Pyrrolo[2,3-c]pyridine derivative, and preparation method therefor and use thereof

Abstract

The present disclosure relates to a pyrrolo[2,3-c]pyridine derivative, and a preparation method therefor and the use thereof. Specifically, the present disclosure relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an isotopically substituted compound of the compound represented by formula (I) or the pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition comprising same, and the use thereof as a tau aggregate imaging agent for the diagnosis of diseases, wherein each group in formula (I) is as defined in the description.

Description

Pyrrolo[2,3-c]pyridine derivatives, and preparation method and use thereof TECHNICAL FIELD

[0001] The present disclosure relates to a pyrrolo[2,3-c]pyridine derivative, and preparation method and use thereof, and belongs to the field of pharmacy. BACKGROUND

[0002] Alzheimer's disease (AD) is the most common cause of senile dementia. The 2022 World Alzheimer's Disease Report shows that more than 55 million people worldwide are affected by the disease. By 2030, the number of patients will reach 82 million. It causes serious social and medical burden and economic burden.

[0003] The pathological features of Alzheimer's disease are the appearance of amyloid beta (Aβ) plaques and tau neurofibrillary tangles (NFTs) in the brain and the appearance of related neuron cells and synaptic degeneration, ultimately leading to dementia. Early exploration of AD treatment has mainly focused on Aβ targets, but there has always been a lack of significant effect in slowing disease progression, leading to a shift in research and development strategies to tau protein. From the onset of cognitive decline in patients, the correlation between tau protein abnormalities and symptoms is stronger than that of Aβ.

[0004] Tau protein is a microtubule-associated protein (MAP) that is widely present in nerve cells and is the highest expressed protein in neurons in the nervous system. It plays an important role in stabilizing the neuronal microtubule system, regulating neural cell growth and development, and neural conduction function, and is essential for maintaining neuronal survival and function. The pathological changes of AD are the deposition of β-amyloid plaques in the brain and the neurofibrillary tangles caused by hyperphosphorylated Tau protein. Medical institutions and international medical organizations in many countries have included the concentration of tau protein and Aβ protein in cerebrospinal fluid and blood as an important indicator for the diagnosis of Alzheimer's disease in their guidelines for the diagnosis and treatment of AD. Body fluid examination usually requires invasive lumbar puncture, and patient compliance is poor. Tau protein positron emission tomography (PET) brain imaging can directly show the aggregation and distribution of tau protein in brain tissue, and has positive clinical significance in the diagnosis and assessment of tau protein disease. In Alzheimer's disease (AD), tau protein PET brain imaging has been maturely developed. WO2015191506A discloses a class of compounds for tau protein PET imaging, wherein the compound MK6240 has carried out related clinical research. Considering the necessity of the development of tau protein PET imaging compounds, it is of great significance to develop more such compounds. SUMMARY

[0005] The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopically substituted forms thereof,

[0006] wherein R 1 each independently is selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and -(CH2)nN(R)2, said C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, haloC A alkyl, and haloC A alkoxy, each independently optionally substituted with one or more R 1-6 selected from halogen, C 1- alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC a alkoxy;

[0007] X1and X2are CR 2 or N, and at least one is N;

[0008] R a and R 1-6 each independently is selected from hydrogen, halogen, hydroxyl, C 2-6 alkyl, C 1-6 alkenyl, C 1- alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and -(CH2)nN(R)2, said C 2-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC B alkoxy, each independently optionally substituted with one or more R B selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, and haloC 1-6 alkoxy, amino;

[0009] Ring A is a 5-10 membered aryl or 5-10 membered heteroaryl;

[0010] R 3 each independently is selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, haloC1-6 alkyl, haloC 1-6 alkoxy and -(CH2)nN(R)2, said C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 each independently optionally substituted with one or more R C substituted, said R C selected from the group consisting of halogen, haloC 1-6 alkoxy, amino and hydroxy;

[0011] each independently selected from the group consisting of hydrogen, C 1-6 alkyl and haloC 1-6 alkyl;

[0012] n is an integer from 0 to 6;

[0013] m is 0, 1, 2 or 3;

[0014] p is 1, 2 or 3.

[0015] In some embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopically substituted compounds thereof, which is a compound represented by Formula (I-1) or (I-1-A) or a pharmaceutically acceptable salt thereof and isotopically substituted compounds thereof,

[0016] wherein, said R 3 is -(CH2)nN(R)2, each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl and haloC 1-6 alkyl, and n is 0 or 1.

[0017] said p is 0 or 1.

[0018] said R 1 , m, R 2 , X1, X2and ring A are defined as in the compound of Formula (I).

[0019] In optional embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopically substituted compounds thereof, which is a compound represented by Formula (I-1) or (I-1-A) or a pharmaceutically acceptable salt thereof and isotopically substituted compounds thereof, wherein, said R 3 is -(CH2)nN(R)2, each R is independently selected from the group consisting of hydrogen, C 1-3 alkyl and haloC 1-3 alkyl, and n is 0 or 1.

[0020] In alternative embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, which is a compound represented by Formula (I-1) or (I-1-A) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the R 3 each is independently selected from amino,

[0021] In alternative embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, which is a compound represented by Formula (I-1) or (I-1-A) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the p is 0.

[0022] In alternative embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, which is a compound represented by Formula (I-1) or (I-1-A) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the p is 1.

[0023] In some embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the R 3 is haloC 1-6 alkyl or haloC 1-6 alkyl, the haloC 1-6 alkyl or haloC 1-6 alkyl is optionally substituted with one or more R C , the R C is amino or hydroxyl;

[0024] the p is 1.

[0025] In alternative embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the R 3 is haloC 1-3 alkyl or haloC 1-3 alkyl, the haloC 1-3 alkyl or haloC 1-3 alkyl is optionally substituted with one or more R C , the R C is amino or hydroxyl;

[0026] the p is 1.

[0027] In alternative embodiments, the present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and isotopologues thereof, wherein the R 3 is selected from

[0028] the p is 1.

[0029] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein R 3 is and p is 1.

[0030] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein R 3 is and p is 1.

[0031] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein R 3 is and p is 1.

[0032] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein R 3 is and p is 1.

[0033] In some embodiments, the present disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein the compound is represented by Formula (I-2) or (I-1-2),

[0034] wherein X3is oxygen or CH2;

[0035] q is 0, 1, 2, 3, or 4;

[0036] R 1 , m, R 2 , X1, X2, and ring A are defined as in the compound of Formula (I).

[0037] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein only one of X1and X2is N.

[0038] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein X1is N and X2is CR a , or X1is CR a and X2is N.

[0039] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein X1is N and X2is CR a .

[0040] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopologues thereof, wherein X1is CR aX2is N.

[0041] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein ring A is phenyl.

[0042] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein ring A is pyridyl.

[0043] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein is selected from

[0044] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein the R 1 each independently is selected from hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, and -(CH2)nN(R)2, said C 1-6 alkoxy, and haloC 1-6 alkoxy are each independently optionally substituted with one or more R A substituents, said R A is halogen.

[0045] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein the R 1 each independently is selected from hydrogen, hydroxyl, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, fluoromethoxy, fluoroethoxy, amino, methylamino, and dimethylamino.

[0046] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-l), (I-2), (I-l-A), (I-2-A), or a pharmaceutically acceptable salt thereof and isotopically enriched forms thereof, wherein the R 1 each independently is hydrogen.

[0047] In some embodiments, the present disclosure provides a compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically- substituted forms thereof, wherein each R 2 and R a is independently selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy, the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and halogenated C 1-6 alkoxy are each independently optionally substituted with one or more R B , which is halogen or amino. B

[0048] In some embodiments, the present disclosure provides a compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically- substituted forms thereof, wherein each R 2 and R a is independently selected from hydrogen and fluorine.

[0049] In some embodiments, the present disclosure provides a compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically- substituted forms thereof, wherein each R 2 and R a is independently hydrogen.

[0050] In some embodiments, the present disclosure provides a compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically- substituted forms thereof, wherein each R 1 is independently hydrogen;

[0051] each R 2 and R a is independently hydrogen.

[0052] In some embodiments, the present disclosure provides a compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically- substituted forms thereof, selected from the following compounds or a pharmaceutically acceptable salt thereof, and isotopically-substituted forms thereof,

[0053] ​In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically-substituted forms thereof, wherein the isotopes of the isotopically-substituted forms thereof are selected from: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I or 131 I.

[0054] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically-substituted forms thereof, wherein the isotopes of the isotopically-substituted forms thereof are 18 F.

[0055] In some embodiments, the present disclosure provides a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically-substituted forms thereof, selected from the following compounds or pharmaceutically acceptable salts thereof, and isotopically-substituted forms thereof:

[0056] The present disclosure further provides a pharmaceutical composition comprising a compound represented by Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or a pharmaceutically acceptable salt thereof, and isotopically-substituted forms thereof, and one or more pharmaceutically acceptable excipients.

[0057] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0058] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing compound or pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1-99% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2-98% of the foregoing compound or pharmaceutically acceptable salt thereof.

[0059] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the foregoing pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the foregoing pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1-99% of the foregoing pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2-98% of the foregoing pharmaceutically acceptable excipient.

[0060] The present disclosure further provides use of the foregoing compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or pharmaceutically acceptable salt thereof, and isotopically- substituted versions thereof, or the foregoing pharmaceutical composition, for tau aggregate imaging.

[0061] The present disclosure further provides use of the foregoing compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or pharmaceutically acceptable salt thereof, and isotopically- substituted versions thereof, or the foregoing pharmaceutical composition, for the manufacture of a medicament for diagnosing or monitoring a disease selected from the group consisting of Alzheimer’s disease, Down’s syndrome, cognitive deficits in schizophrenia, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease, schizophrenia, pain disorders, sleep disorders, and Parkinson’s disease.

[0062] In another aspect, the present disclosure provides the foregoing compound of Formula (I), (I-1), (I-2), (I-1-A), (I-2-A), or pharmaceutically acceptable salt thereof, and isotopically- substituted versions thereof, or the foregoing pharmaceutical composition, for use as a medicament.

[0063] This disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I-1), (I-2), (I-1-A), (I-2-A), or their pharmaceutically acceptable salts and isotopic substitutes, or the aforementioned pharmaceutical compositions, for the diagnosis or monitoring of diseases selected from Alzheimer's disease, Down syndrome, cognitive deficits in schizophrenia, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease, schizophrenia, pain disorders, sleep disorders, and Parkinson's disease.

[0064] On the other hand, this disclosure further provides a method for diagnosing or monitoring a patient’s disease, comprising administering to a patient a compound represented by the aforementioned formulas (I), (I-1), (I-2), (I-1-A), (I-2-A) or a pharmaceutically acceptable salt thereof and its isotopic substitutes or the aforementioned pharmaceutical composition, wherein the patient suffers from Alzheimer’s disease, Down syndrome, cognitive deficits of schizophrenia, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease, schizophrenia, pain disorder, sleep disorder or Parkinson’s disease.

[0065] In some implementations, the aforementioned diagnosis or monitoring is performed via positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging, or autoradiography.

[0066] This disclosure also provides a method for preparing the aforementioned compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes, wherein the compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes are compounds of formula (I-1-A), comprising the compound of formula (I-1-A-1) or its pharmaceutically acceptable salt and K[ 18 The step of reacting to obtain the compound of formula (I-1-A) or a pharmaceutically acceptable salt thereof.

[0067] Wherein, the R 1 m, R 2 X1, X2, R 3 p and ring A are defined in compounds as shown in formula (I).

[0068] In an optional embodiment, the method for preparing the compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes provided in this disclosure, wherein the compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes is compound 3, comprising compound 3c or its pharmaceutically acceptable salt and K[ 18 F] is the step of reacting to give compound 3 or its pharmaceutically acceptable salt.

[0069] A compound or a pharmaceutically acceptable salt thereof, as shown below:

[0070] This disclosure provides a method for preparing the compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (I-1-A-2) with the compound of formula (I-1-A-3) under the action of a palladium catalyst and a base to obtain the compound of formula (I-1-A-1):

[0071] Wherein, the R 1 m, R 2 X1, X2, R 3 p and ring A are defined in compounds of formula (I);

[0072] The Y is a halogen, which can be chlorine or iodine.

[0073] In an optional embodiment, this disclosure provides a method for preparing a compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof and its isotopic substitutes are compound 3c, comprising the step of reacting compound 3a and compound 3b under the action of a palladium catalyst and a base to obtain compound 3c:

[0074] Optionally, the palladium catalyst is bis(diphenylphosphine)ferrocene palladium dichloride, and the base is potassium carbonate.

[0075] In some embodiments, the method for preparing the compound of formula (I) provided in this disclosure or its pharmaceutically acceptable salt and its isotopic substitutes may optionally include steps in the method for preparing the compound of formula (I-1-A-1).

[0076] This disclosure further provides a compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof.

[0077] Wherein, the R 1 m, R 2 X1, X2, R 3 p and ring A are defined in compounds as shown in formula (I).

[0078] In an optional embodiment, the compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof provided in this disclosure is a compound or a pharmaceutically acceptable salt thereof as shown below.

[0079] This disclosure also provides a method for preparing the aforementioned compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes, wherein the compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes are compounds of formula (I-2-A), comprising the compound of formula (I-2-A-1) or its pharmaceutically acceptable salt and K[ 18 The step of reacting to obtain the compound of formula (I-2-A) or a pharmaceutically acceptable salt thereof.

[0080] Wherein, ring B is aryl or heteroaryl (e.g., phenyl);

[0081] R 4 Selected from hydrogen, halogens, C 1-6 Alkyl groups (e.g., methyl, ethyl) and halogenated C 1-6 alkyl;

[0082] v is 0, 1, 2, or 3;

[0083] X3 is oxygen or CH2;

[0084] The value of q is 0, 1, 2, 3, or 4;

[0085] The R 1 m, R 2 X1, X2 and ring A are defined in compounds as shown in formula (I).

[0086] This disclosure further provides a method for preparing the compound of formula (I-2-A-1) or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound of formula (I-2-A-2) with the compound of formula (I-2-A-3) under the action of a base (e.g., an organic base or an inorganic base) to obtain the compound of formula (I-2-A-1):

[0087] Among them, rings B and R 4 v, X3, q, R 1 m, R 2 X1, X2 and ring A are as defined above.

[0088] In some embodiments, the method for preparing the compound of formula (I) provided in this disclosure or its pharmaceutically acceptable salt and its isotopic substitutes may optionally include steps in the method for preparing the compound of formula (I-2-A-2) or its pharmaceutically acceptable salt.

[0089] This disclosure further provides a method for preparing the compound shown in formula (I-2-A-2), comprising the step of reacting the compound shown in formula (I-2-A-4) with the compound shown in formula (I-2-A-5) under the action of a base (e.g., an organic base or an inorganic base) to obtain the compound shown in formula (I-2-A-2):

[0090] Where X4 is a halogen (e.g., chlorine, bromine);

[0091] X3 is oxygen;

[0092] The q, R 1 m, R 2 X1, X2 and ring A are as defined above.

[0093] In some embodiments, the method for preparing the compound of formula (I) or its pharmaceutically acceptable salt and its isotopic substitutes provided in this disclosure, or the method for preparing the compound of formula (I-2-A-1) or its pharmaceutically acceptable salt, optionally further includes the steps in the method for preparing the compound of formula (I-2-A-2).

[0094] In some embodiments, the compound represented by formula (I-2-A-4) provided in this disclosure is optionally prepared by the following route:

[0095] Among them, R 5 Hydroxyl protecting agents (e.g., methyl);

[0096] X5 and X6 are each independently selected from halogens (bromine, iodine, chlorine).

[0097] This application further requires the provision of the reaction intermediates and products used in the aforementioned preparation method.

[0098] This disclosure further provides a compound comprising (I-2-A-1), (I-2-A-2), or a pharmaceutically acceptable salt thereof,

[0099] Among them, rings B and R 4 v, X3, q, R 1 m, R 2 X1, X2 and ring A are as defined above.

[0100] The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure can react with acidic or basic substances to form the corresponding salts.

[0101] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0102] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0103] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0104] This disclosure also includes compounds in various deuterated forms. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of the compounds by referring to relevant literature. Commercially available deuterated starting materials can be used in the preparation of the deuterated forms of the compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0105] definition

[0106] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0107] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0108] prefix "C" u-v The colon "" indicates that the following group has between u and v carbon atoms. For example, "C 1-3 "Alkyl" means that an alkyl group has 1 to 3 carbon atoms, specifically alkyl groups having 1, 2 or 3 carbon atoms.

[0109] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group comprising 1 to 20 carbon atoms, such as 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof.

[0110] "Alkenyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, and C3-C8 groups. 12 And C3-C6 alkenyl groups. Including but not limited to vinyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotonyl), etc.

[0111] The term "alkylene" refers to the portion of an alkane molecule remaining after the removal of two hydrogen atoms, including straight-chain and branched subgroups with 1 to 20 carbon atoms. Alkylenes containing 1 to 6 carbon atoms include, in non-limiting examples, methylene (-CH2-) and ethylene (such as -CH2CH2- or -CH(CH3)-).

[0112] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted.

[0113] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0114] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 The alkynyl group, 3 to 6 cycloalkoxy group, 3 to 6 heterocycloalkoxy group, 3 to 8 cycloalkenyl group, 5 to 6 aryl group, or heteroaryl group may be selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0115] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5- or 6-membered. Examples, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, etc.

[0116] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0117] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C4 groups, etc. 1-6 Alkyl or C 1-6 Alkyl group.

[0118] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0119] The term "hydroxyl group" refers to -OH.

[0120] The term "cyano" refers to -CN.

[0121] The term "amino" refers to -NH2.

[0122] The term "oxo" refers to the =O substituent.

[0123] The "amino protecting group" disclosed herein is a group known in the art that can be used to protect amino groups, see reference (Protective Groups in Organic Synthesis, 5). Th Amino protecting groups in Ed.TWGreene & P.GMWuts. Examples include, but are not limited to, urethane protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimide and dithiosuccinyl.

[0124] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently replaced by the corresponding number of substituents. When the substituent is a ketone or an oxo (i.e., =O), two (2) hydrogen atoms on the atom are replaced.

[0125] "Pharmaceutical composition" means a mixture containing one or more of the active ingredients described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0126] "Pharmaceutically acceptable carriers, diluents, or excipients" include any material that, when combined with an active ingredient, allows the ingredient to retain its biological activity and does not serve the intended therapeutic purpose. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solutions, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0127] "Treatment" means administering a therapeutic agent, such as a fusion protein or insulin analog comprising any of the present disclosure, to a subject who has, is suspected of having, or is predisposed to having one or more diabetes or hyperglycemia-related diseases or their symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, in treated subjects or populations, a therapeutic agent is administered in an amount that effectively relieves symptoms of one or more diseases by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test method commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patients to be treated are mammals, and preferably humans.

[0128] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also includes an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0129] "Prevention" means reducing the risk or incidence of one or more conditions, symptoms, complications or symptoms, or eliminating or slowing the progression of one or more conditions, symptoms, complications or symptoms.

[0130] "Subject" and "patient" refer to mammals, especially primates, and particularly humans.

[0131] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1- "6-alkyl" means that a halogen or cyano group may or may not be present. This description includes cases where the alkyl group is substituted by a halogen or cyano group and cases where the alkyl group is not substituted by a halogen or cyano group.

[0132] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.” Attached Figure Description

[0133] Figure 1. Results of the autoradiography inhibition experiment on a 10 nM test sample in an AD human brain slice (95 years old, female, temporal lobe). Detailed Implementation

[0134] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0135] Experimental methods not specifying specific conditions in the embodiments or test examples disclosed herein are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents not specifying their source are commercially available, conventional reagents.

[0136] Abbreviation Explanation: t-BuXPhos-Pd G3: Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) DMF: N,N-dimethylformamide LC-MS: Thermo Fisher Scientific RSLC-ISQ EC NMR: Bruker AVANCE II 400

[0137] Example 1

[0138] 1-(5-(2-fluoropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0139] Weigh 0.10 g (0.48 mmol) of 2-chloro-5-(2-fluoro-4-pyridyl)pyrazine, 84.5 mg (0.72 mmol) of 6-azaindole, 0.31 g (0.96 mmol) of cesium carbonate, and 45.2 mg (0.06 mmol) of t-BuXPhos-Pd G3 into 5 mL of DMF. Purge the mixture three times with nitrogen and heat to 50 °C overnight. After the reaction is complete, concentrate the reaction solution, and purify the residue by column chromatography (n-heptane:ethyl acetate) to give compound 1 (50 mg).

[0140] MS m / z(ESI): 292.2 [M+1] + .

[0141] 1 H NMR (400MHz, DMSO-d6) δ9.90(s,1H),9.50(dd,J=11.3,1.4Hz,2H),8.62(d,J=3.6Hz,1H),8.51(d,J=5.2Hz,1H),8.43( d,J=5.3Hz,1H),8.20(dt,J=5.3,1.7Hz,1H),7.99(d,J=1.5Hz,1H),7.78(dd,J=5.3,1.1Hz,1H),7.05(d,J=3.5Hz,1H).

[0142] Example 2

[0143] 1-(6-(2-fluoropyridin-4-yl)pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridine

[0144] Weigh 0.20 g (0.95 mmol) of 3-chloro-6-(2-fluoro-4-pyridyl)pyridazine, 0.17 g (1.43 mmol) of 6-azaindole, 0.62 g (1.91 mmol) of cesium carbonate, and 90.5 mg (0.11 mmol) of t-BuXPhos-Pd G3 into 5 mL of DMF. Purge the mixture three times with nitrogen and heat to 50 °C overnight. After the reaction is complete, concentrate the reaction solution and purify the residue by column chromatography (n-heptane:ethyl acetate) to give compound 2 (50 mg).

[0145] MS m / z(ESI): 292.2 [M+1] + .

[0146] 1 H NMR (400MHz, DMSO-d6): δ9.84(s,1H),8.62(d,J=9.3Hz,1H),8.46–8.38(m,3H),8.31(d,J=5.3Hz,1H), 8.17(dt,J=5.3,1.7Hz,1H), 7.96(d,J=1.5Hz,1H), 7.66(dd,J=5.3,1.1Hz,1H), 6.93(d,J=3.5Hz,1H).

[0147] Example 3

[0148] [ 18 F]1-(5-(2-fluoropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0149] Step 1. Preparation of 1-(5-chloropyrazin-2-yl)pyrrolo[2,3-c]pyridine (3a)

[0150] Weigh 6-azaindole (0.50 g, 4.23 mmol), 2-bromo-5-chloropyrazine (2.04 g, 10.58 mmol), tBuXPhos-Pd-G3 (0.34 g, 0.42 mmol), and cesium carbonate (2.76 g, 8.46 mmol) and mix them in N-methylpyrrolidone (20 mL). The mixture is purged three times with nitrogen and heated to 30-35 °C. The reaction mixture is added to an ice-water mixture, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness, and column chromatography (dichloromethane:methanol = 100%-90%) to give compound 3a (0.7 g).

[0151] MS m / z(ESI): 231.4 [M+1] + .

[0152] Step 2. Preparation of 1-(5-(2-nitropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine (3c)

[0153] Weigh out 500 mg (2.17 mmol) of 1-(5-chloropyrazin-2-yl)pyrrolo[2,3-c]pyridine, 650 mg (2.6 mmol) of 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine, 159 mg (217 μmol) of bis(diphenylphosphino)ferrocene palladium dichloride, and 599 mg (4.33 mmol) of potassium carbonate and mix them in 10 mL of dioxane. After purging with nitrogen three times, the mixture was heated to 75 °C and reacted overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 3c (300 mg).

[0154] MS m / z(ESI): 319.2 [M+1] + .

[0155] 1 H NMR(400MHz, DMSO-d6)δ9.98(s,1H),9.61(dd,J=10.2,1.4Hz,2H),9.14(d,J=3.5Hz,1H),9.01(d,J=1.4Hz,1H),8.8 9 (d, J = 5.0 Hz, 1H), 8.68 (dd, J = 5.0, 1.6 Hz, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.31 (d, J = 6.1 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H).

[0156] Step 3. 18 Preparation of F]1-(5-(2-fluoropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine (3)

[0157] oxygen 18 [O] Water (Jiangsu Huayi) was injected into the liquid target cavity of a proton accelerator (GE, GE860) and bombarded with a 60 μA beam for 30 min to obtain fluorine [ 18 F] ion solution. Fluorine [ 18 F] ions were captured on an anion exchange column pretreated with 0.5 M potassium carbonate aqueous solution (10 mL) and sterile water for injection (10 mL), and then eluted into the reaction vessel with tetrabutylammonium bicarbonate eluent (15 mg, 0.5 mL water, 0.5 mL acetonitrile). The water-acetonitrile azeotrope was evaporated to dryness at 85 °C, and then subjected to two acetonitrile evaporations to remove water and dryness to obtain dried [F]. 18 F] - .

[0158] Weigh 1.0 mg of 1-(5-(2-nitropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine and add it to 0.5 mL of dimethylacetamide. After dissolving, add the solution to the reaction vessel and react at 150 °C for 15 min. The reaction solution is purified by semi-preparative HPLC (mobile phase A: water; mobile phase B: acetonitrile, gradient: 90%-10% A). Collect the corresponding peak of the product and capture the product using C-18 Sep-Pak. Elute the residual acetonitrile with a small amount of water, and then elute the product to a sterile container with 0.5 mL of ethanol.

[0159] Example 4

[0160] 1-(5-(2-(2-fluoroethoxy)pyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0161] Step 1. Preparation of 2-chloro-5-(2-methoxypyridin-4-yl)pyrazine (4b)

[0162] (2-Methoxypyridin-4-yl)boric acid (1000 mg, 6.53 mmol), 2-bromo-5-chloropyrazine (1264 mg, 6.53 mmol), bis(diphenylphosphine)ferrocene palladium dichloride (477 mg, 0.653 mmol), and potassium carbonate (1805 mg, 1.306 mmol) were weighed and mixed in a dioxane:water ratio of 10:1 (20 mL). After purging with nitrogen three times, the mixture was heated to 80 °C and reacted overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 4b (950 mg).

[0163] MS m / z(ESI): 222.4 [M+1] + .

[0164] Step 2. Preparation of 1-(5-(2-methoxypyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine (4c)

[0165] 2-Chloro-5-(2-methoxypyridin-4-yl)pyrazine (900 mg, 4.07 mmol), 6-azaindole (958 mg, 8.14 mmol), cesium carbonate (2.67 g, 8.14 mmol), and t-BuXPhos-Pd G3 (90.5 mg, 0.4 mmol) were weighed and mixed in DMF (10 mL). The mixture was purged with nitrogen three times and heated to 60 °C for 4 h. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by column chromatography (n-heptane: ethyl acetate) to give compound 4c (980 mg).

[0166] MS m / z(ESI): 304.1 [M+1]+ .

[0167] Step 3. Preparation of 4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-ol (4d)

[0168] 900 mg (2.97 mmol) of 1-(5-(2-methoxypyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine was mixed in 8 mL of dioxane hydrobromic acid solution. After purging with nitrogen three times, the mixture was heated to 60 °C and reacted overnight. After the reaction was complete, the reaction solution was filtered to give compound 4d (680 mg).

[0169] MS m / z(ESI): 290.3 [M+1] + .

[0170] Step 4. Preparation of 1-(5-(2-(2-fluoroethoxy)pyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine (4)

[0171] 4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-ol (180 mg, 0.62 mmol), 2-fluoroethyl 4-methylbenzenesulfonate (160 mg, 0.93 mmol), and potassium carbonate (167 mg, 1.24 mmol) were mixed in N,N-dimethylformamide (3 mL). After purging with nitrogen three times, the mixture was heated to 60 °C and reacted overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 4 (120 mg).

[0172] MS m / z(ESI): 336.2 [M+1] + .

[0173] Example 5

[0174] [ 18 F]1-(5-(2-(2-fluoroethoxy)pyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0175] Step 1. 2-((4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-yl)

[0176] Preparation of (5b) ethane-1-ol (oxy)

[0177] 4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-ol (200 mg, 0.69 mmol), 2-bromoethanol (180 mg, 2.07 mmol), and potassium carbonate (470 mg, 3.45 mmol) were mixed in N,N-dimethylformamide (3 mL). After purging with nitrogen three times, the mixture was heated to 80 °C and reacted for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 5b (140 mg).

[0178] MS m / z(ESI): 334.2 [M+1] + .

[0179] Step 2. 2-((4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-yl)

[0180] Preparation of oxyethyl 4-methylbenzenesulfonate (5c)

[0181] 2-((4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-yl)oxy)ethane-1-ol (120 mg, 0.36 mmol), p-toluenesulfonyl chloride (120 mg, 0.54 mmol), and triethylamine (110 mg, 1.08 mmol) were mixed in N,N-dimethylformamide (3 mL). After purging with nitrogen three times, the mixture was heated to 60 °C and reacted overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 5c (65 mg).

[0182] MS m / z(ESI): 488.1 [M+1] + .

[0183] Step 3. 18 Preparation of F]1-(5-(2-(2-fluoroethoxy)pyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine (5)

[0184] Will[ 18 F] Fluoride was captured on an anion exchange column pretreated with 0.5 M potassium carbonate aqueous solution (10 mL) and sterile water for injection (10 mL), and then eluted into the reaction vessel with tetrabutylammonium bicarbonate eluent (15 mg, 0.5 mL water, 0.5 mL acetonitrile). The water-acetonitrile azeotrope was evaporated to dryness at 85 °C, and then subjected to two acetonitrile evaporations to remove water and dryness to obtain dried [F]. 18 F] - .

[0185] Weigh 1.0 mg of 2-((4-(5-(1H-pyrrolo[2,3-c]pyridin-1-yl)pyrazin-2-yl)pyridin-2-yl)oxy)ethyl 4-methylbenzenesulfonate and add it to acetonitrile (0.5 mL). After dissolving, add the solution to the reaction vessel and react at 100 °C for 10 min. The reaction solution is purified by semi-preparative HPLC (mobile phase A: water; mobile phase B: acetonitrile, gradient: 90%-10% A). Collect the corresponding peak of the product and capture the product using C-18 Sep-Pak. Elute the residual acetonitrile with a small amount of water, and then elute the product to a sterile container with ethanol (0.5 mL) to obtain compound 5.

[0186] Example 6

[0187] 1-(5-(3-fluoropyridin-4-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0188] Weigh 1H-pyrrolo[2,3-c]pyridine (135.3 mg, 1.15 mmol), 2-chloro-5-(3-fluoro-4-pyridyl)pyrazine (200 mg, 0.95 mmol), Xantphos Pd G3 (90.6 mg, 0.10 mmol), and cesium carbonate (621.8 mg, 1.91 mmol) and mix them in DMF (5 mL). Purge with nitrogen three times and react at 60 °C. After the reaction, concentrate under reduced pressure. The crude product is purified by preparative high-performance liquid chromatography (HPLCONE, 5C18A, 5 μm, 250 × 20 mm, mobile phase: aqueous phase (water + 0.1% trifluoroacetic acid), organic phase (acetonitrile + 0.1% trifluoroacetic acid), gradient ratio: organic phase 10%-90%) to obtain 50 mg of product, with a yield of 17.9%.

[0189] MS m / z(ESI): 292.4 [M+1] + .

[0190] H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.61(d,J=1.5Hz,1H),9.23(t,J=1.6Hz,1H),9.16(d,J=3.5Hz,1H),8.84(d,J=2.8Hz,1H ), 8.67 (dd, J = 5.0, 1.2 Hz, 1H), 8.60 ( d, J = 6.2 Hz, 1H), 8.34 ( d, J = 6.2 Hz, 1H), 8.08 ( dd, J = 6.8, 4.9 Hz, 1H), 7.38 ( d, J = 3.4 Hz, 1H).

[0191] Example 7

[0192] 1-(5-(6-fluoropyridin-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0193] Following the synthetic method for compound 6, 2-chloro-5-(3-fluoro-4-pyridyl)pyrazine was replaced with 2-chloro-5-(6-fluoro-2-pyridyl)pyrazine to obtain the product in 18.2% yield.

[0194] MS m / z(ESI): 292.3 [M+1] + .

[0195] 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.48(d,J=1.5Hz,1H),9.41(d,J=1.4Hz,1H),9.07(d,J=3.5Hz,1H),8.5 6(d,J=6.2Hz,1H),8.31(dd,J=7.1,2.3Hz,1H),8.28–8.18(m,2H),7.41–7.34(m,1H),7.32(d,J=3.4Hz,1H).

[0196] Example 8

[0197] 1-(5-(6-fluoropyridin-3-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine

[0198] Following the synthetic method of compound 6, 2-chloro-5-(3-fluoro-4-pyridyl)pyrazine was replaced with 2-chloro-5-(6-fluoro-3-pyridyl)pyrazine to synthesize the product in 28.7% yield.

[0199] MS m / z(ESI): 292.1 [M+1] + .

[0200] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.49(d,J=1.5Hz,1H),9.39(d,J=1.5Hz,1H),9.09(dd,J=10.3,3.0Hz,2H),8.77( td,J=8.2,2.6Hz,1H),8.59(d,J=6.3Hz,1H),8.32(d,J=6.2Hz,1H),7.44(dd,J=8.6,2.8Hz,1H),7.35(d,J=3.4Hz,1H).

[0201] Example 9

[0202] 1-(2'-Fluoro-[3,4'-Bipyridine]-6-yl)-1H-pyrrolo[2,3-c]pyridine

[0203] Weigh 200 mg (0.73 mmol) of 1-(5-bromopyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine, 59.5 mg (0.08 mmol) of Pd(dppf)Cl2, and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine (244.2 mg, 1.09 mmol) and mix them in 5 mL of 1,4-dioxane. The mixture was purged with nitrogen three times and heated to 60 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLCONE, 5C18A, 5µm, 250×20mm, mobile phase: aqueous phase (water + 0.1% trifluoroacetic acid), organic phase (acetonitrile + 0.1% trifluoroacetic acid), gradient ratio: organic phase 10%-90%) to obtain 940 mg of the compound, with a yield of 18.8%.

[0204] MS m / z(ESI): 291.5 [M+1] + .

[0205] 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.20(d,J=2.4Hz,1H),9.08(d,J=3.4Hz,1H),8.67(dd,J=8.7,2.5Hz,1H),8.56(d,J=6.3Hz,1H) ,8.41(d,J=5.3Hz,1H),8.30(d,J=6.3Hz,1H),8.24(d,J=8.7Hz,1H),7.92(dt,J=5.3,1.8Hz,1H),7.79(s,1H),7.32(d,J=3.4Hz,1H).

[0206] Biological evaluation

[0207] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0208] Test Example 1. Determination of the binding ability of the test sample to Tau protein aggregates on human brain tissue sections with Alzheimer's disease (AD).

[0209] 1. Experimental Objective

[0210] This study aims to semi-quantitatively determine the specific binding ability of the test sample to Tau protein aggregates in the brains of Alzheimer's disease (AD) patients using an in vitro autoradiography inhibition assay.

[0211] 2. Materials and Equipment

[0212] 2.1 Test sample

[0213] Positive control 19 The preparation method of F-MK6240 is referenced in J Med Chem. 2016, 59(10):4778-89.

[0214] The human brain tissue sample was provided by the Human Brain Tissue Bank of Xiangya School of Medicine, Central South University. The donor was a 95-year-old woman. The brain tissue was from the temporal lobe, with an Aβ grade of Thal-5 and a Tau pathological grade of Braak-V.

[0215] 2.2 Experimental Reagents

[0216] Table 1. Experimental Reagent Information

[0217] 2.3 Equipment and Instrument Information

[0218] Table 2. Equipment and Instrument Information

[0219] 3. Experimental Procedure

[0220] 3.1 Radioactive ligands [ 18 Preparation of F]MK-6240 solution

[0221] Calibration 18 The radioactivity of F]MK-6240 was measured by preparing an aqueous solution with a radioactivity concentration of approximately 0.8 MBq / mL, with a total volume of 50 mL. The solution was prepared fresh for each use.

[0222] 3.2 Preparation of the incubation solution for inhibition experiment

[0223] Preparation of inhibitor solution: Based on the sample list provided by the client, dissolve the test sample in the corresponding volume of DMSO solution to prepare a solution with a concentration of 10. -3 A stock solution of inhibitor at a concentration of mol / L was prepared. 10 μL of this solution was added to 0.99 mL of anhydrous ethanol solution, and mixed thoroughly to obtain a 10 μM inhibitor solution. Then, 100 μL of the 10 μM inhibitor solution was added to 0.9 mL of anhydrous ethanol solution, and mixed thoroughly to obtain a 1 μM inhibitor solution. This process was repeated to obtain a final 0.1 μM inhibitor solution for later use. The positive control […]. 19 F]MK-6240 requires an additional ethanol solution with a final concentration of 5μM for later use.

[0224] Preparation of autoradiography inhibition group solutions: Take 100 μL of 0.1 μM inhibitor solution and add 900 μL of radioactive solution with a concentration of approximately 0.8 MBq / mL. 18 F]MK-6240 solution, that is, the radioactive autoradiography inhibition group solution, should be prepared fresh for use. In addition, take 5μM of [ 19 100 μL of F]MK-6240 solution was added, along with 900 μL of [a radioactive solution with a concentration of approximately 0.8 MBq / mL]. 18 F]MK-6240 solution was used to obtain a non-specific binding inhibition group solution, which is ready for use.

[0225] Preparation of autoradiography blank control solution: Take 100 μL of anhydrous ethanol and add 900 μL of [a radioactive solution with a concentration of approximately 0.8 MBq / mL]. 18 F]MK-6240 solution, thus obtaining the blank control group solution.

[0226] 3.3 In vitro autoradiography experiment

[0227] 1) Immerse paraffin sections of brain tissue in xylene solution for 5 minutes to dewax, then rinse with anhydrous ethanol for 2 minutes and then rinse with sterile water for injection for 2 minutes, and air dry.

[0228] 2) Cover the surface of brain tissue slices with 1000 μL of radioactive autoradiography inhibition group solution and blank control group solution respectively, and incubate at room temperature for 60 min;

[0229] 3) Discard the solution on the surface of the tissue section and rinse with anhydrous ethanol for 2 min*2 times; then, add 50% ethanol-water solution to the surface of the tissue section and incubate again at room temperature for 30 min.

[0230] 4) Discard the solution on the surface of the tissue sections and rinse with anhydrous ethanol for 2 min*2 times;

[0231] 5) After drying, place the slices under a phosphor screen and expose them to light for 60 minutes.

[0232] 6) The phosphor screen is placed inside the phosphor screen storage system for scanning, and the image resolution is set to 600 dpi.

[0233] 4. Data Analysis

[0234] In OptiQuant software, autoradiographic images are analyzed; regions rich in Tau aggregates are delineated, and the signal value per unit surface area (digital light units / mm) of these regions is exported. 2 DLU / mm 2 The inhibition rate is calculated. The specific calculation method is as follows:

[0235] Gray matter regions exhibiting specific signals were selected from slices of the blank control and inhibition groups, and their signal values ​​per unit surface area (digital light units / mm²) were calculated using the software. 2 DLU / mm 2 The inhibition rate of the inhibitor is calculated using the following formula (where Total binding (TB) is the DLU / mm³ of the blank control group). 2 Non-specific binding (NSB) is the DLU / mm of the non-specific binding group. 2 Inhibitor binding (IB) is the DLU / mm² of each inhibitor group. 2 ).

[0236] Data rounding rules: This experiment was conducted in triplicate. The inhibition rate of each group was calculated as the average of three independent brain tissue slices, and the data were rounded to two decimal places.

[0237] 5. Research Results and Conclusions

[0238] The test sample is against [ 18 The inhibitory effect of MK6240 on Tau aggregates in AD brain slices is shown in Table 3 and Figure 1. Among them, the inhibition rate of MK6240 positive control was 45.31%, and the inhibition rate of compound 1 was the highest, at 75.37%.

[0239] Table 3. Inhibition rates of the compounds disclosed herein (results are expressed as the average ± deviation of three parallel samples).

[0240] Note: The MK6240 structure is as follows:

[0241] The operation was repeated, and the inhibition rates of compounds 6-9 were tested as shown in Table 4.

[0242] Table 4

[0243] Test Example 2. In vitro affinity (IC50) between the test sample and Tau protein aggregates on AD human brain slices. 50 Determination of )

[0244] 1. Experimental Objective

[0245] This study aims to quantitatively assess the in vitro affinity (IC50) between the test sample and Tau protein aggregates on AD human brain slices using an in vitro competitive binding assay. 50 ).

[0246] 2. Materials and Equipment

[0247] 2.1. Sections of human brain tissue in patients with Alzheimer's disease (AD)

[0248] The human brain tissue samples were provided by the Human Brain Tissue Bank of Xiangya School of Medicine, Central South University. Sample 1 was from an 87-year-old female, with the brain tissue being from the temporal lobe, Aβ grade Thal-2, and Tau pathological grade Braak-III. Sample 2 was from a 95-year-old female, with the brain tissue being from the temporal lobe, Aβ grade Thal-5, and Tau pathological grade Braak-V. The paraffin sections were prepared by our institution, with a section thickness of 6 μm.

[0249] 2.2. Experimental Reagents

[0250] Table 5

[0251] 2.3. Equipment and Instruments

[0252] Table 6

[0253] 3. Incubation system

[0254] Table 7

[0255] 4. Experimental Procedure

[0256] 4.1. Radioactive ligands [ 18 Preparation of F]MK6240 solution

[0257] Use PBS buffered saline solution to [ 18 F]MK6240 diluted to a solution of 0.8 MBq / mL is ready for use.

[0258] 4.2. Preparation of gradient concentration solutions for test sample / positive control

[0259] Accurately weigh the test sample / positive control solid and prepare a 1 mmol / L DMSO solution. Dilute it with ethanol to prepare solutions of different concentrations (10). -4 10 -5 10 -6 10 -7 10 -8 10 -9 10 -9.5 10 -10 (mol / L). The solution should be prepared fresh before the start of the in vitro competitive binding experiment.

[0260] 4.3. In vitro competitive binding experiment

[0261] MK6240 (10) contains a gradient concentration of test sample / positive control. -4 10 -5 10 -6 10 -7 10-8 10 - 9 10 -9.5 10 -10 mol / L) of 18 F]MK6240 solution was sequentially added dropwise to the surface of 8 adjacent brain tissue sections and incubated at room temperature for 60 min. Then, the solution on the tissue section surface was discarded, and the sections were rinsed twice with anhydrous ethanol for 2 min each time. Next, 50% ethanol-water solution was added dropwise to the tissue section surface, and the sections were incubated again at room temperature for 30 min. The solution on the tissue section surface was discarded again, and the sections were rinsed twice with anhydrous ethanol for 2 min each time. After air-drying, the sections were placed under a phosphorus storage screen and exposed to light for 60 min. An imaging system using a phosphorus storage screen was used. Plus scan, image resolution set to 600dpi.

[0262] 4.4. Data Processing

[0263] The main computerized systems used in this experiment at our institution are as follows:

[0264] Table 8

[0265] In OptiQuant software, autoradiographic images are analyzed; regions rich in Tau aggregates are delineated, and the signal value per unit surface area (digital light units / mm) of these regions is exported. 2 DLU / mm 2 Using log[analyte concentration] as the X-axis and the corresponding signal value per unit surface area as the Y-axis, the IC was calculated in GraphPad Prism 8.0 software using a unit point combined with model fitting. 50 value.

[0266] Data rounding rules: This experiment tested two samples, with 2-3 independent parallel groups for each sample. The results of the two samples were calculated independently, and the data were presented as averages, retaining four significant figures. The error caused by rounding does not affect the authenticity of the data.

[0267] 5. Results and Discussion

[0268] This experiment is based on [ 18 [F]MK6240 is a radioactive ligand, and Tau protein aggregates on AD human brain slices are the target protein. The affinity constants of the test sample and positive control MK6240 to Tau protein aggregates were quantitatively determined by competitive binding experiments.

[0269] Table 9

[0270] The results showed that compound 1 had an IC50 value in both samples.50 Both were significantly lower than MK6240. This suggests that compound 1 has a better ability to compete for radioligands than MK6240, meaning that compound 1 has a better binding ability to Tau protein aggregates than MK6240.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, and an isotopically substituted compound of formula (I) or a pharmaceutically acceptable salt thereof, It is selected from the compounds shown below or their pharmaceutically acceptable salts, and isotopic substitutions of the compounds shown below or their pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, or an isotopic substitute of a pharmaceutically acceptable salt thereof, wherein the isotope is selected from: 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N, and 18 F.

3. The compound of formula (I) according to claim 2, or an isotopic substitute of a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts thereof, 4. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, an isotopic substitute of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

5. Use of the compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an isotopic substitute of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of a tau aggregate imaging agent.

6. The use of the compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an isotopic substitute of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition of claim 4 in the preparation of a medicament for diagnosing or monitoring a disease, wherein the disease is selected from Alzheimer's disease, Down syndrome, cognitive deficits in schizophrenia, frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), primary age-related tau proteinopathy (PART), aerophilic granulomatosis (AGD), glioblastomatosis (GGT), Pick's disease, schizophrenia, pain disorders, sleep disorders, and Parkinson's disease.

7. The use according to claim 6, wherein the diagnosis or monitoring is performed by positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging, or autoradiography.

8. A method for preparing a compound of formula (I-1-A) or a pharmaceutically acceptable salt thereof, comprising the compound of formula (I-1-A-1) or a pharmaceutically acceptable salt thereof and K[ 18 The step of reacting to obtain the compound of formula (I-1-A) or a pharmaceutically acceptable salt thereof. The compound represented by formula (I-1-A-1) or its pharmaceutically acceptable salt is selected from the compounds shown below or their pharmaceutically acceptable salts. The compound represented by formula (I-1-A) or its pharmaceutically acceptable salt is selected from the compounds shown below or their pharmaceutically acceptable salts.

9. The preparation method according to claim 8, further comprising: The step of reacting the compound of formula (I-1-A-2) with the compound of formula (I-1-A-3) in the presence of a palladium catalyst and a base to give the compound of formula (I-1-A-1) is as follows. The compound represented by formula (I-1-A-3) is selected from the compounds shown below. The Y is a halogen, preferably chlorine or iodine. The compound represented by formula (I-1-A-2) is as shown below.

10. The preparation method according to claim 8, comprising compound 3c or a pharmaceutically acceptable salt thereof and K[ 18 F] is the step of reacting to give compound 3 or its pharmaceutically acceptable salt.

11. The preparation method according to claim 10, further comprising the step of reacting compound 3a and compound 3b in the presence of a palladium catalyst and a base to obtain compound 3c.

12. A compound as shown below or a pharmaceutically acceptable salt thereof:

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