Deubiquitinating enzyme inhibitors and their applications

Abstract

The present invention relates to a compound represented by formula (I) and its racemate, stereoisomer, tautomer, isotopically labeled compound, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, pharma- ceutically acceptable salt or prodrug, and pharmaceutical compositions containing them, and their pharmaceutical use. The above compounds have activity to inhibit USP28 and / or USP25, and have potential medical uses as drugs for the treatment of diseases related to cancer, inflammation, autoimmune diseases, viral infections, bacterial infections, etc. The structure of the above formula I is as follows: [Formula 1] JPEG2025516222000033.jpg31169

Description

Detailed Description of the Invention

[0001] The present invention claims the priority of a prior application filed with the State Intellectual Property Office of China on April 28, 2022, with the patent application number 202210471474.9 and the title "Deubiquitinating Enzyme Inhibitor and Its Application". The full text of the prior application is incorporated herein by reference.

[0002] 〔Technical Field〕 The present invention belongs to the field of drugs, and specifically relates to a deubiquitinating enzyme inhibitor and its application.

[0003] 〔Background Art〕 Cells function normally due to the homeostasis of intracellular proteins, and this homeostasis is maintained by the dynamic balance of protein synthesis and degradation. Protein ubiquitination by ubiquitinating enzymes is the main pathway of proteasomal degradation, while protein deubiquitination generated by deubiquitinating enzymes is a necessary supplement for precisely regulating protein homeostasis. USP25 and USP28 are deubiquitinating enzymes with very close genes but located in different regions of cells, and both are closely correlated with the occurrence and progression of multiple types of neoplastic diseases. USP25 and USP28 maintain the homeostasis of these proteins by deubiquitinating multiple types of cancer proteins, epigenetic drivers, immune regulatory proteins, and other cytokines. Inhibiting the deubiquitinating activity of USP25 and USP28 can lead to excessive degradation of target proteins and ultimately cause cell death. Therefore, small molecule compounds having USP25 and USP28 inhibitory activities have potential medical uses as therapeutic agents for diseases correlated with cancer, inflammation, autoimmune diseases, viral infections, and bacterial infections.

[0004] 〔Summary of the Invention〕 The present invention provides a compound represented by the following formula I and its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug,

[0005]

Chem.

[0006] Among them, X is selected from N or CH, Y is

[0007]

Chem.

[0008] selected from Z is NR 8 , O, S or CR 9 R 10 selected from, and the dashed bond indicates that it may or may not be a bond, a is selected from 0, 1, 2, 3, 4, 5 or 6, b is selected from 1 or 2, c is selected from 1, 2, 3 or 4, d is selected from 1, 2 or 3, e is selected from 0 or 1, f is selected from 1 or 2, R 1 is hydrogen, optionally unsubstituted or substituted (C 1 ~C 12 ) selected from aliphatic hydrocarbon groups, R 2 is hydrogen, halogen or optionally unsubstituted or substituted (C 1 ~C 12 ) selected from aliphatic hydrocarbon groups, R 3 is halogen, hydroxy group, optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon oxy group, optionally unsubstituted or substituted (C 1 ~C 12 ) selected from aliphatic hydrocarbon amino groups, Each R 4may be the same or different and, independently of one another, are selected from hydrogen, halogen and optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups, each R 5 and R 7 may be the same or different and, independently of one another, are selected from hydrogen, halogen, hydroxy group, amino group, optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups and optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon oxy groups, R 6 is hydrogen, halogen, hydroxy group, amino group, and optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon group, or an unsubstituted or optionally substituted 3- to 20-membered heterocyclic group or 5- to 20-membered heteroaryl group containing one, two or more N atoms and / or O atoms substituted with one, two or more R 11 , R 8 , R 9 and R 10 are selected from hydrogen and optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups, each R 11 may be the same or different and, independently of one another, are selected from hydrogen, halogen, hydroxy group, amino group and optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups, According to an embodiment of the present invention, the above-mentioned "unsubstituted (C 1 ~C 12 ) aliphatic hydrocarbon group" is a linear or branched, saturated or unsaturated, chain or cyclic hydrocarbon group composed of 1 to 12 carbon atoms and corresponding hydrogen atoms, and the types of the above aliphatic hydrocarbon groups are selected from groups such as alkyl group, alkenyl group or alkynyl group, and the above "substituted (C 1 ~C 12) The "aliphatic hydrocarbon group" is a "(C 1 ~C 12 ) aliphatic hydrocarbon group" containing one, two or more halogen and / or oxygen, sulfur, nitrogen, phosphorus atoms, among which halogen, oxygen, sulfur, nitrogen, phosphorus may be on the straight or branched chain of the (C 1 ~C 12 ) aliphatic hydrocarbon group, or at any one position of the straight or branched chain. The above "(C 1 ~C 12 ) aliphatic hydrocarbon group" is preferably a "(C 1 ~C 10 ) aliphatic hydrocarbon group", "(C 1 ~C 8 ) aliphatic hydrocarbon group" and "(C 1 ~C 6 ) aliphatic hydrocarbon group". For example, the following groups, namely, (C 1 ~C 6 ) aliphatic hydrocarbon group, (C 1 ~C 6 ) aliphatic hydrocarbon oxy group, N-(C 1 ~C 6 ) aliphatic hydrocarbon amine group, N,N-di-(C 1 ~C 3 ) aliphatic hydrocarbon amine group, (C 1 ~C 6 ) aliphatic hydrocarbon mercapto group, halogenated (C 1 ~C 6 ) aliphatic hydrocarbon group, halogenated (C 1 ~C 6 ) aliphatic hydrocarbon oxy group, (mono- or di-N-substituted) halogenated (C 1 ~C 6 ) aliphatic hydrocarbon amine group, halogenated (C 1 ~C 6 ) aliphatic hydrocarbon mercapto group, (C 1 ~C 6 ) aliphatic hydrocarbon oxy (C 1 ~C 6 ) aliphatic hydrocarbon group, (C 1 ~C 6 ) aliphatic hydrocarbon mercapto (C 1 ~C 6 ) aliphatic hydrocarbon group, N-(C 1 ~C6 ) an aliphatic hydrocarbon amino (C 1 ~C 6 ) aliphatic hydrocarbon group, N,N-di-(C 1 ~C 3 ) aliphatic hydrocarbon amino (C 1 ~C 6 ) may be selected from. More specifically, methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, pentyl group and isopentyl group, methoxymethyl group, ethoxymethyl group, propoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, methoxypropyl group, ethoxypropyl group, propoxypropyl group, N-methylaminomethyl group, N-methylaminoethyl group, N-ethylaminoethyl group, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group or N,N-diethylaminoethyl group, cyano group, nitrile methyl group, nitrile ethyl group, nitrile propyl group, nitrile butyl group, nitrile pentyl group may be used.

[0009] According to an embodiment of the present invention, X is selected from CH.

[0010] According to an embodiment of the present invention, Y is

[0011]

Chemical formula

[0012] selected from, among which, Z, R 5 , R 6 , and d independently have the above definitions, and Y is, for example,

[0013]

Chemical formula

[0014] selected from.

[0015] According to an embodiment of the present invention, Z is nitrogen-hydrogen (NH), oxygen (O), sulfur (S), or a methylene group (CH 2 ) and is selected therefrom.

[0016] According to an embodiment of the present invention, the above R 1 is selected from hydrogen, an unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon group, for example, H, a (C 1 ~C 6 ) aliphatic hydrocarbon group, a halogenated (C 1 ~C 6 ) aliphatic hydrocarbon group. According to an embodiment of the present invention, the above R 1 is selected from hydrogen, an optionally unsubstituted or substituted (C 1 ~C 6 ) alkyl group, for example, H, a (C 1 ~C 6 ) alkyl group, a halogenated (C 1 ~C 6 ) alkyl group. According to an embodiment of the present invention, the above R 1 is the following group, that is, H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group, CF 3 , CHF 2 CH, CH 2 FCH, CF 3 CH 2 , CHF 2 CH 2 , CH 2 FCH 2 and is selected therefrom.

[0017] According to an embodiment of the present invention, the above R 2 is selected from hydrogen, an optionally unsubstituted or substituted (C 1 ~C 6 ) alkyl group, for example, H, a (C 1 ~C 6 ) alkyl group, a halogenated (C 1 ~C 6 ) alkyl group.

[0018] According to an embodiment of the present invention, the above R 3 is selected from a halogen, a hydroxy group, an unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon amino group, and an unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon oxy group. For example, it is a halogen, a (C 1 ~C 6 ) hydrocarbon amino group, a halogenated (C 1 ~C 6 ) hydrocarbon amino group, a (C 1 ~C 6 ) hydrocarbon oxy group, or a halogenated (C 1 ~C 6 ) hydrocarbon oxy group, According to an embodiment of the present invention, the above R 3 is selected from a halogen, a hydroxy group, optionally an unsubstituted or substituted (C 1 ~C 6 ) alkyloxy group, and optionally an unsubstituted or substituted (C 1 ~C 6 ) alkylamino group. For example, it is F, Cl, Br, I, a (C 1 ~C 6 ) alkylamino group, a halogenated (C 1 ~C 6 ) alkylamino group, a (C 1 ~C 6 ) alkyloxy group, or a halogenated (C 1 ~C 6 ) alkyloxy group, According to an embodiment of the present invention, the above R 3 is one of the following groups, namely, Cl, methylamino group (Me-NH), fluoromethylamino group (CH 2 F-NH), difluoromethylamino group (CHF 2 -NH), trifluoromethylamino group (CF 3 -NH), ethylamino group (Et-NH), propylamino group ( n Pr-NH), isopropylamino group ( i Pr-NH), or methoxy group (CH 3 O).

[0019] According to an embodiment of the present invention, the above R 4 is selected from hydrogen, optionally unsubstituted or substituted (C 1 ~C 6 ) alkyl group. For example, it is H, (C 1 ~C 6 ) alkyl group, halogenated (C 1 ~C 6 ) alkyl group, and According to an embodiment of the present invention, the above R 4 is selected from the following groups, namely, H and methyl group.

[0020] According to an embodiment of the present invention, the above R 5 is selected from hydrogen, halogen, optionally unsubstituted or substituted (C 1 ~C 6 ) alkyl group, optionally unsubstituted or substituted (C 1 ~C 6 ) alkoxy group. For example, it is H, F, Cl, Br, I, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) alkoxy group, and According to an embodiment of the present invention, the above R 5 is selected from the following groups, namely, H, F, Br, methyl group, and methoxy group.

[0021] According to an embodiment of the present invention, the above R 6 is selected from hydrogen, halogen, hydroxy group, amino group, and optionally unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon group, or an unsubstituted or optionally substituted 3- to 14-membered heterocyclic group or 5- to 14-membered heteroaryl group containing one, two, or more N atoms and / or O atoms substituted with one, two, or more R 11 . Each R 11 is the same or different and independently of one another is selected from hydrogen, halogen, hydroxy group, amino group, and optionally unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon group, and According to an embodiment of the present invention, R 6 is a 3- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, which may be unsubstituted or optionally substituted with one, two or more R 11 each R 11 is the same or different and independently of one another is selected from hydrogen, (C 1 ~C 6 ) alkyl groups, According to an embodiment of the present invention, the above R 6 is selected from 6- to 8-membered heterocyclic groups containing one or two N atoms and / or O atoms, for example, the following groups, namely,

[0022]

Chemical formula

[0023] selected from.

[0024] According to an embodiment of the present invention, the above R 7 , R 8 , R 9 , R 10 are the same or different and independently of one another are selected from hydrogen, optionally unsubstituted or substituted (C 1 ~C 6 ) alkyl groups, for example, H, (C 1 ~C 6 ) alkyl groups, halogenated (C 1 ~C 6 ) alkyl groups, According to an embodiment of the present invention, the above R 7 , R 8 , R 9 , R 10 are selected from the following groups, namely, H, methyl group.

[0025] According to an embodiment of the present invention, the structure of the above formula I is further selected from the structures of formula II-a and formula II-b,

[0026]

Chemical formula

[0027] The Rs described in Formula II-a and Formula II-b 1 , R 2 , R 4 , R 5 , R 6 , R 7 and the definitions of c are the same as those in Formula I, and the above R 3 ’ is a (C 1 ~C 6 ) aliphatic hydrocarbon group or a (C 1 ~C 6 ) aliphatic hydrocarbon group containing one, two, or more halogen and / or hydroxy group substitutions. Further, R 3 ’ is preferably a methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, ethyl group, propyl group, or isopropyl group.

[0028] According to an embodiment of the present invention, it is preferably the following compound (I-01 to I-33) or its tautomer, optical isomer, isotope-labeled compound, nitrogen oxide, solvate, pharmaceutically acceptable salt, or prodrug.

[0029]

Chemical formula

[0030] The present invention further provides a pharmaceutical composition containing, as an active ingredient, a compound represented by Formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug.

[0031] According to an embodiment of the present invention, the above pharmaceutical composition further contains a therapeutically effective amount of the compound of Formula (I) or its tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt, or prodrug, and a pharmaceutically acceptable carrier.

[0032] The carrier in the above pharmaceutical composition is "acceptable", which is compatible with the active ingredient of the composition (and preferably can stabilize the active ingredient), and is not harmful to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients to deliver the active compound.

[0033] The present invention further provides the use of the compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug or the above pharmaceutical composition in the manufacture of a drug for treating and inhibiting a disease or disorder correlated with USP28.

[0034] The present invention further provides the use of the compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug or the above pharmaceutical composition in the manufacture of a drug for treating and inhibiting a disease or disorder correlated with USP25.

[0035] The present invention further provides the use of the compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug or the above pharmaceutical composition in the manufacture of a drug for treating and inhibiting a disease or disorder correlated with both USP25 and USP28.

[0036] The present invention further provides a method for treating or preventing a disease or disorder correlated with the regulation of USP28 and / or USP25, the method comprising administering to a patient suffering from at least one of the above diseases or disorders a compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, nitrogen oxide, solvate, crystal polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug.

[0037] According to an embodiment of the present invention, the diseases or disorders correlated with the above USP25 and / or USP28 include cancer, inflammation, autoimmune diseases, viral infections, and bacterial infections.

[0038] According to an embodiment of the present invention, the pharmaceutical composition may be in a form suitable for oral administration, for example, tablets, dragees, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The oral composition may be manufactured according to any method for manufacturing a pharmaceutical composition known in the art, and such a composition may contain one or more components selected from sweeteners, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically acceptable formulation that looks good and tastes good. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, adhesives, and lubricants. These tablets may not be coated, or may be coated by known techniques that provide a sustained release effect over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.

[0039] According to an embodiment of the present invention, in the above pharmaceutical composition, a soft gelatin capsule in which an active ingredient and an inert solid diluent, or an active ingredient therein and a water-soluble carrier or an oily solvent are mixed provides an oral preparation, and the aqueous suspension contains an active substance and an excipient for mixing suitable for the production of the aqueous suspension. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweetening agents, and the oily suspension may be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oily suspension may contain a thickening agent. In order to provide a palatable preparation, the above sweetening agents and flavoring agents may be added. By adding an antioxidant, these compositions may be preserved, and by adding water, dispersible powders and granules suitable for the production of an aqueous suspension may provide an active ingredient and a dispersing agent, a wetting agent, a suspending agent and one or more preservatives for mixing. Suitable dispersing agents or wetting agents and suspending agents may be illustrated by the above examples. Also, other excipients such as sweetening agents, flavoring agents and colorants may be added. By adding an antioxidant such as ascorbic acid, these compositions are preserved.

[0040] According to an embodiment of the present invention, the above pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain a sweetening agent, a flavoring agent, a preservative and an antioxidant. Such a preparation may also contain a soothing agent, a preservative, a colorant and an antioxidant.

[0041] According to an embodiment of the present invention, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Permissible usable solvents or solubilizers include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be an oil-in-water type microemulsion in sterile injectable water in which the active ingredient is dissolved in the oil phase, and the injection solution or microemulsion may be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is optimal to administer the solution and the microemulsion according to a method capable of maintaining a certain circulating concentration of the compound of the present invention. In order to maintain such a certain concentration, a continuous intravenous administration device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 type intravenous injection pump.

[0042] According to an embodiment of the present invention, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution or an oil suspension for intramuscular and subcutaneous administration. The suspension may be prepared using the above-mentioned appropriate dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable preparation may be a sterile injection solution or suspension produced in a non-parenterally acceptable non-toxic diluent or solvent. Otherwise, a sterile fixed oil may be conveniently used as a solvent or a suspending medium. For this purpose, any compounding fixed oil may be used. Otherwise, fatty acids may also be used to produce the injection.

[0043] According to an embodiment of the present invention, the compound of the present invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions may be produced by mixing the drug with a suitable excipient that is solid at normal temperature but liquid in the rectum and thus melts in the rectum to release the drug without irritation.

[0044] As is well known to those skilled in the art, the dosage of a drug depends on multiple factors, including but not limited to the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the administration time, the administration method, the excretion rate, the combination of drugs, etc. Also, the optimal treatment method, such as the treatment mode, the daily dosage of the general formula compound (I) or the type of pharmaceutically acceptable salt, may be verified based on the conventional treatment regimen.

[0045] Beneficial effects The present invention provides deubiquitinating enzyme inhibitor compounds, and the compounds of this series have good inhibitory activity against USP25 and / or USP28, and may be used to prevent or treat diseases correlated with deubiquitinating enzymes as drugs.

[0046] Definition and explanation of terms Unless otherwise specified, the definitions of the groups and terms described in the specification and claims of this application include their exemplary definitions, illustrative definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., and they may be arbitrarily combined or joined with each other. The definitions of the groups and the structures of the compounds after such combination and joining should belong to the scope described in the specification of this application.

[0047] The numerical ranges described in the specification and claims of this application should be understood that when the numerical values are defined as "integers", the two endpoints of the range and each integer within the range are described. For example, "integers from 0 to 6" should be understood that each integer of 0, 1, 2, 3, 4, 5, and 6 is described. "More than that" indicates three or more.

[0048] The term "halogen" refers to F, Cl, Br, and I.

[0049] The term "aliphatic hydrocarbon group" includes saturated or unsaturated, linear or branched chain, chain or cyclic hydrocarbon groups. The types of the above aliphatic hydrocarbon groups may be selected from alkyl groups, alkenyl groups, alkynyl groups, etc. The number of carbon atoms of the above aliphatic hydrocarbon group is preferably 1 to 12, and may also be 1 to 10, more preferably 1 to 6. Specifically, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylvinyl group, 1-butenyl group, 1-ethylvinyl group, 1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 1-hexenyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group are included, but not limited thereto. The above aliphatic hydrocarbon group may optionally contain one or more other suitable substituents. Examples of the above substituents may include groups such as hydroxyl group, halogen, cyano group and amino group. For example, the above aliphatic hydrocarbon group may contain one, two or more halogens, that is, it means that one, two or more hydrogen atoms of the aliphatic hydrocarbon group may be substituted with the same number of halogens. When the above hydrocarbon group contains more than one carbon, those carbons do not necessarily have to be connected to each other. For example, at least two of them may be connected via a suitable element or group. That is, the above aliphatic hydrocarbon group may optionally contain one, two or more heteroatoms (or it is interpreted that the optional heteroatoms are inserted into the optional C-C bonds and C-H bonds in the aliphatic hydrocarbon group). Suitable heteroatoms will be apparent to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicon. The aliphatic hydrocarbon group containing the above heteroatoms is the following group, that is, (C 1 ~C 6 ) aliphatic hydrocarbon oxy group, (C 1 ~C6 ) An aliphatic hydrocarbon mercapto group, a halogenated (C 1 ~C 6 ) aliphatic hydrocarbon group, a halogenated (C 1 ~C 6 ) aliphatic hydrocarbon oxy group, a halogenated (C 1 ~C 6 ) aliphatic hydrocarbon thio group, (C 1 ~C 6 ) aliphatic hydrocarbon oxy (C 1 ~C 6 ) aliphatic hydrocarbon group, (C 1 ~C 6 ) aliphatic hydrocarbon mercapto (C 1 ~C 6 ) aliphatic hydrocarbon group, N-(C 1 ~C 3 ) aliphatic hydrocarbon amine (C 1 ~C 6 ) aliphatic hydrocarbon group, N,N-di-(C 1 ~C 3 ) aliphatic hydrocarbon amine (C 1 ~C 6 ) selected from aliphatic hydrocarbon groups, for example, methoxymethyl group, ethoxymethyl group, propoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, methoxypropyl group, ethoxypropyl group, propoxypropyl group, N-methylaminomethyl group, N-methylaminoethyl group, N-ethylaminoethyl group, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group, N,N-diethylaminoethyl group, cyano group, nitrile methyl group, nitrile ethyl group, nitrile propyl group, nitrile butyl group, nitrile pentyl group, and the "aliphatic hydrocarbon group" part included in other groups is as described above.

[0050] The term "3- to 20-membered heterocyclic group" means a saturated monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3- to 10-membered heterocyclic group". The term "3- to 10-membered heterocyclic group" means a saturated monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3 heteroatoms selected from N, O, and S. The above heterocyclic group may be linked to the rest of the molecule by any one of the above carbon atoms or a nitrogen atom (if present). In particular, the above heterocyclic group may include a 4-membered ring such as an azetidinyl group or an oxetidinyl group, a 5-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a pyrrolinyl group, or a 6-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a 7-membered ring such as a diazepanyl group, but is not limited thereto. Optionally, the above heterocyclic group may be benzo-fused. The above heterocyclic group may be bicyclic, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, but is not limited thereto. The nitrogen atom-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydrooxazolyl group, or a 4H-[1,4]thiazinyl group, but is not limited thereto, or it may be benzo-fused, for example, a dihydroisoquinolinyl group, but is not limited thereto. According to the present invention, the above heterocyclic group is non-aromatic. The above 3- to 10-membered heterocyclic group may further be

[0051]

Chemical formula

[0052] selected from.

[0053] Unless otherwise specified, all possible isomeric forms, such as positional isomers, are included for the complex cyclic group or heteroaryl group. Thus, for some illustrative and non-limiting examples, the pyridinyl group or pyridinylidene group includes pyridinyl-2-yl, pyridinylidene-2-yl, pyridinyl-3-yl, pyridinylidene-3-yl, pyridinyl-4-yl and pyridinylidene-4-yl, and the thienyl group or thienylidene group includes thienyl-2-yl, thienylidene-2-yl, thienyl-3-yl and thienylidene-3-yl.

[0054] In any method for producing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any related molecules. This may be achieved by conventional protecting groups, for example, those described in textbooks and reference books in this field. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. Those skilled in the art will recognize that other reagents can be used in the deprotection step depending on the specific protecting group, but include, but are not limited to, Pd / C, Pd(OH) 2 , PdCl 2 , Pd(OAc) 2 / Et 3 SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, etc.

[0055] The target compound may be separated by known methods, for example, extraction, filtration, column chromatography, FCC or preparative HPLC.

[0056] Due to the molecular structure of the compounds of the present invention, they may be chiral, and thus various enantiomeric forms may exist. Therefore, these compounds may exist in racemic form or optically active form. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or may be used in this form for synthesis. In the case of racemic amines, diastereomers are produced from the mixture by reaction with an optically active resolving reagent. Examples of suitable resolving reagents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography can also be advantageously carried out with an optically active resolving reagent (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers). Suitable eluents used for this purpose are solvent mixtures containing water or alcohol, such as hexane / isopropanol / acetonitrile.

[0057] Those skilled in the art understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen needs to have a lone pair of electrons available for oxidation to the oxide. However, those skilled in the art can identify nitrogen-containing heterocycles that can form N-oxides. It is also recognized by those skilled in the art that tertiary amines can form N-oxides. Synthetic methods for producing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, and the above synthetic methods involve oxidizing heterocycles and tertiary amines using peroxyacids such as peroxyacetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, and dioxiranes such as sodium perborate and dimethyldioxirane. Methods for producing these N-oxides have already been widely described and summarized in the literature.

[0058] Pharmaceutically acceptable salts may be, for example, acid addition salts of the compounds of the present invention having a nitrogen atom in the chain or ring and sufficient basicity, for example, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfates, or formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or acid addition salts formed with organic acids such as thiocyanic acid.

[0059] Also, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol. As an example, the above pharmaceutically acceptable salts include salts formed from a -COOH group and sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol.

[0060] Also, the basic nitrogen-containing group may be quaternized with reagents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate, long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides, and aralkyl halides such as benzyl and phenethyl bromides. As an example, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or meglumine salt, etc.

[0061] Since the compounds of the present invention may have multiple salt-forming sites, the above-mentioned "pharmaceutically acceptable salts" include not only salts formed at one salt-forming site in the compounds of the present invention, but also salts formed at two, three or all of the salt-forming sites therein. Therefore, in the above-mentioned "pharmaceutically acceptable salts", the molar ratio of the compound of formula (I) to the ion (anion) of the acid or the cation of the base required for salt formation may vary within a relatively wide range, for example, it may be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0062] According to the present invention, the pharmaceutically acceptable anions include those selected from anions generated by ionizing inorganic acids or organic acids. The above-mentioned "inorganic acids" include, but are not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid. The above-mentioned "organic acids" include, but are not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid.

[0063] Depending on the position and nature of different substituents, the compounds of the present invention may further contain one or more asymmetric centers. The asymmetric carbon atoms may exist in the (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is formed, and when multiple asymmetric centers are included, a mixture of diastereoisomers is obtained. In some cases, asymmetry may also occur because the rotation around a specific bond is hindered. For example, the central bond is bonded to two substituted aromatic rings of a specific compound. Moreover, the substituents may exist in the form of cis or trans isomers.

[0064] The compounds of the present invention further include all possible stereoisomers thereof, which are in the form of a single stereoisomer or any mixture of the above stereoisomers (e.g., R-isomer or S-isomer, or E-isomer or Z-isomer) in any ratio. The separation of a single stereoisomer (e.g., a single enantiomer or a single diastereoisomer) of the compounds of the present invention may be achieved by any suitable conventional technique (e.g., chromatography, especially, for example, chiral chromatography).

[0065] The term "tautomer" refers to a functional group isomer formed by the rapid movement of an atom within a molecule between two positions. The compounds of the present invention may exhibit the phenomenon of tautomerism. Tautomeric compounds may exist in two or more interconvertible forms. Proton-transfer tautomers are due to the movement of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium state, and when attempting to separate a single tautomer, a mixture is usually produced whose physicochemical properties match those of a mixture of compounds. The position of the equilibrium is determined by the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenol, the enol form predominates. The present invention includes all tautomeric forms of the compounds.

[0066] In the present invention, such compounds also include compounds labeled with isotopes, and the compounds labeled with the above isotopes are the same as those represented by formula (I), but one or more of the atoms therein are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number that is usually naturally present. Examples of isotopes that may be incorporated into the compounds of the present invention are isotopes of H, C, N, O, S, F, and Cl, for example, 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, or pharmaceutically acceptable salts of the above compounds or the above prodrugs are within the scope of the present invention. Compounds labeled with certain isotopes of the present invention, for example, compounds incorporated with radioactive isotopes (e.g., 3 H and 14 C) may be used for measuring the tissue distribution of drugs and / or primers. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because they are easy to manufacture and have detectability. In addition, substitution with relatively heavy isotopes (e.g., deuterium, i.e., 2 H) may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased half-life in vivo or reduced required dosage), and accordingly, may be preferred in certain cases. The compounds of the present invention claimed by the claims may be particularly limited to be substituted with deuterium or tritium. Otherwise, hydrogen appearing in the substituents is not listed alone with the terms deuterium or tritium, but does not indicate that deuterium or tritium is excluded, and deuterium or tritium may also be included.

[0067] The terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of a compound described in the present invention to achieve the desired application (including, but not limited to, the treatment of the diseases defined below). The therapeutically effective amount may vary depending on the desired application (in vitro or in vivo), or the condition of the subject and the disease to be treated, such as the weight and age of the subject, the severity of the condition, and the method of administration, which may be readily determined by those skilled in the art. The specific dosage will vary depending on the particular compound selected, the method of administration to be followed, the presence or absence of co-administration with other compounds, the time schedule of administration, the tissue to be administered to, and the physical delivery system to be carried.

[0068] The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the types of excipients include, but are not limited to, adhesives, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. The excipients may improve the handling properties of the pharmaceutical formulation, i.e., by enhancing fluidity and / or adhesiveness to make the formulation more suitable for direct compression. Examples of typical pharmaceutically acceptable carriers suitable for the above formulations include sugars such as lactose, sucrose, mannitol, and sorbitol; starches such as corn starch, tapioca starch, and potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; alkali earth metal stearates such as sodium stearate, magnesium stearate, and calcium stearate; vegetable oils such as stearic acid, peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic, and anionic surfactants; glycol polymers; fatty alcohols; cereal hydrolyzates; and other non-toxic and compatible fillers, adhesives, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, etc., which are adjuvants commonly used in pharmaceutical formulations.

[0069] The term "solvate" refers to those forms of the compounds of the present invention that form a complex by coordination with solvent molecules in a solid or liquid state. A hydrate is a specific form of a solvate in which the coordination occurs with water. In the present invention, the preferred solvate is a hydrate. Furthermore, the pharmaceutically acceptable solvates (hydrates) of the compounds of general formula (I) of the present invention refer to co-crystals and clathrate compounds formed by the compound (I) and stoichiometrically one or more molecules of water or other solvents. Solvents that can be used for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol, and acetic acid.

[0070] The term "prodrug" or "drug precursor" refers to a compound that is converted in vivo to a compound represented by the above general formula or specific compound. Such a transformation is affected by the prodrug being hydrolyzed in the blood or being transformed to the parent structure via an enzyme in the blood or tissue. The prodrugs of the present invention may be esters. In the present invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1 ~C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound of the present invention contains a hydroxyl group or a carboxyl group, i.e., it is acylated to obtain a compound in prodrug form. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the hydroxyl group in the parent compound.

[0071] The "cancer" described in the present invention includes, but is not limited to, bladder cancer, breast cancer (e.g., ductal carcinoma), cervical cancer (e.g., squamous cell carcinoma), colorectal cancer (e.g., adenocarcinoma), esophageal cancer (e.g., squamous cell carcinoma), gastric cancer (e.g., adenocarcinoma, medulloblastoma, colon cancer, villous cancer, squamous cell carcinoma), head and neck cancer, blood cancer (e.g., acute lymphoblastic anemia, acute myeloid leukemia, acute lymphoblastic leukemia B cells, anaplastic large cell lymphoma, B cell lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, chronic eosinophilic leukemia / hypereosinophilic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, mantle cell lymphoma, multiple myeloma, T cell acute lymphoblastic leukemia), lung cancer (e.g., bronchioloalveolar adenocarcinoma, mesothelioma, mucoepidermoid carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lymphoma, nervous system cancer (e.g., spongioblastoma, neuroblastoma, glioma), ovarian cancer (e.g., adenocarcinoma), pancreatic cancer (e.g., ductal carcinoma), prostate cancer (e.g., adenocarcinoma), kidney cancer (e.g., renal cell carcinoma, clear cell renal carcinoma), sarcoma (e.g., chondrosarcoma, Ewing sarcoma, fibrosarcoma, multiple sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma), skin cancer (e.g., melanoma, epidermoid carcinoma, squamous cell carcinoma), thyroid cancer (e.g., medullary carcinoma), uterine cancer, etc.

[0072] The "autoimmune disease" or "autoimmune disorder" described in the present invention refers to an immune-mediated disease caused by an attack on self-tissues, but may also relate to the immune response to microorganisms. Examples of autoimmune diseases include, but are not limited to, multiple sclerosis, psoriasis, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, rheumatoid arthritis, polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, skin erythema, cutaneous lupus erythematosus (frostbite lupus erythematosus, lupus nephritis, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, dermatomyositis, polymyositis, idiopathic edema, chronic thyroiditis, Guillain-Barré syndrome, Graves' disease, myasthenia gravis, Sjögren's syndrome, polyarteritis nodosa, autoimmune enteric disease, uveitis, autoimmune oophoritis, chronic immune thrombocytopenic purpura, colitis, diabetes, psoriasis, pemphigus vulgaris, proliferative glomerulonephritis, Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome, chronic arthritis, inflammatory chronic rhinitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophageal cancer, inflammatory gastritis, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, and autoimmune-mediated blood diseases).

[0073] 〔Mode for Carrying Out the Invention〕 Hereinafter, in accordance with specific examples, the technical solution of the present invention will be described in more detail. It should be understood that the following examples are merely illustrative explanations and interpretations of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0074] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be manufactured by known methods.

[0075] Unless otherwise specified, the experimental methods in the examples described below are all general methods. The obtained compounds were analyzed by a Varian Mercury-Plus 400 nuclear magnetic resonance apparatus and a Waters Q-TOF-Ultima mass spectrometer for their 11H NMR spectra and mass spectra were measured. The above raw materials, reagents and biological materials are all commercially available unless otherwise specified.

[0076] Explanation of abbreviations used in the following examples and elsewhere in this specification

[0077]

Table 1

[0078] Synthetic method of the compound The compounds described in the present invention may be prepared by methods known in the field of organic synthesis, may be prepared from commercially available starting materials, or may be synthesized using known organic, inorganic and / or enzymatic methods. By way of example, the compounds of the present invention may be prepared using the general schemes described below. Under basic conditions (e.g., DIEA, TEA or DMAP), carboxylic acid I-A and amine I-B form amide I' by the action of a peptide coupling reagent (e.g., EDCI-HOBt, BOP or HATU), and then the target compound I is obtained by substituting a halogen atom with a hydrocarbylamino group or a hydrocarbyloxy group and removing a protecting group (e.g., Tfac and / or Boc).

[0079]

Chemical formula

[0080] (R x =Cl, Br, A = NH, O, R 1 , R 2 , R 4 , a, b, X and Y are defined the same as in formula I, and R 3 ' is defined the same as in formulas II-a and II-b.) Example 1 Production of Compound I-01 (N-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)phenethyl-4-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide) and I-02 (N-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)phenethyl-1-ethyl-4-methylamino-1H-pyrrolo[2,3-b]pyridine-5-carboxamide)

[0081]

Chemical formula

[0082] Step a) In a reaction flask (250 mL), add p-bromophenethylamine b-1 (10.00 g, 50 mmol), KI (0.41 g, 2.5 mmol), K 2 CO 3 (16.58 g, 120 mmol) and acetonitrile (100 mL), heat up to reflux, and add BnCl (20.89 g, 165 mmol) dropwise. After the addition is complete, reflux for 2 h to react. Filter and remove the inorganic salts from the reaction solution, concentrate the filtrate under reduced pressure to remove acetonitrile, add chloroform (200 mL) to the concentrate, wash with saturated NaCl solution (100 mL×2), and dry with anhydrous Na 2 SO 4 and concentrate under reduced pressure to obtain the crude product. Concentrate the crude product under reduced pressure to remove excess BnCl and the by-product benzyl alcohol, and obtain b-2 (18.39 g of pale yellow liquid, 97%).

[0083] b) In a reaction flask (250 mL), add b-3 (4.25 g, 20 mmol), b-2 (9.13 g, 24 mmol), Pd(OAc) 2 (449 mg, 2 mmol), X-phos (953 mg, 2 mmol), Cs 2 CO 3 (13.03 g, 40 mmol) and toluene (80 mL), evacuate to remove N 2It was replaced, heated up to 100 °C, and reacted for 18 h. The reaction solution was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure, the concentrate was passed through a silica gel column, and gradient elution was carried out with PE:EA = 19:1 and 9:1 to obtain b-4 (8.59 g, 84%).

[0084] c) Into the reaction flask (250 mL), b-4 (8.15 g, 15.9 mmol), HCO 2 NH 4 (20.09 g, 318.5 mmol), Pd(OH) 2 / C (2.26 g, containing 15% Pd) and MeOH (65 mL) were added, and N 2 was replaced by evacuation, heated up to 60 °C, and reacted overnight. The reaction solution was filtered to remove insoluble substances, the filtrate was concentrated under reduced pressure to remove methanol, chloroform (200 mL) was added to the concentrate, washed with saturated NaCl solution (50 mL × 3), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product. The crude product was passed through a silica gel column and gradient eluted with CHCl 3 -MeOH 20:1 → 8:2 to obtain I-B01 (5.15 g, 93%). ESI-MS: m / z 332 ([M+H] + ).

[0085] d) Into the reaction flask (50 mL), a-1 (1053 mg, 5.0 mmol) and dry DMF (10 mL) were added, cooled to 0 °C, 60% NaH (240 mg, 6.0 mmol) was added, and reacted for 30 min. Then, EtI (936 mg, 6.0 mmol) was added dropwise at 0 °C for 5 min, and after the addition was complete, reacted at room temperature for 1 h. Water (10 mL) and 10 N NaOH solution (1.0 mL) were added to the reaction solution, heated up to 60 °C and reacted for 1 h. After the reaction solution was cooled to room temperature, water (20 mL) was added, cooled to 0 °C, 18% hydrochloric acid was added dropwise to adjust the pH to 3, and a white solid was precipitated. After stirring continuously at room temperature for 15 min, suction filtration was carried out, and washed with water until the filtrate became neutral. The crude product was recrystallized from 35 mL of ethanol to obtain a-2 (white solid, 934 mg, 83.2%).

[0086] e) To a reaction flask (10 mL), a-2 (225 mg, 1.0 mmol), I-B01 (331 mg, 1.0 mmol), HOBt (149 mg, 1.1 mmol) and EDCI (230 mg, 1.2 mmol) were added. Further, anhydrous DMF (4 mL) and DIEA (524 μL, 3.0 mmol) were added, and the reaction was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, and silica gel column chromatography (25 g, eluted with PE / EtOAc = 1:1) was used to obtain I’-01 (white-like solid, 439 mg, 81.6%).

[0087] f) I’-01 (54 mg, 0.1 mmol) and TFA (150 μL, 10 mmol) were stirred in anhydrous CHCl 3 (2 mL) for 30 min. The reaction solution was concentrated under reduced pressure to remove the solvent, and silica gel column chromatography (20 g, CHCl 3 / MeOH / NH 3 ·H 2 O = 9:1:0.05) was used for separation to obtain I-01 (white-like solid, 38 mg, 86.5%). 1 1H NMR (CDCl 3 , 400 MHz) δ: 8.58 (s, 1H), 7.29 (d, J = 3.5 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 3.5 Hz, 1H), 6.35 (t, J = 5.5 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H), 4.14 (br s, 2H), 3.73 (q, J = 6.4 Hz, 2H), 3.47 (br d, J = 12.0 Hz, 2H), 3.42 (br d, J = 12.0 Hz, 2H), 2.90 (t, J = 6.8 Hz, 2H), 2.24 (m, 2H), 2.05 (m, 2H), 1.46 (t, J = 7.3 Hz, 3H). ESI-MS m / z: 438 ([M+H] + ). g) In a thick-walled pressure-resistant reaction flask (15 mL), I'-01 (108 mg, 0.2 mmol), 40% aqueous methylamine solution (173 μL, 2 mmol), and 1,4-dioxane (2 mL) were added. The temperature was raised to 100 °C and the reaction was carried out for 6 - 10 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and anhydrous CHCl 3 (1 mL) and TFA (297 μL, 20 mmol) were added. The temperature was raised to 60 °C and the reaction was carried out for 2 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and silica gel column chromatography (20 g, CHCl 3 / MeOH / NH 3 ·H 2 O = 9:1:0.05 for elution) was used to obtain I-02 (pale yellow gel-like, 59 mg, 67.0%). 1 H NMR (DMSO-d 6 , 400 MHz) δ: 8.97 (q, J = 5.3 Hz, 1H), 8.28 (t, J = 5.4 Hz, 1H), 8.25 (s, 1H), 7.22 (d, J = 3.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 3.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.96 (br s, 2H), 3.51 (br d, J = 11.1 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H), 3.22 (d, J = 5.4 Hz, 3H), 2.97 (br d, J = 11.1 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.94 - 1.84 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). ESI-MS m / z 433 ([M+H] + ). Using appropriate synthetic precursors, with reference to the reagents and reaction conditions for Example 1 (compounds I-01 and I-02) above, compounds I-03 - I-33 in Table 1 were synthesized.

[0088]

Table 2

[0089] Example 2 The ubiquitin-rhodamine 110 (Ub-Rh110) method was adopted to measure the USP28 activity.

[0090] Purified USP28 and Ub-Rh110, a primer for measuring deubiquitination enzyme activity, were purchased from Andy Biotechnology Co., Ltd. (R&D Systems). The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then diluted to the desired concentration [containing 20 mM Tris-HCl (pH 8.0), 2 mM CaCl 2 , 3 mM BME, 0.01% Prionex, 0.01% Triton X-100] (where the DMSO content ≦ 0.5%). Solutions of the test compound at different prepared concentrations were pre-mixed uniformly with USP28 (final concentration 4 nM) in a 96-well plate and incubated at r.t. for 30 minutes, and then Ub-Rh110 was added until it reached 125 nM. The final volume of the total reaction was 20 μL. Immediately after adding the primer, the detection of the fluorescence emitted (excitation wavelength 485 nm, emission wavelength 535 nm) with a microplate reader was started. A blank control group (DMSO instead of the test compound) and a primer group (without adding USP28) were set up simultaneously. The inhibition rate of the test compound against USP28 was calculated according to the following formula.

[0091] Inhibition % = (1 - [(fluorescence value 測定化合物 - fluorescence value プライマー ) / (fluorescence value 対照 - fluorescence value プライマー )] × 100% Based on the inhibition rate of the test compound against USP28 at different concentrations, its IC 50 value was calculated. The IC 50 values of the exemplified compounds I-01 to I-33 of the present invention against USP28 are shown in Table 2.

[0092] Example 3 The Ub-Rh110 method was adopted to measure the USP25 activity.

[0093] The purified USP25 was purchased from Andy Biotech. The experimental method was the same as that in Example 2. Among them, the final concentration of USP25 was 15 nM, the final concentration of the primer Ub-Rh110 was 125 nM, and the final volume of the total reaction was 20 μL.

[0094] The IC 50 values of the exemplified compounds I-01 to I-33 of the present invention against USP25 are shown in Table 2.

[0095]

Table 3

[0096] Example 4 With reference to Example 2 and Example 3, inhibition activity tests of the representative exemplified compounds of the present invention and the following comparative compound structures against USP28 and USP25 were carried out. The test results (comparative compound IC 50 / IC of the compound of the present invention 50 ) are shown in Table 3, and the results further indicated that the compound structure of the present invention has good inhibition activity.

[0097]

Table 4

[0098] The embodiments of the technical solution of the present invention have been exemplarily described above. It should be understood that the claims of the present invention are not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of not departing from the gist and principles of the present invention should all be included within the scope of the claims of this application.

Claims

1. A compound of formula I and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, crystal polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, wherein 【Chemical 1】 Among them, X is selected from N or CH, Y is [Chemical Formula 2] selected from Z is NR 8 , O, S or CR 9 R 10 and is selected from the group consisting of, and the dashed bond indicates that the bond may or may not be present a is selected from 0, 1, 2, 3, 4, 5 or 6, b is selected from 1 or 2, c is selected from 1, 2, 3 or 4, d is selected from 1, 2 or 3, e is selected from 0 or 1, f is selected from 1 or 2, R 1 is selected from hydrogen, optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups, R 2 is selected from hydrogen, halogen or optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon groups, R 3 is selected from a halogen, a hydroxy group, an optionally unsubstituted or substituted (C 1 to C 12 ) aliphatic hydrocarbon oxy group, and an optionally unsubstituted or substituted (C 1 to C 12 ) aliphatic hydrocarbon amino group, Each R 4 may be the same or different and, independently of one another, is selected from hydrogen, halogen and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon groups, Each R 5 and R 7 may be the same or different and, independently of one another, are hydrogen, halogen, a hydroxy group, an amino group, an optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group and an optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon oxy group, R 6 is selected from hydrogen, halogen, hydroxy group, amino group, and optionally unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group, or an unsubstituted or optionally substituted 3- to 20-membered heterocyclic group or 5- to 20-membered heteroaryl group containing one, two or more N atoms and / or O atoms substituted with one, two or more R 11 s, R 8 、R 9 and R 10 are each independently selected from hydrogen, an optionally unsubstituted or substituted (C 1 ~C 12 ) aliphatic hydrocarbon group, Each R 11 may be the same or different and, independently of one another, is hydrogen, halogen, a hydroxy group, an amino group and optionally an unsubstituted or substituted (C 1 -C 12 ) aliphatic hydrocarbon group selected from A compound of formula I and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, crystal polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs.

2. X is selected from CH, Preferably, Y is [Chemical Formula 3] selected from, among which, Z, R 5 , R 6 and d independently have the definitions described above, and Y is, for example, 【Chemical 4】 selected from Preferably, Z is selected from nitrogen hydride (NH), oxygen (O), sulfur (S), or a methylene group (CH 2 ), characterized by The compound according to claim 1.

3. Said R 1 is selected from hydrogen, unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon groups, for example, H, (C 1 -C 6 ) aliphatic hydrocarbon groups, halogenated (C 1 -C 6 ) aliphatic hydrocarbon groups, and Preferably, the R 1 is selected from hydrogen, optionally unsubstituted or substituted (C 1 -C 6 ) alkyl group, for example, H, (C 1 -C 6 ) alkyl group, halogenated (C 1 -C 6 ) alkyl group, and Preferably, said R 1 is one of the following groups, namely, H, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, pentyl group, isopentyl group, sec-pentyl group, CF 3 , CHF 2 CH, CH 2 FCH, CF 3 CH 2 , CHF 2 CH 2 , CH 2 FCH 2 selected from, Preferably, the R 2 is selected from hydrogen, optionally unsubstituted or substituted (C 1 -C 6 ) alkyl groups, for example, H, (C 1 -C 6 ) alkyl group, halogenated (C 1 -C 6 ) alkyl group, and Preferably, said R 3 is selected from a halogen, a hydroxy group, an unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon amino group, and an unsubstituted or substituted (C 1 -C 6 ) aliphatic hydrocarbon oxy group. For example, a halogen, a (C 1 -C 6 ) alkylamino group, a halogenated (C 1 -C 6 ) alkylamino group, a (C 1 -C 6 ) alkyloxy group, or a halogenated (C 1 -C 6 ) alkyloxy group, and Preferably, the R 3 is selected from a halogen, a hydroxy group, an optionally unsubstituted or substituted (C 1 -C 6 ) alkyloxy group, and an optionally unsubstituted or substituted (C 1 -C 6 ) alkylamino group, for example, F, Cl, Br, I, (C 1 -C 6 ) alkylamino group, a halogenated (C 1 -C 6 ) alkylamino group, (C 1 -C 6 ) alkyloxy group, a halogenated (C 1 -C 6 ) alkyloxy group, and Preferably, the said R 3 is one of the following groups, namely, Cl, methylamino group (Me-NH), fluoromethylamino group (CH 2 F-NH), difluoromethylamino group (CHF 2 -NH), trifluoromethylamino group (CF 3 -NH), ethylamino group (Et-NH), propylamino group ( n Pr-NH), isopropylamino group ( i Pr-NH), methoxy group (CH 3 O), and is selected from them. Preferably, said R 4 is selected from hydrogen, optionally unsubstituted or substituted (C 1 -C 6 ) alkyl group, for example, H, (C 1 -C 6 ) alkyl group, halogenated (C 1 -C 6 ) alkyl group, for example, H, methyl group, Preferably, said R 5 is selected from hydrogen, halogen, optionally unsubstituted or substituted (C 1 -C 6 alkyl group, optionally unsubstituted or substituted (C 1 -C 6 alkoxy group, for example, H, F, Cl, Br, I, (C 1 -C 6 alkyl group, (C 1 -C 6 alkoxy group, for example, H, F, Br, methyl group, methoxy group, characterized in that, The compound according to claim 1 or 2.

4. Said R 6 is selected from hydrogen, halogen, hydroxy group, amino group and optionally unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon group, or an optionally unsubstituted or optionally substituted 3- to 14-membered heterocyclic group or 5- to 14-membered heteroaryl group containing one, two or more N atoms and / or O atoms substituted with one, two or more R 11 , each R 11 is the same or different and independently of one another is selected from hydrogen, halogen, hydroxy group, amino group and optionally unsubstituted or substituted (C 1 ~C 6 ) aliphatic hydrocarbon group. Preferably, R 6 is a 3- to 10-membered heterocyclic group containing one or two heteroatoms containing N, which is unsubstituted or optionally substituted with one, two or more R 11 , and each R 11 is the same or different and independently of one another is hydrogen, (C 1 -C 6 ) alkyl group selected from, Preferably, the R 6 is selected from 6- to 8-membered heterocyclic groups containing one or two N atoms and / or O atoms, for example, the following groups, namely, [Chemical Formula 5] characterized in that it is selected from The compound according to any one of claims 1 to 3.

5. Said R 7 , R 8 , R 9 , R 10 are the same or different and, independently of one another, are hydrogen, an optionally unsubstituted or substituted (C 1 -C 6 ) alkyl group, for example, H, a (C 1 -C 6 ) alkyl group, a halogenated (C 1 -C 6 ) alkyl group, for example, H, a methyl group, characterized in that The compound according to any one of claims 1 to 4.

6. The compound represented by formula I is selected from structures II-a or II-b, [[Chemical Formula 6]] R as described in Formula II-a and Formula II-b 2 , R 4 , R 5 , R 7 and c have the definitions described in any one of claims 1 to 5, and said R 3 ’ is optionally a (C 1 -C 6 ) aliphatic hydrocarbon group or an (C 1 -C 6 ) aliphatic hydrocarbon group containing one, two or more halogen and / or hydroxy group substitutions, and is selected from, for example, R 3 ’ is a methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, ethyl group, propyl group and isopropyl group, characterized in that The compound according to any one of claims 1 to 5.

7. The compound represented by formula I is the following compound 【Chemical Formula 7】 【Chem.】 characterized in that it is selected from The compound according to any one of claims 1 to 6.

8. A pharmaceutical composition, characterized in that it contains a compound represented by formula I according to any one of claims 1 to 7 and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, crystal polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, A pharmaceutical composition.

9. Use of a compound represented by formula I according to any one of claims 1 to 7 and its racemates, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, crystal polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 8, in the manufacture of a drug for use in the treatment and inhibition of a disease or disorder correlated with USP28 and / or USP25.

10. The disease or disorder correlated with the said USP28 and / or USP25 is characterized in that it includes cancer, inflammation, autoimmune diseases, viral infections and bacterial infections, The use according to claim 9.

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