CN111247119A - 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 PDFInfo
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Abstract
The compound shown in the formula (I), a pharmaceutical composition, a pharmaceutical preparation and the application of the compound in preparing medicines for preventing or treating diseases related to IDO activity or IDO mediated immunosuppression.
Description
The invention relates to novel amidine and guanidine derivatives as IDO inhibitors, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in medicines.
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. IDO was first found intracellularly in the Hayaishi group in 1969 (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 depression, senile dementia, cataract, etc. In addition, IDO is also implicated in neurological and psychiatric disorders (e.g., mood disorders) as well as other chronic diseases caused by tryptophan degradation due to IDO activation, such as viral infections (e.g., AIDS), autoimmune diseases, bacterial infections such as lyme disease and streptococcal infections, and the like. Therefore, inhibition of IDO activity has great therapeutic value.
The IDO small molecule inhibitor, Epacadostat, developed by Incyte, 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 (NLG-8189) in combination with other drugs, for example in phase II/III trials in the treatment of metastatic melanoma in combination with the PD-1 antibody keytruda or Nivolumab. Published patent applications for IDO inhibitors include WO2016073770, WO2016073734, WO2016073738 and the like. However, no IDO inhibitors are currently on the market. In order to achieve better therapeutic effects and better meet market demands, development of new IDO inhibitors with high efficiency and low toxicity is urgently needed.
Disclosure of Invention
An aspect of the present invention provides a safe and effective IDO inhibitor having a novel structure. The IDO inhibitor is a compound of formula I, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:
wherein:
n is 0 or 1;
R1is selected from C6-C14Aryl, 5-14 membered heteroaryl, or 9-10 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl may be optionally substituted with 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; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with 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、-SO2NR7R8、-NR7R8；
R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, 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 the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl, said 4-7 membered heterocyclyl being optionally substituted with: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, or R2、R3And together with the C atom to which they are attached form a P ring selected from C3-C6Cycloalkyl or 4-7 membered heterocyclyl;
R4and R5Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, 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 the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、-C(O)NR7R8、-NR9C(O)R10；
R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6Haloalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8(ii) a Preferably R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, C3-C7The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6Haloalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-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, 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 are optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclyl; when a plurality of R7When present simultaneously, each R7May be the same or different; when a plurality of R8When present simultaneously, each R8May be the same or different; when a plurality of R9When present simultaneously, each R9May be the same or different;
R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl, 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 the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C or S atoms to which they are attached form a 4-7 membered heterocyclyl; when a plurality of R10When present simultaneously, each R10May be the same or different;
x is NR11Or CHNO2；
R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13，
R12Is selected from C1-C6Alkyl radical, C3-C6A cycloalkyl group; said C1-C6Alkyl radical, C3-C6Cycloalkyl is optionally substituted with the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe24-7 membered heterocyclyl;
R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, 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 the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl.
In some embodiments of the invention, the compound has the structure of formula II, III, IV or V:
wherein R is1、R5、R6And X is as defined above for formula I;
wherein R is1、R2、R3、R5、R6And X is as defined above for formula I; preferably, R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6An alkyl group;
wherein R is1、R4、R5、R6And X is as defined above for formula I; preferably, R4Is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, 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 the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、-C(O)NR7R8、-NR9C(O)R10；
Wherein R is1P ring, R5、R6And X is as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula II-1, II-2, III-1, III-2, IV-1, IV-2, V-1, or V-2:
wherein R is1、R5、R6And X is as defined above for formula I;
wherein R is1、R2、R3、R5、R6And X is as defined above for formula I; preferably, R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6An alkyl group;
wherein R is1、R4、R5、R6And X is as defined above for formula I; preferably, R4Is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, 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 the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8、-NR9C(O)R10；
Wherein R is1P ring, R5、R6And X is as defined above for formula I.
In some preferred embodiments of the invention, R1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with 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; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with 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、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined above.
In a more preferred embodiment of the invention, R1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -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; said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined above.
In a more preferred embodiment of the invention, R1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: halogen, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl, -C (O) NR7R8(ii) a Said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl groups may be optionally substituted with the following substituents: OH, -NR7R8；R7、R8As defined above.
In a more preferred embodiment of the invention, R1Selected from phenyl, quinolyl, pyridyl, indazolyl,
The phenyl, the quinolyl, the pyridyl, the indazolyl,
Optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, -C (O) NH (CH)3)、-C(O)N(CH3)2、-OCH2CH2OH、-OCH2CH2NH(CH3)、-OCH2CH2N(CH3)2。
In a preferred embodiment of the invention, R1Selected from phenyl, quinolyl and pyridyl, wherein the phenyl, quinolyl and pyridyl are in a structure of a general formula,The pyridyl group may be optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy.
In a preferred embodiment of the invention, R1Selected from phenyl, p-methoxyphenyl, quinolyl, pyridyl,
In a preferred embodiment of the present invention, n ═ 1.
In a preferred embodiment of the present invention, n ═ 0.
In a preferred embodiment of the invention, R2And R3Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl radical of said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl groups may be optionally substituted with the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl, said 4-7 membered heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4Hydroxyalkyl, or R2、R3And together with the C atom to which they are attached form a P ring selected from C3-C6Cycloalkyl or 4-7 membered heterocyclyl.
In a more preferred embodiment of the invention，R2And R3Each independently selected from hydrogen and C1-C4Alkyl or R2、R3And together with the C atom to which they are attached form a P ring selected from C3-C5A cycloalkyl group.
In a more preferred embodiment of the invention, R2And R3Each independently selected from hydrogen, methyl, ethyl, propyl, or R2、R3And together with the C atom to which they are attached form a P ring selected from cyclopropane, cyclobutane or cyclopentane.
In a more preferred embodiment of the invention, R2And R3Each independently selected from hydrogen, methyl, ethyl, propyl; preferably, R2And R3Each independently selected from hydrogen, methyl.
In some preferred embodiments of the invention, R4And R5Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Alkoxy radical, C2-C4Hydroxyalkyl radical, C2-C4alkyl-OC2-C4Alkyl radical, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C2-C4Hydroxyalkyl radical, C2-C4alkyl-OC2-C4Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C1-C4Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8、-NR9C(O)R10；R7、R8、R9、R10As defined above.
In a more preferred embodiment of the invention, R4And R5Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Hydroxyalkyl of said C1-C4Alkyl groups may be optionally substituted with the following substituents: halogen, -NR7R8，R7、R8As defined above.
In a more preferred embodiment of the invention, R4And R5Each independently selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, -CH2CH2NH(CH3)、-CH2CH2N(CH3)2。
In a more preferred embodiment of the invention, R4And R5Each independently selected from hydrogen, methyl, ethyl, propyl; preferably, R4And R5Each is hydrogen.
In some preferred embodiments of the invention, R6Is selected from C6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, C3-C7Cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, C3-C7The cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl can be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl, -OC1-C4alkyl-OC1-C4Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4Hydroxyalkyl radical, OC1-C4alkyl-OC1-C4Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl radical, C1-C4Haloalkyl, -OC1-C4alkyl-OC1-C4Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined above.
In a more preferred embodiment of the invention, R6Selected from C optionally substituted by substituents6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl, said C6-C10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl cocoa, optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4Alkoxy radical, C2-C4Hydroxyalkyl, -OC2-4alkyl-OH, -OC2-4alkyl-NR7R84-7 membered heterocyclyl, R7、R8As defined above.
In a more preferred embodiment of the invention, R6Selected from phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridinyl, thiazolyl, pyrrolidinyl, 2, 3-dihydrobenzo [ b][1,4]Dioxinyl, said phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridinyl, thiazolyl, pyrrolidinyl, 2, 3-dihydrobenzo [ b][1,4]The dioxinyl group may be optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CN, hydroxyethyl, hydroxypropyl, -OCH2CH2OH、-OCH2CH2NHCH3、-OCH2CH2N(CH3)2Pyrrolidinyl, 3-hydroxypyrrolidinyl.
In a more preferred embodiment of the invention, R6Is phenyl optionally substituted with fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or CN; preferably, R6Is phenyl, optionally substituted with fluoro, chloro, methoxy or CN.
In some preferred embodiments of the invention, R7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-7 membered heterocyclic group, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl and 4-7 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclic group.
In a more preferred embodiment of the invention, R7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclic group, said C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclic group.
In a more preferred embodiment of the invention, R7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Alkoxy radical, said C1-C4Alkyl radical, C2-C4Alkoxy may be optionally substituted for NH by2、NHMe、NMe2。
In a more preferred embodiment of the invention, R7、R8And R9Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.
In some preferred embodiments of the invention, R10Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-7 membered heterocyclic group, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl and 4-7 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C or S atoms to which they are attached form a 4-7 membered heterocyclyl.
In a more preferred embodiment of the invention, R10Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclic ringA group of C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C atoms to which they are attached form a 4-7 membered heterocyclyl.
In a more preferred embodiment of the invention, R10Is selected from C1-C4Alkyl radical, C2-C4Alkoxy radical, said C1-C4Alkyl radical, C2-C4Alkoxy groups may be optionally substituted with the following substituents: NH (NH)2、NHMe、NMe2。
In a more preferred embodiment of the invention, R10Selected from methyl, ethyl, propyl, isopropyl.
In some preferred embodiments of the invention, X is NR11Or CHNO2(ii) a Preferably, X is NR11；
R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13，
R12Is selected from C1-C4Alkyl radical, C3-C6A cycloalkyl group; said C1-C4Alkyl radical, C3-C6Cycloalkyl groups may be optionally substituted with the following substituents: OH, OC1-C4Alkyl, NH2、NHMe、NMe24-7 membered heterocyclyl;
R13is selected from C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, said C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl groups may be optionally substituted with the following substituents:OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl;
in a preferred embodiment of the invention, X is selected from NR11Or CHNO2(ii) a Preferably, X is NR11；
R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13，
R12Is selected from C1-C4Alkyl radical, C3-C5A cycloalkyl group;
R13is selected from C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, said C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl groups may be optionally substituted with the following substituents: OH, halogen, C1-C4Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-6 membered heterocyclyl.
In a more preferred embodiment of the invention, X is selected from NR11Or CHNO2Preferably, X is NR11(ii) a Wherein R is11Selected from CN, -SO2R12；R12Is selected from C1-C4Alkyl radical, C3-C5A cycloalkyl group.
In a more preferred embodiment, X is selected from NR11Or CHNO2Preferably, X is NR11(ii) a Wherein R is11Selected from CN, -SO2R12；R12Selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane; preferably, X is selected from NR11Or CHNO2More preferably, X is NR11(ii) a Wherein R is11Selected from CN, -SO2Me、-SO2Et、-SO2Pr、-SO2-i-Pr、-SO2-cyclopropane, -SO2-cyclobutane; further preferablyX is selected from N-SO2Me、N-CN、CH-NO2(ii) a Even more preferably, X is selected from N-SO2Me、N-CN。
In an embodiment of the invention, the compounds of the invention are selected from, but not limited to:
preparation method
One aspect of the present invention provides a process for preparing a compound of the present invention, said process comprising:
synthesis of intermediate A
R1As defined above for formula I.
The first step is as follows: compound A-1 in base and PhNTf2Under the action of (1), or Tf2And generating an enolization intermediate A-2 under the action of O and 2, 6-di-tert-butyl-4-methylpyridine.
The alkali is LiHMDS, LDA, NaHMDS, KHMDS,tBuOK, NaH or NaOH, etc., and solvent is THF, CH3CN, DCM or DCE, etc., at-78 deg.C to 25 deg.C;
the second step is that: combining A-2 with R1Boronic acids or esters are subjected to a coupling reaction (e.g. a Suzuki reaction) to yield intermediate a-3.
The catalyst used is Pd (PPh)3)4Or Pd (dppf) Cl2Etc., the base used is Cs2CO3、K3PO4、Na2CO3、AcOK、NaHCO3Or K2CO3Etc., the solvent is Dioxane/H2O、DMF/H2O、DMSO/H2O or CH3CN/H2O, etc. at the temperature of 60-120 ℃;
the third step: compound a-3 is reduced to intermediate a-4 under catalytic hydrogenation conditions.
The catalyst used is Pd/C, PtO2Or Pd (OH)2C, etc., the solvent is MeOH or EtOH, etc., and the temperature is rt to 80 ℃;
the fourth step: and removing the Boc protecting group of the compound A-4 under the action of acid to obtain an intermediate A.
The acid used is a solution of HCl in Dioxane or TFA in DCM, etc., at a temperature of 0 ℃ to rt.
Synthesis of intermediate B
R1As defined above for formula I, R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6An alkyl group.
The first step is as follows: compound B-1 in base and PhNTf2Under the action of (1), or Tf2And generating an enolization intermediate B-2 under the action of O and 2, 6-di-tert-butyl-4-methylpyridine.
The reaction conditions were as described in the first step of the process for the preparation of intermediate a.
The second step is that: compounds B-2 and R1Boronic acids or esters are subjected to a coupling reaction (e.g. a Suzuki reaction) to yield intermediate B-3.
The reaction conditions were as described in the second step of the process for the preparation of intermediate a.
The third step: compound B-3 is reduced to intermediate B-4 under catalytic hydrogenation conditions.
The reaction conditions were as described in the third step of the process for the preparation of intermediate a.
The fourth step: and the compound B-4 is subjected to alkylation reaction in the presence of alkali to generate an intermediate B-5.
The alkylating agent used is R2-L1And/or R3-L1(L1is-Cl, -Br, -I or-OMs, etc.), is subjected to one and/or two alkylations, the bases used are BuLi, LiHMDS, LDA,tBuOK、NaH、Cs2CO3、K2CO3Or NaOH, etc., and the solvent is THF or CH3CN, DCM, DMF, DMSO, DCE or Acetone, etc., at-78 deg.C to rt;
the fifth step: the compound B-5 is hydrolyzed in the presence of alkali to obtain an intermediate B-6.
The base is LiOH, NaOH or KOH, etc., and the solvent is MeOH/H2O or EtOH/H2O, etc. at a temperature of 0 to 80 ℃;
and a sixth step: compound B-6 undergoes Curtius rearrangement to produce intermediate B-7.
The base used is Et3N, DIPEA, the reagent is DPPA, and the solvent istBuOH, toluene, DCM,tA mixed solvent of BuOH and toluene, etc., at a temperature of 40 to 110 ℃.
The seventh step: the compound B-7 is hydrolyzed under alkaline conditions to generate a product B.
The base is NaOH, LiOH or KOH, etc., and the solvent is Dioxane/H2O，MeOH/H2O，EtOH/H2O, etc., at a temperature of rt to 80 ℃.
Synthesis of intermediate C
R1As defined above for formula I, R4Is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6alkyl-OC1-C6Alkyl groups may be optionally substituted with the following substituents: OH, CN, -NR7R8、-C(O)NR7R8、-NR9C(O)R10。
The first step is as follows: the compound A-4 reacts with R under the action of alkali4-L1(L1is-Cl, -Br, -I or-OMs, etc.), or with R4The OH is subjected to a Mitsunobu reaction to generate an intermediate C-1.
The base used for alkylation is BuLi, LiHMDS, LDA,tBuOK、NaH、Cs2CO3、K2CO3Or NaOH, etc., and the solvent is THF or CH3CN, DCM, DMF, DMSO, DCE or Acetone, etc., at-78 deg.C to 60 deg.C; if the Mitsunobu reaction occurs, the reagent used is generally DIAD or DEAD, etc., and the solvent is THF, DCM or DCE, etc., at a temperature of 0 ℃ to 80 ℃;
the second step is that: and removing the Boc protecting group of the intermediate C-1 under the action of acid to generate an intermediate C.
The reaction conditions were as described in the fourth step of the process for the preparation of intermediate a.
Synthesis of intermediate D
R1As defined above for formula I, ring P is C3-C6Cycloalkyl or 4-7 membered heterocyclyl.
The first step is as follows: compound R1-L2(L2Cl, Br, I or OTf, etc.) with D-1a or D-1bIntermediate D-2 is formed via a coupling reaction (e.g., a Suzuki reaction).
The reaction conditions were as described in the second step of the process for the preparation of intermediate a. The second step is that: the compound D-2 generates an intermediate D-3 under reducing conditions.
The reaction conditions were as described in the third step of the process for the preparation of intermediate a.
The third step: the compound D-3 generates an intermediate D-4 under the action of acid.
The acid is HCl or H2SO4P-toluenesulfonic acid or methanesulfonic acid, and the like, and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH3CN, Dioxane, Acetone or Toluene and the like, and the temperature is between rt and 100 ℃;
the fourth step-A: the compound D-4 and the compound D-5 generate an intermediate D-6 under the alkaline condition.
The alkali used is LDA, n-BuLi,tBuOK, NaOH, NaH, LiHMDS, NaHMDS or KHMDS etc., and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH3CN, Dioxane or Toluene, etc., at-78 deg.C to rt;
the fourth step-B: the compound D-4 and amine are subjected to reductive amination to obtain an intermediate A
The amine source is ammonium chloride, ammonium acetate, NH3In aqueous or MeOH, etc., the reducing agent being NaBH3CN、NaBH4、NaBH(OAc)3Etc., the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH3CN, Dioxane or Toluene, etc., at a temperature of 0 ℃ to 80 ℃.
The fifth step: the compound D-6 is dehydrated to obtain an intermediate D-7.
The dehydrating agent is an acid, such as HCl, H2SO4Or TFA, or the like, or with Burgess dehydrating agent in the form of THF, DCM, DCE, MeOH, EtOH, DMF, CH3CN, Dioxane or Toluene, etc.
And a sixth step: the compound D-7 generates an intermediate D-8 under reducing conditions.
The reaction conditions were as described in the third step of the process for the preparation of intermediate a.
The seventh step: the compound D-8 is hydrolyzed under alkaline/acidic conditions to generate an intermediate D-9.
The acid is HCl or H2SO4P-toluenesulfonic acid or methanesulfonic acid, etc., the base is LiOH, NaOH or KOH, etc., and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH3CN, Dioxane or Toluene, etc., at the temperature of rt to 100 ℃;
eighth step: compound D-9 undergoes Curtius rearrangement to yield intermediate D-10.
The reaction conditions were as described in the sixth step of the process for the preparation of intermediate B.
The ninth step: compound D-10 is hydrolyzed under basic conditions to intermediate D.
The reaction conditions were as described in the seventh step of the process for the preparation of intermediate B.
Synthesis of intermediate E
R5、R6As defined above for formula I.
The compound E-1 and the compound E-2 generate an intermediate E under the action of alkali. The base is LiHMDS, LDA, NaHMDS, KHMDS, TEA, DIPEA, or mixtures thereof,tBuOK, NaH or Cs2CO3Etc., the solvents used are THF, DCM, DCE, DMF, DMSO, CH3CN, Dioxane, MeOH, EtOH or Toluene, etc., at a temperature of-10 ℃ to 140 ℃.
Synthesis of intermediate F
R5、R6、R12As defined above for formula I.
The compound F-1 and the compound E-2 generate an intermediate F under the action of alkali.
The reaction conditions were as described in the first step of the process for the preparation of intermediate E.
Synthesis of intermediate G
R5、R6As defined above for formula I.
The compound G-1 and the compound E-2 generate an intermediate G under the action of alkali.
The reaction conditions were as described in the first step of the process for the preparation of intermediate E.
Synthesis of Compounds of formula II-formula V (method one)
R1、R5、R6、R12As defined above for formula I, R4As defined above for intermediate C, R2And R3As defined for intermediate B above, the P ring is as defined for intermediate D above, and X is N-CN, N-SO2R12Or CH-NO2。
The first step is as follows: reaction of intermediate A, B, C or D with intermediate E, F or G under basic conditions produces compounds of formula II, formula III, formula IV, and formula V, respectively.
Specifically, intermediate a is reacted with intermediate E, F, G, respectively, under basic conditions to produce the compound of formula II.
Specifically, intermediate B is reacted with intermediate E, F, G, respectively, under basic conditions to produce the compound of formula III.
Specifically, intermediate C is reacted with intermediate E, F, G, respectively, under basic conditions to produce the compound of formula IV.
Specifically, intermediate D is reacted with intermediate E, F, G, respectively, under basic conditions to produce the compound of formula V.
The reaction conditions were as described in the first step of the process for the preparation of intermediate E.
Synthesis of Compounds of formula II-formula V (method two)
R1、R5、R6、R12As defined above for formula I, R4As defined above for intermediate C, R2And R3As defined in the above intermediate B, the P ring is as defined in the above intermediate D, and X is N-CN, N-SO2R12Or CH-NO2And X' is PhO or MeS.
The first step is as follows: reaction of intermediate A, B, C or D with intermediate E-1, F-1 or G-1, respectively, under basic conditions produces intermediates A ', B', C 'or D'.
Specifically, the intermediate A reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate the intermediate A'.
Specifically, the intermediate B reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate B'.
Specifically, the intermediate C reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate C'.
Specifically, the intermediate D reacts with the intermediates E-1, F-1 and G-1 respectively under alkaline conditions to generate an intermediate D'.
The reaction conditions were as described in the first step of the process for the preparation of intermediate E.
The second step is that: intermediates A ', B', C 'or D' and intermediate R5-NH-R6Respectively reacting under alkaline conditions to generate compounds of formula II, formula III, formula IV and formula V.
In particular, intermediate A' and intermediate R5-NH-R6Under alkaline conditions to produce the compound of formula II.
In particular, intermediate B' and intermediate R5-NH-R6Under alkaline conditions to produce the compound of formula III.
In particular, intermediate C' and intermediate R5-NH-R6Under alkaline conditions to produce the compound of formula IV.
In particular, intermediates D' andintermediate R5-NH-R6Under alkaline conditions to produce the compound of formula V.
The reaction conditions were as described in the first step of the process for the preparation of intermediate E.
Pharmaceutical compositions, formulations, methods of making pharmaceutical compositions, and methods of treatment
Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical compositions are used to treat diseases associated with IDO activity or IDO-mediated immunosuppression.
Another aspect of the invention provides a method of making a pharmaceutical composition, the method comprising combining a compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, with one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical compositions are used to treat diseases associated with IDO activity or IDO-mediated immunosuppression.
Another aspect of the invention provides a pharmaceutical formulation comprising a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition of the invention.
Another aspect of the present invention provides a compound of the present invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a co-crystal, or a solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for use in the manufacture of a medicament for the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression.
Another aspect of the present invention provides a compound of the present invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a co-crystal, or a solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention, for use in the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression.
Another aspect of the present invention provides a method for preventing or treating a disease associated with IDO activity or IDO-mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and optionally comprising administering to a subject in need thereof an additional agent for the treatment of a disease, such as cancer.
Another aspect of the present invention provides a method for the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a stereoisomer, tautomer or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and comprising administering to the subject in need thereof a PD-1 antibody or a PD-L1 antibody.
The diseases related to IDO activity or IDO mediated immunosuppression comprise but are not limited to tumors, depression, senile dementia and the like.
Such tumors include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
In the present invention, the "subject in need thereof" includes mammals, such as bovine, equine, porcine, canine, feline, rodent, primate; such as a human.
Another aspect of the invention provides a formulation comprising a compound of the invention, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in modulating (e.g., reducing or inhibiting) IDO activity in cells of an individual (e.g., a mammal, e.g., a bovine, equine, porcine, canine, feline, rodent, primate, e.g., human).
Another aspect of the invention provides a compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in the manufacture of a formulation for modulating (e.g., reducing or inhibiting) IDO activity in a cell (e.g., mammalian, e.g., bovine, equine, porcine, canine, feline, rodent, primate; e.g., human) of a subject.
Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, for use in modulating (e.g., reducing or inhibiting) the activity of IDO in the cells of a subject (e.g., a mammal, e.g., a bovine, equine, porcine, canine, feline, rodent, primate, e.g., human).
Another aspect of the invention provides a method of modulating (e.g., reducing or inhibiting) the activity of IDO in a cell of a subject (e.g., a mammal, e.g., a bovine, an equine, a porcine, a canine, a feline, a rodent, a primate; e.g., a human), comprising administering to the cell an effective amount of a compound of the invention, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, polymorph, co-crystal, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound.
In some embodiments, the formulation is administered to a subject to modulate (e.g., reduce or inhibit) the activity of IDO in cells in the subject; alternatively, the formulation is administered to cells in vitro (e.g., cell lines or cells from an individual) to modulate (e.g., reduce or inhibit) the activity of IDO in the cells.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to 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 may be optionally substituted with one or more (such as 1 to 3) suitable substituents such as halo (when the group is referred to as" haloalkyl ", e.g., CF3、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, for example, 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, which may be 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, as defined above, appended to the parent molecular moiety through an oxygen atom. C1-C6Of alkoxy groupsRepresentative 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. For example, as used herein, the term "C6-C14Aryl "means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl. Aryl groups may optionally be substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)2、C1-C6Alkyl, etc.).
As used herein, the term "arylheterocyclo" refers to a cyclic group formed by an aryl group and a heterocyclyl group sharing two adjacent carbon atoms with each other, with the point of attachment to the other group being on the aryl group. Wherein aryl or heterocyclyl is as defined herein. For example, as used herein, the term "9-12 membered arylheterocyclo" means a group containing a total of 9-12 ring atoms of the arylheterocyclo group, particularly a phenyl 5-8 membered heterocyclyl, particularly a phenyl 5-6 membered heterocyclyl (9-10 membered benzoheterocyclyl), examples of which include, but are not limited to: indazolyl group,
As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl group or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (a heteroaromatic ring refers to an aromatic ring system containing at least one heteroatom), which is attached to the heteroaromatic ring at the point of attachment to other groups, has, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 7, 8, 9, or 10 ring atoms, and which contains one or more (e.g., 1, 2,3,4, or 5) heteroatoms (e.g., oxygen, nitrogen, or sulfur) which may be the same or different, and which, in each case, may share two adjacent atoms with each other with the aryl, heterocyclyl, or cycloalkyl group to form a cyclic group. For example, as used herein, the term "5-10 membered heteroaryl" meansRefers to heteroaryl groups containing 5 to 10 ring atoms (including 5-6 membered heteroaryl groups, examples of which include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like) and fused ring derivatives thereof, and fused ring derivatives are not limited to heteroaryloaryl, heteroaryloacyclyl, or heteroaryloacyclyl, particularly 5-6 membered heteroaryloaryl, 5-6 membered heterocyclyl, or 5-6 membered heteroaryloaryl C4-6Cycloalkyl (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,
And the like.
As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2,3,4,5, 6, 7, 8, 9 carbon atoms and one or more (e.g., 1, 2,3, or 4) groups selected from C (═ O), O, S, S (═ O), S (═ O)2, and NR (R represents a hydrogen atom or a substituent such as, but not limited to, alkyl or cycloalkyl) in the ring, the point of attachment of which to other groups is on the heterocycle. As used herein, the term "3-14 membered heterocyclyl" means a heterocyclyl group containing 3-14 ring atoms (including 3-7 membered heterocyclyl groups, examples of which include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), and the like), and fused derivatives thereof, andring derivatives include, but are not limited to, heterocyclo-heterocyclics, heterocyclo-aryls, heterocyclo-heteroaryls, heterocyclo-cycloalkyls, especially 3-7-membered heterocyclo-3-7-membered heterocyclics, 3-7-membered heterocyclo-aryls, 3-7-membered heterocyclo-heteroaryls, 3-7-membered heterocyclo-cycloalkyls, especially 3-7-membered heterocyclo-phenyls, 3-7-membered heterocyclo-5-10-membered heteroaryls, 3-7-membered heterocyclo-C4-6Cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentaazepyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinmorpholinyl, piperidinyl-morpholinyl, piperidinyl-pyrrolidinyl, piperidinyl-piperidinyl,
Or spiro derivatives, e.g. but not limited to
And the like.
As used herein, the term "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
As used herein, the term "hydroxyalkyl" means that a hydrogen atom of an alkyl group is substituted with one or more (e.g., 1, 2,3, or 4) hydroxy groups, as used herein, the term "C1-6Hydroxyalkyl "means C1-C6The hydrogen atoms of the alkyl groups are substituted with one or more (e.g., 1, 2,3, or 4) hydroxyl groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.
The term "substituted" means that one or more (e.g., 1, 2,3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency 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 with one or more (e.g., 1, 2,3, or 4) substituents. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.
If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same 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 (stable isotopic derivatives) 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. in18F) (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 mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:
it is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Unless otherwise indicated, the compounds of the present invention are intended to exist 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 use of the wavy lines "to" herein to indicate bonds in the structural formulae is intended to indicate that the structures represent cis or trans isomers, or mixtures of cis and trans isomers in any proportion.
Advantageous effects of the invention
The compound of the present invention has high inhibitory activity on IDO in cells, and has excellent properties such as good pharmacokinetic properties and good safety.
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The abbreviations in the present invention have the following meanings:
the structure of the compound is determined by nuclear magnetic resonance spectrum (1H NMR) and/or Mass Spectrometry (MS). The reaction was monitored by silica gel Thin Layer Chromatography (TLC) (GF 254 is stationary phase) or LCMS.
1H NMR spectrometer Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).
LC/MS mass spectrometer: aglient 1260 Infinity/Aglient 6120 Quadrupole.
The microwave reaction was performed using a BiotageInitiator microwave reactor.
The column chromatography generally uses 200-300 mesh silica gel (Qingdao sea) as a carrier. Flash column chromatography was performed using a biotage technologies instrument.
In the following examples, the reaction temperature was room temperature (15 ℃ C. to 30 ℃ C.), unless otherwise specified.
Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Tereber Chemical, among others.
Example 1: n- (((4-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 2) and its cis-trans isomers
The first step is as follows: n- (4-chlorophenyl) -N' - (methylsulfonyl) thioiminomethyl ester 2c
Compound 2a (59mg) and compound 2b (100mg) were placed in a 50mL three-necked flask, and anhydrous THF (5mL) was added, followed by addition of 1.6mL of a 1.0M solution of LiHMDS in THF under nitrogen. LCMS monitors for complete conversion of substrate and 0.5mL saturated NH is added4The reaction was quenched with Cl, concentrated to dryness under reduced pressure, dissolved with a small amount of DCM and purified by preparative silica gel plate (PE: EA ═ 2:1) to give compound 2c (55 mg). MS m/z (ESI): 279.0[ M + H]+。
The second step is that: 4- ((tert-Butoxycarbonyl) amino) cyclohex-1-en-1-yl trifluoromethanesulfonate 2e
Adding 2d (2.0g, 9.4mmol) into THF (20mL), cooling to-70 deg.C under nitrogen protection, adding 20.0mL of 1.0M LiHMDS dropwise at-60-70 deg.C, keeping the temperature for 1h, and adding PhNTf2(3.7g, 10.0mmol) was slowly added dropwise thereto at-60 to-70 ℃ and reacted overnight at room temperature. After the reaction is finished, saturated NH is used4The reaction was quenched with Cl solution (50mL), extracted with ethyl acetate, and the organic phases were combined and washed with anhydrous Na2SO4Drying, removing the solvent by evaporation under reduced pressure, and separating by silica gel column chromatography (PE: EA 99:1-80:20) to obtain compound 2e (2.4 g). MS m/z (ESI): 346.1[ M + H]+。
The third step: synthesis of tert-butyl (2,3,4, 5-tetrahydro- [1,1' -biphenyl ] -4-yl) carbamate 2f
2e (2.4g, 7.0mmol), phenylboronic acid (1.3g, 10mmol), potassium phosphate (3.0g, 14mmol) and Pd (dppf) Cl under nitrogen2(57mg, 0.07mmol) was dissolved in dioxane (20mL) and heated to 90 deg.C and the reaction stirred overnight. TLC (PE: EA: 5:1) showed completion of the reaction, then cooled to room temperature, and the reaction solution was poured intoIn water (50mL), methyl tert-butyl ether was extracted, the organic phases combined and washed with anhydrous Na2SO4Drying, removing the solvent by evaporation under reduced pressure, and separating by silica gel column chromatography (PE: EA 99:1-80:20) to obtain compound 2f (0.8 g). MS m/z (ESI): 274.2[ M + H]+。
The fourth step: synthesis of tert-butyl (4-phenylcyclohexyl) carbamate (2 g)
2f (0.8g, 2.9mmol) was dissolved in methanol (10mL), 10% palladium on carbon (100mg) was added, the reaction was carried out overnight at room temperature under a hydrogen atmosphere, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to dryness to give 2g (0.8g) of the compound. MS m/z (ESI): 276.2[ M + H]+。
The fifth step: synthesis of 4-phenylcyclohexylamine hydrochloride 2h
2g (0.8g, 2.9mmol) was added to a 4N HCl Dioxane solution (8mL) and reacted at room temperature for 3h, and the reaction solution was concentrated to dryness to give compound 2h (0.6 g). MS m/z (ESI): 176.1[ M + H]+
And a sixth step: n- (((4-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 2)
Compound 2c (55mg) and compound 2h in free form (47mg) were placed in a 10mL microwave reaction tube, DMF (3mL) was added and dissolved with stirring, DIPEA (200mg) was added, and the reaction was carried out for 4h at 100 ℃ under microwave conditions. LC-MS monitors that the substrate is completely converted, and after the reaction is finished, the substrate is poured into 50mL of water, extracted by EtOAc and subjected to anhydrous Na2SO4Drying, evaporation of the solvent under reduced pressure and purification by Prep-HPLC gave Compound 2(50 mg). The compound 2 is separated again by Prep-HPLC to obtain cis-or trans-isomer, 2A (peak 1, 11mg, collection time 5.8-6.1 min); 2B (Peak 2, 9mg, Collection time 6.2-6.4 min). MS m/z (ESI): 406.1[ M + H]+。
2A：1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.77(br,1H),7.48-7.10(m,9H),4.18(brs,1H),2.93(s,3H),2.65-2.58(m,1H),1.98-1.52(m,8H).
2B：1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.45-7.09(m,10H),3.80-3.71(m,1H),2.89(s,3H),2.53-2.50(m，1H)，2.07-2.04(m,2H),1.85(d,J＝12.8Hz,2H),1.62-1.33(m,4H).
Example 2: 1- (4-chlorophenyl) -2-cyano-3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) guanidine (Compound 3)
The first step is as follows: 6-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline 3b
Pd (dppf) Cl under the protection of nitrogen2(1000mg，1.4mmol)、3a(6.5g，29.0mmol)、B2pin2(9.6g, 38.0mmol) and AcOK (8.5g, 87.0mmol) were dissolved in dioxane (70mL) and reacted at 80 ℃ for 4h, after the reaction was completed, cooled to room temperature, filtered and washed with EtOAc, the mother liquor was concentrated under reduced pressure, 100mL of EtOAc was added, washed with water (20 mL. multidot.3), and the combined organic layers were washed with anhydrous Na2SO4Drying and separation by silica gel column chromatography (PE: EA ═ 10:1) gave target compound 3b (6.0g), MS m/z (esi): 274.1[ M + H]+。
The second step is that: (4- (6-Fluoroquinolin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 3c
Pd (dppf) Cl under the protection of nitrogen2(292mg, 0.4mmol), 3b (2.0g, 7.3mmol), 2e (2.5g, 7.3mmol) and K2CO3(2.0g, 14.6mmol) was dissolved in dioxane/water (20mL/0.2mL) and reacted at 80 ℃ for 4 h. Cooled to room temperature, filtered and washed with EtOAc, the mother liquor was concentrated under reduced pressure and then 50mL of EtOAc was added, washed with water (10 mL. times.3) and the organic layer was washed with anhydrous Na2SO4Drying and separation by silica gel column chromatography (PE: EA ═ 10:1) gave the title compound 3c (2.0g), MS m/z (esi): 343.2[ M + H]+。
The third step: (4- (6-Fluoroquinolin-4-yl) cyclohexyl) carbamic acid tert-butyl ester 3d
To a solution of 3c (2.8g, 8.1mmol) in methanol (20mL) was added wet palladium on carbon (280mg, 10%) at room temperature and reacted under 1atm hydrogen atmosphere for 16 h. After the LC-MS detection reaction is finished, filtering to remove palladium carbon, and concentrating the mother liquor under reduced pressure to dryness to obtain a target compound 3d (2.3g), wherein MS m/z (ESI): 345.2[ M + H]+。
The fourth step: 4- (6-Fluoroquinolin-4-yl) cyclohexylamine 3e
A solution of 3d (2.3g, 6.6mmol) in trifluoroacetic acid/dichloromethane (10mL/10mL) was stirred at room temperature for 4h and checked by LC-MS for completion. Concentration to dryness under reduced pressure gave the hydrochloride salt of the target product 3e (2.5g), MS m/z (esi): 245.1[ M + H]+。
The fifth step: 1- (4-chlorophenyl) -2-cyano-3- (4- (6-fluoroquinolin-4-yl) cyclohexyl) guanidine (Compound 3)
Compound 3e (100mg, 0.4mmol), 2c (1.8mg, 0.4mmol) and DIPEA (200mg, 1.6mmol) were dissolved in acetonitrile, reacted at 100 ℃ for 1h under microwave conditions, cooled to room temperature after completion of the reaction, the solvent was evaporated under reduced pressure, and compound 3(25mg), MS m/z (esi), was isolated by Prep-HPLC: 422.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.86-8.82(m,1H),8.15–7.91(m,2H),7.67(td,J＝8.8,2.7Hz,1H),7.47(t,J＝4.6Hz,1H),7.43–7.30(m,3H),7.26-7.24(m,2H),4.26–3.74(m,1H),3.43-3.25(m,1H),3.27(s,0H),2.06–1.62(m,8H).
Example 3: n- (((3-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (compound 4) and its cis-trans isomers
The first step is as follows: n- (3-chlorophenyl) -N' - (methylsulfonyl) thioimidodicarbonic acid methyl ester 4b
4a (248mg) and 2b (353mg) were placed in a 100mL three-necked flask, and 5mL of anhydrous THF was added, cooled to 0 deg.C, and 5.0mL of a 1.0M solution of LiHMDS in THF was added under nitrogen. LCMS detection, adding 0.5mL saturated NH after substrate completely disappears4The reaction was quenched with Cl, the solvent was evaporated under reduced pressure, and the product was separated by silica gel column chromatography (PE: EA ═ 3: 1-5: 1) to give compound 4b (420 mg). MS m/z (ESI): 279.0[ M + H]+。
The second step is that: n- (((3-chlorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 4)
Compound 4b (220mg) and 2h in free form (11)8mg) was placed in a 20mL microwave tube, DMF (5mL) was added to dissolve completely, DIPEA (350mg) was added, and the reaction was stirred at 100 ℃ for 4 hours under microwave conditions. Obvious product formation. After the reaction was complete, it was cooled to room temperature, poured into 50mL of water, extracted with EtOAc, and the organic phases were combined and washed with anhydrous Na2SO4Drying, filtering, evaporating under reduced pressure to remove solvent, and separating and purifying by Prep-HPLC to obtain compound 4(180mg), and separating compound 4 again to obtain cis-or trans-isomer, 4A (peak 1, 44mg, collection time 5.6-6.1 min); 4B (Peak 2, 34mg, Collection time 6.2-6.9 min). MS m/z (ESI): 406.1[ M + H]+。
4A：1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),7.80(br,1H),7.51(t,J＝2.0Hz,1H),7.43-7.13(m,8H),4.18(brs,J＝7.8Hz,1H),2.94(s,3H),2.67-2.55(m,1H),1.99-1.83(m,2H),1.80-1.55(m,6H).
4B：1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.64-6.93(m,10H),3.78-3.73(m,1H),2.90(s,3H),2.53-2.50(m，1H)，2.07-2.04(m,2H),1.85(d,J＝11.9Hz,2H),1.67-1.34(m,4H).
Example 4: n- (((3-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (Compound 5) and its cis-trans isomers
The first step is as follows: n- (((3-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (Compound 5)
Dissolving 3e (50mg,0.2mmol), 4b (0.3g) and DIPEA (40mg, 0.3mmol) in DMF (5mL), reacting at 100 deg.C under microwave for 2h, cooling to room temperature after reaction, pouring the reaction solution into water (50mL), extracting with ethyl acetate, combining organic phases, anhydrous Na2SO4Drying, evaporation of the solvent under reduced pressure and preparative silica gel plate separation (DCM: MeOH 10:1) gave the cis-or trans-isomer. 5A (15mg, relatively less polar isomer); 5B (10mg, relatively polar larger isomer), MS m/z (ESI): 475.1[ M + H]+。
5A：1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.87-8.86(d,J＝4.4Hz,1H),8.13-8.05(m,2H),7.69(br,1H),7.71-7.66(m,1H),7.52(s,1H),7.42-7.33(m,3H),7.20-7.16(m,1H),4.26(brs,1H),3.53-3.47(m,1H),2.96(s,3H),1.98-1.66(m,8H)。
5B：1H NMR(400MHz,DMSO-d6)δ8.87-8.82(m,2H),8.13-8.01(m,2H),7.70-7.65(m,1H),7.46-7.42(m,2H),7.38-7.32(m,3H),7.22-7.20(m,1H),3.84-3.82(m,1H),3.35-3.33(m,1H),2.92(s,3H),2.02-2.01(m,2H)，1.96-1.94(m,2H)，1.70-1.65(m,4H)。
Example 5: n- (((4-chlorophenyl) amino) ((4 (6-fluoroquinolin-4-yl) cyclohexyl) amino) methyl) methanesulfonamide (Compound 6) and its cis-trans isomers
The cis-or trans-isomer of compound 6 was synthesized according to the synthesis scheme for compound 5, substituting compound 2c for 4 b. 6A (6mg, relatively less polar isomer); 6B (5mg, relatively polar larger isomer). MS m/z (ESI): 475.1[ M + H]+。
6A：1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.87-8.86(d,J＝4.4Hz,1H),8.11-8.05(m,2H),7.81(br,1H),7.71-7.66(m,1H),7.44-7.38(m,5H),4.26(brs,1H),3.53-3.47(m,1H),2.94(s,3H),1.98-1.95(m,4H)，1.84-1.66(m,4H)。
6B：1H NMR(400MHz,DMSO-d6)δ8.87-8.82(m,2H),8.11-8.07(m,1H),8.03-8.01(d，J＝9.6Hz,1H)，7.77-7.65(m,1H),7.42-7.36(m,5H),7.27-7.25(d，J＝8Hz,1H),3.84(brs,1H),3.38-3.35(m,1H),2.91(s,3H),2.13(brs,2H)，1.95(brs,2H)，1.73-1.64(m,4H)。
Example 6: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) guanidine (Compound 7)
The first step is as follows: ethyl 2- (4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-en-1-yl) acetate 7b
Trifluoromethanesulfonic anhydride (11.9mL, 70.86mmol) was added to a solution of 2, 6-di-tert-butyl-4-methylpyridine (18.19g,88.58mmol) in dichloromethane (200mL) and after 30min of reaction, a solution of 7a (10.88g,59.05mmol) in dichloromethane (50mL) was added and the reaction continued at room temperature for 10h, after the reaction was over, water was added to quench the reaction, and the organic phase was quenched with anhydrous Na2SO4After drying, the solvent was evaporated under reduced pressure, and the product was subjected to silica gel column chromatography (PE: EA 99: 1-3: 1) to obtain 7b (15 g).
The second step is that: 2- (4- (2-methylpyridin-4-yl) cyclohex-3-en-1-yl) acetic acid ethyl ester 7d
Under the protection of nitrogen, 7b (1.50g, 4.75mmol), 7c (650mg, 4.75mmol) and K are reacted2CO3(1.31g, 9.50mmol) and Pd (dppf) Cl2(350mg, 0.48mmol) was dissolved in 40mL dioxane and 10mL water and heated to 80 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel column chromatography (PE: EA ═ 65: 35 to 100: 0) to isolate intermediate 7d (1.5 g). MS m/z (ESI): 260.2[ M + H ]]+。
The third step: 2- (4- (2-methylpyridin-4-yl) cyclohexyl) acetic acid ethyl ester 7e
7d (1.5g, 5.79mmol) was dissolved in 15mL of methanol, 150mg Pd/C was added, the reaction was carried out for 4h under a hydrogen atmosphere, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to dryness to give intermediate 7e (1.5 g). MS m/z (ESI): 262.2[ M + H]+。
The fourth step: 2- (4- (2-methylpyridin-4-yl) cyclohexyl) propanoic acid ethyl ester 7f
Dissolving 7e (1.5g, 5.79mmol) in anhydrous THF (15mL) under nitrogen protection, cooling to-78 deg.C, slowly adding 8.1mL 1M solution of LiHMDS in THF, raising the temperature to-50 deg.C, reacting for 4h, and adding CH3I (987mg, 6.95mmol) and stirring was continued for 2 h. After the reaction, the reaction mixture was saturated with 15mL of NH4Quenching with aqueous Cl, extracting with ethyl acetate, combining the organic phases and extracting with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure to drynessIntermediate 7f (1.0g) was isolated by silica gel column chromatography (PE: EA ═ 100: 0 to 65: 35). MS m/z (ESI): 276.1[ M + H]+.
The fifth step: 7g of 2- (4- (2-methylpyridin-4-yl) cyclohexyl) propionic acid
7f (1.0g, 3.64mmol) was dissolved in methanol (10mL) and water (2mL), then NaOH (436mg,10.9mmol) was added, heated to 70 ℃ and stirred overnight, after the reaction was completed, pH was adjusted to 3-4 with 2M hydrochloric acid, and concentrated under reduced pressure to dryness to give 7g (1.5g) of crude product, which was used in the next reaction without further purification. MS m/z (ESI): 248.2[ M + H]+.
And a sixth step: (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) carbamoyl azide 7h
7g (500mg), DPPA (668mg, 2.43mmol) and DIPEA (391mg, 3.03mmol) were dissolved in toluene (10mL) and tert-butanol (10mL), heated to 110 ℃ for 4h, cooled, added to 20mL water, extracted with ethyl acetate, the organic phases combined and then over anhydrous Na2SO4Drying, filtration and concentration of the filtrate to dryness under reduced pressure gave intermediate 7h (200mg) which was isolated by silica gel column chromatography (DCM: MeOH ═ 100: 0-90: 10). MS m/z (ESI): 288.2[ M + H]+.
The seventh step: 1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethylamine hydrochloride 7i
Dissolving 7h (200mg, 0.697mmol) in dioxane (6mL) and water (0.5mL), adding NaOH (84mg, 2.09mmol), reacting at room temperature for 2h, then adding 4M HCl dioxane solution to adjust the pH to 3-4, and concentrating under reduced pressure to dryness to obtain a crude product of intermediate 7i (180mg), which is used in the next reaction without further purification. MS m/z (ESI): 219.1[ M + H]+。
Eighth step: phenyl N- (4-chlorophenyl) -N' -cyanooxoiminophenyl ester 7k
Dissolving 2a (0.16g, 1.3mmol), N-cyanocarbodiimidate diphenyl ester 7j (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 the reaction is finished, pouring the reaction solution into water (50mL), extracting with ethyl acetate, and extracting with anhydrous Na2SO4Drying, and concentrating the organic phase to obtainIntermediate 7k (0.3g) crude, which was used in the next reaction without further purification, MS m/z (esi): 272.1[ M + H]+。
The ninth step: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) guanidine (Compound 7)
7k (30mg, 0.11mmol), 7i (34mg, 0.13mmol) and DIPEA (43mg, 0.33mmol) were dissolved in DMF (5mL) and heated to 90 ℃ for reaction overnight. After the reaction was completed, it was cooled, 10mL of water was added, extraction was performed with ethyl acetate, and the organic phases were combined and washed with saturated brine and anhydrous Na2SO4Drying, filtering, concentrating the filtrate to dryness under reduced pressure, and separating by Prep-HPLC to obtain compound 7(8mg, collection time 9.8-10.2min), MS m/z (esi): 396.2[ M + H]+。
1H NMR(400MHz,CD3OD)δ8.29-8.25(m,1H),7.38-7.36(m,2H),7.25-7.10(m,4H),3.84-3.80(m,1H),2.70-2.68(m,1H),2.50(s,3H),2.00-1.82(m,3H),1.70-1.60(m,4H),1.50-1.46(m,2H),1.19(t,J＝3.2Hz，3H).
Example 7: n- (((4-chlorophenyl) amino) ((1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 8)
The first step is as follows: n- (((4-chlorophenyl) amino) ((1- (4- (2-methylpyridin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 8)
2c (31mg, 0.11mmol), 7i (34mg, 0.13mmol) and DIPEA (43mg, 0.33mmol) were dissolved in DMF (5mL) and the reaction was stirred at 90 ℃ overnight. After cooling, 10mL of water was added, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous Na2SO4Drying, filtration and concentration of the filtrate to dryness under reduced pressure followed by Prep-HPLC separation gave compound 8(6mg, collection time 8.9-9.3min), MS m/z (esi): 449.1[ M + H]+。
1H NMR(400MHz,CD3OD)δ8.28-8.25(m,1H),7.40-7.24(m,4H),7.18-7.10(m,2H),3.84-3.81(m,1H),3.02(s,3H)，2.70-2.68(m,1H),2.49(s,3H),1.98-1.93(m,3H),1.74-1.50(m,6H),1.13(brs,3H).
Example 8: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) guanidine (Compound 9)
The first step is as follows: 2- (4- (6-Fluoroquinolin-4-yl) cyclohex-3-en-1-yl) acetic acid ethyl ester 9a
Pd (dppf) Cl under the protection of nitrogen2(500mg, 0.7mmol), 3b (4.0g, 14.0mmol), 7b (4.2g, 14.0mmol) and K2CO3(5.8g, 42.0mmol) was dissolved in dioxane/water (40mL/2mL) and heated to 80 ℃ for reaction for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration, the mother liquor was concentrated under reduced pressure, 100mL of ethyl acetate was added, and the organic layer was washed with water and then with anhydrous Na2SO4Drying, evaporation of the solvent under reduced pressure, and silica gel column chromatography (PE: EA ═ 10:1) gave target compound 9a (2.0g), MS m/z (esi): 314.1[ M + H]+。
The second step is that: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) acetic acid ethyl ester 9b
Adding wet palladium carbon (200mg, 10%) into a methanol (20mL) solution of 9a (2.0g, 6.6mmol) at room temperature, reacting for 16h under a hydrogen atmosphere, detecting by LC-MS after the reaction is finished, filtering to remove the palladium carbon, and concentrating the mother liquor under reduced pressure to dryness to obtain a target compound 9b (1.5g), MS m/z (ESI): 316.1[ M + H]+。
The third step: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) propanoic acid ethyl ester 9c
10mL of a 1.0M THF solution of LiHMDS was added to a solution of compound 9b (1.5g, 4.9mmol) in anhydrous THF (10mL) at-78 deg.C, and the reaction was maintained at-78 deg.C for 1h, after which CH was added3A solution of I (1.4g, 9.8mmol) in anhydrous THF was slowly added to the reaction system, and after reaction at-78 ℃ for 2h, the temperature was slowly raised to room temperature for further reaction for 2 h. TLC monitoring (PE: EA: 5:1) completion of the reaction, saturated NH was added4The reaction was quenched with Cl solution (10mL), extracted with ethyl acetate, and combined withThe organic phase is combined with anhydrous Na2SO4Drying, evaporation of the solvent under reduced pressure, and separation and purification by silica gel column chromatography (PE: EA ═ 5:1) gave the target compound 9c (500mg), MS m/z (esi): 330.2[ M + H]+。
The fourth step: 2- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) propanoic acid 9d
NaOH (140mg,3.5mmol) was added to the H of Compound 9c (500mg, 1.6mmol)2Adding O/MeOH (5mL/1mL) in the mixed solution, reacting at 50 ℃ for 2h, adding 1M hydrochloric acid to adjust the pH value to 1 after the reaction is finished, extracting with ethyl acetate, and then adding anhydrous Na2SO4Drying and concentration under reduced pressure gave crude intermediate 9d (400mg) which was used in the next reaction without further purification, MS m/z (esi): 302.2[ M + H]+。
The fifth step: (1- (4- (6-Fluoroquinolin-4-yl) cyclohexyl) ethyl) carbamoyl azide 9e
A solution of 9d (400mg, 1.3mmol), DPPA (536mg, 1.95mmol) and triethylamine (408mg, 4.0mmol) in toluene/tert-butanol (2mL/2mL) was reacted at 90 ℃ for 4h under nitrogen, cooled to room temperature and the solvent was evaporated under reduced pressure and the target product 9e (350mg), MS m/z (esi), was obtained by silica gel column chromatography (PE: EA ═ 5: 2): 342.2[ M + H]+。
And a sixth step: 1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethylamine 9f
NaOH (50mg,1.2mmol) was added to a dioxane/water (5mL/1mL) mixed solution of compound 9e (350mg, 0.9mmol), the reaction was carried out at room temperature for 2h, after the reaction was completed, 1M hydrochloric acid was added to adjust pH to 1, and the solvent was distilled off under reduced pressure to obtain a crude product of 9f (400mg), MS M/z (ESI): 273.2[ M + H]+。
The seventh step: 1- (4-chlorophenyl) -2-cyano-3- (1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) guanidine (Compound 9)
A solution of 9f (150mg, crude), 7k (150mg, 0.5mmol) and DIPEA (200mg, 1.6mmol) in DMF was reacted at 90 ℃ for 16h and LC-MS monitored for completion. Isolation by Prep-HPLC gave target compound 9(10mg), MS m/z (ESI): 450.2[ M + H ]]+。
1H NMR(400MHz,CD3OD)δ8.75(dd,J＝10.4,4.7Hz,1H),8.07(dd,J＝9.3,5.6Hz,1H),7.89(dd,J＝10.7,2.7Hz,1H),7.62–7.56(m,1H),7.55–7.46(m,1H),7.39(dd,J＝8.7,1.4Hz,2H),7.29–7.21(m,2H),3.48-3.40(m,1H),2.11–1.56(m,9H),1.46-1.38(m,1H),1.19-1.16(m,3H)。
EXAMPLE 9N- (((4-chlorophenyl) amino) ((1- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethyl) amino) methylene) methanesulfonamide (Compound 10)
A solution of compound 9f (150mg, crude), 2c (100mg, 0.5mmol) and DIPEA (200mg, 1.6mmol) in DMF was reacted at 90 ℃ for 16h, LC-MS monitored completion of the reaction and cooled to room temperature, and Prep-HPLC isolated to give the title compound 10(15mg), MS m/z (ESI): 503.2[ M + H]+。
1H NMR(400MHz,CD3OD)δ8.77–8.72(m,1H),8.07(dd,J＝9.2,5.6Hz,1H),7.89(dt,J＝10.6,3.0Hz,1H),7.59(ddd,J＝9.4,6.7,2.7Hz,2H),7.48–7.27(m,5H),3.46(d,J＝16.7Hz,1H),2.97(s,3H),2.12–1.76(m,8H),1.66-1.64(m,1H),1.44-1.43(m,1H),1.26(d,J＝12.2Hz,3H).
Example 10N- (((4-methoxyphenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 11) and its cis-trans isomer
The first step is as follows: n- (4-methoxyphenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 11b
2b (165mg, 1.0mmol) and 11a (123mg, 1.5mmol) were dissolved in anhydrous THF under nitrogen, cooled to 0 deg.C, 2.0mL of a 1.0M solution of LiHMDS in THF were added, and the mixture was stirred at room temperature for 3 h. Adding saturated ammonium chloride solution after the reaction is finished to quench the reaction, extracting with EtOAc, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA is 99:1-55:45) to obtain the target compoundSubstance 11b (110 mg). MS m/z (ESI): 275.0[ M + H]+。
The second step is that: n- (((4-methoxyphenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 11
DIPEA (122.48mg, 0.95mmol) was added to a solution of 11b (130mg, 0.27mmol) and 2h (83mg,0.18mmol) in DMF (4mL) at room temperature. The reaction was heated to 120 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, adding ethyl acetate (50mL) for dilution, washing with water (10mL x 3), drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, separating and purifying by Prep-HPLC to obtain a compound 11(70mg), separating and purifying the compound 11 by using the Prep-HPLC again to obtain cis-isomer or trans-isomer, 11A (peak 1, 25mg, collecting time 6.7-7.0 min); 11B (Peak 2, 16mg, Collection time 7.3-7.5 min). MS m/z (ESI): 402.3[ M + H]+。
11A：1H NMR(400MHz,CD3OD)δ7.28-7.13(m,7H),6.98-6.96(m,2H),4.08-4.07(m,1H),3.81(s,3H),2.97(s,3H),2.59-2.58(m,1H),1.96-1.94(m,2H),1.75-1.58(m,6H).
11B：1H NMR(400MHz,CD3OD)δ7.20-7.12(m,7H),6.98-6.96(m,2H),3.82-3.77(m,1H),3.81(s,3H),2.98(s,3H),2.48-2.46(m,1H),2.06-2.04(m,2H),1.88-1.86(m,2H),1.57-1.55(m,2H),1.41-1.38(m,2H).
Example 11N- (((4-chlorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 18) and its cis-trans isomer
The first step is as follows: (4 '-methoxy-2, 3,4, 5-tetrahydro- [1,1' -biphenyl ] -4-yl) carbamic acid tert-butyl ester 18b
18a (310.11mg,2mmol), 2e (727.02mg,2.00mmol), Pd (dppf) Cl under nitrogen2*CH2Cl2(83.27mg, 100.00. mu. mol) and K2CO3(563.27mg,4.00mmol) was placed in a reaction flask and Dioxane (10mL) and H were added2O (2mL) in a mixed solvent, heated to 90 ℃ for reaction, monitored by TLC (PE): EA 10:1) until complete conversion of the feedstock. After the reaction was complete, it was cooled to room temperature, filtered and washed with EtOAc, then diluted with 50mL of EtOAc, washed three times with water and the organic layer was washed with anhydrous Na2SO4Drying, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA: 95:1-90:10) to obtain target product 18b (250 mg).
The second step is that: (4- (4-methoxyphenyl) cyclohexyl) carbamic acid tert-butyl ester 18c
18b (263mg, 0.82mmol) was dissolved in MeOH (10mL) at room temperature, 10% Pd/C (100mg, 0.08mmol) was added, the reaction was carried out under hydrogen atmosphere (1atm), and monitored by TLC (PE: EA ═ 10:1) until complete conversion of the starting material. After the reaction was completed, the reaction mixture was filtered through celite and washed with methanol, and the solvent was distilled off under reduced pressure, and the obtained crude product was used in the next reaction without further purification.
The third step: 4- (4-methoxyphenyl) cyclohexylamine hydrochloride 18d
18c (263.16mg, 818.57. mu. mol) was dissolved in 3.0mL of 4N HCl in dioxane at room temperature, LC-MS monitored complete conversion of starting material after 2h reaction, solvent was evaporated under reduced pressure after completion of the reaction, and the crude product was carried on to the next reaction without further purification. MS m/z (ESI): 206.2[ M + H]+.
The fourth step: n- (((4-chlorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide 18
18d (188.78mg,765.23 μmol), 2c (217.68mg,765.23 μmol) and DIPEA (302.75mg,2.30mmol) were dissolved in 6.0mL DMF, heated to 100 ℃ for reaction and monitored by TLC (PE: EA ═ 5:1) until complete conversion of the starting material. After the reaction was complete, it was cooled to room temperature, diluted with 50mL EtOAc, washed with water and the organic phase was washed with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure to dry, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of compound 18, 18A (peak 1, 45mg, collection time 9.2-9.6 min); 18B (Peak 2, 42mg, Collection time 9.7-9.9 min). MS m/z (ESI): 436.1[ M + H]+.
18A：1H NMR(400MHz,CD3OD)δ7.42-7.39(m,4H),7.19(d,J＝8.4Hz，2H),6.87(d,J＝8.4Hz，2H),4.11-4.13(m,1H),3.79(s,3H),3.01(s,3H),2.63-2.57(m,1H),2.06-2.00(m,2H),1.86-1.73(m,6H).
18B：1H NMR(400MHz,CD3OD)δ7.41(d,J＝8.0Hz，2H),7.34(d,J＝8.0Hz，2H),7.16(d,J＝8.8Hz，2H),6.86(d,J＝8.8Hz，2H),3.82-3.78(m，1H)，3.78(s,3H),3.00(s,3H),2.48-2.51(m,1H),2.11-2.16(m,2H),1.91-1.94(m,2H),1.67-1.58(m,2H)，1.51-1.46(m,2H).
Example 12N- (((4-cyanophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 25) and its cis-trans isomer
The first step is as follows: n- (4-cyanophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 25b
25a (79.66mg, 674.31. mu. mol) and 2b (112mg, 561.93. mu. mol) were dissolved in dry THF (3mL) under nitrogen, cooled to 0 ℃ and 2.5mL of a THF solution of LiHMDS (561.93. mu. mol) were added, after which stirring was completed at room temperature for 3 h. After the reaction was completed, water was added to quench the reaction, extracted with EA, the organic phases were combined and dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure after filtration, and separated and purified by silica gel column chromatography (100% EA) to obtain compound 25b (150 mg). MS m/z (ESI): 270.0[ M + H]+
The second step is that: n- (((4-cyanophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 25
25b (150mg, 556.91. mu. mol) and 2h (97.61mg, 556.91. mu. mol) were dissolved in DMF (4mL), DIPEA (287.90mg,2.23mmol) was added, and the mixture was heated to 100 ℃ under microwave conditions for 4 h. LCMS detects that the raw materials are completely converted, the reaction solution is cooled to room temperature after the reaction is finished, the reaction solution is poured into water and extracted by EA, organic phases are combined and dried by anhydrous sodium sulfate, filtered, decompressed and concentrated to be dry, and separated and purified by Prep-HPLC to obtain the cis-isomer or the trans-isomer of 25. 25A (Peak 1, 15mg, Collection time 9.8-10.2 min); 25B (Peak 2, 111mg, Collection time 10.3-10.8 min). MS m/z (ESI): 397.2[ M + H]+
25A：1H NMR(400MHz,DMSO-d6)δ：9.12(s,1H),7.90(d,J＝8.3Hz,1H),7.79-7.77(m,2H),7.63(d,J＝8.4Hz,2H),7.34-7.18(m,5H),4.24(brs,1H),2.98(s,3H),2.66-2.59(m,1H),1.90(d,J＝12.8Hz,2H),1.78-1.62(m,6H).
25B：1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.81-7.77(m,2H),7.56(d,J＝8.3Hz,2H),7.42(brs,1H),7.32-7.17(m,5H),3.84-3.77(m,1H),2.93(s,3H),2.56-2.53(m,1H),2.10-2.06(m,2H),1.88-1.84(m,2H),1.62-1.40(m,4H).
EXAMPLE 13N- (((4-chlorophenyl) amino) ((4- (2-methylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 35)
The first step is as follows: 2-methyl-4- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) pyridine 35c
Pd (dppf) Cl was added to a mixture of 35a (3.23g, 18.79mmol), compound 35b (5.0g, 18.79mmol), potassium carbonate (7.78g, 56.36mmol), water (5mL) and dioxane (50mL) under nitrogen2(692.30mg, 939.36. mu. mol). Then the reaction solution is heated to 90 ℃ for reaction for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, insoluble materials were removed by filtration, and the filtrate was separated and purified by silica gel column chromatography (PE: EA ═ 5: 2) to obtain the objective product 35c (3.5 g).
The second step is that: 2-methyl-4- (1, 4-dioxaspiro [4.5] decan-8-yl) pyridine 35d
A solution of 35C (3.37g, 13.84mmol) and Pd/C (85.85mg, 1.38mmol) in methanol was reacted under a balloon of hydrogen pressure for 3 hours at room temperature. After the reaction was complete, the reaction was filtered and washed with MeOH, and the filtrate was concentrated to dryness under reduced pressure to give 35d (3.1 g).
The third step: 4- (2-methylpyridin-4-yl) cyclohexanone 35e
To a solution of compound 35d (3.1g, 13.29mmol) in acetone was added 10mL of 6M hydrochloric acid at room temperature, and the reaction was stirred at room temperature for 5 h. The solvent was then removed by concentration under reduced pressure, water (10mL) was added and made basic with saturated sodium bicarbonate, EtOAc (10mL x 3) was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure to give the title product 35e (2.2 g).
The fourth step: 4- (2-methylpyridin-4-yl) cyclohexylamine 35f
At room temperature, adding NH4Cl (282.69mg, 5.28mmol) was added to a solution of compound 35e (500mg, 2.64mmol) in MeOH (2.5mL) and the reaction stirred at room temperature for 2 h. Then NaBH is added3CN (121.48mg, 5.28mmol) was added to the reaction and stirring was continued for 16h while maintaining room temperature. After completion of the reaction, most of the solvent was removed by concentration under reduced pressure, water (10mL) was added, EtOAc extraction (15mL × 3) was performed, the organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated to dryness under reduced pressure and separated and purified by silica gel column chromatography (DCM: MeOH ═ 100: 3) to give 35f (300 mg). MS m/z (ESI): 191.2[ M + H]+。
The fifth step: n- (((4-chlorophenyl) amino) ((4- (2-methylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide 35
DIPEA (135.84mg, 1.05mmol) was added to a solution of compound 2c (146.51mg, 525.53. mu. mol), 35f (100mg, 525.53. mu. mol) in acetonitrile (2mL) at room temperature. Heating to 100 ℃ under the microwave condition and reacting for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the product was separated and purified by Prep-HPLC to obtain Compound 35(18mg, collection time 4.2-5.4 min). MS m/z (ESI): 421.1[ M + H]+。
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.40-8.36(m,1H),7.42-7.33(m,4H),7.19-7.12(m,3H),3.79–3.70(m,1H),2.91(s,3H),2.55-2.51(m,1H),2.46(s,3H),2.06-2.04(s,1H),1.87-1.85(m,2H),1.74-1.37(m,5H).
Example 14N- (((4-chlorophenyl) amino) ((4- (4-methylpyridin-3-yl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 36) and its cis-trans isomer
The first step is as follows: (4- (4-methylpyridin-3-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 36b
36a (100mg, 730.23. mu. mol), 2e (327.82mg, 949.29. mu. mol), potassium carbonate (201.54mg,1.46mmol) and Pd (dppf) Cl under nitrogen2(534.53mg, 730.23. mu. mol) to a mixture was added dioxane (15mL) and water (5mL), and the mixture was heated to 80 ℃ for 10 hours. LCMS monitored complete conversion of starting material reaction. After the reaction is finished, cooling to room temperature, filtering, adding water into filtrate for dilution, extracting with EA, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA is 3: 1) to obtain the compound 36 b. MS m/z (ESI): 289.2[ M + H]+。
The second step is that: (4- (4-methylpyridin-3-yl) cyclohexyl) carbamic acid tert-butyl ester 36c
36b (80mg, 277.41. mu. mol) was dissolved in methanol (6mL) at room temperature, Pd/C (10mg) was added, and the reaction was carried out for 10 hours under a hydrogen atmosphere (1 atm). LCMS monitored complete conversion of starting material reaction. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to dryness to give a crude product (79mg) of the objective product 36c, which was used in the next reaction without further purification. MS m/z (ESI): 291.2[ M + H ]]+。
The third step: 4- (4-methylpyridin-3-yl) cyclohexylamine hydrochloride 36d
36c (80mg, 275.48. mu. mol) was dissolved in 3.0mL of 4M HCl in dioxane, stirred at 25 ℃ for 1h and concentrated under reduced pressure to dryness to give the crude product of the desired product 36d (50mg) which was used in the next step without further purification. MS m/z (ESI): 191.1[ M + H]+。
The fourth step: n- (((4-chlorophenyl) amino) ((4- (4-methylpyridin-3-yl) cyclohexyl) amino) methylene) methanesulfonamide 36
36d (50mg, 176.41. mu. mol), 2c (61.47mg, 220.51. mu. mol) and DIPEA (57.00mg, 441.02. mu. mol) were dissolved in DMF (5mL) and heated to 125 ℃ for reaction for 5 h. LCMS monitored complete conversion of starting material. After the reaction is finished, cooling to room temperature, adding water for dilution, extracting with EA, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by Prep-HPLC to obtain the compound 36 cis-isomer or trans-isomer. 36A (Peak 1, 20mg, Collection time 5.8-6.1 min); 36B (Peak 2, 15mg, Collection time 6.1-6.5 min))。MS m/z(ESI)：421.1[M+H]+。
36A：1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.40(s,1H),8.26(d,J＝5.2Hz,1H),7.80(br,1H),7.43-7.37(m,4H),7.16(d,J＝4.8Hz,1H),4.23-4.21(m,1H),2.94(s,3H),2.87-2.85(m,1H),2.26(s,3H),1.96-1.93(m,2H),1.74-1.65(m,6H).
36B：1H NMR(400MHz,DMSO-d6)δ8.74(br,1H),8.38(s,1H),8.25(d,J＝4.8Hz,1H),7.43-7.37(m,4H),7.16-7.14(m,2H),3.82-3.80(m,1H),2.94(s,3H),2.75-2.73(m,1H),2.31(s,3H),2.07-2.05(m,2H),1.62-1.59(m,2H),1.53-1.51(m,2H),1.49-1.43(m,2H).
Example 15N- (((4-chlorophenyl) amino) ((4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 37) and its cis-trans isomer
Under the protection of nitrogen, 37a (100mg,537.49 mu mol) and B2pin2(163.83mg,644.99μmol)、KOAc(158.00mg,1.61mmol)、Pd(dppf)Cl2(39.34mg, 53.75. mu. mol) was placed in a reaction flask, dioxane (20mL) was added, and the mixture was heated to 80 ℃ and stirred for 10 h. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the product was separated and purified by silica gel column chromatography (PE: EA ═ 1:2) to obtain the target product 37b (60 mg). MS m/z (ESI): 152.1[ M + H]+。
The second step is that: (4- (2, 6-dimethylpyridin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 37c
37b (80mg, 529.91. mu. mol), 2e (182.99mg, 529.91. mu. mol), potassium carbonate (146.25mg,1.06mmol) and Pd (dppf) Cl under nitrogen2(58.18mg, 79.49. mu. mol) was placed in a reaction flask, and water (1.00mL) and dioxane (5.00mL) were added, heated to 90 ℃ and stirred for 10 h. Cooling to room temperature after reaction, diluting with water, extracting with EA, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (PE: EA ═99:1-55:45) was isolated and purified to give intermediate 37c (80 mg). MS m/z (ESI): 303.2[ M + H]+。
The third step: (4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) carbamic acid tert-butyl ester 37 d.
37c (80mg, 264.54. mu. mol) was dissolved in methanol (5mL) at room temperature, palladium on carbon (10mg) was added, and the mixture was stirred under hydrogen atmosphere (1atm) for 6 hours. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to dryness to give 37d of crude product (80mg), which was used in the next reaction without further purification. MS m/z (ESI): 305.2[ M + H]+。
The fourth step: synthesis of 4- (2, 6-dimethylpyridin-4-yl) cyclohexylamine hydrochloride 37e
37d (60mg,197.09 μmol) was added to 4.0mL of 4M HCl in dioxane, stirred at 25 ℃ for 1h, then concentrated under reduced pressure to dryness to give crude 37e (50mg) which was used in the next reaction without further purification. MS m/z (ESI): 205.2[ M + H]+。
The fifth step: n- (((4-chlorophenyl) amino) ((4- (2, 6-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide 37
37e (50mg, 207.67. mu. mol), 2c (57.89mg, 207.67. mu. mol, FR) and DIPEA (53.68mg, 415.33. mu. mol) were dissolved in DMF (5mL) and heated to 125 ℃ for reaction for 6 h. After the reaction is finished, cooling to room temperature, adding water for dilution, extracting by EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to dryness, and separating and purifying cis-isomer or trans-isomer of the compound 37 by Prep-HPLC. 37A (Peak 1, 17mg, Collection time 6.5-7.0 min); 37B (Peak 2, 15mg, Collection time 7.1-7.4 min). MS m/z (ESI): 435.1[ M + H]+。
37A：1H NMR(400MHz,CD3OD)δ7.37-7.35(m,4H),6.99(s,2H),4.11-4.10(m,1H),2.98(s,3H),2.62-2.60(m,1H),2.46(s,6H),2.00-1.98(m,2H),1.77-1.70(m,6H).
37B：1H NMR(400MHz,CD3OD)δ7.40-7.29(m,4H),6.96(s,2H),3.79-3.78(m,1H),2.98(s,3H),2.50-2.46(m,1H),2.45(s,6H),2.11-2.10(m,2H),1.90-1.88(m,2H),1.67-1.57(m,2H),1.49-1.40(m,2H).
Example 16N- (((4-chlorophenyl) amino) ((4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 42) and its cis-trans isomer
The first step is as follows: 2- (4-bromophenoxy) -N, N-dimethylethylamine 42c
42a (500mg,2.89mmol) and potassium carbonate (997.07mg,7.23mmol) were charged to a 100mL one-neck flask, Acetone (30mL) was added, 42b (499.55mg,3.47mmol) was added, and the reaction was heated to 60 ℃ after stirring for 15 min. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give 42c (553 mg).
The second step is that: 2- (4- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) phenoxy) -N, N-dimethylethylamine 42d
42c (554mg,2.27mmol), 35b (603.95mg,2.27mmol), Pd (dppf) Cl under nitrogen2·CH2Cl2(92.66mg, 113.47. mu. mol) and K2CO3(782.91mg,5.67mmol) was placed in a reaction flask and dioxane (15mL) and H were added2O (3mL), heated to 100 ℃ for reaction. LCMS monitoring until complete conversion of starting material. After completion of the reaction, it was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (DCM: MeOH ═ 96:4) to give 42d (688 mg).
The third step: 2- (4- (1, 4-dioxaspiro [4.5] decan-8-yl) phenoxy) -N, N-dimethylethylamine 42e
42d (720mg,2.37mmol) was dissolved in MeOH (15mL), Pd/C (288.22mg,2.37mmol) was added, the reaction was heated to 30 ℃ under hydrogen atmosphere (1atm), and LCMS was used to monitor until complete conversion of the starting material. After the reaction was completed, the reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure, whereby the obtained crude 42e (720mg) was used in the next reaction without further purification.
The fourth step: 4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexanone 42f
42e (720mg,2.36mmol) was dissolved in acetone (10mL), HCl (aq) (2.36mmol,10mL) was added, stirred at room temperature, and LCMS checked until complete conversion of starting material. After completion of the reaction, the pH was adjusted to be alkaline with 6M NaOH (aq) solution, EA was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, and after filtration, separation and purification by silica gel column chromatography (DCM: MeOH ═ 97:3) to give compound 42f (379mg)
The fifth step: 42g of 4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexylamine
42f (379mg,1.45mmol) was dissolved in MeOH (10mL) and NH was added4AcO (335.32mg,4.35mmol), heated to 60 ℃ and stirred for 2 h. Then NaBH is added3CN (182.25mg,2.90mmol), stirring was continued for 6h and LCMS detection indicated complete conversion of starting material. After the reaction was finished, it was cooled to room temperature, quenched with sodium bicarbonate 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 to give 42g of crude product (153mg) which was used in the next reaction without further purification.
And a sixth step: n- (((4-chlorophenyl) amino) ((4- (4- (2- (dimethylamino) ethoxy) phenyl) cyclohexyl) amino) methylene) methanesulfonamide 42
42g (153.06mg, 571.67. mu. mol, FR), 2c (162.62mg, 571.67. mu. mol, FR) and DIPEA (226.17mg,1.72mmol, 98% purity) were dissolved in DMF (5mL) under nitrogen and heated to 100 ℃ for 6 h. After the reaction, the reaction mixture was cooled to room temperature, diluted with 50ml of LEtOAc and washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and purified by Prep-HPLC to obtain the cis-or trans-isomer of compound 42, 42A (peak 1) and 42B (peak 2). The 42A and 42B were again purified by Prep-HPLC to give high purity 42A (7mg, collection time 5.0-5.8min) and 42B (24mg, collection time 6.1-6.4min), respectively. MS m/z (ESI): 493.2[ M + H]+。
42A：1H NMR(400MHz,CD3OD)δ7.42-7.37(m,4H),7.23(d,J＝8.0Hz，2H),6.95(d,J＝8.8Hz，2H),4.25-4.22(t,J＝4.8Hz，2H),4.14-4.12(t,J＝2.8Hz，1H),3.23-3.20(t,J＝5.2Hz，2H),3.01(s,3H),2.70(s,6H),2.65-2.59(m,1H),2.04-2.01(m,2H),1.87-1.74(m,6H).
42B：1H NMR(400MHz,CD3OD)δ7.42(d,J＝8.4Hz，2H),7.33(d,J＝8.4Hz，2H),7.17(d,J＝8.4Hz，2H),6.91(d,J＝8.8Hz，2H),4.16-4.13(t,J＝5.2Hz，2H),3.82-3.80(m,1H)，3.00(s,3H),2.97-2.94(t,J＝5.2Hz，2H),2.54-2.51(m,1H)，2.50(s,6H),2.16-2.12(m,2H),1.94-1.91(m,2H),1.67-1.58(m,2H)，1.51-1.43(m,2H).
Example 17N- (((4- (2-hydroxyethoxy) phenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 48) and its cis-trans isomer
The first step is as follows: n' -methylsulfonyl-N- (4-phenylcyclohexyl) thioiminocarboxylic acid methyl ester 48a
DIPEA (518.74mg, 4.01mmol) was added to a solution of compound 2h (175.87mg, 1.00mmol) and 2b (200mg,1.00mmol) in acetonitrile (5mL) at room temperature, then warmed to 90 ℃ for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (DCM: MEOH ═ 100: 3) to obtain the objective compound 48a (200 mg).
The second step is that: n- (((4- (2-hydroxyethoxy) phenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 48
DIPEA (47.50mg, 367.56. mu. mol) was added to a solution of compound 48b (28.15mg, 183.78. mu. mol) and 48a (60mg, 183.78. mu. mol) in acetonitrile (2mL) at room temperature and heated to 100 ℃ under microwave conditions for 2 h. After the reaction is finished, cooling to room temperature, removing the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of the target compound 48. 48A (Peak 1, 10mg, Collection time 8.6-9.0 min); 48B (Peak 2, 20mg, Collection time 9.4-9.8 min). MS m/z (ESI): 432.3[ M + H]+。
48A：1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.61(br,1H),7.31(t,J＝7.5Hz,2H),7.27–7.16(m,5H),6.92(d,J＝8.8Hz,2H),4.88(t,J＝5.5Hz,1H),4.13-4.11(m,1H),3.97(t,J＝5.0Hz,2H),3.71(dd,J＝10.2,5.3Hz,2H),2.88(s,3H),2.62-2.60(m,1H),1.99-1.88(m,2H),1.79–1.55(m,6H).
48B：1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.32–7.14(m,7H),6.94(d,J＝8.8Hz,2H),4.88(t,J＝5.5Hz,1H),3.98(t,J＝5.0Hz,2H),3.72-3.69(m,3H),2.86(s,3H),2.49–2.41(m,1H),2.02(brs,2H),1.83(d,J＝11.8Hz,2H),1.60-1.51(m,2H),1.45-1.37(m,2H).
Example 18N- (((4-methoxybenzyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 86) and its cis-trans isomer
2b (200mg,1.00mmol), 86a (165.18mg,1.20mmol) and DIPEA (259.37mg,2.01mmol) were dissolved in ethanol (20mL) and the reaction was stirred at 75 ℃ for 10 h. LCMS was monitored for complete conversion of starting material, after reaction was complete, cooled to room temperature, the solvent was removed under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 1: 1) to afford the desired product 86 b. MS m/z (ESI): 289.1[ M + H]+。
The second step is that: n- (((4-methoxybenzyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 86
86b (50mg, 173.38. mu. mol), 2h (30.39mg, 173.38. mu. mol) and DIPEA (44.81mg, 346.76. mu. mol) were dissolved in DMF (2.50mL) and the reaction was stirred at 125 ℃ for 6 h. And (3) monitoring complete conversion of the raw materials by LCMS, cooling to room temperature after the reaction is finished, adding water for dilution, then extracting by EA, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by Prep-HPLC to obtain the cis-isomer or trans-isomer of the compound 86. 86A (Peak 1, 25mg, Collection time 9.7-9.9 min); 86B (Peak 2, 7mg, Collection time 9.9-10.1min) two enantiomers. MS m/z (ESI): 416.2[ M + H]+。
86A：1H NMR(400MHz,DMSO-d6)δ7.50(br,1H),7.25-7.15(m,7H),6.93(d,J＝8.4Hz,2H),6.90(br,1H),4.33(d,J＝5.6Hz,2H),3.75(s,3H),3.57-3.55(m,1H),2.76(s,3H),2.51-2.50(m,1H),1.98-1.96(m,2H),1.84-1.82(m,2H),1.56-1.50(m,2H),1.44-1.36(m,2H).
86B：1H NMR(400MHz,CD3OD)δ7.33-7.20(m,4H),7.20-7.13(m,3H),6.89(d,J＝8.4Hz,2H),4.41(s,2H),3.91-3.90(m,1H),3.75(s,3H),2.85(s,3H),2.55-2.53(m,1H),1.92-1.89(m,2H),1.71-1.60(m,6H).
Example 19N- (((4-chlorophenyl) amino) ((4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 87) and its cis-trans isomer
The first step is as follows: (2, 3-dimethylpyridin-4-yl) boronic acid 87b
87a (100mg, 537.49. mu. mol), B2pin2(163.83mg, 644.99. mu. mol), KOAc (158.00mg,1.61mmol) and Pd (dppf) Cl2(39.34mg, 53.75. mu. mol) was placed in a reaction flask, dioxane (20mL) was added, and the mixture was heated to 80 ℃ under nitrogen and stirred for 10 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure, which was then separated and purified by silica gel column chromatography (PE: EA ═ 1:2) to obtain 87b (60 mg). MS m/z (ESI): 152.1[ M + H]+。
The second step is that: (4- (2, 3-dimethylpyridin-4-yl) cyclohex-3-en-1-yl) carbamic acid tert-butyl ester 87c
87b (80mg, 529.91. mu. mol), 2e (182.99mg, 529.91. mu. mol), potassium carbonate (146.25mg,1.06mmol) and Pd (dppf) Cl2(58.18mg, 79.49. mu. mol) was placed in a reaction flask, water (1.00mL) and dioxane (5.00mL) were added, and the mixture was heated to 90 ℃ under nitrogen and stirred for 10 h. After the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with EA, the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE: EA 99:1-55:45) to obtain 87c (80 mg). MS m/z (ESI): 303.2[ M + H]+。
The third step: (4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) carbamic acid tert-butyl ester 87d
87C (80mg, 264.54. mu. mol) was dissolved in methanol (5mL) at room temperature, Pd/C (10mg) was added, and the mixture was stirred under hydrogen atmosphere (1atm) was stirred for 6 h. Then filtered and the filtrate concentrated under reduced pressure to dryness to give 87d of crude product (80mg) which was used in the next reaction without further purification. MS m/z (ESI): 305.2[ M + H]+。
The fourth step: 4- (2, 3-dimethylpyridin-4-yl) cyclohexylamine hydrochloride 87e
87d (60mg,197.09 μmol) was added to 4.0mL of 4M HCl in dioxane, stirred at 25 ℃ for 1h, and then the solvent was removed under reduced pressure to give crude 87e (50mg) which was used in the next reaction without further purification. MS m/z (ESI): 205.2[ M + H]+。
The fifth step: n- ((4-chlorophenyl) amino) ((4- (2, 3-dimethylpyridin-4-yl) cyclohexyl) amino) methylene) sulfonamide 87
87e (50mg, 207.67. mu. mol), 2c (57.89mg, 207.67. mu. mol, FR) and DIPEA (53.68mg, 415.33. mu. mol) were dissolved in DMF (5mL) and heated to 125 ℃ for reaction for 6 h. Cooling to room temperature after the reaction is finished, adding water for dilution, EA extracting, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to be dry, and separating and purifying cis-isomer or trans-isomer of the compound 87 by Prep-HPLC, wherein the 87A (peak 1, 20mg, collection time is 8.1-8.4 min); 87B (Peak 2, 15mg, Collection time 8.6-8.9 min). MS m/z (ESI): 435.1[ M + H]+。
87A：1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.21(d,J＝5.2Hz,1H),7.77(br,1H),7.43-7.37(m,4H),7.03(d,J＝5.2Hz,1H),4.21-4.20(m,1H),2.93(s,3H),2.93-2.91(m,1H),2.44(s,3H),2.23(s,3H),1.94-1.93(m,2H),1.76-1.74(m,2H),1.61-1.54(m,4H).
87B：1H NMR(400MHz,CD3OD)δ8.13(d,J＝5.2Hz,1H),7.38-7.35(m,2H),7.32-7.29(m,2H),7.15-7.09(m,1H),3.83-3.82(m,1H),2.97(s,3H),2.91-2.86(m,1H),2.49(s,3H),2.28(s,3H),2.14-2.13(m,2H),1.84-1.83(m,2H),1.58-1.53(m,2H),1.53-1.48(m,2H).
EXAMPLE 20N- (((2-fluorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide (Compound 88) and its cis-trans isomer
The first step is as follows: n- (2-fluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 88b
88a (148mg,1.33mmol) and 2b (221.23mg,1.11mmol) were dissolved in anhydrous THF (7mL) under nitrogen protection, cooled to-5 deg.C, then 1.66mL of 1.0M solution of LiHMDS in THF was added, reaction was quenched by addition of saturated ammonium chloride after 3h, EA extraction was performed, the organic phases were combined and dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure, and the desired product 88b (150mg) was isolated and purified by silica gel column chromatography (PE: EA ═ 3: 1). MS m/z (ESI): 263.0[ M + H]+。
The second step is that: n- (((2-fluorophenyl) amino) ((4-phenylcyclohexyl) amino) methylene) methanesulfonamide 88
88b (50mg, 190.60. mu. mol), 2h (40.09mg, 228.72. mu. mol, FR) and DIPEA (49.27mg, 381.21. mu. mol) were dissolved in DMF (5mL) and heated to 120 ℃ with stirring for 6 h. Cooling to room temperature after the reaction is finished, adding water for dilution, EA extracting, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to be dry, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of the compound 88, 88A (peak 1, 10mg, collection time 8.8-9.2 min); 88B (Peak 2, 20mg, Collection time 9.4-9.6 min). MS m/z (ESI): 390.1[ M + H]+。
88A：1H NMR(400MHz,DMSO-d6)δ8.82(br,1H),7.86(br,1H),7.34-7.18(m,9H),4.13-4.12(m,1H),2.84(s,3H),2.63-2.60(m,1H),1.95-1.93(m,2H),1.74-1.58(m,6H).
88B：1H NMR(400MHz,DMSO-d6)δ8.74(br,1H),7.16-7.34(m,10H),3.75-3.73(m,1H),2.83(s,3H),2.51-2.50(m,1H),2.07-2.03(m,2H),1.85-1.83(m,2H),1.54-1.40(m,4H).
Example 21N- (((2, 4-difluorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide (Compound 89) and its cis-trans isomer
The first step is as follows: n- (2, 4-difluorophenyl) -N' - (methylsulfonyl) thioiminocarboxylic acid methyl ester 89b
89a (777.31mg,6.02mmol) and 2b (1.0g,5.02mmol) were dissolved in THF (10mL), cooled to 0 deg.C, LiHMDS (5.02mmol,21mL) was added slowly and the reaction was allowed to warm to room temperature for 5 h. After completion of the reaction, water was added to quench the reaction, and the solvent was distilled off under reduced pressure, followed by separation and purification by silica gel column chromatography (PE: EA 75:25) to obtain 89b (578 mg).
The second step is that: n- (((2, 4-difluorophenyl) amino) ((4- (4-methoxyphenyl) cyclohexyl) amino) methylene) methanesulfonamide 89
18d (168.42mg, 661.82. mu. mol) and 89b (214.81mg, 728.01. mu. mol) were dissolved in DMF (5.0mL) at room temperature, followed by DIPEA (426mg,3.3mmol) and then raised to 100 ℃ for 27 h. After completion of the reaction, it was cooled to room temperature, diluted with EtOAc and washed with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, followed by separation and purification by Prep-HPLC to obtain the cis-or trans-isomer of compound 89, 89A (peak 1) and 89B (peak 2). The 89A and 89B were purified by Prep-HPLC to obtain 89A (50mg, collection time 7.6-8.0min) and 89B (43mg, collection time 11.3-11.5min) with high purity, respectively. MS m/z (ESI): 438.1[ M + H]+。
89A：1H NMR(400MHz,CDCl3)δ8.73(br,1H),7.41(br,1H),7.03-6.96(m,4H),6.84(d,J＝8.8Hz，2H),4.64(br,1H),4.13(br,1H),3.79(s,3H),3.05(s,3H),2.56-2.50(m,1H),1.91-1.87(m,2H),1.78-1.64(m,6H).
89B：1H NMR(400MHz,CDCl3)δ8.68(br,1H),7.33(br,1H),7.09(d,J＝8.8Hz，2H),7.01-6.95(m，2H),6.85-6.82(m，2H),4.28(br,1H),3.83(br,1H),3.78(s,3H),3.06(s,3H),2.42-2.36(m,1H),2.14-2.11(m,2H),1.92-1.89(m,2H)，1.60-1.51(m,2H)，1.26-1.17(m,2H).
The compounds of the invention (except compounds 5 and 6) were purified by HPLC using Aglient 1260, both at 25 ℃ and under the other separation conditions as shown in the following table:
biological evaluation
The following examples further illustrate the invention but are not intended to limit the scope of the invention.
EXAMPLE 1 measurement of IDO enzyme inhibitory Activity in Hela cells
The effect of compounds on intracellular IDO enzyme activity was determined using the NFK Green method.
Reagent: NFK Green fluorescent dye (NTRC); l-tryptophan (Sigma-Aldrich); recombinant Human IFN-gamma Protein (R & D systems)
The experimental method comprises the following steps:
cell culture: in vitro monolayer culture of tumor cells, wherein the culture conditions are as follows: hela cells, DMEM plus 10% fetal bovine serum at 37 deg.C with 5% CO2Cultured in an incubator. Digesting with pancreatin-EDTA for 2-3 times a week for passage. When the cells are in exponential growth phase, the cells are harvested, counted and plated. The cell concentration (10000 HeLa cells/well) was adjusted, and the cells were seeded in a 96-well plate at 70. mu.L/well. The cover of the 96-well plate is marked and put into an incubator to be cultured for 24 hours. Test wells without added cells were set as negative controls.
Compound preparation: dissolving a compound to be detected by DMSO to prepare a mother solution, sucking a proper amount of the mother solution into the culture solution, mixing uniformly, and preparing the drug solution into a corresponding incubation concentration. Add 10. mu.L of the prepared compound solution to each well and continue incubating the cells for 1 h.
IDO stimulation and substrate addition: mu.L of 500ng/mL IFN-. gamma.IFN (Recombinant Human IFN-gamma Protein) (dissolved in complete medium) was added, together with 10. mu.L of sterile 0.5mM L-tryptophan solution (dissolved in 20mM Hepes), and incubated for 48 h.
And (3) detection: after completion of incubation, 25. mu.L of the supernatant was transferred to 384-well plates, 5. mu.L of NFK Green was added to each well, and incubated at 37 ℃ for 4h with a lid. Fluorescence is detected by a microplate reader, and Ex./Em. is 400 +/-25 nm/510 +/-20 nm.
Data processing: compound inhibition (%) (1-Savg/Cavg) × 100%; savg is the average value of the fluorescence readings of the compounds to be detected, and Cavg is the average value of the fluorescence readings of the negative control group, IC50Calculated by GraphPad Prism software.
As a result:
TABLE 1 inhibition of IDO enzyme Activity IC in Hela cells by Compounds of the invention50
| Compound numbering | IC 50(nM) |
| 2 | 7.5 |
| 2A | 9.1 |
| 3 | 39.4 |
| 4A | 21.2 |
| 5A | 15.7 |
| 6A | 2.2 |
| 6B | 33.3 |
| 8 | 6.1 |
| 9 | 9.4 |
| 10 | 4.3 |
| 18A | 0.88 |
| 25A | 10.0 |
| 36A | 17.4 |
| 87A | 5.5 |
| 89A | 7.0 |
As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on the IDO enzyme in Hela cells.
Experimental example 2: hERG experiments
Using PredictorTMThe hERG Fluorescence Polarization Assay Kit (manufacturer: ThermoFisher) was used to test the inhibition of compounds on hERG potassium channel at a concentration of 10. mu.M according to the Kit instructions, and the results are shown in Table 2.
TABLE 2 inhibition of hERG by the compounds
| Compound (I) | Inhibition ratio (%) of 10. mu.M |
| 2A | 9.96±11.83 |
| 4A | 38.05±8.64 |
| 25A | 19.33±2.80 |
| 89A | 7.51±0.82 |
The results indicate that compounds 2A, 4A, 25A and 89A tested had no significant inhibition of hERG and had little potential to cause prolongation of cardiac QT interval.
Experimental example 3: CYP enzyme inhibition assay
CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, of which the most important are CYP1a2, CYP2D6, and CYP3a 4. In the inhibition assay for CYP450 enzymes, P450-Glo was usedTM CYP1A2 Screening System、
CYP2D6Cyan Screening Kit and
CYP3A4Red Screening Kit, according to the Kit instructions, respectively measuring the inhibitory activity of the compound on CYP1A2, CYP2D6 and CYP3A4, and the test concentration is 1 mu M and 10 mu M. TestingThe results are shown in Table 3.
TABLE 3 inhibition of CYP enzymes by Compounds
The results show that the compounds 2A, 4A, 25A, 87A and 89A have no obvious inhibition effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.
Various modifications of the invention in addition to those described herein, in light of the foregoing description, are intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.
Claims (23)
- A compound of formula I, a stereoisomer, a tautomer, or a mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound:
wherein:n is 0 or 1;R1is selected from C6-C14Aryl, 5-14 membered heteroaryl, or 9-10 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, 9-10 membered aryl and heterocyclyl are optionally substituted with 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; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with 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、-SO2NR7R8、-NR7R8；R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl radical of said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, C1-C6Hydroxyalkyl is optionally substituted with the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl, said 4-7 membered heterocyclyl being optionally substituted with: OH, halogen, CN, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, or R2、R3And together with the C atom to which they are attached form a P ring selected from C3-C6Cycloalkyl or 4-7 membered heterocyclyl;R4and R5Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、-C(O)NR7R8、-NR9C(O)R10；R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl radical, 5-a 10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6Haloalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8(ii) a Preferably R6Is selected from C6-C14Aryl, 5-14 membered heteroaryl, -CH2-C6-C14Aryl, -CH2-5-14 membered heteroaryl, C3-C7Cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclo; said C6-C14Aryl, 5-14 membered heteroaryl, C3-C7The cycloalkyl, 3-14 membered heterocyclyl, 9-12 membered aryl and heterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl, -OC1-C6alkyl-OC1-C6Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6Haloalkyl, -OC1-C6alkyl-OC1-C6Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-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, 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 are optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclyl; when a plurality of R7When present simultaneously, each R7May be the same or different; when a plurality of R8When present simultaneously, each R8May be the same or different; when a plurality of R9When present simultaneously, each R9May be the same or different;R10is selected from C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl, 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 are optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C or S atoms to which they are attached form a 4-7 membered heterocyclyl; when a plurality of R10When present simultaneously, each R10May be the same or different;x is NR11Or CHNO2；R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13，R12Is selected from C1-C6Alkyl radical, C3-C6A cycloalkyl group; said C1-C6Alkyl radical, C3-C6Cycloalkyl is optionally substituted with the following substituents: OH, OC1-C6Alkyl, NH2、NHMe、NMe24-7 membered heterocyclyl;R13is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl. - The compound of claim 1, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl is optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -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; said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined in formula I;preferably, R1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -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; said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl radical, C6-C10Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl may be optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C1-C4Alkoxy, -OC1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined in formula I;preferably, R1Is selected from C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl is optionally substituted with the following substituents: halogen, C1-C4Alkyl radical, C3-C6Cycloalkyl group, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl, -C (O) NR7R8(ii) a Said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl is optionally substituted with the following substituents: OH, -NR7R8，R7、R8As defined in formula I;more preferably, R1Selected from phenyl, quinolyl, pyridyl, indazolyl,
The phenyl, the quinolyl, the pyridyl, the indazolyl,
Optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, -C (O) NH (CH)3)、-C(O)N(CH3)2、-OCH2CH2OH、-OCH2CH2NH(CH3)、-OCH2CH2N(CH3)2；
More preferably, R1Selected from benzenePhenyl, quinolyl and pyridyl, wherein the phenyl, quinolyl and pyridyl can be optionally substituted by the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy;more preferably, R1Selected from phenyl, p-methoxyphenyl, quinolyl, pyridyl,
- The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is2And R3Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl radical of said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, C1-C4Hydroxyalkyl is optionally substituted with the following substituents: OH, halogen, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl, said 4-7 membered heterocyclyl being optionally substituted with: OH, halogen, CN, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4Hydroxyalkyl, or R2、R3And together with the C atom to which they are attached form a P ring, saidP ring is selected from C3-C6Cycloalkyl or 4-7 membered heterocyclyl;preferably, R2And R3Each independently selected from hydrogen and C1-C4Alkyl, or R2、R3And together with the C atom to which they are attached form a P ring selected from C3-C5A cycloalkyl group;more preferably, R2And R3Each independently selected from hydrogen, methyl, ethyl, propyl, or R2、R3And the C atom to which they are attached, form a P ring selected from cyclopropane, cyclobutane or cyclopentane;more preferably, R2And R3Each independently selected from hydrogen, methyl, ethyl, propyl;more preferably, R2And R3Each independently selected from hydrogen, methyl.
- The compound of any one of claims 1-3, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is4And R5Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Alkoxy radical, C2-C4Hydroxyalkyl radical, C2-C4alkyl-OC2-C4Alkyl radical, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C2-C4Hydroxyalkyl radical, C2-C4alkyl-OC2-C4Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C4Haloalkyl, CN, CO2H、-NR7R8、C(O)NR7R8、-NR9C(O)R10；R7、R8、R9、R10As defined in formula I;preferably, R4And R5Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Hydroxyalkyl of said C1-C4Alkyl is optionally substituted with the following substituents: halogen, -NR7R8，R7、R8As defined in formula I;more preferably, R4And R5Each independently selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, -CH2CH2NH(CH3)、-CH2CH2N(CH3)2；More preferably, R4And R5Each independently selected from hydrogen, methyl, ethyl, propyl;more preferably, R4And R5Each is hydrogen.
- The compound of any one of claims 1-4, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is6Is selected from C6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, C3-C7Cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl; said C6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, C3-C7Cycloalkyl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl, -OC1-C4alkyl-OC1-C4Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8、C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl; said C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl radical, C1-C4Hydroxyalkyl radical, OC1-C4alkyl-OC1-C4Alkyl radical, C6-C10Aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl is optionally substituted with the following substituents: OH, CN, halogen, CO2H、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl radical, C1-C4Haloalkyl, -OC1-C4alkyl-OC1-C4Alkyl, -C (O) R10、-C(O)OR7、-SO2R10、-C(O)NR7R8、-NR9C(O)R10、-NR9SO2R10、-SO2NR7R8、-NR7R8；R7、R8、R9、R10As defined in formula I;preferably, R6Selected from C optionally substituted by substituents6-C10Aryl, 5-10 membered heteroaryl, -CH2-C6-C10Aryl, -CH2-5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl, said C6-C10Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, 9-12 membered benzoheterocyclyl may be optionally substituted with the following substituents: OH, halogen, CN, NO2、CO2H、C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4Alkoxy radical, C1-C4Hydroxyalkyl, -OC2-4Alkyl OH, -OC2-4Alkyl radical NR7R84-7 membered heterocyclyl, R7、R8As defined in formula I;more preferably, R6Selected from benzeneA group, a piperidyl group, an oxopiperidinyl group, a tetrahydropyranyl group, a pyridyl group, a thiazolyl group, a pyrrolidinyl group, a2, 3-dihydrobenzo [ b ]][1,4]Dioxinyl, said phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridinyl, thiazolyl, pyrrolidinyl, 2, 3-dihydrobenzo [ b][1,4]The dioxinyl group may be optionally substituted with the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CN, hydroxyethyl, hydroxypropyl, -OCH2CH2OH、-OCH2CH2NH(CH3)、-OCH2CH2N(CH3)2Pyrrolidinyl, 3-hydroxypyrrolidinyl;more preferably, R6Is phenyl optionally substituted with fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or CN;more preferably, R6Is phenyl, optionally substituted with fluoro, chloro, methoxy or CN.
- The compound of any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-7 membered heterocyclic group, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl and 4-7 membered heterocyclyl are optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclyl;preferably, R7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclic group, said C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclyl is optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R7、R8And together with the N atom to which they are attached form a 4-7 membered heterocyclyl;preferably, R7、R8And R9Each independently selected from hydrogen and C1-C4Alkyl radical, C2-C4Alkoxy radical, said C1-C4Alkyl radical, C2-C4Alkoxy may be optionally substituted for NH by2、NHMe、NMe2；More preferably, R7、R8And R9Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.
- The compound of any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein R is10Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6CycloalkanesBase, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-7 membered heterocyclic group, said C1-C4Alkyl radical, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl and 4-7 membered heterocyclyl are optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C or S atoms to which they are attached form a 4-7 membered heterocyclyl;preferably, R10Is selected from C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclic group, said C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkoxy radical, C3-C6Cycloalkyl radical, C2-C4Hydroxyalkyl radical, C1-C4alkyl-OC1-C4Alkyl, 4-6 membered heterocyclyl is optionally substituted with the following substituents: OH, CN, halogen, NH2、NHMe、NMe2、CO2H, or R9、R10And together with the N and C atoms to which they are attached form a 4-7 membered heterocyclyl;preferably, R10Is selected from C1-C4Alkyl radical, C2-C4Alkoxy radical, said C1-C4Alkyl radical, C2-C4Alkoxy groups may be optionally substituted with the following substituents: NH (NH)2、NHMe、NMe2；More preferably, R10Selected from methyl, ethyl, propyl, isopropyl.
- The compound of any one of claims 1-7, a stereoisomer, a tautomer, or a mixture thereofA compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, wherein X is NR11Or CHNO2；R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13；R12Is selected from C1-C4Alkyl radical, C3-C6A cycloalkyl group; said C1-C4Alkyl radical, C3-C6Cycloalkyl is optionally substituted with the following substituents: OH, OC1-C4Alkyl, NH2、NHMe、NMe24-7 membered heterocyclyl;R13is selected from C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, said C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C6Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-7 membered heterocyclyl;preferably, X is selected from NR11Or CHNO2；R11Selected from hydrogen, OH, CN, NH2、NHMe、NMe2、-SO2R12、-C(O)R13；R12Is selected from C1-C4Alkyl radical, C3-C5A cycloalkyl group;R13is selected from C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl radical, said C1-C4Alkyl radical, C3-C5Cycloalkyl radical, C1-C4alkyl-OC1-C4Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C4Haloalkyl, CN, C (O) NH2、NH2、NHMe、NMe24-6 membered heterocyclyl;more preferably, X is selected from NR11Or CHNO2Wherein R is11Selected from CN, -SO2R12；R12Selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane; more preferably, X is selected from NR11Or CHNO2Wherein R is11Selected from CN, -SO2Me、-SO2Et、-SO2Pr、-SO2-i-Pr、-SO2-cyclopropane, -SO2-cyclobutane;more preferably, X is selected from N-SO2Me、N-CN、CH-NO2；More preferably, X is selected from N-SO2Me、N-CN。
- The compound of any one of claims 1-8, a stereoisomer, a tautomer, or a mixture thereof of said compound, 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, said compound having the structure of formula II:
wherein R is1、R5、R6And X is as defined in any one of claims 1 to 8. - The compound of claim 9, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, said compound having the structure of II-1 or II-2:
wherein R is1、R5、R6And X is as defined in any one of claims 1 to 8. - The compound of any one of claims 1-8, a stereoisomer, a tautomer, or a mixture thereof of said compound, 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, said compound having the structure of formula III:
wherein R is1、R2、R3、R5、R6And X is as defined in any one of claims 1 to 8;preferably, R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6An alkyl group. - The compound of claim 11, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, said compound having the structure of formula III-1 or III-2:
wherein R is1、R2、R3、R5、R6And X is as defined in any one of claims 1 to 8;preferably，R2And R3Each independently selected from hydrogen and C1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C6Cycloalkyl radical, C1-C6alkyl-OC1-C6An alkyl group. - The compound of any one of claims 1-8, a stereoisomer, a tautomer, or a mixture thereof of said compound, 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, said compound having the structure of formula IV:
wherein R is1、R4、R5、R6And X is as defined in any one of claims 1 to 8;preferably, R4Is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、-C(O)NR7R8、-NR9C(O)R10。 - The compound of claim 13, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, said compound having the structure of formula IV-1 or IV-2:
wherein R is1、R4、R5、R6And X is as defined in any one of claims 1 to 8;preferably, R4Is selected from C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl radical, said C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Hydroxyalkyl radical, C1-C6alkyl-OC1-C6Alkyl is optionally substituted with the following substituents: OH, halogen, C1-C6Haloalkyl, CN, CO2H、-NR7R8、-C(O)NR7R8、-NR9C(O)R10。 - The compound of any one of claims 1-8, a stereoisomer, a tautomer, or a mixture thereof of said compound, 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, said compound having the structure of formula V:
wherein R is1P ring, R5、R6And X is as defined in any one of claims 1 to 8. - The compound of claim 15, a stereoisomer, tautomer, or mixture thereof of said compound, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotopic derivative, metabolite or prodrug of said compound, said compound having the structure of formula V-1 or V-2:
wherein R is1P ring, R5、R6And X is as defined in any one of claims 1 to 8. - The compound of any one of claims 1-16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a metabolite or prodrug of said compound, selected from the group consisting of:
- a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-17, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, stable isotopic derivative, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
- The pharmaceutical composition of claim 18, which is administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.
- A pharmaceutical formulation comprising a compound of any one of claims 1-17, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a co-crystal, or a solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutical composition of any one of claims 18 or 19.
- Use of a compound of any one of claims 1 to 17, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, stable isotope derivative, metabolite, or prodrug thereof, or a pharmaceutical composition of any one of claims 18 or 19, or a pharmaceutical formulation of claim 20, for the manufacture of a medicament for the prophylaxis or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression;preferably, said diseases associated with IDO activity or IDO-mediated immunosuppression include, but are not limited to, tumors, depression, alzheimer's disease;more preferably, the tumor includes, but is not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
- A compound of any one of claims 1-17, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, stable isotope derivative, metabolite, or prodrug thereof, or a pharmaceutical composition of any one of claims 18 or 19, or a pharmaceutical formulation of claim 20, for use in the prevention or treatment of a disease associated with IDO activity or IDO-mediated immunosuppression;preferably, said diseases associated with IDO activity or IDO-mediated immunosuppression include, but are not limited to, tumors, depression, alzheimer's disease;more preferably, the tumor includes, but is not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
- A method for preventing or treating a disease associated with IDO activity or IDO-mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 17, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, stable isotope derivative, metabolite, or prodrug thereof, or a pharmaceutical composition of any one of claims 18 or 19, or a pharmaceutical formulation of claim 20, and optionally comprising administering to the subject in need thereof an additional agent for the treatment of a disease, such as cancer;preferably, said diseases associated with IDO activity or IDO-mediated immunosuppression include, but are not limited to, tumors, depression, alzheimer's disease;more preferably, the tumor includes, but is not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, cancer of the female genital tract, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
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| PCT/CN2019/070339 WO2019141095A1 (en) | 2018-01-19 | 2019-01-04 | Amidine and guanidine derivative, preparation method therefor and medical use thereof |
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| CN111247119B (en) | 2023-02-03 |
| WO2019141095A1 (en) | 2019-07-25 |
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