Heterocyclic compound, pharmaceutical composition and application thereof

Abstract

The invention provides a heterocyclic compound as shown in a formula I, and a pharmaceutical composition and application thereof. The heterocyclic compound has remarkable regulation activity on GPR6 receptor activity.

Description

[0001] Cross Reference to Related Applications

[0002] This application is based on CN application with application number 202411360330.1 and filing date of September 26, 2024, CN application with application number 202510390227.X and filing date of March 31, 2025, and CN application with application number 202510632994.7 and filing date of May 16, 2025, and claims priority to them, the contents of all of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present application relates to heterocyclic compounds, pharmaceutical compositions thereof, methods of preparation, and uses thereof. BACKGROUND

[0004] G protein-coupled receptor 6 (GPR6) is a high-activity G protein-coupled receptor (GPCR) that exhibits highly specific expression in the indirect pathway of medium spiny neurons (D2-MSNs) positive for dopamine D2 receptors in the striatum, while the expression level is significantly lower in the direct pathway of MSNs expressing D1 dopamine receptors, other brain regions, and peripheral tissues. Studies have shown that GPR6 activates adenylyl cyclase by coupling with Gs protein, promotes the accumulation of intracellular cyclic adenosine monophosphate (cAMP), and further regulates the activity of the indirect pathway of the striatum. In GPR6 knockout mouse models, the cAMP level of the striatal tissue is significantly reduced, suggesting that GPR6 plays a key role in the activation of the indirect pathway. Further in vitro experiments have confirmed that the inhibition of GPR6 function (such as antagonism or reverse agonism) can effectively reduce the overactive state of the indirect pathway of D2-MSNs, which provides a potential target for the treatment of movement disorder diseases such as Parkinson's Disease (PD).

[0005] The pathological features of Parkinson's Disease are closely related to the imbalance of the basal ganglia circuit, especially the overactivation of the indirect pathway, which can lead to motor function decline and motor complications. Preclinical studies have shown that in PD animal models, GPR6 gene deletion or pharmacological inhibition can significantly improve motor function, manifested as increased motor activity and reduced levodopa-induced abnormal involuntary movements (such as dyskinesia). These findings suggest that modulators targeting GPR6 may become a new strategy for the treatment of PD by restoring the balance of the indirect pathway activity.

[0006] Currently, some progress has been made in the development of GPR6 drugs. For example, CVN424, a clinical candidate compound as a GPR6 inverse agonist, has shown potential to significantly improve PD motor symptoms in preclinical models, and has entered the phase III clinical trial stage in combination with levodopa. However, there are still some unresolved problems in existing research: first, the selectivity and pharmacokinetic properties of existing GPR6 modulators still need to be optimized to reduce off-target effects and improve brain bioavailability; in addition, the compensatory signal pathway changes and potential safety risks that may be caused by long-term inhibition of GPR6 need to be further evaluated.

[0007] In summary, developing new GPR6 modulators with high efficiency, high selectivity and good drug-likeness is still a core problem that needs to be broken through in this field. SUMMARY

[0008] In one aspect, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof, wherein the compound has a structure as shown in Formula I:

[0009]

[0010] wherein,

[0011] ring A1 is selected from C 6-10 aromatic ring and 5-10 membered heteroaromatic ring; the aromatic ring or heteroaromatic ring is optionally substituted with one or more R3;

[0012] ring A2 is selected from C 6-10 aromatic ring and 5-10 membered heteroaromatic ring;

[0013] ring Sp is selected from C 6-13 spirocyclic group and 6-13 membered heterospirocyclic group;

[0014] L1 is selected from covalent bond, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NR b )-, -S(=NR b )2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=O)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=O)-, -N(R b )-C(=O)-, -C(=O)-, -C(=O)-C 1-6 alkylene-, C 1-6alkylene, -0-C 1-6 alkylene; said alkylene is optionally substituted with one or more R a substituents;

[0015] Q is selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO2, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl;

[0016] L2 is selected from the group consisting of a covalent bond, -0-, -S-, -S(O)-, -S(0)2-, -S(=0)(=NR b )-, -S(=NR b )2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=0)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=0)-, -N(R b )-C(=0)-, -C(=0)-, -C(=0)-C 1-6 alkylene-, C 1-6 alkylene, -0-C 1-6 alkylene; said alkylene is optionally substituted with one or more R a substituents;

[0017] R1 and R2 are each independently absent, or each independently selected from the group consisting of H, hydroxy, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=0)R 22 , -S(=0)2R22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl; or, said R1 and R2 together with the atoms they are attached to form C 5-8 Cycloalkyl, 5-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 membered heteroaryl; the alkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: halogen, CN, hydroxyl, oxo (=O), C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0018] R3 is independently selected from hydroxyl, halogen, CN, and C each time it appears. 1-6 Alkyl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 membered heteroaryl; the alkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: halogen, CN, hydroxyl, oxo (=O), C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0019] R4 is independently selected from hydroxyl, halogen, CN, and C each time it appears. 1-6 Alkyl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 membered heteroaryl; the alkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: halogen, CN, hydroxyl, oxo (=O), C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0020] R5 is independently selected from hydroxyl, halogen, CN, and C each time it appears. 1-6 Alkyl, -NR 20a R 20b -OR21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a -C(=O)R 23b -C(=O)NR 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b , and -NR 33a -C(=O)R 33b ;

[0021] R a is at each occurrence independently selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy; each of said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, and C 1-6 alkoxy;

[0022] R b is at each occurrence independently selected from the group consisting of H, C 1-6 alkyl, C 3-8 cycloalkyl and 5-10 membered heterocyclyl; each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl and C 1-4 haloalkoxy;

[0023] R 20a , R20b R 23a R 23b each independently selected from H, OH, C 1-6 alkyl, C 1-6 alkoxy, and C 3-8 cycloalkyl; or R 20a and R 20b R 23a and R 23b or R 25a and R 25b together with the atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl; each of said alkyl, alkoxy, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from OH, CN, halo, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

[0024] R 30a R 30b R 33a R 33b each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0025] R 21 R 22 R 31 R 32 each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, and 5-10 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from OH, halo, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, and 4-10 membered heterocyclyl;

[0026] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0027] n is 0, 1, 2, 3, 4, or 5;

[0028] wherein:

[0029] (1) when L1is a covalent bond, L2is O, and Q is pyrazolyl, pyridyl, or pyrazinyl, ring Sp is not and,

[0030] (2) when L1is a covalent bond, L2is a covalent bond, R1and R2together with the atoms to which they are attached form a 6-membered nitrogen-containing heterocyclyl substituted with an acetyl group, and Q is pyrazolyl, ring Sp is not

[0031] A second aspect of the application provides a pharmaceutical composition comprising a compound of the application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled version, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0032] A third aspect of the application provides a kit comprising:

[0033] a) at least one compound of the application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled version, metabolite, or prodrug thereof, as a first therapeutic agent, or a pharmaceutical composition comprising the same as a first pharmaceutical composition;

[0034] b) optionally at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising the other therapeutic agent as a second pharmaceutical composition; and

[0035] c) optionally packaging and / or instructions.

[0036] A fourth aspect of the application provides the use of a compound of the application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled version, metabolite, or prodrug thereof, or a pharmaceutical composition, or a kit of the application, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with GPR6 activity.

[0037] A fifth aspect of the application provides a compound of the application, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled version, metabolite, or prodrug thereof, or a pharmaceutical composition, or a kit of the application, for use in the treatment and / or prevention of a disease or condition associated with GPR6 activity.

[0038] In a sixth aspect, the present application provides a method of treating and / or preventing a disease or condition associated with GPR6 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled version, metabolite or prodrug thereof, or a pharmaceutical composition, or a kit product.

[0039] In a seventh aspect, the present application provides a method of preparing a compound of the present application.

[0040] Definitions

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to techniques used in the present application are intended to refer to those techniques generally understood in the art, including those variations or substitutions of techniques that would be apparent to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate a better understanding of the present application.

[0042] The terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or "encompasses", and variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Those skilled in the art will appreciate that the terms "comprising", "including", and the like, when used in the following description, specify the presence of stated features but do not preclude the presence or addition of one or more other features.

[0043] The term "one or more" or similar expressions "at least one" means, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0044] When a lower limit and an upper limit of a numerical range are disclosed, any number or any sub-range falling within the range is expressly disclosed. In particular, every numerical range disclosed herein (e.g., of the form "from about a to about b", or equivalently "from approximately a to b", or equivalently "about a to b") should be interpreted as specifically disclosing every number and sub-range within the range. For example, the range of "from about 1 to about 10" should be interpreted to specifically disclose the range "from 1 to 10". 1-6 " should be interpreted to specifically disclose the range "from 1 to 10". 2-5 " should be interpreted to specifically disclose the range "from 1 to 10". 3-4 " should be interpreted to specifically disclose the range "from 1 to 10". 1-2 " should be interpreted to specifically disclose the range "from 1 to 10". 1-3 " should be interpreted to specifically disclose the range "from 1 to 10". 1-4 " should be interpreted to specifically disclose the range "from 1 to 10". 1-5and C1, C2, C3, C4, C5, C6, etc. For example, "3-10 membered" is understood to encompass any sub-range therein and each individual point value, such as 3-4 membered, 3-5 membered, 3-6 membered, 3-7 membered, 3-8 membered, 3-9 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 5-7 membered, 5-8 membered, 6-7 membered, etc., and 3, 4, 5, 6, 7, 8, 9, 10 membered, etc.

[0045] As used herein, denotes the point of attachment of a structural fragment to the rest of the molecule.

[0046] The term "alkyl" defines straight-chained or branched saturated aliphatic hydrocarbon groups. In some embodiments, alkyl groups have 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "alkyl" refers to linear or branched groups of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl), which are optionally substituted with 1 or more (such as 1, 2, or 3) suitable substituents.

[0047] The term "alkylene" refers to a divalent radical resulting from the loss of two hydrogen atoms from the same or different carbon atoms of a straight-chained or branched "alkyl" group. For example, the term "C 1-6 "alkylene" refers to alkylene groups having 1-6 carbon atoms, including but not limited to methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), =CH2, =CHCH3, =CHCH2CH3, etc. Alkylene groups can be attached to two atoms, e.g., methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-); or to one atom, e.g., =CH2, =CHCH3, =CHCH2CH3, if valence requirements are met.

[0048] The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above. For example, the term "C 1-6 "hydroxyalkyl" refers to hydroxyalkyl groups having 1-6 carbon atoms. Common hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH(OH)2, -(CH2)3OH.

[0049] The term "amine alkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above. For example, the term "C 1-6"Aminoalkyl" refers to an alkyl group having 1-6 carbon atoms which is substituted with one or more (such as 1-3) amino groups. Common aminoalkyl groups include, but are not limited to, -CH2-NH2, -CH2CH2-NH2, -CH2CH(NH2)2, -(CH2)3-NH2.

[0050] The term "alkenyl" refers to straight-chain or branched aliphatic hydrocarbon groups having one or more carbon-carbon double bonds. For example, the term "C 2-6 Alkenyl" refers to an alkenyl group having 2-6 carbon atoms and one, two, or three carbon-carbon double bonds (such as ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like), which is optionally substituted with one or more (such as 1-3) substituents described herein.

[0051] The term "alkynyl" refers to straight-chain or branched aliphatic hydrocarbon groups having one or more carbon-carbon triple bonds. For example, the term "C 2-6 Alkynyl" refers to an alkynyl group having 2-6 carbon atoms and one, two, or three carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like), which is optionally substituted with one or more (such as 1-3) substituents described herein.

[0052] The term "cycloalkyl" refers to saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon groups; for example, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused, or bridged rings (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, or decahydronaphthyl, and the like). For example, the term "C 3-12 Cycloalkyl" refers to a cycloalkyl group having 3-12 (such as 3, 4, 5, 6, 7, 8, 9, or 10) ring carbon atoms. The term "C 3-8 Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, for example, C 3-8 Cycloalkyl, which can be a monocycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or a bicycloalkyl group, for example, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl, or C5-6 Fused cycloalkyl groups.

[0053] As used herein, the term "spirocyclic (base)" refers to a ring system formed by two or more carbon rings sharing a single ring atom with each other.

[0054] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic cyclic structure whose ring atoms consist of a carbon atom and at least one (e.g., 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. The heterocyclic group can be attached to the rest of the molecule via any one ring atom, provided the valence requirements are met. The term also covers cases where the C or P atom in the ring can be substituted with an oxo group (=O), the S atom in the ring can be substituted with one or two oxo groups (=O), or the N atom on the ring can form a nitride. The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spirocyclic system. "Heterocyclic group" or "heterocyclic alkyl group" can be characterized by the number of ring atoms. For example, 3-12 membered heterocyclic groups or heterocyclic alkyl groups can contain 3-12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 3, 4, 5, 6, 7, 8, 9, and 10 ring atoms. If valence requirements are met, heterocyclic alkyl groups can be linked to other groups (or segments) through any carbon atom or heteroatom in the ring. Examples of 3-12, 3-8, 3-6, and 3-5 membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, aziridine, oxobutidine, thiobutidine, tetrahydrofuranyl, dioxacyclopentyl, dioxacyclohexyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine.

[0055] The term "saturated heterocycle" refers to a fully saturated heterocycle, such as the tetrahydrofuran ring, piperidine ring, tetrahydropyran ring, piperazine ring, etc. The term "partially saturated heterocycle" refers to a heterocycle that contains both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, dihydrofuran, etc.

[0056] As used herein, the term "3-8 membered heterocyclyl" or "3-8 membered heterocycloalkyl" means a heterocyclyl group containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, 3-7 membered heterocyclyl, 4-6 membered nitrogen-containing heterocyclyl, 4-6 membered oxygen-containing heterocyclyl, 4-6 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, and the like, each of which optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of "4-6 membered heterocyclyl" or "4-6 membered heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, dioxanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.

[0057] The term "oxygen-containing heterocycle" refers to a heterocycle as previously described in which one or more (e.g., 1, 2, or 3) ring atoms is an oxygen atom, for example, a 5-6 membered oxygen-containing heterocycle, a five-membered oxygen-containing heterocycle, specific examples include, but are not limited to, an oxirane ring, a tetrahydrofuran ring, a furan ring, a tetrahydropyran ring, a pyran ring, a 1,3-dioxolane ring, and the like.

[0058] The "nitrogen-containing heterocycle" as described herein refers to a heterocycle as previously described in which one or more (e.g., 1, 2, or 3) ring atoms is a nitrogen atom.

[0059] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed from two or more saturated rings sharing one ring atom, including but not limited to a 6-13 membered spiroheterocycle, a 6-13 membered nitrogen-containing spiroheterocycle, a 6-13 membered oxygen-containing spiroheterocycle, a 6-13 membered sulfur-containing spiroheterocycle, and the like, for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more additional heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-13 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6-13 ring atoms and at least one of which is a nitrogen atom.

[0060] The term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic ring system that has a conjugated π-electron system. As used herein, the term "C 6-10 The term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic ring system that has a conjugated π-electron system. As used herein, the term "C

[0061] The term "heteroaryl" or "heteroaromatic ring" means a monocyclic or fused ring aromatic group having a conjugated pi-electron system with one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) in the ring and one or more (e.g., 1, 2, 3, or 4) heteroatoms each independently selected from N, O, P, and S. Heteroaryl groups can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 7, 8, 9, 10 ring atoms. If valence requirements are met, a heteroaryl group can be attached to the parent molecular moiety through any one of the ring atoms. Examples of heteroaryl groups are thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridine, pyrimidine, pyrazine, pyridazine, and the like. The term also encompasses the case where the heteroaryl group is optionally further fused to an aryl (e.g., benzene) or heteroaryl ring to form a fused ring system.

[0062] The term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl (heteroaromatic ring) containing 5 to 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and the like. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", and "sulfur-containing heteroaryl" each optionally contain one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, as well as 5-10 membered annulated groups containing these groups.

[0063] The term "fused ring system (fused ring)" means a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbocyclic or heterocyclic rings, including cycloalkyl and aryl for the carbocyclic rings and heterocycloalkyl and heteroaryl for the heterocyclic rings, sharing a ring edge. The fused ring system is, for example, a fused ring system of cycloalkyl and cycloalkyl, a fused ring system of cycloalkyl and heterocycloalkyl, a fused ring system of cycloalkyl and aryl, a fused ring system of cycloalkyl and heteroaryl, a fused ring system of heterocycloalkyl and heteroaryl, a fused ring system of heterocycloalkyl and aryl, a fused ring system of heteroaryl and heteroaryl, a fused ring system of heteroaryl and aryl, and the like.

[0064] The term "fused heteroaryl" refers to an aromatic group having a fused ring with a conjugated pi-electron system having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms each independently selected from N, O, P, and S. For example, the term "8-10 membered fused heteroaryl" refers to a fused heteroaryl group containing 8-10 (e.g., 8, 9, 10) ring atoms, which can be attached to the parent molecular moiety through any one of the ring atoms, if valence requirements are met. Examples of "8-10 membered fused heteroaryl" groups are benzopyridyl, thiazolopyridyl, oxazolopyridyl, pyrazolopyrimidyl.

[0065] The term "haloalkyl" or "halogen substituted alkyl" refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 haloalkyl" or "halogen substituted C 1-6 alkyl" refers to a C 1-6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens can be the same or different and can be located on the same or different C atoms. Examples of haloalkyl groups are, for example, -CH2F, -CHF2, -CF3, -CC13, -C2F5, -C2C15, -CH2CF3, -CH2C1, or -CH2CH2CF3, and the like. 1-4 The term "haloalkyl" or "halogen substituted C 1-4 alkyl" refers to a C 1-4 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens can be the same or different and can be located on the same or different C atoms. Examples of haloalkyl groups are, for example, -CH2F, -CHF2, -CF3, -CC13, -C2F5, -C2C15, -CH2CF3, -CH2C1, or -CH2CH2CF3, and the like.

[0066] The term "haloalkyl" or "halogen substituted C 1-6 alkyl" refers to a C 1-6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens can be the same or different and can be located on the same or different C atoms. Examples of haloalkyl groups are, for example, -CH2F, -CHF2, -CF3, -CC13, -C2F5, -C2C15, -CH2CF3, -CH2C1, or -CH2CH2CF3, and the like. 1-4 The term "haloalkyl" or "halogen substituted C 1-4 alkyl" refers to a C 1-6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens can be the same or different and can be located on the same or different C atoms. Examples of haloalkyl groups are, for example, -CH2F, -CHF2, -CF3, -CC13, -C2F5, -C2C15, -CH2CF3, -CH2C1, or -CH2CH2CF3, and the like. 1-4 The term "alkoxy" refers to a group having the structure "alkyl-O-" in which alkyl is as defined above. For example, C 1-3 alkoxy, C 1-2 alkoxy, C 1-6 alkoxy, or C1-2 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. Alkyl groups in the present application are optionally substituted with one or more substituents described herein.

[0068] The term "alkoxyalkyl" means an alkyl group having from 1 to 6 carbon atoms, substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups. Common alkyl groups include, but are not limited to, CH3O-CH2-, C2H5-O-CH2-, C2H5-O-CH2CH2-, and the like. The term "alkyl" as used herein means a straight, branched, or cyclic alkyl group having from 1 to 6 carbon atoms. Common alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. Alkyl groups in the present application are optionally substituted with one or more substituents described herein. 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, and the like. Alkyl groups in the present application are optionally substituted with one or more substituents described herein.

[0069] The term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0070] The term "each independently" or "independently" as used herein means that at least two groups (or moieties) present in a structure that have the same or similar range of values can have the same or different meanings in a particular instance. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, -CN, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, -CN, alkyl, or aryl; and similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, -CN, alkyl, or aryl.

[0071] If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more substituents from a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with an independently selected optional substituent, alone or together. If a nitrogen of a substituent is described as optionally substituted with one or more substituents from a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with an independently selected optional substituent.

[0072] If a functional group or structural moiety is described as "substituted or unsubstituted," the functional group or structural moiety can be (1) unsubstituted or (2) substituted.

[0073] The term "substituted" means that one or more (e.g., 1, 2, 3, 4, or 5) hydrogens on the designated compound or structural fragment are replaced by a substituent, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By way of example, the following groups each independently consist of one or more of the following structures: -O-, -S-, -NR'-, halo, -CN, -OH, -NH2, -NO2, -CN, =O, C 1-6 (alkyl)alkenyl, C 1-6 halo(alkyl)alkenyl, C 1-6 alkoxy, C 2-6 (alkyl)alkenyl, C 2-6 (alkyl)alkynyl, C 3-8 (cycloalkyl)alkyl, 3-8 membered (hetero)cycloalkyl, C 6-10 (aryl)alkyl, and 5-10 membered (hetero)aryl, etc. If a substituent is described as "selected from the group consisting of" a list of functional groups, each substituent is selected independently from another. Thus, each substituent can be the same or different from another.

[0074] Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

[0075] It is also to be understood that certain compounds of the application can exist in free form for treatment, or as appropriate, in the form of a pharmaceutically acceptable derivative. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs of the compounds of the application which, upon administration to a patient in need thereof, are capable of providing (directly or indirectly) a compound of the application or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the application" is meant to encompass all such derivative forms, as well.

[0076] The term "pharmaceutically acceptable salt" means a salt of a compound of the application that is substantially non-toxic to the organism. Pharmaceutically acceptable salts of the compounds of the application include the acid addition and base salts thereof.

[0077] The term "pharmaceutically acceptable ester" means an ester of a compound of the application that is substantially non-toxic to the organism and that hydrolyzes in the organism's body to yield the compound of the application or its salt. In addition, the compound of the application itself can be the ester.

[0078] The term "isomer" means a compound having the same molecular formula but different physical properties, due to a difference in bonding or molecular orientation.

[0079] The term "stereoisomers" (or "optical isomers") refers to stable isomers having a fixed orientation of atoms in space, resulting from the presence of at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) that is capable of producing an optical rotation. Since the compounds of the present application can possess asymmetric centers and other chemical structures that can lead to stereoisomers, the present application also includes these stereoisomers and mixtures thereof. Since the compounds of the present application (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in single stereoisomer form, racemates, mixtures of enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in racemic form. However, if desired, pure stereoisomers can be prepared or isolated from such mixtures of compounds, either as single enantiomers or diastereomers, or as mixtures of single stereoisomers that are enriched (purity > 99%, > 98%, > 97%, > 96%, > 95%, > 90%, > 85%, > 80%, > 75%, > 70%, > 65%, or > 60%) in one stereoisomer. As described below, single stereoisomers of the compounds are prepared from optically pure starting materials that contain the desired chiral center, or are prepared by resolution of mixtures of enantiomeric products, for example, by separation of mixtures of diastereoisomers followed by separation or recrystallization, chromatography, using chiral resolving agents, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry can be obtained either commercially or by methods described below and resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are mirror images of each other and are not superimposable. The term "diastereomers" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture of equal amounts of single enantiomers (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture of unequal amounts of single enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present application are within the scope of the present application.

[0080] A solid line A solid wedge or a dashed wedge Carbon-carbon bonds of compounds of the application are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the depicted stereoisomer is present. Unless otherwise indicated, compounds of the present application are intended to include stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. Compounds of the present application can exhibit more than one type of isomerism, and are intended to encompass any and all stereoisomers.

[0081] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of polymorphs in any ratio.

[0082] The term "solvate" refers to a substance having been formed by the combination of a compound of the present application (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule by non-covalent intermolecular forces. The compounds of the present application can exist in solvate form, which includes a polar solvent as an integral part of the crystal lattice. The amount of polar solvent can be present in stoichiometric or non-stoichiometric amounts.

[0083] The term "isotopically-labeled" refers to a derivative compound formed by replacing a particular atom in a compound of the present application with an isotopic atom thereof. Unless otherwise indicated, the compounds of the present application include isotopes of H, C, N, O, F, P, S, CI, such as 2 H(D), 3 H(T), 13 C, 14 C, 13 N, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 34 S, 35 S, 36 S, 37 CI, and 125 I. For example, 12 C can be replaced by 13 C, or 14 C; 1 H can be replaced by2 H (D, deuterium) or 3 H (T, tritium) substitution; 16 O can be 18 O, etc.

[0084] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since nitrogen requires an available lone pair of electrons to oxidize to an oxide. One skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0085] The term "metabolite" refers to a derivative compound formed upon metabolism of a compound of the application, e.g., by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like. The present application encompasses all possible metabolite forms of a compound of the application, i.e., substances formed in vivo from a compound of the application after administration to a subject. Metabolites of a compound can be identified using well-known techniques, and their activity can be determined by testing.

[0086] The term "prodrug" refers to a derivative compound of a compound of the application which, upon administration to a subject, is capable of providing directly or indirectly a compound of the application. Particularly preferred derivative compounds or prodrugs are compounds which increase the bioavailability of a compound of the application when administered to a subject (e.g., are more readily absorbed into the blood), or which facilitate the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise specified, all prodrug forms of a compound of the application are within the scope of the present application, and various prodrug forms are known to the art, in addition, the present application encompasses compounds of the application containing protecting groups. During any of the processes for preparation of the compounds of the present application, protecting groups may

[0087] The compounds of the present application can optionally be substituted with suitable substituents at the various available positions, selected from: hydroxy, halogen, CN, NO2, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl.

[0088] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

[0089] The term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") as used herein refers to the amount of active ingredient which will achieve some desired effect, e.g., relief from one or more symptoms of the disorder being treated or prevention of the occurrence of the disorder or its symptoms.

[0090] The term "treatment" as used herein means reversing, alleviating, ameliorating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0091] The term "prevention" as used herein includes inhibition and delay of the onset of a disease, and includes not only prevention prior to development of a disease, but also prevention of recurrence of a disease after treatment.

[0092] "Individual" as used herein includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, domestic animals, and / or laboratory models (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0093] Compounds

[0094] In some embodiments, the present application provides a compound of Formula I:

[0095]

[0096] wherein,

[0097] Ring A1is selected from C 6-10 aryl and 5-10 membered heteroaryl; said aryl or heteroaryl is optionally substituted with one or more R3;

[0098] Ring A2is selected from C 6-10 aryl and 5-10 membered heteroaryl;

[0099] Ring Sp is selected from C 6-13 spirocyclyl and 6-13 membered heterospirocyclyl;

[0100] L1 is selected from covalent bonds, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NR b )-、-S(=NR b )2-、-N(R b )-、-N(R b )-C 1-6 Alkylene-, -N(R) b )-C(=O)-C 1-6 alkylene-, -C 1-6 Alkylene-N(R) b -C(=O)-、-N(R) b )-C(=O)-, -C(=O)-, -C(=O)-C 1-6 Alkylene-, C 1-6 Alkylene, -OC 1-6 alkylene-; the alkylene group is optionally surrounded by one or more R a replace;

[0101] Q is selected from hydroxyl, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, oxo (=O), C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl;

[0102] L2 is selected from covalent bonds, -O-, -S-, -S(O)-, -S(O)2-, -S(=O)(=NR b )-、-S(=NR b )2-、-N(R b )-、-N(R b )-C 1-6 Alkylene-, -N(R) b )-C(=O)-C 1-6 alkylene-, -C 1-6 Alkylene-N(R) b -C(=O)-、-N(R)b )-C(=O)-, -C(=O)-, -C(=O)-C 1-6 alkylene-, C 1-6 alkylene, -O-C 1-6 alkylene-; said alkylene is optionally substituted with one or more R a substituents;

[0103] R1and R2are each independently absent, or are each independently selected from H, hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , and -NR 23a C(=O)R 23b , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; or, said R1and R2together with the atom to which they are attached form a C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0104] R3is at each occurrence independently selected from hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21-S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C(=O)NR 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b and -NR 33a C(=O)R 33b ;

[0105] R4is at each occurrence independently selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C(=O)NR 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0106] R5is at each occurrence independently selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , C 3-8 ycloalkyl, C 3-8 ycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ;

[0107] R a is at each occurrence independently selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy; each of said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, and C1-6 alkoxy;

[0108] R b each independently selected at each occurrence from H, C 1-6 alkyl, C 3-8 cycloalkyl and 5-10 membered heterocyclyl; each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halo, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl and C 1-4 haloalkoxy;

[0109] R 20a , R 20b , R 23a , and R 23b each independently selected at each occurrence from H, OH, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl; or R 20a and R 20b , R 23a and R 23b or R 25a and R 25b together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl; each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halo, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl and C 1-4 haloalkoxy;

[0110] R 30a , R 30b , R 33a , and R 33b each independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0111] R 21 , R 22 , R 31 and R 32 each independently selected at each occurrence from C 1-6 alkyl, C 1-6 alkoxy, C 3-8cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl, each of which alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of OH, halo, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;

[0112] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0113] n is 0, 1, 2, 3, 4, or 5;

[0114] wherein:

[0115] (1) when L1is a covalent bond, L2is O, and Q is pyrazolyl, pyridinyl, or pyrazinyl, ring Sp is other than and,

[0116] (2) when L1is a covalent bond, L2is a covalent bond, R1and R2together with the atoms to which they are attached form a 6-membered nitrogen-containing heterocyclyl substituted with an acetyl group, and Q is pyrazolyl, ring Sp is other than

[0117] In some embodiments, the ring A1is selected from phenyl and 5-6 membered heteroaryl; preferably, the ring A1is selected from phenyl and 5-6 membered nitrogen-containing heteroaryl; further preferably, the ring A1is selected from phenyl and 6 membered nitrogen-containing heteroaryl; for example, the ring A1is phenyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

[0118] In some embodiments, R1and R2are each independently absent, or are each independently selected from H, hydroxyl, halo, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , C 3-8 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or, R1and R2together with the atom to which they are attached form a C 5-8cycloalkyl, 5-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=0)2R 32 , -C(=0)R 31 , -C(=0)NR 33a R 33b , and -NR 33a C(=0)R 33b .

[0119] In some embodiments, R1and R2are each independently absent, or each independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, -S(=0)2-C 1-6 alkyl, -C(=0)-C 1-6 alkyl, -C(=0)NH2, -C(=0)NH-C 1-6 alkyl, -NHC(=0)-C 1-6 alkyl, C 3-8 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or said R1and R2together with the atom to which they are attached form a C 5-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NH2, -NH-C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -S(=0)2C 1-6 alkyl, -C(=0)C 1-6 alkyl, -C(=0)NH2, -C(=0)NH-C 1-6 alkyl, and -NR 33a C(=0)C 1-6 alkyl.

[0120] In some embodiments, R1and R2are each independently absent, or each independently selected from H, halogen, CN, C1-4 alkyl, -S(=O)2-C 1-3 alkyl, -C(=O)-C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or, said R1and R2together with the atoms to which they are attached form a C 5-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from halo, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NH2, -NH-C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -S(=O)2C 1-6 alkyl, and -C(=O)C 1-6 alkyl.

[0121] In some embodiments, R1and R2are each independently absent, or each independently selected from H, halo, CN, C 1-4 alkyl, -S(=O)2-C 1-3 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl; or, said R1and R2together with the atoms to which they are attached form a 5-8 membered heterocyclyl, 5-6 membered heteroaryl; each of said alkyl, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted with one or more substituents selected from halo, CN, hydroxyl, oxo (=O), C 1-4 alkyl, and -C(=O)C 1-6 alkyl.

[0122] In some embodiments, R3is at each occurrence independently selected from hydroxyl, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

[0123] In some embodiments, L1is selected from a covalent bond, -O-, -S-, -S(O)-, -S(O)2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=O)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=O)-, -N(R b)-C(=O)-, -C(=O)-, -C(=O)-C 1-6 Alkylene-, C 1-6 Alkylene, -OC 1-6 alkylene-; the alkylene group is optionally surrounded by one or more R a replace.

[0124] In some implementations, L1 is selected from covalent bonds, -O-, -S-, -S(O)2-, -N(R)2- ...S(O)2-, -S(O)2-, -S(O)2-, -S(O)2-, -S(O)2-, - b )-、-N(R b -C(=O)-、-C(=O)-、C 1-6 Alkylene; the alkylene optionally contains one or more R a replace.

[0125] In some implementations, L1 is selected from covalent bonds, -O-, -S-, -S(O)2-, -N(R)2- ...S(O)2-, -S(O)2-, -S(O)2-, -S(O)2-, -S(O)2-, - b )-、-N(R b -C(=O)-、-C(=O)-、C 1-6 Alkylene.

[0126] In some implementations, L1 is selected from covalent bonds, -O-, -S-, -S(O)2-, -NH-, -NH-C(=O)-, -C(=O)-, C 1-6 Alkylene.

[0127] In some implementations, L1 is selected from covalent bonds, -O-, -S-, -NH-, and -NH-C(=O)-.

[0128] In some implementation schemes, R a Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups.

[0129] In some implementation schemes, R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl group; the alkyl group may optionally be substituted by one or more substituents selected from the following: OH, CN, halogen, C 1-4 Alkyl group.

[0130] In some implementation schemes, R b For H.

[0131] In some implementations, Q is selected from hydroxyl, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C6-12 aryl, 5-10 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO2, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl.

[0132] In some embodiments, Q is selected from the group consisting of hydroxy, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 alkoxy.

[0133] In some embodiments, Q is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 alkoxy.

[0134] In some embodiments, Q is selected from the group consisting of C 1-4 alkyl, 4-6 membered nitrogen-containing heterocyclyl, 4-6 membered oxygen-containing heterocyclyl, 5-6 membered nitrogen-containing heteroaryl, each of said alkyl, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 alkoxy.

[0135] In some embodiments, Q is selected from C 1-4 alkyl, 4-6 membered nitrogen-containing heterocyclyl, 4-6 membered oxygen-containing heterocyclyl, 5-6 membered nitrogen-containing heteroaryl, each of said alkyl, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from hydroxy, halogen, CN, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 alkoxy.

[0136] In some embodiments, the ring Sp is selected from 6 to 13 membered heterospirocyclyl; preferably, the ring Sp is selected from 6 to 11 membered heterospirocyclyl.

[0137] In some embodiments, the heterocyclyl in the heterospirocyclyl is one or two of a nitrogen atom, an oxygen atom or a sulfur atom, preferably a nitrogen atom.

[0138] In some embodiments, the number of heterocyclic atoms in the heterospirocyclyl is 1 to 4, preferably 1 to 2.

[0139] In some embodiments, the ring Sp is selected from 6-13 membered nitrogen-containing heterospirocyclyl; preferably, the number of nitrogen atoms in the nitrogen-containing heterospirocyclyl is 1 to 2.

[0140] In some embodiments, R4is at each occurrence independently selected from hydroxy, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

[0141] In some embodiments, the m is 0 or 1; preferably, the m is 0.

[0142] In some embodiments, the ring Sp is selected from the following groups:

[0143]

[0144] In some embodiments, L2is selected from a covalent bond, -0-, and C 1-6 alkylene, -0-C 1-6 alkylene-; said alkylene being optionally substituted with one or more R a substituents.

[0145] In some embodiments, L2is selected from a covalent bond, -0-, and C 1-6 alkylene, -0-C 1-6 alkylene-.

[0146] In some embodiments, R5is each independently at each occurrence selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, -NH2, -NHC 1-6 alkyl, and -O-C 1-6 alkyl.

[0147] In some embodiments, R5is halogen, such as F or CI.

[0148] In some embodiments, n is 0, 1 or 2; preferably, n is 1 or 2.

[0149] In some embodiments, the compound has a structure according to Formula II:

[0150]

[0151] wherein: Y1, Y2, Y3, Y4, Y5are each independently selected from the group consisting of: N, CH, and CR5; R1, R2, R4, R5, A1, L1, L2, Sp, and m are each independently as described in any one of the above.

[0152] In some embodiments, the compound has a structure according to Formula III:

[0153]

[0154] wherein: Y1, Y2, Y3, Y4, Y5, R1, R2, R4, R5, A1, L1, L2, Sp, and m are each independently as described in any one of the above.

[0155] In some embodiments, the compound of the present application is selected from the group consisting of:

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] In some embodiments, the compound of the present application is selected from:

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Methods of Preparation

[0176] In another aspect, the present application provides a method of preparing a compound of Formula I, said method employing the steps of:

[0177]

[0178] wherein each of ring A1, ring A2, ring Sp, Q, R1, R2, R4, R5, L1, L2, m and n is independently as described in any one of the above; and said is a nitrogen-containing C 6-13 spirocyclyl or 6-13 membered heterospirocyclyl; LG is a leaving group; for example, LG is F, Cl or Br, preferably, LG is Cl.

[0179] Synthetic Intermediates

[0180] In some embodiments, the present application also provides the following synthetic intermediates:

[0181]

[0182] Pharmaceutical Compositions, Formulations, and Kits

[0183] In some embodiments, the present application provides a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers, said pharmaceutically acceptable form being selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug.

[0184] It is a further object of the present application to provide a method of preparing a pharmaceutical composition of the present application, comprising combining a compound of the present application or a pharmaceutically acceptable form thereof or a mixture thereof, selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled, metabolite or prodrug, or one or more pharmaceutically acceptable carriers.

[0185] In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutical excipient.

[0186] In some embodiments, the pharmaceutically acceptable carrier comprises, but is not limited to, a sterile liquid.

[0187] The pharmaceutical composition can be administered in any form, as long as it achieves the prevention, alleviation, prevention or cure of the symptoms of a human or animal patient. For example, various suitable dosage forms can be prepared according to the route of administration.

[0188] When administered orally, the pharmaceutical composition can be prepared in any orally acceptable dosage form.

[0189] When administered transdermally or topically, the pharmaceutical composition can be prepared in the form of an appropriate ointment, lotion or liniment, in which the active ingredient can be suspended or dissolved in one or more carriers.

[0190] The pharmaceutical composition can also be administered in the form of an injection, including an injection solution, a sterile powder for injection and a concentrated solution for injection.

[0191] Another aspect of the present application also relates to a pharmaceutical preparation comprising a compound of the present application or a pharmaceutically acceptable form thereof or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present application, the pharmaceutically acceptable form thereof being selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled, metabolite or prodrug.

[0192] In some embodiments, the form of the preparation is a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.

[0193] A further object of the present invention is to provide an article of manufacture, for example, provided in the form of a medicine box. The article of manufacture as used herein is intended to include, but is not limited to, pharmaceutical compositions and packaging. For example, the article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, said pharmaceutically acceptable form being selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs; and (c) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat diseases or conditions for which GPR6 inhibitors are applicable, such as Parkinson's disease, levodopa-induced motor disorders, Huntington's disease, drug addiction, eating disorders, cognitive impairment, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety, and depression.

[0194] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0195] Methods of Treatment and Uses

[0196] The object of this invention is to provide the use of the compounds described herein or pharmaceutically acceptable forms thereof, or pharmaceutical compositions, or kit products, in the preparation of medicaments for the treatment and / or prevention of diseases or symptoms associated with GPR6 receptor activity; wherein the pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0197] Another object of the present invention is to provide the compounds described herein or pharmaceutically acceptable forms thereof, or pharmaceutical compositions, or kit products, for the treatment and / or prevention of diseases or symptoms associated with GPR6 receptor activity; said pharmaceutically acceptable forms are selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs.

[0198] Another object of the present application is to provide a method of treating and / or preventing a disease or condition associated with GPR6 receptor activity, comprising administering to an individual in need thereof an effective amount of a compound or a pharmaceutically acceptable form thereof, or a pharmaceutical composition, or a kit product of the present application; the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled, metabolite or prodrug.

[0199] Another object of the present application is to provide a method of treating and / or preventing a disease or condition associated with GPR6 receptor activity, comprising administering to an individual in need thereof an effective amount of a compound or a pharmaceutically acceptable form thereof, or a pharmaceutical composition, or a kit product of the present application; the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled, metabolite or prodrug.

[0200] In some embodiments, the disease or condition associated with GPR6 receptor activity includes, but is not limited to, a neoplastic or cancerous disease or condition.

[0201] In some embodiments, the disease or condition associated with GPR6 receptor activity is selected from the group consisting of Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorder, cognitive impairment, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety and depression.

[0202] Advantages

[0203] The present application provides a novel class of GPR6 receptor activity modulators, which can achieve at least one of the following technical effects:

[0204] (1) Significant modulation of GPR6 receptor activity.

[0205] (2) Excellent physicochemical properties (e.g. solubility, physical and / or chemical stability).

[0206] (3) Excellent pharmacokinetic properties (e.g. good bioavailability, appropriate half-life and duration of action).

[0207] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. DETAILED DESCRIPTION

[0208] The application is further described by the following examples, which are only used to illustrate the technical solutions of the application, and are not used to limit the scope of the application. Those skilled in the art can make some non-essential improvements and adjustments, which still belong to the protection scope of the application.

[0209] Unless otherwise specified, the examples were carried out under conventional conditions or under the conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used were conventional products that can be obtained commercially.

[0210] The abbreviations used herein have the following meanings:

[0211]

[0212] Synthetic Examples

[0213] Synthesis of intermediate Int-01:

[0214]

[0215] Step one: synthesis of compound Int-01-2

[0216] Compound Int-01-1 (10 g, 91.63 mmol, 1 eq.) was dissolved in diethyl oxalate (100 mL) at room temperature, heated to 100°C for 6 hours. Cooled to room temperature, filtered, collected the solid, washed with a mixture of ethyl acetate / ethanol=1 / 1 100 mL, then added 100 mL acetic acid to dissolve, heated to 80°C for 3 hours, slowly reduced to room temperature with stirring for 3 hours, filtered, and the solid obtained Int-01-2 (11.2 g, 68.65 mmol)

[0217] Step two: synthesis of compound Int-01

[0218] Int-01-2 (8.3 g, 50.88 mmol) was dissolved in POCl3(134.00 g, 873.92 mmol, 80 mL), and the temperature was raised to 65°C. N,N-dibutylformamide (DBF, 80 mL) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued for 3 hours. TLC showed that the starting material was completely converted. Ethyl acetate (80 mL) was slowly added dropwise, and the temperature was reduced to 20°C for stirring for 8 hours. Filtration gave intermediate compound Int-01 (8.8 g, 43.99 mmol).

[0219] 1 H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.73 (d, J = 6.6, 0.6 Hz, 1H), 7.90 (d, J = 6.6 Hz, 1H).

[0220] Synthesis of intermediate Int-02:

[0221]

[0222] Compound Int-01 (500 mg, 2.50 mmol), compound Int-02-1 (283.11 mg, 3.25 mmol), DIPEA (1.32 g, 10.25 mmol, 1.79 mL) were added into 1,4 dioxane (10 mL) and reacted at room temperature for 12 hours. TLC showed the reaction was complete; the reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by medium pressure flash chromatography to give compound Int-02 (107 mg, 426.83 µmol). MS (ESI): m / z = 251.1 [M+H] + .

[0223] Synthesis of intermediate Int-03

[0224]

[0225] Step one: Synthesis of compound Int-03-2.

[0226] Compound Int-03-1 (15 g, 86.22 mmol) was added into DMF (150 mL) under ice bath, then DIPEA (33.42 g, 258.63 mmol) and Int-02-1 (9 g, 103.47 mmol) were added and reacted for 2 hours. LCMS showed the starting material was completely converted. Diluted with H2O (150 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by medium pressure flash chromatography to give compound Int-03-2 (19.5 g, 77.04 mmol). MS (ESI): m / z = 242.1 [M+H] + .

[0227] Step two: Synthesis of compound Int-03-4.

[0228] Compound Int-03-2 (13 g, 57.35 mmol) was added to DMAc (130 mL) and H2O (13 mL) under nitrogen atmosphere, then compound Int-03-3 (25.93 g, 114.71 mmol), Pd(dppf)Cl2(12.59 g, 17.21 mmol) and cesium carbonate (56.56 g, 173.6 mmol) were added, and after being protected by nitrogen, the reaction was heated to 120 °C for 4 hours. LCMS showed that the starting material was completely converted. Diluted with H2O (150 mL), extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by medium pressure flash chromatography to give compound Int-03-4 (11 g, 37.89 mmol). MS (ESI): m / z = 288.7 [M+H] + .

[0229] Step three: synthesis of compound Int-03-5.

[0230] Int-03-4 (4 g, 13.78 mmol) was added to ethanol (60 mL), then palladium on carbon (4.00 g, 3.76 mmol, 10% purity) was added, and after hydrogen replacement, the reaction was stirred at room temperature for 12 hours. TLC showed that the starting material was completely converted. The reaction solution was diluted with methanol and filtered through diatomite to give a crude product, which was purified by medium pressure flash chromatography to give compound Int-03-5 (2.4 g, 8.21 mmol). MS (ESI): m / z = 291.1 [M+H] + .

[0231] Step four: synthesis of compound Int-03-6.

[0232] Compound Int-03-5 (2.4 g, 8.21 mmol) was added to methanol (50 mL), then Raney nickel (0.5 g, 8.52 mmol) was added, and after hydrogen replacement, the reaction was heated to 60 °C under a pressure of 15 Psi for 4 hours. LCMS showed that the starting material was completely converted. The reaction solution was diluted with methanol and filtered through diatomite to give a crude product, which was purified by medium pressure flash chromatography to give compound Int-03-6 (1.8 g, 7.25 mmol). MS (ESI): m / z = 395.3 [M+H] + .

[0233] Step five: synthesis of compound Int-03

[0234] Dissolve compound Int-03-6 (1.8 g, 7.25 mmol) in CHCl3(18 mL), then add NBS (1.23 g, 6.89 mmol), and react at room temperature for 1 hour. LCMS shows that the starting material is completely converted. Dilute with H2O (150 mL), and extract with ethyl acetate (30 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous Na2SO4, filter, and concentrate to give a crude product. Purify the crude product by medium pressure flash chromatography to give compound (6 g, 6.11 mmol). MS (ESI): m / z = 327.1 [M+H] + .

[0235] Example 1: Synthesis of compound 61A

[0236]

[0237] Step one: Synthesis of compound 1-03

[0238] Dissolve 1-01 (500 mg, 2.35 mmol), 2,4-difluorophenol (366.7 mg, 2.82 mmol, ), PPh3 (739.7 mg, 2.82 mmol) in THF (5 mL) under nitrogen atmosphere, and slowly drop DIAD (570.2 mg, 2.82 mmol) while stirring and cooling to 0 °C. React at 0 °C for 1 hour, then at room temperature for 12 hours. TLC shows that the starting material is completely converted. Quench the reaction with water, and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous Na2SO4, filter, and concentrate to give a crude product. Purify the crude product by medium pressure flash chromatography to give compound 1-03 (1.1 g). MS (ESI): m / z = 326.2 [M+H] +

[0239] Step two: Synthesis of compound 1-04

[0240] Dissolve 1-03 (1.1 g) in DCM (10 mL) under ice bath, then add TFA (4 mL), and react at room temperature for 2 hours. LCMS shows that the starting material is completely converted. Adjust the reaction mixture to neutral pH with NaHCO3solution, dilute with H2O (50 mL), and extract with ethyl acetate (30 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous Na2SO4, filter, and concentrate to give crude product 1-04 (1.2 g, crude). MS (ESI): m / z = 226.2 [M+H] +

[0241] Step three: Synthesis of compound 1-05

[0242] Int-01 (0.8 g, 4.26 mmol), 1-04 (1.2 g, 5.33 mmol), TEA (1.62 g, 15.98 mmol) were dissolved in DMAc (10 mL), cooled to -5 °C in ice-salt bath, and reacted for 2 hours. LCMS showed that the starting material was completely converted. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by medium pressure flash chromatography to give compound 1-05 (620 mg, 1.59 mmol). MS (ESI): m / z = 389.2 [M+H] +

[0243] Step four: synthesis of compound 61A

[0244] Compound 1-05 (620 mg, 1.59 mmol), (R)-3-amino furan (166.71 mg, 1.91 mmol), KF (92.64 mg, 1.59 mmol), TEA (645.47 mg, 6.38 mmol) were dissolved in DMSO (10 mL), warmed to 65 °C and reacted for 12 hours. LCMS showed that the starting material was completely converted. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by reverse phase preparation to give compound 61A (600 mg, 1.37 mmol). MS (ESI): m / z = 440.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.42 - 7.23 (m, 2H), 7.12 - 6.94 (m, 2H), 6.52 (d, J = 5.4 Hz, 1H), 4.78 - 4.66 (m, 1H), 4.57 - 4.49 (m, 1H), 4.40 (s, 2H), 4.33 (s, 2H), 3.99 (dd, J = 8.8, 6.4 Hz, 1H), 3.92 - 3.81 (m, 1H), 3.79 - 3.71 (m, 1H), 3.64 (dd, J = 8.8, 4.4 Hz, 1H), 2.85 - 2.71 (m, 2H), 2.37 - 2.27 (m, 2H), 2.28 - 2.14 (m, 1H), 2.03 - 1.92 (m, 1H).

[0245] Example 2: synthesis of compound 64A

[0246]

[0247] Step one: synthesis of compound 2-01

[0248] Compound 61 (150 mg, 0.34 mmol), benzyl bromide (175 mg, 1 mmol) were dissolved in acetone (1.00 mL), after nitrogen protection, the mixture was reacted at 60 °C for 3 hours. After removing acetone by concentration, the crude product was obtained, and the crude product was purified by medium pressure flash chromatography to obtain compound 2-01 (160 mg, 301.55 μmol,). MS (ESI): m / z = 530.2 [M+H] +

[0249] Step two: synthesis of compound 2-02

[0250] Compound 2-01 (160 mg, 301.55 μmol) was dissolved in DCM (3 mL), and sodium triacetoxyborohydride (383.47 mg, 1.81 mmol) was added under nitrogen protection. The mixture was reacted at room temperature for 12 hours, and LCMS showed that the starting material was completely converted. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product 2-02 (165 mg, crude), MS (ESI): m / z = 534.2 [M+H] +

[0251] Step three: synthesis of compound 2-03

[0252] Compound 2-02 (50 mg, 93.70 μmol) and palladium on carbon (20 mg, 187.93 μmol) were added to methanol (8 mL) at room temperature, and the mixture was reacted for 12 hours after hydrogen replacement. LCMS showed that the starting material was completely converted. Filtration and concentration of the filtrate obtained the crude product 2-03 (30 mg, crude). MS (ESI): m / z = 444.2 [M+H] +

[0253] Step four: synthesis of compound 64A

[0254] Compound 2-03 (30 mg) was dissolved in THF (1 mL), and acetic anhydride (6.91 mg, 67.65 μmol) was added. The reaction was completed after 1 hour, LCMS showed that the reaction was completed. Diluted with H2O (10 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product. The crude product was purified by reversed phase preparation to obtain compound 64A (0.8 mg, 1.65 μmol). MS (ESI): m / z = 486.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 6.90 - 6.81 (m, 2H), 6.77 - 6.71 (m, 1H), 4.62 - 4.54 (m, 1H), 4.40 (s, 2H), 4.39 - 4.32 (m, 1H), 4.06 - 3.82 (m, 7H), 3.77 - 3.65 (m, 3H), 3.60 - 3.53 (m, 1H), 2.72 - 2.62 (m, 3H), 2.59 (t, J = 6.0 Hz, 1H), 2.30 - 2.23 (m, 2H), 2.22 - 2.14 (m, 1H), 2.09 (s, 3H), 1.91 - 1.79 (m, 1H).

[0255] Example 3: Synthesis of compound 1A

[0256]

[0257] Compound Int-02 (30 mg, 119.67 μmol), compound 1-04 (32.35 mg, 143.61 μmol) and DIPEA (46.40 mg, 359.02 μmol) were dissolved in 1,4 dioxane (1 mL), warmed to 80 °C for 8 hours. LCMS showed the starting material was completely converted, extracted with water (10 mL) and ethyl acetate (10 mL*3), combined organic phase, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to get the crude product, which was prepared by reversed phase to get compound 1A (23.5 mg, 51.78 μmol). MS (ESI): m / z = 440.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.10 - 6.97 (m, 2H), 6.84 (d, J = 5.8 Hz, 1H), 4.78 - 4.68 (m, 1H), 4.64 - 4.55 (m, 1H), 4.32 (s, 2H), 4.26 (s, 2H), 3.97 (dd, J = 8.8, 6.4 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.75 (td, J = 8.0, 6.0 Hz, 1H), 3.65 (dd, J = 8.8, 4.4 Hz, 1H), 2.82 - 2.74 (m, 2H), 2.37 - 2.28 (m, 2H), 2.27 - 2.16 (m, 1H), 2.08 - 1.96 (m, 1H).

[0258] Example 4: Synthesis of compound 65

[0259]

[0260] Step 1: synthesis of compound 4-02

[0261] Sodium hydride (12.60 mg, 524.94 μmol) was added into a three-necked flask under nitrogen protection, THF (1 mL) was added to cool to 0 °C, isopropyl alcohol (31.55 mg, 524.94 μmol) was added, and the mixture was reacted at 0 °C for 0.5 h. Compound Int-01 (100 mg, 499.94 μmol) was added and the mixture was reacted for 1 h. LCMS was used to monitor the reaction. H2O (20 mL) was added for dilution, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by a medium-pressure flash chromatograph to obtain compound 4-02 (15 mg, 67.07 μmol). MS (ESI): m / z = 224.2 [M+H] +

[0262] Step 2: synthesis of compound 65

[0263] Compound 4-02 (10 mg, 44.71 μmol) was added into 1,4-dioxane (1 mL), DIPEA (18 mg, 135 μmol), and compound 1-04 (12.08 mg, 53.65 μmol) was added. The mixture was warmed to 80 °C and reacted for 12 h. LCMS was used to monitor the reaction. H2O (20 mL) was added for dilution, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by a reversed-phase preparation to obtain compound 65 (4.9 mg, 11.81 μmol). MS (ESI): m / z = 413.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.36 (s, 1H), 7.58-7.43 (m, 1H), 6.91-6.83 (m, 1H), 6.82-6.75 (m, 2H), 5.59-5.49 (m, 1H), 4.68-4.59 (m, 1H), 4.68-4.59 (m, 4H), 2.83-2.73 (m, 2H), 2.56-2.45 (m, 2H), 1.45 (d, J = 6.2 Hz, 6H).

[0264] Example 5: synthesis of compound 62A

[0265]

[0266] Step 1: synthesis of compound 5-02

[0267] Compound 5-01 (500 mg, 2.35 mmol), 2,4-difluorobenzaldehyde (394 mg, 2.77 mmol), TEA (755.59 mg, 7.57 mmol) were dissolved in DCM (5 mL) under nitrogen atmosphere, the reaction was carried out for 30 min, sodium borohydride (1.6 g, 7.57 mmol, 3 eq.) was added slowly, the reaction was continued for 12 h. TLC monitoring showed that the reaction was complete. Diluted with H2O, extracted with ethyl acetate, combined organic phase, washed with saturated brine, dried over anhydrous Na2SO4, filtered the organic phase and concentrated under reduced pressure to obtain the crude product. The crude product was purified by medium pressure flash chromatography to obtain compound 5-02 (1.1 g). MS (ESI): m / z = 325.2 [M+H] +

[0268] Step two: synthesis of compound 5-03

[0269] Compound 5-02 (1.1 g) was dissolved in DCM (10 mL) under ice bath, TFA (4 mL) was added, and the reaction was carried out at room temperature for 2 h, LCMS showed that the starting material was completely converted. The reaction mixture was adjusted to neutral pH with saturated NaHCO3 solution, diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered the organic phase and concentrated under reduced pressure to obtain the crude compound 5-03 (1.0 g, crude). MS (ESI): m / z = 225.2 [M+H] +

[0270] Step three: synthesis of compound 5-04

[0271] Intermediate Int-01 (0.8 g, 4.00 mmol), crude compound 5-03 (1 g, crude), TEA (1.21 g, 12 mmol) were dissolved in DMAc (10 mL), cooled to -5 °C in ice-salt bath for 2 h, LCMS showed that the reaction was complete. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered the organic phase and concentrated under reduced pressure to obtain the crude product, which was purified by medium pressure flash chromatography to obtain compound 5-04 (300 mg, 3.84 mmol). MS (ESI): m / z = 388.2 [M+H] +

[0272] Step four: synthesis of compound 62A

[0273] Compound 5-04 (300 mg, 3.84 mmol), Int-02-1 (80.87 mg, 0.928 mmol), KF (44.94 mg, 0.773 mmol) and TEA (1.21 g, 12 mmol) were dissolved in DMSO (10 mL), and the mixture was warmed to 65 °C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by reverse phase preparative purification to give compound 62A (260 mg, 592.95 µmol). MS (ESI): m / z = 439.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.34 (d, J = 5.4 Hz, 1H), 7.23 – 7.16 (m, 1H), 7.06 (td, J = 8.4, 2.0 Hz, 1H), 6.49 (d, J = 5.4 Hz, 1H), 4.57 – 4.49 (m, 1H), 4.39 (s, 4H), 3.98 (dd, J = 8.8, 6.2 Hz, 1H), 3.90 – 3.83 (m, 1H), 3.75 (td, J = 8.0, 5.8 Hz, 1H), 3.63 (dd, J = 8.8, 4.4 Hz, 1H), 3.54 (s, 2H), 3.35 (s, 4H), 2.28 – 2.16 (m, 1H), 2.04 – 1.93 (m, 1H).

[0274] Example 6: Synthesis of compound 63A

[0275]

[0276] Compound 63A can be obtained according to the above synthetic route by referring to the synthetic method of Example 5.

[0277] MS (ESI): m / z = 467.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.20 (d, J = 5.4 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.29 (d, J = 5.4 Hz, 1H), 7.24 - 7.12 (m, 1H), 7.05 (dd, J = 8.4, 7.4 Hz, 1H), 6.61 (d, J = 5.2 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.05 - 3.96 (m, 1H), 3.91 - 3.83 (m, 1H), 3.81 - 3.71 (m, 3H), 3.70 - 3.56 (m, 5H), 2.66 - 2.60 (m, 1H), 2.55 (d, J = 9.2 Hz, 2H), 2.48 - 2.41 (m, 1H), 2.30 - 2.18 (m, 1H), 2.05 - 1.96 (m, 1H), 1.94 - 1.73 (m, 4H).

[0278] Example 7: Synthesis of compound 12A

[0279]

[0280] Step one: Synthesis of compound 7-01

[0281] Compound 6-01 (200 mg, 883.73 μmol), 1-bromo-2,4-difluoro-benzene (204.66 mg, 1.06 mmol, 119.82 μL), sodium tert-butoxide (254.79 mg, 2.65 mmol), 1,1'-binaphthalene-2,2'-diphenylphosphine (BINAP) (110.06 mg, 176.75 μmol), and tris(dibenzylideneacetone)dipalladium (80.92 mg, 88.37 μmol) were added into DMF (2 mL) under nitrogen protection, heated to 85 °C for 12 hours. LCMS showed the reaction was complete. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by medium pressure flash chromatography to give compound 7-01 (270 mg, 797.89 μmol). MS (ESI): m / z = 339.2 [M+H] +

[0282] Step two: Synthesis of compound 7-02

[0283] Referring to the reaction conditions of Example 5, step two, compound 7-02 (35 mg, crude) was obtained. MS (ESI): m / z = 239.1 [M+H] +

[0284] Step three: Synthesis of compound 12A

[0285] Reference to the reaction conditions of Example 4, Step two, compound 12A (4.9 mg, 10.83 μmol) was obtained. MS (ESI): m / z = 453.2 [M+H] + . 1 H NMR (400 MHz, MeOD) d 8.68 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 6.89 - 6.69 (m, 3H), 4.76 - 4.69 (m, 1H), 4.10 - 4.05 (m, 1H), 4.04 - 3.97 (m, 1H), 3.91 - 3.79 (m, 4H), 3.76 - 3.66 (m, 2H), 3.50 - 3.43 (m, 2H), 3.40 - 3.32 (m, 2H), 2.46 - 2.32 (m, 1H), 2.15 - 2.00 (m, 5H).

[0286] Example 8: Synthesis of compound 5A

[0287]

[0288] Step one: Synthesis of compound 8-02

[0289] Under nitrogen atmosphere, 2,4-difluorobromobenzene (300 mg, 1.55 mmol) was dissolved in THF (3 mL), cooled to -78 °C with dry ice bath, 1.6 M n-butyllithium solution (1.07 mL, 1.71 mmol) was added dropwise slowly, after the addition was completed, the temperature was maintained for 30 minutes, then compound 8-01 (409.21 mg, 1.71 mmol) was added slowly, the reaction was carried out for 1 hour, LCMS showed that the starting material was completely converted. Diluted with saturated NH4Cl solution (50 mL), extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine, dried over anhydrous Na2SO4, the organic phase was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by medium pressure flash chromatography to obtain compound 8-02 (400 mg, 1.13 mmol). MS (ESI): m / z = 354.2 [M+H] +

[0290] Step two: Synthesis of compound 8-03

[0291] Dissolve 8-02 (670 mg, 1.90 mmol) in DCM (3 mL) under ice bath, add trifluoroacetic acid (3.87 g, 33.96 mmol, 2.62 mL) and triethylsilane (3.95 g, 33.96 mmol, 5.42 mL), warm up to 40 °C for 12 hours, LCMS shows the starting material is completely converted. Dilute with H2O (50 mL), extract with ethyl acetate (30 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous Na2SO4, filter the organic phase and concentrate under reduced pressure to give the crude compound 8-03 (500 mg, crude). MS (ESI): m / z = 236.2 [M+H] +

[0292] Step three: synthesis of compound 8-04

[0293] Dissolve 8-03 (500 mg, 2.13 mmol) in methanol (1 mL) under nitrogen protection, add platinum dioxide (40.00 mg, 176.15 μmol), replace with hydrogen for 3 times, react at room temperature under 15 Psi for 18 hours, LCMS shows the starting material is completely converted. Dilute with MeOH (20 mL) and filter with celite to give the crude product, purify the crude product on a flash chromatograph to give compound 8-04 (300 mg, 252.86 μmol, 59.49% yield). MS (ESI): m / z = 238.2 [M+H] +

[0294] Step four: synthesis of compound 5A

[0295] Dissolve compound Int-02 (100 mg, 398.91 μmol), compound 8-04 (94.66 mg, 398.91 μmol), DIPEA (51.56 mg, 398.91 μmol) in 1,4-dioxane (1 mL), warm up to 80 °C for 12 hours, LCMS shows the starting material is completely converted. Dilute with H2O (50 mL), extract with ethyl acetate (30 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous Na2SO4, filter the organic phase and concentrate under reduced pressure to give the crude product. Purify the crude product on a reverse phase preparative column to give compound 5A (56.7 mg, 125.17 μmol). MS (ESI): m / z = 452.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.40 - 7.10 (m, 3H), 7.05 (t, J = 8.7 Hz, 1H), 6.80 - 6.70 (m, 1H), 4.68 - 4.58 (m, 1H), 4.09 (s, 2H), 4.04 - 3.94 (m, 3H), 3.93 - 3.84 (m, 1H), 3.82 - 3.70 (m, 1H), 3.67 (dd, J = 8.8, 4.4 Hz, 1H), 2.99 - 2.73 (m, 1H), 2.30 - 2.18 (m, 1H), 2.13 - 1.97 (m, 3H), 1.92 - 1.77 (m, 1H), 1.76 - 1.47 (m, 5H).

[0296] Example 9: Synthesis of compound 9A

[0297]

[0298] Referring to the synthesis method of compound 5A in Example 8, compound 9A (35.8 mg, 81.83 μmol) was obtained according to the above synthesis route. MS (ESI): m / z = 438.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.22 (s, 1H), 7.36 - 7.23 (m, 2H), 7.09 - 6.99 (m, 2H), 6.97 - 6.91 (m, 1H), 4.66 - 4.55 (m, 1H), 4.04 - 3.95 (m, 1H), 3.94 - 3.84 (m, 1H), 3.84 - 3.64 (m, 6H), 3.61 (s, 1H), 2.47 - 2.35 (m, 4H), 2.29 - 2.17 (m, 1H), 2.15 - 2.00 (m, 2H), 1.94 (t, J = 6.8 Hz, 1H).

[0299] Example 10: Synthesis of compound 69A

[0300]

[0301] Step one: Synthesis of compound 10-02

[0302] Compound 10-01 (2 g, 13.42 mmol), (R)-3-aminotetrahydrofuran hydrochloride (1.17 g, 9.46 mmol) and DIPEA (5.21 g, 40.27 mmol) were dissolved in DMF (5 mL) at room temperature, and the mixture was heated to 70 °C for 12 h. LCMS showed that the starting material was completely converted. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase medium pressure flash chromatography to give compound 10-02 (600 mg, 3.01 mmol). MS (ESI): m / z = 200.0 [M+H] +

[0303] Step two: synthesis of compound 69A

[0304] Compound 10-02 (100 mg, 500.91 µmol), compound 8-04 (111.83 mg, 500.91 µmol) were dissolved in DMF (2 mL) under nitrogen atmosphere, and cesium carbonate (163.21 mg, 500.91 µmol) was added. The mixture was heated to 80 °C for 12 h. LCMS showed that the starting material was completely converted. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase preparative purification to give compound 69A (11.8 mg, 29.73 µmol). MS (ESI): m / z = 401.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 3.0 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.34 – 7.21 (m, 2H), 7.20 – 7.09 (m, 1H), 7.04 (t, J = 8.8 Hz, 1H), 5.67 – 5.56 (m, 1H), 4.42 – 4.33 (m, 1H), 3.96 – 3.79 (m, 4H), 3.77 – 3.65 (m, 3H), 3.57 (dd, J = 8.8, 4.4 Hz, 1H), 2.22 – 2.10 (m, 1H), 2.08 – 1.98 (m, 2H), 1.97 – 1.89 (m, 1H), 1.89 – 1.76 (m, 1H), 1.75 – 1.45 (m, 5H).

[0305] Example 11: synthesis of compound 24A

[0306]

[0307] Compound 24A (11.8 mg, 29.73 μmol) was obtained according to the synthetic method of Reference Example 10, Step two. MS (ESI): m / z = 387.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (dd, J = 10.8, 3.0 Hz, 1H), 7.35 (dd, J = 9.6, 3.0 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.09 - 6.97 (m, 2H), 5.76 (t, J = 5.3 Hz, 1H), 4.42 - 4.30 (m, 1H), 3.96 - 3.80 (m, 2H), 3.80 - 3.67 (m, 2H), 3.64 - 3.55 (m, 2H), 3.54 - 3.45 (m, 1H), 3.45 - 3.38 (m, 2H), 2.45 - 2.29 (m, 4H), 2.23 - 2.12 (m, 1H), 2.11 - 2.03 (m, 1H), 2.01 - 1.86 (m, 2H).

[0308] Example 12: Synthesis of compound 66A

[0309]

[0310] Int-03 (68.94 mg, 210.71 μmol), 8-04 (60 mg, 252.86 μmol) were dissolved in DMF (1 mL), cesium carbonate (205.96 mg, 632.14 μmol) was added, and the mixture was heated to 130 °C in a microwave reactor for 1 h. LCMS showed the starting material was completely converted. Diluted with H2O (50 mL), extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase preparative purification to give compound 66A (26.4 mg, 54.60 μmol). MS (ESI): m / z = 484.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 5.5 Hz, 1H), 7.39 - 7.09 (m, 2H), 7.04 (t, J = 8.8 Hz, 1H), 5.68 - 5.52 (m, 1H), 4.41 - 4.30 (m, 1H), 4.23 - 4.09 (m, 2H), 3.95 - 3.76 (m, 4H), 3.75 - 3.64 (m, 3H), 3.51 (dd, J = 8.8, 4.8 Hz, 1H), 2.99 - 2.73 (m, 3H), 2.74 - 2.59 (m, 2H), 2.21 - 2.08 (m, 1H), 2.00 (d, J = 12.0 Hz, 2H), 1.97 - 1.75 (m, 2H), 1.70 - 1.45 (m, 5H).

[0311] Example 13: Synthesis of compound 67A

[0312]

[0313] Referring to the synthesis method of Reference Example 12, compound 67A (7.6 mg, 16.19 μmol) was obtained. MS (ESI): m / z = 470.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.85 (m, 1H), 7.34 - 7.22 (m, 1H), 7.03 (t, J = 8.1 Hz, 2H), 5.80 - 5.69 (m, 1H), 4.40 - 4.27 (m, 1H), 4.21 - 4.08 (m, 2H), 3.96 - 3.43 (m, 4H), 3.55 - 3.43 (m, 4H), 2.91 - 2.79 (m, 2H), 2.73 - 2.59 (m, 2H), 2.42 - 2.30 (m, 4H), 2.25 - 2.10 (m, 2H), 2.09 - 2.00 (m, 1H), 1.98 - 1.82 (m, 2H).

[0314] Example 14: Synthesis of compound 73A

[0315]

[0316] Compound Int-03 (50 mg, 176.85 umol) and compound 1-04 (47.80 mg, 212.22 umol), cesium carbonate (69.15 mg, 212.22 umol) were dissolved in DMF (1 mL) and warmed to 130 °C for 3 h under nitrogen atmosphere in a microwave. LCMS showed complete conversion of starting material, the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get a residue. The residue was purified by Prep-HPLC to get compound 73A (29.4 mg, 62.35 umol). MS (ESI): m / z = 472.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 5.6 Hz, 1H), 7.33 - 7.24 (m, 1H), 7.09 - 6.95 (m, 2H), 5.68 (d, J = 5.8 Hz, 1H), 4.75 - 4.65 (m, 1H), 4.38 - 4.28 (m, 1H), 4.22 - 4.10 (m, 2H), 4.07 - 4.00 (m, 2H), 4.00 - 3.93 (m, 2H), 3.89 (dd, J = 8.8, 6.2 Hz, 1H), 3.85 - 3.78 (m, 1H), 3.70 (td, J = 7.8, 6.0 Hz, 1H), 3.49 (dd, J = 8.8, 4.8 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.78 - 2.69 (m, 2H), 2.68 - 2.61 (m, 2H), 2.31 - 2.22 (m, 2H), 2.18 - 2.06 (m, 1H), 1.96 - 1.84 (m, 1H).

[0317] Example 15: Synthesis of compound 75A

[0318]

[0319] Step one: Synthesis of compound 15-02

[0320] Compound 15-01 (3 g, 21.11 mmol) was dissolved in 30 mL of methanol, TosNHNH2 (3.39 g, 21.11 mmol) was added, stirred at room temperature for 1 hour. Solid precipitated, filtered, the solid was washed with methanol three times, dried to get compound 15-02 (6.5 g, 20.95 mmol).

[0321] Step two: Synthesis of compound 15-04

[0322] Compound 15-02 (2 g, 6.44 mmol) was dissolved in 20 mL of dichloromethane, sodium hydride (356 mg, 15.47 mmol) was added under ice bath, after stirring at room temperature for 1 hour, silver trifluoromethanesulfonate (414 mg, 1.61 mmol) and compound 15-03 (1.3 g, 7.73 mmol) were added under nitrogen protection, and the reaction was heated to 40°C for 12 hours under nitrogen protection. The reaction was monitored by LCMS to be complete, extracted with dichloromethane, and the organic phase was dried and evaporated. The residue was purified by normal phase column chromatography to obtain the target compound 15-04 (530 mg, 1.79 mmol). MS (ESI): m / z = 296.1 [M+H] + .

[0323] Step three: synthesis of compound 15-05

[0324] Compound 15-04 (530 mg, 1.79 mmol) was dissolved in 6 mL of dichloromethane, 2 ml of trifluoroacetic acid was added, and stirred at room temperature for 1 hour. The reaction was monitored by LCMS to be complete, the pH was adjusted to about 10 with aqueous sodium hydroxide solution, extracted with dichloromethane, and the organic phase was dried to obtain the crude compound 15-05 (110 mg, 564 μmol).

[0325] Step four: synthesis of compound 75A

[0326] Compound 15-05 (50 mg, 256 μmol) was dissolved in 1 mL of 1,4-dioxane, Int-03 (93 mg, 281.7 μmol), Ruphos (12 mg, 25.6 μmol), Ruphos Pd G3 (22 mg, 25.6 μmol), cesium carbonate (167 mg, 512 μmol) were added in turn, replaced with nitrogen for three times, heated to 100°C for 12 hours. LCMS monitoring showed that the product was generated, cooled to room temperature, filtered with diatomite, and the crude product was purified by Prep-HPLC to obtain compound 75A (4.5 mg, 10.2 μmol), MS (ESI): m / z = 442.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 7.85 (t, J = 5.4 Hz, 1H), 7.58 - 7.42 (m, 1H), 7.21 - 7.05 (m, 1H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 6.18 (d, J = 5.8 Hz, 1H), 5.34 (t, J = 7.6 Hz, 1H), 5.04 - 4.98 (m, 2H), 4.69 (d, J = 14.0 Hz, 1H), 4.45 - 4.27 (m, 1H), 4.16 - 4.04 (m, 1H), 4.02 - 3.80 (m, 3H), 3.78 - 3.66 (m, 1H), 3.61 - 3.45 (m, 2H), 3.00 (dd, J = 15.2, 7.0 Hz, 1H), 2.90 - 2.72 (m, 2H), 2.66 - 2.56 (m, 2H), 2.48 - 2.39 (m, 1H), 2.23 - 2.09 (m, 1H), 1.99 - 1.85 (m, 1H).

[0327] Referring to the synthetic method of Example 15, the following compounds can be synthesized:

[0328]

[0329]

[0330] Other compounds of the present application can also be prepared by referring to the above synthetic methods.

[0331] Biological Tests

[0332] Experimental Example 1: In vitro activity evaluation of compounds for GPR6 inverse agonism

[0333] In this study, a HEK-293T cell line stably expressing GPR6 receptor (purchased from ATCC) was used. After stimulation with different concentrations of test compounds, the inverse agonism of the compounds on the GPR6 receptor was determined by Ultra cAMP Kit kit.

[0334] The GPR6 stable expressing HEK-293T cell line was cultured in DMEM medium containing 10% fetal bovine serum and 5 μg / ml Doxycycline, at 37 °C and 5% CO2. The compounds were diluted with DMSO to 2x final concentration stock solutions, and 5 uL of each was added to a 384-well plate. The stable cell line was cultured to 80% confluence, and the cells were collected by trypsinization and counted. Then 5 uL of the cells were seeded into a 384-well plate and incubated at 37 °C for 40 min. The Eu-cAMP was diluted with Detection buffer to working concentration, and 5 uL of the solution was added to the corresponding wells. The ULight TM The anti-cAMP antibody was diluted with Detection buffer to working concentration, and 5 uL of the solution was added to the corresponding wells. After centrifugation, the plate was incubated at room temperature for 1 h. After incubation, the plate was detected by a microplate reader at 320 nm excitation and 665 nm and 620 nm emission. The EC 50 : Y = Bottom + (Top-Bottom) / (1+10^((LogEC 50 X)*HillSlope)), where Y is the GPR6 receptor activity corresponding to the compound concentration, Top and Bottom are the maximum and minimum values of the fitted curve, X is the logarithmic concentration of the compound, and HillSlope is the slope of the curve. The test results are shown in Table 1.

[0335] Table 1 Inverse agonist activity of the compounds of the present application on GPR6 receptor

[0336] Compound Number Example Number EC 50 (nM) 1A 3 1～850 65 4 1～2300 64A 2 1～2300 9A 9 1～3000 67A 13 1～1500

[0337] The experimental results show that the compounds of the present application exhibit good inverse agonist activity on GPR6 receptor.

[0338] The methods and products of the present application have been described by preferred embodiments, and the related skilled person can obviously make modifications or appropriate changes and combinations to the methods and products described herein without departing from the content, spirit and scope of the present application, to realize the technology of the present application. It is particularly pointed out that all similar substitutions and modifications are obvious to the skilled person, and they are considered to be included in the spirit, scope and content of the present application.

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof: in, Ring A1is selected from C 6-10 aryl and 5-10 membered heteroaryl; said aryl or heteroaryl is optionally substituted with one or more R3; Ring A2is selected from C 6-10 aryl and 5-10 membered heteroaryl; Ring Sp is selected from C 6-13 spirocyclyl and 6-13 membered heterospirocyclyl; L1is selected from a covalent bond, -0-, -S-, -S(O)-, -S(0)2-, -S(=0)(=NR b )-, -S(=NR b )2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=0)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=0)-, -N(R b )-C(=0)-, -C(=0)-, -C(=0)-C 1-6 alkylene-, C 1-6 alkylene, -0-C 1-6 alkylene-; said alkylene groups being optionally substituted by one or more R a groups; Q is selected from the group consisting of hydroxy, halogen, CN, NO2, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO2, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; L2is selected from a covalent bond, -0-, -S-, -S(O)-, -S(0)2-, -S(=0)(=NR b )-, -S(=NR b )2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=0)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=0)-, -N(R b )-C(=0)-, -C(=0)-, -C(=0)-C 1-6 alkylene-, C 1-6 alkylene, -0-C 1-6 alkylene-; said alkylene groups being optionally substituted by one or more R a groups; R1and R2are each independently absent, or are each independently selected from H, hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , and -NR 23a C(=O)R 23b ; C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; or, said R1and R2together with the atom to which they are attached form a C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ; R3 is independently selected from hydroxyl, halogen, CN, and C each time it appears. 1-6 Alkyl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 membered heteroaryl; the alkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: halogen, CN, hydroxyl, oxo (=O), C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -C(=O)R 31 -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ; R4is each independently at each occurrence selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ; R5is each independently at each occurrence selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -SR 21 , -S(=O)R 22 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , C 3-8 ycloalkyl, C 3-8 ycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; each of said alkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, oxo (=O), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)R 32 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ; R a each independently at each occurrence is selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy; each of said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, hydroxyl, and C 1-6 alkoxy; R b at each occurrence, is independently selected from the group consisting of H, C 1-6 alkyl, C 3-8 cycloalkyl, and 5-10 membered heterocyclyl; each of said alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halo, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 20a , R 20b , R 23a , and R 23b are each independently selected from H, OH, C 1-6 alkyl, C 1-6 alkoxy, and C 3-8 cycloalkyl; or R 20a and R 20b , R 23a and R 23b , or R 25a and R 25b together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl; each of said alkyl, alkoxy, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from OH, CN, halo, NO2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 30a , R 30b , R 33a , and R 33b are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 21 , R 22 , R 31 and R 32 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of OH, halo, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, and 4-10 membered heterocyclyl; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; n is 0, 1, 2, 3, 4, or 5; in: (1) when L1is a covalent bond, L2is O, and Q is pyrazolyl, pyridyl, or pyrazinyl, ring Sp is other than and, (2) when L1is a covalent bond, L2is a covalent bond, R1and R2together with the atoms to which they are attached form a 6-membered nitrogen-containing heterocyclyl substituted with an acetyl group, and Q is pyrazolyl, ring Sp is other than 2. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, satisfies one or more of the following conditions: (1) The ring A1 is selected from phenyl and 5-6-membered heteroaryl; preferably, the ring A1 is selected from phenyl and 5-6-membered nitrogen-containing heteroaryl; more preferably, the ring A1 is selected from phenyl and 6-membered nitrogen-containing heteroaryl; for example, the ring A1 is phenyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl; (2) R1and R2are each independently absent, or each independently selected from H, hydroxyl, halogen, CN, C 1-6 alkyl, -NR 20a R 20b , -OR 21 , -S(=O)2R 22 , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b , C 3-8 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or, said R1and R2together with the atom to which they are attached form a C 5-8 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; or, said R1and R2together with the atom to which they are attached form a C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, -NR 30a R 30b , -OR 31 , -SR 31 , -S(=O)2R 32 , -C(=O)R 31 , -C(=O)NR 33a R 33b , and -NR 33a C(=O)R 33b ; (3) R3is independently selected at each occurrence from hydroxyl, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl; (4) L1is selected from a covalent bond, -O-, -S-, -S(O)-, -S(O)2-, -N(R b )-, -N(R b )-C 1-6 alkylene-, -N(R b )-C(=O)-C 1-6 alkylene-, -C 1-6 alkylene-N(R b )-C(=O)-, -N(R b )-C(=O)-, -C(=O)-, -C(=O)-C 1-6 alkylene-, C 1-6 alkylene, -O-C 1-6 alkylene-; said alkylene groups being optionally substituted by one or more R a groups; preferably, L1is selected from a covalent bond, -O-, -S-, -S(O)2-, -N(R b )-, -N(R b )-C(=O)-, -C(=O)-, C 1-6 alkylene; said alkylene groups being optionally substituted by one or more R a groups; (5) R a each independently at each occurrence is selected from the group consisting of hydroxyl, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl; (6) R b at each occurrence is independently selected from H and C 1-6 alkyl; said alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, CN, halogen, C 1-4 alkoxy; preferably, R b is H; (7) Q is selected from the group consisting of hydroxy, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, NO2, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; Preferably, Q is selected from the group consisting of hydroxy, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, CN, oxo (=0), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 alkoxy; (8) The ring Sp is selected from 6- to 13-membered heterospirocyclic bases; preferably, the ring Sp is selected from 6- to 11-membered heterospirocyclic bases; Preferably, the cyclic Sp is selected from the following groups: (9) L2is selected from a covalent bond, -O-, and C 1-6 alkylene, -O-C 1-6 alkylene-; said alkylene is optionally substituted with one or more R a ; preferably, L2is selected from a covalent bond, -O-, and C 1-6 alkylene, -O-C 1-6 alkylene-.

3. The compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite, or prodrug thereof of claim 1 or 2, wherein, The structure of the compound is shown in Formula II: Wherein: Y1, Y2, Y3, Y4, Y5 are each independently selected from: N, CH, and CR5; R1, R2, R4, R5, A1, L1, L2, Sp, and m are each independently as described in claim 1 or 2.

4. The compound or pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled, metabolite or prodrug thereof of any one of claims 1 to 3, wherein, The structure of the compound is shown below: Preferably, the compound is selected from:

5. A pharmaceutical composition comprising the compound of any one of claims 1-4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

6. Use of any compound of claims 1-4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug of the present invention, or the pharmaceutical composition of claim 5, in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with GPR6 receptor activity.

7. The compound of any one of claims 1-4 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of claim 5, for the treatment and / or prevention of diseases or symptoms associated with GPR6 receptor activity.

8. A method for treating and / or preventing diseases or symptoms associated with GPR6 receptor activity, the method comprising administering to an individual in need an effective amount of any one of claims 1-4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug, or the pharmaceutical composition of claim 5.

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