochloride (3d)
3c (460mg) was dissolved in dioxane (3mL), 10.0mL 4M HCl in dioxane was added and TLC monitored until complete conversion of starting material. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain the hydrochloride of compound 3 d.
MS m/z(ESI):248.2[M+H]+.
The fourth step: n- (((4-chlorophenyl) amino) ((((1- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) piperidin-4-yl) methyl) amino) methylene) methanesulfonamide (26)
3d and compound Int-1(340mg, 1.22mmol) were dissolved in DMF (5mL) and stirred to dissolve completely, followed by the addition of DIPEA (1.00g) and heating to 80 ℃ and stirring for 15 h. After the reaction, the reaction mixture was cooled to room temperature, poured into saturated brine, and extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, the filtrate was purified by separation by Prep-HPLC to give compound 26(140mg, yield 28%).
ESI-MS(m/z):477.8[M+H]+.
1H NMR(400MHz,DMSO-d6):8.74(s,1H),7.41-7.31(m,5H),6.48(d,J＝8.4Hz,1H),6.16(d,J＝2.4Hz,1H),6.09(dd,J＝8.8,J＝2.8Hz,1H),5.56(s,1H),4.02(t,J＝4.4Hz,2H),3.42(d,J＝12.0Hz,2H),3.24-3.21(m,4H),2.88(s,3H),2.52-2.47(m,2H),1.74-1.65(m,3H),1.33-1.27(m,2H)。
Example 27: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 27)
Figure PCTCN2019078301-APPB-000080
The first step is as follows: 2- (1-Benzylpiperidin-4-ylidene) propionic acid ethyl ester (4c)
4b (8.58g,36.00mmol) was dissolved in 50mL THF, cooled to 0 deg.C, NaH (827.63mg,36.00mmol) was added slowly, reaction was carried out for 30min, 4a (5.68g,30mmol) was added, and the reaction was heated to 70 deg.C. After 24h, the reaction was stopped, cooled to room temperature, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 19:1-9:1) to give 4c (3.5 g).
MS m/z(ESI)：274.2[M+H]+。
The second step is that: 2- (piperidin-4-yl) propionic acid ethyl ester (4d)
4C (3.5g,12.80mmol) was dissolved in dry methanol (40mL), 680mg of 10% Pd/C was added, the reaction was carried out under hydrogen atmosphere (1atm), and TLC was monitored until the starting material was completely converted. After the reaction was completed, it was filtered through celite and washed with a mixed solvent of DCM: MeOH ═ 10:1, and the filtrate was concentrated to dryness under reduced pressure to give crude 4d (2.34g) which was used in the next reaction without further purification.
MS m/z(ESI)：186.1[M+H]+。
The third step: ethyl 2- (1- (4-methoxyphenyl) piperidin-4-yl) propionate (4e)
Under the protection of nitrogen, 4d (800mg, 4.3mmol), 4-iodoanisole (843mg, 3.6mmol) and Pd2(dba)3(164mg, 0.18mmol), RuPhos (168mg, 0.36mmol) andtBuONa (692mg, 7.2mmol) was placed in a 50mL three-necked flask, followed by addition of 15.0mL of toluene, heating to 100 ℃ for reaction, and TLC monitored until complete conversion of the starting material. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, washed with EtOAc, and purified by preparative TLC separation (PE: EA ═ 19:1-9:1) to give the target compound 4e (750 mg).
MS m/z(ESI)：292.2[M+H]+。
The fourth step: 2- (1- (4-methoxyphenyl) piperidin-4-yl) propionic acid (4f)
Dissolving 4e (800mg, 2.75mmol) in methanol (15mL) and water (5mL), adding NaOH (275mg,6.86mmol), heating to 50 ℃, stirring overnight, adjusting pH to 3-4 with 1M hydrochloric acid after the reaction is finished, concentrating under reduced pressure to dryness to obtain a crude product of 4f, dissolving the crude product in a solution of DCM: MeOH ═ 5:1, pulping, filtering, concentrating the filtrate under reduced pressure to dryness, and directly using the obtained 4f (680mg) in the next reaction without further purification.
MS m/z(ESI)：264.2[M+H]+。
The fifth step: (1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) carbamoyl azide (4g)
4f (527mg,2.0mmol), DPPA (1.46g, 6.0mmol) and Et3N (606mg, 6.0mmol) was dissolved in toluene (10mL), heated to 100 ℃ for reaction, monitored by TLC until complete conversion of the starting material, cooled to room temperature after the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was isolated by silica gel column chromatography (methanol/dichloromethane ═ 0-10%) to give 4g (220 mg).
MS m/z(ESI)：304.2[M+H]+。
And a sixth step: 1- (1- (4-methoxyphenyl) piperidin-4-yl) ethylamine (4h)
4g (303mg, 1.0mmol) was dissolved in MeOH (20mL), an aqueous solution (5.0mL) of NaOH (1.6g, 40.0mmol) was added, the reaction mixture was reacted at room temperature for 2 hours, then heated to 95 ℃ and reacted for 96 hours, after completion of the reaction, cooled to room temperature, and the pH was adjusted to 3-4 with 1N HCl. The solvent was evaporated under reduced pressure and the crude product was slurried once with each solution of DCM: MeOH 10:1 and 5:1, respectively, filtered and the solvent evaporated under reduced pressure to give 4h of a crude hydrochloride salt (220mg) which was used directly in the next reaction.
MS m/z(ESI)：235.3(M-HCl+1)。
The seventh step: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide
4h (234mg, 1.0mmol), Int-1(352mg,1.2 mmol) and DIPEA (645mg, 5.0mmol) were dissolved in 10.0mL DMF, heated to 100 deg.C for 21h, cooled to room temperature after the reaction was complete, diluted with EtOAc and washed with water, and the organic layer was washed with anhydrous Na2SO4Drying, filtering, vacuum evaporating to remove solvent, filtering, and vacuum evaporatingPrep-HPLC separation and purification gave the title compound 27(30 mg).
MS m/z(ESI)：464.9[M+H]+。
1H NMR(400MHz,CD3OD)7.39-7.28(m,4H),6.99-6.95(m,2H),6.85-6.81(m,2H),3.94-3.90(m,1H),3.73(s,3H),3.49-3.47(m,2H),2.96(s,3H),2.61-2.58(m,2H),1.94-1.85(m,2H),1.57-1.47(m,3H),1.27-1.18(m,3H)。
Example 28: 1- (4-chlorophenyl) -2-cyano-3- (1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) guanidine (Compound 28)
Figure PCTCN2019078301-APPB-000081
4h (40mg, 0.15mmol), Int-6(48mg, 0.18mmol) and DIPEA (39mg, 0.30mmol) were dissolved in 3.0mL DMF, heated to 100 ℃ for reaction until complete conversion of starting material, cooled to room temperature after reaction, diluted with EtOAc and washed with water, and the organic layer was washed with anhydrous Na2SO4After drying, filtration and evaporation of the solvent under reduced pressure, the target compound 28(15mg) was isolated and purified by Prep-HPLC.
MS m/z(ESI)：412.0[M+H]+。
1H NMR(400MHz,CD3OD)7.38(d,J＝8.8Hz,2H),7.23(d,J＝8.4Hz,2H),6.99-6.96(m,2H),6.85-6.81(m,2H),3.88-3.85(m,1H),3.74(s,3H),3.53-3.49(m,2H),2.61-2.54(m,2H),1.88-1.81(m,2H), 1.57-1.46(m,3H),1.23(d,J＝6.8Hz,3H)。
Example 29: n- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 29)
Figure PCTCN2019078301-APPB-000082
4h (70mg, 0.30mmol), Int-3(106mg, 0.36mmol) and DIPEA (116mg, 0.90mmol) were dissolved in 3.0mL DMF, heated to 100 ℃ for reaction until complete conversion of the starting material, and cooled to room temperature after the reaction was completeWarm, dilute with EtOAc and wash with water, organic layer with anhydrous Na2SO4After drying, filtration and evaporation of the solvent under reduced pressure, the objective compound 29(23mg) was obtained by separation and purification by Prep-HPLC.
MS m/z(ESI)：483.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.83(br,1H),8.52(br,0.5H),7.53(s,1H),7.37-7.28(m,2.5H),6.89(d,J＝9.2Hz,2H),6.80(d,J＝8.8Hz,2H),3.82-3.76(m,1H),3.67(s,3H),3.59-3.52(m,2H),2.78(br,3H),2.52-2.49(m,2H),1.85-1.71(m,2H),1.53-1.38(m,3H),1.23-1.05(m,3H)。
Examples 30 and 31: (S) -N- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide and (R) -N- (((4-chloro-2-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide
Figure PCTCN2019078301-APPB-000083
Compound 29 has one chiral center and thus has both the (S) -isomer and the (R) -isomer. The two isomers can be obtained by chiral separation. Specifically, under the separation conditions described below, compound 29 was separated by a chiral column to give compound 29A (peak 1, RT ═ 5.25min) and compound 29B (peak 2, RT ═ 6.63 min).
The instrument comprises the following steps: shimadzu LC-20 AT; a chromatographic column: CHIRALCEL OZ-H (OZH0CD-VF004) (0.46cm I.D.. times.15 cm L); column temperature: 35 ℃; detection wavelength: UV 254 nm; flow rate: 1.0 mL/min; mobile phase: 50 percent of n-hexane/ethanol.
Compound 29A:1H NMR(DMSO-d6,400MHz)8.82(br,1H),8.53(br,0.5H),7.54(s,1H),7.38–7.27(m,2.5H),6.89(d,J＝9.2Hz,2H),6.80(d,J＝8.8Hz,2H),3.82-3.77(m,1H),3.67(s,3H),3.55(br,2H),2.79(br,3H),2.58-2.50(m,2H),1.85-1.71(m,2H),1.54-1.36(m,3H),1.23-1.06(m,3H).
compound 29B:1H NMR(DMSO-d6,400MHz)8.81(br,1H),8.53(br,0.5H),7.53(s,1H),7.35-7.29(m,2.5H),6.89(d,J＝9.2Hz,2H),6.82-6.79(m,2H),3.82-3.77(m,1H),3.68(s,3H),3.56(br,2H),2.80(br,3H),2.58-2.50(m,2H),1.85-1.71(m,2H),1.55-1.33(m,3H),1.23-1.05(m,3H).
example 32: n- (((4-chloro-3-fluorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (compound 30)
Figure PCTCN2019078301-APPB-000084
4h (19mg, 0.08mmol), Int-5(29mg, 0.96mmol) and DIPEA (52mg, 0.40mmol) were dissolved in 3.0mL DMF, heated to 100 ℃ for reaction until complete conversion of starting material, cooled to room temperature after reaction, diluted with EtOAc and washed with water, and the organic layer was washed with anhydrous Na2SO4After drying, filtration and evaporation of the solvent under reduced pressure, the target compound 30(5mg) was isolated and purified by Prep-HPLC.
MS m/z(ESI)：483.1[M+H]+。
1H NMR(400MHz,CD3OD)7.50-7.46(m,1H),7.36(br,1H),7.19(d,J＝7.6Hz,1H),7.03-6.98(m,2H),6.88-6.84(m,2H),3.90-3.83(m,1H),3.77(s,3H),3.58-3.55(m,2H),3.00(s,3H),2.66-2.62(m,2H),1.95-1.87(m,2H),1.57-1.52(m,3H),1.35-1.27(m,3H)。
Example 33: n- (((5-Chloropyridin-2-yl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 31)
Figure PCTCN2019078301-APPB-000085
Compound 4h (146mg, 0.5mmol, 80% Purity), Int-7(155mg, 0.5mmol, 90% Purity) and DIPEA (330mg, 2.5mmol) were dissolved in DMF (5.0mL) under nitrogen and heated to 100 ℃ for 22 h. After the reaction was complete the mixture was cooled to rt, diluted with EtOAc and washed with water and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the objective compound 31(50 mg).
MS m/z(ESI)：466.1[M+H]+。
1H NMR(400MHz,DMSO-d6)10.05(d,J＝8.4Hz,1H),9.88(s,1H),9.32(d,J＝2.0Hz,1H),7.95-7.92(dd,J＝8.8Hz,J＝2.4Hz,1H),7.16(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,2H),6.79(d,J＝8.8Hz,2H),3.97-3.89(m,1H),3.67(s,3H),3.58-3.52(m,2H),2.97(s,3H),2.57-2.50(m,2H),1.81-1.69(m,2H),1.61-1.53(m,1H),1.44-1.33(m,2H),1.19(d,J＝6.8Hz,3H)。
Example 34: n- (((4-chlorophenyl) amino) ((1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 32)
Figure PCTCN2019078301-APPB-000086
First step Ethyl 2- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) propionate (5b)
Under nitrogen protection, 4d (205mg,1.0mmol, 90% Purity), 5a (287mg,1.2mmol), Pd2(dba)3(46mg,0.05mmol), Ruphos (47mg,0.1mmol) and sodium tert-butoxide (196mg,2.00mmol) were dissolved in toluene (5.0mL) and heated to 100 ℃ for 2 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was evaporated to dryness under reduced pressure to remove the solvent, followed by preparative TLC separation and purification (PE: EA ═ 10:1) to give 5b (150 mg).
The second step is that: 2- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) propionic acid (5c)
5b (150mg,0.5mmol, 95% Purity) was dissolved in methanol (5.0mL), NaOH (52mg,1.28mmol) in water (2.0mL) was added, heated to 50 ℃ for reaction, monitored by TLC (PE: EA ═ 5:1) until complete conversion of the starting material. After the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 3 to 4 with 1N HCl, and the solvent was evaporated under reduced pressure. Pulping the obtained crude product with DCM (MeOH) ═ 5:1, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a crude product, wherein the crude product is directly used for the next reaction without further purification.
MS m/z(ESI)：265.2[M+H]+。
The third step: (1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) carbamoyl azide (5d)
5c (147mg,0.5mmol, 95% Purity), triethylamine (155mg,1.50mmol) and DPPA (372mg,1.50mmol) were dissolved in toluene (5.0mL) under nitrogen and heated to 80 ℃ for 1 h. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was dissolved in DCM and purified by preparative TLC separation (PE: EA ═ 4:1 containing 5% DCM) to give product 5d (95 mg).
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 the reaction was carried out at room temperature, monitored by TLC (PE: EA ═ 5:1) until complete conversion of the starting material. A solution of NaOH (464mg,11.6mmol) in water (2mL) was then added and the reaction was heated to 95 ℃ for 96 h. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated under reduced pressure to give the crude product of 5 e. The crude product was used in the next reaction without further purification.
MS m/z(ESI)：236.2[M+H]+。
The fifth step: n- (((4-chlorophenyl) amino) ((1- (1- (6-methoxypyridin-3-yl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (32)
The crude 5e from the previous step and Int-1(82mg, 0.28mmol) were dissolved in DMF (5.0mL), DIPEA (258mg, 1.96mmol) was added and reacted at 100 ℃ for 9 h. After the reaction was complete the mixture was cooled to room temperature, diluted with EtOAc and washed with water and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, followed by separation and purification by Prep-HPLC to give the objective compound 32(60 mg).
MS m/z(ESI)：466.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.76(br,1H),7.78(s,1H),7.45-7.36(m,5H),7.18(br,1H),6.69(d,J＝8.8Hz,1H),3.87-3.80(m,1H),3.76(s,3H),3.61-3.55(m,2H),2.87(s,3H),2.58-2.50(m,2H),1.82-1.72(m,2H),1.56-1.49(m,1H),1.40-1.32(m,2H),1.16(br,3H)。
Example 35: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) amino) methylene) methanesulfonamide (Compound 36)
Figure PCTCN2019078301-APPB-000087
The first step is as follows: 4- (1-ethoxy-1-oxobutan-2-ylidene) piperidine-1-carboxylic acid benzyl ester (6c)
6b (4.63g,18.00mmol) was dissolved in 50mL THF, cooled to 0 deg.C, NaH (689.70mg,18.00mmol) was added slowly, after 30min of reaction 6a (3.57g,15mmol) was added and the temperature was raised to 80 deg.C for 15 h. After the reaction was complete the mixture was cooled to rt, diluted with EtOAc and washed with water and the aqueous phase extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 19:1-9:1) to give 6c (3.3 g).
The second step is that: 2- (piperidin-4-yl) butanoic acid ethyl ester (6d)
At room temperature, 6C (3.3g,9.96mmol) was dissolved in methanol (50mL), 10% Pd/C (604mg,0.57mmol) was slowly added, the reaction was carried out under hydrogen atmosphere and monitored by TLC (PE: EA ═ 5:1) until complete conversion of the starting material. After the reaction was complete the mixture was filtered through celite and washed with MeOH, and the filtrate was evaporated to dryness under reduced pressure to afford 6d of crude product (1.90g), which was used directly in the next reaction without further purification.
MS m/z(ESI)：200.2[M+H]+。
The third step: 2- (1- (4-methoxyphenyl) piperidin-4-yl) butanoic acid ethyl ester (6e)
Mixing 6d (221mg,1.0mmol, 90% Purity), 1a (286mg,1.20mmol), Pd2(dba)3(46mg,0.05mmol), Ruphos (48mg,0.1mmol) and sodium tert-butoxide (196mg,2.00mmol) were placed in a 100mL round bottom flask, toluene (5.0mL) was added under nitrogen and heated to 100 ℃ for 1 h. After completion of the reaction, the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and separation and purification by preparative TLC (PE: EA ═ 10:1) gave 6e (100 mg).
The fourth step: 2- (1- (4-methoxyphenyl) piperidin-4-yl) butanoic acid (6f)
6e (100mg,0.29mmol, 90% Purity) was dissolved in water (2.0mL), NaOH (120mg,2.95mmol) in methanol (5mL) was added, and the mixture was heated to 90 ℃ for reaction for 17 h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and the solvent was evaporated under reduced pressure. The resulting crude product was dissolved in a mixed solvent of DCM: MeOH ═ 5: 1(50 mL) and slurried. Filtration and subsequent evaporation of the solvent under reduced pressure gave 6f as a crude product which was used in the next reaction without further purification.
MS m/z(ESI)：278.2[M+H]+。
The fifth step: (1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) carbamoyl azide (6g)
The crude 6f from the previous step, DPPA (191mg,0.77mmol) and triethylamine (79mg,0.77mmol) were dissolved in toluene (5.0mL) under nitrogen and heated to 80 ℃ for 1 h. After completion of the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the mixture was separated and purified by preparative TLC (PE: EA ═ 5:1) to obtain 6g (60 mg).
MS m/z(ESI)：318.2[M+H]+。
And a sixth step: 1- (1- (4-methoxyphenyl) piperidin-4-yl) propan-1-amine hydrochloride (6h)
6g (60mg,0.17mmol, 90% Purity) was dissolved in methanol (10.0mL), and a solution of NaOH (20mg,0.51mmol) in water (2.0mL) was added, followed by reaction at room temperature for 30min, addition of a solution of NaOH (253.09mg,6.20mmol) in water (2.0mL), and heating to 120 ℃ 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, the solvent was evaporated under reduced pressure, and the obtained crude product was directly subjected to the next reaction without further purification.
MS m/z(ESI)：249.3[M+H]+。
The seventh step: n- (((4-chlorophenyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) propyl) amino) methylene) methanesulfonamide (36)
The 6h crude product from the previous step was dissolved in DMF (5.0mL) with Int-1(35mg,0.12mmol) and DIPEA (95mg,0.72mmol) under nitrogen and heated to 100 deg.C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc, washed with water, and then the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and separation and purification by preparative HPLC gave the objective compound 36(15 mg).
MS m/z(ESI)：479.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.78(br,1H),7.38-7.20(brs,5H),6.88(d,J＝9.2Hz,2H),6.79(d,J＝9.2Hz,2H),3.78-3.72(m,1H),3.67(s,3H),3.55(t,J＝10.2Hz,2H),2.86(s,3H),2.56-2.50(m,2H),1.78-1.70(m,2H),1.55(br,2H),1.41(br,3H),0.92(br,3H)。
Example 36: n- (((4-chlorobenzyl) amino) ((1- (1- (4-methoxyphenyl) piperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 38)
Figure PCTCN2019078301-APPB-000088
Compound 4h (146mg, 0.5mmol, 80% Purity)), Int-7(163mg, 0.5mmol, 90% Purity)) and DIPEA (330mg, 2.5mmol) were dissolved in DMF (5.0mL) under nitrogen blanket and heated to 100 ℃ for 16 h. After the reaction was complete the mixture was cooled to room temperature, diluted with EtOAc and washed with water and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to obtain the objective compound 38(50 mg).
MS m/z(ESI)：479.1[M+H]+。
1H NMR(400MHz,DMSO-d6)7.60(br,1H),7.42(d,J＝8.4Hz,2H),7.31(d,J＝7.2Hz,2H),7.00(br,1H),6.87(d,J＝8.8Hz,2H),6.79(d,J＝8.8Hz,2H),4.38(s,2H),3.67(s,3H),3.63(br,1H),3.52-3.48(m,2H),2.72(s,3H),2.50-2.42(m,2H),1.68-1.62(m,2H),1.45-1.23(m,3H),1.10(br,3H)。
Example 37: n- (((4-chlorophenyl) amino) ((1- (1-phenylpiperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (Compound 40)
Figure PCTCN2019078301-APPB-000089
The first step is as follows: 2- (1-Phenylpiperidin-4-yl) propionic acid ethyl ester (7b)
Under nitrogen protection, 7a (250mg,1.2mmol), 4d (206mg,1mmol, 90% Purity), Pd2(dba)3(46mg,0.05mmol), Ruphos (48mg,0.1mmol) and sodium tert-butoxide (196.12mg,2.00mmol) were dissolved in toluene (5.0mL) and heated to 100 ℃ for 2.5 h. After completion of the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was separated and purified by preparative TLC (PE: EA ═ 10:1) to give 7b (240 mg).
MS m/z(ESI)：262.2[M+H]+。
The second step is that: 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 ℃ for reaction, and monitored by TLC (PE: EA ═ 5:1) until complete conversion of the starting material. After the reaction was completed, the mixture was cooled to room temperature, pH was adjusted to 3-4 with 1N HCl, the solvent was evaporated under reduced pressure, the resulting crude product was dissolved in a mixed solvent of DCM: MeOH 5:1 and slurried, filtered, and then the solvent was evaporated under reduced pressure to give a crude product of 7c, which was directly subjected to the next reaction without further purification.
MS m/z(ESI)：234.1[M+H]+。
The third step: (1- (1-phenylpiperidin-4-yl) ethyl) carbamoyl azide (7d)
The crude product of 7c from the previous step, DPPA (744mg,3.0mmol) and triethylamine (309mg,3.0mmol) were dissolved in toluene (10.0mL) under nitrogen and heated to 80 ℃ for 1 h. After the reaction was complete the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and purified by preparative TLC (PE: EA ═ 5:1 containing 5% DCM) to give 7d (200 mg).
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), and a solution of NaOH (89.60mg,2.20mmol) in water (1.0mL) was added to react at room temperature for 1 hour, and then a solution of NaOH (1.18g,28.97mmol) in water (1.0mL) was added to react at 95 ℃ for 40 hours. TLC (PE: EA ═ 5:1) was monitored until complete conversion of starting material. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 3-4 with 1N HCl, and then the solvent was evaporated under reduced pressure. The resulting crude product was dissolved in a mixed solvent of DCM: MeOH ═ 5:1, slurried, filtered, and then the solvent was evaporated under reduced pressure to afford the crude product of 7e, which was directly subjected to the next reaction without further purification.
MS m/z(ESI)：205.2[M+H]+。
The fifth step: n- (((4-chlorophenyl) amino) ((1- (1-phenylpiperidin-4-yl) ethyl) amino) methylene) methanesulfonamide (40)
The crude product of 7e from the previous step, Int-1(352mg,1.20mmol) and DIPEA (528mg,4.00mmol) were dissolved in DMF (10.0mL) under nitrogen and heated to 95 ℃ for 15 h. After the reaction was complete the mixture was cooled to room temperature, diluted with EtOAc and washed with water and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to give the objective compound 40(180 mg).
MS m/z(ESI)：435.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.76(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)
Figure PCTCN2019078301-APPB-000090
The first step is as follows: 4- (((trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylic acid benzyl ester (8c)
LiHMDS (1.0M,11.00mL) was dissolved in 10mL of anhydrous THF and cooled to-78 ℃. A solution of 8a (2.38g,10.0mmol) in THF (10mL) was added slowly and the reaction was completed at-78 deg.C for 30 min. Then a solution of 8b (4.01g,11.00mmol) in THF (10mL) was added slowly and the reaction was held at-78C for 2h after the addition was complete. The cooling liquid was then removed, and the reaction was slowly warmed to room temperature and reacted for 2 h. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and then separated and purified by silica gel column chromatography (PE: EA ═ 19:1-4:1) to give 8c (3.45 g).
The second step is that: 4- (4-methoxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid benzyl ester (8e)
Under nitrogen protection, 8d (1.44g,9.3mmol), 8c (3.25g,8.45mmol), Pd (dppf) Cl2*CH2Cl2(352mg,0.42mmol) and potassium carbonate (2.38g,16.9mmol) were placed in a 100mL reaction flask, DMF (20mL) and water (5mL) were added, and then heated to 90 ℃ for 2 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was washed with water, and the organic phase was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and separation and purification by silica gel column chromatography (PE: EA ═ 19:1-9:1) gave 8e (700 mg).
MS m/z(ESI)：324.1[M+H]+。
The third step: 4- (4-methoxyphenyl) piperidine (8f)
8e (700mg,2.16mmol) was dissolved in methanol (30mL), 10% Pd/C (115.18mg, 108.23. mu. mol) was added, the reaction was carried out under hydrogen atmosphere (1atm), and monitored by TLC until complete conversion of the starting material. After the reaction was complete, the mixture was filtered through celite and washed with MeOH. The solvent was evaporated under reduced pressure to dryness to afford crude 8f (400mg) which was used in the next reaction without further purification.
MS m/z(ESI)：192.2[M+H]+。
The fourth step: n- (4-chlorophenyl) -4- (4-methoxyphenyl) -N' - (methylsulfonyl) piperidine-1-carboxamidine (41)
8f (60mg,0.30mmol), Int-1(88mg,0.30mmol) and DIPEA (196mg,1.49mmol) were dissolved in DMF (5.0mL) under nitrogen and heated to 100 ℃ for 8 h. After the reaction was complete the mixture was cooled to room temperature, diluted with EtOAc and washed with water and the aqueous phase was extracted twice with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure, followed by separation and purification by Prep-HPLC to obtain the objective compound 41(40 mg).
MS m/z(ESI)：422.1[M+H]+。
1H NMR(400MHz,DMSO-d6)8.68(s,1H),7.40-7.37(m,2H),7.18-7.13(m,4H),6.86-6.83(m,2H),3.96-3.91(m,2H),3.71(s,3H),2.99-2.93(m,2H),2.87(s,3H),2.71-2.65(s,1H),1.74-1.68(m,2H),1.58-1.48(m,2H)。
The separation and purification method comprises the following steps:
in the invention, except that the compound 32 is separated and purified by Waters type HPLC, the other compounds are separated and purified by Aglient 1260 type HPLC, the column temperature is 25 ℃, and the other separation conditions are shown in the following table:
Figure PCTCN2019078301-APPB-000091
Figure PCTCN2019078301-APPB-000092
Figure PCTCN2019078301-APPB-000093
biological evaluation
The following examples further describe and explain the present invention and are not intended to limit the scope of the invention.
EXAMPLE 1 determination of the inhibitory Effect of Compounds on the intracellular IDO enzyme of Hela
The effect of compounds on intracellular IDO enzyme activity was determined using the NFK Green method.
Reagent: NFK Green fluorescent dye (NTRC); l-tryptophan (Sigma-Aldrich); recombinant Human IFN-gamma Protein (R & D systems)
The experimental scheme is as follows:
hela cells were cultured in complete medium (DMEM containing 10% fetal bovine serum) (37 ℃ C., 5% inCO2The incubator of (1). Digesting with pancreatin-EDTA for 2-3 times a week for passage. When the cells are in exponential growth phase, the cells are harvested, counted and plated. The cell concentration (10000 cells/well) was adjusted, and the cells were seeded in a 96-well plate in an amount of 70. mu.L/well, and placed in an incubator to be cultured for 24 hours.
Preparing a compound to be detected into a mother solution by DMSO, sucking a proper amount of the mother solution into a complete culture medium, and uniformly mixing to prepare a compound solution to be detected with a corresponding concentration. Add 10. mu.L of test compound solution to each well and incubate for 1 h. Wells with DMSO alone were set as negative controls.
mu.L of 500ng/mL IFN-. gamma.IFN (Recombinant Human IFN-gamma Protein) (dissolved in complete medium) and 10. mu.L of sterile 0.5mM L-tryptophan solution (dissolved in 20mM Hepes) were added and incubation continued for 48 h.
After incubation was complete, 25. mu.L of the supernatant was transferred to 384-well plates, 5. mu.L of NFK Green was added to each well, the plates were sealed and incubated at 37 ℃ for 4 h. Fluorescence is detected by a microplate reader, and Ex./Em. is 400 +/-25 nm/510 +/-20 nm.
Data processing, compound inhibition rate (%) (1-Savg/Cavg) × 100%; Savg is the average value of the fluorescence readings of the test compound, the average value of the fluorescence readings of the Cavg negative control group, and IC50Calculated by GraphPad Prism software.
As a result:
TABLE 1 inhibition of IDO enzyme Activity in Hela cells by Compounds of the invention IC50
Compound numbering IC 50(nM)
4 5.5
12 8.1
13 29.4
15 10.1
16 8.4
17 10.8
18 6.2
19 14.5
20 13.3
23 23.3
24 17.0
25 14.2
27 3.6
29 4.8
29A 1.5
30 3.9
32 8.0
36 9.6
40 15.3
41 10.9
As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on the IDO enzyme in Hela cells.
Experimental example 2: hERG assay
Using PredictorTMThe hERG Fluorescence Polarization Assay Kit (manufacturer: ThermoFisher) was used to test the inhibition of compounds (10. mu.M concentration) on the hERG potassium channel according to the Kit instructions, and the results are shown in Table 2.
TABLE 2 inhibition of hERG by Compounds
Compound (I) IC 50(μM)
15 >10
29A >10
32 >10
40 >10
41 >10
The results indicate that the compounds of the invention (e.g., compounds 15, 29A, 32, 40 and 41) have no significant inhibitory effect on hERG, resulting in a low probability of prolonged cardiac QT interval.
Experimental example 3: CYP enzyme inhibition assay
CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, of which the most important are CYP1a2, CYP2D6, and CYP3a 4.
In assays for measuring inhibition of CYP450 enzymes by fluorescence, P450-Glo is usedTM CYP1A2 Screening System、
Figure PCTCN2019078301-APPB-000094
CYP2D6 Cyan Screening Kit and
Figure PCTCN2019078301-APPB-000095
CYP3A4 Red Screening Kit, the inhibitory activity of the compound on CYP1A2, CYP2D6 and CYP3A4 is respectively measured according to the Kit instructions. The test results are shown in Table 3A.
TABLE 3A. inhibition of CYP enzymes by Compounds
Figure PCTCN2019078301-APPB-000096
The inhibition of CYP3a4 by compound 29A was determined by LC-MS method as follows:
reagents and controls:
CYP3A4 probe substrate selects testosterone and midazolam, positive inhibitor selects ketoconazole, incubation medium is mixed Human Liver Microsome (HLM)
The test method comprises the following steps:
after pre-incubation (at 37 ℃) for 5min with a mixture of probe substrate (50. mu.l), PBS (49. mu.l), test compound 29A or the positive control compound ketoconazole (1. mu.l) and HLM (50. mu.l), NADPH (50. mu.l) was added and incubation continued for 30 min. Wherein the incubation concentration of HLM is 0.1mg/ml, the incubation concentration of testosterone is 50 mu M, and the incubation concentration of midazolam is 2 mu M. After the reaction for the corresponding time, 600. mu.l of glacial acetonitrile containing the internal standard is added into the reaction incubation liquid of testosterone to terminate the reaction, and 800. mu.l of glacial acetonitrile containing the internal standard is added into the reaction incubation liquid of midazolam to terminate the reaction. All samples were vortexed, centrifuged and the supernatant was taken and assayed.
The determination method comprises the following steps:
LC-MS/MS: mass spectra were taken with Sciex API 5500. The liquid chromatography is performed by using a Waters acquisition UPLC I-CLASS system. The chromatographic column is Hypersil GOLD C18(2.1mm × 50mm,1.9 μm.) the mobile phase, phase A, water + 0.1% formic acid, phase B, acetonitrile, flow rate of 0.4ml/min, column temperature of 40 ℃, ion source in ESI source positive ion mode, and scanning for Multiple Reaction Monitoring (MRM).
The half maximal Inhibitory Concentration (IC) of the compound against CYP3A4 was determined by measuring the concentration of the major metabolite produced by the probe substrate at different concentrations of the compound, using the vehicle group (DMSO) as a negative control50)。
TABLE 3B inhibition of CYP3A4 by Compound 29A
Figure PCTCN2019078301-APPB-000097
Compound 29A showed no significant inhibition of CYP3A4 (IC)50>10μM)。
The results show that the compounds of the present invention (e.g., compounds 4, 12, 13, 15, 19, 25, 27, 29A, 30 and 32) do not have significant inhibitory effects on CYP1a2, CYP2D6 and CYP3a4 enzymes.
Experimental example 4: pharmacokinetic (PK) studies in rats
SPF grade male SD rats were administered the compounds of the present invention via vein (IV) and gavage (PO), respectively, to investigate pharmacokinetic characteristics.
All animals were fasted for 10-14 hours before dosing and returned to food 4 hours after dosing. The dosages of IV and PO were 1mg/kg and 5mg/kg, respectively, with IV vehicle being 5% DMSO: 5% Solutol: 90% physiological saline, and PO vehicle being 0.5% MC (sodium methyl cellulose). Blood was collected before IV administration (0h) and at 0.083, 0.25, 0.5, 1, 2,4, 6, 8 and 24h post-administration, blood was collected before PO administration (0h) and at 0.25, 0.5, 1, 2,4, 6, 8 and 24h post-administration, blood was EDTA.K2Anticoagulating, centrifuging within 30min after blood collection to obtain plasma sample, and storing at-80 deg.C. Plasma samples were processed for precipitated protein and analyzed by LC-MS/MS. Mass spectrometry was performed using Sciex API 5500 and liquid chromatography was performed using a Waters ACQUITY I-CLASS system; chromatographic column using Hypersil GOLD C18(2.1mm × 50mm,1.9 μm), mobile phase A is 0.1% formic acid aqueous solution, B is acetonitrile, flow rate is 0.5ml/min, column temperature is 40 ℃, ion source is ESI source positive ion mode, scanning mode is Multiple Reaction Monitoring (MRM), WinNonlin 6.3 software is applied, pharmacokinetic parameters are calculated by using non-compartmental model, and the results are shown in the following table 4:
TABLE 4 pharmacokinetic parameters of the Compounds
Figure PCTCN2019078301-APPB-000098
The results show that the compounds of the invention (e.g., compounds 1, 12, 15, 18 and 29A) have good PK properties in SD rats.
Various modifications of the invention in addition to those described herein, in light of the foregoing description, are intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims (40)

  1. A compound of formula I-A, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound:
    Figure PCTCN2019078301-APPB-100001
    R1is selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    X is NR11Or CHNO2；
    m is 0, 1 or 2;
    n is 0 or 1;
    t is 0, 1 or 2;
    q is CH, N, COH, CF, CMe, CNH2CNHMe or CNMe2；
    R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group; or
    R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl and C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl or C1-C6A hydroxyalkyl group; or
    R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and 4-7 membered heterocyclyl;
    R4and R5Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
    R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、 -NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
    R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2-(C6-C14Aryl), -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl and 3-14 membered heterocyclyl, said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo, -CH2- (5-to 14-membered heteroaryl), C3-C7Cycloalkyl, 3-14 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8(ii) a Or
    R5And R6Linked to form, together with the N atom to which they are attached, a 5-14 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    R7、R8And R9Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclyl;
    R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclic group, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl;
    R11selected from hydrogen, OH, CN, -SO2R12and-C (O) R13；
    R12Is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
    R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl and C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
    with the following conditions:
    (1) when m is 1, n is 1 and t is 1, Q is not CH;
    (2) when N is 0, m is 1, t is 1, Q is N, X is NR11，R11Is H, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
    Figure PCTCN2019078301-APPB-100002
    (3) When N is 0, m is 2, t is 0, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
    Figure PCTCN2019078301-APPB-100003
    And
    (4) when N is 0, m is 0, t is 2, Q is N, X is NR11，R11Is CN, R4Is H, R5Is H and R6Is C as defined above6When aryl is present, R1Is not that
    Figure PCTCN2019078301-APPB-100004
  2. A compound of formula I-a according to claim 1, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R1、R6each independently selected from C6-C14Aryl, 5-14 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1、R6Each independently selected from C6-C10Aryl, 5-10 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C10Aryl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1、R6Each independently selected from C6-C10Aryl, 5-10 membered heteroaryl and 9-10 membered arylheterocyclo, C6-C10Aryl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclo may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8。
  3. A compound of formula I-a according to claim 1 or 2, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R1、R6each independently selected from the group consisting of phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and
    Figure PCTCN2019078301-APPB-100005
    wherein ring P' is phenyl or 5-7 membered heteroaryl, which phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and 5-7 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolyl and isoquinolinePhenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1、R6Each independently selected from the group consisting of phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl, said phenyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl and pyridoimidazolyl being optionally substituted by oneOr a plurality of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
    preferably, R1、R6Each independently selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzimidazolyl and pyridoimidazolyl, which may optionally be substituted with one or more of the following substituents: F. cl, methyl, CN or methoxy.
  4. A compound of formula I-a according to any one of claims 1 to 3, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R1selected from phenyl, pyridyl and quinolyl, which may be optionally substituted by one or more of the following substituents: F. cl, CN or methoxy;
    preferably, R1Selected from:
    Figure PCTCN2019078301-APPB-100006
    Figure PCTCN2019078301-APPB-100007
  5. the compound of formula I-A according to any one of claims 1 to 4, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R6selected from phenyl and pyridyl, which may be optionally substituted with one or more of the following substituents: F. cl, CN or methoxy;
    preferably, R6Selected from:
    Figure PCTCN2019078301-APPB-100008
  6. a compound of formula I-a according to claim 1 or 2, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R1is selected from
    Figure PCTCN2019078301-APPB-100009
    Wherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl group、C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1Is composed of
    Figure PCTCN2019078301-APPB-100010
    Wherein ring P' is a 5-6 membered heterocyclic ring, said 5-6 membered heterocyclic ring may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R1Is selected from
    Figure PCTCN2019078301-APPB-100011
    Figure PCTCN2019078301-APPB-100012
    Figure PCTCN2019078301-APPB-100013
    Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
    preferably, R1Is selected from
    Figure PCTCN2019078301-APPB-100014
  7. A compound of formula I-a according to claim 1, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R6is selected from-CH2-(C6-C14Aryl) and-CH2- (5-14 membered heteroaryl), the-CH2-(C6-C14Aryl) and-CH2- (5-to 14-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R6Is selected from-CH2-(C6-C10Aryl) and-CH2- (5-to 10-membered heteroaryl), the-CH2-(C6-C10Aryl) and-CH2- (5-to 10-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C: (O)OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R6Is selected from-CH2-phenyl and-CH2- (5-6 membered heteroaryl), the-CH2-phenyl and-CH2- (5-to 6-membered heteroaryl) may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R6Is selected from-CH2-phenyl and-CH2-pyridyl, -said-CH2-phenyl and-CH2-the pyridyl group may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
    preferably, R6is-CH2-phenyl, said-CH2-phenyl may be optionally substituted with one or more of the following substituents: f or Cl;
    preferably, R6Is composed of
    Figure PCTCN2019078301-APPB-100015
  8. A compound of formula I-a according to any one of claims 1 to 7, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    R2and R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl and C1-C6A hydroxyalkyl group; or
    R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl and C1-C6A hydroxyalkyl group; or
    R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and 4-7 membered heterocyclyl containing O, S or N;
    preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2、C3-C6Cycloalkyl or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group;
    preferably, R2And R3Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl and C1-C3Hydroxyalkyl radical of said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, C1-C3Haloalkyl, methoxy, ethoxy, C3-C6Cycloalkyl and C1-C3A hydroxyalkyl group; or R2And R3Are linked so as to form, together with the C atom to which they are linked, a P ring selected from C3-C6Cycloalkyl and O-containing 4-7 membered heterocyclyl, more preferably selected from
    Figure PCTCN2019078301-APPB-100016
    More preferably, R2And R3Each independently selected from hydrogen, methyl, ethyl, cyclopropyl and-CH2-a cyclopropyl group; or, R2And R3Are linked together with the C atom to which they are attached to form a P ring which is
    Figure PCTCN2019078301-APPB-100017
  9. A compound of formula I-a according to any one of claims 1 to 8, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    R4and R5Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
    Preferably, R4And R5Are all hydrogen.
  10. A compound of formula I-a according to claim 1, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R5and R6Are connected with each otherThereby forming, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo group, which 5-10 membered heteroaryl, 9-10 membered arylheterocyclo group may be optionally substituted with one or more of the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R5And R6Are linked so as to form, together with the N atom to which they are attached, a 5-10 membered heteroaryl or 9-10 membered arylheterocyclo, said 5-10 membered heteroaryl, 9-10 membered arylheterocyclo being optionally substituted with one or more of the following substituents: OH, F,Cl、CN、NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R5And R6Are linked to form together with the N atom to which they are attached
    Figure PCTCN2019078301-APPB-100018
    Which may be optionally substituted with one or more of the following substituents: OH, F, Cl, CN, NO2、CO2H、C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl, -C (O) OR7、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、-C(O)R10、-SO2R10、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; c as herein described1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl, -OC1-C3alkyl-OC1-C3Alkyl radical, C1-C3Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8or-NR7R8；
    Preferably, R5And R6Are linked to form together with the N atom to which they are attached
    Figure PCTCN2019078301-APPB-100019
    Which may be optionally substituted with one or more of the following substituents: F. cl, CN, methyl, CF3、CHF2Or a methoxy group;
    preferably, R5And R6Are linked to form together with the N atom to which they are attached
    Figure PCTCN2019078301-APPB-100020
    Which may be optionally substituted with one or more of the following substituents: f or Cl;
    preferably, R5And R6Together with the N atom to which they are attached form
    Figure PCTCN2019078301-APPB-100021
  11. A compound of formula I-a according to claim 10, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R4selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8or-NR9C(O)R10；
    Preferably, R4Is hydrogen.
  12. A compound of formula I-a according to any one of claims 1 to 11, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R7、R8and R9Each independently selected from hydrogen and C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclic group, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R7And R8Are linked so as to form, together with the N atom to which they are attached, a 4-7 membered heterocyclic group.
  13. A compound of formula I-a according to any one of claims 1 to 12, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R10is selected from C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclic group, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl and 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NH2、NHMe、NMe2Or CO2H; or, R9And R10Are linked so as to form, together with the N and C or S atoms to which they are attached, a 4-7 membered heterocyclyl.
  14. A compound of formula I-a according to any one of claims 1 to 13, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R11selected from CN and-SO2R12。
  15. A compound of formula I-a according to any one of claims 1 to 14, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein:
    R12is selected from C1-C6Alkyl and C3-C6Cycloalkyl radical, said C1-C6Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
    preferably, R12Is selected from C1-C3Alkyl and C3-C6Cycloalkyl radical, said C1-C3Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with one or more of the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group;
    preferably, R12Is methyl or C3-C6A cycloalkyl group;
    preferably, R12Is methyl.
  16. A compound of formula I-a according to any one of claims 1 to 15, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    R13is selected from C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl and C1-C3alkyl-OC1-C3Alkyl radical, said C1-C3Alkyl radical, C1-C3Alkoxy radical, C3-C6Cycloalkyl radical, C1-C3Hydroxyalkyl radical, C1-C3alkyl-OC1-C3Alkyl groups may be optionally substituted with one or more of the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe2Or a 4-7 membered heterocyclic group.
  17. A compound of formula I-a according to any one of claims 1 to 16, a stereoisomer, an tautomeric form or a mixture thereof, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    m is 0 or 1, preferably m is 1.
  18. A compound of formula I-a according to any one of claims 1 to 17, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    n is 0 or 1.
  19. A compound of formula I-a according to any one of claims 1 to 18, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    t is 0 or 1, preferably t is 1.
  20. A compound of formula I-a according to any one of claims 1 to 19, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, wherein:
    q is CH or N;
    preferably, Q is N.
  21. A compound of formula I-a according to any one of claims 1 to 9 and 12 to 20, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula II:
    Figure PCTCN2019078301-APPB-100022
    wherein R is1、R6And X is as defined in any one of claims 1 to 9 and 12 to 20.
  22. A compound of formula I-a according to any one of claims 1 to 9 and 12 to 20, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula III:
    Figure PCTCN2019078301-APPB-100023
    wherein R is1、R6X and R2As defined in any one of claims 1 to 9 and 12 to 20;
    preferably, R2Is H, C1-C3Alkyl radical, C3-C6Cycloalkyl or-CH2-(C3-C6Cycloalkyl groups);
    preferably, R2Is H, methyl, ethyl, cyclopropyl or-CH2-cyclopropyl.
  23. The compound of formula I-a according to claim 22, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, wherein the compound has the structure of formula IV:
    Figure PCTCN2019078301-APPB-100024
  24. a compound of formula I-B, a stereoisomer, a tautomer, or a mixture thereof of said compound, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound:
    Figure PCTCN2019078301-APPB-100025
    wherein R is1、R5、R6X, m and t are as defined in any one of claims 1 to 7, 9 to 10, 12 to 17 and 19.
  25. A compound of formula I-B according to claim 24, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein m-1.
  26. A compound of formula I-B according to claim 24 or 25, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, a metabolite, or a prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein t ═ 1.
  27. A compound of formula I-B according to any one of claims 24-26, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein the compound has the structure of formula V:
    Figure PCTCN2019078301-APPB-100026
  28. a compound of formula I-B according to any one of claims 24 to 27, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R1is phenyl, said phenyl optionally being substituted by one or more C1-C6Alkoxy, preferably C1-C3Alkoxy, more preferably methoxy;
    preferably, R1Is composed of
    Figure PCTCN2019078301-APPB-100027
  29. A compound of formula I-B according to any one of claims 24 to 28, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    R6is phenyl, which may optionally be substituted with one or more halogens, preferably F or Cl, more preferably Cl;
    preferably, R6Is composed of
    Figure PCTCN2019078301-APPB-100028
  30. A compound of formula I-B according to any one of claims 24 to 29, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, wherein R is5Is hydrogen.
  31. A compound of formula I-B according to any one of claims 24 to 30, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, wherein:
    x is NR11，
    Wherein R is11is-SO2R12(ii) a And wherein R12Is C1-C6Alkyl, preferably C1-C3Alkyl, more preferably methyl.
  32. The compound of claim 1 or 24, a stereoisomer, a tautomer, or a mixture thereof of the compound, a stable isotopic derivative, a metabolite, or a prodrug of the compound, or a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, wherein the compound is selected from the group consisting of:
    Figure PCTCN2019078301-APPB-100029
    Figure PCTCN2019078301-APPB-100030
  33. a pharmaceutical composition comprising a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, and one or more pharmaceutically acceptable carriers.
  34. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutical composition according to claim 33, and one or more pharmaceutically acceptable carriers.
  35. Use of a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, a metabolite, or a prodrug of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of said compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical formulation according to claim 34, in the manufacture of a medicament for the prevention, alleviation, and/or treatment of a disease or disorder associated with IDO activity,
    preferably, the disease or disorder associated with IDO activity is selected from the group consisting of tumors, depression and senile dementia.
  36. The use of claim 35, wherein the medicament further comprises an additional agent for preventing, ameliorating and/or treating a disease or disorder associated with IDO activity.
  37. Use of a compound according to any one of claims 1 to 32, a stereoisomer, a tautomer, or a mixture thereof, a stable isotopic derivative, a metabolite, or a prodrug of said compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of said compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical formulation according to claim 34, for the manufacture of a medicament for the prevention, alleviation, and/or treatment of a disease or condition caused by immunosuppression,
    preferably, the disease or condition due to immunosuppression is selected from the group consisting of a tumor, a viral infection, an autoimmune disease.
  38. The use of claim 37, wherein the medicament further comprises an additional agent for preventing, ameliorating and/or treating a disease or condition caused by immunosuppression.
  39. A 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 said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a pharmaceutical composition according to claim 33, or a pharmaceutical formulation according to claim 34, for use in the prevention, alleviation, and/or treatment of a disease or condition (e.g. a tumor, a viral infection, or an autoimmune disease) caused by immunosuppression.
  40. Methods of preventing, ameliorating and/or treating diseases or conditions caused by immunosuppression, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-32, stereoisomers, tautomers or mixtures thereof of said compounds, stable isotopic derivatives, metabolites or prodrugs of said compounds, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, the pharmaceutical composition of claim 33, or a pharmaceutical preparation according to claim 34, and optionally comprising a combination with other drugs for the prevention, alleviation and/or treatment of diseases or disorders due to immunosuppression (e.g. tumors, viral infections or autoimmune diseases), preferably with PD-1, PDL-1 antibodies.
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