CN114394965B - Triazolopyridine compound and preparation method and application thereof - Google Patents

Abstract

A triazolopyridine compound is at least one of a compound shown in a general formula A or a meso form, a racemate, an enantiomer, a diastereoisomer, a tautomer, a prodrug and a pharmaceutically acceptable salt thereof. The compound can effectively inhibit kinase activity, has good inhibition effect on protein tyrosine kinase activity, has clinical application prospect, and can be used for preparing medicaments for preventing and/or treating related diseases.

Description

Triazolopyridine compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a triazolopyridine compound, a preparation method and application thereof.

Background

Intracellular signaling processes are an effective way for cells to respond to external stimuli and ultimately elicit specific biological effects. Cytokines are capable of intracellular signaling through a variety of signaling pathways, thereby involving in the regulation of many important biological functions related to hematopoiesis and immunity. The Janus kinase (JAK) family of protein tyrosine kinases and the activator of transcription (STAT) play an important role in cytokine signaling.

The existing JAK inhibitors mainly comprise tofacitinib and Filgotinib of Galapagos company in Belgium, however, tofacitinib can bring about side effects while relieving the symptoms of Rheumatoid Arthritis (RA), and certain infections, malignant tumors and lymphomas are caused. Filgotinib has relatively weak activity and is administered in relatively high clinical doses.

Disclosure of Invention

The invention provides a triazolopyridine compound, a preparation method and application thereof.

According to a first aspect, in one embodiment there is provided a triazolopyridine compound, said triazolopyridine compound being a compound represented by general formula a or at least one of a meso, racemate, enantiomer, diastereomer, tautomer, prodrug, pharmaceutically acceptable salt thereof:

according to a second aspect, there is provided in an embodiment a process for preparing the triazolopyridines of the first aspect, comprising at least one of the following processes:

1) When p=0, r ⁸ When oxygen is used, bromo-compound containing pinacol borate is synthesized into a compound shown in a general formula I through steps of coupling, iodination and carbonyl insertion;

2) When p=1, q is imino, R ⁸ In the case of oxygen, from triazolo [1,5-a ] ]The pyridine-2-amine compound is subjected to acylation, methylation and coupling steps to prepare a compound shown in a general formula II;

3) When p=1, q is imino, R ⁸ When oxygen is used, the intermediate is subjected to coupling, acylation and methylation steps to prepare the compound shown in the general formula II。

According to a third aspect, in one embodiment there is provided a pharmaceutical composition comprising a triazolopyridine compound of the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.

According to a fourth aspect, there is provided in an embodiment the use of a triazolopyridine compound of the first aspect, or of a pharmaceutical composition of the third aspect, for the preparation of an enzyme inhibitor.

According to a fifth aspect, there is provided in an embodiment the use of a triazolopyridine compound of the first aspect, or of a pharmaceutical composition of the third aspect, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with enzymatic activity.

According to the triazolopyridine compound, the preparation method and the application thereof, the compound can effectively inhibit kinase activity, has good inhibition effect on protein tyrosine kinase activity, has clinical application prospect, and can be used for preparing medicaments for preventing and/or treating related diseases.

Detailed Description

The present application will be described in further detail with reference to the following specific embodiments. Wherein like elements in different embodiments are numbered alike in association. In the following embodiments, numerous specific details are set forth in order to provide a better understanding of the present application. However, one skilled in the art will readily recognize that some of the features may be omitted, or replaced by other elements, materials, or methods in different situations. In some instances, related operations of the present application have not been shown or described in the specification in order to avoid obscuring the core portions of the present application, and may be unnecessary to persons skilled in the art from a detailed description of the related operations, which may be presented in the description and general knowledge of one skilled in the art.

Furthermore, the described features, operations, or characteristics of the description may be combined in any suitable manner in various embodiments. Also, various steps or acts in the method descriptions may be interchanged or modified in a manner apparent to those of ordinary skill in the art. Thus, the various orders in the description are for clarity of description of only certain embodiments, and are not meant to be required, unless otherwise indicated, to be followed.

The numbering of the components itself, e.g. "first", "second", etc., is used herein merely to distinguish between the described objects and does not have any sequential or technical meaning. The term "coupled" as used herein includes both direct and indirect coupling (coupling), unless otherwise indicated.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH ₂ - "ethylene" means- (CH) ₂ ) ₂ - "propylene" means- (CH) ₂ ) ₃ "butylene" means- (CH) ₂ ) ₄ -and the like.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5 to 20 membered monocyclic rings, which may contain at least one double bond, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein at least one ring may contain at least one double bond, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain at least one double bond, but no one ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, at least one of which is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably containing 5 to 6 ring atoms, where1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between 5-to 20-membered monocyclic rings, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain at least one double bond, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, at least one of which may contain at least one double bond, but none of which has a fully conjugated pi-electron system, wherein at least one ring atom is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain at least one double bond, but none of the rings has a fully conjugated pi electron system, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably at least one group independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

The term "haloalkyl" refers to an alkyl group substituted with at least one halogen, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen, wherein the alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an-OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to = O.

The term "carboxy" refers to-C (O) OH.

The term "mercapto" refers to-SH.

The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl is as defined above.

The term "acyl" refers to compounds containing a-C (O) R group, wherein R is alkyl, cycloalkyl, aryl, heteroaryl.

The term "sulfonic acid group" means-S (O) ₂ OH。

The term "sulfonate" refers to-S (O) ₂ O (alkyl) or-S (O) ₂ O (cycloalkyl), wherein alkyl is as defined above.

The term "imino" refers to a = NR group or-NR-group, where R may be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, etc.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that at least one hydrogen atom, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

JAK kinases, a family of intracellular non-receptor tyrosine kinases, mediate cytokine-produced signals and are transmitted down through the JAK-STAT signaling pathway.

JAK kinases belong to the family of non-receptor protein tyrosine kinases. Including four members of JAK1, JAK2, JAK3, tyk2, play an important role in the signal transduction of cytokine receptor superfamily members.

The Janus kinase (JAK) family plays a role in cytokine-dependent regulation of cell proliferation and function involving immune responses. Currently, there are four known mammalian JAK family members: jak1 (also known as Janus kinase-1), jak2 (also known as Janus kinase-2), jak3 (also known as Janus kinase, leukocyte; JAKL1; L-JAK and Janus kinase-3), tyk2 (also known as protein-tyrosine kinase 2). Jak1, jak2 and Tyk2 are widely present in various tissues and cells, while Jak3 is present only in the bone marrow and lymphatic system.

Tyk2 is the first JAK kinase discovered and plays an important role in regulating the biological response of IL-12 and bacterial Lipopolysaccharide (LPS), and also participates in IL-6, IL-10 and IL-12 mediated signal transduction pathways. Targeting Tyk2 may be a novel strategy for treating IL-12-, IL-23-, or type I IFN-mediated diseases including, but not limited to, rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, psoriatic arthritis, inflammatory bowel disease, uveitis, sarcoidosis, and cancer.

In some embodiments, a series of compounds containing a triazolopyridine skeleton are designed and synthesized, and the results show that the compounds have outstanding JAK kinase resistance and can be developed into medicines for treating diseases related to JAK kinase activity.

According to a first aspect, in some embodiments there is provided a triazolopyridine compound being at least one of a compound represented by general formula a, or a meso, racemate, enantiomer, diastereomer, tautomer, prodrug, pharmaceutically acceptable salt thereof:

wherein:

R ⁸ selected from O or S;

p is 0 or 1;

when p is 0, R ¹ Selected from-O (O) CR ^a 、-NR ^a R ^b 、-NHC(O)R ^a 、-NHS(O)R ^a 、-NHS(O) ₂ R ^a Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylAny one of aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one R ⁷ Substitution;

each R ⁷ Each independently selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ^a 、-O(O)C R ^a 、-C(O)O R ^a 、-C(O)N R ^a R ^b 、-N R ^a R ^b 、-NHC(O)R ^a 、-S(O)R ^a 、-S(O) ₂ R ^a 、-S(O)N R ^a R ^b 、-S(O) ₂ N R ^a R ^b 、-NHS(O)R ^a 、-NHS(O) ₂ R ^a The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one group selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

when P is 1, Q is at least one selected from imino, S, wherein hydrogen on the imino is optionally unsubstituted or is optionally further substituted with at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, R ¹ Selected from-NHR ^a 、-NR ^a R ^b 、-NHC(O)R ^a 、-NHS(O)R ^a 、-NHS(O) ₂ R ^a 、-O(O)CR ^a Any one of them;

R ² at least one selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Each R ³ Independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R ^4a and R is ^4b Each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy,Mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one group selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ⁵ selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally unsubstituted or optionally further substituted with at least one R ⁶ Substitution;

each R ⁶ Each independently selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, imino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ^3a 、-O(O)CR ^3a 、-C(O)OR ^3a 、-C(O)NR ^3a R ^2b 、-NR ^3a R ^2b 、-NHC(O)R ^3a 、-S(O)R ^3a 、-S(O) ₂ R ^3a 、-S(O)NR ^3a R ^2b 、-S(O) ₂ NR ^3a R ^2b 、-NHS(O)R ^3a 、-NHS(O) ₂ R ^3a The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one group selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^a 、R ^b 、R ^3a 、R ^2b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or are optionally further substituted with a member selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclylAt least one group of aryl, heteroaryl;

n1 is an integer from 1 to 4;

m1 is an integer from 1 to 4;

cy is selected from C6-C10 aryl or 5-10 membered heteroaryl.

In some embodiments, when P is 1, and R ¹ Selected from-O (O) CR ^a When Q is selected from any one of imino, S, wherein hydrogen on the imino is unsubstituted or optionally further substituted with at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In some embodiments, the triazolopyridine compound is a compound of formula I or II or at least one of a meso, racemate, enantiomer, diastereomer, tautomer, prodrug, pharmaceutically acceptable salt thereof:

wherein R is ^2a Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or optionally further substituted with at least one group selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^b1 、R ^b2 each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo,at least one group selected from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

cy is selected from C6-C10 aryl or 5-10 membered heteroaryl.

In some embodiments, R ² Selected from hydrogen, R ³ Selected from hydrogen, m1 is 4, and Cy is selected from C6-C10 aryl or 5-10 membered heteroaryl.

In some embodiments, the triazolopyridine compound is a compound of formula III or at least one of a meso, racemate, enantiomer, diastereomer, tautomer, prodrug, pharmaceutically acceptable salt thereof:

R ^4a 、R ^4b 、n1、R ⁵ As defined in formula a; r is R ^2a Selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or optionally further substituted with at least one group selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In some embodiments, the triazolopyridine compound is a compound represented by formula IV, V or at least one of a meso, racemate, enantiomer, diastereomer, tautomer, prodrug, pharmaceutically acceptable salt thereof:

wherein R in the general formulae IV, V ⁹ Independently selected from any one of the following groups:

R ¹ r is as defined above ^2a 、R ^5a At least one selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or optionally further substituted with at least one group selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In some embodiments, R ^2a Any one selected from the following groups:

wherein "×" denotes a bond which can be attached to other groups.

In some embodiments, R in formula V ¹ Any one selected from the following groups:

in some embodiments, the triazolopyridine compound is selected from at least one of the following:

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according to a second aspect, in some embodiments, there is provided a process for the preparation of the triazolopyridines of the first aspect, comprising at least one of the following processes:

1) When p=0, r ⁸ When oxygen is used, the bromo-compound Ia containing the pinacol borate is subjected to the steps of coupling, iodination and carbonyl inserting to prepare the compound shown in the general formula I, and the main reaction process is as follows:

2) When p=1, q is imino, R ⁸ In the case of oxygen, from triazolo [1,5-a ]]The pyridine-2-amine compound Ic is subjected to acylation, alkylation and coupling steps to prepare a compound shown in a general formula II, and the main reaction process is as follows:

3) When p=1, q is imino, R ⁸ When the compound is oxygen, the intermediate Ib is subjected to coupling, acylation and alkylation steps to prepare the compound shown in the general formula II, and the main reaction process is as follows:

r in the general formula I ^2a R in the general formula II ^b1 、R ^b2 Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or optionally further substituted with at least one group selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In some embodiments, method 1) comprises:

corresponding bromine compound Ia and compound R containing pinacol borate at high temperature in the presence of alkaline agent ⁵ H is reacted to obtain an intermediate Ib, wherein the temperature is preferably at 80 ℃ under the condition of acetonitrile reflux, and the alkaline condition is preferably potassium carbonate; under the condition of high temperature (100-125 ℃) of the obtained intermediate Ib, under the action of a first catalyst, performing bell wood (Suzuki) reaction with a triazolopyridine-2-amine compound Ic to obtain an intermediate Id; the intermediate Id is heated with HI and NaNO ₂ Reacting to obtain an intermediate Ie; intermediate Ie undergoes a carbointercalation reaction with R under heating conditions (typically 40-60 ℃) by the action of a second catalyst ^a -NH ₂ The reagent reacts to obtain the compound shown in the general formula I.

Suzuki reaction, also called Suzuki reaction, suzuki coupling reaction, suzuki-Miyaura reaction, is an organic coupling reaction in which aryl or alkenyl boric acid or boric acid ester and chlorine, bromine, iodo-aromatic hydrocarbon or olefin are cross-coupled under the catalysis of zero-valent or divalent palladium complex.

In some embodiments, the bromine compound Ia containing pinacol borate is mixed with the compound R ⁵ In the reaction of H, the alkaline reagent includes, but is not limited to, at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydrogen, etc., preferably potassium carbonate.

In some embodiments, whatThe first catalyst and the second catalyst are each independently selected from zero-valent palladium (such as Pd ₂ (dba) ₃ 、Pd(dba) ₂ 、Pd ₂ dba ₂ Etc.), divalent palladium (e.g., palladium acetate, palladium chloride, etc.).

In some embodiments, the method 2) comprises:

reacting a triazolopyridine-2-amine compound Ic with corresponding acyl chloride at a low temperature (-10 ℃ to 0 ℃) in the presence of a first alkaline reagent to obtain an intermediate If; intermediate If with alkylating agent I-R in the presence of a second alkaline agent ^b1 Or Br-R ^b1 (alkyl bromide or iodide) to obtain an intermediate Ig; the intermediate Ig and corresponding bromoform Ib containing the pinacol borate undergo Suzuki reaction to obtain a general formula compound II.

In some embodiments, the first alkaline reagent, the second alkaline reagent includes, but is not limited to, at least one of sodium hydride, sodium t-butoxide, potassium t-butoxide, DBU, cesium carbonate, potassium carbonate, and the like, preferably potassium carbonate.

In some embodiments, the method 3) comprises:

under the condition of high temperature (100-120 ℃), the intermediate Ib reacts with a triazolopyridine-2-amine compound Ic under the action of a catalyst to obtain an intermediate Ih; reacting the intermediate Ih with corresponding acyl chloride at a low temperature (-10 ℃ to 0 ℃) in the presence of a first alkaline reagent to obtain an intermediate Ii; intermediate Ii is reacted with alkylating agent I-R in the presence of a second alkaline agent ^b1 Or Br-R ^b1 (alkyl bromide or iodide) to produce the compound of formula II.

In some embodiments, the first alkaline reagent, the second alkaline reagent includes, but is not limited to, at least one of sodium hydride, sodium t-butoxide, potassium t-butoxide, DBU, cesium carbonate, potassium carbonate, and the like.

According to a third aspect, in some embodiments, there is provided a pharmaceutical composition comprising a triazolopyridine compound of the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the compounds of formula a of the present invention may form pharmaceutically acceptable acid addition salts with acids according to methods conventional in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like are particularly preferable.

In addition, in some embodiments, the invention also includes prodrugs of the compounds of formula a of the invention. Prodrugs of the invention are derivatives of the compounds of formula a, which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or otherwise) after administration.

In some embodiments, the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.

In some embodiments, the oral formulation may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.

In some embodiments, the aqueous suspension contains the active substance and excipients for mixing that are suitable for preparing aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

In some embodiments, the oil suspension may be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

In some embodiments, dispersible powders and granules suitable for use in preparing aqueous suspensions also may be formulated by the addition of water to provide the active ingredient in combination with dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

In some embodiments, the pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

In some embodiments, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

In some embodiments, the pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

In some embodiments, the compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

In some embodiments, as is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of compound (I) of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

In some embodiments, the present invention may comprise a compound having a [1,2,4] triazolo [1,5-a ] pyridine skeleton of formula a, and pharmaceutically acceptable salts, hydrates or solvates thereof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier or excipient to prepare a composition and to prepare a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, as well as in combination with other agents for the treatment of diseases associated with JAK activity. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.

In some embodiments, the compounds of the present invention have been found to have significant activity in modulating Janus kinase activity by the activity assays of Jak1, jak2, jak3 and Tyk2, and thus the compounds of the present invention may be used to treat and/or prevent diseases associated with the activity of JAK, such as inflammatory, autoimmune, cancer or other diseases. In particular for the preparation of a medicament for the treatment and/or prophylaxis of rheumatoid arthritis, psoriasis, and/or diseases involving cartilage degeneration and bone joint degeneration.

According to a fourth aspect, in some embodiments there is provided the use of a triazolopyridine compound of the first aspect, or a pharmaceutical composition of the third aspect, in the preparation of an enzyme inhibitor.

An enzyme inhibitor is a substance that can inhibit the activity of a specific enzyme associated with a disease in an organism, thereby achieving a therapeutic effect.

In some embodiments, the enzyme inhibited by the enzyme inhibitor includes, but is not limited to, a kinase.

Kinases (kinase) are a class of biochemical molecules that transfer phosphate groups from high energy donor molecules (such as ATP) to specific target molecules (substrates), a process called phosphorylation.

In some embodiments, the kinase includes, but is not limited to, a protein tyrosine kinase.

Protein tyrosine kinases (protein tyrosine kinase, PTK) are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, can catalyze the phosphorylation of various substrate protein tyrosine residues, and play an important role in cell growth, proliferation, and differentiation. Many of the protein tyrosine kinases found to date are oncogene products belonging to oncogenic RNA viruses and can also be produced from vertebrate protooncogenes. PTKs can be classified into non-receptor and membrane receptor types based on whether they exist at cell membrane receptors.

In some embodiments, the protein tyrosine kinase includes, but is not limited to, JAK kinase.

In some embodiments, the protein tyrosine kinase includes, but is not limited to, at least one of JAK1 kinase (also known as Janus kinase-1), JAK2 kinase (also known as Janus kinase-2), JAK3 kinase (also known as Janus kinase, leukocyte; JAKL1; L-JAK and Janus kinase-3), tyK kinase (also known as protein-tyrosine kinase 2), and the like. JAK1, JAK2 and TyK kinases are widely present in various tissues and cells, whereas JAK3 kinase is present only in the bone marrow and lymphatic system.

According to a fifth aspect, in some embodiments there is provided the use of a triazolopyridine compound of the first aspect, or a pharmaceutical composition of the third aspect, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with enzymatic activity.

In some embodiments, the enzyme includes, but is not limited to, a kinase.

In some embodiments, the kinase includes, but is not limited to, a protein tyrosine kinase.

In some embodiments, the disease includes, but is not limited to, at least one of inflammation, autoimmune disease, cancer.

In some embodiments, the inflammation includes, but is not limited to, at least one of arthritis, inflammatory bowel disease, uveitis, psoriasis.

In some embodiments, the arthritis includes, but is not limited to, at least one of rheumatoid arthritis, psoriatic arthritis.

In some embodiments, the autoimmune disease includes, but is not limited to, at least one of multiple sclerosis, lupus.

In some embodiments, the cancer includes, but is not limited to, at least one of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid kidney tumor, head and neck tumor, leukemia, lymphoma, myeloma, non-small cell lung cancer.

In the following examples, yield = molar amount of desired product actually produced/molar amount of theoretical product produced of desired product x 100%.

In the examples below, room temperature refers to 25 ℃ + -5 ℃.

Example 1

The compounds synthesized in this example are as follows:

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the synthetic route for this example is as follows:

the synthesis of compound 1 includes the following steps:

step 1: preparation of 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -benzyl) thiomorpholine-1, 1-dioxide, intermediate 1A.

4-bromomethylphenylboronic acid pinacol ester (25.00 g,8.42 mmol), 1-dioxide thiomorpholine (13.68 g,10.12mol, also known as thiomorpholine-1, 1-dioxide, CAS number 39093-93-1, formula C) ₄ H ₅ NO ₂ S), potassium carbonate (13.96 g,10.10 mmol) was added to the flask, 250mL of N, N-dimethylformamide was added thereto, and the reaction was stirred at 80℃for 4 hours. Cooled to room temperature, the reaction solution was poured into 625mL ice water, stirred for 30 minutes, and suction filtration was performed to obtain the product, namely intermediate 1A, 24.1g of a white solid, with a yield of 81%.

Step 2: synthesis of 4- (4- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine-1, 1-dioxide, intermediate 1B.

5-bromo- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-amine (15.00 g,0.07 mol) was added to a 0.5L three-necked flask to which was added in sequence 4- (4, 5-tetramethyl- [1,3, 2) ]Dioxapentaborane-2-yl) -benzyl) -1, 1-dioxo-1-thiomorpholine (29.25 g,0.075mol, intermediate 1A), dioxane (200 mL, also known as dioxane), potassium carbonate (29.30 g,0.21 mmol), water (50 mL), pd (dppf) Cl ₂ (2.89 g,0.0035 mol). The mixture was warmed to 90 ℃ under argon and stirred for 16 hours. After the reaction was completed, cooled to room temperature, 200mL of methylene chloride was added, and then washed twice with 40mL of water each time, and the organic layer was collected, concentrated to dryness under reduced pressure, and passed through the column layerThe residue was purified by chromatography (by volume, eluent: dichloromethane: methanol=99:1) to give the product, intermediate 1B, as a pale yellow solid, 12.9g, yield 51%.

Step 3: synthesis of 4- (4- (2-iodo- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine 1, 1-dioxide, intermediate 1C.

HI (8 mL) and DMSO (40 mL) were added to a 250mL reaction flask; stirred at room temperature and added slowly to it is a solution of 4- (4- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine-1, 1-dioxide (intermediate 1B) (4.0 g,11 mmol) and sodium nitrite (3.08 g,44 mol) in dimethyl sulfoxide (60 mL). The remaining insoluble sodium nitrite was added to 20mL of water, stirred to complete dissolution, and then added to the reaction. The reaction temperature of the reaction system was raised to 40 ℃ (which may be usually 35-55 ℃), and stirred for 6 hours. After the reaction, cooling to room temperature, adding a potassium carbonate aqueous solution to adjust the pH to 9, adding 400mL of ethyl acetate for extraction, combining organic phases, washing with 400mL of a 5wt% sodium thiosulfate saturated aqueous solution, sequentially drying with anhydrous sodium sulfate, filtering to remove a desiccant, and concentrating by reduced pressure distillation to obtain a target product, wherein the target product is 3.2g of pale yellow solid which is intermediate 1C without further purification, and the yield is 61%.

Step 4: preparation of 5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) -N-phenyl- [1,2,4] -triazolo [1,5-a ] pyridine-2-carboxamide, compound 1.

4- (4- (2-iodo- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine 1, 1-dioxide (1C, 2.34g,5 mmol) was dissolved in toluene solvent (50 mL), palladium acetate (56 mg,0.05mmol, also known as palladium acetate), triphenylphosphine (228 mg,0.15 mmol) and a substituent of benzylamine (1.07 g,10mmol, also known as benzylamine) were added, and the reaction was carried out at room temperature or under a reaction atmosphere heated to 60℃for 15 hours, filtered after the completion of the reaction, washed three times with ethyl acetate, the ethyl acetate amount was 50mL for each washing, the organic phase was collected, dried over sodium sulfate, filtered to remove the drying agent, concentrated by distillation under reduced pressure, and the remaining product was isolated by column chromatography to give the corresponding amide compound 1 as a yellow solid with a mass of 1.80g and a yield of 78%.

ESI-MS[M+H](m/z):476.2。

Example 2

The compounds prepared in this example are as follows:

in the same manner as in example 1, 2-aminopyridine was used in place of benzylamine in step 4 to obtain compound 2.

ESI-MS[M+H](m/z):463.2.

Example 3

The compounds prepared in this example are as follows:

In the same manner as in the production method of example 1, in step 4, cyclopropylamine was used instead of benzylamine, to obtain compound 3.

ESI-MS[M+H](m/z):426.2.

Example 4

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 1, in step 4, 1-methyl-5-aminopyrazole was used instead of benzylamine, to obtain compound 4.

ESI-MS[M+H](m/z):466.3。

Example 5

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 1, in step 4, 1, 3-oxazolidine-2-imine was used instead of benzylamine, to obtain compound 5.

ESI-MS[M+H](m/z):455.1。

Example 6

The compounds prepared in this example are as follows:

in the same manner as in example 1, in step 4, 3-fluoro-5-methoxyaniline was used instead of benzylamine to obtain compound 6.

ESI-MS[M+H](m/z):510.2。

Example 7

The compounds prepared in this example are as follows:

in the same manner as in example 1, in step 4, piperidine was used instead of benzylamine to obtain compound 7.

ESI-MS[M+H](m/z):454.2。

Example 8

The compounds prepared in this example are as follows:

in the same manner as in example 1, 2-amino-5-methoxypyridine was used instead of benzylamine in step 4 to obtain compound 8.

ESI-MS[M+H](m/z):493.2。

Example 9

The compounds prepared in this example are as follows:

in the same manner as in example 1, 2-aminothiophene was used in place of benzylamine in step 4 to obtain compound 9.

ESI-MS[M+H](m/z):468.1。

Example 10

The compounds prepared in this example are as follows:

in the same manner as in the preparation of example 1, in step 1, cis-perhydroisoindole was used instead of 1, 1-dioxide thiomorpholine and in step 4, piperidine was used instead of benzylamine to obtain compound 10.

ESI-MS[M+H](m/z):444.3。

Example 11

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 1, in step 4, 1- (3-aminoazetidin-1-yl) ethanone was used instead of benzylamine, to obtain compound 11.

ESI-MS[M+H](m/z):483.2。

Example 12

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 1, isopropylamine was used in place of benzylamine in step 4 to obtain compound 12.

ESI-MS[M+H](m/z):428.2。

Example 13

The compounds prepared in this example are as follows:

the synthetic route for this example is as follows:

the synthesis steps are as follows:

step 1: preparation of tert-butyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenyl) piperazine-1-carboxylate, intermediate 13A.

4-Bromomethylphenylboronic acid pinacol ester (40.00 g,13.47 mmol), 1-t-butoxycarbonyl piperazine (30.11 g,16.17mmol, molecular formula: C) ₉ H ₁₈ N ₂ O ₂ CAS number: 57260-71-6), potassium carbonate (22.33 g,16.16 mmol) was added to the flask, 250mL of N, N-dimethylformamide was added thereto, and the mixture was stirred at 80℃for 4 hours. Cooled to room temperature, the reaction solution was poured into 1250mL of ice water, stirred for 30 minutes, and suction filtration was performed to obtain the product, namely intermediate 13A, as a white solid, 38.01g, with a yield of 80.2%.

Step 2: preparation of tert-butyl-4- (4- (2-amino- [1,2,4] triazolo [1.5-a ] pyridin-5-yl) phenyl) piperazine-1-carboxylate, intermediate 13B.

5-bromo- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-amine (15.00 g,0.07 mol) was added to a 0.5L three-necked flask, to which tert-butyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (intermediate 1A,30.2g,0.075 mol), dioxane (200 mL), potassium carbonate (29.30 g,0.21 mmol), water (50 mL), pd (dppf) Cl were added sequentially ₂ (2.89 g,0.0035 mol). The mixture was warmed to 90 ℃ under argon and stirred for 16 hours. After the reaction was completed, cooled to room temperature, 200mL of methylene chloride was added, then washed twice with 40mL of water each time, the organic layer was collected, dried with anhydrous sodium sulfate, concentrated under reduced pressure until almost no solvent was present, and the residue was obtained, which was purified by column chromatography (methylene chloride in eluent: methanol=99:1 by volume) to obtain the product, namely intermediate 13B, 17.7g as pale yellow solid, yield 62%.

Step 3: preparation of tert-butyl-4- (4- (2- (1-ethylazetidine-3-carboxamide) - [1,2,4] triazol [1,5-a ] pyridin-5-yl) phenyl) piperazine-1-carboxylate (intermediate 13C).

Tert-butyl-4- (4- (2-amino- [1,2,4] triazolo [1.5-a ] pyridin-5-yl) phenyl) piperazine-1-carboxylate (13B, 4.08g,10.0 mmol) was added to a 100mL reaction flask followed by 20mL dichloromethane, 2.78mL (20 mmol) triethylamine. 1-Ethylazetidin-3-yl chloride (2.95 g,12 mmol) was dissolved in 10mL of methylene chloride and added dropwise to the reaction solution, the temperature of the reaction system at the time of the addition was controlled at 0℃and the reaction was carried out for 24 hours after the completion of the addition. After the reaction, 100mL of 10wt% aqueous hydrochloric acid was added, and a brown solid was precipitated and allowed to stand for 2 hours. Suction filtration was performed using a sand core funnel, the filtrate was left to stand for delamination, the aqueous layer was retained, the pH of the aqueous layer was adjusted to 10-11 with 10wt% aqueous NaOH solution, extraction was performed three times with 100mL of methylene chloride, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the product, namely intermediate 13C, 4.414g of yellow solid, yield 85%.

Step 4, tert-butyl-4- (4-2 (1-ethyl-N-methylazetidine-3-carboxamide) - [1,2,4] triazolo [1,5-a ] pyridin-5-yl) piperazine-1-carboxylate compound (intermediate 13D) was prepared.

The compound tert-butyl-4- (4- (2- (1-ethylazetidine-3-carboxamide) - [1,2,4] triazol [1,5-a ] pyridin-5-yl) phenyl) piperazine-1-carboxylate (intermediate 13c,2.6g,5.0 mmol) was added to a 50mL reaction flask, tetrahydrofuran (25 mL), sodium hydride (240 mg,10 mmol) and MeI (i.e. methyl iodide, 851.4mg,6.0 mmol) were added at 0 ℃ and the reaction was stirred at ambient temperature for 10h. After completion of the reaction, ice water (10 mL) was added, ethyl acetate (10 mL) was added, the mixture was separated using a separating funnel, and the aqueous phase was extracted three times with ethyl acetate (20 mL each). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to give the product, intermediate 13D, as a yellow solid, 2.24g in 84% yield.

Step 5, 1-ethyl-N-methyl-N- (5- (4- (piperazin-1-ylmethyl) phenyl) - [12,4] triazolo [1,5-a ] pyridin-2-yl) azetidine-3-carboxamide, compound 13.

Tert-butyl-4- (4-2 (1-ethyl-N-methylazetidine-3-carboxamide) - [1,2,4] triazolo [1,5-a ] pyridin-5-yl) piperazine-1-carboxylate (intermediate 13d,1.5g,3.46 mmol) was added to a 100mL reaction flask containing dichloromethane (30 mL), trifluoroacetic acid (3 mL) was added, stirring at room temperature for 4 to 10 hours, after completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) was added, the separating funnel was separated, the aqueous phase was extracted three times with dichloromethane (30 mL each), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dichloromethane in the eluent phase was separated and purified (methanol=95:5) to give compound 13 as a yellow solid 1.36g in 91% yield.

ESI-MS[M+H](m/z):434.3。

Example 14

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 13, in step 1, 4-t-butoxycarbonyl aminopiperidine (CAS: 73874-95-0) was used instead of 1-t-butoxycarbonyl piperazine, to obtain compound 14.

ESI-MS[M+H](m/z):448.3。

Example 15

The compounds prepared in this example are as follows:

in the same manner as in example 13, in step 1, 4- [ (tert-butyldimethylsilyl) oxy ] -piperidine was used instead of 1-tert-butoxycarbonyl piperazine, and in step 5, tetrabutylammonium fluoride was used instead of trifluoroacetic acid, to obtain compound 15.

ESI-MS[M+H](m/z):449.3。

Example 16

The compounds prepared in this example are as follows:

the synthetic route for this example is as follows:

the method specifically comprises the following steps:

step 1: synthesis of 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenoxy) tetrahydro-2H-thiopyran 1, 1-dioxide, intermediate 16A.

4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenol (22 g,0.1 mol) and 4-iodotetrahydro-2H-thiopyran 1, 1-dioxide (31.2 g,0.12 mol) were added to a reaction flask (500 mL), followed by 1, 4-dioxane solution (250 mL), potassium carbonate (27.6 g,0.2 mol) and stirred at room temperature for 24 hours. After the reaction was completed, the liquid was collected, washed with ethyl acetate (250 mL), 300mL of water was added to the mother liquor, the liquid was separated, the aqueous phase was extracted three times with ethyl acetate (300 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure in vacuo, and purified by column chromatography (petroleum ether: ethyl acetate=6:1 in the eluting phase by volume) to give the product, intermediate 16A, 26.78g as a white solid, in 76% yield.

Step 2: synthesis of 4- (4- (2-amino [1,2,4] triazolo [1,5-a ] pyridin-5-yl) phenoxy) tetrahydro-2H-thiopyran 1, 1-dioxide, intermediate 16B.

5-bromo- [1,2,4]Triazolo [1,5-a ] ]Pyridin-2-amine (15.00 g,0.07 mol) was added to a 0.5L three-necked flask, to which was sequentially added 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenoxy) tetrahydro-2H-thiopyran 1, 1-dioxide (intermediate 16A,25g,0.071 mmol), 1, 4-dioxane (200 mL), potassium carbonate (29.30 g,0.21 mmol), water (50 mL), pd (dppf) Cl ₂ (2.89 g,0.0035 mol). The mixture was warmed to 90 ℃ under argon and stirred for 16 hours. After the reaction was completed, cooled to room temperature, 200mL of methylene chloride was added, then washed twice with 40mL of water each time, and the organic layer was collected, concentrated under reduced pressure in vacuo until almost no solvent was present, and purified by silica gel column chromatography (eluent: methylene chloride: methanol=99:1) to leaveThe remainder gave the product, intermediate 16A, 16.6g of pale yellow solid in 66% yield.

Step 3: synthesis of N- (5- (4- ((1, -tetrahydro-2H-thiopyran-4-yl) oxy) phenyl) - [1,2,4] triazol [1,5-a ] pyridin-2-yl) -1-ethylazetidin-3-carboxamide, intermediate 16C.

4- (4- (2-amino [1,2,4] triazolo [1,5-a ] pyridin-5 yl) phenoxy) tetrahydro-2H-thiopyran 1, 1-dioxide (intermediate 16B,3.6g,10 mmol) was added to a 100mL reaction flask followed by 20mL dichloromethane, 2.78mL (20 mmol) triethylamine. 1-Ethylazetidine-3-carbonyl chloride (2.95 g,12 mmol) was dissolved in 10mL of methylene chloride and added dropwise to the reaction solution, the temperature of the reaction system at the time of the addition was controlled at 0℃and the reaction was carried out for 24 hours after the completion of the addition. After the completion of the reaction, 100mL of a 10% aqueous hydrochloric acid solution was added, and a brown solid was precipitated and allowed to stand for 2 hours. Suction filtration using a sand core funnel, standing the filtrate to separate layers, leaving a water layer, adjusting the pH of the water layer to 10-11 with 10% aqueous NaOH, extracting three times with 100mL of methylene chloride, collecting the organic phase, drying over anhydrous sodium sulfate, concentrating to dryness by spin evaporation under reduced pressure to give the product N- (5- (4- ((1, -tetrahydro-2H-thiopyran-4-yl) oxy) phenyl) - [1,2,4] triazol [1,5-a ] pyridin-2-yl) -1-ethylazetidine-3-carboxamide, intermediate 16C, 4.1g as a yellow solid in 87% yield.

Step 4: synthesis of N- (5- (4- ((1, 1-tetrahydro-2H-thiopyran-4-yl) oxy) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -1-ethyl-N-methylazetidine-3-carboxamide, compound 16.

The compound N- (5- (4- ((1, -tetrahydro-2H-thiopyran-4-yl) oxy) phenyl) - [1,2,4] triazol [1,5-a ] pyridin-2-yl) -1-ethylazetidine-3-carboxamide (intermediate 16C,2.58g,5.5 mmol) was added to a 50mL reaction flask, tetrahydrofuran (25 mL), sodium hydride (240 mg,10 mmol) and MeI (i.e., methyl iodide) were added at 0deg.C and the reaction was stirred at ambient temperature for 10H. After completion of the reaction, ice water (20 mL) was added, followed by ethyl acetate (20 mL), and the mixture was separated using a separating funnel, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated by rotary evaporation and purified by column chromatography to give the product as a wash (dichloromethane: methanol=95:5 in the eluent phase by volume), compound 16 as a yellow solid, 2.24g, in 84% yield.

ESI-MS[M+H](m/z):484.2。

Example 17

The compounds prepared in this example are as follows:

in the same manner as in example 16, in step 1, 4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenol was replaced with 2-hydroxy-5-boronic acid pinacol ester pyridine to obtain compound 17.

ESI-MS[M+H](m/z):484.2。

Example 18

The compounds prepared in this example are as follows:

in the same manner as in example 13, in step 1, thiomorpholine 1, 1-dioxide was used instead of 1-t-butoxycarbonyl piperazine, and 2- (bromomethyl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine was used instead of 4-bromomethylbenzobromic acid as the intermediate, and a step of removing nitrogen protecting group by trifluoroacetic acid was not required to obtain compound 18.

ESI-MS[M+H](m/z):484.2。

Example 19

The compounds prepared in this example are as follows:

in the same manner as in example 13, in step 3, acryloyl chloride was used instead of 1-ethylazetidin-3-yl chloride to obtain compound 19.

ESI-MS[M+H](m/z):377.2。

Example 20

The compounds prepared in this example are as follows:

the same procedures as in example 13 were repeated except for using propynyl chloride instead of 1-ethylazetidin-3-yl chloride to give compound 20.

ESI-MS[M+H](m/z):375.2。

Example 21

The compounds prepared in this example are as follows:

in the same manner as in example 13, in step 1, morpholine was used instead of 1-t-butoxycarbonyl piperazine; in step 3, methacryloyl chloride was used instead of 1-ethylazetidin-3-yl chloride, and no denitrification protecting group reaction was required by trifluoroacetic acid to give compound 21.

ESI-MS[M+H](m/z):392.2。

Example 22

The compounds prepared in this example are as follows:

In the same manner as in example 21, in step 3, 1-ethylazetidin-3-yl chloride was used instead of methacryloyl chloride to obtain compound 22.

ESI-MS[M+H](m/z):434.2。

Example 23

The compounds prepared in this example are as follows:

in the same manner as in the production method of example 21, in step 3, benzoyl chloride was used instead of methacryloyl chloride to obtain compound 23.

ESI-MS[M+H](m/z):427.2。

Example 24

The compounds prepared in this example are as follows:

in the same manner as in example 13, in step 1, morpholine was used instead of 1-t-butoxycarbonyl piperazine; in step 3, tert-butyl-2- (chlorocarbonyl) -1H-indole-1-carboxylate compound is used in place of 1-ethylazetidin-3-yl chloride; in step 4, benzyl bromide was used instead of methyl iodide to give compound 24.

ESI-MS[M+H](m/z):541.2。

Test example 1: in vitro kinase Activity assay

Experimental materials: sources of materials such as JAKI, JAK2 and JAK3 kinase, substrates GFP-STAT1, ATPLan thaScreen Tb-anti-PSTATI of the kinase, EDTA, and buffer TR-FRET Dilution Buffer for kinase reaction are shown in Table 1 below.

TABLE 1

Name of the name	Source
		JAK1	Invitrogen
JAK2	Invitrogen
		JAK3	Invitrogen
GFP-STAT1	Invitrogen
		LanthaScreen TMTb-anti-pSTATl	Invitrogen
TR-FRET Dilution Buffer	Perkin Eimer
		Centrifuge	Eppendorf

Preparing a medicine: the test compound synthesized in the example of the present invention was dissolved in DMS0 solvent to prepare a 10mM mother solution. The final compound was reacted at a maximum concentration of 10. Mu.M, 3-fold dilution, 10 concentration gradients, 3 multiplex wells per concentration gradient.

The experimental method comprises the following steps: JAK1 (500 ng/mL), JAK2 (15 ng/mL) and JAK3 (250 ng/mL) were added to 384 reaction plates containing the test compound, respectively, and incubated in a constant temperature incubator at 25 ℃ for 15 minutes; then, 4. Mu.L of the substrate mixture (20. Mu.M ATP and 0.1. Mu.M GFP-STAT 1) was added to 384 reaction plates containing JAK kinase and the compound, and reacted in a constant temperature incubator at 25℃for 1 hour; mu.L of the antibody mixture (10 mM EDTA and 2nM antibody) was added to 384 reaction plates and reacted in a constant temperature incubator at 25℃for 1 hour, and 384 reaction plates were removed and read on an Envision multifunctional plate reader.

IC of the compound was obtained using the following nonlinear fitting equation ₅₀ (half inhibition concentration).

Y＝Bottom+(Top-Bottom)/(1+10^((Log IC ₅₀ -X)*HillSlope))；

X: log of compound concentration;

y: emissivity (Emission Ratio);

bottom: lowest value, top: highest value, hillSlope: slope.

The inhibitory activity of the compounds of the present invention against JAK1, JAK2 and JAK3 is shown in table 2 below.

TABLE 2 IC for in vitro JAK kinase inhibitory Activity of test Compounds ₅₀

In Table 2, IC ₅₀ A is marked with a value of 0-10 nM; 10-100nM labeled B; more than 100nM marked C; NT represents untested.

As can be seen from table 2, the compounds of the present invention have excellent inhibitory activity against three kinases, JAK1, JAK2 and JAK 3.

The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.

Claims (8)

1. A triazolopyridine compound, characterized in that the triazolopyridine compound is selected from at least one of the following compounds:

。

2. a pharmaceutical composition comprising a triazolopyridine compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

3. The use of a triazolopyridine compound of claim 1 or a pharmaceutical composition of claim 2 in the preparation of an enzyme inhibitor,

the enzyme inhibited by the enzyme inhibitor is at least one of JAK1 kinase, JAK2 kinase, JAK3 kinase and TyK kinase.

4. The use of the triazolopyridines according to claim 1 or the pharmaceutical composition according to claim 2 for the preparation of a medicament for the prophylaxis and/or treatment of diseases which are associated with enzymatic activity,

the disease is at least one selected from inflammation, autoimmune disease and cancer.

5. The use according to claim 4, wherein the inflammation is selected from at least one of arthritis, inflammatory bowel disease, uveitis, psoriasis.

6. The use according to claim 5, wherein the arthritis is selected from at least one of rheumatoid arthritis, psoriatic arthritis.

7. The use according to claim 4, wherein the autoimmune disease is selected from at least one of multiple sclerosis, lupus.

8. The use of claim 4, wherein the cancer is selected from at least one of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid kidney tumor, head and neck tumor, leukemia, lymphoma, myeloma, non-small cell lung cancer.