Isoindolinone and dihydropyrrolopyridone compounds and uses thereof

Abstract

Isoindolinone compounds and pharmaceutical compositions comprising the compounds are described herein. In addition, methods for treating a patient such as Huntington's disease; and methods for treating the patient such as Huntington's disease, such as Huntington's disease; hD).

Description

[0001] Cross-references

[0002] This application claims international application No. PCT / CN2023 / 098598, filed on June 6, 2023, and international application No. PCT / CN2023 / 117262, filed on September 6, 2023, the entire contents of which are hereby incorporated by reference. Background Technology

[0003] Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by involuntary movements, cognitive impairment, and deteriorating mental status. Death often occurs 13 to 15 years after symptom onset, usually caused by pneumonia or coronary artery disease. In Western European populations, the incidence of HD is three to seven individuals per 100,000. In North America, an estimated 30,000 people have HD, while another 200,000 are at risk of inheriting the disease from affected parents. The disease is caused by the uninterrupted amplification of the trinucleotide CAG repeat in the "mutant" huntingtin (Htt) gene, resulting in HTT (Htt protein) with an amplified polyglutamine (polyQ) extension (also known as the "CAG repeat" sequence). Currently, there are no small molecule therapies targeting the underlying cause of the disease, resulting in a significant unmet need for drugs that can be used to treat or improve HD. Therefore, there is still a need to identify and provide small molecule compounds for the treatment or improvement of HD. Summary of the Invention

[0004] This article discloses a compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0005]

[0006] in,

[0007] The ring C is a 4- to 10-membered heterocyclic alkyl or a 4- to 10-membered heterocyclic alkenyl;

[0008] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0009] Two Rs 1 Together they form an oxygen group; or

[0010] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0011] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0012] Each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or

[0013] X represents non-existent, -CH2-, -O-, -OCH2-, -S-, or -NR. 3 -;

[0014] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0015] Each A is independently N or CR 4 Where at least two A's are N;

[0016] Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0017] Or R 3 And an R 4 Together they form 5- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups;

[0018] B is N or CR 5 ;

[0019] D is N or CR 6 ;

[0020] E is N or CR 7 ;

[0021] F is N or CR 8 ;

[0022] R 5 R 6 R 7 R 8 each independently is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OCH2R a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or -O-(C1-C6alkylene)-5- to 10-membered heteroaryl; wherein said alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is each optionally substituted with 1 to 4 substituents independently selected from R e ;

[0023] wherein at least one of R 5 , R 6 , R 7 , or R 8 is C2-C6alkenyl, C3-C6cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or -O-(C1-C6alkylene)-5- to 10-membered heteroaryl, wherein said alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ;

[0024] each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is each optionally substituted with 1 to 4 substituents independently selected from R e ;

[0025] each R bindependently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;

[0026] R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;

[0027] each R e is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; and

[0028] p is an integer from 1-9.

[0029] In another aspect, disclosed herein is a compound having the structure of Formula (I’):

[0030]

[0031] wherein,

[0032] Ring C is 4- to 10-membered heterocycloalkyl or 4- to 10-membered heterocyclenylidene;

[0033] each R 1 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SRa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or

[0034] two R 1 groups together form an oxo group; or

[0035] two R 1 groups together form a bond, C1-C3 alkylene, or C1-C3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or

[0036] two R 1 groups together form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;

[0037] each R 2 is independently hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or

[0038] two R 2 groups together form an oxo group;

[0039] X is absent, -CH2-, -O-, -S-, or -NR 3 -;

[0040] R 3 is hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0041] each A is independently N or CR 4 , wherein at least two A are N;

[0042] each R 4 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl;

[0043] B is N or CR 5 ;

[0044] D is N or CR6 ;

[0045] E is N or CR 7 ;

[0046] F is N or CR 8 ;

[0047] R 5 and R 8 are each independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl; wherein the alkyl, haloalkyl, and hydroxyalkyl and aminoalkyl groups are each optionally substituted with 1 to 4 substituents independently selected from R e ;

[0048] R 6 or R 7 is 5- to 10-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and the other of R 6 or R 7 is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R dC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; 7 ; ;

[0049] ; each R 10 is independently halogen, -CN, -NO2, -OH, -OR a , c ; R d is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; or ;

[0050] ; two R 10 are taken together to form an oxo group; ;

[0051] ; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; ;

[0052] ; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; ;

[0053] R c and R d ;each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;

[0054] each R e is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; and

[0055] p is an integer from 1-9.

[0056] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0057] Also disclosed herein is a method of treating a neurodegenerative disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.

[0058] In some embodiments, the neurodegenerative disease or disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease (HD), Parkinson's disease, prion disease, and spinocerebellar ataxia. In some embodiments, the neurodegenerative disease or disorder is Huntington's disease (HD).

[0059] Further aspects and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description, wherein like reference numerals refer to like elements throughout. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various apparent respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. DETAILED DESCRIPTION

[0060] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and applications cited herein are incorporated by reference.

[0061] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations of the word, such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In addition, the use of the term "including" as well as "comprising" is used in the sense of "including but not limited to."

[0062] References herein to "some embodiments" or "an embodiment" mean at least one embodiment of the described feature, structure, or characteristic. Therefore, use of the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Moreover, unless the context clearly indicates otherwise, as used herein, the singular forms "a," "an," and "the" include plural referents. It is also noted that the terms "or" and "and" as used herein generally mean "and / or," unless otherwise indicated.

[0063] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0064] "Oxy" means =0.

[0065] "Carboxyl" means -COOH.

[0066] "Cyano" means -CN.

[0067] "Alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" or "Ci-6 alkyl" are intended to refer to alkyl groups having from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the term "alkyl" without a numerical range is also intended to encompass the term "alkyl" as it appears herein. In some embodiments, alkyl is Ci-6 alkyl. In some embodiments, alkyl is Ci-5 alkyl. In some embodiments, alkyl is Ci-4 alkyl. In some embodiments, alkyl is Ci-3 alkyl. Unless otherwise specifically stated in the specification, an alkyl group can optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkyl group is optionally substituted with halogen. 10 "Alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" or "Ci-6 alkyl" are intended to refer to alkyl groups having from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the term "alkyl" without a numerical range is also intended to encompass the term "alkyl" as it appears herein. In some embodiments, alkyl is Ci-6 alkyl. In some embodiments, alkyl is Ci-5 alkyl. In some embodiments, alkyl is Ci-4 alkyl. In some embodiments, alkyl is Ci-3 alkyl. Unless otherwise specifically stated in the specification, an alkyl group can optionally be substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkyl group is optionally substituted with halogen.

[0068] "Alkenyl" refers to a straight or branched chain monovalent hydrocarbon group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in the cis or trans configuration around the double bond, and it is to be understood that both isomers are included. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butenyl, and the like. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl," means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the appearance of the term "alkenyl" without any numerical range is also encompassed by this definition. Unless otherwise specifically excluded, an alkenyl group can be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl group is optionally substituted with halogen.

[0069] "Alkynyl" refers to a straight or branched chain monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl," means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the appearance of the term "alkynyl" without any numerical range is also encompassed by this definition. Unless otherwise specifically excluded, an alkynyl group can be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkynyl group is optionally substituted with halogen.

[0070] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, alkylene may optionally be substituted with, for example, an oxo group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene may optionally be substituted with, for example, a halogen, -CN, -OH, or -OMe. In some embodiments, alkylene may optionally be substituted with a halogen.

[0071] "Alkoxy" refers to the formula -OR a The group, wherein R a Alkyl groups are defined as such. Unless otherwise specifically stated in this specification, the alkoxy group may optionally be substituted with, for example, an oxo group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc. In some embodiments, the alkoxy group may optionally be substituted with, for example, a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group may optionally be substituted with, for example, a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group may optionally be substituted with a halogen.

[0072] "Aryl" means a radical derived by removal of a hydrogen atom from a monovalent aromatic ring system or a multivalent aromatic hydrocarbon ring system. The monovalent aromatic ring system or the multivalent aromatic hydrocarbon ring system can contain only carbon and hydrogen, and contain five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) pi electron system according to Hückel theory. The ring system from which the aryl group is derived includes, but is not limited to, groups such as, for example, benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused rings (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracenylene, naphthalenylene, phenanthrenylene, anthracene, azulene, benzene, benzvalene, chrysene, fluorene, indacene, isobenzofuane, indene, naphthalene, octalene, phenalene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the aryl group can be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogen.

[0073] "Carbocycle" means a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can include 3- to 10-membered monocyclic, 6- to 12-membered bicyclic, and 6- to 12-membered bridged rings. The rings of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring (e.g., phenyl) can be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle when valence permits. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, dihydroindenyl, and naphthyl. Unless otherwise specifically stated in the specification, a carbocycle can be optionally substituted.

[0074] "Cycloalkyl" means a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused rings (when fused with an aryl or heteroaryl ring, the cycloalkyl group is bonded through a non-aromatic ring atom), spiro rings, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having from three to fifteen carbon atoms (e.g., C3-C 15 A fully saturated cycloalkyl group or C3-C15 Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10 Cycloalkyl groups are 3 to 10-membered fully saturated cycloalkyl groups or 3 to 10-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 3 to 6-membered fully saturated cycloalkyl groups or 3 to 6-membered cycloalkenyl groups. In some embodiments, the cycloalkyl group is 5 to 6-membered fully saturated cycloalkyl groups or 5 to 6-membered cycloalkenyl groups. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups may optionally be substituted, for example, with the following: oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted with one of the following: an oxo group, a halogen, a methyl group, an ethyl group, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with one of the following: an oxo group, a halogen, a methyl group, an ethyl group, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0075] "Cycloalkenyl" refers to an unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, preferably having three to twelve carbon atoms and containing at least one double bond, including fused rings or bridged ring systems. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be linked to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0076] "Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, the halo is fluoro or chloro. In some embodiments, the halo is fluoro.

[0077] "Haloalkyl" or "haloalkane" as used herein means an alkyl group as defined above substituted with one or more halo groups, for example trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of halo-substituted alkane ("haloalkane") include halo-methane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalo- and trihalo-methane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkane (or substituted alkane) and halo (e.g., Cl, Br, F, I, and the like). When the alkyl group is substituted with more than one halo group, each halo can be independently selected, for example 1-chloro, 2-fluoroethane.

[0078] "Fluoroalkyl" means an alkyl group as defined above substituted with one or more fluoro groups, for example trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0079] "Hydroxyalkyl" means an alkyl group as defined above substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0080] "Aminoalkyl" means an alkyl group as defined above substituted with one or more amino groups. In some embodiments, the alkyl group is substituted with one amino group. In some embodiments, the alkyl group is substituted with one, two, or three amino groups. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0081] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, a heteroalkyl group is a C1-C6heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl group is optionally substituted by halogen.

[0082] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and one to eight heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group comprises one to three nitrogens. In some embodiments, the heterocycloalkyl group comprises one or two nitrogens. In some embodiments, the heterocycloalkyl group comprises one nitrogen. In some embodiments, the heterocycloalkyl group comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having the following number of carbon atoms: two to fifteen carbon atoms (e.g., C2-C15heterocycloalkyl), two to ten carbon atoms (e.g., C2-C10heterocycloalkyl), two to nine carbon atoms (e.g., C2-C9heterocycloalkyl), two to eight carbon atoms (e.g., C2-C8heterocycloalkyl), two to seven carbon atoms (e.g., C2-C7heterocycloalkyl), two to six carbon atoms (e.g., C2-C6heterocycloalkyl), two to five carbon atoms (e.g., C2-C5heterocycloalkyl), two to four carbon atoms (e.g., C2-C4heterocycloalkyl), two to three carbon atoms (e.g., C2-C3heterocycloalkyl), or three carbon atoms (e.g., C3heterocycloalkyl). In some embodiments, a heterocycloalkyl group is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl group is optionally substituted by halogen. 15 fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), two to ten carbon atoms (e.g., C2-C10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkenyl), two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C6 heterocyclic alkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkenyl). Examples of such heterocyclic alkyl groups include, but are not limited to, azahexacyclopropenyl, azahexacyclobutyl, oxacyclobutyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolidinyl, Pyrazolyl, quinoline, thiazolyl, tetrahydrofuranyl, trithiayl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl, and 2-oxo-1,3-m-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl, the number of carbon atoms in the heterocyclic alkyl is different from the total number of atoms (including heteroatoms) constituting the heterocyclic alkyl (i.e., the skeletal atoms of the heterocyclic alkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specifically stated in this specification, the heterocyclic alkyl group may optionally be substituted as described below, for example, by: oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc.In some embodiments, the heterocyclic alkyl group is optionally substituted with one of the following: an oxo group, a halogen, a methyl group, an ethyl group, a -CN group, a -COOH group, a COOMe group, a -CF3 group, an -OH group, an -OMe group, an -NH2 group, or a -NO2 group. In some embodiments, the heterocyclic alkyl group is optionally substituted with one of the following: a halogen, a methyl group, an ethyl group, a -CN group, a -CF3 group, an -OH group, or an -OMe group. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0083] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl group comprises one to three nitrogen atoms. In some embodiments, a heteroaryl group comprises one or two nitrogen atoms. In some embodiments, a heteroaryl group comprises one nitrogen atom. A heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include a fused ring (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded by aromatic ring atoms) or a bridged ring system; the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, a heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, a heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, acrylonitrile, benzimidazolyl, benzothiazolyl, benzoindolyl, benzom-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxylalkyl, benzonaphthuryl, benzooxazolyl, benzom-dioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, and dibenzothienyl. Furanyl, furanoneyl, isothiazolyl, imidazolyl, indazole, indoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoachenginyl, oxazolyl, ethylene oxide, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridineyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl groups may optionally be substituted, for example, with the following: halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the heteroaryl group is optionally substituted with one of the following: halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with one of the following: halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0084] The term "substituted" refers to a portion having a substituent that replaces one or more hydrogen atoms or substituted heteroatoms, such as NH, on one or more carbons of the structure. It should be understood that "substituted" or "replaced by" includes implicit limitations: such substitution is consistent with the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.). In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, for example, replacing two hydrogen atoms on a single carbon atom with an oxo group, imino group, or thio group. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy the valence of heteroatoms as described herein.

[0085] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0086] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases that can be derivatized include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0087] As used herein, the phrases “parenteral administration” and “administered parenterally” refer to administration methods other than enteral and local administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-sacral, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0088] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0089] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of compatibility with the other components of the formulation and harmlessness to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogenic water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic compatible substances used in pharmaceutical formulations.

[0090] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound that, when administered to an individual mammal as a single dose or as part of a series of doses, effectively produces the desired therapeutic effect.

[0091] The terms “treat,” “treating,” or “treatment” include relieving, alleviating, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, reducing a disease or condition, causing a disease or condition to subside, alleviating symptoms caused by a disease or condition, or terminating the symptoms of a disease or condition.

[0092] The compounds disclosed herein

[0093] This article describes compounds or their pharmaceutically acceptable salts or solvates that can be used to treat neurodegenerative diseases.

[0094] In one aspect, this disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0095]

[0096] in,

[0097] The ring C is a 4- to 10-membered heterocyclic alkyl or a 4- to 10-membered heterocyclic alkenyl;

[0098] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0099] Two Rs 1 Together they form an oxygen group; or

[0100] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0101] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0102] Each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or

[0103] X represents non-existence, -CH2-, -O-, -OCH2-, or -NR. 3 -;

[0104] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0105] Each A is independently N or CR 4 Where at least two A's are N;

[0106] Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0107] Or R 3 And an R 4 Together they form 5- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups;

[0108] B is N or CR 5 ;

[0109] D is N or CR 6 ;

[0110] E is N or CR 7 ;

[0111] F is N or CR 8 ;

[0112] R 5 R 6 R 7 Or R 8 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, 5- to 10-membered heteroaryl, or O-(C1-C6 alkylene)-5- to 10-membered heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0113] Where R 5 R 6 R 7 Or R 8 At least one of them is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or -O-(C1-C6 alkylene)-5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl and heteroaryl are optionally selected from 1 to 4 of R e Substituents of the substituents;

[0114] Each Ra Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0115] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0116] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0117] Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and

[0118] p is an integer from 1 to 9.

[0119] On the other hand, this disclosure provides a compound represented by formula (I') or a pharmaceutically acceptable salt or solvate thereof:

[0120]

[0121] in,

[0122] The ring C is a 4- to 10-membered heterocyclic alkyl or a 4- to 10-membered heterocyclic alkenyl;

[0123] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0124] Two Rs 1 Together they form an oxygen group; or

[0125] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0126] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0127] Each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or

[0128] Two Rs 2 Together they form an oxygen group;

[0129] X represents non-existence, -CH2-, -O-, -S-, or -NR. 3 -;in

[0130] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0131] Each A is independently N or CR 4 Where at least two A's are N;

[0132] Each R 4Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0133] B is N or CR 5 ;

[0134] D is N or CR 6 ;

[0135] E is N or CR 7 ;

[0136] F is N or CR 8 ;

[0137] R 5 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0138] R 6 Or R 7 One of them is optionally selected from 1 to 4 independently chosen from R 10 The substituents are 5 to 10-membered heteroaryl groups; and R 6 Or R 7 The other one is hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NRc R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents of R; where R 7 Not a pyridinyl group substituted with two methoxy groups;

[0139] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0140] Two Rs 10 Together they form an oxygen group;

[0141] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0142] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0143] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0144] Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and

[0145] p is an integer from 1 to 9.

[0146] In some embodiments of formula (I"), (I') or (I), each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), or (I), each R 2 Independently halogenated. In some embodiments of formula (I"), (I') or (I), each R 2 Independently, each R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), or (I), each R 2 Independently, each R is a C1-C6 alkyl group. In some embodiments of formula (I"), (I') or (I), each R 2 Independently, each R is a C1-C6 haloalkyl group. In some embodiments of formula (I"), (I') or (I), each R 2 Independently, it is a C1-C6 hydroxyalkyl group. In some embodiments of formula (I"), (I') or (I), each R 2Independently, it is a C1-C6 aminoalkyl group. In some embodiments of formula (I"), (I') or (I), each R 2 Independently -OH. In some embodiments of formula (I"), (I') or (I), each R 2 It is hydrogen independently.

[0147] In some embodiments of formula (I"), (I') or (I), the two R 2 Together with the atoms they are attached to, they form oxo groups.

[0148] In some embodiments of formula (I"), (I') or (I), D is CR 6 In some embodiments of formula (I"), (I') or (I), D is N.

[0149] In some embodiments of formula (I") or (I'), R 6 To be optionally selected from 1 to 4 R 10 The substituents are 5 to 10-membered heteroaryl groups; and R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl and heteroaryl groups are each optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I') or (I), R 6 To be optionally selected from 1 to 4 R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR cR d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl and heteroaryl groups are each optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I') or (I), R 6 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments of formula (I"), (I'), or (I), R 6 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 7 Hydrogen, halogen, -OH, -OR a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of formula (I"), (I') or (I), R 6 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 7 It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of formula (I"), (I'), or (I), R 6 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R7 It is hydrogen.

[0150] In some embodiments of formula (I") or (I'), R 7 To be optionally selected from 1 to 4 R 10 The substituents are 5 to 10-membered heteroaryl groups; wherein R 7 Not a pyridinyl group substituted with two methoxy groups; and R 6 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl and heteroaryl groups are each optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I') or (I), R 7 To be optionally selected from 1 to 4 R 10 The substituents are 5 to 8-membered heteroaryl groups; wherein R 7 Not a pyridinyl group substituted with two methoxy groups; and R 6 Hydrogen, halogen, -CN, -NO 2 -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl and heteroaryl groups are each optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I') or (I), R 7 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 6 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments of formula (I"), (I'), or (I), R 7 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 6 Hydrogen, halogen, -OH, -OR a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of formula (I"), (I') or (I), R 7 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 6 It is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of formula (I"), (I'), or (I), R 7 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 8-membered heteroaryl groups; and R 6 It is hydrogen.

[0151] In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 10-membered heterocyclic alkenyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 8-membered heterocyclic alkenyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 6-membered heterocyclic alkenyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 7-membered heterocyclic alkenyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is an 8-membered heterocyclic alkenyl group.

[0152] In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 10-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 8-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 4-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 5-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 6-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is a 7-membered heterocyclic alkyl group. In some embodiments of formula (I"), (I'), or (I), the ring C is an 8-membered heterocyclic alkyl group.

[0153] In some embodiments of formula (I"), (I'), or (I), ring C is piperidine, piperazine, or morpholine. In some embodiments of formula (I"), (I'), or (I), ring C is piperidine. In some embodiments of formula (I"), (I'), or (I), ring C is piperazine. In some embodiments of formula (I"), (I'), or (I), ring C is morpholine.

[0154] In some embodiments of formula (I"), (I') or (I), for ,

[0155] in,

[0156] Z is CH or N;

[0157] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from Re Substituents; or

[0158] Two Rs 1 Together they form an oxygen group; or

[0159] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0160] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0161] R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents;

[0162] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0163] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents; and

[0164] Each R eIndependently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl.

[0165] In some embodiments of formula (I"), (I') or (I), for ,

[0166] in,

[0167] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0168] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0169] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0170] R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents;

[0171] Each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0172] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents; and

[0173] Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl.

[0174] In some embodiments of formula (I"), (I') or (I), for ,

[0175] in,

[0176] Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0177] Two Rs 1 Together they form a C1-C3 alkylene or a C1-C3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0178] Two Rs 1 Together they form C3-C6 cycloalkyl groups; and

[0179] R 9 It is hydrogen.

[0180] In some embodiments of formula (I"), (I') or (I), for ,

[0181] in,

[0182] Each R 1 Independently hydrogen or C1-C6 alkyl; or

[0183] Two Rs 1 Together they form C1-C3 alkylene groups; or

[0184] Two Rs 1 Together they form C3-C6 cycloalkyl groups; and

[0185] R 9 It is hydrogen.

[0186] In some embodiments of formula (I"), (I') or (I), for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0187] In some embodiments of formula (I"), (I') or (I), for , , , , , , , , , , , , , , , , , , , , , , , , or .

[0188] In some embodiments of formula (I"), (I') or (I), for or .

[0189] In some embodiments of formula (I"), (I') or (I), for .

[0190] In some embodiments of formula (I"), (I') or (I), for .

[0191] On the other hand, this disclosure provides a compound represented by formula (II') or a pharmaceutically acceptable salt or solvate thereof:

[0192]

[0193] in,

[0194] Ring G is a 5- to 10-membered heteroaryl group;

[0195] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R eSubstituents; or

[0196] Two Rs 1 Together they form an oxygen group; or

[0197] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0198] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0199] X represents a bond, -CH2-, -O-, -S-, or -NR. 3 -,in

[0200] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0201] Z is CH or N, when X is -O-, -S-, or -NR. 3 When -, then Z is CH;

[0202] Each A is independently N or CR 4 Where at least two A's are N;

[0203] Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl;

[0204] B is N or CR 5 ;

[0205] E is N or CR 7 ;

[0206] F is N or CR 8 ;

[0207] R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)Ra -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0208] R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents;

[0209] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0210] Two Rs 10 Together they form an oxygen group;

[0211] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0212] Each R bIndependently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0213] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0214] Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl;

[0215] p is 8; and

[0216] q can be 0, 1, 2 or 3.

[0217] In some embodiments of formula (I"), (I'), or (II'), both A's are N. In some embodiments of formula (I"), (I'), or (II'), all three A's are N. In some embodiments of formula (I"), (I'), or (II'), each A' is N. In some embodiments of formula (I"), (I'), (I), (II), or (II'), for , , , or .

[0218] In some embodiments of formula (I"), (I'), (I), (II) or (II'), for , or .

[0219] In some embodiments of formula (I"), (I'), (I), (II) or (II'), for .

[0220] In some embodiments of formula (I"), (I'), (I), (II) or (II'), for .

[0221] In some embodiments of formula (I"), (I'), (I), (II) or (II'), for .

[0222] In some embodiments, this disclosure provides a compound represented by formula (III') or a pharmaceutically acceptable salt or solvate thereof:

[0223]

[0224] in,

[0225] Ring G is a 5- to 10-membered heteroaryl group;

[0226] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0227] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0228] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0229] X is -CH2-, -O-, -S-, or -NR 3 -;in

[0230] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, or C3-C6 cycloalkyl;

[0231] A is either N or CH;

[0232] B is N or CR 5 ;

[0233] E is N or CR 7 ;

[0234] F is N or CR 8 ;

[0235] R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0236] R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents;

[0237] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0238] Two Rs 10 Together they form an oxygen group;

[0239] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0240] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0241] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0242] Each R eIndependently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and

[0243] q can be 0, 1, 2 or 3.

[0244] In some embodiments of formulas (II), (II'), (III) or (III'), R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents are substituted. In some embodiments of formula (II), (II'), (III), or (III'), R 9 It is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of formula (II), (II'), (III), or (III'), R 9 It is hydrogen or C1-C6 alkyl. In some embodiments of formula (II), (II'), (III), or (III'), R 9 It is a C1-C6 haloalkyl group. In some embodiments of formula (II), (II'), (III), or (III'), R 9 It is a C1-C6 alkyl group. In some embodiments of formula (II), (II'), (III), or (III'), R 9 It is hydrogen.

[0245] In some embodiments of formulas (II), (II), (III), or (III'), the two R 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents are substituted. In some embodiments of formula (II), (II), (III), or (III'), the two R groups are substituted. 1 Together they form a bond. In some embodiments of formulas (II), (II'), (III), or (III'), the two R... 1Together they form a C1-C3 alkylene group. In some embodiments of formula (II), (II'), (III), or (III'), the two R groups... 1 Together they form or C1-C3 heteroalkylene groups.

[0246] In some embodiments, compounds of formula (III') have the structure of formula (IIIa') or a pharmaceutically acceptable salt or solvate thereof:

[0247]

[0248] in,

[0249] Y is a C1-C3 alkylene group.

[0250] Ring G is a 5- to 10-membered heteroaryl group;

[0251] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0252] X is -CH2-, -O-, or -NR 3 -,in

[0253] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0254] A is either N or CH;

[0255] B is N or CR 5 ;

[0256] E is N or CR 7 ;

[0257] F is N or CR 8 ;

[0258] R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a-S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0259] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0260] Two Rs 10 Together they form an oxygen group;

[0261] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0262] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0263] Rc and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0264] Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and

[0265] q can be 0, 1, 2 or 3.

[0266] In some embodiments of formula (IIIa'), Y is -CH2CH2CH2-. In some embodiments of formula (IIIa'), Y is -CH2CH2-. In some embodiments of formula (IIIa'), Y is -CH2-.

[0267] In some embodiments, compounds of formula (III') have the structure of formula (IIIb') or a pharmaceutically acceptable salt or solvate thereof:

[0268]

[0269] in,

[0270] Ring G is a 5- to 10-membered heteroaryl group;

[0271] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0272] Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0273] X is -CH2-, -O-, -S-, or -NR 3 -,in

[0274] R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0275] A is either N or CH;

[0276] B is N or CR 5 ;

[0277] E is N or CR 7 ;

[0278] F is N or CR 8 ;

[0279] R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0280] Each R 10Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0281] Two Rs 10 Together they form an oxygen group;

[0282] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0283] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0284] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0285] Each R eIndependently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and

[0286] q can be 0, 1, 2 or 3.

[0287] In some embodiments of equation (II'), when X is -O-, -S-, or -NR 3 When X is a bond, Z is CH. In some embodiments of formula (II) or (II'), when X is a bond, Z is CH or N. In some embodiments of formula (II) or (II'), when X is a bond, Z is N. In some embodiments of formula (II) or (II'), when X is -CH2-, Z is CH or N. In some embodiments of formula (II) or (II'), when X is -CH2-, Z is CH. In some embodiments of formula (II) or (II'), when X is -CH2-, Z is N.

[0288] In some embodiments of formula (I"), (I') or (II'), X is -O-, -S- or -NR. 3 - In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), or (IIIb'), X is -O- or -NR. 3 - In some embodiments of formula (I"), (I'), or (II'), X is -S-. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), or (IIIb'), X is -O-. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), or (IIIb'), X is -NR. 3- In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), or (IIIb'), X is -NH-. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (II'), (IIIa), (IIIa'), (IIIb), or (IIIb'), X is -NCH3-. In some embodiments of formula (I'), (I), (II), (III), (IIIa), or (IIIb), X is -CH2. In some embodiments of formula (I"), X is -OCH2-.

[0289] In some embodiments of formula (I"), (I'), (I), (II) or (II'), X is absent.

[0290] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is hydrogen, C1-C3 alkyl, or C1-C3 hydroxyalkyl. In some embodiments of formula (I"), (I'), (II'), (IIIa'), or (IIIb), R 3 It is a C3-C6 cycloalkyl group. In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), or (IIIb'), R 3 It is cyclopropyl or cyclobutyl. In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), or (IIIb'), R 3 It is cyclopropyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is hydrogen or C1-C3 alkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is a C1-C3 hydroxyalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3It is a C1-C3 haloalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is a C1-C3 alkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is hydrogen or methyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is methyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb) or (IIIb'), R 3 It is hydrogen.

[0291] On the other hand, this disclosure provides a compound represented by formula (IV') or a pharmaceutically acceptable salt or solvate thereof:

[0292]

[0293] in,

[0294] Ring G is a 5- to 10-membered heteroaryl group;

[0295] Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or

[0296] Two Rs 1 Together they form an oxygen group; or

[0297] Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or

[0298] Two Rs1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents;

[0299] Z is CH or N;

[0300] A is either N or CH;

[0301] B is N or CR 5 ;

[0302] E is N or CR 7 ;

[0303] F is N or CR 8 ;

[0304] R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents;

[0305] R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents;

[0306] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or

[0307] Two Rs 10 Together they form an oxygen group;

[0308] Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents;

[0309] Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0310] R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents;

[0311] Each R eIndependently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl;

[0312] p is 8; and

[0313] q can be 0, 1, 2 or 3.

[0314] In some embodiments of formulas (II), (II'), (IV), or (IV'), Z is N. In some embodiments of formulas (II), (II'), (IV), or (IV'), Z is CH.

[0315] In some embodiments of formula (I"), (I'), (I), (II) or (II'), at least one A is N.

[0316] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb), (IV) or (IV'), each A is N. In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each A is independently CR. 4 .

[0317] In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each A is independently N or CH. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each A is CH.

[0318] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV'), or (IV'), B is CR 5 In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), B is CH. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), B is N.

[0319] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), E is CR 7 In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), E is CH. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), E is N.

[0320] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), F is CR 8 In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), F is CH. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), F is N.

[0321] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently, it is a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CHF2. In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 1Independently, it is hydrogen, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 1 Independently halogenated. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently, it is Cl, Br, or F. In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 Independently, it is F. In some embodiments of equations (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 1 It is hydrogen independently.

[0322] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV) or (IV'), the two R 1 Together they form C3-C6 cycloalkyl groups. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV) or (IV'), the two R groups... 1 Together they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV), or (IV'), the two R 1 Together they form a cyclopropyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV) or (IV'), the two R groups... 1 Together they form a cyclobutyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV) or (IV'), the two R groups... 1Together they form a cyclopentyl group. In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV), or (IV'), the two R groups... 1 Together they form a cyclohexyl group.

[0323] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIb), (IIIb'), (IV) or (IV'), the two R 1 Together they form an oxygen group.

[0324] In some embodiments of formula (I"), (I'), (I), (II) or (II'), each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), or (II'), each R 4 Independently hydrogen, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), or (II'), each R 4 Independently hydrogen, halogen, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of formula (I"), (I'), (I), (II), or (II'), each R 4 Independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of formula (I"), (I'), (I), (II), or (II'), each R 4 Independently halogenated. In some embodiments of formula (I"), (I'), (I), (II) or (II'), each R 4 Independently, each R is a C1-C6 alkyl group. In some embodiments of formula (I"), (I'), (I), (II) or (II'), each R 4 It is hydrogen independently.

[0325] In some embodiments of formula (I), R 3 And an R 4Together they form 5- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups.

[0326] In some embodiments of formula (I), R 5 R 6 R 7 Or R 8 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of R; and R 5 R 6 R 7 Or R 8 At least one of them is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 8-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally selected from 1 to 4 of R e Substituents are substituted. In some embodiments of formula (I), R... 5 R 6 R 7 Or R 8 Independently, it is hydrogen, halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, or 5- to 10-membered heteroaryl. In some embodiments of formula (I), R 5 R 6 R 7 Or R 8 It can be independently hydrogen, halogen, -CN, C3-C6 cycloalkyl or 5 to 10 heteroaryl.

[0327] In some embodiments of formula (I), R 5It is a 5- to 10-membered heteroaryl group; and R 6 R 7 and R 8 Independently, it is hydrogen, halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or C1-C6 haloalkyl. In some embodiments of formula (I), R 6 It is a 5- to 10-membered heteroaryl group; and R 5 R 7 and R 8 Independently, it is hydrogen, halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or C1-C6 haloalkyl. In some embodiments of formula (I), R 7 It is a 5- to 10-membered heteroaryl group; and R 5 R 6 and R 8 Independently, it is hydrogen, halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, or C1-C6 haloalkyl. In some embodiments of formula (I), R 8 It is a 5- to 10-membered heteroaryl group; and R 5 R 6 and R 7 It can be hydrogen, halogen, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0328] In some embodiments of formula (I), B is CR 5 , where R 5 It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e The substituent is substituted; and F is N.

[0329] In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), (IIIb'), or (IV'), D is CR 6 , where R 6 It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e The substituents are substituted; and E is N. In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), (IIIb'), or (IV'), D is CR. 6 , where R 6It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e The substituents are substituted; and F is N. In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), (IIIb') or (IV'), D is CR. 6 , where R 6 It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e Substituents are substituted; B is N; and F is N. In some embodiments of formula (I"), (I'), (II'), (III'), (IIIa'), (IIIb'), or (IV'), D is CR. 6 , where R 6 It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e Substituents are substituted; E is N; and F is N.

[0330] In some embodiments of equation (I), F is CR 8 , where R 8 It is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl, and heteroaryl are optionally composed of 1 to 4 selected from R e The substituents are substituted; and E is N.

[0331] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally substituted with 1 to 4 substituents, wherein the substituents are hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is a C1-C6 alkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is a C1-C6 haloalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is a C1-C6 hydroxyalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is halogen or hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5It is a halogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is fluorine. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 5 It is chlorine.

[0332] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR aC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is a C1-C6 alkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is a C1-C6 haloalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is a C1-C6 hydroxyalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is halogen or hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is a halogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 6 It is hydrogen.

[0333] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7It is a C1-C6 alkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is a C1-C6 haloalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is a C1-C6 hydroxyalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is halogen or hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is a halogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is fluorine. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is chlorine. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 7 It is a hydroxyl group. In some embodiments of formula (I'), (I), (II), (III), (IIIa), (IIIb) or (IV), R 7 It is a methoxy group.

[0334] In some embodiments of formulas (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally substituted with 1 to 4 substituents, wherein the substituents are hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is a C1-C6 alkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8It is a C1-C6 haloalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is a C1-C6 hydroxyalkyl group. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is halogen or hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is a halogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is hydrogen. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is fluorine. In some embodiments of formula (I"), (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), R 8 It is chlorine.

[0335] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is optionally composed of 1 or 4 rings selected from R. 10 The substituents are 5 to 6-membered heteroaryl groups.

[0336] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is optionally composed of one or two rings selected from R. 10The substituent is a 5-membered heteroaryl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyrrole, imidazole, triazole, tetraazole, thiophene, oxazole, thiazole, or thiadiazole. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyrrole, imidazole, oxazole, triazole, thiazole, or thiadiazole. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyrrole, imidazole, oxazole, or thiadiazole. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyrrole. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is imidazole. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is thiadiazole. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is oxazole.

[0337] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), ring G is:

[0338] , , , , , , , , , , , , , , , , , , , , or ;

[0339] in,

[0340] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl are each optionally selected independently from 1 to 4 members of R e Substituents of the substituents;

[0341] Each R 10a Independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents; and

[0342] q can be 0, 1, 2 or 3.

[0343] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'): each R10 is independently a halogen, -CN, -NO2, -OH, -ORa, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; each R 10a It is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl; and p is 0, 1 or 2.

[0344] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for:

[0345] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .、 , , , , , , , , , , , , , , , , or .

[0346] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for:

[0347] , , , , , , , , , , , , , , , , , , , , , , , , , .、 , , , or .

[0348] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for:

[0349] , , , , , , , , , , , , or .

[0350] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for: , , or In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), for: In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), for: In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), for: In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), for: .

[0351] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is optionally composed of 1 to 4 rings selected from R. 10 The substituents are substituted into the 6-membered heteroaryl group.

[0352] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyridine, pyrimidine, or triazine. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is pyrimidine. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is triazine.

[0353] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), ring G is:

[0354] , , , , , , , , , or ;

[0355] in,

[0356] Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl are each optionally selected independently from 1 to 4 members of R e Substituents; and

[0357] q can be 0, 1, 2 or 3.

[0358] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for: , , , , , , , , or .

[0359] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G comprises 1 to 3 heteroatoms selected from N, O, and S, and is optionally surrounded by 1 to 4 heteroatoms selected from R. 10 The 8- to 10-membered bicyclic heteroaryl group is substituted with substituents. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is a heteroatom comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 to 4 heteroatoms selected from R. 10 The 10-membered bicyclic heteroaryl group is substituted with substituents. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is a heteroatom comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 to 4 heteroatoms selected from R. 10The 8-membered bicyclic heteroaryl group is substituted with substituents. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), ring G is a heteroatom comprising 1 to 3 heteroatoms selected from N, and optionally substituted with 1 to 4 heteroatoms selected from R. 10 The substituents are substituted into the 8-membered bicyclic heteroaryl group.

[0360] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), ring G is imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, pyrazo[1,5-a]pyrimidine, pyrazo[1,5-a]pyrimidine or 2-methyl-2H-indazole.

[0361] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), for , , , , , , or .

[0362] In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently -CN, -NO2, -OH, -OR a or -NRc R d In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10 Independently -OH or -OR a In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10 Independently -OH or -OMe. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently, it is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10 Independently, it is a halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10 Independently, it is a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of formula (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently, each R is a C1-C6 haloalkyl group. In some embodiments of formula (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R10 Independently -CF3 or -CHF2. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently, each R is a C1-C6 alkyl group. In some embodiments of formula (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb), (IV), or (IV'), each R 10 Independently, it is methyl. In some embodiments of formula (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently halogenated. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently, it is fluorine or chlorine. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 Independently, it is fluorine. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10 It is chlorine on its own.

[0363] In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10Independently -F, -Cl, -CN, methyl, ethyl, -OCH3, -CF3, -CHF2, or -CH2F. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10 It can be -F, -Cl, methyl, -CF3 or -CHF2 independently.

[0364] In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), the two R 10 Together they form an oxygen group.

[0365] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is a C3-C6 cycloalkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10a Independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently cyclopropyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently cyclopropyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10aIndependently, it is a 4- to 6-membered heterocyclic alkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is a 4-membered heterocyclic alkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is a 5-membered heterocyclic alkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is a 6-membered heterocyclic alkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10a Independently, it is oxatanyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, each R is a C1-C6 haloalkyl group. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), each R 10a Independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, each R is a C1-C6 alkyl group. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10aIndependently, it is methyl. In some embodiments of formula (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a It is hydrogen independently.

[0366] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), each R 10a Independently, it is hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CF3, CHF2, CH2F, -CH2CF3, -CH2SO2CH3, cyclopropyl, oxetyl, , or .

[0367] In some embodiments of equations (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is an integer from 1 to 9. In some embodiments of equations (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is an integer from 1 to 8. In some embodiments of equations (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is an integer from 1 to 6. In some embodiments of equations (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is an integer from 1 to 4. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1, 2, 3, 4, 5, or 6. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1, 2, 3, or 4. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is 1, 2, 3, 4, 5, or 6. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is 1, 2, or 3. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), p is 1, 2, 3, 4, 5, or 6.In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1 or 2. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1, 2, 3, 4, 5, or 6. In some embodiments of formulas (I'), (I), (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 2. In some embodiments of formulas (I'), (I), (II), (II'), (III), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV) or (IV'), p is 1.

[0368] In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 1, 2, or 3. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 3. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 1 or 2. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 2. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 1. In some embodiments of formulas (II), (II'), (III), (III'), (IIIa), (IIIa'), (IIIb), (IIIb'), (IV), or (IV'), q is 0.

[0369] In some embodiments of the compounds disclosed herein, each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents are substituted. In some embodiments of the compounds disclosed herein, each R a Independently, each R is a C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocyclic alkyl. In some examples of the compounds disclosed herein, each R a Independently, each R is a C1-C6 alkyl or C1-C6 haloalkyl. In some examples of the compounds disclosed herein, each R a Independently, each R is a C1-C6 alkyl group. In some examples of the compounds disclosed herein, each R a Independently methyl, ethyl, isopropyl, tert-butyl, -OCH3, -CF3, or -CHF2, in some examples of the compounds disclosed herein, each R a It can be methyl, ethyl, isopropyl or tert-butyl independently.

[0370] In some embodiments of the compounds disclosed herein, each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocyclic alkyl. In some examples of the compounds disclosed herein, each R... b Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some examples of the compounds disclosed herein, each R... b Independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b All are hydrogen. In some embodiments of the compounds disclosed herein, each R b Independently, each R is a C1-C6 alkyl group. In some examples of the compounds disclosed herein, each R bIndependently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -OCH3, -CF3, or -CHF2, in some examples of the compounds disclosed herein, each R b Independently, it is hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of the compounds disclosed herein, each R... b It can be hydrogen or methyl on its own.

[0371] In some embodiments of the compounds disclosed herein, R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents are substituted. In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some examples of the compounds disclosed herein, each R... c and R d Independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d All are hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d Independently, each R is a C1-C6 alkyl group. In some examples of the compounds disclosed herein, each R c and R d Independently, R is methyl, ethyl, isopropyl, tert-butyl, -OCH3, -CF3, or -CHF2. In some examples of the compounds disclosed herein, each R... c and R d Independently, it is hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen or methyl. In some embodiments of the compounds disclosed herein, each R... c and R d It is a methyl group.

[0372] In some embodiments of the compounds disclosed herein, each R eIndependently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -CH2S(=O)2CH3, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R e Independently, each R is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl. In some examples of the compounds disclosed herein, each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -C(=O)C1-6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -NHC(=O)C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments, R e It is a -NHC(=O)C1-3 alkyl group, for example -NHC(=O)CH3. In some embodiments of the compounds disclosed herein, each R e It is independently a halogen, -CN, -OH, or C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R... e It is independently a halogen, -OH, or C1-C6 alkyl group. In some examples of the compounds disclosed herein, each R... e Independently, it is a halogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R...e Independently, it is a halogen. In some embodiments of the compounds disclosed herein, each R... e Independently -Cl or -F. In some embodiments of the compounds disclosed herein, each R... e Independently, it is a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments, each R e Independently, it is -F, -Cl, -OH, -CH2S(=O)2CH3, methyl, ethyl, isopropyl, tert-butyl, -OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or aziridine, oxybutane, piperidine, piperazine, or morpholine. In some embodiments, each R e Independently, it is -F, -OH, -CF3, -CHF2, -OCH3, or methyl. In some embodiments, each R e Independently -F, -CF3, -CHF2, or methyl. In some embodiments, each R e All are methyl groups.

[0373] In some embodiments of the compounds disclosed herein, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 10a R a R b R c R d and R e One or more of the groups contain a percentage of deuterium higher than the natural abundance of deuterium.

[0374] In some embodiments of the compounds disclosed herein, one or more of the following groups 1 H is replaced by one or more deuteriums: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R9 R 10 R 10a R a R b R c R d and R e .

[0375] In some embodiments of the compounds disclosed herein, molar ratio R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 10a R a R b R c R d and R e The deuterium abundance in each of them is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0376] This document considers any combination of groups described above for various variables. Throughout this specification, groups and their substituents are selected by those skilled in the art to obtain stable moieties and compounds.

[0377] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts or solvates are one of the compounds in Table 1A, Table 1B or Table 1C.

[0378] Table 1A.

[0379] Table 1B.

[0380] Table 1C.

[0381] C. Other forms of the compounds disclosed herein

[0382] Isomers / stereoisomers

[0383] In some embodiments, the compounds described herein exist in geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (R), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, each center existing in an R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomeric compounds produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomeric compounds, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, diastereomers are separated by chiral chromatography.

[0384] Labeled compounds

[0385] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but with one or more atoms replaced by atoms whose atomic mass or mass number differs from that commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H (D), 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes described herein containing the aforementioned isotopes and / or other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotope-labeled compounds, such as those incorporating radioactive isotopes (e.g., 3 H and 14 Compounds of type C) can be used for drug and / or substrate tissue distribution analysis. Tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0386] In some embodiments, the deuterium abundance in each of the substituents disclosed herein, on a molar basis, is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%. In some embodiments, one or more of the substituents disclosed herein contain a percentage of deuterium higher than the natural abundance of deuterium. In some embodiments, one or more of the substituents disclosed herein... 1 H is replaced by one or more deuterium atoms.

[0387] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0388] Pharmaceutically acceptable salts

[0389] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering these pharmaceutically acceptable salts as pharmaceutical compositions.

[0390] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified, free compounds with suitable acids or bases and separating the resulting salts.

[0391] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases. These salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, gluconate, glyceryl phosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, and γ-hydroxybutyrates. Salts, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malonates, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmitates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pentanoates, propionates, pyrosulfates, pyrophosphates, propionates, phthalates, phenylacetates, phenylbutyrates, sodium propanesulfonate, salicylates, succinates, sulfates, sulfites, succinates, octanoates, sebacic acid salts, sulfonates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and xylenesulfonates.

[0392] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts, which are formed by reacting the free base form of the compounds with a pharmaceutically acceptable inorganic or organic acid, including but not limited to: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, etc. Citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (e.g., oxalic acid), although not pharmaceutically acceptable on their own, are used to prepare salts that can be used as intermediates to obtain the compounds, solvates, or stereoisomers thereof described herein, and their pharmaceutically acceptable acid addition salts.

[0393] In some embodiments, the compounds comprising free acid groups described herein react with a suitable base (e.g., hydroxide, carbonate, bicarbonate, sulfate) of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2O. + (C 1-4 Alkyl)4, etc.

[0394] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0395] solvates

[0396] In some embodiments, the compounds described herein are present in the form of solvates. In some embodiments, this disclosure provides a method of treating a disease by applying compounds in these solvate forms. In some embodiments, this disclosure provides a method of treating a disease by applying a composition comprising compounds in these solvate forms. The solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, the solvates are formed during crystallization using pharmaceutically acceptable solvents.

[0397] tautomer

[0398] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In the bond arrangement where tautomerism is possible, a chemical equilibrium of tautomers will exist. Consider all tautomer forms of the compounds disclosed herein. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0399] Treatment

[0400] This article discloses a method for treating neurodegenerative diseases or conditions in patients in need, the method comprising administering to the patient a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof.

[0401] In some embodiments, the neurodegenerative disease or condition is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxia. In some embodiments, the neurodegenerative disease or condition is Alzheimer's disease. In some embodiments, the neurodegenerative disease or condition is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease or condition is Huntington's disease. In some embodiments, the neurodegenerative disease or condition is Parkinson's disease. In some embodiments, the neurodegenerative disease or condition is a prion disease. In some embodiments, the neurodegenerative disease or condition is spinocerebellar ataxia.

[0402] Dosage

[0403] In some embodiments, a composition containing the compounds described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or symptom in an amount sufficient to cure or at least partially stop at least one symptom of the disease or symptom. The effective amount for this purpose depends on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may optionally be determined by a method, including but not limited to dose escalation and / or dose range clinical trials.

[0404] In some embodiments where the patient’s condition does not improve, the compound is administered long-term, i.e., for a prolonged period of time, including the patient’s entire lifespan, based on the physician’s judgment, to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0405] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in specific embodiments, the dose or frequency of administration, or both, is reduced based on symptoms.

[0406] The amount of a given agent corresponding to this type of quantity varies depending on factors such as: the specific compound, the disease symptom and its severity, the identity of the individual or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the situation, including, for example, the specific agent administered, the route of administration, the symptom being treated, and the individual or host being treated.

[0407] In some embodiments, the dosage for treatment in adults is typically in the range of 0.01 mg to 5000 mg per day. In some embodiments, the daily dose suitable for the compounds described herein or pharmaceutically acceptable salts thereof is about 0.01 to about 50 mg / kg body weight. In various embodiments, the daily dose and unit dose vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's requirements, the severity of the disease or condition being treated, and the practitioner's judgment.

[0408] Application route

[0409] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nasal, and topical administration. Additionally, to name just a few examples, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0410] In some embodiments, compounds as described herein are administered locally rather than systemically, such as by direct injection into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in the form of a targeted drug delivery system, such as liposomes coated with organ-specific antibodies. In these embodiments, the liposomes target the organ and are selectively absorbed by the organ. In yet another embodiment, the compounds as described herein are provided in the form of a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation.

[0411] Pharmaceutical Compositions / Formulations

[0412] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In some embodiments, the compounds described herein are administered to animals.

[0413] On the other hand, this document provides pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that promote the processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, the following: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, (NY, 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0414] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0415] Example

[0416] The following examples are provided to illustrate the claimed invention, but are not intended to limit the scope of the invention. The examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0417] The following collective procedures are provided for illustrative and not limiting purposes. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to prepare them in a similar manner as described below, using appropriate starting materials and modifying the synthetic route as needed. Generally, starting materials and reagents are available from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0418] The compounds and salts of formulas (I), (II), (III), (IIIa), (IIIb), and (IV) can be synthesized according to one or more illustrative procedures described herein and / or techniques known in the art. The materials used herein may be commercially available or prepared by synthetic methods generally known in the art. These procedures are not limited to the compounds listed in the examples or any specific substituents used for illustrative purposes. Although various steps are described and depicted in the synthetic procedures below, in some cases, the steps may be performed in a different order than shown below. Numbers or R groups in the procedures do not necessarily correspond to numbers or R groups in the claims or other procedures or tables herein.

[0419] abbreviation

[0420] AcOH: Acetic acid

[0421] Boc2O: Ditert-butyl dicarbonate

[0422] MeCN or ACN: Acetonitrile

[0423] DavePhos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

[0424] DCC: N,N'-Dicyclohexylcarbodiimide

[0425] DCM: Dichloromethane

[0426] DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

[0427] Dioxane: 1,4-Dioxane

[0428] DIPEA: N,N-Diisopropylethylamine

[0429] DMF dimethylformamide

[0430] DMSO dimethyl sulfoxide

[0431] EDCl: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0432] eq equivalent

[0433] Ethyl acetate (EtOAc)

[0434] Et3N: Triethylamine

[0435] g grams

[0436] h hours

[0437] HATU: Hexafluorophosphate, aziridinetriazole, tetramethylureaium

[0438] HOBT: 1-Hydroxybenzotriazole

[0439] HOSu: N-hydroxysuccinimide

[0440] LCMS: Liquid Chromatography-Mass Spectrometry

[0441] LAH: Lithium Aluminum Hydrogenation

[0442] MeOH: Methanol

[0443] mg mg

[0444] min minutes

[0445] mL / ml

[0446] mmol millimole

[0447] MS mass spectrometry

[0448] MTBE: Methyl tert-butyl ether

[0449] NCS: N-chlorosuccinimide

[0450] NMR: Nuclear Magnetic Resonance

[0451] PCC: Pyridinium Chlorochromate

[0452] Pd: Palladium

[0453] Pd2(dba)3: Tris(diphenylmethylacetone)dipalladium

[0454] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0455] RP-HPLC: Reverse high performance liquid chromatography

[0456] rt or RT: Room temperature, ambient temperature, approximately 25°C

[0457] THF: Tetrahydrofuran

[0458] TLC: Thin-layer chromatography

[0459] Example 1. Synthesis of 2-(6-(((1S,3R,5R)-2,2-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 82)

[0460] Process 1.

[0461]

[0462] Step 1: At -65°C, LiHMDS (15.8 mL, 15.8 mmol) was added to a solution of 2-methylpropyl-2-yl 1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid (2.50 g, 9.87 mmol) in THF (30 mL). The reaction mixture was stirred for 1.5 h, followed by the addition of TMSCl (1.6 mL, 12.83 mmol), and the reaction mixture was stirred again at -78°C for 2 h. After the reaction mixture was consumed, it was diluted with EA and H2O. The organic layer was separated, washed with a separate saturated NaCl solution, and concentrated under vacuum to give 1,5-dimethyl-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid 2-methylpropyl-2-yl ester (3.0 g, 93.4%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI, cation) m / z 326.5 [M+H] + .

[0463] Step 2: Selectfluor (5.24 g, 14.8 mmol) was added to a solution of 1,5-dimethyl-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]octane-2-en-8-carboxylic acid 2-methylpropyl-2-yl ester (3.0 g, 9.22 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred overnight at room temperature. After the reactants were consumed, the mixture was quenched with water and then diluted with EA (100 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH = 20 / 1 to give (1R,4S,5S)-4-fluoro-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (1.8 g, 71.98%) as a white solid. MS (ESI, cation) m / z 272.3 [M+H] + .

[0464] Step 3: 2-methylpropyl-2-yl ester of (1R,4S,5S)-4-fluoro-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid (1.3 g, 4.79 mmol) was dissolved in THF (30 mL), and LiHMDS (7.67 mL, 7.67 mmol) was added at 80 °C. The reaction mixture was stirred at -65 °C for 1.5 h, followed by the addition of TMSCl (0.79 mL, 6.23 mmol). The reaction mixture was then stirred at -78 °C for another 2 h. After the reaction mixture was consumed, it was diluted with EA and H2O. The organic layer was separated, washed with a separate saturated NaCl solution, and concentrated under vacuum to give (1S,5R)-2-fluoro-1,5-dimethyl-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid 2-methylpropyl-2-yl ester (1.6 g, 97.22%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI, cation) m / z 343.5 [M+H] + .

[0465] Step 4: Selectfluor (1.65 g, 4.66 mmol) was added to a solution of 1,5-dimethyl-3-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid 2-methylpropyl-2-yl ester (1.6 g, 4.66 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred overnight at room temperature. After the reactants were consumed, the mixture was quenched with water and diluted with EA (100 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH=20 / 1 to give (1S,5R)-2,2-difluoro-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (837 mg, 3.04 mmol, 65.39%) as a white solid. MS (ESI, cation) m / z 276.3 [M+H] + .

[0466] Step 5: Dissolve (1S,2S,4R,5R)-2,4-difluoro-5-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (200 mg, 0.69 mmol) in EtOH (1–5 mL), and add NaBH4 (32 mg, 0.83 mmol) at 80 °C. Reflux the reaction mixture for 3 h. After the reaction mixture is consumed, cool the mixture to room temperature, quench with water, and dilute with EA (50 mL). Wash the mixture with brine, collect the organic layer, dry it with sodium sulfate, and concentrate it under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH to give (1S,3R,5R)-2,2-difluoro-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg, 0.29 mmol, 39.71%) as a white solid. MS (ESI, cation) m / z 291.1 [M+H] + .

[0467] Step 6: Add NaH (16.5 mg, 0.41 mmol) to a solution of (1S,2S,4R,5R)-2,4-difluoro-3-hydroxy-5-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (80 mg, 0.29 mmol) in THF (6 mL), and stir the reaction mixture for 20 min. Next, add 3,6-dibromo-1,2-diazine (85 mg, 0.35 mmol), and stir the reaction mixture overnight at room temperature. After the reactants are consumed, cool the mixture to room temperature, quench with water, and dilute with EA (50 mL). Wash the mixture with brine, collect the organic layer, dry it with sodium sulfate, and concentrate it under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH to give (1S,3R,5R)-3-((6-bromopyridazin-3-yl)oxy)-2,2-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (55 mg, 40.62%) as a white solid. MS (ESI, cation) m / z 449.3 [M+H] + .

[0468] Step 7: Add (1R,2R,3s,4S,5S)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-2,4-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (55 mg, 0.12 mmol), XantPhos Pd G4 (11.81 mg, 0.01 mmol), and Cs2CO3 (119.91 mg, 0.37 mmol) to a solution of 6-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (28 mg, 0.12 mmol) in dioxane (6 mL), and stir the reaction mixture overnight at 90 °C. After the reactants are consumed, dilute them with EA and H2O. The organic layer was separated, washed with a separate saturated NaCl solution, concentrated under vacuum, and then purified by silica gel column chromatography with DCM / MeOH elution to give (1S,3R,5R)-3-((6-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridazin-3-yl)oxy)-2,2-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15 mg, 0.03 mmol, 20.53%). MS (ESI, cation) m / z 596.6 [M+H] + .

[0469] Step 8: Dissolve 3-({6-[6-(1,3-dimethylpyrazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-2-yl]-1,2-diazin-3-yl}oxy)-2,4-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (15 mg, 20.53%) in HCl (5 mL, in dioxane). Stir the reaction mixture at room temperature for 3 h. After the reactants are consumed, concentrate them under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH to give 2-(6-(((1S,3R,5R)-2,2-difluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (8.9 mg, 71.2%) as a white solid.

[0470] 1 H NMR (DMSO-d6) δ = 8.99 (s, 1H), 8.76 (br d, J = 9.6 Hz, 1H), 8.39(s, 1H), 7.90 (s, 1H), 7.49 (br d, J = 9.8 Hz, 1H), 5.72-5.84 (m, 1H), 5.25(s, 2H), 3.82 (s, 3H), 2.48 (s, 3H), 2.27-2.40 (m, 2H), 1.81-2.03 (m, 2H), 1.60-1.66 (m, 2H), 1.22 (s, 6H). LC / MS (ESI): 496.5 [M+H] + .

[0471] Example 2. Synthesis of 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(6-(((1S,2R,3R,5R)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 215)

[0472] Process 2.

[0473]

[0474] Step 1: Add NaH (15.80 mg, 0.66 mmol) to a solution of (1S,3S,4S,5R)-4-fluoro-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (120 mg, 0.44 mmol) in THF (6 mL). Stir the reaction mixture for 20 min, and then add 3,6-dibromo-1,2-diazine (156.64 mg, 0.66 mmol). Stir the reaction mixture further overnight at room temperature. After the reactants are consumed, cool the mixture to room temperature, quench with water, and dilute with EA (50 mL). Wash the mixture with brine, collect the organic layer, dry it with sodium sulfate, and concentrate it under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH to give (1S,3S,4S,5R)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-4-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (50 mg, 26.47%) as a white solid.

[0475] MS (ESI, cation) m / z 431.3 [M+H]+. ¹H NMR (chloroform-d) δ = 7.43 (d, ¹H, J = 9.2 Hz), 6.81 (d, ¹H, J = 9.2 Hz), 5.48–5.61 (m, ¹H), 4.62 (dd, ¹H, J = 51.0, 8.4 Hz), 2.37–2.44 (m, ¹H), 1.97–2.09 (m, ¹H), 1.67–1.89 (m, ³H), 1.54–1.59 (m, ¹H), 1.49 (s, ³H), 1.45 (s, ³H), 1.42 (s, 9H).

[0476] Step 2: Add (1S,3S,4S,5R)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-4-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (43.36 mg, 0.10 mmol), XantPhos Pd G4 (9.70 mg, 0.01 mmol), and Cs2CO3 (98.33 mg, 0.30 mmol) to a solution of 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (23 mg, 0.10 mmol) in dioxane (6 mL). Stir the reaction mixture overnight at 90 °C. After the reactants are consumed, dilute them with EA and H2O. The organic layer was separated, washed with saturated NaCl solution, concentrated under vacuum, and then purified by silica gel column chromatography with DCM / MeOH elution to give (1R,2S,5S)-3-({6-[3-(1,3-dimethylpyrazol-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-6-yl]-1,2-diazin-3-yl}oxy)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (13 mg, 22.33%). MS (ESI, cation) m / z 578.7 [M+H] + .

[0477] Step 3: Dissolve 13 mg (0.02 mmol) of 2-methylpropyl-2-yl octane-8-carboxylic acid (1R,2R,5S)-3-({6-[3-(1,3-dimethylpyrazol-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-6-yl]-1,2-diazin-3-yl}oxy)-2-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid in HCl (5 mL in dioxane) and stir the reaction mixture at room temperature for 3 h. After the reactants are consumed, concentrate the mixture under vacuum. Next, the crude mixture was purified by silica gel column chromatography with DCM / MeOH to give 3-(1,3-dimethylpyrazol-4-yl)-6-(6-{[(1S,4S,5R)-4-fluoro-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]oxy}-1,2-diazin-3-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (8 mg, 0.02 mmol, 74.44%) as a white solid.

[0478] 1H NMR (DMSO-d6) δ = 8.95-9.02 (m, 1H), 8.75 (d, J = 9.6 Hz, 1H), 8.13-8.26 (m, 3H), 7.43 (d, J = 9.6 Hz, 1H), 5.43-5.57 (m,1H), 5.19 (s, 2H), 4.34-4.77 (m, 1H), 3.83 (s, 3H), 2.37 (s, 3H), 1.95-2.23 (m, 2H), 1.67-1.95(m, 2H), 1.50-1.64 (m, 2H), 1.22 (s, 6H). LC / MS (ESI): 478.2 [M+H] + .

[0479] Example 3. Synthesis of 2-(6-(2,7-diazaspiro[3.5]nonane-2-yl)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoroisoindoline-1-one (Compound No. 154)

[0480] Step 3.

[0481]

[0482] Step 1: Add DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 eq) to a solution of (2S)-2-({[(9H-fluorene-9-ylmethyl)oxy]carbonyl}amino)-3,3-dimethylbutyric acid (10 g, 28.29 mmol, 1.0 eq) and methyl glycine (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL), and then stir the reaction mixture at room temperature for 16 h. After the reactants were consumed, the reaction mixture was filtered to give a pale yellow solid, {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-ylmethyl ester (9.5 g, 22.38 mmol, 79.09%). MS m / z 425.5 [M+H] + .

[0483] Step 2: A solution of {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-yl methyl ester (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred at room temperature for 16 h. After the reactants were consumed, the solution was concentrated under vacuum to give a yellow solid of {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-yl methyl ester (4.85 g, 11.43 mmol, 97.00%). MS m / z 171.2 [M+H] + .

[0484] Step 3: In an ice bath, LiAlH4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorously stirred solution of (3S)-3-(2-methylpropyl-2-yl)piperazine-2,5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL), and the mixture was further stirred at 70 °C for 16 h. After the reactants were consumed, the mixture was poured into KOH (6N) in an ice bath. The resulting mixture was further stirred for 1 h, filtered, and the filtrate was collected. The filtrate was extracted with EA, washed with brine, dried over Na2SO4, and concentrated under vacuum to give (2S)-2-(2-methylpropyl-2-yl)piperazine (1.2 g, 8.44 mmol, 89.74%) as a yellow oil. MS m / z 143.2 [M+H] + .

[0485] Step 4: At room temperature, DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorously stirred solution of (2S)-2-(2-methylpropyl-2-yl)piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3,6-diiodo-1,2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL), and the mixture was stirred at 120 °C for 16 h. After the reactants were consumed, the mixture was concentrated under vacuum to obtain a residue, which was diluted with EA, washed with water and brine, dried over Na2SO4, and concentrated under vacuum to give 6-iodo-3-[(3S)-3-(2-methylpropyl-2-yl)piperazin-1-yl]-1,2-diazine (450 mg, 1.30 mmol, 36.98%) as a yellow solid. MS m / z 347.2 [M+H] + .

[0486] Step 5: Pd(dppf)Cl2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorously stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (250 mg, 1.20 mmol, 1.0 eq), 3-bromo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq), and K2CO3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using DCM / MeOH 10 / 1 v / v to give 3-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (135 mg, 0.63 mmol, 52.51%) as a pale yellow solid. MS m / z 215.2 [M+H] + .

[0487] Step 6: 6-(1-methylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (50 mg, 0.23 mmol, 1.0 eq) and 6-iodo-3-[(3S)-3-(2-methylpropyl-2-yl)piperazin-1-yl]-1,2-diazine (80 mg, 0.23 mmol, 1.0 eq) were dissolved in DMF (2 mL), and CuI (4 mg, 0.02 mmol, 0.10 eq), K2CO3 (97 mg, 0.70 mmol, 3.0 eq) and (1R,2R)-cyclohexane-1,2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) were added, and the reaction mixture was stirred at 100 °C for 16 h. After the reactants were consumed, the mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by pre-HPLC to obtain 2-{6-[(3S)-3-(2-methylpropyl-2-yl)piperazin-1-yl]-1,2-diazin-3-yl}-6-(1-methylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (24.19 mg, 21.55%) as a white solid.

[0488] 1H NMR (400 MHz, DMSO-d6) δ = 9.12 (d, J = 2.0 Hz, 1H), 8.48 (d, J =9.9 Hz, 1H), 8.44 (s, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.18 (s, 1H), 8.14 (s,1H), 7.46 (d, J = 10.0 Hz, 1H), 5.13 (s, 2H), 4.39 - 4.31 (m, 1H), 4.10 (brd, J = 12.0 Hz, 1H), 3.89 (s, 3H), 3.08 - 3.03 (m, 1H), 2.86 - 2.55 (m, 3H),2.35 - 2.31 (m, 1H), 0.96 (s, 9H). LC / MS (ESI): 433.5 [M+H] + .

[0489] Example 4. Synthesis of 6-(6-((4-azabispiro[2.1.25.33]decane-9-yl)oxy)pyridazin-3-yl)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 232)

[0490] Step 4.

[0491]

[0492] Step 1: 5 mL of MeOH containing spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-one (500 mg, 3.31 mmol) was added to a 100 mL round-bottom flask. NaBH4 (0.18 mL, 4.96 mmol) was then added at 0 °C for 5 min, yielding a grayish-white suspension. The resulting mixture was stirred at room temperature for 1 h. LC-MS showed the desired MS (M+H: 154.1). The mixture was cooled to 0 °C and quenched with HCl (2 M, 0.5 mL), followed by concentration under vacuum. The resulting mixture was added to a silica gel column and eluted with DCM:MeOH (20:1) (0.1% TEA). Spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-ol (475 mg, 2.98 mmol, 90.00%) was obtained as a yellow solid. MS (ESI, cation) m / z 154.1 [M+H] + .

[0493] Step 2: At 0 °C, NaH (270.20 mg, 4.50 mmol) was added to a solution of spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-ol (460 mg, 3.00 mmol) in THF (10 mL), and the resulting mixture was stirred at room temperature for 30 min. Next, 3,6-dibromo-1,2-diazine (928.42 mg, 3.90 mmol) was added at 0 °C, and the resulting mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), and the aqueous layer was extracted with EA (50 mL x 3). The organic layer was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, PE:EA = 0–50%, 30 min) to obtain 7-[(6-bromo-1,2-diazin-3-yl)oxy]spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane] (360 mg, 1.11 mmol, 37.11%). MS (ESI, cation) m / z 310.05 [M+H] + .

[0494] Step 3: Under nitrogen atmosphere, add 7-[(6-bromo-1,2-diazin-3-yl)oxy]spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane] (50 mg, 0.16 mmol), Cs₂CO₃ (157.56 mg, 0.48 mmol), and 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b] ... The residue was dissolved in DCM (3 mL), and ACN (2 mL) was added dropwise to obtain a white slurry. The off-white solid was filtered to give 3-(1,3-dimethylpyrazol-4-yl)-6-[6-(spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-yloxy)-1,2-diazin-3-yl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (4 mg, 0.01 mmol, 5.05%) as an off-white solid.

[0495] MS (ESI, cation) m / z 458.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ = 8.89 -8.79 (m, 2H), 8.14 (d, J = 1.9 Hz, 1H), 7.56 (s, 1H), 7.05 (d, J = 9.6 Hz,1H), 5.75 - 5.65 (m, 1H), 5.28 (s, 2H), 3.92 (s, 3H), 2.44 (s, 3H), 2.02 -1.89 (m, 2H), 1.86 - 1.77 (m, 2H), 0.75 - 0.52 (m, 6H), 0.46 - 0.39 (m, 2H).

[0496] Example 5. Synthesis of 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 162)

[0497] Step 5.

[0498]

[0499] Step 1: Amyl nitrite (2.18 mL, 18.29 mmol) was added to a solution of 6-bromo-1,2,4-triazine-3-amine (2.0 g, 11.43 mmol) and CuCl2 (1.47 g, 14.86 mmol) in MeCN (25 mL), and the reaction mixture was stirred at 70 °C for 2 h. Next, the reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, PE:EA = 10:1) to give 6-bromo-3-chloro-1,2,4-triazine (220 mg, 1.13 mmol, 9.90%) as a yellow solid.

[0500] Step 2: DIEA (0.34 mL, 2.06 mmol) was added to a solution of 6-bromo-3-chloro-1,2,4-triazine (200 mg, 1.03 mmol) and 2,2,6,6-tetramethyl-4-(methylamino)hexahydropyridine (192.71 mg, 1.13 mmol) in toluene (10 mL), and the reaction mixture was stirred at 120 °C for 3 h. LCMS showed that the reaction was complete. Next, the reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, DCM:MeOH = 10:1) to give 6-bromo-3-[methyl(2,2,6,6-tetramethylhexahydropyridine-4-yl)amino]-1,2,4-triazine (0.23 g, 67.65%) as a yellow solid.

[0501] Step 3: BrettPhos Pd G4 (13.61 mg, 0.01 mmol) and Cs2CO3 (146.62 mg, 0.45 mmol) were added to a solution of 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (35 mg, 0.15 mmol) and 6-bromo-3-[methyl(2,2,6,6-tetramethylhexahydropyridin-4-yl)amino]-1,2,4-triazine (52 mg, 0.16 mmol) in dioxane (10 mL). The reaction mixture was stirred at 90 °C under N2 for 16 h. LCMS showed that the reaction was complete. The reaction mixture was then filtered and concentrated. The residue was purified by prep-HPLC (TFA) to give 3-(1,3-dimethylpyrazol-4-yl)-6-{3-[methyl(2,2,6,6-tetramethylhexahydropyridin-4-yl)amino]-1,2,4-triazin-6-yl}-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (8 mg, 10.97%) as a yellow solid.

[0502] MS (ESI, cation) m / z: 476.3 [M+H] + . 1 ¹H NMR (400 MHz, DMSO-d⁶) δ = 9.41 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.22 - 8.14 (m, 2H), 5.14 (m, 3H), 3.83 (s, 3H), 3.09 (s, 3H), 2.35 (s, 3H), 1.99 - 1.82 (m, 4H), 1.51 (s, 6H), 1.43 (s, 6H), ¹H not observed (NH).

[0503] Example 6. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)(methyl)amino)pyridazin-3-yl)-4-fluoroisoindoline-1-one (Compound No. 274)

[0504] Step 6.

[0505]

[0506] Step 1: Under N2 at 0°C, nitrosonium tetrafluoroborate (480 mg, 4.10 mmol) was added fractionally to a solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL) to obtain a yellow solution, which was stirred at 0°C for 1 h. Then, oxylene (30 mL) was added, and the reaction mixture was refluxed at 130°C for 3 h. Next, the reaction mixture was cooled to room temperature and poured into H2O. The aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography using PE / EA 10 / 1v / v to give methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%).

[0507] Step 2: AIBN (57 mg, 0.35 mmol) was added to a solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl)benzene (10 mL). The reaction mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was then cooled to room temperature and poured into H2O. The aqueous layer was extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 70%).

[0508] Step 3: Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 2.5 mmol) was dissolved in THF (7 mL), and NH4OH (7 mL) was added. The reaction mixture was stirred at room temperature for 4 h, then filtered and concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0509] Step 4: Potassium carbonate (118 mg, 0.86 mmol) and PdCl2 (dppf) (31 mg, 0.043 mmol) were added to a solution of 6-bromo-4-fluoroisoindoline-1-one (100 mg, 0.43 mmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (96 mg, 0.43 mmol) in dioxane:H2O (5:1) (2 mL:0.4 mL). The reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA. The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoroisoindolin-1-one (85 mg, 81%) as a yellow solid.

[0510] MS m / z 231.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.51 - 8.33 (m, 2H), 8.04 (s, 1H), 7.64 - 7.60 (m, 1H), 7.55 (d, J = 10.3 Hz, 1H), 7.31 (d, J =10.0 Hz, 1H), 5.13 (s, 2H), 5.11 - 5.03 (m, 1H), 3.81 (s, 3H), 2.90 (s, 3H), 2.36 (s, 3H), 2.16 (br d, J = 8.1 Hz, 2H), 2.03 - 1.87 (m, 4H), 1.80 (br dd,J = 5.4, 13.6 Hz, 2H), 1.45 (s, 6H).

[0511] Example 7. Synthesis of 6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyridazin-3-yl)-2-(2,4-dimethylthiazo-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Compound No. 111)

[0512] Step 7.

[0513]

[0514] Step 1: At room temperature, MeI (5.41 mL, 86.92 mmol) was added to a mixture of 2-chloro-5-methylpyrimidin-4-carboxylic acid (5.0 g, 28.97 mmol) and K₂CO₃ (8.01 g, 57.95 mmol) in DMF (10 mL), and the mixture was stirred for 16 h. After the reaction was complete, the mixture was filtered, quenched with H₂O, and extracted with EA. The combined organic layers were washed with aqueous NaCl solution, dried over Na₂SO₄, and concentrated. The resulting residue was purified by silica gel chromatography (PE:EA = 5:1) to give 2-chloro-5-methylpyrimidin-4-carboxylic ester (5.0 g, 92.49%) as a white solid.

[0515] Step 2: At room temperature and under N2, NBS (6.20 g, 34.84 mmol) and AIBN (0.44 g, 2.68 mmol) were added to a mixture of methyl 2-chloro-5-methylpyrimidin-4-carboxylate (5.0 g, 26.80 mmol) in CCl4 (100 mL), and the resulting mixture was stirred at 95 °C for 2 h. Next, NBS (2.38 g, 13.40 mmol) was added, and the mixture was stirred at 95 °C for 1 h. Then, NBS (1.43 g, 8.04 mmol) was added, and the mixture was stirred at 95 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with H2O, and extracted with DCM. The combined organic layers were washed with aqueous NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 5:1) to obtain 5-(bromomethyl)-2-chloropyrimidine-4-carboxylate (4.0 g, 56.26%) in oil form.

[0516] Step 3: The mixture of methyl 5-(bromomethyl)-2-chloropyrimidin-4-carboxylate (4.0 g, 15.07 mmol) and NH3-dioxane (30 mL) was stirred at room temperature for 1 h. LCMS analysis showed that the reaction was complete. The mixture was filtered and concentrated to give 1.3 g, 50.98%, of 2-chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-7-one as a red solid.

[0517] Step 4: At room temperature and under N2, PdCl2(dppf)CH2Cl2 (52.98 mg, 0.06 mmol) and K2CO3 (268.95 mg, 1.95 mmol) were added to a mixture of 2-chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-7-one (110 mg, 0.65 mmol) and 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3-thiazole (201.67 mg, 0.84 mmol) in dioxane:H2O=5:1 (6 mL), and the mixture was stirred at 95 °C for 3 h. LCMS analysis showed that the reaction was complete. Next, the mixture was concentrated, and the residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give 2-(2,4-dimethyl-1,3-thiazolyl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-7-one (0.1 g, 62.50%) as a yellow solid.

[0518] Step 5: At room temperature and under N2, XantPhos Pd G4 (42.76 mg, 0.03 mmol) and Cs2CO3 (257.97 mg, 0.79 mmol) were added to a mixture of 2-(2,4-dimethyl-1,3-thiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-7-one (65 mg, 0.26 mmol), (1R,3s,5S)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (119.70 mg, 0.29 mmol) in dioxane (20 mL), and the mixture was stirred at 95 °C for 16 h. LCMS analysis showed that the reaction was complete. Next, the mixture was filtered and concentrated to give a yellow solid (1S,3s,5R)-3-({6-[2-(2,4-dimethyl-1,3-thiazo-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-1,2-diazin-3-yl}oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (150 mg, 98.39%), which was used in the next step without further purification.

[0519] Step 6: At room temperature, TFA (1 mL) was added to a mixture of (1S,3s,5R)-3-({6-[2-(2,4-dimethyl-1,3-thiazo-5-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-1,2-diazin-3-yl}oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (100 mg, 0.17 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 0.5 h. LCMS analysis showed that the reaction was complete. Next, the mixture was concentrated and the residue was purified by pre-HPLC (TFA) to give 2-(2,4-dimethyl-1,3-thiazolyl-5-yl)-6-(6-{[(1S,3s,5R)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl]oxy}-1,2-diazin-3-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-7-one (72 mg, 87.09%) as a white solid.

[0520] MS (ESI, cation) m / z: 478.3 [M+H] + . 1 HNMR (DMSO-d6) δ = 9.32 (s, 1H), 8.94 (br s, 1H), 8.86 (br s, 1H), 8.74 (dd, J = 9.6, 0.9 Hz, 1H), 7.43 (d, J = 9.5Hz, 1H), 5.49-5.60 (m, 1H), 5.21 (s, 2H), 2.84 (s, 3H), 2.67 (s, 3H), 2.42-2.48 (m, 2H), 2.17 (br d, J = 8.1 Hz, 2H), 1.89 (br d, J = 8.3 Hz, 2H), 1.76-1.85 (m, 2H), 1.46 (s, 6H).

[0521] Example 8. Synthesis of (2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6-(2,4-dimethylthiazolyl-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 69)

[0522] Step 8.

[0523]

[0524] Step 1: A solution of methyl 5-bromo-2-chloroisonicotinic acid (5 g, 20 mmol, 1.0 eq), methylboronic acid (1.79 g, 29.8 mmol, 1.5 eq), K3PO4 (14.8 g, 69.9 mmol, 3.5 eq), P(Cy)3 (1.11 g, 3.97 mmol, 0.2 eq), and Pd(OAc)2 (448 mg, 2.00 mmol, 0.1 eq) in toluene (95 mL) and H2O (4.5 mL) was degassed three times with N2. The mixture was then stirred at 100 °C for 2 hours under N2 atmosphere. When complete conversion was achieved, the reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / l to 15 / l) to give methyl 2-chloro-5-methylisonicotinic acid (2 g, 54% yield) as a yellow solid.

[0525] Step 2: 2-Chloro-5-methylisonicotinic acid ester (15.0 g, 81.7 mmol, 1.0 eq), N-bromosuccinimide (20.3 g, 113.9 mmol, 1.4 eq), and benzoyl peroxide (448.0 mg, 1.85 mmol, 0.03 eq) were combined with carbon tetrachloride (250 mL). The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography with PE / EA to give methyl 5-(bromomethyl)-2-chloroisonicotinic acid ester (17.0 g, 79%) as a brown solid. LC / MS (ESI): 263.9, 265.9 [M+H] + .

[0526] Step 3: Methyl 5-(bromomethyl)-2-chloroisonicotinic acid (17.0 g, 64.6 mmol, 1.0 eq) was suspended in a 28% aqueous solution of ammonium hydroxide, and the mixture was stirred at room temperature for 8 hours. The mixture was then filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum, and used in the next step without further purification. LC / MS (ESI): 169.0, 171.0 [M+H] + .

[0527] Step 4: 6-Chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (336.0 mg, 2.0 mmol, 1.0 eq), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)thiazole (526.1 mg, 2.20 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8.0 mL), and PdCl2(dppf)CH2Cl2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask. The flask was evacuated and backfilled three times with nitrogen. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85°C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (100 mL). The filtrate was washed with brine, and the organic layer was collected and dried over sodium sulfate, followed by concentration under vacuum. The crude mixture was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(2,4-dimethylthiazol-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (245 mg, 52%) as a brown solid. LC / MS (ESI): 246.0 [M+H] + .

[0528] Step 5: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(2,4-dimethylthiazolyl-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (36.7 mg, 0.15 mmol, 1.0 eq), (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, then heat at 90 °C for 8 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v to give (1R,3s,5S)-3-((6-(6-(2,4-dimethylthiazolyl-5-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (42.2 mg), which was dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6-(2,4-dimethylthiazolyl-5-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (12.2 mg, 17.3%) as a white solid.

[0529] 1H NMR (DMSO-d6, 400 MHz) δ = 9.06 (s, 1H), 8.69 (d, J = 9.6 Hz, 1H), 8.24 (s, 1H), 7.92 (s, 1H), 7.35 (d, J = 9.6 Hz, 1H), 5.49 (s, 1H), 5.28 (s,2H), 2.65 (s, 6H), 2.22 (br dd, J = 5.9, 12.3 Hz, 2H), 1.88 (br d, J = 7.4Hz, 2H), 1.60 (br d, J = 6.9 Hz, 2H), 1.49 (br t, J = 11.4 Hz, 2H), 1.25 (s, 6H); LC / MS (ESI): 477.2 [M+H] + .

[0530] Example 9. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 72)

[0531] Step 9.

[0532]

[0533] Step 1: At 0°C, add 60 mL of water containing potassium hydroxide (74.8 g, 1.33 mol, 4.5 eq) to a vigorously stirred solution of 3-oxoglutaric acid (82.8 g, 0.566 mol, 4.5 eq) and hexane-2,5-dione (34.0 g, 35.0 mL, 0.298 mol, 1.0 eq) in water (120 mL). After this addition, add ammonium chloride (47.8 g, 0.896 mol, 3.0 eq) and 200 mL of water containing sodium acetate (49.0 g, 0.596 mol, 2.0 eq), maintaining the temperature at 5°C. Adjust the pH to approximately 9 using solid KOH. Stir the mixture at room temperature for 4 days, adjusting the pH to approximately 9 during this period using additional solid KOH. The solution was diluted with 100 mL of water, cooled to 5 °C with vigorous stirring, and acidified with pure sulfuric acid until pH = 2 (-60 mL). Gas release was observed during acidification. The aqueous layer was divided into two batches. Each batch was washed with EtOAc (2 × 100 mL) and alkalized with solid KOH under cooling until pH = 10. The aqueous layer was extracted with DCM containing 15% MeOH (4 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give 1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-one (17.3 g, 37.5%) as a dark brown oil. LC / MS (ESI): 154.1 [M+H] + .

[0534] Step 2: Pyridine (4.0 mL, 49.0 mmol, 2.5 eq) was added to an ice-cold solution of 1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-one (3 g, 19.6 mmol, 1.0 eq) in DCM (60 mL). Triphosgene (2.33 g, 7.84 mmol, 0.4 eq) was dissolved in DCM (20 mL) and added dropwise to the above solution. After 30 minutes, t-BuOH (3.78 mL, 39.2 mmol, 2.0 eq) was added, and the mixture was gradually heated to room temperature and stirred for 8 hours. The reaction mixture was quenched with water and diluted with DCM (300 mL). The mixture was washed with 1N HCl (1 × 50 mL), saturated sodium bicarbonate (1 × 50 mL), and brine (1 × 50 mL). The organic layer was collected, dried over sodium sulfate, and then concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using a PE / EA 20 / 1 v / v apparatus to give (1R,5S)-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.3 g, 9.1 mmol, 46.3%) as a pale yellow oil. LC / MS (ESI): 254.2 [M+H] + .

[0535] Step 3: Dissolve (1R,5S)-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.3 g, 9.1 mmol) in EtOH (50 mL) and heat the solution to reflux. Add sodium borohydride (336 mg, 1.0 eq) and stir the mixture for 15 min. Cool the mixture to room temperature and quench it with an aqueous ammonium chloride solution. Remove the organic solvent under vacuum and redissolve the residue in EtOAc (100 mL). Wash the mixture with brine, collect the organic layer and dry it with sodium sulfate, then concentrate it under vacuum. The crude mixture was purified by silica gel column chromatography with PE / EtOAc to give (1R,3r,5S)-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.2 g, 52%, PE / EtOAc 3 / 1, v / v) and (1R,3s,5S)-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.1 g, 48%, PE / EtOAc 2 / 1, v / v) as white solids. LC / MS (ESI): 256.2 [M+H] + .

[0536] Step 4: Add NaH (60 wt%, 208 mg, 5.21 mmol, 1.2 eq) to a solution of (1R,3s,5S)-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 4.34 mmol, 1.0 eq) in anhydrous THF (20 mL). Stir the solution at room temperature for 30 min, then add 3,6-dibromopyridazine (1.24 g, 5.21 mmol, 1.2 eq), and stir the mixture at room temperature for 8 h. Quench the reaction mixture with saturated ammonium chloride and dilute with EtOAc (100 mL). Wash the mixture with brine, dry it with sodium sulfate, and then concentrate it under vacuum. The crude mixture was purified by silica gel column chromatography using a PE / EA 20 / 1 v / v apparatus to give (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.28 g, 72%) as a white solid. LC / MS (ESI): 412.2, 414.2 [M+H] + .

[0537] Step 5: At room temperature and under N2, Xantphos Pd G4 (149.05 mg, 0.09 mmol) and Cs2CO3 (897.04 mg, 2.76 mmol) were added to a mixture of 6-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (210 mg, 0.92 mmol), (1R,3s,5S)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (379.36 mg, 0.92 mmol) in dioxane (30 mL), and the mixture was stirred at 95 °C for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography and eluted with DCM:MeOH = 10:1 to give (1R,3s,5S)-3-({6-[6-(1,3-dimethylpyrazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-2-yl]-1,2-diazin-3-yl}oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (400 mg, 77.68%) as a yellow solid.

[0538] Step 6: At room temperature, add HCl-dioxane (20 mL) to a mixture of (1R,3s,5S)-3-({6-[6-(1,3-dimethylpyrazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-2-yl]-1,2-diazin-3-yl}oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (360 mg, 0.64 mmol) in DCM (10 mL) and stir the mixture for 1 h. The reaction mixture was concentrated and the residue was purified by pre-HPLC (HCl) to give 6-(1,3-dimethylpyrazol-4-yl)-2-(6-{[(1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]oxy}-1,2-diazin-3-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (248 mg, 83.90%) as a yellow solid.

[0539] 1 H NMR (DMSO-d6, 400 MHz) δ = 8.98 (s, 1H), 8.71 (d, J = 9.6 Hz, 1H), 8.37 (s, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.37 (d, J = 9.6 Hz, 1H),5.51 (brt, J = 5.7 Hz, 1H), 5.23 (s, 2H), 3.81 (s, 3H), 2.47-2.48 (s, 3H), 2.36 (brdd, J = 13.0, 5.9 Hz, 2H), 2.06 (br d, J = 7.8 Hz, 2H), 1.79 (br d, J = 8.0Hz, 2H), 1.69 (br t, J = 11.9 Hz, 2H), 1.38 (s, 6H); LC / MS (ESI): 460.2 [M+H] + .

[0540] Example 10. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1S,3R,5R)-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 98)

[0541] Step 10.

[0542]

[0543] Step 1: At 5 °C, a solution of pentanoyl chloride (41.96 mL, 341.03 mmol) in anhydrous THF (50 mL) was added dropwise to a stirred and ice-cooled solution of 4-oxopentanoic acid (31.86 mL, 310.02 mmol) and triethylamine (128.92 mL, 930.07 mmol) in anhydrous THF (300 mL). The solution was stirred at 5 °C for 1.5 h, and the precipitate of Et3N·HCl was filtered off. The solid salt was washed with THF. The combined filtrate and washings were dried (MgSO4) and concentrated under vacuum to give 2,2-dimethylpropionic acid 4-oxopentanoic acid anhydride (57 g, 284.67 mmol, 91.82%) as a colorless oil, which was immediately used in the next step. LC / MS (ESI): 201.1 [M+H] + .

[0544] Step 2: At -60°C and under N2, a solution of EtMgBr in THF (1 M, 323.14 mL, 313.14 mmol) was added dropwise to a stirred and cooled solution of 2,2-dimethylpropionic acid 4-oxovalerate anhydride (57 g, 284.67 mmol) in anhydrous THF (300 mL) for 30 min. After the addition, the mixture was stirred at -60°C for 30 min. Subsequently, the cooling bath was removed, and the mixture was stirred for another 1 h. The reactants were quenched by adding ice and NH4Cl solution, followed by extraction with EA. The EA solution was washed successively with water and brine, dried over MgSO4, and concentrated under vacuum. The residues obtained from the two rounds were combined and distilled under vacuum to give a colorless oil of heptane-2,5-dione (25 g, 195.05 mmol, 68.52%). LC / MS (ESI): 129.1 [M+H] + .

[0545] Step 3: At 0°C, add 50 mL of water containing KOH (49.25 g, 877.74 mmol) to a vigorously stirred solution of heptane-2,5-dione (25 g, 195.05 mmol) and 3-oxoglutaric acid (42.30 mL, 370.60 mmol) in water (250 mL). At 5°C, add 200 mL of water containing NH4Cl (20.59 mL, 585.16 mmol) and KOAc (38.29 g, 390.11 mmol). Adjust the pH to approximately 9 using solid KOH. Stir the mixture at room temperature for 4 days, adjusting the pH to approximately 9 using additional solid KOH during this period. Dilute the solution with 300 mL of water, transfer it to a 2 L beaker, cool to 5°C, and acidify with pure sulfuric acid until pH = 2. Gas release is observed during acidification. Divide the aqueous layer into two batches. Each batch was washed with EA (2 × 1000 mL) and alkalized with solid KOH until pH = 10. The aqueous layer was extracted with DCM containing 15% MeOH (4 × 1000 mL). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give (1S,5R)-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-3-one (9 g, 53.81 mmol, 27.59%) as a dark brown oil. LC / MS (ESI): 169.1 [M+H] + .

[0546] Step 4: Pyridine (10.86 mL, 134.53 mmol) was added to an ice-cold solution of (1S,5R)-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-3-one (9 g, 53.81 mmol) in DCM (80 mL). Trichloromethyl [(trichloromethyl)oxy]formate (3.59 mL, 21.52 mmol) was dissolved in DCM (20 mL) and added dropwise to the reaction mixture. After 30 minutes, 2-methylprop-2-ol (10.23 mL, 107.62 mmol) was added, and the mixture was gradually heated to room temperature and stirred for 8 h. The reaction mixture was quenched with water and diluted with DCM (300 mL). The mixture was washed with 1N HCl (1 × 50 mL), saturated sodium bicarbonate (1 × 100 mL), and brine (1 × 100 mL). The organic layer was collected and dried over sodium sulfate, then concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using a PE / EA 20 / 1 v / v spectrophotometer to give (1R)-5-ethyl-1-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (7.5 g, 28.05 mmol, 52.13%) as a pale yellow oil. LC / MS (ESI): 268.2 [M+H] + .

[0547] Step 5: Dissolve (1R)-5-ethyl-1-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (7.5 g, 28.05 mmol) in EtOH (60 mL) and heat the solution to reflux. Add NaBH4 (0.31 mL, 8.42 mmol) and stir the mixture for 15 min. Cool the mixture to room temperature and quench it with an aqueous solution of ammonium chloride. Remove the organic solvent under vacuum and redissolve the residue in EA (200 mL). Wash the mixture with brine, collect the organic layer and dry it with sodium sulfate, then concentrate it under vacuum. The residue was purified by silica gel column chromatography with PE / EtOAc to give (1R)-5-ethyl-3-hydroxy-1-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (3.7 g, 13.74 mmol, 48.97%). LC / MS (ESI): 270.2 [M+H] + .

[0548] Step 6: Add NaH (0.33 g, 13.74 mmol) to a solution of (1R)-5-ethyl-3-hydroxy-1-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (3.7 g, 13.74 mmol) in anhydrous THF (35 mL). Stir the solution at room temperature for 30 min, then add 3,6-dibromo-1,2-diazine (3.27 g, 13.74 mmol), and stir the mixture at room temperature for 8 h. Quench the reaction mixture with saturated ammonium chloride and dilute with EA (200 mL). Wash the mixture with brine, collect the organic layer and dry it with sodium sulfate, then concentrate it under vacuum. The crude substance was purified by silica gel column chromatography using a PE / EA 20 / 1 v / v apparatus to give (1R)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-5-ethyl-1-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (2 g, 4.69 mmol, 34.15%) as a white solid. LC / MS (ESI): 426.1 [M+H] + .

[0549] Step 7: Add 1,4-dioxane (4 mL) to a round-bottom flask containing (1S)-3-[(6-bromo-1,2-diazin-3-yl)oxy]-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (150 mg, 0.35 mmol), 6-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (88.33 mg, 0.39 mmol), Cs₂CO₃ (102.23 mg, 0.31 mmol), and XantPhos Pd G₄ (16.94 mg, 0.01 mmol). Degas the reaction mixture with argon for 5 min, and then heat at 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give (1S,5R)-3-({6-[6-(1,3-dimethylpyrazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-2-yl]-1,2-diazin-3-yl}oxy)-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (60 mg), which was dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by RP HPLC using MeCN and H2O to give 6-(1,3-dimethylpyrazol-4-yl)-2-(6-{[(1S,5R)-1-ethyl-5-methyl-8-azabicyclo[3.2.1]octane-3-yl]oxy}-1,2-diazin-3-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (20 mg, 0.04 mmol, 12.00%) as a white solid.

[0550] 1H NMR (DMSO-d6, 400 MHz) δ= 8.98 (s, 1H), 8.70 (d, J = 9.6 Hz, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.34 (d, J = 9.6 Hz, 1H), 5.51 (s,1H), 5.24 (s, 2H), 3.81 (s, 3H), 2.48 (s, 3H), 2.26 (br dd, J = 5.6, 12.4 Hz,2H), 1.90 (br t, J = 7.1 Hz, 2H), 1.71 - 1.48 (m, 6H), 1.30 (s, 3H), 0.91 (t,J = 7.4 Hz, 3H); LC / MS (ESI): 474.2 [M+H] + .

[0551] Example 11. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-((5,5-dimethyl-4-azaspiro[2.5]octan-7-yl)oxy)pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 59)

[0552] Step 11.

[0553]

[0554] Step 1: A solution of 1-ethoxy-1-[(trimethylsilyl)oxy]cyclopropane (11.5 mL, 57.37 mmol, 1.0 eq) in MeOH (100 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and used directly in the next step without purification.

[0555] Step 2: A solution of 1-ethoxycyclopropane-1-ol (5.9 g, 57.38 mmol, 1.0 eq) and benzoic acid (1.4 g, 11.48 mmol, 0.2 eq) in toluene (6 mL) was stirred at 110 °C for 15 min. Next, ethyl (triphenyl-λ5-phosphine) (20.0 g, 57.38 mmol, 1.0 eq) was added, and the mixture was stirred at 110 °C for 48 h. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography, eluting with PE, to give ethyl cyclopropane (3.1 g, 42.4%).

[0556] Step 3: A solution of ethyl cyclopropionate (1.7 g, 13.47 mmol, 1.0 eq) and ethyl 3-amino-3-methylbutyrate (2.3 g, 16.17 mmol, 1.2 eq) in DIEA (2.99 mL, 18.06 mmol, 1.34 eq) was stirred at 60 °C for 3 h. The reaction was monitored by TLC and LC / MS. The crude product was purified by silica gel chromatography, eluting with PE:EA (5:1) to give ethyl 3-((1-(2-ethoxy-2-oxoethyl)cyclopropyl)amino)-3-methylbutyrate (1.2 g, 32.2%). LC / MS (ESI): 272.1 [M+H] + .

[0557] Step 4: At 0 °C and under a N2 atmosphere, t-BuOK (5.46 mL, 5.46 mmol) was added to a solution of ethyl 3-((1-(2-ethoxy-2-oxoethyl)cyclopropyl)amino)-3-methylbutyrate (980 mg, 3.64 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was stirred at 0 °C for 1 h. LC / MS showed the desired mass. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (10 mL). The resulting mixture was extracted with EA (2 × 20 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel chromatography, eluting with PE / EA (3:1) to give ethyl 5,5-dimethyl-7-oxo-4-azaspiro[2.5]octane-8-carboxylate (618 mg, 76.1%). LC / MS (ESI): 226.1 [M+H] + .

[0558] Step 5: A solution of ethyl 7-oxospiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-8-carboxylate (618.0 mg, 2.77 mmol, 1.0 eq) in a mixture of H₂O (5 mL) and H₂SO₄ (5 mL) was stirred at 120 °C for 1 h. LC / MS was performed to show the desired mass. The reaction mixture was poured into ice water. The aqueous layer was adjusted to a pH greater than 9 and extracted with EA (3 × 20 mL). The crude material was concentrated under reduced pressure to give 5,5-dimethyl-4-azaspiro[2.5]octane-7-one (326.0 mg, 77.9%). LC / MS (ESI): 154.1 [M+H] + .

[0559] Step 6: At 0 °C, NaBH4 (64.5 mg, 1.71 mmol, 3.0 eq) was added to a solution of spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-one (86.0 mg, 0.57 mmol, 1.0 eq) in MeOH (5 mL). The mixture was stirred at room temperature for 1 h. LC / MS showed the desired mass. The reaction mixture was diluted with H2O and the pH was adjusted to 7. The aqueous layer was extracted with EA (2 × 10 mL) and (DCM / propan-2-ol:IPA, 10:1). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was used directly in the next step without further purification. LC / MS (ESI): 156.1 [M+H] + .

[0560] Step 7: At 0 °C under a N2 atmosphere, NaH (39.0 mg, 0.98 mmol, 1.4 eq) was added to a solution of 5,5-dimethyl-4-azaspiro[2.5]octane-7-ol (106.0 mg, 0.69 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was stirred at 0 °C under a N2 atmosphere for 20 min. Then, 3,6-diiodo-1,2-diazine (252.5 mg, 0.76 mmol, 1.1 eq) was added, and the mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature and diluted with DMF (5 mL), and then stirred at 100 °C for another 3 h. The desired mass was obtained by LC / MS. The reaction mixture was cooled to room temperature and then poured into water. The aqueous layer was extracted with EA (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel chromatography, eluting with PE:EA (1:1) to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-((5,5-dimethyl-4-azaspiro[2.5]octane-7-yl)oxy)pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (146.0 mg, 59.1%). LC / MS (ESI): 360.0 [M+H] + .

[0561] Step 8: A solution of 7-((6-ioridazin-3-yl)oxy)-5,5-dimethyl-4-azaspiro[2.5]octane (48.0 mg, 0.13 mmol, 1.0 eq), 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (32.2 mg, 0.14 mmol, 1.05 eq), (1R,2R)-cyclohexane-1,2-diamine (1.5 mg, 0.01 mmol, 0.1 eq), CuI (2.7 mg, 0.01 mmol, 0.1 eq), and K₂CO₃ (55.7 mg, 0.40 mmol, 3.0 eq) in DMF (3 mL) was stirred overnight at 120 °C under a N₂ atmosphere. LC / MS was used to show the desired mass and reactant consumption. The reaction mixture was evaporated to dryness. The crude product was purified by silica gel chromatography with DCM / MeOH (10:1) followed by prep-HPLC (FA) to give 3-(1,3-dimethylpyrazol-4-yl)-6-[6-(spiro[4-azaspiro[2.5]octane-5,1'-cyclopropane]-7-yloxy)-1,2-diazin-3-yl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (12.92 mg, 19.1%).

[0562] 1 H NMR (DMSO-d6, 400MHz) δ = 8.98 (s, 1H), 8.69 (d, J = 9.6 Hz, 1H), 8.37 (s, 1H), 8.19 (br s, 1H), 7.88 (s, 1H), 7.32 (d, J = 9.6 Hz, 1H), 5.63 -5.53 (m, 1H), 5.24 (s, 2H), 3.81 (s, 3H), 2.48 (s, 3H), 2.11 (br dd, J = 3.6,12.3 Hz, 1H), 1.88 - 1.80 (m, 1H), 1.63 (br dd, J = 4.3, 11.8 Hz, 1H), 1.37(t, LC / MS (ESI): 460.1 [M+H] + .

[0563] Example 12. Synthesis of 2-(6-(((2S,6S)-2,6-dicyclopropylpiperidin-4-yl)oxy)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 104)

[0564] Step 13.

[0565]

[0566] Step 1: Cyclopropaneformaldehyde (2.876 g, 41 mmol) was added to a solution of pyruvate (3.0 g, 0.5 mmol) in water (20 mL), followed by fractional addition of (2,4-dimethoxyphenyl)methylamine (2.8 g, 20.5 mmol) over 10 min. The resulting reaction mixture was stirred at room temperature for 3 days. The reaction mixture was extracted with DCM (3 × 60 mL), and the combined extracts were washed with brine, dried over anhydrous Na₂SO₄ and under vacuum to give a brown residue. The isomeric piperidinone was separated by silica gel chromatography using hexane / ethyl acetate (7 / 1, v / v). The desired compound (3.4 g, 54%) was given as a pale yellow oil.

[0567] Step 2: At room temperature and under N2, NaBH4 (0.57 g, 15.18 mmol) was added to a mixture of 2,6-dicyclopropyl-1-(3,4-dimethylbenzyl)piperidin-4-one (5.0 g, 15.18 mmol) in MeOH (50 mL), and the mixture was stirred for 2 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give 2,6-dicyclopropyl-1-(3,4-dimethylbenzyl)piperidin-4-ol (2.0 g, 39.76%) as an oil.

[0568] Step 3: At room temperature and under N2, NaH (0.48 g, 12.07 mmol) was added to a mixture of 2,6-dicyclopropyl-1-(3,4-dimethylbenzyl)piperidin-4-ol (2.0 g, 6.03 mmol) and THF (30 mL), and the mixture was stirred for 1 h. Next, 3,6-dibromo-1,2-diazine (1.87 g, 7.84 mmol) was added, and the mixture was stirred at 50 °C for 16 h. The mixture was quenched with MeOH and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (PE:EA=10:1-5:1) to give 3-bromo-6-(((2S,6S)-2,6-dicyclopropylpiperidin-4-yl)oxy)pyridazine (440 mg, 14.93%) and 3-bromo-6-(((2R,4s,6S)-2,6-dicyclopropylpiperidin-4-yl)oxy)pyridazine (800 mg, 1.64 mmol, 27.16%) as white solids.

[0569] Step 4: At room temperature and under N2, XantPhos Pd G4 (49.68 mg, 0.03 mmol) and Cs2CO3 (299.77 mg, 0.92 mmol) were added to a mixture of 6-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-3-one (70 mg, 0.31 mmol) and 3-bromo-6-(((2S,6S)-2,6-dicyclopropylpiperidin-4-yl)oxy)pyridazine (149.79 mg, 0.31 mmol) in dioxane (10 mL), and the mixture was stirred at 95 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM:MeOH=10) to give 2-(6-(((2S,6S)-2,6-dicyclopropyl-1-(3,4-dimethylbenzyl)piperidin-4-yl)oxy)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 86.36%) as a yellow solid.

[0570] Step 5: Stir the mixture of 2-(6-(((2S,6S)-2,6-dicyclopropyl-1-(3,4-dimethylbenzyl)piperidin-4-yl)oxy)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 0.27 mmol) in TFA (20 mL) at 110 °C for 48 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by pre-HPLC (TFA) to give 6-(1,3-dimethylpyrazol-4-yl)-2-(6-{[(2S,6S)-2,6-dicyclopropylhexahydropyridin-4-yl]oxy}-1,2-diazin-3-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (78.73 mg, 60.56%) as a yellow solid.

[0571] 1 H NMR (DMSO-d6) δ = 8.98 (s, 1H), 8.73 (d, J = 9.6 Hz, 1H), 8.34 (s,1H), 7.88 (s, 1H), 7.38 (d, J = 9.6 Hz, 1H), 5.64 (dt, J = 9.0, 4.7 Hz, 1H),5.25 (s, 2H), 3.82 (s, 3H), 2.90-3.00 (m, 2H), 2.46-2.49 (m, 3H), 2.40-2.46(m, 1H), 2.29-2.38 (m, 1H),1.85-2.06 (m, 2H), 1.24-1.34 (m, 1H), 1.18 (td, J = 8.5, 4.0 Hz, 1H), 0.53–0.70 (m, 5H), 0.35–0.51 (m, 3H), not observed in 1H (NH); LC / MS (ESI): 486.2 [M+H] + .

[0572] Example 13. Synthesis of 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 206)

[0573] Step 13.

[0574]

[0575] Step 1: 4-Bromo-2,5-dimethyl-2H-1,2,3-triazole (262.0 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (762 mg, 3.0 mmol, 3.0 eq), potassium acetate (300 mg, 3.0 mmol, 3.0 eq), and PdCl2 (dppf) were added to the CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq), and the solids were degassed under N2. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 90 °C. After the reaction was complete, the reaction mixture was cooled to room temperature. Next, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (211.9 mg, 1.0 mmol, 1.0 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2 (dppf) were added, and the mixture was heated to 90 °C. After the reaction was complete, the mixture was cooled, filtered through diatomaceous earth, and washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and then concentrated under vacuum. The crude mixture was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v to give 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (116 mg, 51%) as a brown solid. LC / MS (ESI): 230.1 [M+H] + .

[0576] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (37.4 mg, 0.15 mmol, 1.0 eq), (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq), and degas the reaction mixture with argon for 5 minutes. The mixture was heated to 90 °C for 8 h. The reaction mixture was cooled to room temperature and diluted with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v, and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl and stirred at room temperature for 1 h. The product was concentrated under reduced pressure, and the resulting residue was purified by RPHPLC using MeCN and H2O as eluents to give 3-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (37.8 mg, 54.7%) as a white solid.

[0577] 1H NMR (DMSO-d6, 400MHz) δ = 9.18 (d, J = 2.0 Hz, 1H), 8.87 (br d, J =10.6 Hz, 1H), 8.79 (br s, 1H), 8.75 (d, J = 9.6 Hz, 1H), 8.39 (d, J = 2.0 Hz,1H), 7.41 (d, J = 9.5 Hz, 1H), 5.55 (tt, J = 10.9, 5.6 Hz, 1H), 5.24 (s, 2H), 4.19 (s, 3H), 2.46 (br d, J = 6.1 Hz, 2H), 2.18 (br d, J = 8.0 Hz, 2H), 1.90(br d, J = 8.3 Hz, 2H), 1.80 (br t, J = 12.1 Hz, 2H), 1.46 (s, 6H), 3H not observed (triazole methyl overlap with DMSO-d6 residue); LC / MS (ESI): 461.2 [M+H] + .

[0578] Example 14. Synthesis of 3-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 190)

[0579] Step 14.

[0580]

[0581] Step 1: Under nitrogen atmosphere, 4-bromo-2,5-dimethyl-2H-1,2,3-triazole (262.0 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (762 mg, 3.0 mmol, 3.0 eq), potassium acetate (300 mg, 3.0 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were transferred to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 90 °C. When complete conversion was achieved, the reaction mixture was cooled to room temperature. 4-Bromo-3-fluoro-1-methyl-1H-pyrazole (177.9 mg, 1.0 mmol, 1.0 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added, and the mixture was heated to 90 °C. When complete conversion was achieved, the mixture was cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v to give 3-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (116 mg, 51%) as a brown solid. LC / MS (ESI): 233.1 [M+H] + .

[0582] Step 2: 3-[1-(trifluoromethyl)pyrazol-4-yl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (106 mg, 0.46 mmol), 3-bromo-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (149.39 mg, 0.46 mmol), XantPhos Pd G4 (73.95 mg, 0.05 mmol), and Cs2CO3 (446.18 mg, 1.37 mmol) were dissolved in dioxane (8 mL), and the reaction mixture was stirred overnight at 90 °C. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water, and diluted with EA (100 mL). The mixture was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH to give 3-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (24.1 mg, 0.05 mmol, 10.91%) as a white solid.

[0583] 1 ¹H NMR (DMSO-d⁶, 400MHz) δ = 8.99–9.09 (m, 1H), 8.68 (d, J = 9.6 Hz, 1H), 8.37–8.47 (m, 1H), 8.22–8.31 (m, 1H), 7.24–7.36 (m, 1H), 5.57–5.68 (m, 1H), 5.19 (s, 2H), 3.80 (s, 3H), 2.05–2.07 (m, 2H), 1.24–1.29 (m, 2H), 1.23 (s, 6H), 1.08–1.13 (m, 6H), ¹H not observed (NH); LC / MS (ESI): 466.2 [M+H] + .

[0584] Example 15. Synthesis of 3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 172)

[0585] Step 15.

[0586]

[0587] Step 1: Under nitrogen atmosphere, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (312.0 mg, 1.5 mmol, 1.5 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were transferred into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give a brown solid, 3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (183.2 mg, 62%). LC / MS (ESI): 297.1 [M+H] + .

[0588] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (44.4 mg, 0.15 mmol, 1.0 eq), (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs2CO3 (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). The reaction mixture was degassed with argon for 5 min and then heated to 90 °C for 8 h. The reaction mixture was cooled to room temperature and diluted with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v. The residue was purified by RPHPLC using MeCN and H2O as eluents to give 3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (42.35 mg, 53.3%) as a white solid.

[0589] 1 H NMR (400 MHz, DMSO-d6) δ = 8.92 (d, 1H, J = 2.0 Hz), 8.71 (d, 1H, J= 9.6 Hz), 8.50 (s, 1H), 8.32 (s, 1H), 8.19 (d, 1H, J = 2.0 Hz), 7.35 (d, 1H,J = 9.6 Hz), 5.64 (s, 1H), 5.24 (s, 2H), 4.30 (q, 2H, J = 7.3 Hz), 2.17 (dd,2H, J = 3.9, 12.4 Hz), 1.5-1.5 (m, 3H), 1.4-1.5 (m, 2H), 1.34 (s, 6H), 1.24(s, 6H); LC / MS (ESI): 530.2 [M+H] + .

[0590] Example 16. Synthesis of 3-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 198)

[0591] Step 16.

[0592]

[0593] Step 1: Ethyl[di(prop-2-yl)]amine (18.82 mL, 113.56 mmol) and diphenyl azidophosphonate (15.99 mL, 73.81 mmol) were added to a solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (6.58 mL, 56.78 mmol) in 2-methylprop-2-ol (200 mL), and the reaction mixture was stirred at 90 °C under N2 for 4 h. The mixture was diluted with EA (10 mL x 3) and H2O (30 mL), and the organic layer was washed with brine (5 mL x 3), dried over sodium sulfate, and then concentrated under vacuum. The crude product was purified by silica gel column chromatography using a PE / EA 10 / 1 v / v apparatus to give tert-butyl (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)carbamate (13.2 g, 53.39 mmol, 94.03%). LC / MS (ESI): 248.1 [M+H] + .

[0594] Step 2: 4M HCl-MeOH (60 mL) was added to a solution of (3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl)carbamate tert-butyl ester (13.2 g, 53.39 mmol) in MeOH (30 mL), and the reaction mixture was stirred overnight at 25 °C. The reaction mixture was then concentrated to give the crude product 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine (10.2 g), which was used in the next step without further purification. LC / MS (ESI): 148.1 [M+H] + .

[0595] Step 3: 2-methyl-2-(nitrosooxidanyl)propane (3.67 mL, 30.59 mmol) and copper bromide (I) (1.24 mL, 40.78 mmol) were added to a solution of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine (3 g, 20.39 mmol) in acetonitrile (30 mL), and the reaction mixture was stirred at 70 °C for 1 h. The mixture was diluted with EA (50 mL x 3) and H2O (50 mL), and the organic layer was then washed with brine (30 mL x 3), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using PE / EA (50 / 1-20 / 1-10 / 1, v / v) to give 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (2.3 g, 10.90 mmol, 53.46%). LC / MS (ESI): 210.9, 212.9 [M+H] + .

[0596] Step 4: Under nitrogen atmosphere, 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (316.5 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (762 mg, 3.0 mmol, 3.0 eq), potassium acetate (300 mg, 3.0 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were transferred to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 90 °C. When complete conversion was achieved, the reaction mixture was cooled to room temperature. Next, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (211.9 mg, 1.0 mmol, 1.0 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added, and the mixture was heated to 90 °C. When complete conversion was achieved, the mixture was cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give a brown solid, 3-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (164.7 mg, 62%). LC / MS (ESI): 265.1 [M+H] + .

[0597] Step 5: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39.4 mg, 0.15 mmol, 1.0 eq), 6-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G₄ (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat at 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1, and the residue was further purified by RP HPLC using MeCN and H2O as eluents to give 3-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (3.83 mg, 5.0%) as a white solid.

[0598] 1 H NMR (400 MHz, methanol-d4) δ : 8.97 (d, J = 2.0 Hz, 1H), 8.63 (d, J =9.9 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 7.29 (d, J = 10.0 LC / MS (ESI): 511.2 [M+H] + .

[0599] Example 17. Synthesis of (S)-6-(6-(3-cyclopropylpiperazin-1-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 155)

[0600] Step 17.

[0601]

[0602] Step 1: DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 eq) were added to a solution of (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-cyclopropylacetyl)glycine methyl ester (9.5 g, 22.38 mmol, 79.09%) in acetonitrile (50 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered to obtain (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-cyclopropylacetyl)glycine methyl ester (9.5 g, 22.38 mmol, 79.09%) as a pale yellow solid. LC / MS (ESI): 409.2 [M+H] + .

[0603] Step 2: A solution of (S)-(2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-2-cyclopropylacetyl)glycine methyl ester (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred at room temperature for 16 h. After the reaction was complete, the solution was concentrated under vacuum to give (S)-3-cyclopropylpiperazine-2,5-dione (4.85 g, 11.43 mmol, 97.00%) as a pale yellow solid. LC / MS (ESI): 155.1 [M+H] + .

[0604] Step 3: In an ice bath, LiAlH4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorously stirred solution of (S)-3-cyclopropylpiperazine-2,5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL), and the reaction mixture was then stirred at 70 °C for 16 h. After the reaction was complete, the mixture was poured into KOH (6N) and stirred in an ice bath for 1 h. The mixture was then filtered, and the filtrate was extracted with EA, washed with brine, dried over Na2SO4, and concentrated under vacuum to give (S)-2-cyclopropylpiperazine (1.2 g, 8.44 mmol, 89.74%) as a yellow oil. LC / MS (ESI): 127.1 [M+H] + .

[0605] Step 4: DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorously stirred solution of (2S)-2-(2-methylpropyl-2-yl)piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3,6-diiodo-1,2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL), and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was diluted with EA, washed with water and brine, dried over Na₂SO₄, and concentrated under vacuum to give (S)-3-(3-cyclopropylpiperazin-1-yl)-6-iodadiazine (450 mg, 1.30 mmol, 36.98%) as a yellow solid. LC / MS (ESI): 331.1 [M+H] + .

[0606] Step 5: Pd(dppf)Cl2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorously stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (250 mg, 1.20 mmol, 1.0 eq), 3-bromo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq), and K2CO3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 10 / 1 v / v to give a pale yellow solid, 3-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (135 mg, 0.63 mmol, 52.51%). LC / MS (ESI): 215.2 [M+H] + .

[0607] Step 6: 6-(1-methylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (50 mg, 0.23 mmol, 1.0 eq) and (S)-3-(3-cyclopropylpiperazin-1-yl)-6-iodridazine (80 mg, 0.23 mmol, 1.0 eq) were dissolved in DMF (2 mL), and CuI (4 mg, 0.02 mmol, 0.10 eq), K₂CO₃ (97 mg, 0.70 mmol, 3.0 eq), and (1R,2R)-cyclohexane-1,2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) were added. The reaction mixture was stirred at 100 °C for 16 h. Next, the reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by pre-HPLC to obtain (S)-6-(6-(3-cyclopropylpiperazin-1-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (24.19 mg, 21.55%) as a white solid.

[0608] 1 H NMR (DMSO-d6, 400 MHz) δ = 9.12 (d, J = 1.6 Hz, 1H), 8.49 (d, J =9.8 Hz, 1H), 8.44 (s, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.14 (s, 1H), 7.51 (d, J= 10.0 Hz, 1H), 5.13 (s, 2H), 4.27 (br d, J = 11.1 Hz, 1H), 4.15 (br d, J =10.8 Hz, 1H), 3.89 (s, 3H), 3.14 - 3.03 (m, 2H), 2.95 (br t, J = 11.5 Hz,1H), 2.84 - 2.74 (m, 2H), 0.84 (br d, J = 7.1 Hz, 1H), 0.48 (br s, 2H), 0.33 (br s, 2H), 1H not observed (NH); LC / MS (ESI): 417.2 [M+H] + .

[0609] Example 18. Synthesis of 6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-3-(4-methylthiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 248)

[0610] Step 18.

[0611]

[0612] Step 1: Under nitrogen atmosphere, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)thiazole (375 mg, 1.5 mmol, 1.5 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 3-(4-methylthiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (143.2 mg, 62%) as a brown solid. LC / MS (ESI): 232.1 [M+H] + .

[0613] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(4-methylthiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (44.4 mg, 0.15 mmol, 1.0 eq), (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat to 90 °C for 8 h. The reaction mixture was cooled to room temperature and diluted with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v, and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-3-(4-methylthiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20.37 mg, 29.4%) as a white solid.

[0614] 1 HNMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 9.00 (s, 1H), 8.72 (br d, J= 9.5 Hz, 1H), 8.29 (br d, J = 12.3 Hz, 3H), 7.38 (br d, J = 9.5 Hz, 1H),5.56 - 5.48 (m, 1H), 5.24 (s, 2H), 2.53 - 2.51 (m, 3H), 2.35 (br dd, J = 5.3,12.4 Hz, 2H), 2.06 (br d, J = 7.5 Hz, 2H), 1.88 - 1.73 (m, 4H), 1.41 (br s,6H); LC / MS (ESI): 463.2 [M+H] + .

[0615] Example 19. Synthesis of 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(6-((6,6-dimethyl-5-azaspiro[3.5]nonane-8-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 249)

[0616] Step 19.

[0617]

[0618] Step 1: CDI (10.75 g, 66.28 mmol, 1.20 eq) was added to a solution of 3-((tert-butoxycarbonyl)amino)-3-methylbutyric acid (12.0 g, 55.23 mmol, 1.0 eq) in THF (100 mL), and the reaction mixture was stirred at room temperature for 1 h. Next, MgCl2 (2.62 g, 43.08 mmol, 0.78 eq) and potassium 3-(tert-butoxy)-3-oxopropionate (16.43 g, 82.85 mmol, 1.5 eq) were added, and the reaction mixture was stirred overnight at 50 °C. The reaction mixture was then concentrated and diluted with H2O (40 mL). The aqueous layer was extracted with EA (3 × 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with PE:EA (10:1) to give tert-butyl 5-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate (10.5 g, 20.27%). LC / MS (ESI): 260.2 [M+H] + .

[0619] Step 2: HCl / dioxane (5 mL) was added to a solution of 5-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate tert-butyl ester (5.0 g, 15.85 mmol, 1.0 eq) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was concentrated to give 5-amino-5-methyl-3-oxohexanoate tert-butyl ester (3.4 g, 99.9%). LC / MS (ESI): 216.2 [M+H] + .

[0620] Step 3: K₂CO₃ (4.98 g, 36.0 mmol, 2.5 eq) and cyclobutanone (5.43 mL, 70.09 mmol, 5.0 eq) were added to a solution of tert-butyl 5-amino-5-methyl-3-oxohexanoate (3.1 g, 16.84 mmol, 1.0 eq) in DCM (18 mL), and the reaction mixture was stirred at room temperature for 72 h. LC / MS was performed to show the desired mass. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over Na₂SO₄, and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EA (3:1) to give tert-butyl 6,6-dimethyl-8-oxo-5-azaspiro[3.5]nonane-9-carboxylate (1.2 g, 31.1%). LC / MS (ESI): 268.2 [M+H] + .

[0621] Step 4: Add tert-butyl 6,6-dimethyl-8-oxo-5-azaspiro[3.5]nonane-9-carboxylate (1200 mg, 4.49 mmol, 1.0 eq) to a solution of H2O (18 mL) and H2SO4 (2 mL), and stir the reaction mixture at 120 °C for 1 h. LC / MS showed the desired mass. Pour the reaction mixture into ice water and adjust the pH to above 9. Extract the aqueous layer with EA (3 × 20 mL). Dry the organic layer with Na2SO4 and concentrate under reduced pressure. Purify the crude product by silica gel chromatography, eluting with DCM:MeOH (10:1) to give 6,6-dimethyl-5-azaspiro[3.5]nonane-8-one (620 mg, 81.27%). LC / MS (ESI): 168.2 [M+H] + .

[0622] Step 5: At 0 °C, NaBH4 (140 mg, 3.71 mmol, 1.0 eq) was added to a solution of 6,6-dimethyl-5-azaspiro[3.5]nonane-8-one (620 mg, 3.71 mmol, 1.0 eq) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 h. LC / MS was performed to show the desired mass. The reaction mixture was diluted with H2O and the pH was adjusted to approximately 7. The aqueous layer was extracted with EA (2 × 10 mL) and (DCM / propanol:IPA, 10:1). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with DCM:MeOH (10:1, 0.5% TEA) to give 6,6-dimethyl-5-azaspiro[3.5]nonane-8-ol (540 mg, 86.01%). LC / MS (ESI): 170.2 [M+H]+ .

[0623] Step 6: At 0 °C under a N2 atmosphere, NaH (153.13 mg, 3.83 mmol, 1.2 eq, 60%) was added to a solution of 6,6-dimethyl-5-azaspiro[3.5]nonane-8-ol (540.0 mg, 3.19 mmol, 1.0 eq) in THF (10 mL), and the reaction mixture was stirred for 20 min. Next, 3,6-dibromo-1,2-diazine (758.88 mg, 3.19 mmol, 1.0 eq) was added, and the resulting mixture was stirred overnight at 60 °C. The reaction mixture was then cooled to room temperature and poured into water. The aqueous layer was extracted with EA (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by silica gel chromatography, eluting with DCM:MeOH (10:1, 0.5% TEA) to give 8-((6-bromopyridazin-3-yl)oxy)-6,6-dimethyl-5-azaspiro[3.5]nonane (860 mg, 82.60%). LC / MS (ESI): 326.2 [M+H] + .

[0624] Step 7: Under nitrogen atmosphere, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (211.0 mg, 1.0 mmol, 1.0 eq), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (244.1 mg, 1.10 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf).CH2Cl2 adduct (73.3 mg, 0.1 mmol, 0.1 eq) were transferred to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85°C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (150.1 mg, 68%) as a brown solid. LC / MS (ESI): 229.1 [M+H] + .

[0625] Step 8: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (34.2 mg, 0.15 mmol, 1.0 eq), 8-((6-bromopyridazin-3-yl)oxy)-6,6-dimethyl-5-azaspiro[3.5]nonane (48.9 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with A. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoindolin-1-one (42.2 mg), which was dissolved in HCl-dioxane (2 mL, 4.0 mol / L). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(6-((6,6-dimethyl-5-azaspiro[3.5]nonane-8-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (4.94 mg, 6.9%) as a white solid.

[0626] 1 H NMR (DMSO-d6, 400 MHz) δ = 8.95 (d, J = 2.0 Hz, 1H), 8.71 (d, J =9.6 Hz, 1H), 8.22 (s, 1H), 8.19 - 8.15 (m, 2H), 7.35 (d, J = 9.6 Hz, 1H),5.57 - 5.46 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 2.57 - 2.52 (m, 1H), 2.36(s, 3H), 2.21 - 2.07 (m, 4H), 1.94 - 1.85 (m, 1H), 1.83 - 1.65 (m, 2H), 1.55- 1.40 (m, 2H), 1.21 (s, 3H), 1.16 (s, 3H); LC / MS (ESI): 474.2 [M+H]+ .

[0627] Example 20. Synthesis of 3-(2,4-dimethylthiazo-5-yl)-6-(6-(2-oxopiperazin-1-yl)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 255)

[0628] Step 20.

[0629]

[0630] Step 1: A solution of 2-methylpropyl-2-yl 3-oxoperazine-1-carboxylic acid (2.00 g, 9.99 mmol, 1.00 eq), 3,6-dibromo-1,2-diazine (11.89 g, 99.90 mmol, 5.00 eq), Cs₂CO₃ (9.76 g, 29.97 mmol, 3.00 eq), Pd(dba)Cl₂ (1.00 g, 1.00 mmol, 0.10 eq), and Xanphos (1.00 g, 2.00 mmol, 0.20 eq) in 1,4-dioxane (150 mL) was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using a PE / EA 20 / 1~5 / 1 v / v apparatus to give a yellow solid, 2-methylpropyl-2-yl-4-(6-bromo-1,2-diazin-3-yl)-3-oxopiperazine-1-carboxylate (655 mg, 1.83 mmol, 18.36%). LC / MS (ESI): 357.2 [M+H] + .

[0631] Step 2: A mixture of 3-(2,4-dimethyl-1,3-thiazolyl-5-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (100 mg, 0.41 mmol, 1.0 eq), 4-(6-bromo-1,2-diazin-3-yl)-3-oxopiperazin-1-carboxylic acid 2-methylpropyl-2-yl ester (174.75 mg, 0.49 mmol, 1.2 eq), Cs₂CO₃ (398.48 mg, 1.22 mmol, 3.0 eq), and XantPhos Pd G4 (66.04 mg, 0.04 mmol, 0.1 eq) in dioxane (1 mL) was stirred at 100 °C for 3 h under N₂. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give a brown solid, 2-methylpropyl-2-yl 4-{6-[3-(2,4-dimethyl-1,3-thiazo-5-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-6-yl]-1,2-diazin-3-yl}-3-oxopiperazine-1-carboxylic acid (100 mg, 47.03%). LC / MS (ESI): 522.18 [M+H] + .

[0632] Step 3: A solution of 4-{6-[3-(2,4-dimethyl-1,3-thiazo-5-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-6-yl]-1,2-diazin-3-yl}-3-oxopiperazine-1-carboxylic acid 2-methylpropyl-2-yl ester (100 mg, 0.19 mmol) in 1,4-dioxane (4 M, 4 mL) containing HCl (g) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 50:1-25:1-10:1). The product was ground with MeOH and filtered to give a white solid 3-(2,4-dimethyl-1,3-thiazo-5-yl)-6-[6-(2-oxopiperazin-1-yl)-1,2-diazin-3-yl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (20.28 mg, 25.09%). LC / MS (ESI): 422.1 [M+H] + .

[0633] 1H NMR (400 MHz, DMSO- d6) δ= 9.77 (br s, 2H), 8.98 (d, J = 2.1 Hz,1H), 8.84 (d, J = 9.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 9.8 Hz,1H), 5.29 (s, 2H), 4.31 - 4.22 (m, 2H), 4.02 (s, 2H), 3.65 - 3.58 (m, 2H),2.68 (s, 3H), 2.43 (s, 3H); LC / MS (ESI): 422.95 [M+H] + .

[0634] Example 21. Synthesis of (S)-6-(6-(3-isopropylpiperazin-1-yl)pyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 157)

[0635] Step 21.

[0636]

[0637] Step 1: Under nitrogen atmosphere, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H-pyrazole (312.0 mg, 1.5 mmol, 1.5 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (183.2 mg, 85.2%) as a brown solid. LC / MS (ESI): 215.1 [M+H] + .

[0638] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (32.2 mg, 0.15 mmol, 1.0 eq), (S)-4-(6-bromopyridazin-3-yl)-2-isopropylpiperazine-1-carboxylic acid tert-butyl ester (57.6 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G₄ (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, followed by heating at 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. Wash the organic phase with brine, dry over sodium sulfate, and concentrate under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v, and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (9.51 mg, 15.2%) as a white solid.

[0639] 1 H NMR (DMSO-d6, 400 MHz) δ 9.12 (d, 1H, J = 2.0 Hz), 8.48 (d, 1H, J =10.0 Hz), 8.44 (s, 1H), 8.37 (d, 1H, J = 2.1 Hz), 8.18 (s, 1H), 8.14 (s, 1H),7.48 (d, 1H, J = 9.9 Hz), 5.14 (s, 2H), 4.27-4.34 (m, 1H), 4.11-4.19 (m, 1H),3.90 (s, 3H), 3.02-3.15 (m, 1H), 2.82-2.92 (m, 1H), 2.79-2.86 (m, 1H), 2.62-2.72 (m, 2H), 1.66-1.72 (m, 1H), 0.97 (d, 6H, J = 6.8 Hz); LC / MS (ESI): 419.2[M+H] + .

[0640] Example 22. Synthesis of 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)(methyl)amino)-1,2,4-triazin-6-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 175)

[0641] Step 22.

[0642]

[0643] Step 1: Amyl nitrite (2.18 mL, 18.29 mmol) was added to a solution of 6-bromo-1,2,4-triazine-3-amine (2.0 g, 11.43 mmol) and CuCl2 (1.47 g, 14.86 mmol) in MeCN (25 mL), and the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was then concentrated, and the resulting residue was purified by column chromatography (SiO2, PE:EA = 10:1) to give 6-bromo-3-chloro-1,2,4-triazine (220 mg, 1.13 mmol, 9.90%) as a yellow solid.

[0644] Step 2: DIEA (0.34 mL, 2.06 mmol) was added to a solution of 6-bromo-3-chloro-1,2,4-triazine (200 mg, 1.03 mmol) and (1R,5S)-N,1,5-trimethyl-8-azabicyclo[3.2.1]octane-3-amine (192.71 mg, 1.13 mmol) in toluene (10 mL), and the reaction mixture was stirred at 120 °C for 3 h. LC / MS showed that the reaction was complete. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (SiO2, DCM:MeOH = 10:1) to give (1R,3s,5S)-N-(6-bromo-1,2,4-triazine-3-yl)-N,1,5-trimethyl-8-azabicyclo[3.2.1]octane-3-amine (0.23 g, 67.65%) as a yellow solid.

[0645] Step 3: BrettPhos Pd G4 (13.61 mg, 0.01 mmol) and Cs₂CO₃ (146.62 mg, 0.45 mmol) were added to a solution of 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (35 mg, 0.15 mmol) and (1R,3S,5S)-N-(6-bromo-1,2,4-triazin-3-yl)-N,1,5-trimethyl-8-azabicyclo[3.2.1]octane-3-amine (52 mg, 0.16 mmol) in dioxane (10 mL); and the reaction mixture was stirred at 90 °C under N₂ for 16 h. LC / MS showed the reaction was complete. The reaction mixture was filtered and concentrated. The resulting residue was purified by pre-HPLC (TFA) to give 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(3-(((1R,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)(methyl)amino)-1,2,4-triazin-6-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (30.25 mg, 39.86%) as a yellow solid.

[0646] 1 ¹H NMR (DMSO-d₆, 400MHz) δ = 9.34 (s, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.18 (s, 2H), 5.13 (s, 2H), 5.01–5.10 (m, 1H), 3.82 (s, 3H), 3.02 (s, 3H), 2.36 (s, 3H), 1.78 (br d, J = 7.4 Hz, 2H), 1.51–1.65 (m, 6H), 1.20 (s, 6H), not observed in 1H (NH); LC / MS (ESI): 474.3 [M+H] + .

[0647] Example 23. Synthesis of 6-(6-((7-azabispiro[5.1.58.36]hexadecane-15-yl)oxy)pyridazin-3-yl)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound No. 243)

[0648] Step 23.

[0649]

[0650] Step 1: A solution of ethyl 5-bromo-2-methylnicotinate (3.00 g, 12.35 mmol, 1.00 eq), benzoyl peroxide (5.98 g, 24.70 mmol, 2.00 eq), and N-bromosuccinimide (4.37 g, 24.70 mmol, 2.00 eq) in carbon tetrachloride (30 mL) was stirred at 80 °C for 16 h. After the starting materials were consumed, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using a PE / EA 20 / 1~5 / 1 v / v filter to give ethyl 5-bromo-2-(bromomethyl)nicotinate (2.37 g, 7.41 mmol, 61.03%) as a white solid. LC / MS (ESI): 324.0 [M+H] + .

[0651] Step 2: A solution of ethyl 5-bromo-2-(bromomethyl)nicotinate (2.00 g, 6.23 mmol, 1.00 eq) and ammonia (1.06, 62.30 mmol, 10.0 eq) in isopropanol (10 mL) was stirred at 25 °C for 6 h. After the starting material was consumed, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 50 / 1~10 / 1 v / v to give 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (1.06 g, 5.04 mmol, 81.32%) as a white solid. LC / MS (ESI): 214.0 [M+H] + .

[0652] Step 3: Under nitrogen atmosphere, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (1.00 g, 5.0 mmol, 1.00 eq), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)thiazole (1.31 g, 5.50 mmol, 1.10 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf)CH2Cl2 adduct (365.7 mg, 0.50 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 3-(2,4-dimethylthiazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (335 mg, 68%) as a brown solid. LC / MS (ESI): 246.0 [M+H] + .

[0653] Step 4: A solution of 2,2,6,6-tetramethylhexahydropyridin-4-one (10.0 g, 64.42 mmol, 1.00 eq), cyclohexanone (18.97 g, 193.25 mmol, 3.00 eq), and NH4Cl (20.67 g, 386.50 mmol, 6.00 eq) in DMSO (30 mL) was stirred at 80 °C for 48 h. After the starting materials were consumed, the mixture was cooled to room temperature and diluted with 100 mL of water. The aqueous layer was extracted with EA (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography using a PE / EA 20 / 1~1 / 1 v / v filter to give spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane]-4-one (15 g, 57.99 mmol, 90.03%) as a white solid. LC / MS (ESI): 237.2 [M+H] + .

[0654] Step 5: At 0 °C, NaBH4 (0.51 g, 13.60 mmol, 0.50 eq) was added to a solution of spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane]-4-one (6.40 g, 27.19 mmol, 1.00 eq) in MeOH (65 mL); and the reaction mixture was stirred at room temperature for 3 h. After the starting material was consumed, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 50 / 1~20 / 1 v / v to give spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane]-4-ol (3.40 g, 14.32 mmol, 52.67%) as a yellow oil. LC / MS (ESI): 239.2 [M+H] + .

[0655] Step 6: At 0 °C for 30 min, NaH (0.76 g, 31.59 mmol, 2.50 eq) was added dropwise to a solution of spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane]-4-ol (3.00 g, 12.64 mmol, 1.00 eq) in THF (30 mL). The resulting mixture was then stirred at 25 °C under N2 for 0.5 h. Next, 3,6-dibromo-1,2-diazine (3.61 g, 15.16 mmol, 1.20 eq) was added, and the reaction mixture was stirred at 25 °C under N2 for 24 h. After the starting material was consumed, the reaction mixture was quenched with saturated ammonium chloride, and the reactants were concentrated under vacuum. The residue was extracted with EA (3 × 30 mL), and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using a PE / EtOAc 20 / 1~1 / 1 column to give a yellow solid 4-[(6-bromo-1,2-diazin-3-yl)oxy]spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane] (1.80 g, 4.43 mmol, 35.03%). LC / MS (ESI): 395.3 [M+H] + .

[0656] Step 7: At 25 °C, XPhos Pd G4 (0.20 g, 0.23 mmol, 0.10 eq) was added to a solution of 4-[(6-bromo-1,2-diazin-3-yl)oxy]spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane] (0.9 g, 2.28 mmol, 1.00 eq), 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (0.63 g, 2.74 mmol, 1.20 eq) and Cs2CO3 (2.23 g, 6.85 mmol, 3.00 eq) in 1,4-dioxane (15 mL); and the reaction mixture was stirred at 90 °C under N2 for 4 h. After the starting materials were consumed, the reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 50 / 1~10 / 1 v / v to give 3-(1,3-dimethylpyrazol-4-yl)-6-[6-(spiro[1-azaspiro[5.5]undecane-2,1'-cyclohexane]-4-yloxy)-1,2-diazin-3-yl]-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (0.43 g, 0.79 mmol, 34.82%) as a white solid.

[0657] 1 H NMR (400 MHz, DMSO-d6) δ = 8.95 (d, J = 2.0 Hz, 1H), 8.70 (d, J =9.6 Hz, 1H), 8.21 - 8.16 (m, 3H), 7.32 (d, J = 9.6 Hz, 1H), 5.61 - 5.51 (m,1H), 5.20 (s, 2H), 3.82 (s, 3H), 2.36 (s, 3H), 1.79 - 1.49 (m, 10H), 1.49 -1.30 (m, 14H); LC / MS (ESI): 542.4 [M+H] + .

[0658] Example 24. Synthesis of 6-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-4-fluoroisoindoline-1-one (Compound No. 283)

[0659] Step 24.

[0660]

[0661] Step 1: At 0 °C and under N2, nitrosonium tetrafluoroborate (480 mg, 4.10 mmol) was added fractionally to a solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL); the reaction mixture was stirred at 0 °C for 1 h. Then, ethylene oxide (30 mL) was added, and the reaction mixture was refluxed at 130 °C for 3 h. The reaction mixture was cooled to room temperature and poured into H2O, and the aqueous layer was extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%).

[0662] Step 2: AIBN (57 mg, 0.35 mmol) was added to a solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl)benzene (10 mL); and the reaction mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was then cooled to room temperature and poured into H2O. The aqueous layer was extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 70%).

[0663] Step 3: Add NH4OH (7 mL) to a solution of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 2.5 mmol) in THF (7 mL), and stir the reaction mixture at room temperature for 4 h. Filter the reaction mixture and concentrate it under vacuum. The crude product is used directly in the next step.

[0664] Step 4: Under nitrogen atmosphere, 6-bromo-4-fluoroisoindoline-1-one (343.0 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (762 mg, 3.0 mmol, 3.0 eq), potassium acetate (300 mg, 3.0 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were transferred to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the mixture was heated to 90 °C. When complete conversion was achieved, the reaction mixture was cooled to room temperature. Next, 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (211.9 mg, 1.0 mmol, 1.0 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf)CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added, and the mixture was heated to 90 °C. When complete conversion was achieved, the mixture was cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v to give 6-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-4-fluoroisoindolin-1-one (81.5 mg, 33%) as a brown solid. LC / MS (ESI): 247.1 [M+H] + .

[0665] Step 5: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-4-fluoroisoindoline-1-one (36.9 mg, 0.15 mmol, 1.0 eq), (1R,3S,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat at 90 °C for 8 h. The reaction mixture was cooled to room temperature and then diluted with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with DCM / MeOH 20 / 1 v / v and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-4-fluoroisoindolin-1-one (28.8 mg, 40.3%) as a white solid.

[0666] 1 H NMR (400 MHz, DMSO-d6) δ : 9.42 (br d, J = 7.4 Hz, 1H), 9.31 - 9.17(m, 1H), 8.72 (d, J = 9.6 Hz, 1H), 7.89 (s, 1H), 7.83 (dd, J = 0.8, 9.9 Hz,1H), 7.39 (d, J = 9.6 Hz, 1H), 5.52 (td, J = 5.3, 10.8 Hz, 1H), 5.27 (s, 2H),4.16 (s, 3H), 2.48 (s, 3H), 2.41 (br dd, J = 5.8, 13.3 Hz, 2H), 2.13 (br d, J= 8.0 Hz, 2H), 1.95 - 1.81 (m, 4H), 1.48 (s, 6H); LC / MS (ESI): 478.2 [M+H] + .

[0667] Example 25. Synthesis of (S)-2-(6-(3-(tert-butyl)piperazin-1-yl)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoroisoindoline-1-one (Compound No. 295)

[0668] Step 25.

[0669]

[0670] Step 1: DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 eq) were added to a solution of (2S)-2-({[(9H-fluorene-9-ylmethyl)oxy]carbonyl}amino)-3,3-dimethylbutyric acid (10 g, 28.29 mmol, 1.0 eq) and methyl glycine (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered to obtain a pale yellow solid, {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-ylmethyl ester (9.5 g, 22.38 mmol, 79.09%). LC / MS (ESI): 425.5 [M+H] + .

[0671] Step 2: A solution of {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-yl methyl ester (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was concentrated under vacuum to give {[(7S)-8,8-dimethyl-3,6-dioxo-5-aza-2-oxonon-7-yl]amino}carboxylic acid 9H-fluorene-9-yl methyl ester (4.85 g, 11.43 mmol, 97.00%) as a pale yellow solid. LC / MS (ESI): 171.2 [M+H] + .

[0672] Step 3: In an ice bath, LiAlH4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorously stirred solution of (3S)-3-(2-methylpropyl-2-yl)piperazine-2,5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL), and the resulting reaction mixture was stirred at 70 °C for 16 h. Next, the mixture was poured into KOH (6N), stirred in an ice bath for 1 h, and then filtered. The filtrate was extracted with EA, washed with brine, dried over Na2SO4, and concentrated under vacuum to give (2S)-2-(2-methylpropyl-2-yl)piperazine (1.2 g, 8.44 mmol, 89.74%) as a yellow oil. LC / MS (ESI): 143.2 [M+H] + .

[0673] Step 4: At room temperature, DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorously stirred solution of (2S)-2-(2-methylpropyl-2-yl)piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3,6-diiodo-1,2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL), and the reaction mixture was stirred at 120 °C for 16 h. Next, the mixture was concentrated under vacuum, and the resulting residue was diluted with EA, washed with water and brine, dried over Na₂SO₄, and concentrated under vacuum to give 6-iodo-3-[(3S)-3-(2-methylpropyl-2-yl)piperazin-1-yl]-1,2-diazine (450 mg, 1.30 mmol, 36.98%) as a yellow solid. LC / MS (ESI): 347.2 [M+H] + .

[0674] Step 5: Pd(dppf)Cl2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorously stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (250 mg, 1.20 mmol, 1.0 eq), 3-bromo-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq) and K2CO3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL), and the resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 10 / 1 v / v to give a pale yellow solid, 3-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-5-one (135 mg, 0.63 mmol, 52.51%). LC / MS (ESI): 215.2 [M+H] + .

[0675] Step 6: At 0 °C and under N2, nitrosonium tetrafluoroborate (480 mg, 4.10 mmol) was added fractionally to a solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL), and the resulting reaction mixture was stirred at 0 °C for 1 h. Then, ethylene oxide (30 mL) was added, and the reaction mixture was refluxed at 130 °C for 3 h. The reaction mixture was cooled to room temperature and poured into H2O. The aqueous layer was extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%).

[0676] Step 7: AIBN (57 mg, 0.35 mmol) was added to a solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl)benzene (10 mL); and the reaction mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was then cooled to room temperature and poured into H2O. The aqueous layer was extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 70%).

[0677] Step 8: Add NH4OH (7 mL) to a solution of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (800 mg, 2.5 mmol) dissolved in THF (7 mL), and stir the reaction mixture at room temperature for 4 minutes. Filter the reaction mixture and concentrate it under vacuum. The crude product is used directly in the next step.

[0678] Step 9: Under nitrogen atmosphere, 6-bromo-4-fluoroisoindoline-1-one (228 mg, 1.0 mmol, 1.0 eq), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (244.1 mg, 1.10 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf).CH2Cl2 adduct (73.3 mg, 0.1 mmol, 0.1 eq) were transferred to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the reaction mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoroisoindolin-1-one (134.7 mg, 55%) as a brown solid. LC / MS (ESI): 246.1 [M+H] + .

[0679] Step 10: 6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoroisoindoline-1-one (50 mg, 0.23 mmol, 1.0 eq) and 6-iodo-3-[(3S)-3-(2-methylpropyl-2-yl)piperazin-1-yl]-1,2-diazine (80 mg, 0.23 mmol, 1.0 eq) were dissolved in DMF (2 mL), and CuI (4 mg, 0.02 mmol, 0.10 eq), K₂CO₃ (97 mg, 0.70 mmol, 3.0 eq), and (1R,2R)-cyclohexane-1,2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) were added. The resulting reaction mixture was stirred at 100 °C for 16 h. Next, the reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by pre-HPLC to obtain (S)-2-(6-(3-(tert-butyl)piperazin-1-yl)pyridazin-3-yl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoroisoindololin-1-one (24.19 mg, 21.55%) as a white solid.

[0680] 1 H NMR (DMSO-d6, 400MHz) δ = 8.46 (d, J = 9.9 Hz, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.61 - 7.56 (m, 1H), 7.47 (d, J = 10.0 Hz, 1H), 5.18 (s, 2H),4.36 (br d, J = 12.1 Hz, 1H), 4.12 (br d, J = 11.9 Hz, 1H), 3.80 (s, 3H),3.08 (br d, J = 11.4 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.65 - 2.57 (m, 1H), 2.39(dd, J = 2.4 (10.8 Hz, 1H), 2.35 (s, 3H), 0.96 (s, 9H), 1H not observed (NH); LC / MS (ESI): 464.2 [M+H] + .

[0681] Example 26. Synthesis of 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridazin-3-yl)-6-(2,4-dimethylthiazo-5-yl)-4-fluoroisoindololin-1-one (Compound No. 300)

[0682] Step 26.

[0683]

[0684] Step 1: Under nitrogen atmosphere, 6-bromo-4-fluoroisoindoline-1-one (457.9 mg, 2.0 mmol, 1.0 eq), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)thiazole (526.1 mg, 2.20 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf)·CH2Cl2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were transferred into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the reaction mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(2,4-dimethylthiazol-5-yl)-4-fluoroisoindolin-1-one (273.6 mg, 57%) as a brown solid. LC / MS (ESI): 263.1 [M+H] + .

[0685] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(2,4-dimethylthiazol-5-yl)-4-fluoroisoindoline-1-one (37.4 mg, 0.15 mmol, 1.0 eq), 7-(6-bromopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (55.2 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and then dilute with EA. Wash the organic phase with brine, dry with sodium sulfate, and concentrate under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)isoindolin-1-one (42.2 mg), which was dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)pyridazin-3-yl)-6-(2,4-dimethylthiazo-5-yl)-4-fluoroisoindolin-1-one (13.59 mg, 20.1%) as a white solid.

[0686] 1 HNMR (400 MHz, DMSO-d6) δ = 8.44 (d, J = 9.9 Hz, 1H), 8.15 (d, J =1.0 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.63 (s, 1H), 7.44 (d, J = 10.0 Hz, 1H),5.24 (s, 2H), 3.58 - 3.53 (m, 2H), 3.44 (s, 2H), 2.89 (br d, J = 4.5 Hz, 2H),2.66 (s, 3H), 2.43 (s, 3H), 0.51 (br d, J = 9.8 Hz, 4H); LC / MS (ESI): 451.1[M+H] + .

[0687] Example 27. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)isoindoline-1-one (Compound No. 416)

[0688] Step 27.

[0689]

[0690] Step 1: Under nitrogen atmosphere, 6-bromoisoindoline-1-one (426.0 mg, 2.0 mmol, 1.0 eq), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (488 mg, 2.20 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf).CH2Cl2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were transferred into a three-necked 100 mL round-bottom flask. Anhydrous dioxane (9 mL) was added, and the reaction mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)isoindolin-1-one (335 mg, 68%) as a brown solid. LC / MS (ESI): 228.1 [M+H] + .

[0691] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(1,3-dimethyl-1H-pyrazol-4-yl)isoindoline-1-one (34.2 mg, 0.15 mmol, 1.0 eq), (1R,3s,5S)-3-((6-bromopyridazin-3-yl)oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61.8 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and then dilute with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v, and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)isoindoline-1-one (16.84 mg, 23.4%) as a white solid.

[0692] 1 H NMR (DMSO-d6, 400 MHz) δ = 8.73 (d, J = 9.6 Hz, 1H), 8.20 (br d, J= 4.5 Hz, 1H), 8.06 (s, 1H), 7.81 - 7.77 (m, 2H), 7.76 - 7.73 (m, 1H), 7.33(d, J = 9.5 Hz, 1H), 5.49 (s, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.34 (s, 3H),2.33 - 2.29 (m, 2H), 2.03 - 1.93 (m, 2H), 1.72 (br d, J = 2.5 Hz, 2H), 1.66 -1.56 (m, 2H), 1.34 (br s, 6H); LC / MS (ESI): 459.3 [M+H] + .

[0693] Example 28. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 116)

[0694] Step 28.

[0695]

[0696] Step 1: At -78°C and under N2, LDA (48 mL, 2.0 mol in THF) was added dropwise to a solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.52 mmol) in 200 mL of THF, and the reaction mixture was stirred at -78°C for 2 h. The mixture was then poured into THF containing CO2 (solid). The reaction mixture was then concentrated under vacuum. The pH of the residue was adjusted to 3 with 2 M HCl. The resulting mixture was extracted with EA, washed with brine, dried over MgSO4, and concentrated under vacuum to give the desired product (12 g, crude material) as a white solid.

[0697] Step 2: MeI (3.4 mL, 54.7 mmol) was added fractionally to a solution of 5-bromo-2-chloro-3-fluoroisonicotinic acid (12 g, 51.2 mmol) and K₂CO₃ (5.7 g, 41.7 mmol) in DMF (80 mL); the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H₂O. The aqueous layer was extracted with EA. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 5-bromo-2-chloro-3-fluoroisonicotinic acid (10 g, 79%).

[0698] Step 3: Potassium carbonate (2600 mg, 18.8 mmol) and PdCl2 (dppf) (500 mg, 0.94 mmol) were added to a solution of 5-bromo-2-chloro-3-fluoroisonicotinic acid ester (2500 mg, 9.4 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboroxane in dioxane (25 mL); and the reaction mixture was stirred at 110 °C for 1 h under N2. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA. The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using PE / EA 10 / 1 v / v to give methyl 2-chloro-3-fluoro-5-methylisonicotinic acid ester (673 mg, 35.3%).

[0699] Step 4: Add BPO (40 mg, 0.16 mmol) to a solution of methyl 2-chloro-3-fluoro-5-methylisonicotinic acid (320 mg, 1.6 mmol) and NBS (285 mg, 1.6 mmol) in CCl4 (10 mL); and stir the reaction mixture at 80 °C under N2 for 16 h. Cool the mixture to room temperature and then pour it into H2O. Extract the aqueous layer with EA. Wash the organic layer with brine, dry over MgSO4, filter and concentrate. Purify the crude product by silica gel column chromatography with PE / EA 5 / 1 v / v to give methyl 5-(bromomethyl)-2-chloro-3-fluoroisonicotinic acid (356 mg, 80%).

[0700] Step 5: Methyl 5-(bromomethyl)-2-chloro-3-fluoroisonicotinic acid (356 mg, 1.26 mmol) was dissolved in THF (5 mL), and NH4OH (5 mL) was added; the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was used directly in the next step.

[0701] Step 6: Under nitrogen atmosphere, 6-chloro-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (186.0 mg, 1.0 mmol, 1.0 eq), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (312 mg, 1.5 mmol, 1.5 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2(dppf).CH2Cl2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were added to a three-necked 100 mL round-bottom flask, followed by the addition of anhydrous dioxane (9 mL), and the reaction mixture was heated to 85 °C overnight. The mixture was cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100.8 mg, 41.2%) as a brown solid. LC / MS (ESI): 247.1 [M+H] + .

[0702] Step 7: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(1,3-dimethyl-1H-pyrazol-4-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (36.9 mg, 0.15 mmol, 1.0 eq), (S)-4-(6-bromopyridazin-3-yl)-2-isopropylpiperazine-1-carboxylic acid tert-butyl ester (57.6 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G₄ (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, and then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v, and then dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-7-fluoro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (3.93 mg, 5.6%) as a white solid.

[0703] 1 HNMR (400 MHz, methanol-d4) δ = 8.72 - 8.67 (m, 2H), 8.44 (s, 1H), 8.00(d, J = 3.3 Hz, 1H), 7.15 (d, J = 9.6 Hz, 1H), 5.58 - 5.44 (m, 1H), 5.18 (s,2H), 3.81 (s, 3H), 2.45 - 2.38 (m, 5H), 2.16 (br d, J = 8.3 Hz, 2H), 1.90 -1.82 (m, 2H), 1.68 (br t, J = 12.0 Hz, 2H), 1.40 (s, 6H); LC / MS (ESI): 478.2[M+H] + .

[0704] Example 29. Synthesis of 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound No. 93)

[0705] Step 29.

[0706]

[0707] Step 1: H₂O₂ (42.16 mL, 351.35 mmol) was added to TFA (50 mL) containing methyl 2-chloro-3-methylisonicotinic acid (5000 mg, 27.03 mmol), and the mixture was stirred for 4 h. The mixture was cooled to room temperature and quenched with aqueous Na₂SO₃ solution. The mixture was concentrated under vacuum, and the residue was redissolved in EA (300 mL). The mixture was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with PE / EtOAc to give 2-chloro-4-(methoxycarbonyl)-3-methylpyridine 1-oxide (3000 mg, 14.85 mmol, 54.95%). LC / MS (ESI): 202.0 [M+H] + .

[0708] Step 2: At room temperature, POBr3 (6398.79 mg, 22.32 mmol) was added to a solution of 2-chloro-4-(methoxycarbonyl)-3-methylpyridine 1-oxide (3000 mg, 14.88 mmol) in toluene (30 mL), and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and quenched with aqueous Na2CO3 solution. This mixture was extracted with EA (3 × 100 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 2:1, to give methyl 6-bromo-2-chloro-3-methylisonicotinic acid (1500 mg, 5.67 mmol, 38.11%) as a white solid. LC / MS (ESI): 263.9 [M+H] + .

[0709] Step 3: Methyl 6-bromo-2-chloro-3-methylpyridine-4-carboxylate (1500 mg, 5.67 mmol), NBS (1513.80 mg, 8.50 mmol), and AIBN (0.17 mL, 1.13 mmol) were combined with carbon tetrachloride (40 mL); the reaction mixture was heated to 80 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography with PE / EA to give ethyl 6-bromo-3-(bromomethyl)-2-chloropyridine-4-carboxylate (1150 mg, 3.35 mmol, 59.05%) as a brown solid. LC / MS (ESI): 341.8 [M+H] + .

[0710] Step 4: Methyl 6-bromo-3-(bromomethyl)-2-chloropyridine-4-carboxylate (1150 mg, 3.35 mmol) was suspended in a 28% aqueous solution of ammonium hydroxide, and the mixture was stirred at room temperature for 8 h. The mixture was then filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum, and used in the next step without further purification. LC / MS (ESI): 246.9 [M+H] + .

[0711] Step 5: 6-Bromo-4-chloro-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (550 mg, 2.22 mmol), 2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3-triazole (545.35 mg, 2.44 mmol), K₂CO₃ (921.41 mg, 6.67 mmol), and Pd(dppf)Cl₂ (162.62 mg, 0.22 mmol) were placed in a 100 mL round-bottom flask. The flask was placed under nitrogen atmosphere, and anhydrous dioxane (9 mL) and water (1 mL) were added. The mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth filter, and washed with EA (50 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give a brown solid, 4-chloro-6-(2,5-dimethyl-1,2,3-triazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (400 mg, 1.52 mmol, 68.26%). LC / MS (ESI): 263.1 [M+H] + .

[0712] Step 6: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 4-chloro-6-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (120 mg, 0.46 mmol), 2-methylpropyl-2-yl(1S,3s,5R)-3-[(6-iodo-1,2-diazin-3-yl)oxy]-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate (230.80 mg, 0.50 mmol), Cs₂CO₃ (446.50 mg, 1.37 mmol), and XantPhos Pd G4 (43.96 mg, 0.05 mmol). Degas the reaction mixture with argon for 5 min, and then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and then dilute with EA. The organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give (1S,3s,5R)-3-({6-[4-chloro-6-(1,3-dimethylpyrazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-2-yl]-1,2-diazin-3-yl}oxy)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid 2-methylpropyl-2-yl ester (40 mg), which was dissolved in dioxane (2 mL, 4.0 mol / L) containing HCl. The reaction mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by RP HPLC using MeCN and H2O as eluents to give 4-chloro-6-(1,3-dimethylpyrazol-4-yl)-2-(6-{[(1S,3s,5R)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl]oxy}-1,2-diazin-3-yl)-2,3-dihydro-1H-pyrrolo[4,3-c]pyridin-1-one (10.3 mg, 0.02 mmol, 4.53%) as a white solid.

[0713] 1H NMR (DMSO-d6, 400 MHz) δ=8.96 (br d, J = 8.8 Hz, 1H), 8.85 (br d, J= 9.3 Hz, 1H), 8.70 (d, J = 9.6 Hz, 1H), 8.47 (s, 1H), 7.94 (s, 1H), 7.41 (d,J = 9.6 Hz, 1H), 5.61 - 5.47 (m, 1H), 5.16 (s, 2H), 3.82 (s, 3H), 2.48 - 2.42(m, 5H), 2.16 (br d,J = 8.0 Hz, 2H), 1.95 - 1.75 (m, 4H), 1.45 (s, 6H); LC / MS (ESI): 494.1 [M+H] + .

[0714] Example 30. Synthesis of 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(7-ethyl-2,7-diazaspiro[4.4]nonane-2-yl)pyridazin-3-yl)-5-fluoroisoindoline-1-one (compound number 414)

[0715] Step 30.

[0716]

[0717] Step 1: Ethyl 5-bromo-4-fluoro-2-methylbenzoate (2.60 g, 10.0 mmol, 1.0 eq), N-bromosuccinimide (2.49 g, 14.0 mmol, 1.4 eq), and benzoyl peroxide (242 mg, 1.0 mmol, 0.1 eq) were combined with carbon tetrachloride (150 mL). The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography with PE / EA to give ethyl 5-bromo-2-(bromomethyl)-4-fluorobenzoate (2.61 g, 77%) as a brown solid. LC / MS (ESI): 338.9, 340.9, 342.9 [M+H] + .

[0718] Step 2: Ethyl 5-bromo-2-(bromomethyl)-4-fluorobenzoate (2.61 g, 7.7 mmol, 1.0 eq) was suspended in 28% ammonium hydroxide aqueous solution, and the mixture was stirred at room temperature for 8 h. The mixture was then filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum, and used in the next step without further purification. LC / MS (ESI): 230.0, 232.0 [M+H] + .

[0719] Step 3: Under nitrogen atmosphere, 6-bromo-5-fluoroisoindoline-1-one (456.0 mg, 2.0 mmol, 1.0 eq), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (488 mg, 2.20 mmol, 1.1 eq), potassium carbonate aqueous solution (2 M, 8 mL), and PdCl2(dppf).CH2Cl2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask, and anhydrous dioxane (9 mL) was added. The mixture was heated to 85 °C overnight. The mixture was cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoroisoindolin-1-one (298.9 mg, 61%) as a brown solid. LC / MS (ESI): 246.1 [M+H] + .

[0720] Step 4: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 6-(1,3-dimethyl-1H-pyrazol-4-yl)isoindoline-1-one (34.2 mg, 0.15 mmol, 1.0 eq), 7-(6-bromopyridazin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (57.3 mg, 0.15 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G₄ (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. Wash the organic phase with brine, dry with sodium sulfate, and concentrate under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give tert-butyl 7-(6-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoro-1-oxoisoindoline-2-yl)pyridazin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (69 mg, 77%) as a brown solid. LC / MS (ESI): 578.3 [M+H] + .

[0721] Step 5: Add MeOH (4 mL) to a round-bottom flask containing 7-(6-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoro-1-oxoisoindoline-2-yl)pyridazin-3-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (69 mg, 0.12 mmol, 1.0 eq) and acetaldehyde (0.3 mL, 1.52 mmol, 12.0 eq); and stir the reaction mixture at 0 °C for 1 h. Then, add NaBH3CN (37.24 mg, 0.76 mmol, 6.0 eq), and stir the reaction mixture at room temperature for 1 h. The reactants were concentrated, and the resulting residue was purified by RP-HPLC using MeCN and H2O as eluents to give 6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(6-(7-ethyl-2,7-diazaspiro[4.4]nonane-2-yl)pyridazin-3-yl)-5-fluoroisoindolin-1-one (9.02 mg, 0.01 mmol, 12.6%) as a white solid.

[0722] 1H NMR (400 MHz, methanol-d4) δ : 8.58 (d, J = 9.9 Hz, 1H), 7.85 (d, J =6.9 Hz, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 9.9 Hz, 1H), 7.07 (d, J =9.9 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 3.64 - 3.50 (m, 4H), 3.10 (br t, J =6.8 Hz, 2H), 3.05 - 2.97 (m, 2H), 2.89 (q, J = 7.3 Hz, 2H), 2.33 (s, 3H),2.20 - 2.10 (m, 2H), 2.04 (dt, J = 2.6, 7.1 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H); LC / MS (ESI): 476.3 [M+H] + .

[0723] Example 31. Synthesis of 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoindoline-1-one (Compound No. 451)

[0724] Procedure 31.

[0725]

[0726] Step 1: Under nitrogen atmosphere, 5-bromoisoindoline-1-one (315 mg, 1.5 mmol, 1.5 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (762 mg, 3.0 mmol, 3.0 eq), potassium acetate (300 mg, 3.0 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added to a three-necked 100 mL round-bottom flask, along with anhydrous dioxane (9 mL), and the mixture was heated to 90 °C. When complete conversion was achieved, the reaction mixture was cooled to room temperature. Next, 5-bromo-3-methyl-1,2,4-thiadiazole (177.3 mg, 1.0 mmol, 1.0 eq), potassium carbonate aqueous solution (2 M, 2 mL), and PdCl2 (dppf)CH2Cl2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added, and the reaction mixture was heated to 90 °C. When complete conversion was achieved, the mixture was cooled, filtered through a diatomaceous earth pad, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v to give 5-(3-methyl-1,2,4-thiadiazole-5-yl)isoindolin-1-one (71.9 mg, 31%) as a brown solid. LC / MS (ESI): 232.1 [M+H] + .

[0727] Step 2: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 5-(3-methyl-1,2,4-thiadiazol-5-yl)isoindoline-1-one (34.8 mg, 0.15 mmol, 1.0 eq), 3-bromo-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (50.0 mg, 0.16 mmol, 1.1 eq), Cs₂CO₃ (148.9 mg, 0.46 mmol, 3.0 eq), and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq). Degas the reaction mixture with argon for 5 min, then heat to 90 °C for 8 h. Cool the reaction mixture to room temperature and dilute with EA. Wash the organic phase with brine, dry over sodium sulfate, and concentrate under vacuum. The crude product was purified by silica gel column chromatography using DCM / MeOH 20 / 1 v / v. The resulting residue was further purified by RP HPLC using MeCN and H2O as eluents to give 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoindoline-1-one (20.68 mg, 29.7%) as a white solid.

[0728] 1 H NMR (400 MHz, DMSO-d6) δ = 9.16 (d, J = 1.9 Hz, 1H), 8.74 (dd, J =2.6, 9.4 Hz, 1H), 8.71 - 8.67 (m, 1H), 8.47 - 8.44 (m, 1H), 8.42 (d, J = 2.0Hz, 1H), 8.16 (s, 1H), 5.23 (d, J = 5.5 Hz, 2H), 4.13 (br s, 1H), 4.06 - 4.03(m, 1H), 3.90 (s, 3H), 3.54 - 3.44 (m, 1H), 2.76 (br d, J = 14.6 Hz, 1H),2.44 - 2.34 (m, 1H), 2.22 - 2.14 (m, 1H), 2.11 - 2.07 (m, 1H), 2.06 - 1.96(m, 2H), 1.85 - 1.70 (m, 1H), 1.58 (br d, J = 8.0 Hz, 1H); LC / MS (ESI): 402.2[M+H] + .

[0729] Example 32. Synthesis of 3-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(6-(((1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl)(methyl)amino)pyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (Compound No. 452)

[0730] Procedure 32.

[0731]

[0732] Step 1: Under nitrogen atmosphere, methyl 6-bromo-3-chloropyrazine-2-carboxylate (400 mg, 1.59 mmol, 1.0 eq), (2,5-dimethylpyrazol-3-yl)boronic acid (222.52 mg, 1.59 mmol, 1.0 eq), sodium carbonate (505.57 mg, 4.77 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (116.28 mg, 0.16 mmol, 0.1 eq) were placed into a three-necked 100 mL round-bottom flask, and anhydrous dioxane (9 mL) and water (1 mL) were added. The reaction mixture was heated to 85 °C overnight. The mixture was then cooled, filtered through a diatomaceous earth mat, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using a PE / EA 5 / 1v / v filter to give methyl 3-chloro-6-(1,3-dimethylpyrazol-4-yl)pyrazin-2-carboxylate (300 mg, 70.72%). LC / MS (ESI): 267.0 [M+H] + .

[0733] Step 2: Under nitrogen atmosphere, methyl 3-chloro-6-(1,3-dimethylpyrazol-5-yl)pyrazin-2-carboxylate (500 mg, 1.87 mmol, 1.2 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (1.29 mL, 2.25 mmol, 1.0 eq), potassium carbonate (777.31 mg, 5.62 mmol, 3.0 eq), and PdCl2(dppf).CH2Cl2 adduct (137.05 mg, 0.19 mmol, 0.1 eq) were added to a three-necked 100 mL round-bottom flask. Anhydrous dioxane (10 mL) was added, and the reaction mixture was heated to 110 °C for 3 h. The mixture was then cooled, filtered through a diatomaceous earth filter, and the filter cake was washed with EA (100 mL). The filtrate was washed with brine, and the organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using PE / EA 5 / 1 v / v to give methyl 6-(1,3-dimethylpyrazol-5-yl)-3-methylpyrazine-2-carboxylate (430 mg, 93.13%). LC / MS (ESI): 247.1 [M+H] + .

[0734] Step 3: Methyl 6-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxylate (430 mg, 1.75 mmol, 1.0 eq), N-bromosuccinimide (371.67 mg, 2.10 mmol, 1.2 eq), and benzoyl peroxide (129.17 mg, 0.79 mmol, 0.45 eq) were combined with carbon tetrachloride (10 mL), and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography with PE / EA to give methyl 3-(bromomethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazine-2-carboxylate (440 mg, 77.32%) as a brown solid. LC / MS (ESI): 325.1, 327.1 [M+H] + .

[0735] Step 4: Methyl 3-(bromomethyl)-6-(1,3-dimethylpyrazol-4-yl)pyrazin-2-carboxylate (440 mg, 1.35 mmol, 1.0 eq) was suspended in 28% ammonium hydroxide aqueous solution, and the mixture was stirred at room temperature for 8 h. The mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum, and used in the next step without further purification. LC / MS (ESI): 230.1 [M+H] +

[0736] Step 5: Add 1,4-dioxane (4 mL) to a round-bottom flask containing 3-(1,3-dimethylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyrazin-5-one (40...

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof: in, The ring C is a 4- to 10-membered heterocyclic alkyl or a 4- to 10-membered heterocyclic alkenyl; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form an oxygen group; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; Each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or X represents non-existent, -CH2-, -O-, -OCH2-, -S-, or -NR. 3 -; R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each A is independently N or CR 4 Where at least two A's are N; Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl; or R 3 And an R 4 Together they form 5- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups; B is N or CR 5 ; D is N or CR 6 ; E is N or CR 7 ; F is N or CR 8 ; R 5 R 6 R 7 or R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -OCH2R a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, 5- to 10-membered heteroaryl or -O-(C1-C6 alkylene)-5- to 10-membered heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic alkyl or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Where R 5 R 6 R 7 or R 8 At least one of them is a C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl or -O-(C1-C6 alkylene)-5- to 10-membered heteroaryl, wherein the alkenyl, cycloalkyl, heterocycloalkyl and heteroaryl are optionally selected from 1 to 4 of R e Substituents of the substituents; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and p is an integer from 1 to 9.

2. A compound having the structure of formula (I') or a pharmaceutically acceptable salt or solvate thereof: in, The ring C is a 4- to 10-membered heterocyclic alkyl or a 4- to 10-membered heterocyclic alkenyl; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form an oxygen group; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; Each R 2 Independently, it is hydrogen, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; or X represents non-existence, -CH2-, -O-, -S-, or -NR. 3 -; R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each A is independently N or CR 4 Where at least two A's are N; Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl; B is N or CR 5 ; D is N or CR 6 ; E is N or CR 7 ; F is N or CR 8 ; R 5 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents; R 6 or R 7 One of them is optionally selected from 1 to 4 independently chosen from R 10 The substituents are 5 to 10-membered heteroaryl groups; and R 6 or R 7 The other one is hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents of R; where R 7 Not a pyridinyl group substituted with two methoxy groups; Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or Two Rs 10 Together they form an oxygen group; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and p is an integer from 1 to 9.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 2 It is hydrogen independently.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein D is a CR 6 Or E is CR 7 .

5. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 6 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 10 heteroaryl groups; and R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted.

6. The compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 Hydrogen, halogen, -OH, -OR a C1-C6 alkyl or C1-C6 haloalkyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It is hydrogen.

8. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein: R 6 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; wherein each of the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted; and R 7 To be optionally selected from 1 to 4 independently selected from R 10 The substituents are 5 to 10 heteroaryl groups.

9. The compound of claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 Hydrogen, halogen, -OH, -OR a C1-C6 alkyl or C1-C6 haloalkyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 It is hydrogen.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein the ring C is a 6-membered heterocyclic alkyl group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein the ring C is piperidine, piperazine, or morpholine.

13. The compound of claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is piperazine.

14. The compound of claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein ring C is piperidine.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein... in, Z is either N or CH; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form an oxygen group; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents are substituted; and Each R e It can be independently a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 heteroaryl.

16. The compound of claim 14 or a pharmaceutically acceptable salt or solvate thereof, wherein... in, Each R 1 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form a C1-C3 alkylene or a C1-C3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl groups; and R 9 It is hydrogen.

17. The compound according to any one of claims 1 to 12 or 14 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein... for , , , , , , , , , , , , , , , , , , , , , , , or .

18. The compound of claim 17 or a pharmaceutically acceptable salt or solvate thereof, wherein... for or .

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O- or -NR. 3 - 20. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein X is absent; and for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (II') or a pharmaceutically acceptable salt or solvate thereof: in, Ring G is a 5- to 10-membered heteroaryl group; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form an oxygen group; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; X represents a bond, -CH2-, -O-, -S-, or -NR. 3 -; Z is CH or N, where X is -O-, -S-, or -NR. 3 When -, then Z is CH; R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; Each A is independently N or CR 4 Where at least two A's are N; Each R 4 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl; B is N or CR 5 ; E is N or CR 7 ; F is N or CR 8 ; R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents; R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents; Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or Two Rs 10 Together they form an oxygen group; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4 to 6-membered heteroaryl; and p is 8; q can be 0, 1, 2 or 3.

22. The compound of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-, -O-, -S-, or -NR. 3 -; and Z is CH.

23. The compound of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond and Z is N.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein each A is independently N or CH, and wherein two A are N.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein... for , , , or .

26. The compound of claim 25 or a pharmaceutically acceptable salt or solvate thereof, wherein... for , or .

27. The compound of claim 25 or a pharmaceutically acceptable salt or solvate thereof, wherein... for .

28. The compound of claim 25 or a pharmaceutically acceptable salt or solvate thereof, wherein... for .

29. The compound of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (III') or a pharmaceutically acceptable salt or solvate thereof: in, Ring G is a 5- to 10-membered heteroaryl group; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; X is -CH2-, -O-, -S-, or -NR 3 -; R 3 It can be hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; A is either N or CH; B is N or CR 5 ; E is N or CR 7 ; F is N or CR 8 ; R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents; R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents; Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or Two Rs 10 Together they form an oxygen group; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R e Independently, it is a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and q can be 0, 1, 2 or 3.

30. The compound according to any one of claims 21 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form a C1-C3 alkylene or a C1-C3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally composed of 1 to 4 independently selected from R e Substituents are substituted.

31. The compound of claim 30 or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form C1-C3 alkylene groups.

32. The compound of claim 29 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (III') has the structure of formula (IIIa') or a pharmaceutically acceptable salt or solvate thereof: Where Y is a C1-C3 alkylene group.

33. The compound of claim 32 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2CH2-.

34. The compound of claim 29 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (III') has the structure of formula (IIIb') or a pharmaceutically acceptable salt or solvate thereof: 。 35. The compound of claim 34 or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form C3-C6 cycloalkyl groups.

36. The compound of claim 35 or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form a cyclopropyl group.

37. The compound according to any one of claims 21 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted.

38. The compound of claim 37 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 It can be hydrogen, halogen, or C1-C6 alkyl independently.

39. The compound of claim 37 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 It can be hydrogen or methyl on its own.

40. The compound according to any one of claims 21 to 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O- or -NR. 3 - 41. The compound of claim 40 or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

42. The compound of claim 40 or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NR. 3 - 43. The compound of claim 42 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is hydrogen, C1-C3 alkyl or C3-C6 cycloalkyl.

44. The compound of claim 43 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It can be hydrogen, methyl, ethyl, or cyclopropyl.

45. The compound of claim 43 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It can be hydrogen or methyl.

46. ​​The compound of claim 21 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula (IV') or a pharmaceutically acceptable salt or solvate thereof: in, Ring G is a 5- to 10-membered heteroaryl group; Each R 1 Independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SH, -SR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally selected from 1 to 4 independently from R e Substituents; or Two Rs 1 Together they form an oxygen group; or Two Rs 1 Together they form a bond, a C1-C3 alkylene group or a C1-C3 heteroalkylene group, wherein the alkylene group or heteroalkylene group is optionally composed of 1 to 4 independently selected from R e Substituents; or Two Rs 1 Together they form C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl groups, each optionally composed of 1 to 4 independently selected from R e Substituents of the substituents; Z is CH or N; A is either N or CH; B is N or CR 5 ; E is N or CR 7 ; F is N or CR 8 ; R 5 R 7 and R 8 Each can be independently represented as hydrogen, halogen, -CN, -NO2, -OH, or -OR. a -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents of the substituents; R 9 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is independently composed of 1 to 4 elements selected from R e Substituents of the substituents; Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl is optionally selected independently from 1 to 4 members of R e Substituents; or Two Rs 10 Together they form an oxygen group; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently selected from R e Substituents of the substituents; Each R b Independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally selected from 1 to 4 independently from R e Substituents of the substituents; R c and R d Each of the following is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R e Independently, it can be a halogen, oxo group, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl; p is 8; and q can be 0, 1, 2 or 3.

47. The compound of claim 46 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is CH.

48. The compound of claim 46 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

49. The compound according to any one of claims 46 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form a C1-C3 alkylene or a C1-C3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally composed of 1 to 4 independently selected from R e Substituents are substituted.

50. The compound of claim 49 or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form C1-C3 alkylene groups.

51. The compound according to any one of claims 46 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the two Rs 1 Together they form C3-C6 cycloalkyl groups.

52. The compound according to any one of claims 46 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 Independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein each of the alkyl, haloalkyl, or hydroxyalkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted.

53. The compound of claim 52 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 It can be hydrogen, halogen, or C1-C6 alkyl independently.

54. The compound of claim 52 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 It can be hydrogen or methyl on its own.

55. The compound according to any one of claims 21 to 54, or a pharmaceutically acceptable salt or solvate thereof, wherein A is N.

56. The compound according to any one of claims 21 to 54, or a pharmaceutically acceptable salt or solvate thereof, wherein A is CH.

57. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein B is a CR 5 .

58. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein B is N.

59. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 Hydrogen, halogen, -CN, -NO2, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted.

60. The compound of claim 59 or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

61. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein B is CH.

62. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt or solvate thereof, wherein F is a CR 8 .

63. The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable salt or solvate thereof, wherein F is N.

64. The compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 Hydrogen, halogen, -CN, -NO2, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted.

65. The compound of claim 64 or a pharmaceutically acceptable salt or solvate thereof, wherein R 8 It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

66. The compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt or solvate thereof, wherein E is a CR 7 .

67. The compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt or solvate thereof, wherein E is N.

68. The compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; wherein the alkyl, haloalkyl, hydroxyalkyl, and aminoalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted.

69. The compound of claim 68 or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

70. The compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein E is CH.

71. The compound according to any one of claims 21 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is optionally surrounded by one or four rings selected from R. e The substituents are 5 to 6-membered heteroaryl groups.

72. The compound of claim 71 or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is optionally surrounded by one or two molecules selected from R. e The substituents are substituted into the 5-membered heteroaryl group.

73. The compound of claim 72 or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is pyrrole, imidazole, triazole, tetraazole, thiophene, oxazole, thiazole or thiadiazole.

74. The compound according to any one of claims 21 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is: , , , , , , , , , , , , , , , , , , , or ; in, Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl are each optionally selected independently from 1 to 4 members of R e Substituents of the substituents; Each R 10a Independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, cycloalkyl, and heterocyclic alkyl is optionally selected from 1 to 4 independently from R e Substituents are substituted; and q can be 0, 1, 2 or 3.

75. The compound of claim 74 or a pharmaceutically acceptable salt or solvate thereof, wherein... Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; Each R 10a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; and q can be 0, 1, or 2.

76. The compound according to claim 74 or 75, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 It can be -F, -Cl, methyl, ethyl, -OCH3, -CF3, -CHF2 or -CH2F independently.

77. The compound according to any one of claims 74 to 76, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10a Independently, it is a C1-C6 alkyl group, which is optionally substituted by one to four substituents independently selected from the following: halogen, -OH, -CH2S(=O)2CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 hydroxyalkyl.

78. The compound according to any one of claims 74 to 77, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10a Independently, it can be hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CF3, CHF2, CH2F, -CH2CF3, -CH2SO2CH3, cyclopropyl, or oxetanyl. , or .

79. The compound according to any one of claims 21 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein: for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .、 , , , , , , , , , , , , , , , , or .

80. The compound of claim 79 or a pharmaceutically acceptable salt or solvate thereof, wherein... for , , , , , , , , , , , , or .

81. The compound of claim 71 or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is optionally surrounded by 1 to 4 rings selected from R. e The substituents are substituted into the 6-membered heteroaryl group.

82. The compound of claim 81 or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is pyridine, pyrimidine or triazine.

83. The compound according to any one of claims 21 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is: , , , , , , , , , or , in, Each R 10 Independently halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocyclic alkyl are each optionally selected independently from 1 to 4 members of R e Substituents are substituted; and q can be 0, 1, 2 or 3.

84. The compound of claim 83 or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 It is independently -OCH3 or -N(CH3)2; and q is 0, 1 or 2.

85. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein... for , , , , , , , , or .

86. The compound according to any one of claims 21 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is a heteroatom comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally surrounded by 1 to 4 heteroatoms selected from R. e The substituents are 9 or 10-membered bicyclic heteroaryl groups.

87. The compound of claim 86 or a pharmaceutically acceptable salt or solvate thereof, wherein ring G is a heteroatom comprising 1 to 3 heteroatoms selected from N, and optionally surrounded by 1 to 4 heteroatoms selected from R. e The substituents are substituted into the 9-membered bicyclic heteroaryl group.

88. The compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt or solvate thereof, wherein: Each R a Independently, it is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C1-C6 hydroxyalkyl, wherein each of the alkyl, haloalkyl, and hydroxyalkyl is optionally selected from 1 to 4 independently from R e Substituents of the substituents; Each R b Independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, wherein the alkyl, haloalkyl, and hydroxyalkyl are each optionally selected independently from 1 to 4 R e Substituents are substituted; and R c and R d Each is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein the alkyl and haloalkyl are each optionally selected independently from R. e Substituents are substituted.

89. The compound of claim 88 or a pharmaceutically acceptable salt or solvate thereof, wherein: Each R a Independently, it is a C1-C6 alkyl group; Each R b Independently hydrogen or C1-C6 alkyl; and R c and R d Each is independently hydrogen or C1-C6 alkyl.

90. The compound of claim 89 or a pharmaceutically acceptable salt or solvate thereof, wherein: Each R a It can be methyl, ethyl, isopropyl, or tert-butyl independently; Each R b It is independently hydrogen, methyl, or ethyl; and R c and R d Each can be independently hydrogen, methyl, or ethyl.

91. The compound according to any one of claims 1 to 90, or a pharmaceutically acceptable salt or solvate thereof, wherein each R e It can be independently a halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -CH2S(=O)2CH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocyclic alkyl.

92. The compound of claim 91 or a pharmaceutically acceptable salt or solvate thereof, wherein each R e Independently, it can be -F, -Cl, -OH, -CH2S(=O)2CH3, methyl, ethyl, isopropyl, tert-butyl, -OCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or aziridine, oxytane, piperidine, piperazine, or morpholine.

93. The compound of claim 90 or a pharmaceutically acceptable salt or solvate thereof, wherein each R e It can be -F, -OH, -CF3, -CHF2, -OCH3 or methyl independently.

94. The compound of any one of claims 1 to 93, a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the compounds in Table 1A, Table 1B or Table 1C, or their pharmaceutically acceptable salts or solvates.

95. A pharmaceutical composition comprising a compound according to any one of claims 1 to 94 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

96. A method of treating a patient with a neurodegenerative disease or condition, the method comprising administering to the patient a compound according to any one of claims 1 to 94 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 95.

97. The method of claim 96, wherein the neurodegenerative disease or condition is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, prion diseases, and spinocerebellar ataxia.

98. The method of claim 86, wherein the neurodegenerative disease or condition is Huntington's disease (HD).

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