LRRK2 inhibitors

Abstract

The present invention relates to compounds of formula (I) as LRRK2 inhibitors. The inhibitors described herein are useful in the treatment of diseases or conditions associated with LRRK2, such as Parkinson's disease, PD. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit LRRK2, methods of treating diseases or conditions associated with LRRK2, and methods of synthesizing such compounds. # imgabs0 #

Description

[Technical Field]

[0001] This invention relates to inhibitors of leucine-rich repeat kinase 2 (LRRK2). The inhibitors described herein can be used to treat LRRK2-related diseases or conditions, such as Parkinson's disease (PD). Specifically, this invention relates to compounds and pharmaceutical compositions that inhibit LRRK2, methods for treating LRRK2-related diseases or conditions, and methods for synthesizing such compounds. [Background Technology]

[0002] Like many common age-related conditions, Parkinson's disease (PD) is believed to have a significant genetic component. PD is a progressive neurodegenerative disease affecting approximately 2% of individuals over the age of 60.

[0003] Multiple pieces of evidence suggest that leucine-rich repeat kinase 2 (LRRK2) is a crucial factor in understanding the etiology of Parkinson's disease (PD). LRRK2 is a large, multi-domain, and multifunctional protein with widespread expression. LRRK2 mutations are a major cause of both hereditary and sporadic PD. Recently, wild-type LRRK2 has also been considered a potential target for sporadic PD. LRRK2 mutations, particularly the most common mutation Gly2019Ser, have been observed in patients with autosomal dominant PD and in patients with obvious sporadic PD who are clinically indistinguishable from those with idiopathic PD. Pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity, and the discovery that small-molecule LRRK2 kinase inhibitors have neuroprotective effects in preclinical PD models has made LRRK2 a central focus of disease modification research for PD. Increasing evidence emphasizes that LRRK2 controls multiple processes in brain immune cells, microglia, and astrocytes, and suggests that dysregulation of LRRK2 activity in these cells caused by gene mutations may be directly related to the underlying pathological mechanisms of PD. Recent studies have also shown that LRRK2 plays a role in the pathogenesis of idiopathic PD, and therefore, LRRK2 therapy (LRRK2 mutant and wild-type) may be beneficial in this common PD subtype.

[0004] Treatment for Parkinson's disease (PD) should employ a comprehensive approach, including medication, surgery, rehabilitation, and psychotherapy. Medication is the preferred primary treatment. For example, deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a proven therapy for advanced PD, and STN-DBS results are not affected by LRRK2p.G2019S mutations. However, none of these treatments can stop the progression of PD, let alone cure it. The primary goal of all such therapies is to alleviate the motor and non-motor symptoms of PD. Therefore, the need for novel drugs that can reverse, prevent, or slow the progression of PD is one of the main objectives of PD research. [Summary of the Invention]

[0005] The first aspect of this invention relates to a compound of formula (I): Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein V is selected from C and N; W is selected from C and N; And one of V and W is N; key Selected from single and double bonds; key Selected from single and double bonds; The constraint is that when V is N, the bond... It is a single key. It is a double bond with W being C, and when V is C, the bond... It is a double bond, this bond It is a single bond and W is N; X is selected from CR 7 and N; Y is selected from C=O, CR 8 and N; The constraint is that either X or Y is N; key Selected from single and double bonds; r is an integer selected from 0 and 1; The constraint is that when Y is C=0, the bond... It is a single bond and r is 1, and when Y is CR 8 When N or N, the key It is a double bond and r is 0; When Y is C=O or N, Z is selected from CR. 9 and N; When Y is CR 8 When Z is CR 9 ; Q is selected from CH2, NR 5O, S, S(O), S(O)2; R 1 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; R 2 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 3 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl; or R 2 and R 3 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 cycloalkyl and heterocyclic compounds; Each R6 Independently selected from halogens, OH, side radicals, CN, and CONR 10 R 11 NR 10 R 11 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 -S(O)2-C1-C6 alkyl, -C1-C6 alkyldiyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Or two Rs 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; R 7 R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, alkoxy, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 S(O)2R 12 cycloalkyl and heterocyclic compounds; R 10 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)2R 12 The alkyl or cycloalkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is, as appropriate, independently substituted with one or more substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; or R 10 and R 11 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 Selected from C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, septoxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; in, m is an integer selected from 1, 2, 3, or 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Aryl groups are cyclic, aromatic hydrocarbon groups having 1 to 3 aromatic rings; The heterocyclic group is a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused ring, bridging ring or spirocyclic) or 11-14 member tricyclic system (fused ring, bridging ring or spirocyclic) having one or more heteroatoms selected from O, N, S, P, Se or B. Heteroaryl groups are monovalent monocyclic or polycyclic aromatic groups with 5 to 24 ring atoms, containing one or more heteroatoms selected from N, O, S, P or B and the remaining ring atoms being C.

[0006] Another aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may further comprise excipients, diluents, or surfactants.

[0007] Another aspect of the invention relates to a method for treating a disease or condition associated with LRRK2. The method comprises administering to a patient requiring treatment for a disease or condition associated with LRRK2 an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0008] Another aspect of the invention relates to a method for inhibiting LRRK2. This method involves administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0009] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for use in the manufacture of a medicament for inhibiting LRRK2.

[0010] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of diseases and conditions associated with LRRK2.

[0011] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of an agent for the treatment or prevention of a disease or symptom disclosed herein.

[0012] Another aspect of the invention relates to a method for treating or preventing a disease or ailment disclosed herein in an individual in need. This method involves administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof to a patient in need of treatment.

[0013] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the disease or condition disclosed herein.

[0014] The present invention further provides a method for treating diseases or conditions associated with LRRK2, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0015] This invention provides LRRK2 inhibitors, which are therapeutic agents for treating diseases and conditions.

[0016] This invention further provides compounds and compositions that have improved efficacy and safety profiles compared to known LRRK2 inhibitors. This invention also provides agents with novel mechanisms of action against LRRK2 in the treatment of various types of diseases.

[0017] The present invention further provides a method for treating diseases or conditions associated with LRRK2, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0018] This invention provides LRRK2 inhibitors, which are therapeutic agents for treating diseases and conditions.

[0019] This invention further provides a method for treating diseases, symptoms, or conditions selected from autosomal dominant Parkinson's disease 8 (PARK8); hereditary late-onset Parkinson's disease (LOPD); spinocerebellar atrophy; autosomal dominant Klippel-Feil syndrome 1 (KFS1); autosomal dominant cerebellar ataxia (SCA); late-onset Parkinson's disease (PD); juvenile autosomal recessive Parkinson's disease 2 (PARK2); Parkinson's disease; rapid eye movement sleep behavior disorder; Lewy body dementia. Body; DLB); Lrrk2 Parkinson's disease; Autosomal dominant Parkinson's disease 3 (PARK3); Early-onset Parkinson's disease; Multiple system atrophy 1 (MSA1); Spontaneous tremor; Movement disorder; Progressive supranuclear palsy 1 (PSNP1); Krohn-Felix syndrome 1; Dementia; Parkinson's disease 10 (PARK10); Tremor; Frontotemporal dementia (FTD); Post-encephalitis Parkinson's disease; Vascular Parkinson's disease; Aphasia; Autosomal dominant Parkinson's disease 1 (PARK1); Athetosis; Krohn-Felix syndrome (KFS); Kufor-Rakeb syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer's disease 8 (AD8); Crohn's disease Diseases; Rheumatoid arthritis (RA); Alzheimer's disease (AD); Color agnosia; Gaucher disease (Type I; GD1); Early-onset autosomal recessive Parkinson's disease 15 (PARK15); Von Economo's disease; Gerstmann-Straussler disease (GSD); Amyotrophic lateral sclerosis-Parkinson's disease / dementia relapse syndrome 1 (ALS-PDC1); Dystonia; Sphingolipid disease; Radial neuropathy; Toxic encephalopathy; Sleep disorders; Pick's disease of the brain Brain (PIDB); ocular myiasis; Gaucher disease (GD); optic atrophy type 7 with or without auditory neuropathy (OPA7); ulnar neuropathy; inflammatory bowel disease 4 (IBD4); inflammatory bowel disease; type II 3-methylpentadienic aciduria (MGCA3); neurological disorders; amyotrophic lateral sclerosis 1 (ALS1);Nuclear type 1 mitochondrial complex I deficiency (MC1DN1), the method comprising administering to a patient suffering from at least one of these diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] In some embodiments, the present invention provides a compound that can be obtained by or by a method for preparing the compound described herein (e.g., a method comprising one or more steps described in general procedure A, B or C).

[0021] In some embodiments, the present invention provides an intermediate as described in the present invention (e.g., the intermediate is selected from the intermediates described in preparation sections - P1-P44) suitable for use in the preparation of compounds as described in the present invention.

[0022] In some embodiments, the present invention provides a method for preparing the compounds of the present invention.

[0023] In some embodiments, the present invention provides a method for preparing the compounds of the present invention, which comprises one or more steps described in the present invention.

[0024] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In this specification, the singular form also includes the plural unless the context clearly indicates otherwise. Although the invention may be practiced or tested using methods and materials similar to or equivalent to those described herein, suitable methods and materials are described below. All disclosures, patent applications, patents, and other references mentioned in this invention are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be restrictive. In case of conflict between the chemical structures and names of compounds disclosed in this invention, the chemical structure shall prevail.

[0025] Other features and advantages of the invention will become apparent from the following embodiments and the claims of the application. [Summary of the Invention]

[0026] This invention provides a method for treating, preventing, or alleviating diseases or conditions associated with the inhibition of LRRK2 by administering a therapeutically effective amount of a compound as disclosed herein to an individual in need.

[0027] The details of the invention are set forth in the following appended description. Although the invention may be practiced or tested using methods and materials similar to or equivalent to those described herein, illustrative methods and materials are described here. Other features, objects, and advantages of the invention will become apparent from the description and the claims of the application. Unless the context clearly indicates otherwise, the singular form includes the plural in the description and the claims of the appended application. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety. definition

[0028] In this invention, the article “a / an” is used to refer to a grammatical object of one or more articles (i.e., at least one). For example, “an element” means one element or more elements.

[0029] Unless otherwise indicated, the term “and / or” is used in this invention to mean “and” or “or”.

[0030] The term "substitutably substituted" should be understood to mean that a given chemical moiety (e.g., alkyl) may (but does not need to) be bonded to other substituents (e.g., heteroatoms). For example, a substitutably substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the substitutably substituted alkyl group may have one or more substituents different from hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described in this invention at any position along the chain. Thus, the term "substitutably substituted" indicates that a given chemical moiety may contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents used in the substitution of the described groups, as appropriate, include, but are not limited to, halogens, syloxy groups, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alynyl, (C2-C6)alynyl, (C2-C6)alkynyl, -OH, -OP(O)(O H)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and -S(O)N((C1-C6)alkyl)2. These substituents may be substituted as appropriate. As used herein, "substituted as appropriate" also means substituted or unsubstituted, the meaning of which is described below.

[0031] As used in this invention, the term "substituted" indicates that a specified group or portion has one or more suitable substituents, wherein such substituents may be attached to the specified group or portion at one or more positions. For example, a cycloalkyl-substituted aryl group may indicate that the cycloalkyl group is attached to an atom of the aryl group via a bond or by fusion with the aryl group and sharing two or more shared atoms.

[0032] As used in this invention, the term "unsubstituted" means that the specified group does not contain substituents.

[0033] Unless otherwise explicitly defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. In cases containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be substituted with one or more substituents (e.g., one to five substituents) at any connection point, as appropriate. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. These substituents themselves may be substituted as appropriate. Furthermore, when containing two fused rings, the aryl group as defined in this invention may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthraceneyl, propenyl naphthyl, phenanthryl, dihydroindenyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, and similar groups.

[0034] Unless otherwise explicitly defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, or B, and with the remaining ring atoms being C. Polycyclic aromatic groups include two or more fused rings and may further include two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, and similar rings. Unless otherwise explicitly defined, "fused" means that two rings share two ring atoms. Unless otherwise explicitly defined, "spiro-fused" means that two rings share one ring atom. The heteroaryl as defined in this invention also refers to a bicyclic heteroaryl group, wherein the heteroatom is selected from N, O, S, P, or B. The heteroaryl as defined in this invention also refers to a tricyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. The heteroaryl as defined in this invention also refers to a tetracyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B. The aromatic groups may be independently substituted by one or more substituents as described in this invention, depending on the circumstances.Examples include, but are not limited to, furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazoleyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indoleyl, thiophene-2-yl, quinolinyl, benzopiperanyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furan[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thiophene [2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, indolinyl, indolinone, dihydrobenzothiaphenyl, dihydrobenzofuranyl, benzofuran, chromyl, thiochromyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]trizo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl , pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazoleyl, benzoisoxazoleyl, furano[2,3-b]pyridyl, benzothiopheneyl, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a Pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazol[4,3-b]tarazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazol[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazol[1,5-a]pyridyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl and their derivatives. In addition, when containing two or more fused rings, the heteroaryl group as defined in this invention may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described in this invention. Furthermore, when three or more fused rings are present, the heteroaryl group as defined in this invention may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring described in this invention may be substituted with one or more side oxygen groups, depending on the situation. Exemplary ring systems of this type of heteroaryl include, for example, indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, crenoalkyl, thiocrenoalkyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranone, indololinyl, hydroxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopentano[b]pyrazolo[4,3-e]pyridine 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-keto, 3,4-dihydropyrazolo[1,2-a]indole-1(2H)-keto, benzo[c][1,2]oxorbacon-1(3H)-ol, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-keto or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-keto.

[0035] Halogens, or "halogen groups," refer to fluorine, chlorine, bromine, or iodine.

[0036] Alkyl refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, and isohexyl.

[0037] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1-12 carbon atoms and a terminal "O" in the chain, i.e., -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0038] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An alkenyl group contains at least one double bond in its chain. The double bond of the alkenyl group may be non-conjugated or conjugated with the other unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. As defined in this invention, alkenyl groups may be straight-chain or branched.

[0039] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An alkynyl group contains at least one parabonding bond in the chain. Examples of alynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups may be unsubstituted or substituted.

[0040] The term "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups mentioned above can become an alkylene group by withdrawing a second hydrogen atom from the alkyl group. As defined in this invention, alkylene groups can also be C1-C6 alkylene groups. alkylene groups can further be C1-C4 alkylene groups. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and similar groups.

[0041] “Cycloalkyl” refers to a monocyclic or polycyclic saturated carbon ring containing 3-18 carbon atoms. Polycyclic cycloalkyl can be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. Polycyclic cycloalkyl contains at least one non-aromatic ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclic[1.1.1]pentyl, bicyclic[2.2.2]octyl, or bicyclic[2.2.2]octenyl.

[0042] "Heterocyclic group," "heterocycle," or "heterocyclic alkyl" refers to a monocyclic or polycyclic ring containing 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, wherein the ring is not an aromatic ring. Heterocyclic alkyl ring structures may be substituted by one or more substituents. These substituents themselves may be substituted, as appropriate. Examples of heterocyclic groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropiperanyl, pyrrolidyl, oxazolinyl, oxazodinyl, thiazolinyl, thiazodinyl, piperanyl, thiopiperanyl, tetrahydropiperanyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazine, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinone, and homotropanyl.

[0043] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used in this invention, "conjugated system" refers to a p-orbital system connected with nonlocalized electrons, and this system may include lone pairs.

[0044] As used in this invention, the term "haloalkyl" refers to an alkyl group as defined in this invention that has been substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0045] As used in this invention, the term "haloalkoxy" refers to an alkoxy group as defined in this invention that has been substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0046] As used in this invention, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom via a parabolic bond, i.e., C≡N.

[0047] "Spirocycloalkyl" or "spirocycloyl" indicates a carbon-containing bicyclic system in which two rings are linked by a single atom. The rings may differ in size and properties, or be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spiroctane, spirononane, or spirodecane. One or both rings of the spirocyclic ring may be fused with another ring of carbocyclic, heterocyclic, aromatic, or heteroaromatic nature. One or more carbon atoms in the spirocyclic ring may be substituted with heteroatoms (e.g., O, N, S, or P). (C3-C) 12 Spirocycloalkyl groups are spirocyclic rings containing between 3 and 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms.

[0048] The terms “spiroheteroalkyl”, “spiroheterocyclic” or “spiroheterocyclic group” should be understood to mean a spirocycle with at least one heterocyclic ring (e.g., at least one ring being furanyl, morpholinyl or piperidinyl).

[0049] The term "solvate" refers to a complex formed by a solute and a solvent with a variable stoichiometry. For the purposes of this invention, such solvents should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically called hydrates. Hydrates include compositions containing a stoichiometric amount of water as well as compositions containing a variable amount of water.

[0050] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or ability to rotate the polarizing plane (stereoisomers). Regarding stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may appear as racemic mixtures, racemic mixtures, and as individual mirror-image or non-mirror-image isomers.

[0051] This invention also covers isotopically labeled compounds of formula I (e.g., those labeled with...). 2 H and 14 C-labeled compounds). Tritiumization (i.e., 2 H or D) and carbon-14 (i.e., ... 14 C) Isotopes are preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages (e.g., prolonged in vivo half-life or reduced dose requirements) due to greater metabolic stability, and is therefore preferred in some cases. Isotopically labeled compounds of formula I can generally be prepared by replacing unlabeled reagents with appropriately isotopically labeled reagents, following a procedure similar to that disclosed in the schemes and / or examples below.

[0052] This invention also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, for example, water-soluble and non-water-soluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium edetate, camphorsulfonates, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, edetate, ethanedisulfonate, estolate, ethanesulfonate, transbutenedioic acid, gluconate, gluconate, glutamate, glycolyllarsanilate, hexafluorophosphate, and hexylresorcinate. Inate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthyl carboxylate, iodide, hydroxyethanesulfonate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, amygdalinate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, galactosidate, naphthalenesulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthyl carboxylate, oleate, oxalate, palmitate, dihydroxynaphthyl carboxylate, pantothenate, phosphate / bisphosphate, picrate, polygalacturonic acid, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theochloroate, toluenesulfonate, triethyl iodide, and valerate.

[0053] "Patient" or "individual" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0054] When used in combination with a compound, "effective amount" is the amount that is effective in treating or preventing an individual's disease as described in this invention.

[0055] As used in this invention, the term "carrier" encompasses carriers, excipients, and diluents, and refers to a material, composition, or medium involved in the transport or transfer of a pharmaceutical agent from one organ or part of an individual's body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulation materials.

[0056] The term "treatment" in relation to an individual refers to the improvement of at least one symptom of an individual's condition. Treatment includes curing, improving, or at least partially alleviating the condition.

[0057] Unless otherwise indicated, the term "symptom" is used in this invention to refer to the terms disease, condition or ailment and is used interchangeably with such terms.

[0058] As used in this invention, the terms “administer,” “administering,” or “administration” refer to the direct administration to an individual of a medically acceptable salt of the disclosed compound or a disclosed compound or composition, or the administration to an individual of a prodrug derivative or analogue of the compound or a medically acceptable salt of the compound or composition, which may form an equivalent amount of the active compound in the individual’s body.

[0059] As used in this invention, the term "prodrug" refers to a compound that can be converted into the disclosed compound in vivo by metabolic means (e.g., by hydrolysis).

[0060] The term "salt" refers to salt that is acceptable in medicine.

[0061] The term "medically acceptable salt" also refers to the salts of the components and bases of the present invention having acid-like functional groups such as carboxylic acid functional groups.

[0062] As used in this invention, "LRRK2 inhibitor" refers to a compound of formula I that inhibits LRRK2 kinase and / or a composition comprising a compound of formula I.

[0063] The amount of compounds in the compositions described in this invention required to achieve a therapeutic effect can be determined empirically based on known procedures for a particular purpose. Generally, for the administration of therapeutic agents (e.g., compounds or compositions of Formula I described in this invention (and / or additional agents)) for therapeutic purposes, these therapeutic agents are administered at a pharmacologically effective dose. "Pharmacologically effective amount," "pharmacologically effective dose," "therapeuticly effective amount," or "effective amount" means an amount sufficient to produce the desired physiological effect or to achieve the desired result, particularly the treatment of a symptom or disease. As used in this invention, an effective amount will include an amount sufficient, for example, to delay the development of symptoms of a symptom or disease, to alter the course of symptoms of a symptom or disease (e.g., to slow the progression of disease symptoms), to reduce or eliminate one or more symptoms or clinical manifestations of a symptom or disease, and to reverse the symptoms of a symptom or disease. For example, administration of a therapeutic agent to an individual with cancer provides therapeutic benefit not only in eradicating or alleviating the underlying condition but also in the individual reporting a reduction in the severity or duration of disease-related symptoms, such as reduced tumor burden, reduced circulating tumor cells, and prolonged progression-free survival. Treatment benefits also include stopping or slowing the progression of underlying diseases or conditions, regardless of whether improvement is achieved. The compounds of the present invention

[0064] In one embodiment, the present invention provides compounds of formula (I) and their salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers: Where R 1 R 2 R 3 R 4 R 5 R 6 V, W, X, Y, Z, Q, m, n, r, and u are as described in this invention.

[0065] It should be understood that for compounds of formula (I), R 1 R 2 R 3 R 4 R 5 R 6 V, W, X, Y, Z, Q, m, n, r, and u may each be selected from the group described in this invention when applicable, and this invention relates to any R 1 R 2 R 3 R 4 R 5 R 6 Any group described by V, W, X, Y, Z, Q, m, n, r, and u may be used in connection with the present invention with respect to R when applicable. 1 R 2 R3 R 4 R 5 R 6 Any combination of one or more of the remaining parts of V, W, X, Y, Z, Q, m, n, r and u.

[0066] In some embodiments, V is selected from C and N; W is selected from C and N; And one of V and W is N; key Selected from single and double bonds; key Selected from single and double bonds; The constraint is that when V is N, the bond... It is a single key. It is a double bond with W being C, and when V is C, the bond... It is a double bond, this bond It is a single bond and W is N; X is selected from CR 7 and N; Y is selected from C=O, CR 8 and N; The constraint is that either X or Y is N; key Selected from single and double bonds; r is an integer selected from 0 and 1; The constraint is that when Y is C=0, the bond... It is a single bond and r is 1, and when Y is CR 8 When N or N, the key It is a double bond and r is 0; When Y is C=O or N, Z is selected from CR. 9 and N; When Y is CR 8 When Z is CR 9 ; Q is selected from CH2, NH, O, S, S(O), S(O)2 R 1 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; R 2 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 3 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 2 and R 3 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 6 Independently selected from halogens, OH, side radicals, CN, and CONR 10 R 11 NR 10 R 11C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 -S(O)2-C1-C6 alkyl, -C1-C6 alkyldiyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Or two Rs 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; R 7 R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, alkoxy, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 S(O)2R 12 cycloalkyl and heterocyclic compounds; R 10 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)2R 12 The alkyl or cycloalkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is, as appropriate, independently substituted with one or more substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; or R 10 and R 11 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 Selected from C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, septoxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; in, m is an integer selected from 1, 2, 3, or 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0067] In some embodiments, V is C or N. In some embodiments, V is C. In some embodiments, V is N.

[0068] In some embodiments, W is C or N. In some embodiments, W is C. In some embodiments, W is N.

[0069] In some embodiments, V is N, the key For single key, key It is a double bond, and W is C.

[0070] In some embodiments, V is C, the key. It is a double bond, bond For a single bond, W represents N.

[0071] In some embodiments, X is CR 8 Or N. In some embodiments, X is CR 8 In some embodiments, X is N.

[0072] In some embodiments, X is CR 8 .

[0073] In some embodiments, X is N.

[0074] In some embodiments, Y is C=O, CR 9 Or N. In some embodiments, Y is C = O. In some embodiments, Y is CR 9 In some embodiments, Y is N.

[0075] In some embodiments, Y is C=O.

[0076] In some embodiments, Y is CR 9 .

[0077] In some embodiments, Y is N.

[0078] In some embodiments, Z is CH or N. In some embodiments, Z is CH. In some embodiments, Z is N.

[0079] In some embodiments, Z is CH.

[0080] In some embodiments, when Y is N, Z is also N.

[0081] In some embodiments, r is 0. In some embodiments, r is 1.

[0082] In some embodiments, r is 0.

[0083] In some embodiments, r is 1.

[0084] In some embodiments, when Y is C=0, the key It is a single key.

[0085] In some embodiments, when Y is CR 9 When N or N, the key It is a double bond.

[0086] In some embodiments, when Y is C=0, the key It is a single bond and r is 1.

[0087] In some embodiments, when Y is CR 9 When N or N, the key It is a double bond and r is 0.

[0088] In some embodiments, R 1 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl.

[0089] In some embodiments, R 1 It is hydrogen.

[0090] In some embodiments, R 1 It is a halogen.

[0091] In some embodiments, R 1 For F. In some embodiments, R 1 For Cl. In some embodiments, R 1 For Br. In some embodiments, R 1 For I.

[0092] In some embodiments, R 1 It is F.

[0093] In some embodiments, R 1 It is a C1-C6 alkyl group.

[0094] In some embodiments, R 1 For -CH3. In some embodiments, R 1 For -CH2CH3. In some embodiments, R 1 It is -CH2CH2CH3. In some embodiments, R 1 It is -CH(CH3)2.

[0095] In some embodiments, R 1 It is a methyl group.

[0096] In some embodiments, R 1 For -CH2F. In some embodiments, R 1 For -CHF2. In some embodiments, R 1 It is -CF3.

[0097] In some embodiments, R 1 It is a C1-C6 alkoxy group.

[0098] In some embodiments, R 1 For -OCH3. In some embodiments, R 1 It is -OCH2CH3. In some embodiments, R 1 It is -OCH2CH2CH3. In some embodiments, R 1 It is -OCH(CH3)2.

[0099] In some embodiments, R 1 For -OMe.

[0100] In some embodiments, R 1 It is a methoxy group.

[0101] In some embodiments, R 1 It is -OCH(CH3)2.

[0102] In some embodiments, R 1 It is isopropoxy.

[0103] In some embodiments, R 1 It is -OC(CH3)3.

[0104] In some embodiments, R 1 For -OCF3. In some embodiments, R 1 It is -OCF2CF3.

[0105] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, =O, CN, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR. 10 R 11 .

[0106] In some embodiments, R 1 and R 2 Together with the atoms it is attached to and the inserted atoms, it forms a 5-membered heterocycle containing a heteroatom selected from O, N, and S.

[0107] In some embodiments, R 1 and R 2 Together with the atoms it is attached to and the inserted atoms, it forms a 5-membered heterocycle containing a heteroatom -O.

[0108] In some embodiments, R 1 and R 2 Together with the atoms it is attached to and the inserted atoms, it forms a 6-membered heterocycle containing a heteroatom selected from O, N, and S.

[0109] In some embodiments, R 1 and R 2 Together with the atoms it is attached to and the inserted atoms, it forms a 6-membered heterocycle containing a heteroatom -O.

[0110] In some embodiments, R 1 and R 2 Together with the atoms it is connected to and the inserted atoms, it forms

[0111] In some embodiments, R 2 For H. In some embodiments, R 2 It is a halogen. In some embodiments, R 2It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 It is a C1-C6 alkoxy group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 For C3-C 10 Monocyclic cycloalkyl group, which, depending on the case, is independently substituted with one or more of the following substituents: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 It is a C2-C6 alkenyl group, which may be substituted by one or more independent substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 It is a C2-C6 alkynyl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 It is a heterocyclic, aryl, or heteroaryl group, which, depending on the case, is independently substituted by one or more of the following substituents: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl. In some embodiments, R 2 For NR 10 R 11 In some embodiments, R 2 is S(O)2R 12 .

[0112] In some embodiments, R 2 For H.

[0113] In some embodiments, R 2 It is a C1-C6 alkyl group.

[0114] In some embodiments, R 2 methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is propyl. In some embodiments, R 2 It is n-propyl. In some embodiments, R... 2 It is isopropyl. In some embodiments, R... 2 It is butyl. In some embodiments, R 2 It is n-butyl. In some embodiments, R 2 It is isobutyl. In some embodiments, R... 2 It is a secondary butyl group. In some embodiments, R 2 It is a tertiary butyl. In some embodiments, R 2 It is pentyl. In some embodiments, R 2 For oneself.

[0115] In some embodiments, R 2 It is a C1-C6 alkyl group substituted with one or more halogens.

[0116] In some embodiments, R 2 It is a C1-C6 alkyl group substituted with one or more Fs.

[0117] In some embodiments, R 2 For -CH2F. In some embodiments, R 2 For -CHF2. In some embodiments, R 2 For -CF3. In some embodiments, R 2 For -CF2CH3. In some embodiments, R 2 For -CH2CF3. In some embodiments, R 2 For -CF2CF3. In some embodiments, R 2 It is -CF2CH(CH3)2.

[0118] In some embodiments, R 2 for

[0119] In some embodiments, R 2 It is a C1-C6 alkyl group substituted with one or more CN atoms.

[0120] In some embodiments, R 2 For -CH2CN. In some embodiments, R 2 For -CH(CH3)CN. In some embodiments, R 2 It is -C(CH3)2CN.

[0121] In some embodiments, R 2 for

[0122] In some embodiments, R 2 for

[0123] In some embodiments, R 2 It is a C1-C6 alkoxy group.

[0124] In some embodiments, R 2 For -OCH3. In some embodiments, R 2 It is -OCH2CH3. In some embodiments, R 2 It is -OCH2CH2CH3. In some embodiments, R 2 It is -OCH(CH3)2. In some embodiments, R 2 It is -OCH2CH2CH2CH3. In some embodiments, R 2 It is -OCH2CH(CH3)2. In some embodiments, R 2 It is -OCH(CH3)CH2CH3. In some embodiments, R 2 It is -OC(CH3)3.

[0125] In some embodiments, R 2 It is -OCH(CH3)2.

[0126] In some embodiments, R 2 It is isopropoxy.

[0127] In some embodiments, R 2 It is -OC(CH3)3.

[0128] In some embodiments, R 2 It is a tertiary butoxy group.

[0129] In some embodiments, R 2 It is a C1-C6 alkoxy group substituted with one or more halogens.

[0130] In some embodiments, R 2 For -OCH2F. In some embodiments, R 2 For -OCHF2. In some embodiments, R 2 For -OCF3. In some embodiments, R 2 For -OCF2CH3. In some embodiments, R 2 For -OCH2CF3. In some embodiments, R 2 It is -OCF2CF3.

[0131] In some embodiments, R2 for

[0132] In some embodiments, R 2 for

[0133] In some embodiments, R 2 For C3-C 10 Monocyclic cycloalkyl.

[0134] In some embodiments, R 2 It is cyclopropyl. In some embodiments, R 2 It is cyclobutyl. In some embodiments, R 2 It is cyclopentyl. In some embodiments, R 2 It is cyclohexyl. In some embodiments, R 2 It is a cycloheptayl group.

[0135] In some embodiments, R 2 C3-C substituted with one or more halogens 10 Monocyclic cycloalkyl.

[0136] In some embodiments, R 2 C3-C substituted with one or more F 10 Monocyclic cycloalkyl.

[0137] In some embodiments, R 2 C3-C substituted with one halogen 10 Monocyclic cycloalkyl.

[0138] In some embodiments, R 2 C3-C substituted with one F 10 Monocyclic cycloalkyl.

[0139] In some embodiments, R 2 It is a cyclopropyl group substituted with one F. In some embodiments, R 2 It is a cyclobutyl group substituted with one F. In some embodiments, R 2 It is a cyclopentyl group substituted with one F. In some embodiments, R 2 It is a cyclohexyl group substituted with one F. In some embodiments, R 2 It is a cycloheptyl group substituted with one F.

[0140] In some embodiments, R 2 for

[0141] In some embodiments, R 2 C3-C substituted with one or more CNs 10 Monocyclic cycloalkyl.

[0142] In some embodiments, R 2 C3-C replaced by a CN 10 Monocyclic cycloalkyl.

[0143] In some embodiments, R 2 It is a cyclopropyl group substituted with one -CN. In some embodiments, R 2 It is a cyclobutyl group substituted with one -CN. In some embodiments, R 2 It is a cyclopentyl group substituted with one -CN. In some embodiments, R 2 It is a cyclohexyl group substituted with one -CN. In some embodiments, R 2 It is a cycloheptyl group substituted with one -CN.

[0144] In some embodiments, R 2 for

[0145] In some embodiments, R 2 for

[0146] In some embodiments, R 2 for

[0147] In some embodiments, R 2 for

[0148] In some embodiments, R 2 for

[0149] In some embodiments, R 2 for

[0150] In some embodiments, R 2 for

[0151] In some embodiments, R 2 for

[0152] In some embodiments, R 2 For C3-C 10 Cycloalkoxy group.

[0153] In some embodiments, R 2 It is a cyclopropoxy group. In some embodiments, R... 2 It is a cyclobutoxy group. In some embodiments, R... 2 It is a cyclopentoxy group. In some embodiments, R... 2 It is a cyclohexyloxy group. In some embodiments, R... 2It is a cycloheptaoxy group.

[0154] In some embodiments, R 2 for

[0155] In some embodiments, R 2 for

[0156] In some embodiments, R 2 for

[0157] In some embodiments, R 2 for

[0158] In some embodiments, R 2 C3-C alkyl group substituted with one or more C1-C6 alkyl groups 10 Cycloalkoxy group.

[0159] In some embodiments, R 2 C3-C substituted with a C1-C6 alkyl group 10 Cycloalkoxy group.

[0160] In some embodiments, R 2 C3-C substituted with one methyl group 10 Cycloalkoxy group.

[0161] In some embodiments, R 2 for

[0162] In some embodiments, R 2 for

[0163] In some embodiments, R 2 for

[0164] In some embodiments, R 2 for

[0165] In some embodiments, R 2 for

[0166] In some embodiments, R 2 for

[0167] In some embodiments, R 2 for

[0168] In some embodiments, R 2 for

[0169] In some embodiments, R 2 for

[0170] In some embodiments, R 2 for

[0171] In some embodiments, R 2 for

[0172] In some embodiments, R 2 for

[0173] In some embodiments, R 2 It is a heterocyclic ring.

[0174] In some embodiments, R 2 It is a 3-10 member heterocycle containing 1-3 heteroatoms selected from O, N, and S, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, heterocyclic, aryl, heteroaryl.

[0175] In some embodiments, R 2 It is a 5-membered heterocycle containing S(O)2 and substituted with 1-4 substituents selected from the following: OH, =O, NH2, CN, C1-C6 alkyl.

[0176] In some embodiments, R 2 for

[0177] In some embodiments, R 2 for

[0178] In some embodiments, R 2 It is a 5-membered heterocycle containing N and substituted with 1-4 substituents selected from the following: OH, =O, NH2, CN, C1-C6 alkyl.

[0179] In some embodiments, R 2 for

[0180] In some embodiments, R 2 It is a heteroaryl group.

[0181] In some embodiments, R 2It is a heteroaryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl.

[0182] In some embodiments, R 2 It is a heteroaryl group containing at least one heteroatom selected from N, O, or S.

[0183] In some embodiments, R 2 It consists of 5 mixed aromatic compounds.

[0184] In some embodiments, R 2 It consists of 6 mixed aromatic compounds.

[0185] In some embodiments, R 2 It is a 5-membered heteroaryl group containing O.

[0186] In some embodiments, R 2 It is a 5-membered heteroaryl group containing N.

[0187] In some embodiments, R 2 It is a 5-membered heteroaryl group containing S.

[0188] In some embodiments, R 2 It is a 5-membered heteroaryl group containing both O and N.

[0189] In some embodiments, R 2 It is a 5-membered heteroaryl group containing two Ns.

[0190] In some embodiments, R 2 It is a 5-membered heteroaryl group containing S and N.

[0191] In some embodiments, R 2 It is a 6-membered heteroaryl group containing O.

[0192] In some embodiments, R 2 It is a 6-membered heteroaryl group containing N.

[0193] In some embodiments, R 2 It is a 6-membered heteroaryl group containing S.

[0194] In some embodiments, R 2 It is a 6-membered heteroaryl group containing both O and N.

[0195] In some embodiments, R 2 It is a 6-membered heteroaryl group containing two Ns.

[0196] In some embodiments, R 2It is a 6-membered heteroaryl group containing S and N.

[0197] In some embodiments, R 2 It is a heteroaryl group substituted with -CH3.

[0198] In some embodiments, R 2 It is a heteroaryl group substituted with halogen.

[0199] In some embodiments, R 2 It is a heteroaryl group substituted with -CN.

[0200] In some embodiments, R 2 for

[0201] In some embodiments, R 2 for

[0202] In some embodiments, R 2 for

[0203] In some embodiments, R 2 for

[0204] In some embodiments, R 2 For -NR 10 R 11 .

[0205] In some embodiments, R 2 -NHS(O)2R 12 .

[0206] In some embodiments, R 2 -NHS(O)2R 12 , where R 12 It is a C1-C6 alkyl group that is substituted with one or more halogens, depending on the case.

[0207] In some embodiments, R 2 -NHS(O)2R 12 , where R 12 It is a C1-C6 alkyl group that is substituted with one or more Fs, depending on the case.

[0208] In some embodiments, R 2 It is -NHS(O)2CHF2.

[0209] In some embodiments, R 2 is -S(O)2R 12 .

[0210] In some embodiments, R 2 is -S(O)2R12 , where R 12 It is a C1-C6 alkyl group that is substituted with one or more halogens, depending on the case.

[0211] In some embodiments, R 2 It is -S(O)2CH3.

[0212] In some embodiments, R 2 and R 3 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, =O, CN, NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR. 10 R 11 .

[0213] In some embodiments, R 2 and R 3 Together with the atoms it is attached to and the inserted atoms, it forms a 5-membered heterocycle containing a heteroatom selected from O, N, and S.

[0214] In some embodiments, R 2 and R 3 Together with the atoms it is attached to and the inserted atoms, it forms a 5-membered heterocycle containing a heteroatom -O.

[0215] In some embodiments, R 2 and R 3 Together with the atoms it is attached to and the inserted atoms, it forms a 6-membered heterocycle containing a heteroatom selected from O, N, and S.

[0216] In some embodiments, R 2 and R 3 Together with the atoms it is attached to and the inserted atoms, it forms a 6-membered heterocycle containing a heteroatom -O.

[0217] In some embodiments, R 2 and R 3 Together with the atoms it is connected to and the inserted atoms, it forms

[0218] In some embodiments, R 3 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl.

[0219] In some embodiments, R 3 For H.

[0220] In some embodiments, R 3 It is a C1-C6 alkyl group.

[0221] In some embodiments, R 3 methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is propyl. In some embodiments, R 3 It is n-propyl. In some embodiments, R... 3 It is isopropyl. In some embodiments, R... 3 It is butyl. In some embodiments, R 3 It is n-butyl. In some embodiments, R 3 It is isopropyl. In some embodiments, R... 3 It is a secondary butyl group. In some embodiments, R 3 It is a tertiary butyl. In some embodiments, R 3 It is pentyl. In some embodiments, R 3 For oneself.

[0222] In some embodiments, R 3 -CH 3。

[0223] In some embodiments, R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 cycloalkyl and heterocyclic compounds;

[0224] In some embodiments, R 4 For H.

[0225] In some embodiments, when V is C, R 4 It is a halogen.

[0226] In some embodiments, R 4 For F. In some embodiments, R 4 For Cl. In some embodiments, R 4 For Br. In some embodiments, R 4 For I.

[0227] In some embodiments, when V is C, R 4 For CN.

[0228] In some embodiments, when V is N, R 4 It is a C(O)OC1-C6 alkyl group.

[0229] In some embodiments, when V is N, R 4 It is C(O)O-tert-butyl.

[0230] In some embodiments, R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, seroyl group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds.

[0231] In some embodiments, R 5 For H.

[0232] In some embodiments, R 5 It is a C1-C6 alkyl group.

[0233] In some embodiments, R 5 CH3. In some embodiments, R 5 It is C2H5. In some embodiments, R 5It is CH2CH2CH3. In some embodiments, R 5 It is CH(CH3)2. In some embodiments, R 5 It is CH2CH2CH2CH3. In some embodiments, R 5 It is CH2CH(CH3)2.

[0234] In some embodiments, R 5 It is a methyl group.

[0235] In some embodiments, R 5 It is an ethyl group.

[0236] In some embodiments, R 5 It is isopropyl.

[0237] In some embodiments, R 5 It is isobutyl.

[0238] In some embodiments, R 5 It is a C1-C6 alkyl group substituted with one or more halogens.

[0239] In some embodiments, R 5 It is a C1-C6 alkyl group substituted with one or more Fs.

[0240] In some embodiments, R 5 It is -CHF2.

[0241] In some embodiments, R 5 It is -CF3.

[0242] In some embodiments, R 5 For C3-C 10 Cycloalkyl.

[0243] In some embodiments, R 5 It is cyclopropyl.

[0244] In some embodiments, R 5 It is cyclobutyl.

[0245] In some embodiments, R 5 It is cyclopentyl.

[0246] In some embodiments, Q is CH2. In some embodiments, Q is NR. 5 In some embodiments, Q is O. In some embodiments, Q is S. In some embodiments, Q is S(O). In some embodiments, Q is S(O)2.

[0247] In some embodiments, Q is, depending on the situation, transmitted through one or two Rs. 6 The CH2 that is replaced.

[0248] In some embodiments, Q is CH2.

[0249] In some embodiments, Q is CHR 6 .

[0250] In some embodiments, Q is C(R) 6 )2.

[0251] In some embodiments, Q is 0.

[0252] In some embodiments, Q is NR 5 .

[0253] In some embodiments, Q is NH.

[0254] In some embodiments, Q is N (C1-C6 alkyl).

[0255] In some embodiments, Q is NCH3.

[0256] In some embodiments, Q is NCH(CH3)2.

[0257] In some embodiments, Q is N (C1-C6 haloalkyl).

[0258] In some embodiments, Q is NCH2CF3.

[0259] In some embodiments, Q is N (C1-C6 hydroxyalkyl).

[0260] In some embodiments, Q is

[0261] In some embodiments, Q is S(O)2.

[0262] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0263] In some embodiments, m is 1.

[0264] In some embodiments, m is 2.

[0265] In some embodiments, m is 3.

[0266] In some embodiments, m is 4.

[0267] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0268] In some embodiments, n is 0.

[0269] In some embodiments, n is 1.

[0270] In some embodiments, n is 2.

[0271] In some embodiments, n is 3.

[0272] In some embodiments, n is 4.

[0273] In some embodiments, the combination of m and n is selected from the following table: m n 1 0 1 1 1 2 1 3 1 4 2 0 2 1 2 2 2 3 2 4 3 0 3 1 3 2 3 3 3 4 4 0 4 1 4 2 4 3 4 4

[0274] In some embodiments, m is 1 and n is 2.

[0275] In some embodiments, m is 1, n is 2, and Q is CH2.

[0276] In some embodiments, m is 1, n is 2, and Q is CHR. 6 .

[0277] In some embodiments, m is 1, n is 2, and Q is C(R) 6 )2.

[0278] In some embodiments, m is 1, n is 2, and Q is C(CH3)2.

[0279] In some embodiments, m is 1, n is 2, and Q is

[0280] In some embodiments, m is 1, n is 2, and Q is

[0281] In some embodiments, m is 2 and n is 2.

[0282] In some embodiments, m is 2, n is 2, and Q is 0.

[0283] In some embodiments, m is 2, n is 2, and Q is NR. 5 .

[0284] In some embodiments, m is 2, n is 2, and Q is S(O)2.

[0285] In some embodiments, m is 2, n is 2, and Q is CH2.

[0286] In some embodiments, m is 3 and n is 2.

[0287] In some embodiments, m is 3, n is 2, and Q is 0.

[0288] In some embodiments, m is 3, n is 2, and Q is NR. 5 .

[0289] In some embodiments, m is 3, n is 2, and Q is NH.

[0290] In some embodiments, m is 3, n is 2, and Q is NCH3.

[0291] In some embodiments, m is 3, n is 2, and Q is NCH(CH3)2.

[0292] In some embodiments, m is 3, n is 2, and Q is NCH2CF3.

[0293] In some embodiments, m is 3, n is 2, and Q is

[0294] In some embodiments, m is 3, n is 2, and Q is CH2.

[0295] In some embodiments, m is 3, n is 2, and Q is CHCH3.

[0296] In some embodiments, m is 3, n is 2, and Q is C(CH3)2.

[0297] In some embodiments, m is 3, n is 2, and Q is CH (halogen).

[0298] In some embodiments, m is 3, n is 2, and Q is CHF.

[0299] In some embodiments, m is 3, n is 2, and Q is CH(OH).

[0300] In some embodiments, m is 3, n is 2, and Q is C(CH3)OH.

[0301] In some embodiments, m is 3, n is 2, and Q is S(O)2.

[0302] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6.

[0303] In some embodiments, u is 0.

[0304] In some embodiments, u is 1.

[0305] In some embodiments, u is 2.

[0306] In some embodiments, u is 3.

[0307] In some embodiments, u is 4.

[0308] In some embodiments, each R 6 Independently selected from halogens, OH, side radicals, CN, and CONR 10 R 11 NR 10 R 11 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 -S(O)2-C1-C6 alkyl, -C1-C6 alkyldiyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds.

[0309] In some embodiments, R 6 Selected from halogens. In some embodiments, R 6 For example, R is OH. In some embodiments, R 6 R is a side-oxygen group. In some embodiments, R 6 For CN. In some embodiments, R 6 For CONR 10 R 11 In some embodiments, R 6 For NR 10 R 11 In some embodiments, R 6 It is a C1-C6 alkyl group. In some embodiments, R 6 It is a C1-C6 alkoxy group. In some embodiments, R 6 O-C1-C6 alkyl-C(O)NR 10 R 11 In some embodiments, R 6 For NR 10 C(O)R 11 .

[0310] In some embodiments, R 6 It is a halogen.

[0311] In some embodiments, R 6 It is F.

[0312] In some embodiments, R 6 It is OH.

[0313] In some embodiments, R 6It is a C1-C6 alkyl group.

[0314] In some embodiments, R 6 It is -CH3.

[0315] In some embodiments, R 6 It is a C1-C6 haloalkyl group.

[0316] In some embodiments, R 6 It is -CF3.

[0317] In some embodiments, R 6 It is -CH2Cl.

[0318] In some embodiments, R 6 It is a C1-C6 hydroxyalkyl group.

[0319] In some embodiments, R 6 It is -CH2OH.

[0320] In some embodiments, R 6 for

[0321] In some embodiments, R 6 It is a C1-C6 alkyl-C1-C6 alkoxy group.

[0322] In some embodiments, R 6 It is -CH2-O-CH3.

[0323] In some embodiments, R 6 It is -CH2-O-CH2CH3.

[0324] In some embodiments, two R 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 .

[0325] In some embodiments, two symmetric R bits 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl or a 3-14 member heterocycle, wherein the cycloalkyl or heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 .

[0326] In some embodiments, two adjacent R 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 .

[0327] In some embodiments, two separate R 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member cycloalkyl or a 5-14 member heterocycle, wherein the cycloalkyl or heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 .

[0328] In some embodiments, two R 6 Together with the atoms it is connected to and the inserted atoms, it forms

[0329] In some embodiments, two R 6 Together with the atoms it is connected to and the inserted atoms, it forms

[0330] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0331] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0332] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0333] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0334] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0335] In some embodiments, two R 6Together with the atoms it is attached to, it forms

[0336] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0337] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0338] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0339] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0340] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0341] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0342] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0343] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0344] In some embodiments, two R 6 Together with the atoms it is attached to, it forms

[0345] In some embodiments, R 7 For H. In some embodiments, R 7 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 For C3-C 10 Cycloalkyl, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is a C1-C6 alkoxy group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, sideoxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is a C2-C6 alkenyl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, side oxygen, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is a C2-C6 alkynyl group, which, depending on the case, is independently substituted by one or more of the following substituents: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is a heterocyclic ring, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, side oxygen, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is an aryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 7 It is a heteroaryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds.

[0346] In some embodiments, R 7 For H.

[0347] In some embodiments, R 8 For H. In some embodiments, R 8 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 For C3-C 10Cycloalkyl, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is a C1-C6 alkoxy group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, sideoxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is a C2-C6 alkenyl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, side oxygen, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is a C2-C6 alkynyl group, which, depending on the case, is independently substituted by one or more of the following substituents: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is a heterocyclic ring, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, side oxygen, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is an aryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 8 It is a heteroaryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds.

[0348] In some embodiments, R 8 For H.

[0349] In some embodiments, R 8 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11, cycloalkyl and heterocyclic compounds.

[0350] In some embodiments, R 8 It is a C1-C6 alkyl group.

[0351] In some embodiments, R 8 It is -CH3.

[0352] In some embodiments, R 9 For H. In some embodiments, R 9 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl group, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 For C3-C 10 Cycloalkyl, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is a C1-C6 alkoxy group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is a C2-C6 alkenyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl group, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is a C2-C6 alkynyl group, which, depending on the case, is independently substituted by one or more of the following substituents: halogen, oxy group, OH, CN, C1-C6 alkyl group, C1-C6 alkoxy group, NR group. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is a heterocyclic ring, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is an aryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, serogroup, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R11 , cycloalkyl and heterocyclic compounds. In some embodiments, R 9 It is a heteroaryl group, which, depending on the case, is independently substituted by one or more substituents selected from the following: halogen, sero-oxygen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 , cycloalkyl and heterocyclic compounds.

[0353] In some embodiments, R 9 For H.

[0354] In some embodiments, R 9 It is a C1-C6 alkyl group.

[0355] In some embodiments, R 9 It is -CH3.

[0356] In some embodiments, R 10 For H. In some embodiments, R 10 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl group, C1-C6 alkoxy group. In some embodiments, R 10 For C3-C 10 Cycloalkyl, which, depending on the case, is independently substituted with one or more substituents selected from: halogen, oxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy. In some embodiments, R 10 is S(O)2R 12 .

[0357] In some embodiments, R 10 For H.

[0358] In some embodiments, R 10 It is a C1-C6 alkyl group.

[0359] In some embodiments, R 10 It is a methyl group.

[0360] In some embodiments, R 10 is -S(O)2R 12 .

[0361] In some embodiments, R 10 It is an -S(O)2C1-C6 alkyl group.

[0362] In some embodiments, R 10 It is -S(O)2CH3.

[0363] In some embodiments, R 10 It is -S(O)2CHF2.

[0364] In some embodiments, R 11 For H. In some embodiments, R 11 It is a C1-C6 alkyl group, which may be substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl group, C1-C6 alkoxy group. In some embodiments, R 11 For C3-C 10 Cycloalkyl, which, as appropriate, is substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy.

[0365] In some embodiments, R 11 For H.

[0366] In some embodiments, R 11 It is a C1-C6 alkyl group.

[0367] In some embodiments, R 11 It is a methyl group.

[0368] In some embodiments, R 12 It is a C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group.

[0369] In some embodiments, R 12 It is a C1-C6 alkyl group that is substituted with one or more halogens, depending on the case.

[0370] In some embodiments, R 12 It is -CHF2.

[0371] In some embodiments, the compound has formula (II): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined in this invention.

[0372] In some embodiments, the compound has formula (I-II): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined in this invention.

[0373] In some embodiments, the compound has the formula (IO): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0374] In some embodiments, the compound has the formula (IN): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0375] In some embodiments, the compound has the formula (IS): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0376] In some embodiments, the compound has formula (II): Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein X is selected from CR 7 and N; Y is selected from C=O, CR 8 and N; The constraint is that either X or Y is N; key Selected from single and double bonds; r is an integer selected from 0 and 1; The constraint is that when Y is C=0, the bond... It is a single bond and r is 1, and when Y is CR 8 When N or N, the key It is a double bond and r is 0; When Y is C=O or N, Z is selected from CR. 9 and N; When Y is CR 8 When Z is CR 9 ; Q is selected from CH2, NR 5 O, S, S(O), S(O)2 R 1 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; R 2 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 3 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 2 and R 3 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 6 Independently selected from halogens, OH, side radicals, CN, and CONR 10 R 11 NR 10 R 11C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 -S(O)2-C1-C6 alkyl, -C1-C6 alkyldiyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Or two Rs 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; R 7 R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, alkoxy, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 S(O)2R 12 cycloalkyl and heterocyclic compounds; R 10 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)2R 12 The alkyl or cycloalkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is, as appropriate, independently substituted with one or more substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; or R 10 and R 11 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 Selected from C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, septoxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; in, m is an integer selected from 1, 2, 3, or 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Aryl groups are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings.

[0377] In some embodiments, the compound has the formula (II-QN): Or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein fragments Selected from:

[0378] In some embodiments, the compound has formula (IIA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0379] In some embodiments, the compound has the formula (IIB): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0380] In some embodiments, the compound has the formula (IIC): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0381] In some embodiments, the compound has the formula (IID): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0382] In some preferred embodiments, the compound has the formula (IID): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein: Q is selected from CH2, NR 5 O, S, S(O), S(O)2; R 1 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; R 2 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 3 Selected from H, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 The alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 2 and R 3 Together with the atoms it is attached to and any inserted atoms, it forms C3-C. 10 Cycloalkyl, 5-14 member heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, oxy group, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR. 10 R 11 ; R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group.10 R 11 cycloalkyl and heterocyclic compounds; Each R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 The alkyl, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 cycloalkyl and heterocyclic compounds; Each R 6 Independently selected from halogens, OH, side radicals, CN, and CONR 10 R 11 NR 10 R 11 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 -S(O)2-C1-C6 alkyl, -C1-C6 alkyldiyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, oxy group, OH, C1-C6 alkyl, C1-C6 alkoxy group, NR group. 10 R 11 cycloalkyl and heterocyclic compounds; Or two Rs 6 Together with the atoms to which it is attached and any inserted atoms, it forms a 3-14 member cycloalkyl, aryl, 3-14 member heterocyclic, or 5-10 member heteroaryl, wherein the cycloalkyl, aryl, heterocyclic, or heteroaryl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; R 7 R 8 and R 9 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11The alkyl, alkoxy, cycloalkyl, or alkyl-alkoxy group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR. 10 R 11 S(O)2R 12 cycloalkyl and heterocyclic compounds; R 10 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)2R 12 The alkyl or cycloalkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, syloxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, wherein the alkyl or cycloalkyl group is, as appropriate, independently substituted with one or more substituents selected from the following: halogen, oxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; or R 10 and R 11 Together with the atoms to which it is attached and any inserted atoms, it forms a 5-14 member heterocycle, wherein the heterocycle is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 Selected from C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl group is, as appropriate, substituted by one or more independent substituents selected from the following: halogen, septoxy group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy group; in, m is an integer selected from 1, 2, 3, or 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0383] In some preferred embodiments, the compound has the formula (IID-QN): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein fragments Selected from:

[0384] In some embodiments, the compound has the formula (I-II-A): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0385] In some embodiments, the compound has the formula (I-II-B): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0386] In some embodiments, the compound has the formula (I-II-C): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0387] In some embodiments, the compound has the formula (I-II-D): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0388] In some embodiments, the compound has the formula (IIAM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0389] In some embodiments, the compound has the formula (IIBM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0390] In some embodiments, the compound has the formula (IICM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0391] In some embodiments, the compound has the formula (IIDI): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0392] In some embodiments, the compound has the formula (IIDM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0393] In some embodiments, the compound has the formula (IIDMH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0394] In some embodiments, the compound has the formula (IIDMA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0395] In some embodiments, the compound has the formula (IIDM-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0396] In some embodiments, the compound has the formula (IIDM-1*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0397] In some embodiments, the compound has the formula (IIDM-1**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0398] In some embodiments, the compound has the formula (IIDO): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0399] In some embodiments, the compound has the formula (IIDOH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0400] In some embodiments, the compound has the formula (IIDOA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0401] In some embodiments, the compound has the formula (IIDOAH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0402] In some embodiments, the compound has the formula (IIDOA-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0403] In some embodiments, the compound has the formula (IIDOA-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0404] In some embodiments, the compound has the formula (IIDOA--2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0405] In some embodiments, the compound has the formula (IIDOA-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0406] In some embodiments, the compound has the formula (IIDOA-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0407] In some embodiments, the compound has the formula (IIDO-3-AH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0408] In some embodiments, the compound has the formula (IIDOB): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0409] In some embodiments, the compound has the formula (IIDOBH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0410] In some embodiments, the compound has the formula (IIDOB-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0411] In some embodiments, the compound has the formula (IIDOB-1*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0412] In some embodiments, the compound has the formula (IIDOB-1**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0413] In some embodiments, the compound has the formula (IIDOB-1***): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0414] In some embodiments, the compound has the formula (IIDOB-1****): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0415] In some embodiments, the compound has the formula (IIDOC): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0416] In some embodiments, the compound has the formula (IIDOCH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0417] In some embodiments, the compound has the formula (IIDOC-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0418] In some embodiments, the compound has the formula (IIDOC-1*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0419] In some embodiments, the compound has the formula (IIDOC-1**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0420] In some embodiments, the compound has the formula (IIDOD): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0421] In some embodiments, the compound has the formula (IIDODH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0422] In some embodiments, the compound has the formula (IIDOD-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0423] In some embodiments, the compound has the formula (IIDOD-1*):

[0424] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof. In some embodiments, the compound has the formula (IIDOD-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0425] In some embodiments, the compound has the formula (IIDOE): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0426] In some embodiments, the compound has the formula (IIDOEH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0427] In some embodiments, the compound has the formula (IIDOE-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0428] In some embodiments, the compound has the formula (IIDOF): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0429] In some embodiments, the compound has the formula (IIDOFH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0430] In some embodiments, the compound has the formula (IIDOF-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0431] In some embodiments, the compound has the formula (IIDOF-1*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0432] In some embodiments, the compound has the formula (IIDOF-1**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0433] In some embodiments, the compound has the formula (IIDOF-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0434] In some embodiments, the compound has the formula (IIDOF-2*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0435] In some embodiments, the compound has the formula (IIDOF-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0436] In some embodiments, the compound has the formula (IID-II): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0437] In some embodiments, the compound has the formula (IIDZ): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0438] In some embodiments, the compound has the formula (IIDZH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0439] In some embodiments, the compound has the formula (IIDZ-0): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0440] In some embodiments, the compound has the formula (IIDZ-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0441] In some embodiments, the compound has the formula (IIDZ-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0442] In some embodiments, the compound has the formula (IIDZ-1-A): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0443] In some embodiments, the compound has the formula (IIDZ-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0444] In some embodiments, the compound has the formula (IIDZ-1-a*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0445] In some embodiments, the compound has the formula (IIDZ-1-a**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0446] In some embodiments, the compound has the formula (IIDD): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0447] In some embodiments, the compound has the formula (IIDDH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0448] In some embodiments, the compound has the formula (IIDD-0): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0449] In some embodiments, the compound has the formula (IIDD-O-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0450] In some embodiments, the compound has the formula (IIDD-0-A): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0451] In some embodiments, the compound has the formula (IIDD-0-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0452] In some embodiments, the compound has the formula (IIDD-0-B): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0453] In some embodiments, the compound has the formula (IIDD-O-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0454] In some embodiments, the compound has the formula (IIDD-O-C): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0455] In some embodiments, the compound has the formula (IIDD-O-c): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0456] In some embodiments, the compound has the formula (IIDD-O-cc): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0457] In some embodiments, the compound has the formula (IIDD-O-ccc): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0458] In some embodiments, the compound has the formula (IIDD-O-D): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0459] In some embodiments, the compound has the formula (IIDD-O-d): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0460] In some embodiments, the compound has the formula (IIDD-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0461] In some embodiments, the compound has the formula (IIDD-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0462] In some embodiments, the compound has the formula (IIDD-1-A): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0463] In some embodiments, the compound has the formula (IIDD-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0464] In some embodiments, the compound has the formula (IIDD-1-B): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0465] In some embodiments, the compound has the formula (IIDD-1-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0466] In some embodiments, the compound has the formula (IIDD-1-C): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0467] In some embodiments, the compound has the formula (IIDD-1-c): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0468] In some embodiments, the compound has the formula (IIDD-1-cc): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0469] In some embodiments, the compound has the formula (IIDD-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0470] In some embodiments, the compound has the formula (IIDD-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0471] In some embodiments, the compound has the formula (IIDD-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0472] In some embodiments, the compound has the formula (IIDD-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0473] In some embodiments, the compound has the formula (IIDD-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0474] In some embodiments, the compound has the formula (IIDD-4-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0475] In some embodiments, the compound has the formula (IID-III): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0476] In some embodiments, the compound has the formula (IIDP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0477] In some embodiments, the compound has the formula (IIDPH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0478] In some embodiments, the compound has the formula (IIDP-0): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0479] In some embodiments, the compound has the formula (IIDP-0-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0480] In some embodiments, the compound has the formula (IIDP-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0481] In some embodiments, the compound has the formula (IIDP-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0482] In some embodiments, the compound has the formula (IIDP-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0483] In some embodiments, the compound has the formula (IIDP-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0484] In some embodiments, the compound has the formula (IIDP-2-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0485] In some embodiments, the compound has the formula (IIDP-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0486] In some embodiments, the compound has the formula (IIDP-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0487] In some embodiments, the compound has the formula (IIDP-3-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0488] In some embodiments, the compound has the formula (IIDP-3-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0489] In some embodiments, the compound has the formula (IIDP-3-1-a-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0490] In some embodiments, the compound has the formula (IIDP-3-1-a-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0491] In some embodiments, the compound has the formula (IIDP-3-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein q is selected from integers of 1, 2, 3, 4, and 5; p is selected from integers of 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0492] In some embodiments, the compound has the formula (IIDP-3-2-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0493] In some embodiments, the compound has the formula (IIDP-3-2-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0494] In some embodiments, the compound has the formula (IIDP-3-2-a-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0495] In some embodiments, the compound has the formula (IIDP-3-2-a-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0496] In some embodiments, the compound has the formula (IIDP-3-2-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0497] In some embodiments, the compound has the formula (IIDP-3-2-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0498] In some embodiments, the compound has the formula (IIDP-3-2-b-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0499] In some embodiments, the compound has the formula (IIDP-3-2-b-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0500] In some embodiments, the compound has the formula (IIDP-3-2-b-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0501] In some embodiments, the compound has the formula (IIDP-3-2-b-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0502] In some embodiments, the compound has the formula (IIDP-3-2-b-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0503] In some embodiments, the compound has the formula (IIDP-3-2-b-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0504] In some embodiments, the compound has the formula (IIDP-3-2-b-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0505] In some embodiments, the compound has the formula (IIDP-3-2-b-4-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0506] In some embodiments, the compound has the formula (IIDP-3-2-b-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ;R 67 The components are selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and all other variables are as described in this invention.

[0507] In some embodiments, the compound has the formula (IIDP-3-2-b-5-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R 67 The components are selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and all other variables are as described in this invention.

[0508] In some embodiments, the compound has the formula (IIDP-3-2-b-5-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0509] In some embodiments, the compound has the formula (IIDP-3-2-b-5-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0510] In some embodiments, the compound has the formula (IIDP-3-2-b-5-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0511] In some embodiments, the compound has the formula (IIDP-3-2-b-5-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0512] In some embodiments, the compound has the formula (IIDP-3-2-b-5-c): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0513] In some embodiments, the compound has the formula (IIDP-3-2-b-5-cH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0514] In some embodiments, the compound has the formula (IIDP-3-2-c): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0515] In some embodiments, the compound has the formula (IIDP-3-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0516] In some embodiments, the compound has the formula (IIDP-3-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0517] In some embodiments, the compound has the formula (IIDP-3-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R12 The ring H is a 3-8 member saturated or partially unsaturated heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; and all other variables are as described in this invention.

[0518] In some embodiments, the compound has the formula (IIDP-3-4-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 The ring H is a 3-8 member saturated or partially unsaturated heterocyclic group containing 1-3 heteroatoms selected from N, O, and S; and all other variables are as described in this invention.

[0519] In some embodiments, the compound has the formula (IIDP-3-4-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0520] In some embodiments, the compound has the formula (IIDP-3-4-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0521] In some embodiments, the compound has the formula (IIDP-3-4-a-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0522] In some embodiments, the compound has the formula (IIDP-3-4-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0523] In some embodiments, the compound has the formula (IIDP-3-4-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein x and y are integers independently selected from 1, 2 and 3; and all other variables are as described in this invention.

[0524] In some embodiments, the compound has the formula (IIDP-3-4-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein x and y are integers independently selected from 1, 2 and 3; and all other variables are as described in this invention.

[0525] In some embodiments, the compound has the formula (IIDP-3-4-b-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0526] In some embodiments, the compound has the formula (IIDP-3-4-b-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0527] In some embodiments, the compound has the formula (IIDP-3-4-b-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0528] In some embodiments, the compound has the formula (IIDP-3-4-b-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0529] In some embodiments, the compound has the formula (IIDP-3-4-b-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0530] In some embodiments, the compound has the formula (IIDP-3-4-b-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0531] In some embodiments, the compound has the formula (IIDP-3-4-c): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0532] In some embodiments, the compound has the formula (IIDP-3-4-cH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0533] In some embodiments, the compound has the formula (IIDP-3-4-c-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0534] In some embodiments, the compound has the formula (IIDP-3-4-c-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0535] In some embodiments, the compound has the formula (IIDP-3-4-c-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0536] In some embodiments, the compound has the formula (IIDP-3-4-c-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0537] In some embodiments, the compound has the formula (IIDP-3-4-c-2-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0538] In some embodiments, the compound has the formula (IIDP-3-4-c-2-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0539] In some embodiments, the compound has the formula (IIDP-3-4-c-2-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0540] In some embodiments, the compound has the formula (IIDP-3-4-c-2-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0541] In some embodiments, the compound has the formula (IIDP-3-4-d): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0542] In some embodiments, the compound has the formula (IIDP-3-4-dH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0543] In some embodiments, the compound has the formula (IIDP-3-4-d-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0544] In some embodiments, the compound has the formula (IIDP-3-4-d-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0545] In some embodiments, the compound has the formula (IIDP-3-4-d-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0546] In some embodiments, the compound has the formula (IIDP-3-4-d-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0547] In some embodiments, the compound has the formula (IIDP-3-4-d-2-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0548] In some embodiments, the compound has the formula (IIDP-3-4-d-2-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0549] In some embodiments, the compound has the formula (IIDP-3-4-d-2-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0550] In some embodiments, the compound has the formula (IIDP-3-4-d-2-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0551] In some embodiments, the compound has the formula (IIDP-3-4-e): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0552] In some embodiments, the compound has the formula (IIDP-3-4-eH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein w is selected from integers 1, 2, 3, 4 and 5; and all other variables are as described in this invention.

[0553] In some embodiments, the compound has the formula (IIDP-3-4-e-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0554] In some embodiments, the compound has the formula (IIDP-3-4-e-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0555] In some embodiments, the compound has the formula (IIDP-3-4-e-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0556] In some embodiments, the compound has the formula (IIDP-3-4-e-1-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0557] In some embodiments, the compound has the formula (IIDP-3-4-e-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0558] In some embodiments, the compound has the formula (IIDP-3-4-e-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0559] In some embodiments, the compound has the formula (IIDP-3-4-e-2-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0560] In some embodiments, the compound has the formula (IIDP-3-4-e-2-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0561] In some embodiments, the compound has the formula (IIDP-3-4-e-2-b): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0562] In some embodiments, the compound has the formula (IIDP-3-4-e-2-bH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0563] In some embodiments, the compound has the formula (IIDP-3-4-f): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0564] In some embodiments, the compound has the formula (IIDP-3-4-fH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3; p is an integer selected from 0, 1, and 2; R 66Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0565] In some embodiments, the compound has the formula (IIDP-3-4-f-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0566] In some embodiments, the compound has the formula (IIDP-3-4-f-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0567] In some embodiments, the compound has the formula (IIDP-3-4-f-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0568] In some embodiments, the compound has the formula (IIDP-3-4-f-1-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0569] In some embodiments, the compound has the formula (IIDP-3-4-f-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0570] In some embodiments, the compound has the formula (IIDP-3-4-f-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein p is selected from integers 0, 1, and 2; R 66 Selected from halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 All other variables are as described in this invention.

[0571] In some embodiments, the compound has the formula (IIDP-3-4-f-2-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0572] In some embodiments, the compound has the formula (IIDP-3-4-f-2-aH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0573] In some embodiments, the compound has the formula (IID-PP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0574] In some embodiments, the compound has the formula (IID-PP-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0575] In some embodiments, the compound has the formula (IID-PP-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0576] In some embodiments, the compound has the formula (IID-PP-1-a): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0577] In some embodiments, the compound has the formula (IIDA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0578] In some embodiments, the compound has the formula (IIDAH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0579] In some embodiments, the compound has the formula (IIDA-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0580] In some embodiments, the compound has the formula (IIDA-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0581] In some embodiments, the compound has the formula (IIDA-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0582] In some embodiments, the compound has the formula (IIDA-3*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0583] In some embodiments, the compound has the formula (IIDA-3**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0584] In some embodiments, the compound has the formula (IIDA-3***): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0585] In some embodiments, the compound has the formula (IIDA-3****): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0586] In some embodiments, the compound has the formula (IIDA-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0587] In some embodiments, the compound has the formula (IIDA-4*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0588] In some embodiments, the compound has the formula (IIDA-4**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0589] In some embodiments, the compound has the formula (IIDA-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0590] In some embodiments, the compound has the formula (IIDA-6): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0591] In some embodiments, the compound has the formula (IIDA-6*): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0592] In some embodiments, the compound has the formula (IIDA-6**): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0593] In some embodiments, the compound has the formula (IIDA-6***): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0594] In some embodiments, the compound has the formula (IIDA-6****): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0595] In some embodiments, the compound has the formula (IIDA-7): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0596] In some embodiments, the compound has the formula (IIDA-8): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0597] In some embodiments, the compound has the formula (IID-IV): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0598] In some embodiments, the compound has the formula (IIDT): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0599] In some embodiments, the compound has the formula (IIDTH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0600] In some embodiments, the compound has the formula (IID-TZ): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0601] In some embodiments, the compound has the formula (IID-TZ-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0602] In some embodiments, the compound has the formula (I-II-AM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0603] In some embodiments, the compound has the formula (I-II-BM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0604] In some embodiments, the compound has the formula (I-II-CM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0605] In some embodiments, the compound has the formula (I-II-DM): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0606] In some embodiments, the compound has the formula (IIAP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0607] In some embodiments, the compound has the formula (IIBP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0608] In some embodiments, the compound has the formula (IICP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0609] In some embodiments, the compound has the formula (IIDP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0610] In some embodiments, the compound has the formula (I-II-AP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0611] In some embodiments, the compound has the formula (I-II-BP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0612] In some embodiments, the compound has the formula (I-II-CP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0613] In some embodiments, the compound has the formula (I-II-DP): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0614] In some embodiments, the compound has the formula (IIAA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0615] In some embodiments, the compound has the formula (IIBA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0616] In some embodiments, the compound has the formula (IICA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0617] In some embodiments, the compound has the formula (IIDA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0618] In some embodiments, the compound has the formula (I-II-AA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0619] In some embodiments, the compound has the formula (I-II-BA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0620] In some embodiments, the compound has the formula (I-II-CA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0621] In some embodiments, the compound has the formula (I-II-DA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0622] In some embodiments, the compound has the formula (IIA-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0623] In some embodiments, the compound has the formula (IIA-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0624] In some embodiments, the compound has the formula (IIA-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0625] In some embodiments, the compound has the formula (IIA-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0626] In some embodiments, the compound has the formula (IIA-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0627] In some embodiments, the compound has the formula (IIA-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0628] In some embodiments, the compound has the formula (IIA-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0629] In some embodiments, the compound has the formula (IIA-4-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0630] In some embodiments, the compound has the formula (IIA-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers of 1, 2, 3 and 4 and all other variables are as defined in this invention.

[0631] In some embodiments, the compound has the formula (IIA-5-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers of 1, 2, 3 and 4 and all other variables are as defined in this invention.

[0632] In some embodiments, the compound has the formula (IIB-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0633] In some embodiments, the compound has the formula (IIB-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0634] In some embodiments, the compound has the formula (IIC-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0635] In some embodiments, the compound has the formula (IIC-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0636] In some embodiments, the compound has the formula (IID-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0637] In some embodiments, the compound has the formula (IID-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0638] In some embodiments, the compound has the formula (IID-1-H-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0639] In some embodiments, the compound has the formula (IID-1-H-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0640] In some embodiments, the compound has the formula (IID-1-H-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0641] In some embodiments, the compound has the formula (IID-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0642] In some embodiments, the compound has the formula (IID-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0643] In some embodiments, the compound has the formula (IID-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein b is selected from integers of 1, 2 and 3 and all other variables are as defined in this invention.

[0644] In some embodiments, the compound has the formula (IID-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein b is selected from integers of 1, 2 and 3 and all other variables are as defined in this invention.

[0645] In some embodiments, the compound has the formula (IID-3-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0646] In some embodiments, the compound has the formula (IID-3-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0647] In some embodiments, the compound has the formula (IID-3-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0648] In some embodiments, the compound has the formula (IID-3-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0649] In some embodiments, the compound has the formula (IID-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0650] In some embodiments, the compound has the formula (IID-4-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0651] In some embodiments, the compound has the formula (IID-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R S It is H, halogen, CN or CH3 and all other variables are as defined in this invention.

[0652] In some embodiments, the compound has the formula (IID-5-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R S It is H, halogen, CN or CH3 and all other variables are as defined in this invention.

[0653] In some embodiments, the compound has the formula (IID-6): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R S It is H, halogen, CN or CH3 and all other variables are as defined in this invention.

[0654] In some embodiments, the compound has the formula (IID-6-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R S It is H, halogen, CN or CH3 and all other variables are as defined in this invention.

[0655] In some embodiments, the compound has the formula (IID-7): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, where L is CH2, O, S, NH, and all other variables are as defined in this invention.

[0656] In some embodiments, the compound has the formula (IID-7-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, where L is CH2, O, S, NH, and all other variables are as defined in this invention.

[0657] In some embodiments, the compound has the formula (IID-7-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0658] In some embodiments, the compound has the formula (IID-7-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0659] In some embodiments, the compound has the formula (IID-8): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein L is CH2, O, S or NH, and all other variables are as defined in this invention.

[0660] In some embodiments, the compound has the formula (IID-8-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein L is CH2, O, S or NH, and all other variables are as defined in this invention.

[0661] In some embodiments, the compound has the formula (IID-7-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0662] In some embodiments, the compound has the formula (IID-7-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0663] In some embodiments, the compound has the formula (IID-9): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0664] In some embodiments, the compound has the formula (IID-9-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0665] In some embodiments, the compound has the formula (IID-9-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0666] In some embodiments, the compound has the formula (IID-9-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0667] In some embodiments, the compound has the formula (I-II-A-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R A The components are selected from H and C1-C3 alkyl groups, and all other variables are as defined in this invention.

[0668] In some embodiments, the compound has the formula (I-II-A-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R A The components are selected from H and C1-C3 alkyl groups, and all other variables are as defined in this invention.

[0669] In some embodiments, the compound has the formula (I-II-A-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers of 1, 2, 3, 4 and 5 and all other variables are as defined in this invention.

[0670] In some embodiments, the compound has the formula (I-II-A-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers 1, 2, 3, 4 and 5, and all other variables are as defined in this invention.

[0671] In some embodiments, the compound has the formula (I-II-A-2-H-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0672] In some embodiments, the compound has the formula (I-II-A-2-H-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0673] In some embodiments, the compound has the formula (I-II-A-2-H-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0674] In some embodiments, the compound has the formula (I-II-A-2-H-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0675] In some embodiments, the compound has the formula (I-II-A-2-H-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0676] In some embodiments, the compound has the formula (I-II-A-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein ring A is a heterocyclic or heteroaryl group; v is selected from integers 0, 1, and 2; each R H The components are independently selected from halogens, OH, =O, CN, and C1-C6 alkyl groups; and all other variables are as defined in this invention.

[0677] In some embodiments, the compound has the formula (I-II-A-3-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein ring A is a heterocyclic or heteroaryl group; v is selected from integers 0, 1, and 2; each R H The components are independently selected from halogens, OH, =O, CN, and C1-C6 alkyl groups; and all other variables are as defined in this invention.

[0678] In some embodiments, the compound has the formula (I-II-A-3-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0679] In some embodiments, the compound has the formula (I-II-A-3-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0680] In some embodiments, the compound has the formula (I-II-A-3-1-H'): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0681] In some embodiments, the compound has the formula (I-II-A-3-1-H”): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0682] In some embodiments, the compound has the formula (I-II-A-3-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0683] In some embodiments, the compound has the formula (I-II-A-3-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0684] In some embodiments, the compound has the formula (I-II-A-3-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0685] In some embodiments, the compound has the formula (I-II-A-3-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0686] In some embodiments, the compound has the formula (I-II-BH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0687] In some embodiments, the compound has the formula (I-II-CH): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0688] In some embodiments, the compound has the formula (I-II-D-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R A The components are selected from H and C1-C3 alkyl groups, and all other variables are as defined in this invention.

[0689] In some embodiments, the compound has the formula (I-II-D-1-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein R A The components are selected from H and C1-C3 alkyl groups, and all other variables are as defined in this invention.

[0690] In some embodiments, the compound has the formula (I-II-D-1-H-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0691] In some embodiments, the compound has the formula (I-II-D-1-H-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0692] In some embodiments, the compound has the formula (I-II-D-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers 1, 2, 3, 4 and 5, and all other variables are as defined in this invention.

[0693] In some embodiments, the compound has the formula (I-II-D-2-H): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein p is selected from integers 1, 2, 3, 4 and 5, and all other variables are as defined in this invention.

[0694] In some embodiments, the compound has the formula (I-II-D-2-H-1): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0695] In some embodiments, the compound has the formula (I-II-D-2-H-2): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0696] In some embodiments, the compound has the formula (I-II-D-2-H-3): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0697] In some embodiments, the compound has the formula (I-II-D-2-H-4): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0698] In some embodiments, the compound has the formula (I-II-D-2-H-5): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer.

[0699] In some embodiments, the compound is selected from compounds of formula (IIAM), formula (IIBM), formula (IICM), formula (IIDM), formula (I-II-AM), formula (I-II-BM), formula (I-II-CM), or formula (I-II-DM): Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0700] In some embodiments, the compound is selected from compounds of formula (IIAG), formula (IIBG), formula (IICG), or formula (IIDG): Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0701] In some embodiments, the compound is selected from compounds of formula (I-II-AG), formula (I-II-BG), formula (I-II-CG), or formula (I-II-DG): Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers. In some embodiments, the compound is selected from compounds of formula (IIAA), formula (IIBA), formula (IICA), formula (IIDA), formula (I-II-AA), formula (I-II-BA), formula (I-II-CA), or formula (I-II-DA): Or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein u is 0 or 1 and all other variables are as defined in this invention.

[0702] In some preferred embodiments, the compound is compound 27: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0703] In some preferred embodiments, the compound is compound 50: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0704] In some preferred embodiments, the compound is compound 59: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0705] In some preferred embodiments, the compound is compound 62: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0706] In some preferred embodiments, the compound is compound 65: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0707] In some preferred embodiments, the compound is compound 70: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0708] In some preferred embodiments, the compound is compound 74: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0709] In some preferred embodiments, the compound is compound 78: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0710] In some preferred embodiments, the compound is compound 79: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0711] In some preferred embodiments, the compound is compound 81: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0712] In some preferred embodiments, the compound is compound 82: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0713] In some preferred embodiments, the compound is compound 88: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0714] In some preferred embodiments, the compound is compound 92: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0715] In some preferred embodiments, the compound is compound 121: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0716] In some preferred embodiments, the compound is compound 122: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0717] In some preferred embodiments, the compound is compound 123: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0718] In some preferred embodiments, the compound is compound 124: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0719] In some preferred embodiments, the compound is compound 125: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0720] In some preferred embodiments, the compound is compound 126: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0721] In some preferred embodiments, the compound is compound 127: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0722] In some preferred embodiments, the compound is compound 128: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0723] In some preferred embodiments, the compound is compound 129: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0724] In some preferred embodiments, the compound is compound 130: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0725] In some preferred embodiments, the compound is compound 131: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0726] In some preferred embodiments, the compound is compound 132: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0727] In some preferred embodiments, the compound is compound 133: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0728] In some preferred embodiments, the compound is compound 134: Or its pharmaceutically acceptable salts, stereoisomers, solvates or tautomers.

[0729] In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, or tautomers.

[0730] In some embodiments, the compound is selected from the compounds described in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0731] In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0732] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0733] In some embodiments, the compound is selected from the compounds described in Table 1.

[0734] Table 1. Non-limiting illustrative compounds of the present invention

[0735] In some embodiments, the compound is a medically acceptable salt of any of the compounds described in Table 1.

[0736] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any of the compounds described in Table 1.

[0737] In some embodiments, the compound is a salt of any acid described in Table 2 and any of the compounds described in Table 1.

[0738] Table 2. Medically acceptable acids that form salts with compounds of formula (I)

[0739] In some embodiments, the compound is a salt of acetic acid and any of the compounds described in Table 1.

[0740] In some embodiments, the compound is a salt of adipic acid and any of the compounds described in Table 1.

[0741] In some embodiments, the compound is a salt of ascorbic acid (L) and any of the compounds described in Table 1.

[0742] In some embodiments, the compound is a salt of hydrobromic acid and any of the compounds described in Table 1.

[0743] In some embodiments, the compound is a salt of hydrochloric acid and any of the compounds described in Table 1.

[0744] In some embodiments, the compound is a salt of citric acid and any of the compounds described in Table 1.

[0745] In some embodiments, the compound is a salt of glutamic acid and any of the compounds described in Table 1.

[0746] In some embodiments, the compound is a salt of oxalic acid and any of the compounds described in Table 1.

[0747] In some embodiments, the compound is a salt of formic acid and any of the compounds described in Table 1.

[0748] In some embodiments, the compound is a salt of sulfuric acid and any of the compounds described in Table 1.

[0749] In some embodiments, the present invention provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds having the forms disclosed herein.

[0750] In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrug and isotopic derivatives of pharmaceutically acceptable salts.

[0751] In some embodiments, the compound is any of the compounds described in Table 1 and its pharmaceutically acceptable salt isotopic derivatives.

[0752] In some embodiments, the compound is any of the prodrugs of the compounds described in Table 1 and isotopic derivatives of their pharmaceutically acceptable salts.

[0753] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1.

[0754] It should be understood that isotope derivatives can be prepared using any of a variety of techniques recognized in this art. For example, isotope derivatives can generally be prepared by using isotopically labeled reagents instead of unlabeled reagents by implementing the procedures disclosed in the schemes and / or examples described in this invention.

[0755] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0756] In some embodiments, the isotope derivative is a deuterated compound having any of the compounds disclosed in this invention.

[0757] As used in this invention, the term "isotope derivative" refers to a compound derivative in which one or more atoms are isotopically enriched or labeled. For example, compared to the corresponding compound of formula (I), the isotope derivative of the compound of formula (I) is isotopically enriched or labeled with respect to one or more isotopes. In some embodiments, the isotope derivative is with respect to one or more atoms selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 31 P and 34 The atoms of S are concentrated or labeled with one or more of those atoms. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., with respect to one or more of its hydrogen atoms). 2 H concentration).

[0758] In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrug and a deuterated compound of a pharmaceutically acceptable salt.

[0759] In some embodiments, the compound is any of the compounds described in Table 1 and a deuterated compound of a pharmaceutically acceptable salt thereof.

[0760] In some embodiments, the compound is any of the prodrugs of the compounds described in Table 1 and a deuterated compound of a pharmaceutically acceptable salt.

[0761] In some embodiments, the compound is a deuterated compound of any of the compounds described in Table 1.

[0762] It should be understood that deuterium-labeled compounds contain deuterium atoms with a deuterium abundance substantially greater than 0.015% of the naturally occurring deuterium abundance.

[0763] In some embodiments, the deuterium enrichment factor of each deuterium atom in the deuterium-labeled compound is at least 3500 (52.5% deuterium inclusion at each deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion). As used herein, the term "deuterium enrichment factor" refers to the ratio between deuterium abundance and native deuterium abundance.

[0764] It should be understood that deuterium-labeled compounds can be prepared using any of the various techniques known in this art. For example, deuterium-labeled compounds can generally be prepared by replacing undeuterium-labeled reagents with deuterium-labeled reagents by implementing the procedures disclosed in the schemes and / or examples described in this invention.

[0765] Compounds of the present invention containing the aforementioned deuterium atoms, or their pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Furthermore, deuterium (i.e., 2 H) substitutions can offer certain therapeutic advantages due to their higher metabolic stability, such as extended in vivo half-life or reduced dose requirements.

[0766] In some embodiments, the compound is... 18 F-labeled compounds.

[0767] In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds or any combination thereof.

[0768] In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds or any combination thereof.

[0769] It should be understood that 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3S, 34 S, 35 S and / or 36 S-labeled compounds can be prepared using any of a variety of techniques recognized in this art. For example, they can generally be prepared by implementing the procedures disclosed in the embodiments and / or examples described in this invention. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 Deuterium-labeled compounds were prepared by using S-labeled reagents instead of non-isotope-labeled reagents.

[0770] Containing the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and 36 Compounds of the present invention containing one or more of the S atoms, or their pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Additionally, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 S) substitutions can offer certain therapeutic advantages due to their higher metabolic stability, such as extended in vivo half-life or reduced dose requirements.

[0771] For the avoidance of doubt, it should be understood that when a group is defined as “described in this invention” in this specification, the group encompasses the first and broadest definition as well as each and all specific definitions of the group.

[0772] The selection of various functional groups and substituents in compounds of formula (I) typically results in a molecular weight not exceeding 1000 Daltons. More typically, the molecular weight will be less than 900 Daltons, for example less than 800 Daltons, or less than 750 Daltons, or less than 700 Daltons, or less than 650 Daltons. More preferably, the molecular weight is less than 600 Daltons, and for example 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.

[0773] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention having sufficient basicity, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Additionally, suitable pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; ammonium salts; or salts with organic bases providing pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0774] It should be understood that compounds having any of the formulas disclosed in this invention and any pharmaceutically acceptable salt thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomer forms of such compounds.

[0775] As used in this invention, the term "isomer" refers to compounds having the same molecular formula but different atomic bond sequences or atomic spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "non-mirror image isomers," and stereoisomers that are non-overlapping mirror images of each other are called "mirror image isomers" or sometimes optical isomers. A mixture containing equal amounts of individual mirror image isomers with opposite anisotropy is called a "racemic mixture."

[0776] As used in this invention, the term "opposite center" refers to a carbon atom bonded to four different substituents.

[0777] As used in this invention, the term "anti-pivotal isomer" refers to a compound having at least one anti-pivotal center. Compounds having more than one anti-pivotal center may exist as individual non-mirror image isomers or mixtures of non-mirror image isomers, referred to as "non-mirror image isomer mixtures." When one anti-pivotal center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that anti-pivotal center. The absolute configuration refers to the spatial arrangement of substituents attached to the anti-pivotal center. The substituents attached to the anti-pivotal center under consideration are ordered according to the Cahn, Ingold, and Prelog sequence rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0778] As used in this invention, the term "geometric isomer" refers to a non-mirror image isomer that exists due to hindered rotation around a double bond or a cycloalkyl linking group (e.g., 1,3-cyclobutyl). Such configurations are distinguished by the prefixes cis and trans or Z and E in their names, indicating that, according to the Cahn-Ingold-Prelog rule, the groups are located on the same side or opposite side of the double bond in the molecule.

[0779] It should be understood that the compounds of the present invention may be described as different palmar isomers or geometric isomers. It should also be understood that when a compound has palmar or geometric isomers, all isomers are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[0780] It should be understood that the structures and other compounds discussed in this invention include all their transisomers. It should also be understood that not all transisomers possess the same level of activity.

[0781] As used in this invention, the term "transisomer" refers to a type of stereoisomer where the atoms of two isomers differ in spatial arrangement. The presence of transisomers is attributed to rotational restriction caused by the impaired rotation of the larger group around the central bond. Such transisomers typically exist as mixtures; however, due to recent advances in chromatography, it is possible to separate mixtures of two transisomers under selected conditions.

[0782] As used in this invention, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the translocation of hydrogen atoms accompanied by the exchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism. Of the various types of tautomerism that can occur, two are most commonly observed. In keto-enol tautomerism, there is a simultaneous translocation of electrons and hydrogen atoms. As demonstrated by glucose, cyclic-chain tautomerism occurs due to the reaction of the aldehyde group (-CHO) in the sugar chain molecule with a hydroxyl group (-OH) in the same molecule, causing it to take on a cyclic (ring) form.

[0783] It should be understood that the compounds of the present invention can be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have higher activity levels compared to other tautomers.

[0784] Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "non-mirror image isomers," and isomers that are non-overlapping mirror images of each other are called "mirror image isomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, a pair of mirror image isomers may exist. Mirror image isomers can be characterized by the absolute configuration of their asymmetry center and described according to the R-sequence and S-sequence rules of Cahn and Prelog, or characterized by rotating the molecular polarization plane and specifying them as dextrorotatory or levorotatory (i.e., (+)-isomers or (-)-isomers, respectively). Antipodal compounds may exist as individual mirror image isomers or as mixtures thereof. A mixture containing equal proportions of mirror image isomers is called a "racemic mixture."

[0785] The compounds of this invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)-stereoisomers or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of specific compounds in this specification and the claims of the application is intended to include individual mirror-image isomers and mixtures thereof (racemic mixtures or other mixtures). Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolving racemic forms. Some compounds of this invention may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that this invention covers all optical isomers, non-mirror-image isomers, and geometric isomers and mixtures thereof that have inflammatory body inhibitory activity.

[0786] This invention also covers compounds of the invention as defined herein that contain one or more isotope substitutions.

[0787] It should be understood that, where applicable, any compound of any kind described in this invention includes the compound itself, its salts, and its solvates. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on the substituted compound disclosed in this invention. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleic acid, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0788] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxylate group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0789] It should be understood that the compounds of the present invention, such as salts of the compounds, may exist in a hydrated form, an undried (anhydrous) form, or as a solvate with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0790] As used in this invention, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to form solvates by retaining solvent molecules in a fixed molar ratio in a crystalline solid state. If the solvent is water, the formed solvate is a hydrate; and if the solvent is an alcohol, the formed solvate is an alcohol. Hydrates are formed by combining one or more molecules of water with one molecule of a substance, wherein the water retains its molecular state H₂O.

[0791] As used in this invention, the term "analyte" refers to a compound whose structure is similar to another compound but whose composition is slightly different (e.g., one atom is replaced by a different element or a specific functional group is present, or one functional group is replaced by another functional group). Therefore, an analogue is a compound whose function and appearance are similar to or equivalent to the reference compound, but whose structure or origin is not similar to or equivalent to the reference compound.

[0792] As used in this invention, the term "derivative" refers to a compound having a common core structure and being substituted with various groups as described in this invention.

[0793] As used herein, the term "bioreactive compound" refers to a compound produced by the exchange of one atom or group of atoms with another atom or group of atoms that is substantially similar. The purpose of bioreactive substitution is to produce a new compound that has similar biological properties to the parent compound. Bioreactive substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioreactive compounds include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0794] It should also be understood that certain compounds of any of the formulas disclosed in this invention may exist in both solvated and unsolvated forms (such as hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this invention covers all such solvated forms having inflammasome-inhibiting activity.

[0795] It should also be understood that certain compounds of any of the formulations disclosed in this invention may exhibit polymorphism, and this invention covers all such forms or mixtures thereof that have inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, pyrolysis gravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0796] Compounds of any of the formulas disclosed in this invention may exist in a variety of different tautomeric forms, and compounds referring to formula (I) or formula (II) include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all other forms are still included within formula (I) or formula (II). Examples of tautomeric forms include ketone forms, enol forms, and enolized forms, for example in the following tautomeric pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / isonitro.

[0797] Compounds containing amine functional groups in any of the formulas disclosed in this invention can also form N-oxides. Compounds of formula (I) or (II) containing amine functional groups mentioned in this invention also include N-oxides. If the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peroxyacid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, ed. Jerry March, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared by the LWDeady procedure (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0798] The compounds of any of the formulas disclosed in this invention can be administered as prodrugs, which decompose in the human or animal body to release the compounds of this invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of this invention. Prodrugs can be formed when the compounds of this invention contain suitable groups or substituents that can connect to characteristic-modifying groups. Examples of prodrugs include derivatives in which the ester or amide group of any of the formulas disclosed in this invention contains an in vivo cleavable alkyl or acyl substituent.

[0799] Therefore, this invention includes compounds of any of the formulas disclosed herein as defined above, which can be obtained by organic synthesis and are available in the human or animal body via the cleavage of their prodrugs. Thus, this invention includes compounds of any of the formulas disclosed herein produced by organic synthesis, as well as such compounds produced in the human or animal body via the metabolism of precursor compounds; that is, compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[0800] The pharmaceutically acceptable prodrug of any of the compounds disclosed in this invention is a prodrug suitable for administration to humans or animals based on reasonable medical judgment, without inappropriate pharmacological activity and without abnormal toxicity. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, “Design and Application of Pro-drugs”, Chapter 5, H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0801] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxyl group, from any of the formulas disclosed in this invention, are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable ester-forming groups with respect to a hydroxyl group include inorganic esters, such as phosphate esters (including cyclic aminophosphates). Other suitable pharmaceutically acceptable ester-forming groups with respect to a hydroxyl group include C... 1- C 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; C 1- C 10Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2-aminocarbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, N-morpholinylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)alkylpiperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups relative to the hydroxyl group include α-acyloxyalkyl, such as acetoxymethyl and trimethylacetoxymethyl.

[0802] Suitable pharmaceutically acceptable prodrugs of compounds having a carboxyl group, such as amides that are cleavable in vivo, for example, amides formed with: amines, such as ammonia; C 1-4 Alkylamines, such as methylamine; (C1-C4 alkyl)2amines, such as dimethylamine, N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines, such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines, such as benzylamine; and amino acids, such as glycine, or esters thereof.

[0803] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group, such as their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, those with C1-C2 groups. 10 Amides formed from alkyl groups, wherein the alkyl group is such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, N-morpholinylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0804] The in vivo effects of any of the compounds disclosed in this invention may be exerted in part by one or more metabolites formed in the human or animal body following administration of any of the compounds disclosed in this invention. As stated above, the in vivo effects of any of the compounds disclosed in this invention may also be exerted by means of the metabolism of a precursor compound (prodrug). Methods for synthesizing compounds

[0805] The compounds of this invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below.

[0806] Compounds of formula (I) can be prepared in part by methods known in organic synthesis techniques as described in the following synthetic schemes. In the schemes described below, it should be fully understood that, where necessary, protecting groups are used on sensitive or reactive groups according to general principles or chemistry. Protecting groups are operated according to standard methods of organic synthesis (TW Greene and PGM Watts, “Protective Groups in Organic Synthesis”, 3rd edition, Wiley, New York 1999). Such groups are removed at a suitable stage of the compound synthesis using methods obvious to those skilled in the art. The methods, reaction conditions, and sequence chosen by those skilled in the art will identify the presence of stereoisomeric centers in compounds of formula (I). Therefore, the present invention includes two possible stereoisomers (unless specified in the synthesis), and includes not only racemic compounds but also individual mirror-image and / or non-mirror-image isomers. When a compound is required in the form of a single mirror-image or non-mirror-image isomer, it can be obtained by stereospecific synthesis or by analysis of the final product or any suitable intermediate. Analysis of the final product, intermediate, or starting material can be achieved by any suitable method known in this art. See, for example, “Stereochemistry of Organic Compounds”, E.L.E. Liel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0807] The compounds described in this invention can be obtained from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods. Preparation of compounds

[0808] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry or variations thereof known to those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized by following the steps outlined in general procedure A or B, which include sequences of different assembly intermediates or compounds. Starting materials are commercially available or obtained by procedures known in reported literature or as described below. General Procedure A

[0809] Generally, compounds of formula (II) can be prepared using the reaction sequence presented in scheme 1: Option 1

[0810] All reagents may be commercially available compounds themselves or products synthesized from commercially available reagents. The preparation of such reagents may be carried out using a one-step or multi-step synthetic procedure, including but not limited to the procedure described in the preparation section of this invention. General Procedure B

[0811] Generally, compounds of formula (I-II) can be prepared using the reaction sequence presented in scheme 2: Option 2

[0812] Specific, non-restricted instances of this program can be found in R. 1 '、R 2 'or R 3 The preparation reactions of compounds of formula I-II are presented when 'Br' is used.

[0813] All reagents may be commercially available compounds themselves or products synthesized from commercially available reagents. For preparation, such reagents may be used in one-step or multi-step synthetic procedures, including but not limited to the procedures described in the preparation section of this invention. General procedure C

[0814] Generally, compounds of formula (I-II) can be prepared using the reaction sequence presented in scheme 3: Option 3 PG is an appropriate protecting group.

[0815] All reagents may be commercially available compounds themselves or products synthesized from commercially available reagents. For preparation, such reagents may be used in one-step or multi-step synthetic procedures, including but not limited to the procedures described in the preparation section of this invention.

[0816] It will be apparent to those skilled in the art that any of the compounds of formula (I) obtained according to procedure A, procedure B or procedure C above can undergo further transformation and modification to obtain compounds of other formula (I). Bioanalysis

[0817] Once compounds designed, selected, and / or optimized using the methods described above are prepared, a variety of analytical characterization techniques known to those skilled in the art can be used to determine whether the compounds possess biological activity. For example, molecules can be characterized by conventional analyses, including but not limited to the analytical characterization described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[0818] Furthermore, high-throughput screening can be used to accelerate analyses performed using such analytical methods. Therefore, the activity of molecules described in this invention can be rapidly screened using techniques known in this art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput analysis can use one or more different analytical techniques, including but not limited to the analytical techniques described below.

[0819] Various in vitro or in vivo bioanalyses can be applied to detect the effects of the compounds of this invention. Such in vitro or in vivo bioanalyses may include, but are not limited to, enzyme activity analysis, electrophoretic mobility variation analysis, reporter gene analysis, in vitro cell viability analysis, and the analyses described in this invention. Pharmaceutical ingredients

[0820] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of the various types described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0821] As used in this invention, the term "composition" is intended to cover a product containing a specified amount of a specified ingredient, and any product directly or indirectly produced by a combination of the specified amounts of the specified ingredients.

[0822] Solid dosage forms include powders, tablets, pills, capsules, flat capsules, suppositories, and dispersible granules. Solid carriers can be one or more substances and can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrants for tablets, or encapsulating materials. In powders, the carrier is generally a finely powdered solid, a mixture with the finely powdered active ingredient. In tablets, the active ingredient is generally mixed in a suitable proportion with a carrier possessing the necessary binding ability and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, and similar carriers. In addition to the active ingredient, solid dosage forms may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0823] Liquid formulations are also suitable for oral administration, including liquid preparations such as emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. This category includes solid formulations intended to be converted into a liquid form just before use. Emulsions can be prepared in solution, such as in an aqueous solution of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing a finely powdered active ingredient in water in the presence of a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0824] The compounds of the present invention can be formulated for non-enteral administration (e.g., by injection, such as bolus injection or continuous infusion) and can be provided in unit dosage forms in ampoules, pre-filled syringes, small-volume infusions, or multi-dose containers with added preservatives. The composition can be in the form of a suspension, solution, or emulsion in an oily or aqueous medium, such as a solution in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or mediums include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulation agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic separation of a sterile solid or by lyophilization of a solution prepared prior to use with a suitable medium (e.g., sterile, pyrogen-free water).

[0825] The compounds of the present invention can be formulated into forms such as tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions for oral administration. The compounds of the present invention can also be formulated for intravenous (pellet injection or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms well known to those skilled in the art.

[0826] The formulations of the present invention may be in the form of an aqueous solution comprising an aqueous mediator. The aqueous mediator component may comprise water and at least one pharmaceutically acceptable excipient. Acceptable suitable excipients include those selected from the group consisting of: solubilizers, chelating agents, preservatives, tensioning agents, thickeners / suspending agents, buffers, and pH adjusters, as well as mixtures thereof.

[0827] Any suitable solubility enhancer may be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, fully acetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0828] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of: ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate, and mixtures thereof.

[0829] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzenethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thiomercurate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl diguanidine, and butylparaben and sorbic acid, and mixtures thereof.

[0830] Examples of preservatives include those selected from the group consisting of: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl diguanidine, and butylparaben and sorbic acid, and mixtures thereof.

[0831] Aqueous mediators may also include tension agents to adjust surface tension (osmotic pressure). Tension agents may be selected from the group consisting of: glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tension agent is selected from the group consisting of: glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0832] Aqueous mediators may also contain thickeners / suspending agents. Suitable thickeners / suspending agents include those selected from the group consisting of: cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose; polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400); carboxymethylcellulose; hydroxypropyl methylcellulose; and crosslinked acrylic polymers (carbomers), such as polymers crosslinked with acrylic acid and polyolefin ethers or divinyl glycol (Carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and mixtures thereof.

[0833] To adjust the formulation to an acceptable pH value (typically from about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, especially from about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, with preference given to sodium hydroxide and / or hydrochloric acid. Such acidic and / or basic pH adjusters are added to adjust the formulation to an acceptable target pH range. Therefore, it may not be necessary to use both an acid and a base; that is, depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0834] Aqueous buffers may also contain pH-stabilizing buffers. When used, buffers are selected from the group consisting of: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminohexanoic acid, and mixtures thereof.

[0835] The formulation may further include a wetting agent. Suitable categories of wetting agents include those selected from the group consisting of: polypropylene-polyethylene block copolymers (poloxamer), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitan esters (polysorbate), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyethylene 40 stearate, fatty acid diol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0836] Oral formulations generally include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in tablet, sugar-coated tablet, or capsule form. Oral formulations may also be prepared using fluid carriers for use as mouthwashes, wherein the compound in the fluid carrier is administered orally and rinsed, then spat out or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the formulation. Tablets, pills, capsules, sugar-coated tablets and the like may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or sterotes; slurries, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavorings, such as peppermint, methyl salicylate or orange flavoring.

[0837] According to another aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0838] In some embodiments, the pharmaceutical composition described in this invention may further comprise one or more additional pharmaceutical active agents.

[0839] The components of the present invention may be in forms suitable for the following purposes: oral administration (e.g., in the form of lozenges, oral tablets, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), surface administration (e.g., in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), inhalation administration (e.g., in the form of fine powders or liquid aerosols), inhalation administration (e.g., in the form of fine powders), or non-entericidal administration (e.g., in the form of sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or in the form of suppositories for rectal administration).

[0840] The compositions of the present invention can be obtained through conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0841] The therapeutically effective amount of the compounds of the present invention used in the therapy is sufficient to treat or prevent the LRRK2-related conditions mentioned in the present invention, slow their progression, and / or reduce the symptoms associated with the condition.

[0842] The therapeutically effective amount of the compounds of the present invention used in the therapy is sufficient to treat the LRRK2-related conditions mentioned in the present invention, slow their progression, and / or reduce the symptoms associated with the condition.

[0843] The dosage specifications of compounds of formula (I) used for therapeutic or preventative purposes will vary naturally according to the nature and severity of the condition, the age and sex of the animal or individual, and the route of administration, based on well-known principles of the drug. How to use

[0844] In some embodiments, the present invention provides a method for inhibiting LRRK2 (e.g., in vitro or in vivo) comprising contacting cells with a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0845] In some embodiments, the present invention provides a method for treating or preventing a disease or ailment disclosed herein in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0846] In some embodiments, the present invention provides a method for treating or preventing a disease or ailment disclosed herein in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0847] In some embodiments, the disease or condition is associated with LRRK2. In some embodiments, the disease or condition is a disease or condition involving LRRK2.

[0848] The compounds of this invention can also be used to treat diseases associated with LRRK2. For example, diseases and conditions treatable according to the method of this invention include autosomal dominant Parkinson's disease 8 (PARK8); hereditary late-onset Parkinson's disease (LOPD); spinocerebellar atrophy; autosomal dominant Klebsiella pneumoniae syndrome 1 (KFS1); autosomal dominant cerebellar ataxia (SCA); late-onset Parkinson's disease (PD); juvenile autosomal recessive Parkinson's disease 2 (PARK2); Parkinson's disease; REM sleep behavior disorder; Lewy body dementia (DLB); LRRK2 Parkinson's disease. Parkinson's disease; autosomal dominant Parkinson's disease 3 (PARK3); early-onset Parkinson's disease; multiple system atrophy 1 (MSA1); spontaneous tremor; movement disorder; progressive supranuclear palsy 1 (PSNP1); Klebsiella pneumoniae syndrome 1; dementia; Parkinson's disease 10 (PARK10); tremor; frontotemporal dementia (FTD); post-encephalitis Parkinson's disease; vascular Parkinson's disease; aphasia; autosomal dominant Parkinson's disease 1 (PARK1); choreoathetosis; Klebsiella pneumoniae syndrome (KF) S); Kuff & Lacob syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer's disease 8 (AD8); Crohn's disease; Rheumatoid arthritis (RA); Alzheimer's disease (AD); Color agnosia; Gaucher disease type I (GD1); Early-onset autosomal recessive Parkinson's disease 15 (PARK15); Von Ecknome disease; Gerstmann-Straussler disease II (GSD); Amyotrophic Lateral Sclerosis-Parkinson's disease / Dementia Relapse Syndrome 1 (ALS-PDC1); Dystonia; sphingolipid disease; radial neuropathy; toxic encephalopathy; sleep disorders; brain Pick's disease (PIDB); ocular myiasis; Gaucher disease (GD); optic atrophy type 7 (OPA7) with or without auditory neuropathy; ulnar neuropathy; inflammatory bowel disease type 4 (IBD4); inflammatory bowel disease; type II 3-methylpentadienic aciduria (MGCA3); neurological disorders; amyotrophic lateral sclerosis type 1 (ALS1); mitochondrial complex I deficiency (MC1DN1).

[0849] In some embodiments, the disease or condition is Parkinson's disease (PD).

[0850] In some embodiments, the present invention provides a method for treating or preventing Parkinson's disease (PD) in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0851] In some embodiments, the present invention provides a method for treating Parkinson's disease (PD) in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0852] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for inhibiting LRRK2 (e.g., in vitro or in vivo).

[0853] In some embodiments, the present invention provides compounds of the present invention or their pharmaceutically acceptable salts for treating or preventing diseases or conditions disclosed herein.

[0854] In some embodiments, the present invention provides compounds of the present invention or medically acceptable salts thereof for treating diseases or conditions disclosed herein.

[0855] In some embodiments, the present invention provides compounds of the present invention or medically acceptable salts thereof for the treatment or prevention of Parkinson's disease (PD) in individuals in need.

[0856] In some embodiments, the present invention provides compounds of the present invention or medically acceptable salts thereof for the treatment of Parkinson's disease (PD) in individuals in need.

[0857] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of medicaments for inhibiting LRRK2 (e.g., in vitro or in vivo).

[0858] In some embodiments, the present invention provides the use of the compounds of the present invention or their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment or prevention of diseases or conditions disclosed herein.

[0859] In some embodiments, the present invention provides the use of the compounds of the present invention or their pharmaceutically acceptable salts in the manufacture of medicaments for treating the diseases or conditions disclosed herein.

[0860] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment or prevention of Parkinson's disease (PD) in individuals in need.

[0861] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of Parkinson's disease (PD) in individuals in need.

[0862] This invention provides compounds that act as LRRK2 inhibitors (e.g., in vitro or in vivo). Therefore, this invention provides a method for inhibiting LRRK2 in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0863] In some embodiments, the LRRK2 inhibitor is a compound of the present invention.

[0864] The efficacy of the compounds of the present invention can be determined by industry-recognized analytical / disease models, according to standard practices that elucidate efficacy as described in this art, and is found in current common sense.

[0865] The present invention also provides a method for treating an individual with a disease or condition involving LRRK2 that requires such treatment, the method comprising administering to the individual a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0866] In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. Application route

[0867] The compounds of the present invention or pharmaceutical compositions comprising such compounds may be administered to an individual via any suitable route of administration, i.e., systemically / peripherally or topically (i.e., at the desired site of action).

[0868] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, ointments, etc.); transmucosal (including, for example, by patches, ointments, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); non-intestinal, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinous, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal injection; or by implanting, for example, subcutaneous or intramuscular drug reservoirs or collection capsules. Example General synthetic procedures and examples for compound preparation.

[0869] All reagents were commercially available and ready to use without further purification. Yields refer to purified and spectroscopically pure compounds. Thin-layer chromatography (TLC) was performed using a Merck TLC aluminum foil silica gel 60F. 254The NMR spectrum was performed using a disk and observed by fluorescence quenching under UV light. A rapid chromatography method was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) purchased from Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR. 1 H, operated at 400 MHz. Chemical shifts are reported in ppm, with solvent resonance as an internal standard. Data are reported as follows: s = singlet, br = broad peak, d = doublet, t = triplet, q = quartet, m = multiplet, dd = two doublets; coupling constant, expressed in Hz; integral. Purity is recorded on a Waters e2695 separation module / 2998PDA detector HPLC system (column: XBridge C18, 5 μm, 4.6 mm (ID) × 150 mm (L), precipitate: mixture of mobile phase A and mobile phase B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH4OAc, flow rate: 0.5 mL / min, detection: UV, 254 nm).

[0870] The following examples and abbreviations used elsewhere in this invention are: AcOH (acetic acid) anh. (anh) without water aq. aqueous solution br. Broad peak BSA (Bovine Serum Albumin) CPME cyclopentyl methyl ether d double peak DCM dichloromethane DME dimethoxyethane DMEM (Dalberg's Modified Eagle's Medium) (Dulbecco's modified Eagle's medium) DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) DTT dithiothreitol FBS Fetal Bovine Serum h hours HPLC (High-Performance Liquid Chromatography) LCMS (Liquid Chromatography-Mass Spectrometry) LiHMDS Bis(trimethylsilyl)amine lithium m multiplet M molar concentration MHz (million hertz) min minutes Ms. methanesulfonyl NBS N-bromosuccinimide NMR (Nuclear Magnetic Resonance) Pd2(dba)3 (diphenylmethyleneacetone)dipalladium(0) q Quadruple Peak rt room temperature s Single peak s solid SEMCl 2-(trimethylsilyl)ethoxymethyl chloride t Temperature, triplet TFA (trifluoroacetic acid) THF Tetrahydrofuran TLC (Thin Layer Chromatography) TrCl triphenylmethyl chloride TRIS 2-amino-2-(hydroxymethyl)prop-1,3-diol XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene Synthetic constructs Synthesis of 5-bromo-3-chloropyrazine (P2)

[0871] Preparation of methyl 1,5-bromo-2-[(tert-butoxycarbonyl)amino]benzoate (P1). In a sealed tube, a mixture of 3,5-dichloropyrazine (3.4 g, 22.82 mmol, 1.0 eq) and 30% ammonium hydroxide (34 mL) was stirred at 120 °C for 16 hours. The resulting precipitate was collected by filtration and washed with water and ether to give P1 (2.54 g, 86% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6), δ: 8.49 (d, J = 2.4Hz, 1H), 6.82 (br.s, 2H), 6.65 (d, J = 2.4Hz, 1H).

[0872] Preparation of 2,5-bromo-3-chloropyrazine (P2). At 0 °C, copper(II) bromide (7.55 g, 33.81 mmol, 1.5 eq) was added to a solution of P1 (2.92 g, 22.54 mmol, 1.0 eq) and tributyl nitrite (4.02 mL, 33.81 mmol, 1.5 eq) in acetonitrile (60 mL). The reaction mixture was stirred at room temperature for 16 hours, then treated with water and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄ treatment. 4(s)The sample was dried, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (n-hexane:EtOAc = 5:1) to give P2 (2.04 g, 47% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 9.22 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H). Synthesis of 1-(5-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)pyrazin-3-yl)acet-3-ol (P8)

[0873] Preparation of 3,5-isopropoxy-1H-indazole (P3). Cesium carbonate (2.91 g, 8.95 mmol, 1.2 eq) was added to a solution of 1H-indazole-5-ol (1.00 g, 7.46 mmol, 1.0 eq) in DMF (10 mL). The reaction mixture was stirred at room temperature for 15 minutes. 2-Iodopropane (0.89 mL, 8.95 mmol, 1.2 eq) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The mixture was treated with water and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄ treatment. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 3:1) to give P3 (876 mg, 67% yield) as an orange solid. 1 H NMR (400MHz, DMSO-d6), δ: 12.86 (br.s, 1H), 7.92-7.90 (m, 1H), 7.41 (d, J = 9.0Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 6.96 (dd, J=9.0, 2.2Hz, 1H), 4.56 (septet, J=6.0Hz, 1H), 1.27 (d, J=6.0Hz, 6H).

[0874] Preparation of 4,3-iodo-5-isopropoxy-1H-indazole (P4). Potassium carbonate (1.37 g, 9.90 mmol, 2.0 eq) and iodine (1.88 g, 7.42 mmol, 1.5 eq) were added to a solution of P3 (872 mg, 4.95 mmol, 1.0 eq) in acetonitrile (21 mL). After stirring the solution at room temperature for 16 hours, the mixture was passed through a saturated Na2S2O3 solution. 3(aq) Quenching and extraction with ethyl acetate three times. The combined organic layers were then subjected to Na₂SO₄. 4(s)The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 5:1) to give P4 (1.48 g, 99% yield) in an orange foamy form. 1 H NMR (400MHz, DMSO-d6), δ: 13.34 (br.s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2 .0Hz, 1H), 6.75 (d, J = 2.0Hz, 1H), 4.63 (septet, J = 6.0Hz, 1H), 1.28 (d, J = 6.0Hz, 6H).

[0875] Preparation of 5,3-iodo-5-isopropoxy-1-triphenylmethyl-1H-indazole (P5). At 0 °C, a solution of P4 (1.48 g, 4.90 mmol, 1.0 eq) in anhydrous THF (11 mL) was added to a solution of 60% sodium hydride in mineral oil (235.12 mg, 5.88 mmol, 1.2 eq) in anhydrous THF (10 mL). The reaction mixture was stirred at 0 °C for 30 min, followed by the whole-part addition of TrCl (1.50 g, 5.39 mmol, 1.1 eq). The reaction mixture was slowly heated and stirred at room temperature for 16 h. The reaction was quenched with water and extracted three times with diethyl ether. The combined organic layers were subjected to Na2SO4. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 6:1) to give P5 (2.56 g, 96% yield) as an orange solid. 1 H NMR(400MHz, CDCl3), δ:7.32-7.28(m,2H),7.28-7.26(m,3H),7.26-7.24(m,5H),7.22-7.19(m,6H),6.74(d,J=2 .6Hz, 1H), 6.65 (dd, J=9.4, 2.6Hz, 1H), 6.22 (d, J=9.4Hz, 1H), 4.55 (septet, J=6.0Hz, 1H), 1.34 (d, J=6.0Hz, 6H).

[0876] Preparation of 6,5-isopropoxy-3-(trimethyltinyl)-1-triphenylmethyl-1H-indazole (P6). Degas a solution of P5 (1.55 g, 2.85 mmol, 1.0 eq) and hexamethyldistinane (0.86 mL, 4.27 mmol, 1.5 eq) in 1,4-dioxane (26 mL) for 10 min using argon. Tetra(triphenylphosphine)palladium(0) (263.2 mg, 0.228 mmol, 0.08 eq) was added to the mixture. The reaction mixture was stirred at 100 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The product, P6, was dried, filtered, and concentrated under vacuum to obtain P6, which was then used in the next step without further purification. 1 H NMR (400MHz, CDCl3), δ: 7.35-7.29 (m, 5H), 7.25-7.22 (m, 7H), 7.19-7.16 (m, 4H), 7.01 (d, J = 2.4Hz, 1H), 6.59 ( dd,J=9.2,2.4Hz,1H),6.21(d,J=9.2Hz,1H),4.46(septet,J=6.0Hz,1H),1.33(d,J=6.0Hz,6H),0.35(s,9H).

[0877] Preparation of 7,3-(6-chloropyrazine-4-yl)-5-isopropoxy-1-triphenylmethyl-1H-indazole (P7). The solution of crude P6 (2.85 mmol, 1.0 eq) and 5-bromo-3-chloropyrazine (P2, 991.23 mg, 5.12 mmol, 1.8 eq) in anhydrous toluene (70 mL) was degassed with argon for 10 min. Tetra(triphenylphosphine)palladium(0) (263.2 mg, 0.228 mmol, 0.08 eq) was added to the mixture, and the reaction mixture was then stirred at 110 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The sample was dried, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (n-hexane:EtOAc = 20:1 to 10:1) to give P7 as a yellow solid (660 mg, 44% yield). 1 H NMR (400MHz, CDCl3), δ: 9.64 (d, J = 1.8Hz, 1H), 7.87 (d, J = 1.8Hz, 1H), 7.32-7.28 (m, 10H), 7.19-7.16 (m, 6 H), 6.72 (dd, J = 9.4, 2.4Hz, 1H), 6.40 (d, J = 9.4Hz, 1H), 4.58 (septet, J = 6.0Hz, 1H), 1.37 (d, J = 6.0Hz, 6H).

[0878] Preparation of 8,3-(6-chloropyrazine-4-yl)-5-isopropoxy-1-triphenylmethyl-1H-indazole (P8). Triethylamine (0.19 mL, 1.36 mmol, 6.0 eq) and 3-hydroxyacetate hydrochloride (74.3 mg, 0.678 mmol, 3.0 eq) were added to a solution of P7 (120.0 mg, 0.226 mmol, 1.0 eq) in DMSO (1.1 mL). The reaction mixture was stirred at 120 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (dichloromethane:MeOH = 30:1) to give P8 (47 mg, 37% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 9.15 (d, J = 1.6Hz, 1H), 7.30-7.27 (m, 10H), 7.21-7.17 (m, 6H), 6.94 (d, J = 2.2Hz, 1H), 6.68 (dd, J = 9.2, 2.2Hz, 1 H), 6.35 (d, J = 9.2Hz, 1H), 4.89-4.86 (m, 1H), 4.54 (septet, J = 6.0Hz, 1H), 4.47-4.43 (m, 2H), 4.05-4.01 (m, 2H), 1.35 (d, J = 6.0Hz, 6H). Synthesis of (R)-1-(5-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)pyrrolidone-3-yl)pyrrolidone-3-ol (P9)

[0879] Preparation of 9.(R)-1-(5-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)pyrrolidone-3-yl)pyrrolidone-3-ol (P9) Triethylamine (0.2 mL, 1.36 mmol, 6.0 eq) and (R)-pyrrolidone-3-ol (0.055 mL, 0.68 mmol, 3.0 eq) were added to a solution of P7 (120.0 mg, 0.23 mmol, 1.0 eq) in DMSO (1.1 mL). The reaction mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s)The sample was dried, filtered, and concentrated under vacuum to obtain a residue, which was then purified by C-18 reversed-phase column chromatography (mobile phase A: water (containing NH4HCO3), mobile phase B: methanol, UV: 214 and 254 nm, flow rate: 30 mL / min, gradient: 3-90% (%B)) to obtain P9 (113 mg, 86% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3), δ: 9.07 (d, J = 1.8Hz, 1H), 7.32-7.24 (m, 10H), 7.20-7.14 (m, 6H), 7.03 (d, J = 1.8Hz, 1H), 6.66 (dd, J = 9.2, 2.4Hz, 1 H), 6.33 (d, J = 9.2Hz, 1H), 4.69-4.65 (m, 1H), 4.52 (septet, J = 6.0Hz, 1H), 3.78-3.63 (m, 4H), 2.23-2.11 (m, 2H), 1.33 (d, J = 6.0Hz, 6H). Synthesis of 5-isopropoxy-3-(6-(3-methylpyrrolidin-1-yl)pyrazin-4-yl)-1-triphenylmethyl-1H-indazole (P10)

[0880] Preparation of 10,5-isopropoxy-3-(6-(3-methylpyrrolidin-1-yl)pyrazin-4-yl)-1-triphenylmethyl-1H-indazole (P10) Triethylamine (0.2 mL, 1.36 mmol, 6.0 eq) and 3-methylpyrrolidone hydrochloride (82.4 mg, 0.678 mmol, 3.0 eq) were added to a solution of P7 (120.0 mg, 0.23 mmol, 1.0 eq) in DMSO (1.1 mL). The reaction mixture was stirred at 120 °C for 24 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 2:1) to give P10 (66 mg, 50% yield) as a yellow solid. 1H NMR (400MHz, CDCl3), δ: 9.06 (d, J = 1.8Hz, 1H), 7.33 (d, J = 2.2Hz, 1H), 7.31-7.27 (m, 8H), 7.22 -7.16(m,7H),7.01(d,J=1.8Hz,1H),6.68(dd,J=9.2,2.2Hz,1H),6.34(d,J=9.2Hz,1H),4.54(septet,J=6.0Hz,1H),3.81-3.74(m,1H),3.73-3.66( m,1H),3.57-3.50(m,1H),3.15-3.09(m,1H),2.49-2.40(m,1H),2.23-2.1 5(m,1H),1.72-1.66(m,1H),1.35(d,J=6.0Hz,6H),1.17(d,J=6.8Hz,3H). Synthesis of 4-(5-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)pyrazin-3-yl)morpholine (P11)

[0881] Preparation of 11,4-(5-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)pyrazin-3-yl)morpholine (P11) Triethylamine (0.079 mL, 0.56 mmol, 6.0 eq) and morpholine (0.025 mg, 0.28 mmol, 3.0 eq) were added to a solution of P7 (50.0 mg, 0.094 mmol, 1.0 eq) in DMSO (0.50 mL). The reaction mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 2:1) to give P11 as a yellow solid (40 mg, 73% yield). 1 H NMR (400MHz, CDCl3), δ: 9.19 (d, J = 1.6Hz, 1H), 7.34-7.27 (m, 10H), 7.22-7.15 (m, 7H), 6.69 (dd, J = 9.2, 2.4Hz, 1H) ,6.36(d,J=9.6Hz,1H),4.55(septet,J=6.0Hz,1H),3.90-3.85(m,4H),3.68-3.64(m,4H),1.35(d,J=6.0Hz,6H). Synthesis of 5-isopropoxy-3-(6-(pyrrolidin-1-yl)pyrazin-4-yl)-1-triphenylmethyl-1H-indazole (P12)

[0882] Preparation of 12,5-isopropoxy-3-(6-(pyrrolidin-1-yl)pyrazin-4-yl)-1-triphenylmethyl-1H-indazole (P12) Triethylamine (0.4 mL, 2.71 mmol, 1.0 eq) and pyrrolidine (0.110 mL, 1.36 mmol, 3.0 eq) were added to a solution of P7 (240.0 mg, 0.45 mmol, 1.0 eq) in DMSO (2.0 mL). The reaction mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were subjected to Na₂SO₄. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 1:1) to give P12 as a yellow solid (205 mg, 80% yield). 1 H NMR (400MHz, CDCl3), δ: 9.07 (s, 1H), 7.34-7.29 (m, 6H), 7.26-7.15 (m, 10H), 7.04 (s, 1H), 6.68 (d, J = 9.4Hz, 1H) ,6.35(d,J=9.4Hz,1H),4.54(septet,J=6.0Hz,1H),3.58(br.m,4H),2.10-2.04(m,4H),1.35(d,J=6.0Hz,6H). Synthesis of 4-(6-chloro-3-methylpyrazin-4-yl)morpholine (P16)

[0883] Preparation of phenyl 13-hydrazinocarboxylate (P13). Hydrazine hydrate (6.80 g, 140 mmol) was added to a solution of diphenyl carbonate (15.0 g, 70.0 mmol) in DCM (230 mL) and stirred overnight at room temperature. The reaction mixture was concentrated to remove the solvent. The residue was purified by silica gel chromatography (0-100% ethyl acetate / n-hexane) to give P13 (5.5 g, 52%) as a white solid. 1 H NMR (400MHz, DMSO-d6), δ: 8.73 (br.s, 1H), 7.38-7.34 (m, 2H), 7.21-7.16 (m, 1H), 7.06 (d, J = 7.6Hz, 2H), 4.21 (br.s, 2H).

[0884] Preparation of phenyl 14,(E)-2-(3-Synebutyryl-2-yl)hydrazide-1-carboxylate (P14). 2,3-Butanedione (3.40 g, 39.7 mmol) was added to a solution of P13 (5.5 g, 36.1 mmol) in methanol (120 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give crude product P14 (7.9 g, 99%) as a white solid. 1 H NMR (400MHz, DMSO-d6), δ: 11.13 (br.s, 1H), 7.46-7.42 (m, 2H), 7.30-7.23 (m, 2H), 2.32 (s, 3H), 1.96 (s, 3H).

[0885] Preparation of 15,6-methyl-5-(N-morpholinyl)pyrazin-3(2H)-one (P15). Trimethylacetic acid (1.10 mL, 13.6 mmol), magnesium sulfate (540 mg, 4.50 mmol), and morpholine (91 mg, 0.90 mmol) were added to a solution of P14 (1.0 g, 4.5 mmol) in trifluorotoluene (9 mL). The reaction mixture was stirred at 175 °C for 2 hours under microwave irradiation. The reaction mixture was filtered through a diatomaceous earth filter and washed with dichloromethane. The filtrate was concentrated to remove the solvent. The residue was purified by silica gel chromatography (0–10% methanol / dichloromethane) to give P15 (400 mg, 45%) as a brown solid. 1 H NMR (400MHz, CDCl3), δ: 11.00 (br.s, 1H), 6.17 (s, 1H), 3.84 (t, J = 4.6Hz, 4H), 3.01 (t, J = 4.6Hz, 4H), 2.31 (s, 3H).

[0886] Preparation of 16,4-(6-chloro-3-methylpyrazin-4-yl)morpholine (P16). A solution of 6-methyl-5-(N-morpholinyl)pyrazin-3(2H)-one (P15, 110 mg, 0.56 mmol) in POCl3 (5 mL) was refluxed overnight. The reaction mixture was cooled and concentrated. The residue was diluted with ethyl acetate (100 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was subjected to Na2SO4. 4(s) The product was dried, filtered, and concentrated to give crude product (P16, 90 mg, 75% yield). 1 H NMR (400MHz, CDCl3), δ: 6.81 (s, 1H), 3.87 (t, J = 4.8Hz, 4H), 3.08 (t, J = 4.8Hz, 4H), 2.61 (s, 3H). Synthesis of 4-(6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-3-methylpyrazine-4-yl)morpholine (P17)

[0887] Preparation of 17,4-(6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-3-methylpyrazine-4-yl)morpholine (P17). At room temperature, P16 (90 mg, 0.42 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol) were added to a solution of P6 (400 mg, crude) in dioxane (5.0 mL). The reaction was stirred overnight at 100 °C under an argon atmosphere. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated. The residue was purified by preparative TLC (n-hexane:EtOAc = 1:1) to give P17 (40 mg, 19% yield). 1 H NMR (400MHz, CDCl3), δ: 8.20 (d, J = 2.4Hz, 1H), 7.52 (s, 1H), 7.31-7.27 (m, 9H), 7.22-7.20 (m, 6H), 6.65 (dd, J = 2.8, 9.4Hz ,1H),6.23(d,J=9.4Hz,1H),4.75-4.69(m,1H),3.89-3.87(m,4H),3.05-3.03(m,4H),2.69(s,3H),1.34(d,J=6.0Hz,6H). Synthesis of 3-bromo-5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (P19)

[0888] 18,3-bromo-5-isopropoxy-1H-indazole (P18) was prepared. At 0 °C, N-bromosuccinimide (3.32 g, 18.8 mmol) was added to a solution of 5-isopropoxy-1H-indazole (P3, 3.0 g, 17 mmol) in DCM (30 mL). The resulting mixture was stirred overnight at room temperature. The reactants were directly concentrated and purified by silica gel column chromatography (n-hexane:EtOAc = 1:1) to give P18 (4.11 g, 95% yield). 1H NMR (400MHz, CDCl3), δ: 10.37 (br.s, 1H), 7.38 (d, J = 9.0Hz, 1H), 7.10 (dd, J = 9.0, 2. 4Hz, 1H), 6.97 (d, J = 2.4Hz, 1H), 4.62 (septet, J = 6.0Hz, 1H), 1.38 (d, J = 6.0Hz, 6H).

[0889] Preparation of 19,3-bromo-5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (P19). Under an argon atmosphere, 60% NaH (780 mg, 19.4 mmol) in mineral oil was added to a solution of P18 (4.11 g, 16.2 mmol) in DMF (40 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h. 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 3.42 mL, 19.4 mmol) was added to the reaction mixture at 0 °C. After stirring the mixture at room temperature for 2 hours, the solution was poured into water and extracted with EtOAc. The organic phase was dried over MgSO4(s), filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:DCM = 2:1) to give P19 (4.75 g, 76% yield). 1 H NMR (400MHz, CDCl3), δ: 7.46 (d, J = 9.0Hz, 1H), 7.11 (dd, J = 9.0, 2.4Hz, 1H), 6.95 (d, J = 2.4Hz, 1H), 5.64 (s, 2 H), 4.60 (septet, J = 6.0Hz, 1H), 3.57-3.53 (m, 1H), 1.38 (d, J = 6.0Hz, 6H), 0.89-0.85 (m, 2H), -0.06 (s, 9H). Synthesis of 4-(5-(5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1,2,4-triazin-3-yl)morpholine (P24)

[0890] Preparation of 20,3-(methylthio)-1,2,4-triazine-5(2H)-one (P20). At room temperature, methyl iodoform (1.60 mL, 25.6 mmol) and sodium hydroxide (620 mg, 15.5 mmol) were added to a solution of 3-mercapto-1,2,4-triazine-5(4H)-one (1.66 g, 12.8 mmol) in ethanol (83 mL). The reaction mixture was stirred overnight at 40 °C. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic phase was subjected to MgSO4...4(s) The sample was dried, filtered, and concentrated. The residue was purified by passing it through a silica gel column (methanol:DCM = 20:1) to give P20 (556 mg, 31% yield). 1 HNMR (400MHz, DMSO-d6), δ: 7.58 (br.s, 1H), 2.46 (s, 3H).

[0891] Preparation of 21,3-(N-morpholino)-1,2,4-triazine-5(4H)-one (P21). Morpholine (340 mg, 3.98 mmol) was added to a solution of P20 (190 mg, 1.33 mmol) in THF (7.0 mL) at room temperature. The reaction was stirred under reflux overnight. After cooling at 0 °C for 30 min, the resulting solid was collected by filtration and washed with EtOAc. The filter cake was dried under high vacuum to give P21 (190 mg, 79% yield). 1 H NMR (400MHz, DMSO-d6), δ: 12.51 (br.s, 1H), 7.31 (s, 1H), 3.65-3.62 (m, 4H), 3.54-3.51 (m, 4H).

[0892] Preparation of 22,4-(5-chloro-1,2,4-triazin-3-yl)morpholine (P22). At room temperature, N-chlorosuccinimide (220 mg, 1.65 mmol) was added to a solution of triphenylphosphine (432 mg, 1.65 mmol) in dioxane (20 mL). The mixture was stirred at room temperature for 30 minutes, then P21 (100 mg, 0.55 mmol) was added, and the reaction mixture was stirred under reflux for 1 hour. The reaction was cooled to 0 °C, and triethylamine (110 mg, 1.10 mmol) was added. The mixture was stirred at 0 °C for another 1 hour. The reaction mixture was concentrated and then purified by silica gel column chromatography (n-hexane:EtOAc = 3:1) to give P22 (100 mg, 91% yield). 1 H NMR (400MHz, DMSO-d6), δ: 7.34 (s, 1H), 3.65-3.63 (m, 4H), 3.55-3.53 (m, 4H).

[0893] Preparation of 23,4-(5-(trimethyltinyl)-1,2,4-triazin-3-yl)morpholine (P23). Under an argon atmosphere, hexamethyldistin (250 mg, 0.75 mmol) and tetra(triphenylphosphine)palladium (0) (60 mg, 0.05 mmol) were added to a solution of P22 (100 mg, 0.50 mmol) in dioxane (5.0 mL) at room temperature. The reaction mixture was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated to give P23 (100 mg, crude), which was used directly in the next step without purification.

[0894] Preparation of 24,4-(5-(5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1,2,4-triazin-3-yl)morpholine (P24). Under an argon atmosphere, P19 (211 mg, 0.55 mmol) and tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.05 mmol) were added to a solution of P23 (100 mg) in dioxane (5.0 mL) at room temperature. The reaction was stirred overnight at 100 °C. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc = 3:1) to give P24 (30 mg, 12% yield). 1 H NMR (400MHz, CDCl3), δ: 9.37 (s, 1H), 7.88 (d, J = 2.2Hz, 1H), 7.55 (d, J = 9.0Hz, 1H), 7.14 (dd, J = 2.2, 9.0Hz, 1H), 5.78 (s, 2H), 4.57 (se ptet,J=6.0Hz,1H),4.05-4.02(m,4H),3.89-3.87(m,4H),3.61-3.57(m,2H),1.41(d,J=6.0Hz,6H),0.93-0.89(m,2H),-0.06(s,9H). Synthesis of 6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-2-methyl-4-(N-morpholinyl)pyrazin-3(2H)-one (P29)

[0895] Preparation of 25-methyl-4-bromo-6-chloropyrazine-3(2H)-one (P25). In an ice bath, a solution of 4-bromo-6-chloropyrazine-3-amine (20.00 g, 95.95 mol) in acetic acid (440 mL) was added to a solution of sodium nitrite (7.94 g, 115 mol) in concentrated sulfuric acid (130 mL). The mixture was stirred at room temperature until the solution became clear, and then water (660 mL) was added to the mixture. After stirring the solution at room temperature for 2 days, the precipitate was collected by filtration and washed with water to give P25 (15.00 g, 75%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3), δ: 7.68 (s, 1H).

[0896] Preparation of 26,3-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane (P26). Iodomethane (6.70 mL, 108 mmol) was added to a solution of P25 (15.00 g, 71.62 mmol) and cesium carbonate (35.30 g, 108.0 mmol) in DMF (115 mL) in an ice bath. After stirring overnight at room temperature, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–30% EtOAc / n-hexane) to give P26 (9.79 g, 61%) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 7.62 (s, 1H), 3.80 (s, 3H).

[0897] Preparation of 27,6-chloro-2-methyl-4-(N-morpholinyl)pyrazin-3(2H)-one (P27). Morpholine (0.60 mL, 6.7 mmol), cesium carbonate (4.37 g, 13.4 mmol), and Xantphos (388 mg, 0.67 mmol) were added to a solution of P26 (1.5 g, 6.71 mmol) in 1,4-dioxane (56 mL). Argon was bubbled in the mixture for 15 minutes. Tris(diphenylmethyleneacetone)dipalladium(0) (307 mg, 0.34 mmol) was added to the mixture, and the solution was stirred overnight at 80 °C. The mixture was filtered through a diatomaceous earth mat. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–20% EtOAc / n-hexane) to give P27 (1.23 g, 80%) as an orange oil. 1H NMR (400MHz, CDCl3), δ: 6.23 (s, 1H), 3.84 (dd, J = 5.7, 4.0Hz, 4H), 3.70 (s, 3H), 3.52 (dd, J = 5.7, 4.0Hz, 4H).

[0898] Preparation of 28-(1-methyl-5-(N-morpholino)-6-sideoxy-1,6-dihydropyrazin-3-yl)boronic acid (P28). Add bis(pinacolyl)diboron (6.63 g, 26.12 mmol) and potassium acetate (1.026 g, 10.45 mmol) to a solution of P27 (1.20 g, 5.23 mmol) in 1,4-dioxane (60 mL). Bubble the mixture with argon for 15 minutes. Add XPhos (500 mg, 1.05 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (382 mg, 0.52 mmol) to the mixture. Bubble the solution with argon for 15 minutes. After stirring the mixture at 50 °C for 16 hours, filter the solution through a diatomaceous earth mat and concentrate the filtrate to obtain crude product P28, which was used in the next step without further purification.

[0899] Preparation of 29,6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-2-methyl-4-(N-morpholinyl)pyrazine-3(2H)-one (P29). Add P5 (2.37 g, 4.35 mmol) and potassium phosphate (2.77 g, 13.1 mmol) to a solution of P28 (5.23 mmol) in DME (50 mL). Bubble the mixture with argon for 15 minutes. Add the [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (356 mg, 0.44 mmol) to the solution. After stirring overnight at 90 °C, filter the mixture through a diatomaceous earth mat. Concentrate the filtrate under vacuum and then purify by silica gel chromatography (0-30% EtOAc / n-hexane) to give 4.6 g of P29. 1 H NMR (400MHz, CDCl3), δ: 7.79 (d, J = 2.4Hz, 1H), 7.29-7.26 (m, 8H), 7.20-7.17 (m, 7H), 7.06 (s, 1H), 6.65 (dd, J = 9.2, 2.4Hz, 1H)) ,6.21(d,J=9.2Hz,1H),4.59(septet,J=6.0Hz,1H),3.88(s,3H),3.88-3.84(m,4H),3.43-3.40(m,4H),1.37(d,J=6.0Hz,6H). Synthesis of 3-iodo-4-isopropoxy-1-triphenylmethyl-1H-indazole (P32)

[0900] 30,4-Isopropoxy-1H-indazole (P30) was prepared. To a solution of 1H-indazole-4-ol (3.0 g, 22.3 mmol, 1.0 eq) in DMF (29 mL), 2-iodopropane (2.60 mL, 26.8 mmol, 1.2 eq) and cesium carbonate (8.71 g, 26.8 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with water and extracted three times with ethyl acetate. The combined organic layers were then subjected to Na₂SO₄ treatment. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (0-100% ethyl acetate / n-hexane) to give P30 as a yellow solid (3.2 g, 87% yield). 1 H NMR (400MHz, CDCl3), δ: 9.99 (br.s, 1H), 8.13 (d, J = 1.2Hz, 1H), 7.29-7.25 (m, 1H), 7.0 4-7.01(m,1H),6.50-6.48(m,1H),4.75(septet,J=6.0Hz,1H),1.43(d,J=6.0Hz,6H).

[0901] 31,3-iodo-4-isopropoxy-1H-indazole (P31) was prepared. Potassium carbonate (4.9 g, 36.0 mmol, 1.0 eq) and iodine (6.8 g, 27.0 mmol, 1.5 eq) were added to a solution of P30 (3.2 g, 18.0 mmol, 1.0 eq) in acetonitrile (90 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then treated with Na2S2O. 3(aq) Quenching and extraction with ethyl acetate three times. The combined organic layers were then subjected to Na₂SO₄. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (0-50% ethyl acetate / n-hexane) to give P31 (2.0 g, 37% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3), δ: 10.28 (br.s, 1H), 7.29-7.25 (m, 1H), 7.02 (d, J = 8.4Hz, 1H), 6.48 (d, J = 7.6Hz, 1H), 4.73 (septet, J = 6.0Hz, 1H)), 1.47 (d, J = 6.0Hz, 6H).

[0902] Preparation of 32,3-iodo-4-isopropoxy-1-triphenylmethyl-1H-indazole (P32). At 0 °C, sodium hydride (190 mg, 7.9 mmol, 1.2 eq) and TrCl (2.0 g, 7.2 mmol, 1.1 eq) were added to a solution of P31 (2.0 g, 6.6 mmol, 1.0 eq) in 33 mL of THF. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with diethyl ether. The combined organic layers were then subjected to Na2SO4. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (0-50% ethyl acetate / n-hexane) to give P32 (3.3 g, 92% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3), δ:7.25-7.23(m,8H),7.21-7.17(m,7H),6.84-6.80(m,1H),6.34(d ,J=7.6Hz,1H),6.93(d,J=8.4Hz,1H),4.67(septet,J=6.0Hz,1H),1.45(d,J=6.0Hz,6H). Synthesis of 6-(4-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-2-methyl-4-(N-morpholinyl)pyrazin-3(2H)-one (P33)

[0903] Preparation of 33,6-(4-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-2-methyl-4-(N-morpholinyl)pyrazine-3(2H)-one (P33). Add 3-iodo-4-isopropoxy-1-triphenylmethyl-1H-indazole (P32, 1.00 g, 1.84 mmol) and potassium phosphate (2 M in H2O, 2.75 mL, 5.51 mmol) to a solution of (1-methyl-5-(N-morpholinyl)-6-sideoxy-1,6-dihydropyrazine-3-yl)boronic acid (P28, 2.20 mmol) in DME (20 mL). Bubble the mixture with argon for 15 minutes. Add the [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (150 mg, 0.184 mmol) to the mixture and degas it with argon. After stirring the mixture overnight at 90 °C, treat the solution with EtOAc and filter through a diatomaceous earth mat. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (0-50% EtOAc / n-hexane) to obtain P33 (812 mg, 72%) as a brown solid. 1H NMR (400MHz, CDCl3), δ: 7.26-7.19 (m, 15H), 6.88 (dd, J = 8.4, 7.8Hz, 1H), 6.79 (s, 1H), 6.42 (d, J = 7.8Hz, 1H), 6. 02(d,J=8.4Hz,1H),4.766(septet,J=6.0Hz,1H),3.89-3.82(m,7H),3.47-3.39(m,4H),1.34(d,J=6.0Hz,6H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)zoline (P35)

[0904] Preparation of 34,6-bromo-1-(6-chloropyrazin-4-yl)-1H-indazole (P34). P2 (147.3 mg, 0.761 mmol, 1.5 eq), copper iodide (I) (19.3 mg, 0.102 mmol, 0.2 eq), and tripotassium phosphate (215.5 mg, 1.02 mmol, 2.0 eq) were added to a solution of 6-bromo-1H-indazole (100.0 mg, 0.508 mmol, 1.0 eq) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 5 minutes, followed by stirring at 130 °C for 16 hours. After cooling the solution to room temperature, it was treated with water and extracted three times with DCM. The combined organic layers were subjected to Na2SO4. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel column chromatography (n-hexane:EtOAc = 6:1 to 5:1) to give P34 (62 mg, 39% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3), δ: 9.78 (d, J = 2.4Hz, 1H), 8.31 (d, J = 0.8Hz, 1H), 8.10 (d, J = 1.6Hz ,1H),7.92(d,J=2.4Hz,1H),7.74(dd,J=8.4,0.8Hz,1H),7.52(dd,J=8.4,1.6Hz,1H).

[0905] Preparation of 35,6-bromo-1-(6-(pyrrolidin-1-yl)pyrazin-4-yl)-1H-indazole (P35). Triethylamine (0.17 mL, 1.20 mmol, 1.0 eq) and pyrrolidine (0.05 mL, 0.60 mmol, 3.0 eq) were added to a solution of P34 (62.0 mg, 0.20 mmol, 1.0 eq) in DMSO (1.0 mL). The solution was stirred at 110 °C for 16 hours and cooled to room temperature. It was then treated with water and extracted three times with DCM. The combined organic layers were subjected to Na2SO4 treatment. 4(s) The residue was dried, filtered, and concentrated under vacuum. It was then purified by silica gel chromatography (DCM:MeOH = 50:1) to give P35 (58 mg, 84% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3), δ: 9.08 (d, J = 2.2Hz, 1H), 8.23 ​​(s, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.4Hz ,1H),7.42(d,J=8.4Hz,1H),6.92(d,J=2.2Hz,1H),3.68-3.61(m,4H),2.14-2.07(m,4H). Synthesis of 2-(1-(6-chloropyrazin-4-yl)-1H-indazol-6-yl)-2-methylpropionitrile (P36)

[0906] Preparation of 36,2-(1-(6-chloropyrazin-4-yl)-1H-indazol-6-yl)-2-methylpropionitrile (P36). At room temperature, 40 mg of NaH (60% in mineral oil, 1 mmol) was added in whole to a stirred solution of 2-(1H-indazol-6-yl)-2-methylpropionitrile (185 mg, 1 mmol) and 3,5-dichloropyrazine (148 mg, 1 mmol) in 2 mL of DMF. The reaction mixture was stirred at room temperature for 8 hours, then poured onto cold water (50 mL). The precipitate was filtered off and dried under reduced pressure. The yield of P36 was 150 mg (53%). LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes (retention time 1.5-2 minutes). MS (ESI) m / z: 298.5 [M+H] + . 1H NMR (400MHz, DMSO-d6), δ: 9.91 (d, J = 2.2Hz, 1H), 8.66 (s, 1H), 8.33 (d, J = 2.2Hz, 1H), 8 .01(d,J=8.5Hz,1H),7.55(dd,J=8.5,1.5Hz,1H),7.14(d,J=2.2Hz,1H),1.80(s,6H). Synthesis of 1-(1-(6-chloropyrazin-4-yl)-1H-indazol-6-yl)cyclohexaneformonitrile (P37)

[0907] Preparation of 37.1-[1-(6-chloropyrazin-4-yl)indazole-6-yl]cyclohexaneformonitrile (P37). At room temperature, 40 mg of NaH (60% in mineral oil, 1 mmol) was added in whole to a stirred solution of 1-(1H-indazol-6-yl)cyclohexaneformitrile (225 mg, 1 mmol) and 3,5-dichloropyrazine (148 mg, 1 mmol) in 2 mL of DMF. The reaction mixture was stirred at room temperature for 8 hours, then poured into cold water (50 mL). The resulting precipitate was filtered off and dried under reduced pressure. The yield of P37 was 240 mg (71%). LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes (retention time 1.76 min). MS (ESI) m / z: 338.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6), δ: 9.91 (d, J = 2.2Hz, 1H), 8.66 (s, 1H), 8.33 (d, J = 2.2Hz, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7 .64(d,J=8.5Hz,1H),2.21(d,J=12.9Hz,2H),2.07-2.00(m,2H),1.91-1.88(d,2H),1.80-1.64(m,3H),1.42-1.32(m,1H). Synthesis of 1-[1-(6-chlorodiazin-4-yl)indazole-6-yl]cyclopentaneformitrile (P38)

[0908] Preparation of 38.1-[1-(6-chloropyrazin-4-yl)indazole-6-yl]cyclopentaneformitrile (P38). At room temperature, 40 mg NaH (60% in mineral oil, 1 mmol) was added in whole to a stirred solution of 1-(1H-indazol-6-yl)cyclopentanecarboxynitrile (211 mg, 1 mmol) and 3,5-dichloropyrazine (148 mg, 1 mmol) in 2 mL of DMF. The reaction mixture was stirred at room temperature for 8 hours, then poured onto cold water (50 mL). The precipitate formed was filtered off and dried under reduced pressure. The yield of P38 was 241 mg (74%). LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes (retention time 1.65 minutes). MS (ESI) m / z: 324.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6), δ: 9.90 (d, J = 2.2Hz, 1H), 8.67 (s, 1H), 8.35 (d, J = 2.2Hz, 1H), 8.17 (s, 1H), 8. 01(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,1H),2.60-2.55(m,2H),2.29-2.21(m,2H),1.98-1.95(m,4H). Synthesis of 1-[1-(6-chloropyrazin-4-yl)-1H-indazol-6-yl]-1H-pyrrolo-2-carboxynitrile (P42)

[0909] 39,6-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (P39) was prepared. At 0 °C, a 60% NaH dispersion in mineral oil (2.2 g, 55 mmol) was added to an ice-cold solution of 6-bromo-1H-indazole (10 g, 50.7 mmol) in DMF (50 ml) and stirred for one hour. Then, SEM-Cl (10 ml, 9.42 g, 56.5 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for one hour and then overnight at ambient temperature. The solvent was evaporated under vacuum, and the residue was partitioned between DCM and water (100 ml each). The organic layer was separated; the aqueous layer was extracted with DCM (50 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient dissolution: 50–0% hexane / CHCl3) to give 8.2 g (49%) of compound P39. 1H NMR (400MHz, CDCl3), δ: 7.99 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.5Hz, 1H), 7.32 (dd, J = 8.5, 1.3Hz, 1H), 5.71 (s, 2H), 3.57 (dd, J = 25.9, 17.8Hz, 2H), 1.00-0.80 (m, 2H), -0.05 (s, 9H).

[0910] Preparation of 40.1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)-1H-pyrrole-2-carboxynitrile (P40). Weigh compound P39 (1 g, 3.05 mmol), copper iodide (60 mg, 0.31 mmol), sodium iodide (0.96 g, 6.4 mmol), 2-cyanopyrrole (0.3 g, 3.2 mmol), and K3PO4 (1.4 g, 6.6 mmol) into a vial, add a stir bar, seal the vial, and purge with nitrogen. Add 1,4-dioxane (3 mL), followed by trans-N,N'-dimethyl-1,2-diamine (0.04 mg, 0.032 g, 0.37 mmol). Heat the mixture to 110 °C and maintain overnight. Evaporate the mixture under vacuum and then dilute with DCM and water. Filter the mixture through a hydrophobic glass frit and then purify by column chromatography to give compound P40 (0.73 g, 67%). LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes (retention time 2.02 minutes). MS (ESI) m / z: 339.5 [M+H] + . 1 H NMR (400MHz, CDCl3), δ: 8.10 (s, 1H), 7.88 (d, J = 8.5Hz, 1H), 7.67 (s, 1H), 7.33 (dd, J = 8.5, 1.6Hz, 1H), 7.18 (d, J = 1.8Hz, 1H ),7.05(dd,J=3.9,1.4Hz,1H),6.45-6.36(m,1H),5.79(s,2H),3.71-3.46(m,2H),1.02-0.81(m,2H),-0.01--0.14(m,9H).

[0911] Preparation of 41.1-(1H-indazol-6-yl)-1H-pyrrole-2-carboxynitrile (P41). Compound P40 (0.4 g, 1.18 mmol) was dissolved in DCM (10 ml) and TFA (3.4 ml, 5.05 g, 44.2 mmol). The mixture was stirred at ambient temperature for 48 hours. The mixture was then evaporated under vacuum. The residue was treated with an aqueous solution of NaHCO3, and the product was extracted with ethyl acetate (2 × 10 ml). The combined organic layers were dried over MgSO4 and concentrated. Product P41 (0.2 g, 81%) was used without further purification. LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes (retention time 1.47 minutes). MS (ESI) m / z 209.4 [M+H] + . 1 HNMR (400MHz, CDCl3), δ: 10.80 (br.s, 1H), 8.18 (s, 1H), 7.89 (d, J = 8.5Hz, 1H), 7.64 (s, 1 H),7.32-7.23(m,1H),7.18(dd,J=2.3,1.3Hz,1H),7.09-7.02(m,1H),6.46-6.37(m,1H).

[0912] Preparation of 42.1-[1-(6-chloropyrazin-4-yl)-1H-indazol-6-yl]-1H-pyrrole-2-carboxynitrile (P42). At 0 °C, a dispersion of 60% NaH in mineral oil (70.0 mg, 1.75 mmol) was added to a solution of compound P41 (240 mg, 1.15 mmol) in anhydrous DMF (5 mL), and the mixture was stirred for 20 min. Then, 3,5-dichloropyrazine (0.2 mg, 1.34 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with water (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient dissolution: 0-22% EtOAc / hexane) to give 0.17 g (45%) of compound P42. LCMS (C18 column, 20 × 2 mm, 2.5 μm, pore size...) Water-acetonitrile + 0.1% TFA, gradient 5 to 87%, hold for 3 minutes, residence time 1.55 minutes). MS (ESI) m / z: 321.4 [M+H] + . Synthesis of 1-(1H-indazol-6-yl)cyclopropaneformonitrile (P43)

[0913] Preparation of 43,1-(1H-indazol-6-yl)cyclopropaneformonitrile (P43). At 0 °C, LiHMDS (76 mL, 76 mmol, 1 M in THF) was added to a solution of 6-bromo-1H-indazole (5.0 g, 25 mmol), cyclopropaneformonitrile (2.6 g, 39 mmol), Pd₂dba₃ (1.2 g, 1.3 mmol), and NiXantPhos (1.4 g, 2.5 mmol) in THF / CPME (1:1 (v / v), 150 mL). After stirring the reaction mixture at 80 °C for 30 minutes, the mixture was then treated with NH₄Cl. (aq) The organic layer was treated and extracted with EtOAc. The organic layer was then subjected to Na2SO4... 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc / n-hexane) to give P43 (2.95 g, 64%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ10.51(br.s,1H),8.07(s,1H),7.74(dd,J=8.6Hz,1H),7.57( s,1H),7.00(d,J=8.6Hz,1H),1.81-1.78(m,2H),1.51-1.47(m,2H); LRMS(ESI)m / z:C 11 The calculated value for H9N3 is 183.08; the experimental value is 184.1 [M+H]. + HPLC purity: 99.27%, t R =14.56min. Synthesis of 2-(1H-indazol-6-yl)-2-methylpropionitrile (P44)

[0914] 44,2-(1H-indazol-6-yl)-2-methylpropionitrile (P44) was prepared. At 0 °C, LiHMDS (30 mL, 30.45 mmol, 1 M in THF) was added to a solution of 6-bromo-1H-indazole (2.00 g, 10.2 mmol), isobutyronitrile (1.06 g, 15.3 mmol), Pd2dba3 (468 mg, 0.510 mmol), and NiXantPhos (564 mg, 1.02 mmol) in THF / CPME (1:1 (v / v), 60 mL). After stirring the mixture overnight at 80 °C, the mixture was treated with NH4Cl. (aq) The organic layer was treated and extracted with EtOAc. The organic layer was then subjected to Na2SO4... 4(s)The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc / n-hexane) to give P44 (1.16 g, 62%) as a yellow oil. 1 H NMR (400MHz, CDCl3), δ: 10.34 (br.s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.68 (s, 1H), 7.26 (dd, J = 8.4Hz, 1.6Hz, 1H), 1.80 (s, 6H); LRMS (ESI) m / z: C 11 H 11 The calculated value of N3 is 185.10; the experimental value is 186.2 [M+H]. + HPLC purity: 94.14%, t R =15.43min. Synthesis of 2-cyclopropyl-6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-4-(N-morpholinyl)pyrazin-3(2H)-one (P48)

[0915] Preparation of 45,4-bromo-6-chloro-2-cyclopropylpyrazine-3(2H)-one (P45). Cyclopropylboronic acid (1.85 g, 21.5 mmol), pyridine (4.57 mL, 57.3 mmol), and triethylamine (5.00 mL, 35.8 mmol) were added to a solution of P25 (1.50 g, 7.16 mmol) in 1,4-dioxane (10 mL). Argon was bubbled into the mixture for 15 minutes. Copper(II) acetate (1.30 g, 7.16 mmol) was added to the mixture and degassed with argon. The mixture was stirred at 80 °C for 30 minutes, then the solution was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–15% EtOAc / n-hexane) to give P45 (252 mg, 14%) as a white solid. 1 ¹H NMR (400MHz, CDCl₃), δ: 7.57 (s, 1H), 4.11 (s, 1H), 1.13–1.12 (m, 2H), 1.05–1.04 (m, 2H); LCMS (ESI) m / z: Calculated value of C₇H₆BrClN₂O 247.94; Experimental value 248.6 [M+H] + .

[0916] Preparation of 46,6-chloro-2-cyclopropyl-4-(N-morpholinyl)pyrazin-3(2H)-one (P46). Morpholine (0.087 mL, 1.00 mmol) and cesium carbonate (652 mg, 2.00 mmol) were added to a solution of P45 (250 mg, 1.00 mmol) in 1,4-dioxane (10 mL). Argon was bubbled into the mixture for 15 minutes. Xantphos (57.9 mg, 0.100 mmol) and triphenylmethyleneacetone dipalladium (0) (45.8 mg, 0.050 mmol) were added to the mixture, and the mixture was degassed with argon. The mixture was stirred overnight at 80 °C, filtered through a diatomaceous earth mat, and the filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–40% EtOAc / n-hexane) to give P46 (183 mg, 71%) as a yellow gel. 1 H NMR (400MHz, CDCl3), δ: 6.20 (s, 1H), 3.94-3.87 (m, 1H), 3.87-3.81 (m, 4H), 3.55-3.48 (m, 4H), 1.13-0.94 (m, 4H); LCMS (ESI) m / z C 11 H 14 The calculated value of ClN3O2 is 255.08; the experimental value is 255.9 [M+H]. + .

[0917] Preparation of 47.(1-Cyclopropyl-5-(N-morpholino)-6-sideoxy-1,6-dihydropyrazin-3-yl)boronic acid (P47). To a solution of P46 (180 mg, 0.704 mmol) in 1,4-dioxane (7.0 mL), add bis(pinacolyl)diboron (894 mg, 3.52 mmol) and potassium acetate (138 mg, 1.41 mmol). Bubble the mixture with argon for 15 minutes. Add XPhos (67 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.070 mmol) to the mixture and degas the solution with argon for 15 minutes. After stirring the mixture at 50 °C for 16 hours, filter the solution through a diatomaceous earth mat and concentrate the filtrate to obtain crude product P47, which was used in the next step without further purification.

[0918] Preparation of 48,2-cyclopropyl-6-(5-isopropoxy-1-triphenylmethyl-1H-indazol-3-yl)-4-(N-morpholinyl)pyrazine-3(2H)-one (P48). P5 (319 mg, 0.586 mmol) and potassium phosphate (2 M in H2O, 0.80 mL, 1.8 mmol) were added to a solution of P47 (crude, 0.704 mmol) in 1,2-dimethoxyethane (7.0 mL). The mixture was degassed with argon for 15 min. A complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and DCM (48 mg, 0.059 mmol) was added to the mixture, and it was degassed with argon again. The mixture was stirred overnight at 90 °C, and the solution was diluted with EtOAc and filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (0-40% EtOAc / n-hexane) to give P48 (316 mg, 69%) as a brown solid. 1 H NMR (400MHz, CDCl3), δ: 7.72 (d, J = 2.4Hz, 1H), 7.31-7.27 (m, 8H), 7.20-7.14 (m, 7H), 7.04 (s, 1H), 6.63 (dd, J = 9.2, 2.4Hz, 1H), 6.21 (d, J = 9.2H z,1H),4.63-4.54(m,1H),4.32-4.22(m,1H),3.87-3.82(m,4H),3.47-3 .38(m,4H),1.41(s,3H),1.40(s,3H),1.10-1.03(m,4H); LCMS(ESI)m / z C 40 H 39 The calculated value of N5O3 is 637.31; the experimental value is 638.5 [M+H]. + . Synthesis of 2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)-4-(N-morpholinyl)pyrazin-3(2H)-one (P51)

[0919] Preparation of 49,5-(1-methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (P49). Iodine (3.5 g, 14 mmol) was added to a solution of 5-(1-methylcyclopropoxy)-1H-indazole (1.9 g, 10.09 mmol) in acetonitrile (50 mL), followed by the addition of potassium carbonate (1.5 g, 27 mmol) and iodine (3.84 g, 15.14 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / n-hexane) to give P49 (1.8 g, 57%) as a yellow oil.1 H NMR (400MHz, CDCl3), δ: 7.37 (d, J = 8.8 Hz, 1H), 7.12-7.09 (m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 1.07-1.04 (m, 2H), 0.79-0.76 (m, 2H).

[0920] Preparation of 50,3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (P50). A solution of P49 (2.2 g, 7.0 mmol), p-toluenesulfonic acid monohydrate (269 mg, 1.4 mmol), and 3,4-dihydro-2H-piperanone (1.3 mL, 14.0 mmol) in toluene (345 mL) was stirred at 60 °C for 16 hours. The mixture was treated with EtOAc and then dissolved in NaHCO3. 3(aq) Washing. The organic layer is then subjected to Na2SO4. 4(s) The product was dried, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-60% EtOAc / n-hexane) to give P50 (2.29 g, 82%) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.45(d,J=8.8Hz,1H),7.10-7.07(m,1H),7.00(d,J=2.0Hz,1H),5.65-5.62(m,1H),4.03-3.98(m,1H),3.74-3.68 (m,1H),2.56-2.47(m,1H),2.15-2.10(m,1H),2.08-2.03(m,2H),1.77-1.60(m,3H),1.58(s,3H),1.05-1.02(m,2H),0.78-0.74(m,2H).

[0921] Preparation of 51,2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)-4-(N-morpholinyl)pyrazin-3(2H)-one (P51). Add P50 (577 mg, 1.45 mmol) and potassium phosphate (2 M in water, 2.2 mL, 4.35 mmol) to a solution of P28 (crude, 1.74 mmol) in dimethoxyethane (15 mL). Degas the mixture with argon for 15 min. Add the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and DCM (118 mg, 0.15 mmol) to the mixture and degas again with argon. Stir the mixture at 90 °C overnight. Cool the mixture to room temperature and filter through a diatomaceous earth mat. Concentrate the filtrate under vacuum and then purify by silica gel chromatography (0-100% EtOAc / n-hexane). Wash the resulting solid with methanol to give P51 (943 mg) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 8.05 (d, J = 2.4Hz, 1H), 7.48 (d, J = 8.8Hz, 1H), 7.29 (s ,1H),7.10(dd,J=8.8,2.4Hz,1H),5.68(dd,J=9.4,2.4Hz,1H),4.10-3.84(m ,8H),3.77-3.72(m,1H),3.54-3.52(m,4H),2.65-2.55(m,1H),2.13-2.05(m ,2H),1.80-1.72(m,3H),1.61(s,3H),1.09-1.05(m,2H),0.76-0.72(m,2H). Synthesis of 2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)-4-(N-morpholinyl)pyrazin-3(2H)-one (P60)

[0922] Preparation of 52,2-bromo-4-cyclopropoxy-1-nitrobenzene (P52). Cyclopropanol (3.16 mL, 49.9 mmol, 1.1 eq) was added to a solution of 60% sodium hydride in mineral oil (2.36 g, 59.1 mmol, 1.3 eq) in anhydrous DMF (100 mL) at 0 °C. After stirring the reaction mixture at 0 °C for 30 min, 2-bromo-4-fluoro-1-nitrobenzene (10.0 g, 45.4 mmol, 1.0 eq) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 hours, and then diluted with H₂O at 0 °C. The mixture was extracted with EtOAc and treated with 1N HCl. (aq) Washing. The organic layer is then subjected to MgSO4. 4(s)The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc / n-hexane) to give P52 (4.17 g, 35%) as a yellow liquid. 1 H NMR (400MHz, CDCl3): δ7.97 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.05 (dd, J = 9.2, 2.8 Hz, 1H), 3.83-3.79 (m, 1H), 0.91-0.79 (m, 4H).

[0923] 53,4-cyclopropoxy-2-methyl-1-nitrobenzene (P53) was prepared. A solution of P51 (4.45 g, 17.2 mmol, 1.0 eq) in 1,4-dioxane (170 mL) was supplemented with potassium carbonate (2.14 g, 34.5 mmol, 2.0 eq), cesium carbonate (2.52 g, 17.2 mmol, 1.0 eq), and a 50% THF solution of trimethylcycloboroxane (4.34 mL, 34.5 mmol, 2.0 eq). The reaction mixture was degassed with argon, followed by the addition of tetra(triphenylphosphine)palladium(0) (895 mg, 1.72 mmol, 0.1 eq). The reaction solution was stirred at 100 °C for 16 hours, filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure. The crude product was treated with water and extracted with EtOAc. The organic layer was subjected to MgSO4. 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc / n-hexane) to give P53 (2.54 g, 76%) as a yellow liquid. 1 H NMR (400MHz, CDCl3), δ: 8.07 (d, J = 9.2Hz, 1H), 6.97-6.91 (m, 2H), 3.82-3.78 (m, 1H), 3.41 (s, 3H), 0.88-0.77 (m, 4H).

[0924] 54,4-cyclopropoxy-2-methylaniline (P54) was prepared. A solution of P52 (1.39 g, 7.19 mmol, 1.0 eq) in ethanol (10 mL) was added to a solution of Pd / C (139 mg, 10% w / w) in ethanol (75 mL). The solution was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was then filtered through a diatomaceous earth filter and washed with solvent. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc / n-hexane) to give P54 (920 mg, 78%) as a pink liquid. 1H NMR (400MHz, CDCl3), δ: 6.78-6.75 (m, 2H), 6.61 (d, J = 8.4Hz, 1H), 3.68-3.63 (m, 1H), 3.30 (br.s, 2H), 2.16 (s, 3H), 0.73-0.70 (m, 4H).

[0925] Prepare 55,N-(4-cyclopropoxy-2-methylphenyl)acetamide (P55). At 0 °C, triethylamine (0.864 mL, 6.20 mmol, 1.1 eq) and acetic anhydride (0.586 mL, 6.20 mmol, 1.1 eq) were added to a solution of P53 (920 mg, 5.63 mmol, 1.0 eq) in DCM (8.0 mL). The reaction solution was stirred at room temperature for 16 hours, then diluted with water and extracted with EtOAc. The organic layer was subjected to MgSO4... 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc / n-hexane) to give P55 (1.06 g, 92%) as a white solid. 1 H NMR (400MHz, CDCl3), δ: 7.43 (d, J = 8.4Hz, 1H), 6.90-6.86 (m, 3H), 3.72-3.67 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 0.76-0.73 (m, 4H).

[0926] Preparation of 56.1-(5-cyclopropoxy-1H-indazol-1-yl)ethyl-1-one (P56). At room temperature, potassium acetate (760 mg, 7.75 mmol, 1.5 eq) and acetic anhydride (2.19 mL, 23.2 mmol, 4.5 eq) were added to a solution of P55 (1.06 g, 5.16 mmol, 1.0 eq) in toluene (60 mL). The reaction solution was heated to 80 °C, and then amyl nitrite (2.76 mL, 20.6 mmol, 4.0 eq) was added. The reaction solution was stirred at 80 °C for 16 hours. The solution was diluted with water and extracted with EtOAc. The organic layer was subjected to MgSO4... 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc / n-hexane) to give P56 (1.03 g, 92%) as an orange solid. 1H NMR (400MHz, CDCl3), δ: 8.32 (d, J = 9.2Hz, 1H), 8.06 (s, 1H), 7.36 (d, J = 2.4Hz, 1H) ,7.21(dd,J=9.2,2.4Hz,1H),3.81-3.76(m,1H),2.76(s,3H),0.84-0.80(m,4H).

[0927] Preparation of 57,5-cyclopropoxy-1H-indazole (P57). A methanol solution of 7N ammonia (3.40 mL, 23.8 mmol, 5.0 eq) was added to a solution of P56 (1.03 g, 4.76 mmol, 1.0 eq) in methanol (20 mL). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give P57 (869 mg, 100%) as an orange solid, which was used in the next step without purification. 1 H NMR (400MHz, CDCl3), δ: 8.00 (s, 1H), 7.40-7.37 (m, 2H), 7.07 (dd, J = 8.8, 2.4Hz, 1H), 3.79-3.75 (m, 1H), 0.82-0.79 (m, 4H).

[0928] Preparation of 58,5-cyclopropoxy-3-iodo-1H-indazole (P58). Potassium carbonate (2.06 g, 14.9 mmol, 1.0 eq) and iodine (2.53 g, 9.97 mmol, 2.0 eq) were added to a solution of P57 (869 mg, 4.98 mmol, 1.0 eq) in acetonitrile (25 mL). The reaction solution was stirred at room temperature for 4 hours, then diluted with water and extracted with EtOAc. The organic layer was then treated with Na2S2O. 3(aq) Washed, with MgSO 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc / n-hexane) to give P58 (1.25 g, 83%) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 10.32 (br.s, 1H), 7.36 (dd, J = 10.0Hz, 1H), 7.12-7.11 (m, 2H), 3.84-3.81 (m, 1H), 0.88-0.79 (m, 4H).

[0929] Preparation of 59.5-cyclopropoxy-3-iodo-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole (P59). At room temperature, 3,4-dihydropiperanone (700 mg, 8.33 mmol, 2.0 eq) and p-toluenesulfonic acid monohydrate (158 mg, 0.833 mmol, 0.2 eq) were added to a solution of P58 (1.25 g, 4.16 mmol, 1.0 eq) in toluene (20 mL). The reaction solution was stirred at 60 °C for 2 hours, diluted with water, and extracted with EtOAc. The organic layer was then subjected to MgSO42-. 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% EtOAc / n-hexane) to give P59 (1.66 g, 100%) as a yellow oil. 1 H NMR (400MHz, CDCl3), δ: 7.45 (d, J = 9.2Hz, 1H), 7.11-7.06 (m, 2H), 5.64 (dd, J = 9.2, 2.8Hz, 1H), 4.03-3.99 (m, 1H), 3.83-3.7 9(m,1H),3.74-3.68(m,1H),2.57-2.47(m,1H),2.15-2.03(m,2H),1.76-1.70(m,2H),1.67-1.63(m,1H),0.87-0.77(m,4H).

[0930] Preparation of 60,6-(5-cyclopropoxy-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)-2-methyl-4-(N-morpholinyl)pyrazin-3(2H)-one (P60). At room temperature, P59 (150 mg, 0.390 mmol, 1.0 eq) and K3PO4 were added to a crude solution (P28, 0.468 mmol) of (1-methyl-5-(N-morpholino)-6-sideoxy-1,6-dihydropyrazin-3-yl)boronic acid. 4(aq) (0.585 mL) and 1,2-dimethoxyethane (4.5 mL). Argon. (g) The mixture was degassed and then a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (31.8 mg, 0.039 mmol, 0.1 eq) was added. The reaction solution was stirred at 90 °C for 16 hours, then filtered through a diatomaceous earth mat and washed with EtOAc. The filtrate was extracted with EtOAc. The organic layer was washed with water and subjected to MgSO4. 4(s) The sample was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / n-hexane) to give P60 (41 mg, 23%) as a brown solid. 1H NMR (400MHz, CDCl3), δ: 8.09 (d, J = 2.4Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.30 (s, 1H), 7.13 (dd,J=9.2,2.8Hz,1H),5.69(dd,J=9.6,2.8Hz,1H),4.11-4.07(m,1H),3.91-3.89(m,7 H),3.85-3.81(m,1H),3.79-3.73(m,1H),3.55-3.53(m,4H),2.86-2.57(m,1H),2.19-2 .16(m,1H),2.07-2.04(m,1H)1.81-1.76(m,2H),1.67-1.66(m,1H),0.84-0.82(m,4H). Synthesis of 4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furano[3,4-b]pyrrolo-1-yl)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro) -2H-piperan-2-yl)-1H-indazol-3-yl)darazine-3(2H)-one (P60)

[0931] Preparation of 61,6-chloro-4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furano[3,4-b]pyrrolo-1-yl)-2-methylpyrazine-3(2H)-one (P61). Add (3aR,6aS)-3,3-dimethyl-1,2,3a,4,6,6a-hexahydrofurano[3,4-b]pyrrole (190 mg, 1.34 mmol), cesium carbonate (729 mg, 2.24 mmol), and Xantphos (64.7 mg, 0.11 mmol) to a solution of P26 (250 mg, 1.12 mmol) in anhydrous 1,4-dioxane (7.5 mL). Degas the mixture with argon for 15 min. Add 0.06 mmol of triphenylmethyleneacetone dipalladium (0) to the mixture and degas with argon. Stir the mixture overnight at 80 °C, then filter the solution through a diatomaceous earth mat. Treat the filtrate with water and extract with EtOAc. Dry the combined organic layers with Na2SO4, filter, and concentrate. The residue was purified by silica gel chromatography (0-40% EtOAc / n-hexane) to give P61 (69 mg, 28%) as a yellow solid. 1H NMR (400MHz, CD3OD), δ: 6.09 (s, 1H), 4.85 (s, 2H), 3.93-3.89 (m, 1H), 3.80-3.71 (m, 2H), 3.66-3.6 4(m,1H),3.61(s,3H),3.28(br.s,1H),2.59-2.53(m,1H),1.13(s,3H),1.12(s,3H); LCMS(ESI)m / z C 13 H 18 The calculated value of ClN3O2 is 283.11; the experimental value is 284.1 [M+H]. + .

[0932] Preparation of 62,(5-((3aR,6aS)-3,3-dimethylhexahydro-1H-furano[3,4-b]pyrrolo-1-yl)-1-methyl-6-sideoxy-1,6-dihydropyrazin-3-yl)boronic acid (P62). To a solution of P61 (153 mg, 0.54 mmol) in anhydrous 1,4-dioxane (5.4 mL), add bis(pinacolyl)diboron (684 mg, 2.70 mmol), potassium acetate (106 mg, 1.08 mmol), and XPhos (5.1 mg, 0.11 mmol). Bubble the mixture with argon for 15 minutes. Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.05 mmol) to the mixture and then bubble with argon for another 15 minutes. After stirring the mixture overnight at 50 °C, the solution is used in the next step without further purification. LCMS(ESI) m / z C 13 H 20 The calculated value of BN3O4 is 293.15; the experimental value is 294.2 [M+H]. + .

[0933] Preparation of 63,4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furano[3,4-b]pyrrolo-1-yl)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)pyrazin-3(2H)-one (P63). The mixture was degassed with argon in a solution of P62 (crude, 0.54 mmol), P50 (150 mg, 0.38 mmol), and potassium phosphate (242 mg, 1.14 mmol, 2 M in water) in 3.8 mL of 1,2-dimethoxyethane for 15 minutes. A [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (33 mg, 0.04 mmol) was added to the mixture, followed by argon degassed for 15 minutes. The mixture was stirred overnight at 90 °C and then filtered through a diatomaceous earth filter. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (0-50% EtOAc / n-hexane) to give P63 (69 mg, 34%) as a yellow oil. 1 H(399MHz,CD3OD),δ:8.07(d,J=2.4Hz,1H),7.56(d,J=9.2Hz,1H),7.07(dd,J=9.2,2.4Hz,1H),6.96(s,1H ),5.79-5.77(m,1H),5.31(br.s,1H),4.61(br.s,2H),4.03-3.99(m,1H),3.96-3.92(m,1H),3.84(s,3H),3 .79-3.77(m,3H),3.72-3.69(m,1H),3.38(br.s,2H),2.60-2.49(m,2H),2.14-2.11(m,1H),2.07-2.18(m,1 H),1.87-1.67(m,3H),1.60(s,3H),1.13-1.12(m,6H),1.04-1.00(m,2H),0.80-0.77(m,2H); LCMS(ESI)m / z C 29 H 37 The calculated value of N5O4 is 519.28; the experimental value is 520.4 [M+H]. + . Synthesis of 4-((2S,6R)-2,6-dimethyl(N-morpholinyl))-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole -3-yl)-Dazazine-3(2H)-one (P60)

[0934] Preparation of 64,6-chloro-4-((2S,6R)-2,6-dimethyl(N-morpholino))-2-methylpyrazine-3(2H)-one (P64). A solution of P26 (1 g, 4.48 mmol) in anhydrous 1,4-dioxane (30 mL) was supplemented with cis-2,6-dimethylmorpholine (0.6 mL, 4.92 mmol), cesium carbonate (2.9 g, 8.96 mmol), and Xantphos (259 mg, 0.45 mmol). The mixture was degassed with argon for 15 min. Tris(diphenylmethyleneacetone)dipalladium(0) (205 mg, 0.22 mmol) was added to the mixture, and it was degassed again with argon. The mixture was stirred overnight at 80 °C, and the solution was filtered through a diatomaceous earth mat. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–40% EtOAc / n-hexane) to give P64 (472 mg, 40%) as a yellow solid. 1 H NMR (400MHz, CD3OD), δ: 6.22 (s, 1H), 4.12-4.09 (m, 2H), 3.84-3.76 (m, 2H), 3.70 (s, 3H), 2.50-2.45 (m 2H), 1.22 (d, J = 6.0Hz, 6H).

[0935] Preparation of 65,(5-((2S,6R)-2,6-dimethyl(N-morpholinyl))-1-methyl-6-sideoxy-1,6-dihydropyrazin-3-yl)boronic acid (P65). To a solution of P64 (200 mg, 0.78 mmol) in anhydrous 1,4-dioxane (7.8 mL), add bis(pinacolyl)diboron (990 mg, 3.90 mmol), potassium acetate (153 mg, 1.56 mmol), and XPhos (75 mg, 0.16 mmol). Degas the mixture with argon for 15 minutes. Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.08 mmol) to the mixture and then degas with argon for 15 minutes. After stirring the mixture overnight at 50 °C, the solution is used in the next step without further purification. LCMS(ESI) m / z C 13 H 20 The calculated value of BN3O4 is 293.15; the experimental value is 294.2 [M+H]. + .

[0936] Preparation of 66,4-((2S,6R)-2,6-dimethyl(N-morpholinyl))-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)pyrazin-3(2H)-one (P66). The above-mentioned P65 (0.78 mmol), P50 (259 mg, 0.65 mmol), and potassium phosphate (413 mg, 1.95 mmol, 2 M in water) were degassed for 15 minutes in a crude solution of 1,2-dimethoxyethane (6.5 mL). The mixture was then added with a [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (64 mg, 0.08 mmol) and subsequently degassed with argon for 15 minutes. After stirring the mixture overnight at 90 °C, it was filtered through a diatomaceous earth filter. The filtrate was concentrated under vacuum and then purified by silica gel chromatography (0-50% EtOAc / n-hexane) to give P66 (423 mg, 99%) as a yellow solid. 1 H (400MHz, CDCl3), δ: 8.06 (d, J = 2.4Hz, 1H), 7.48 (d, J = 9.2Hz, 1H), 7.11 (dd, J = 9 .2,2.4Hz,1H),6.98(s,1H),5.69(dd,J=9.9,2.6Hz,1H),4.64(br.s,2H),4.17- 4.08(m,3H),3.94-3.85(m,4H),3.79-3.73(m,2H),2.53-2.44(m,2H),2.06-2.0 0(m,4H),1.61(s,3H),1.29-1.28(m,6H),1.10-1.08(m,2H),0.76-0.73(m,2H). Synthesis of 2-cyclopropyl-4-((2S,6R)-2,6-dimethyl(N-morpholinyl))-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-3-yl)pyrazin-3(2H)-one (P69)

[0937] Preparation of 67,6-chloro-2-cyclopropyl-4-((2S,6R)-2,6-dimethyl(N-morpholinyl))pyrazin-3(2H)-one (P67). A solution of P45 (300 mg, 1.20 mmol) in anhydrous 1,4-dioxane (8.6 mL) was supplemented with cis-2,6-dimethylmorpholine (148 μL, 1.20 mmol), cesium carbonate (782 mg, 2.40 mmol), and Xantphos (69 mg, 0.12 mmol). The mixture was degassed with argon for 15 min. Tris(diphenylmethyleneacetone)dipalladium(0) (55 mg, 0.06 mmol) was added to the mixture and degassed with argon. The mixture was stirred overnight at 80 °C, and the solution was filtered through a diatomaceous earth mat. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–40% EtOAc / n-hexane) to give P67 (50 mg, 14%) as a yellow solid. 1 H NMR (400MHz, CDCl3), δ: 6.19 (s, 1H), 4.11-4.09 (m, 2H), 3.92-3.85 (m, 1H), 3.85-3.7...

Claims

1. A compound, characterized in that include: Formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein V is selected from C and N; W is selected from C and N; and one of V and W is N; key is selected from single bonds and double bonds; key is selected from single bonds and double bonds; The restriction is that when V is N, the key is a single key. is a double bond and W is C, and when V is C, then the bond is a double bond. is a single bond and W is N; X is selected from CR 7 and N; Y is selected from C=O, CR 8 and N; The restriction is that one of X and Y is N; key is selected from single bonds and double bonds; r is an integer selected from 0 and 1; The restriction is that when Y is C=O, the bond is a single bond and r is 1, and when Y is CR 8 or N, then the key is a double bond and r is 0; When Y is C=O or N, Z is selected from CR 9 and N; When Y is CR 8 When Z is CR 9 ; Q is selected from CH2, NR 5 , O, S, S(O), S(O)2; R 1 Selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, heteroaryl, NR 10 R 11 and S(O)2R 12 , wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; R 2 Selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 , wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a C3-C 10 Cycloalkyl, 5-14 membered heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR 10 R 11 ; R 3 Selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 and S(O)2R 12 , wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl and heteroaryl; or R 2 and R 3 Together with the atoms to which it is attached and any intervening atoms, it forms a C3-C 10 Cycloalkyl, 5-14 membered heterocyclic, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more substituents independently selected from the following: halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl and NR 10 R 11 ; R 4 Selected from H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein the alkyl, cycloalkyl or alkyl-alkoxy is optionally substituted by one or more substituents independently selected from the following: halogen, pendant oxy, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic ring; Each R 5 Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , wherein the alkyl, cycloalkyl or alkyl-alkoxy is optionally substituted by one or more substituents independently selected from the following: halogen, pendant oxygen, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic ring; Each R 6 independently selected from halogen, OH, pendant oxygen, CN, CONR 10 R 11 NR 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkyloxy, O-C1-C6 alkyl-C(O)NR 10 R 11 NR 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein the alkyl or alkoxy group is optionally substituted by one or more substituents independently selected from the following: halogen, pendant oxygen, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl and heterocyclic ring; or two R 6 Together with the atoms to which it is attached and any intervening atoms, it forms a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 ; R 7 , R 8 and R 9 Each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , wherein the alkyl, alkoxy, cycloalkyl or alkyl-alkoxy is optionally substituted by one or more substituents independently selected from the following: halogen, pendant oxygen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 、S(O)2R 12 , cycloalkyl and heterocyclic ring; R 10 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)2R 12 , wherein the alkyl or cycloalkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, pendant oxygen group, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; or R 10 and R 11 Together with the atoms to which it is attached and any intervening atoms, it forms a 5-14 membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the following: halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 Selected from C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2, wherein the alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, pendant oxy, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; in, m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, 4; u is an integer selected from 0, 1, 2, 3, 4, 5, 6; Aryl is a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings; The heterocyclyl group is a saturated or partially unsaturated 3-10 membered monocyclic ring, a 7-12 membered bicyclic ring (fused ring, bridged ring or spiro ring) or an 11-14 membered tricyclic ring system (fused ring, bridged ring or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms which contains one or more heteroatoms selected from N, O, S, P or B and the remaining ring atoms are C.

2. The compound according to claim 1, characterized in that The compound has formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound according to claim 2, characterized in that The compound has formula (IIA), formula (IIB), formula (IIC) or formula (IID): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound according to claim 1, characterized in that The compound has formula (I-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compound according to claim 4, characterized in that The compound has formula (I-II-A), formula (I-II-B), formula (I-II-C) or formula (I-II-D): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. The compound according to claim 1, characterized in that The compound has the formula (IO): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound according to claim 1, characterized in that The compound has the formula (IN): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

8. The compound according to claim 1, characterized in that The compound has the formula (IC): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

9. The compound according to claim 1, characterized in that The compound has formula (IS): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. The compound according to claim 2, characterized in that The compound has the formula (IOI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

11. The compound according to claim 2, characterized in that The compound has the formula (INI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

12. The compound according to claim 2, characterized in that The compound has the formula (ICI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

13. The compound according to claim 2, characterized in that The compound has the formula (ISI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

14. The compound according to claim 4, characterized in that The compound has the formula (IO-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

15. The compound according to claim 4, characterized in that The compound has the formula (IN-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

16. The compound according to claim 4, characterized in that The compound has the formula (IC-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

17. The compound according to claim 4, characterized in that The compound has the formula (IS-II): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

18. The compound according to claim 3, characterized in that The compound has formula (IIDI), formula (IID-II), formula (IID-III) or formula (IID-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

19. The compound according to any one of claims 1, 2, 3, 4 or 5, characterized in that Snippet Selected from:

20. The compound according to any one of claims 1, 2, 3, 4 or 5, characterized in that R 4 For H.

21. A compound, characterized in that Selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

22. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition according to claim 22, characterized in that Further comprising one or more additional pharmaceutically active agents.

24. A method for inhibiting LRRK2 in a cell, characterized in that The method comprises contacting the cell with a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22 or 23.

25. The method according to claim 24, characterized in that The contacting is performed in vitro or in vivo.

26. A method for treating or preventing a disease or condition associated with LRRK2, characterized in that: Comprising administering a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22 or 23 to a subject in need thereof.

27. The method according to claim 26, characterized in that The disease or condition is selected from the group consisting of: Parkinson Disease 8, Autosomal Dominant; PARK8; Hereditary Late-Onset Parkinson's Disease (LOPD); Spinocerebellar Atrophy; Klippel-Feil Syndrome 1, Autosomal Dominant; KFS1; SCA; Late-Onset Parkinson's Disease (PD); Juvenile Autosomal Recessive Parkinson's Disease 2 (PARK2); Parkinson's Disease; Rapid Eye Movement Sleep Behavior Disorder; Dementia, Lewy Bodies; Body; DLB); Lrrk2 Parkinson's disease; autosomal dominant Parkinson's disease 3 (PARK3); early-onset Parkinson's disease; multiple system atrophy 1 (MSA1); spontaneous tremor; movement disorder; progressive supranuclear palsy 1 (PSNP1); Klein-Ferrer syndrome 1; dementia; Parkinson's disease 10 (PARK10); tremor; frontotemporal dementia (FTD); postencephalitic parkinsonism; vascular parkinsonism; aphasia; autosomal dominant Parkinson's disease 1 (PARK1); cheroothdactyly; Klein-Ferrer syndrome (KFS); Kufor-Rakeb syndrome (KRS); leprosy 3 (LPRS3); Alzheimer's disease 8 (AD8); Crohn's disease (Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer's Disease (AD); Color Agnosia; Gaucher Disease, Type I (GD1); Early-Onset Autosomal Recessive Parkinson's Disease 15 (PARK15); Von Economo's Disease; Gerstmann-Straussler Disease (GSD); Amyotrophic Lateral Sclerosis-Parkinson's Disease / Dementia Complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radial Neuropathy; Toxic Encephalopathy; Sleep Disorders; Pick's Disease of the Brain (Pick's Disease of Brain, PIDB); Eye Myiasis; Gaucher's Disease (GD); Optic Atrophy Type 7 (OPA7) with or without Auditory Neuropathy; Ulnar Neuropathy; Inflammatory Bowel Disease 4 (IBD4); Inflammatory Bowel Disease; 3-Methylglutaconic Aciduria Type III (MGCA3); Nervous System Diseases; Amyotrophic Lateral Sclerosis 1 (ALS1);Mitochondrial complex I deficiency nuclear type 1 (MC1DN1).

28. The method according to claim 26, characterized in that The disease or condition is Parkinson's disease (PD).

29. The method according to any one of claims 24 to 28, characterized in that The individual is a mammal.

30. The method according to claim 29, characterized in that The individual is human.

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