CN114394965A - Triazolopyridine compound and preparation method and application thereof - Google Patents

Abstract

A triazolopyridine compound and a preparation method and application thereof are disclosed, wherein the triazolopyridine compound is a compound shown in a general formula A or at least one of raceme, enantiomer, diastereoisomer, tautomer, prodrug and pharmaceutically acceptable salt thereof. The compound can effectively inhibit the activity of kinase, particularly has good inhibition effect on the activity of protein tyrosine kinase, 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 and a preparation method and application thereof.

Background

Intracellular signaling processes are an efficient way for cells to respond to external stimuli and ultimately elicit specific biological effects. Cytokines are capable of intracellular signaling through a variety of signal transduction pathways, thereby being involved in the regulation of hematopoietic functions and many important biological functions associated with immunity. The Janus kinase (JAK) family of protein tyrosine kinases and the activator of transcription (STAT) play important roles in cytokine signaling.

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

Disclosure of Invention

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

According to a first aspect, in one embodiment, there is provided a triazolopyridine compound, which is at least one of a compound shown in a general formula a or its racemate, enantiomer, diastereomer, tautomer, prodrug, and pharmaceutically acceptable salt:

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

1) when P is 0, R⁸When the oxygen is oxygen, the bromide containing the pinacol borate is synthesized to obtain the compound shown in the general formula I through the steps of coupling, iodination and carbonyl insertion;

2) when P is 1, Q is imino, R⁸When oxygen is present, from triazolo [1,5-a]Carrying out acylation, methylation and coupling on the pyridine-2-amine compound to obtain a compound shown as a general formula II;

3) when P is 1, Q is imino, R⁸When the oxygen is used, the intermediate undergoes the steps of coupling, acylation and methylation to prepare the compound shown in the general formula II.

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

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

According to a fifth aspect, there is provided in one embodiment a triazolopyridine compound of the first aspect, or a pharmaceutical composition of the third aspect, for use in 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 of the triazolopyridine compound, the compound can effectively inhibit the activity of kinase, particularly has good inhibition effect on the activity of protein tyrosine kinase, has clinical application prospect, and can be used for preparing medicines for preventing and/or treating related diseases.

Detailed Description

The present invention will be described in further detail with reference to the following embodiments. Wherein like elements in different embodiments are numbered with like associated elements. In the following description, numerous details are set forth in order to provide a better understanding of the present application. However, those skilled in the art will readily recognize that some of the features may be omitted or replaced with other elements, materials, methods in different instances. In some instances, certain operations related to the present application have not been shown or described in detail in order to avoid obscuring the core of the present application from excessive description, and it is not necessary for those skilled in the art to describe these operations in detail, so that they may be fully understood from the description in the specification and the general knowledge in the art.

Furthermore, the features, operations, or characteristics described in the specification may be combined in any suitable manner to form various embodiments. Also, the various steps or actions in the method descriptions may be transposed or transposed in order, as will be apparent to one of ordinary skill in the art. Thus, the various sequences in the specification are for the purpose of clearly describing one embodiment only and are not meant to be necessarily order unless otherwise indicated where a certain order must be followed.

The numbering of the components as such, e.g., "first", "second", etc., is used herein only to distinguish the objects as described, and does not have any sequential or technical meaning. The term "connected" and "coupled" when used in this application, unless otherwise indicated, includes both direct and indirect connections (couplings).

Unless stated to the contrary, 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 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 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-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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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, 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, carboxy or carboxylate.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH₂-, "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, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group 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, e.g., ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are 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 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain at least one double bond, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with 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, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain at least one double bond, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. The cycloalkyl 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, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 to 6 ring atoms, of which 1-2 or 1-3 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 heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between 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 no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

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

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain at least one double bond, but none of the rings have 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, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

the heterocyclyl 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, carboxy or carboxylate.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share 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:

the aryl group 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, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is 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 joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl 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, carboxy or carboxylate.

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, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are 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, carboxy 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 alkoxy 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 the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

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 the group-C (O) R, where R is alkyl, cycloalkyl, aryl, heteroaryl.

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

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

The term "imino" refers to an ═ NR group or an-NR-group, where R can be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and the like.

"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" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"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 the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

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

JAK kinases belong to the non-receptor protein tyrosine kinase family. Including four members of JAK1, JAK2, JAK3, Tyk2, play an important role in signal transduction of members of the cytokine receptor superfamily.

The Janus kinase (JAK) family plays a role in cytokine-dependent regulation of cellular proliferation and function involved in the immune response. 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; JAKL 1; 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 only present in the bone marrow and lymphatic system.

Tyk2 was the first JAK kinase discovered and plays an important role in regulating the biological response of IL-12 and bacterial Lipopolysaccharide (LPS), and is also involved in IL-6, IL-10 and IL-12 mediated signal transduction pathways. Targeting Tyk2 could be a new 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 research results show that the compounds have outstanding anti-JAK kinase activity and can be developed into drugs for treating diseases related to JAK kinase activity.

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

wherein:

R⁸selected from O or S;

p is 0 or 1;

when p is 0, R¹Selected from the group consisting of-O (O) CR^a、-NR^aR^b、-NHC(O)R^a、-NHS(O)R^a、-NHS(O)₂R^aAny one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one R⁷Substitution;

each R⁷Each independently selected from the group consisting of 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^aR^b、-N R^aR^b、-NHC(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)N R^aR^b、-S(O)₂N R^aR^b、-NHS(O)R^a、-NHS(O)₂R^a(ii) a Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally unsubstituted or 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 selected from at least one of imino and S, wherein hydrogen on the imino is optionally unsubstituted or further optionally substituted by at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl, and R is¹Is selected from-NHR^a、-NR^aR^b、-NHC(O)R^a、-NHS(O)R^a、-NHS(O)₂R^a、-O(O)CR^aAny one of the above;

R²at least one selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R³Independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^4aand R^4bEach independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R⁵selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally unsubstituted or further substituted by at least one R⁶Substitution;

each R⁶Each independently selected from the group consisting of 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^3aR^2b、-NR^3aR^2b、-NHC(O)R^3a、-S(O)R^3a、-S(O)₂R^3a、-S(O)NR^3aR^2b、-S(O)₂NR^3aR^2b、-NHS(O)R^3a、-NHS(O)₂R^3a(ii) a Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or further optionally substituted by a 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^2beach independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or further optionally 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;

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, P is 1, and R¹Selected from the group consisting of-O (O) CR^aWhen Q is selected from any one of imino group and S, hydrogen on the imino group is unsubstituted or is optionally further substituted by at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl.

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

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

R^b1、R^b2each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or 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;

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

In some embodiments, R²Selected from hydrogen, R³Selected from hydrogen, m1 is 4, Cy is selected from C6-C10 aryl or 5-10 membered heteroaryl.

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

R^4a、R^4b、n1、R⁵as defined in formula A; r^2aSelected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally unsubstituted or optionally further substituted by 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 shown in general formulas IV and V, or at least one of racemate, enantiomer, diastereomer, tautomer, prodrug and pharmaceutically acceptable salt thereof:

wherein R in the general formulas IV and V⁹Independently selected from any one of the following groups:

R¹as defined above, R^2a、R^5aAt least one selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or further optionally 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^2aAny one selected from the following groups:

wherein "-" denotes a bond site that may be connected to other groups.

In some embodiments, R in formula V¹Any one selected from the following groups:

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

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

1) when P is 0, R⁸When the oxygen is used, the bromide Ia containing pinacol borate is subjected to coupling, iodination and carbonyl insertion to prepare the compound shown in the general formula I, wherein the main reaction process is as follows:

2) when P is 1, Q is imino, R⁸When oxygen is present, from triazolo [1,5-a]Pyridine compoundThe compound shown in the general formula II is prepared by acylating, alkylating and coupling the-2-amine compound Ic, and the main reaction process is as follows:

3) when P is 1, Q is imino, R⁸When the intermediate Ib is oxygen, the compound shown in the general formula II is prepared through the steps of coupling, acylation and alkylation, and the main reaction process is as follows:

r in the general formula I^2aR in the general formula II^b1、R^b2Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said 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:

under the condition of high temperature and alkaline reagent existence, the corresponding bromide Ia containing pinacol borate and the compound R⁵H, reacting to obtain an intermediate Ib, wherein the temperature is preferably 80 ℃ under the acetonitrile reflux condition, and the alkaline condition is preferably potassium carbonate; under the condition of high temperature (100-125 ℃), the intermediate Ib and a triazolopyridine-2-amine compound Ic are subjected to Suzuki reaction under the action of a first catalyst to obtain an intermediate Id; heating the intermediate Id with HI and NaNO₂Reacting to obtain an intermediate Ie; the intermediate Ie is subjected to the carbonylation reaction under the heating condition (generally 40-60 ℃) by the action of a second catalyst, and reacts with R^a-NH₂Reacting the reagents 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, and aryl or alkenyl boric acid or boric acid ester and chlorine, bromine, iodo arene or olefin are subjected to cross coupling under the catalysis of a zero-valent or divalent palladium complex.

In some embodiments, bromide Ia containing pinacol borate and compound R⁵H, the basic reagent includes but is not limited to at least one of potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydrogen and the like, preferably potassium carbonate.

In some embodiments, the first catalyst and the second catalyst are each independently selected from zero-valent palladium (e.g., Pd)₂(dba)₃、Pd(dba)₂、Pd₂dba₂Etc.), divalent palladium (e.g., palladium acetate, palladium chloride, etc.).

In some embodiments, the method 2) comprises:

reacting the triazolopyridine-2-amine compound Ic with corresponding acyl chloride at low temperature (-10-0 ℃) in the presence of a first alkaline reagent to obtain an intermediate If; reacting intermediate If with alkylating agent I-R in the presence of second alkaline agent^b1Or Br-R^b1(bromide or iodide of alkyl) to obtain an intermediate Ig; and (3) carrying out Suzuki reaction on the intermediate Ig and a corresponding bromide Ib containing pinacol borate to obtain a compound II with a general formula.

In some embodiments, the first basic agent, the second basic agent, and the like include, but are not limited to, at least one of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, DBU, cesium carbonate, potassium carbonate, and the like, preferably potassium carbonate.

In some embodiments, the method 3) comprises:

the intermediate Ib reacts with the triazolopyridine-2-amine compound Ic at high temperature (100-120 ℃) under the action of a catalyst to obtain an intermediate Ih; reacting the intermediate Ih with corresponding acyl chloride at low temperature (-10-0 ℃) in the presence of a first alkaline reagent to obtain an intermediate Ii; intermediate Ii in the presence of a second basic agentWith alkylating agents I-R^b1Or Br-R^b1(bromide or iodide of alkyl) to obtain the compound shown in the general formula II.

In some embodiments, the first basic agent, the second basic agent, and the like include, but are not limited to, at least one of sodium hydride, sodium tert-butoxide, potassium tert-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 according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, the compounds of formula a of the present invention may be formed into pharmaceutically acceptable acid addition salts with acids according to conventional methods in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and particularly preferably 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.

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

In some embodiments, the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, 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: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye 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, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques which 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 hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.

In some embodiments, oral formulations may also be provided by hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or 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 suitable excipients for preparing an aqueous suspension for mixing. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

In some embodiments, oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, 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 preparation of an aqueous suspension may be provided with the active ingredient by the addition of water together with a dispersing or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. 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 emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants. 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 employed 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 the 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 to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk 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 such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

In some embodiments, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared 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 fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use 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 therefore will 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, the dosage of the drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the patient's integuments, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

In some embodiments, the present invention may comprise the compound having a [1,2,4] triazolo [1,5-a ] pyridine skeleton of the general formula a, and pharmaceutically acceptable salts, hydrates or solvates thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into 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 produce other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or may be used in combination with other drugs for the treatment of diseases associated with JAK activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

In some embodiments, the compounds of the present invention have significant activity in modulating Janus kinases as determined by Jak1, Jak2, Jak3 and Tyk2 activity assays, 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 inflammation, autoimmune disorders, 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 and bone joint degeneration.

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

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

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

Kinases (kinases) are a class of biochemical molecules that transfer phosphate groups from a high energy donor molecule (e.g., ATP) to a specific target molecule (substrate), a process known as phosphorylation.

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

Protein Tyrosine Kinases (PTK) are kinases which 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. Most of the protein tyrosine kinases discovered to date are oncogene products belonging to oncogenic RNA viruses, and can also be produced from vertebrate proto-oncogenes. PTK can be classified into non-receptor type and membrane receptor type according to its presence in cell membrane receptors.

In some embodiments, the protein tyrosine kinase includes, but is not limited to, a 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, white blood cells; JAKL 1; L-JAK and Janus kinase-3), TyK2 kinase (also known as protein-tyrosine kinase 2), and the like. JAK1 kinase, JAK2 kinase and TyK2 kinase are widely present in various tissues and cells, while 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, in 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 enteritis, 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, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, non-small cell lung cancer.

In the following examples, the yield was defined as the actual molar amount of the target product/theoretical molar amount of the target product × 100%.

In the following examples, room temperature means 25 ℃. + -. 5 ℃.

Example 1

The compounds synthesized in this example were as follows:

the synthetic route of this example is as follows:

the synthesis of compound 1 comprises the following steps:

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

Pinacol ester of 4-bromomethylphenylboronic acid (25.00g, 8.42mmol), 1-dioxide thiomorpholine (13.68g, 10.12mol, also known as thiomorpholine-1, 1-dioxide, CAS number: 39093-93-1, chemical formula C₄H₅NO₂S) and potassium carbonate (13.96g, 10.10mmol) were added to a reaction flask, 250mL of N, N-dimethylformamide was added, and the reaction was stirred at 80 ℃ for 4 hours. After cooling to room temperature, the reaction solution was poured into 625mL of ice water, stirred for 30 minutes, and filtered by suction to obtain the product, i.e., intermediate 1A, as a white solid in an amount of 24.1g, 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.

Reacting 5-bromo- [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (15.00g,0.07mol) was charged into a 0.5L three-necked flask, and 4- (4- (4,4,5, 5-tetramethyl- [1,3, 2) was sequentially added thereto]Dioxapentaborane-2-yl) -benzyl) -1, 1-dioxo-1-thiomorpholine (29.25g, 0.075mol, intermediate 1A), dioxane (200mL, also known as dioxane), potassium carbonate (29.30g, 0.21mmol), water (50mL), Pd (dppf) Cl₂(2.89g, 0.0035 mol). The mixture was warmed to 90 ℃ under argon and the reaction was stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, 200mL of dichloromethane was added, and then it was washed twice with water, 40mL each, and the organic layer was collected, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 99:1 by volume) to obtain the product, i.e., intermediate 1B, as a pale yellow solid, 12.9g, in 51% yield.

And 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 (8mL) and DMSO (40mL) were added to a 250mL reaction flask; stirring was carried out at room temperature, and a solution of 4- (4- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine-1, 1-dioxide (intermediate 1B) (4.0g, 11mmol) and sodium nitrite (3.08g, 44mol) in dimethylsulfoxide (60mL) was slowly added thereto. The remaining insoluble sodium nitrite was added to 20mL of water, stirred to full solubility, and then added to the reaction. The reaction temperature of the reaction system was raised to 40 deg.C (which may be generally 35-55 deg.C), and stirred for 6 hours. After the reaction is finished, cooling to room temperature, adding a potassium carbonate aqueous solution to adjust the pH value to 9, adding 400mL of ethyl acetate for extraction, combining organic phases, washing with 400mL of 5 wt% sodium thiosulfate saturated aqueous solution, sequentially drying with anhydrous sodium sulfate, filtering to remove a drying agent, and carrying out reduced pressure distillation and concentration to obtain a target product, wherein the target product is not required to be purified again, and 3.2g of a light yellow solid, namely the intermediate 1C, is obtained, and the yield is 61%.

And 4, 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.

Dissolving 4- (4- (2-iodo- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) benzyl) thiomorpholine 1, 1-dioxide (1C, 2.34g, 5mmol) in toluene solvent (50mL), adding a substitute of palladium acetate (56mg, 0.05mmol, also known as palladium acetate), triphenylphosphine (228mg, 0.15mmol) and benzylamine (1.07g, 10mmol, also known as benzylamine), reacting at room temperature or heated to 60 ℃ for 15 hours under a reaction atmosphere of carbon monoxide, filtering after the reaction is finished, washing three times with ethyl acetate, the amount of ethyl acetate used per washing being 50mL, collecting the organic phase, drying with sodium sulfate, filtering to remove the drying agent, concentrating by distillation under reduced pressure, separating the remaining product by column chromatography to obtain the corresponding amide compound 1, it was 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 step 4, 2-aminopyridine was used in place of benzylamine in the same manner as in the preparation of example 1 to obtain compound 2.

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

Example 3

The compounds prepared in this example are as follows:

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

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

Example 4

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):466.3。

Example 5

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):455.1。

Example 6

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):510.2。

Example 7

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):454.2。

Example 8

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):493.2。

Example 9

The compounds prepared in this example are as follows:

in step 4, 2-aminothiophene was used in place of benzylamine in the same manner as in the preparation of example 1, whereby Compound 9 was obtained.

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, cis-perhydroisoindole was used in place of 1, 1-dioxide thiomorpholine in step 1, and piperidine was used in place of benzylamine in step 4, to give compound 10.

ESI-MS[M+H](m/z):444.3。

Example 11

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):483.2。

Example 12

The compounds prepared in this example are as follows:

in step 4, isopropylamine was used instead of benzylamine in the same manner as in the preparation of example 1, 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 of this example is as follows:

the synthesis steps are as follows:

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

4-Bromomethylphenylboronic acid pinaster (40.00g, 13.47mmol), 1-tert-butoxycarbonylpiperazine (30.11g, 16.17mmol, molecular formula: C)₉H₁₈N₂O₂CAS number: 57260-71-6), potassium carbonate (22.33g, 16.16mmol) were added to a reaction flask, 250mL of N, N-dimethylformamide was added, and the reaction was stirred at 80 ℃ for 4 hours. After cooling to room temperature, the reaction solution was poured into 1250mL of ice water, stirred for 30 minutes, and filtered by suction to obtain the product, 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.

Reacting 5-bromo- [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (15.00g,0.07mol) was added to a 0.5L three-necked flask, to which was added tert-butyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate (intermediate 1A, 30.2g, 0.075mol), dioxane (200mL), potassium carbonate (29.30g, 0.21 mmo)l), water (50mL), Pd (dppf) Cl₂(2.89g, 0.0035 mol). The mixture was warmed to 90 ℃ under argon and the reaction was stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, 200mL of dichloromethane was added, and then it was washed twice with water, 40mL each, and the organic layer was collected, dried using anhydrous sodium sulfate, and concentrated under reduced pressure to be almost solvent-free to obtain a residue, which was purified by column chromatography (by volume, dichloromethane: methanol in eluent: 99:1) to obtain the product, i.e., intermediate 13B, as a pale yellow solid, 17.7g, in 62% yield.

And step 3: preparation of tert-butyl-4- (4- (2- (1-ethyl azetidine-3-carboxamide) - [1,2,4] triazolo [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 compound (13B, 4.08g, 10.0mmol) was added to a 100mL reaction flask, followed by 20mL of dichloromethane and 2.78mL (20mmol) of triethylamine. 1-Ethylazetidine-3-carbonyl chloride (2.95g,12mmol) was dissolved in 10mL of dichloromethane, and added dropwise to the reaction mixture, with the temperature of the reaction system being controlled at 0 ℃ at the time of dropwise addition, and reacted for 24 hours after the dropwise addition was completed. After the reaction, 100mL of a 10 wt% aqueous hydrochloric acid solution was added to precipitate a brown solid, and the mixture was allowed to stand for 2 hours. And (3) carrying out suction filtration by using a sand core funnel, standing and layering the filtrate, retaining an aqueous layer, adjusting the pH of the aqueous layer to 10-11 by using 10 wt% of NaOH aqueous solution, extracting for three times by using 100mL of dichloromethane, collecting an organic phase, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain a product, namely an intermediate 13C, a yellow solid 4.414g, and the yield of 85%.

Step 4, preparation of 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).

The compound tert-butyl-4- (4- (2- (1-ethyl azetidine-3-carboxamide) - [1,2,4] triazolo [1,5-a ] pyridin-5-yl) phenyl) piperazine-1-carboxylate (intermediate 13C, 2.6g, 5.0mmol) was added to a 50mL reaction flask, tetrahydrofuran (25mL), sodium hydride (240mg, 10mmol) and MeI (i.e. methyl iodide, 851.4mg, 6.0mmol) were added at 0 ℃, and the reaction was stirred at room temperature for 10 h. After completion of the reaction, ice water (10mL) was added, ethyl acetate (10mL) was added, the mixture was separated by a separatory funnel, and the aqueous phase was extracted three times with ethyl acetate (20mL 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, prepare 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.

Adding tert-butyl-4- (4-2 (1-ethyl-N-methylazetidin-3-carboxamide) - [1,2,4] triazolo [1,5-a ] pyridin-5-yl) piperazine-1-carboxylate compound (intermediate 13D, 1.5g, 3.46mmol) to a 100mL reaction flask containing dichloromethane (30mL), adding trifluoroacetic acid (3mL), stirring at normal temperature for 4 to 10 hours, after the reaction is completed, adding a saturated aqueous sodium bicarbonate solution (30mL), separating with a separating funnel, extracting the aqueous phase three times with dichloromethane (30mL each time), combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography (dichloromethane: methanol in the elution phase: 95:5 by volume) to obtain compound 13, 1.36g of yellow solid, yield 91%.

ESI-MS[M+H](m/z):434.3。

Example 14

The compounds prepared in this example are as follows:

in step 1, in the same manner as in the preparation of example 13, 4-tert-butoxycarbonylaminopiperidine (CAS: 73874-95-0) was used instead of 1-tert-butoxycarbonylpiperazine 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 the preparation of example 13, 4- [ (tert-butyldimethylsilyl) oxy ] -piperidine was used in place of 1-tert-butoxycarbonylpiperazine in step 1, and tetrabutylammonium fluoride was used in place of trifluoroacetic acid in step 5 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 of this example is as follows:

the method specifically comprises the following steps:

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

4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (22g, 0.1mol) and 4-iodotetrahydro-2H-thiopyran 1, 1-dioxide (31.2g, 0.12mol) were charged into a reaction flask (500mL), and a 1, 4-dioxane solution (250mL) and potassium carbonate (27.6g,0.2mol) were sequentially added and stirred at room temperature for 24 hours. After the reaction is finished, suction filtration is carried out, liquid is collected, ethyl acetate (250mL) is washed, 300mL of water is added into mother liquor, liquid separation is carried out, the water phase is extracted for three times by using ethyl acetate (300mL), organic phases are combined, anhydrous sodium sulfate is dried, vacuum concentration is carried out until the water phase is dried, and column chromatography purification (petroleum ether in an elution phase: ethyl acetate is 6: 1 according to volume) is carried out to obtain the product, namely the intermediate 16A, 26.78g of white solid, and the yield is 76%.

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.

Reacting 5-bromo- [1,2,4]Triazolo [1,5-a]Pyridin-2-amine (15)00g,0.07mol) was charged into a 0.5L three-necked flask, and 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) tetrahydro-2H-thiopyran 1, 1-dioxide (intermediate 16A, 25g, 0.071mmol), 1, 4-dioxane (200mL), potassium carbonate (29.30g, 0.21mmol), water (50mL), Pd (dppf) Cl₂(2.89g, 0.0035 mol). The mixture was warmed to 90 ℃ under argon and the reaction was stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, 200mL of dichloromethane was added, and then it was washed twice with water, 40mL each, and the organic layer was collected, concentrated under reduced pressure in vacuo to almost no solvent, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 99:1) to obtain the product, i.e., intermediate 16A, 16.6g of a pale yellow solid, in 66% yield.

And step 3: 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 azetidine-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, 10mmol) was charged to a 100mL reaction flask, followed by 20mL of dichloromethane and 2.78mL (20mmol) of triethylamine. 1-Ethylazetidine-3-carbonyl chloride (2.95g,12mmol) was dissolved in 10mL of dichloromethane, and added dropwise to the reaction mixture, with the temperature of the reaction system being controlled at 0 ℃ at the time of dropwise addition, and reacted for 24 hours after the dropwise addition was completed. After the reaction, 100mL of a 10% aqueous hydrochloric acid solution was added to precipitate a brown solid, and the mixture was allowed to stand for 2 hours. Suction filtration is carried out by using a sand core funnel, filtrate is kept standing for layering, an aqueous layer is reserved, the pH of the aqueous layer is adjusted to 10-11 by using 10% NaOH aqueous solution, extraction is carried out for three times by using 100mL of dichloromethane, an organic phase is collected, drying is carried out by using anhydrous sodium sulfate, and decompression rotary evaporation and concentration are carried out until dryness, so that the product N- (5- (4- ((1, 1-dioxygen tetrahydro-2H-thiopyran-4-yl) oxygen) phenyl) - [1,2,4] triazole [1,5-a ] pyridine-2-yl) -1-ethyl azetidine-3-formamide is obtained, namely an intermediate 16C, 4.1g of yellow solid is obtained, and the yield is 87%.

And 4, 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- ((1,1, -tetrahydro-2H-thiopyran-4-yl) oxy) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) -1-ethyl azetidine-3-carboxamide (intermediate 16C, 2.58g, 5.5mmol) was added to a 50mL reaction flask and tetrahydrofuran (25mL), sodium hydride (240mg, 10mmol) and MeI (i.e., iodomethane, 851.4mg, 6.0mmol) were added at 0 deg.C and the reaction stirred at ambient temperature for 10H. After completion of the reaction, ice water (20mL) was added, followed by ethyl acetate (20mL), followed by separation with a separatory funnel, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The organic phases were combined, 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 by volume in the elution phase), 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 step 1, the 2-hydroxy-5-boronic acid pinacol ester pyridine was used instead of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol in the same manner as in the preparation of example 16 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 the preparation of example 13, in step 1, thiomorpholine 1, 1-dioxide was used in place of 1-tert-butoxycarbonylpiperazine and 2- (bromomethyl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine was used in place of 4-bromomethylbenzeneboronic acid pinaster, and a step of removing a 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 step 3, using acryloyl chloride instead of 1-ethyl azetidine-3-carbonyl chloride, the same procedure was followed as in example 13 to give compound 19.

ESI-MS[M+H](m/z):377.2。

Example 20

The compounds prepared in this example are as follows:

compound 20 was obtained in the same manner as in the preparation of example 13, except that propiolic acid chloride was used instead of 1-ethyl azetidine-3-carboxylic acid chloride.

ESI-MS[M+H](m/z):375.2。

Example 21

The compounds prepared in this example are as follows:

the same procedure as in example 13 was followed, except that in step 1, morpholine was used instead of 1-tert-butoxycarbonylpiperazine; in the step 3, methacryloyl chloride is used for replacing 1-ethyl azetidine-3-acyl chloride, and a denitrification protecting group reaction is carried out without trifluoroacetic acid, so that the compound 21 is obtained.

ESI-MS[M+H](m/z):392.2。

Example 22

The compounds prepared in this example are as follows:

in step 3, 1-ethylazetidine-3-carbonyl chloride was used instead of methacryloyl chloride in the same manner as in the preparation of example 21 to obtain compound 22.

ESI-MS[M+H](m/z):434.2。

Example 23

The compounds prepared in this example are as follows:

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

ESI-MS[M+H](m/z):427.2。

Example 24

The compounds prepared in this example are as follows:

the same procedure as in example 13 was followed, except that in step 1, morpholine was used instead of 1-tert-butoxycarbonylpiperazine; in step 3, a tert-butyl-2- (chlorocarbonyl) -1H-indole-1-carboxylate compound is used for replacing 1-ethyl azetidine-3-acyl chloride; in step 4, benzyl bromide is used instead of methyl iodide to provide compound 24.

ESI-MS[M+H](m/z):541.2。

Test example 1: in vitro kinase Activity assay

Experimental materials: JAKI, JAK2 and JAK3 kinases, substrates of the kinases GFP-STAT1, ATPLAN thaSCreen Tb-anti-PSTATI, EDTA, and a Buffer TR-FRET Dilution Buffer for kinase reaction, and the like are shown in the following table 1.

TABLE 1

Name (R)	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 examples of the present invention was dissolved in DMS0 solvent to prepare a 10mM stock solution. The final compound reaction maximum concentration is 10. mu.M, 3-fold dilution, 10 concentration gradients, each concentration gradient with 3 multiple wells.

The experimental method comprises the following steps: adding JAK1(500ng/mL), JAK2(15ng/mL) and JAK3(250ng/mL) into 384 reaction plates containing the compounds to be detected respectively, and incubating for 15 minutes in an incubator at 25 ℃; then, 4. mu.L of the substrate mixture (20. mu.M ATP and 0.1. mu.M GFP-STAT1) was added to a 384 reaction plate containing JAK kinase and the compound, and the reaction was carried out in an incubator at 25 ℃ for 1 hour; mu.L of the antibody mixture (10mM EDTA and 2nM antibody) was added to the 384 reaction plates and reacted in a 25 ℃ incubator for 1 hour, and the 384 reaction plates were read on an Envision multifunctional plate reader.

IC of the compound was obtained using the following non-linear fit equation₅₀(median inhibitory concentration).

Y＝Bottom+(Top-Bottom)/(1+10^((Log IC₅₀-X)*HillSlope))；

X: log value of compound concentration;

y: emissivity (emision Ratio);

bottom: minimum, Top: highest value, HillSlope: the 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 Compounds₅₀

In Table 2, IC₅₀Values from 0 to 10nM are marked A; 10-100nM is marked B; greater than 100nM is marked C; NT stands for not tested.

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

The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. For a person skilled in the art to which the invention pertains, several simple deductions, modifications or substitutions may be made according to the idea of the invention.

Claims (15)

1. A triazolopyridine compound is a compound shown in a general formula A, or at least one of racemate, enantiomer, diastereoisomer, tautomer, prodrug and pharmaceutically acceptable salt thereof:

wherein:

R⁸selected from O or S;

p is 0 or 1;

when p is 0, R¹Selected from the group consisting of-O (O) CR^a、-NR^aR^b、-NHC(O)R^a、-NHS(O)R^a、-NHS(O)₂R^aAny one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or optionally further substituted with at least one R⁷Substitution;

each R⁷Each independently selected from the group consisting of 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^aR^b、-N R^aR^b、-NHC(O)R^a、-S(O)R^a、-S(O)₂R^a、-S(O)N R^aR^b、-S(O)₂N R^aR^b、-NHS(O)R^a、-NHS(O)₂R^a(ii) a Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally unsubstituted or 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 selected from at least one of imino and S, wherein hydrogen on the imino is optionally unsubstituted or further optionally substituted by at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl, and R is¹Is selected from-NHR^a、-NR^aR^b、-NHC(O)R^a、-NHS(O)R^a、-NHS(O)₂R^a、-O(O)CR^aAny one of the above;

R²at least one selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

each R³Independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy;

R^4aand R^4bEach independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is 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, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R⁵selected from cycloalkyl, heterocyclyl, aryl, heteroaryl; said cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally unsubstituted or further substituted by at least one R⁶Substitution;

each R⁶Each independently selected from the group consisting of 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^3aR^2b、-NR^3aR^2b、-NHC(O)R^3a、-S(O)R^3a、-S(O)₂R^3a、-S(O)NR^3aR^2b、-S(O)₂NR^3aR^2b、-NHS(O)R^3a、-NHS(O)₂R^3a(ii) a Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally unsubstituted or further optionally selected from halogen, amino, nitroCyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R^a、R^b、R^3a、R^2beach independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or further optionally 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;

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.

2. The triazolopyridine compound according to claim 1, wherein P is 1 and R is¹Selected from the group consisting of-O (O) CR^aWhen Q is selected from any one of imino group and S, hydrogen on the imino group is unsubstituted or is optionally further substituted by at least one group selected from alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl.

3. The triazolopyridine compound according to claim 1, wherein the triazolopyridine compound is a compound represented by general formula I or II, or at least one of racemate, enantiomer, diastereomer, tautomer, prodrug and pharmaceutically acceptable salt thereof:

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

R^b1、R^b2each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or 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;

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

4. The triazolopyridine compound according to any one of claims 1 to 3, wherein R is²Selected from hydrogen, R³Selected from hydrogen, m1 is 4, Cy is selected from C6-C10 aryl or 6-10 membered heteroaryl.

5. The triazolopyridine compound according to any one of claims 1 to 3, wherein the triazolopyridine compound is a compound represented by the general formula III or at least one of inner racemate, enantiomer, diastereomer, tautomer, prodrug and pharmaceutically acceptable salt thereof:

R^4a、R^4b、n1、R⁵as defined in claim 1, R^2aAt least one selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstitutedSubstituted or optionally further substituted with at least one group selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

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

6. The triazolopyridine compound according to any one of claims 1 to 3, wherein the triazolopyridine compound is a compound represented by general formulas IV and V or at least one of racemate, enantiomer, diastereomer, tautomer, prodrug and pharmaceutically acceptable salt thereof:

wherein R in the general formulas IV and V⁹Independently selected from any one of the following groups:

R¹as defined in claim 1, R^2a、R^5aAt least one selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally unsubstituted or further optionally 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.

7. The triazolopyridine compound according to claim 5, wherein R is^2aAny one selected from the following groups:

wherein "-" denotes a bond site that may be connected to other groups.

8. The triazolopyridine compound according to claim 6, wherein R in formula V¹Any one selected from the following groups:

9. a triazolopyridine compound according to any one of claims 1 to 3, characterized in that the triazolopyridine compound is selected from at least one of the following compounds:

10. a process for the preparation of triazolopyridines according to any of claims 1 to 9, characterized by at least one process selected from the group consisting of:

1) when P is 0, R⁸When the oxygen is used, the bromide Ia containing pinacol borate is subjected to coupling, iodination and carbonyl insertion to prepare the compound shown in the general formula I, wherein the reaction process is as follows:

2) when P is 1, Q is imino, R⁸When oxygen is present, 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, wherein the reaction process is as follows:

3) when P is 1, Q is imino, R⁸When the intermediate Ib is oxygen, the compound shown in the general formula II is prepared through the steps of coupling, acylation and alkylation, and the reaction process is as follows:

r in the general formula I^2aR in the general formula II^b1、R^b2Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally unsubstituted or further optionally selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, heteroaryl, and mixtures thereof,At least one of cycloalkyl, heterocyclyl, aryl, heteroaryl is substituted.

11. A pharmaceutical composition comprising a triazolopyridine compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, diluent or excipient.

12. Use of a triazolopyridine compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 11 for the preparation of an enzyme inhibitor.

13. The use of claim 12, wherein the enzyme inhibited by the enzyme inhibitor comprises a kinase;

and/or, the enzyme inhibited by the enzyme inhibitor comprises a protein tyrosine kinase;

and/or, the enzyme inhibited by the enzyme inhibitor comprises a JAK kinase;

and/or the enzyme inhibited by the enzyme inhibitor is at least one of JAK1 kinase, JAK2 kinase, JAK3 kinase and TyK2 kinase.

14. Use of a triazolopyridine compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the prevention and/or treatment of a disease associated with an enzymatic activity.

15. The use according to claim 14, wherein the disease is selected from at least one of inflammation, autoimmune disease, cancer;

and/or, the inflammation is selected from at least one of arthritis, inflammatory enteritis, uveitis, psoriasis;

and/or, the arthritis is selected from at least one of rheumatoid arthritis and psoriatic arthritis;

and/or, the autoimmune disease is selected from at least one of multiple sclerosis, lupus;

and/or, the cancer is selected from 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, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.