Nitrogen-containing heterocyclic compound and application thereof

Abstract

The invention relates to a nitrogen-containing heterocyclic compound and application thereof. Specifically, the invention relates to a compound shown in a formula (I) or pharmaceutically acceptable salts thereof and application of the compound or the pharmaceutically acceptable salts thereof in medicines for treating and / or preventing SSTR2 related diseases.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to nitrogen-containing heterocyclic compounds and their uses. Background Technology

[0002] Somatostatin (SST) is a polypeptide hormone that regulates neurotransmission in the brain and hormone secretion from endocrine cells in the anterior pituitary gland, pancreas, and gastrointestinal tract, inhibiting the secretion of growth hormone (GH). It also has inhibitory effects on cell proliferation, angiogenesis, and apoptosis.

[0003] The biological activity of somatostatin is mediated by the somatostatin receptor (SSTR) coupled to the G protein on the target cell membrane. There are five somatostatin receptor subtypes: SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, which are expressed in both normal tissues and tumors. SSTR2 is highly expressed in neuroendocrine tumors such as carcinoid tumors and pancreatic neuroendocrine tumors. SSTRs can directly or indirectly inhibit cell proliferation. After binding to the somatostatin receptor (SSTR), they exert anti-tumor effects by inhibiting DNA synthesis through signaling pathways such as cAMP, MAPK, and PI3K. SSTR2 expression is also associated with endocrine and metabolic diseases, such as acromegaly caused by excessive growth hormone release. By binding to SSTRs, SSTRs can inhibit the secretion of growth hormone (GH), thereby reducing the secretion of growth-promoting insulin-like growth factor-1 (IGF-1) by the liver.

[0004] Currently, somatostatin analogs such as octreotide and lanreotide have been approved for acromegaly and syndromes caused by neuroendocrine tumors, such as carcinoid syndrome, due to their high affinity for somatostatin receptor subtype 2 (SSTR2). However, they are mainly administered via injection in clinical practice, which is inconvenient. Therefore, there is a need to develop a small-molecule SSTR2 agonist.

[0005] Currently, a small molecule non-peptide somatostatin type 2 (SSTR2) receptor agonist, paltusotine, is in phase 3 clinical trials. It can inhibit growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and is being developed for acromegaly and neuroendocrine tumors. Summary of the Invention

[0006] The first aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Where X is N or CR a ;

[0009] R aSelected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy;

[0010] R 1 Selected from C2-C6 alkynyl, C1-C6 alkylamide, C1-C6 alkoxy-C1-C6 alkyl, or 3-7 membered heterocyclic C1-C6 alkyl; The R 1 Optionally by one or more R b replace;

[0011] Each R b They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, aminoacyl, C1-C6 alkylaminoacyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 alkylamino, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0012] R 2 Selected from halogens, C6-C 10 Aryl, C6-C 10 Arylaminoyl, C3-C8 cycloalkylaminoyl or C6-C 10 Aryl amide group; wherein the C6-C 10 Aryl, C6-C 10 Arylaminoyl, C3-C8 cycloalkylaminoyl or C6-C 10 Each aryl amide group is independently and optionally surrounded by one or more R c replace;

[0013] Each R c They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, sulfonylimide, C1-C6 alkylsulfonylimide, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group;

[0014] R 3 Selected from aminoacyl, C6-C 10Aryl, 5-14 membered heteroaryl, C3-C8 cycloalkylaminoyl, 3-12 membered heterocyclic aminoyl, C6-C 10 Arylaminoacyl or 5-14 heteroarylaminoacyl; wherein the C6-C 10 The aryl and 5-14 heteroaryl groups are each independently and optionally bonded by one or more R groups. d Substitution; the C3-C8 cycloalkyl aminoacyl group, 3-12 membered heterocyclic aminoacyl group, C6-C 10 The aryl aminoacyl group or the 5-14 heteroaryl aminoacyl group is independently and optionally surrounded by one or more R e replace;

[0015] Each R d They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, sulfonylimide, C1-C6 alkylsulfonylimide, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group;

[0016] Each R e They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group;

[0017] R 4 Selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy;

[0018] R 5Selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy;

[0019] The condition is that,

[0020] When X is CR a R 1 for The R 1 Optionally by one or more R b When replacing, R 3 Selected from aminoacyl, C6-C substituted with sulfonylimide or C1-C6 alkylsulfonylimide 10 aryl, 5-14 membered heteroaryl substituted with sulfonylimide or C1-C6 alkylsulfonylimide, C3-C8 cycloalkylaminoyl, 3-12 membered heterocyclic aminoyl, C6-C 10 arylaminoyl or 5-14 heteroarylaminoyl; wherein the C6-C group is substituted with a sulfonylimide group or a C1-C6 alkylsulfonylimide group. 10 The aryl group, the 5-14 heteroaryl group substituted with a sulfonylimide group or a C1-C6 alkylsulfonylimide group, each independently and optionally substituted with one or more R groups f Substitution; the C3-C8 cycloalkyl aminoacyl group, 3-12 membered heterocyclic aminoacyl group, C6-C 10 The aryl aminoacyl group or the 5-14 heteroaryl aminoacyl group is independently and optionally surrounded by one or more R e Replace; the R f It is selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy.

[0021] In some implementations, X is N.

[0022] In some implementations, X is CR a .

[0023] In some implementation schemes, R a It is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0024] In some implementation schemes, R a It is hydrogen.

[0025] In some implementation schemes, R 1 Selected from The R 1 Optionally by one or more R b replace.

[0026] In some implementation schemes, R 1 Selected from The R 1 Optionally by one or more R b replace.

[0027] In some implementations, the R 1 Optionally by 1, 2 or 3 R b replace.

[0028] In some implementation schemes, each R b They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, carboxyl, amino, aminoacyl, C1-C3 alkylaminoacyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C1-C3 alkylamino or aminoC1-C3 alkyl.

[0029] In some implementation schemes, R b It is selected from halogen, cyano, hydroxy, amino, aminoacyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxy.

[0030] In some implementation schemes, R 1 Selected from

[0031] In some implementation schemes, R 1 Selected from

[0032] In some implementation schemes, R 1 Selected from

[0033] In some implementation schemes, R 1 Selected from

[0034] In some implementation schemes, R 2 Selected from C6-C 10 Aryl, C6-C 10 Arylaminoyl, C3-C8 cycloalkylaminoyl or C6-C 10 aryl amide group; wherein the R 2 Optionally by one or more R c replace.

[0035] In some implementation schemes, R 2 Selected from phenyl, phenylaminoacyl, cyclopropylaminoacyl, or phenylamido; wherein R 2 Optionally by one or more R c replace.

[0036] In some implementation schemes, R 2 To be optionally used by one or more R c Substituted phenyl groups.

[0037] In some implementation schemes, R 2 For optional use by 1-5 R c Substituted phenyl groups.

[0038] In some implementation schemes, R 2 To be optionally occupied by 1, 2 or 3 R c Substituted phenyl groups.

[0039] In some implementation schemes, R 2 Selected from the following group groups:

[0040] In some implementation schemes, R 2 Selected from the following group groups:

[0041] In some implementation schemes, R c It is selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, or C1-C6 alkylamino.

[0042] In some implementation schemes, R c It is selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxy.

[0043] In some implementation schemes, R c It is selected from halogen, cyano, hydroxy, C1-C3 alkyl or C1-C3 alkoxy.

[0044] In some implementation schemes, R c Selected from fluorine, cyano or methyl.

[0045] In some implementation schemes, R 2 Selected from

[0046] In some implementation schemes, R 2 Selected from

[0047] In some implementation schemes, R 3 Selected from C6-C 10 Aryl, 5-9 membered heteroaryl, C3-C8 cycloalkylaminoyl or C6-C 10 Arylaminoacyl; wherein the C6-C10 The aryl and 5-9 heteroaryl groups are each independently and optionally bonded by one or more R groups. d Substitution; the C3-C8 cycloalkylaminoyl or C6-C 10 Each aryl aminoacyl group is independently and optionally surrounded by one or more R groups. e replace.

[0048] In some implementation schemes, R 3 Selected from C6-C 10 Aryl, C3-C8 cycloalkylaminoyl or C6-C 10 Arylaminoacyl; wherein the C6-C 10 Aryl group is optionally bounded by one or more R d Substitution; the C3-C8 cycloalkylaminoyl or C6-C 10 Each aryl aminoacyl group is independently and optionally surrounded by one or more R groups. e replace.

[0049] In some implementation schemes, R 3 Selected from phenyl, phenylaminoacyl or cyclopropylaminoacyl; wherein the phenyl, Optionally by one or more R d Substitution; the phenylaminoacyl group or cyclopropylaminoacyl group is each independently and optionally replaced by one or more R groups. e replace.

[0050] In some implementation schemes, R 3 Selected from phenyl, phenylaminoacyl, or cyclopropylaminoacyl; wherein the phenyl group is optionally converted to one or more R groups. d Substitution; the phenylaminoacyl group or cyclopropylaminoacyl group is each independently and optionally replaced by one or more R groups. e replace.

[0051] In some implementation schemes, R 3 To be optionally occupied by 1, 2 or 3 R d Substituted phenyl groups.

[0052] In some implementation schemes, R 3 To be optionally bounded by 1 or 2 R d Substituted phenyl groups.

[0053] In some implementation schemes, each R d They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, sulfonylimide or C1-C6 alkylsulfonylimide.

[0054] In some implementation schemes, each R dThey may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, sulfonylimide or C1-C3 alkylsulfonylimide.

[0055] In some implementation schemes, R d It is selected from fluorine, cyano, methanesulfonylimide or hydroxyl.

[0056] In some implementations, the R 3 Selected from phenylaminoacyl or cyclopropylaminoacyl; the R 3 Optionally by 1, 2 or 3 R e replace.

[0057] In some implementations, the R 3 Selected from phenylaminoacyl; the R 3 Optionally by 1, 2 or 3 R e replace.

[0058] In some implementation schemes, R e It is selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy.

[0059] In some implementation schemes, R e It is selected from halogen, cyano, hydroxy or C1-C3 alkyl.

[0060] In some implementation schemes, R e Selected from fluorine, cyano, hydroxy or methyl.

[0061] In some implementation schemes, R 3 Selected from

[0062] In some implementation schemes, R 3 Selected from

[0063] In some implementation schemes, R 3 Selected from

[0064] In some implementations, when R 1 for At that time, R 3 Selected from The R d Selected from sulfonamide group or C1-C6 alkylsulfonamide group; the R fIt is selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy; wherein m is 0, 1 or 2.

[0065] In some implementations, when R 1 for At that time, R 3 Selected from

[0066] In some implementations, m is 0 or 1.

[0067] In some implementations, the R f It is selected from halogen, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy.

[0068] In some implementation schemes, R 4 Selected from hydrogen.

[0069] In some implementation schemes, R 5 Selected from hydrogen.

[0070] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the following characteristics as shown in formula (II):

[0071]

[0072] Where R 1 Selected from C2-C6 alkynyl, amide, C1-C6 alkoxy-C1-C6 alkyl, or 3-7 membered heterocyclic C1-C6 alkyl; The R 1 Optionally by one or more R b replace;

[0073] p is 0, 1, 2 or 3;

[0074] q can be 0, 1, 2, or 3;

[0075] R 4 R 5 R a R b R c R d Each definition is as described in Equation I.

[0076] In some implementations, p is 0, 1, or 2.

[0077] In some implementations, q is 0, 1, or 2.

[0078] In some implementation schemes, R 1 Selected from The R 1 Optionally by one or more R b replace.

[0079] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the following characteristics as shown in formula (III):

[0080]

[0081] Among them, R 6 Selected from hydrogen, halogen, cyano, hydroxyl, amino, C1-C6 alkylamino, aminoacyl, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl or halo-C1-C6 alkoxy;

[0082] R 3 Selected from The R d Selected from sulfonamide group or C1-C6 alkylsulfonamide group; the R f Selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy; wherein m is 0, 1, or 2;

[0083] Or, R 3 Selected from aminoacyl, C3-C8 cycloalkyl aminoacyl, 3-12 membered heterocyclic aminoacyl, C6-C 10 Arylaminoacyl or 5-14 membered heteroarylaminoacyl; wherein the C3-C8 cycloalkylaminoacyl, 3-12 membered heterocyclic aminoacyl, C6-C 10 The aryl aminoacyl group or the 5-14 heteroaryl aminoacyl group is independently and optionally surrounded by one or more R e replace;

[0084] R 2 R 4 R 5 R a R e Each definition is as described in Equation I.

[0085] In some implementation schemes, R 6 Selected from hydrogen, halogen, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, or halo-C1-C3 alkoxy

[0086] In some implementation schemes, R 6 It is hydrogen.

[0087] In some implementation schemes, R 3 for The R dSelected from sulfonamide or C1-C6 alkylsulfonamide, wherein R f Selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, or halo-C1-C3 alkoxy; wherein m is 0, 1, or 2;

[0088] Or R 3 It is a phenylaminoacyl or cyclopropylaminoacyl group, each of which is independently and optionally converted by one or more R groups. e replace.

[0089] In some implementation schemes, R 3 for The R d Selected from C1-C6 alkylsulfonylimide groups, wherein R f Selected from hydrogen, halogen, cyano, hydroxyl, amino, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, or halo-C1-C3 alkoxy; wherein m is 0 or 1;

[0090] Or R 3 It is a phenylaminoyl group, wherein R 3 Optionally by 1, 2 or 3 R e replace.

[0091] In some implementation schemes, R 3 for

[0092] In some implementation schemes, R 3 for

[0093] On the other hand, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0094]

[0095]

[0096] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0097] Another aspect of the present invention provides the use of the first aspect described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect above, in the preparation of a medicament for treating and / or preventing SSTR2-related diseases.

[0098] Another aspect of the present invention provides a method for treating SSTR2-related diseases, comprising the steps of administering a therapeutically effective amount of the first aspect described above or a pharmaceutically acceptable salt thereof to a patient in need, or administering a therapeutically effective amount of the pharmaceutical composition described in the second aspect described above to a patient in need.

[0099] In some implementation schemes, SSTR2-related diseases include, but are not limited to, acromegaly, tumors, ophthalmological diseases, neurological diseases, kidney diseases, respiratory diseases, pain, neurodegenerative diseases, inflammatory diseases, or psychiatric diseases.

[0100] In some implementations, the tumor is a neuroendocrine tumor.

[0101] definition

[0102] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art.

[0103] The term “substituted” or “replaced by” refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0104] The term "optional" or "optionally" means that the event or situation subsequently described may or may not occur, including both the occurrence and non-occurrence of the event or situation. The phrase "optionally replaced by..." as used in this invention includes both "replaced" and "not replaced".

[0105] In this article, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; further, it can be one, two, three, four, or five; and even further, it can be one, two, or three; but the chemical valence bond requirement must be met.

[0106] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0107] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0108] The term "membered ring" refers to the number of skeletal atoms or groups of atoms that make up the ring. For example, groups like C=O, S(=O)2, or S(=O) have skeletal atoms C, S, and S respectively, and are represented as unary. "5-7 membered rings" indicates that the number of skeletal atoms or groups of atoms in the ring is 5, 6, or 7. For example, pyridine and piperidine are six-membered rings, while thiazoles and pyrroles are five-membered rings.

[0109] In This indicates the point where the group is chemically bonded to the rest of the molecule.

[0110] The term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.

[0111] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0112] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the body and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, diluents, disintegrants, binders, flow aids, and wetting agents.

[0113] The compounds of this invention contain asymmetric centers that may lead to stereoisomerism, as well as other chemical structures; therefore, this invention also includes these stereoisomers and mixtures thereof. Since the compounds of this invention (or pharmaceutically acceptable salts thereof) can exist in diastereomer or enantiomeric forms, or mixtures thereof, all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures of said isomers, diastereomer mixtures, and other mixtures are within the scope of this invention. The compounds of this invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0114] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes of different atomic weights or mass numbers than those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, oxygen, nitrogen, and sulfur, such as 2H, 3H, 11C, 13C, 14C, 15O, 17O, 18O, 35S, etc., respectively. Certain isotopically labeled compounds of this application (e.g., those labeled with 3H and 14C) can be used in the analysis of compound and / or substrate tissue distribution. Deuterated (i.e., 2H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emission isotopes, such as 15O and 11C, can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below. Furthermore, substitution with a heavier isotope (such as deuterium (2H)) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in certain cases, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being replaced by at least one deuterium atom.

[0115] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which can be straight-chain or branched. For example, the term "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, etc. The term "C1-C6 alkyl" can further be "C1-C4 alkyl", "C1-C3 alkyl", C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0116] The term "C1-C6 alkoxy" refers to "C1-C6 alkyl-O-", where "C1-C6 alkyl" is as defined above. Non-limiting examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, or 3-pentoxy. The "C1-C6 alkoxy" of this invention can further be "C1-C4 alkoxy" or "C1-C3 alkoxy".

[0117] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "hydroxyl" refers to the -OH group. The term "amino" refers to the -NH2 group. The term "cyano" refers to the -CN group. The term "nitro" refers to the -NO2 group. The term "carboxyl" refers to -C(O)OH.

[0118] In this invention, "halogenated C1-C6 alkyl" or "halogenated C1-C6 alkoxy" means that the alkyl or alkoxy group is replaced by one or more halogen atoms, wherein "halogen," "C1-C6 alkyl," or "C1-C6 alkoxy" are as defined above. Specific examples include, but are not limited to, difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), etc. The term "halogenated C1-C6 alkyl" can further be "halogenated C1-C4 alkyl" or "halogenated C1-C3 alkyl"; the term "halogenated C1-C6 alkoxy" can further be "halogenated C1-C4 alkoxy" or "halogenated C1-C3 alkoxy."

[0119] The term "alkylamide group" means -NHC(O)-R group, where R is an alkyl group as defined above.

[0120] The term "arylamide group" refers to the -NHC(O)-R group, where R is an aryl group as defined above.

[0121] The term "alkylamine" refers to the -NHR group, where R is an alkyl group as defined above.

[0122] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic ring with a conjugated π-electron system. The "C6-C" group described in this invention... 10 "Aryl" can include, but is not limited to, phenyl, naphthyl, anthracene, etc.

[0123] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, for example, one, two, or three. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized, such as sulfur, to form a sulfone or sulfoxide. The "5-14-membered heteroaryl" described in this invention can further be "5-12-membered heteroaryl," "5-10-membered heteroaryl," "5-9-membered heteroaryl," or "5-6-membered heteroaryl." Non-limiting examples of heteroaryl groups include, but are not limited to: furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiophene, pyrazolyl, pyridinone, oxadiazolone, indolone, benzimidazolone, benzopyrrole, etc.

[0124] The term "cycloalkyl" refers to a saturated carbon ring, including monocyclic, bicyclic, or polycyclic fused, bridged, or spirocyclic rings. For example, the term "C3-C..." 10 "Cycloalkyl" refers to a ring containing 3 to 10 carbon atoms, such as 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered ring atoms. It can further be C3-C8 cycloalkyl or C3-C6 cycloalkyl. Non-limiting examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indane, etc.

[0125] The term "heterocyclic group" refers to a saturated or partially saturated non-aromatic ring, in which at least one ring system contains one or more heteroatoms. It can be a monocyclic, bicyclic, polycyclic, spirocyclic, or bridged ring, i.e., containing a monocyclic heterocyclic group, a fused heterocyclic group, a spirocyclic group, or a bridged heterocyclic group. The "3-12 membered heterocyclic group" described in this invention refers to a cyclic group containing one, two, three, four, or five heteroatoms and containing 3-12 (e.g., 5, 6, 5-7, 3-8, 5-12, 3-10, or 8-10) ring atoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized, such as the "-CH2-" group of the heterocyclic group, which may optionally be oxidized to form -C(=O)-; or the sulfur may optionally be oxidized to form a sulfone or sulfoxide. Non-limiting examples of heterocyclic groups include, but are not limited to: pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azacyclic butyl, thiazolyl, azoleyl, piperidinyl, etc.

[0126] The term "aminoacyl" refers to the -C(O)NH2 group.

[0127] The term "alkylaminoacyl" refers to the -C(O)NHR group, where R is an alkyl group as defined above.

[0128] The term "cycloalkylaminoacyl" refers to the -C(O)NHR group, where R is a cycloalkyl group as defined above.

[0129] The term "arylaminoyl" refers to the -C(O)NHR group, where R is an aryl group as defined above.

[0130] The term "heteroarylaminoacyl" refers to the -C(O)NHR group, where R is a heteroaryl group as defined above.

[0131] The term "heterocyclic aminoacyl" refers to the -C(O)NHR group, where R is a heterocyclic group as defined above.

[0132] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, wherein the definition of alkyl is as described above. The "C2-C6 alkenyl" used in this invention refers to an alkenyl group having 2 to 6 carbon atoms. It can be a mono-olefin, diene, or tri-olefin, and non-limiting examples include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, etc.

[0133] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, wherein the definition of an alkyl group is as described above. Optionally, it contains at least one double bond, which is connected to the rest of the molecule by a single bond. The "C2-C6 alkynyl" used in this invention refers to an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0134] The term “3-7 membered heterocyclic C1-C6 alkyl” refers to a C1-C6 alkyl group substituted with a 3-7 membered heterocyclic group, wherein the C1-C6 alkyl group and the 3-7 membered heterocyclic group are groups as defined above.

[0135] The term "hydroxyl C1-C6 alkyl" indicates that an alkyl group is substituted with one or more hydroxyl groups. Wherein, "hydroxyl" or "C1-C6 alkyl" is as defined above. Specific examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, etc. The term "hydroxyl C1-C6 alkyl" can further be "hydroxyl C1-C4 alkyl" or "hydroxyl C1-C3 alkyl".

[0136] The term "amino C1-C6 alkyl" indicates that the alkyl group is replaced by one or more amino groups. Wherein, "amino" and "C1-C6 alkyl" are as defined above. Specific examples include, but are not limited to, -CH2NH2, -(CH2)2NH2, -CH(NH2)CH3, -CH(NH2)CH2NH2, -(CH2)3NH2, etc. The term "amino C1-C6 alkyl" can further be "amino C1-C4 alkyl" or "amino C1-C3 alkyl".

[0137] The term "C1-C6 alkoxy-C1-C6 alkyl" indicates that the alkyl group is replaced by one or more alkoxy groups. "C1-C6 alkoxy" and "C1-C6 alkyl" are as defined above.

[0138] The term "alkylamino" refers to a -NHR group, where R is an alkyl group as defined above. Non-limiting examples of the term "C1-C6 alkylamino" include, but are not limited to, methylamino, ethylamino, propylamino, 2-propylamino, etc.

[0139] The term "sulfonamide group" represents a -N=S=O group.

[0140] The term "alkylsulfonylimide" signifies a -S(=O)(=NH)-R group, where R is an alkyl group as defined above. Non-limiting examples of the term "C1-C6 alkylsulfonylimide" include, but are not limited to, methanesulfonylimide, ethanesulfonylimide, etc. Detailed Implementation

[0141] The following examples and test cases illustrate the present invention in detail, but they do not limit the scope of the invention, and variations can be made without departing from the scope of the invention.

[0142] The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0143] MOMO: Methoxymethyl ether; Me: Methyl; Boc: tert-Butoxycarbonyl; Tf: Trifluoromethanesulfonyl; TFA: Trifluoroacetic acid; DCM: Dichloromethane; PE: Petroleum ether; EtOAc: Ethyl acetate; Cbz: Benzyloxycarbonyl; Bpin: 4,4,5,5-Tetramethyl-1,3,2λ 2 - Dioxaborane; TIPS: Triisopropylsilyl.

[0144] RT refers to retention time. "v / v" refers to volume ratio. UV indicates ultraviolet light. TLC indicates thin-layer chromatography.

[0145] Preparation Example 1: 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzylnitrile

[0146]

[0147] a) 3-Bromo-2-(methoxymethoxy)benzylnitrile (M1-1)

[0148] 3-Bromo-2-hydroxybenzonitrile (25 g) was dissolved in N,N-dimethylformamide (300 mL), potassium carbonate (35 g) was added, the mixture was cooled to 0 °C, and bromomethyl methyl ether (32 g) was slowly added dropwise. The reaction was allowed to proceed overnight at room temperature, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was dried, sand was prepared, and the mixture was purified to give the title compound M1-1 (29 g).

[0149] b) 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzylnitrile (M1)

[0150] Compound M1-1 (29 g) was dissolved in 1,4-dioxane (300 mL), and 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (33.46 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (4.9 g) and potassium acetate (23.5 g) were added. The mixture was purged with nitrogen and stirred at 100 °C for 5 hours. The reaction solution was filtered, concentrated, and purified to obtain the title compound M1 (29 g). 1H NMR (400MHz, DMSO-d6) δ7.93 (ddd, J=9.5, 7.6, 1.8Hz, 2H), 7.33 (t, J=7.6Hz, 1H), 5.19 (s, 2H), 3.57 (s, 3H), 1.31 (s, 12H).

[0151] Example 1: 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-1,7-naphthidin-6-yl)-2-hydroxybenzyl nitrile

[0152]

[0153] a) 3-Bromo-6-chloro-1,7-naphthyridine-4-ol (1a)

[0154] Under nitrogen atmosphere, N-bromosuccinimide (2.8 g) was added to a solution of 6-chloro-1,7-naphthidine-4-ol (2.9 g) in N,N-dimethylformamide (40 mL). The mixture was stirred under nitrogen atmosphere at room temperature for 12 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (3 × 100 mL). The combined mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give title compound 1a (3.1 g).

[0155] b) 3-Bromo-4,6-dichloro-1,7-naphthylpyridine (1b)

[0156] Compound 1a (1.5 g) and phosphorus oxychloride (300 mL) were added to a reaction flask at room temperature. The mixture was stirred at 100 °C for 3 hours under nitrogen. The reaction solution was dissolved in ethyl acetate, and the reaction was quenched with an aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3 × 200 mL). The combined mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give title compound 1b (0.85 g).

[0157] c)(1-(3-bromo-6-chloro-1,7-naphthid-4-yl)piperidin-4-yl)tert-butyl carbamate (1c)

[0158] Compound 1b (0.83 g), tert-butyl piperidin-4-ylcarbamate (0.6 g), N,N-diisopropylethylamine (0.8 mL), and N,N-dimethylaniline (30 mL) were added to a reaction flask. The mixture was stirred at 120 °C under nitrogen for 4 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give title compound 1c (0.923 g).

[0159] d)(1-(6-chloro-3-(3,5-difluorophenyl)-1,7-naphthid-4-yl)piperidin-4-yl)tert-butyl carbamate (25d)

[0160] Compound 1c (740 mg), (3,5-difluorophenyl)boric acid (212 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (120 mg), and cesium carbonate (554 mg) were dissolved in water / 1,4-dioxane (1:39 (v / v), 28 mL). The reaction was carried out at 120 °C for 16 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The reaction solution was concentrated to give crude compound 1d (0.25 g).

[0161] e)(1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)-1,7-naphthid-4-yl)piperidin-4-yl)tert-butyl carbamate (1e)

[0162] Compound 1d (230 mg), cyclohexylphosphine (27 mg), tris(dibenzylacetone)palladium (46 mg), potassium phosphate (318 mg), and (3-cyano-2-(methoxymethoxy)phenyl)boronic acid (104 mg) were dissolved in 1,4-dioxane / water (8 mL). The mixture was microwave-stirred at 120 °C under nitrogen for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give title compound 1e (100 mg).

[0163] f) 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-1,7-naphthidin-6-yl)-2-hydroxybenzylnitrile (Compound 1)

[0164] Compound 1e (90 mg) was dissolved in a solution of 1,4-dioxane hydrochloride (3 mL) under nitrogen atmosphere at room temperature. The mixture was stirred at 70 °C for 16 hours. The reaction solution was concentrated to give a crude product. The crude product was then purified by reversed-phase high-performance liquid chromatography (column: C18-I, conventional C18 20-40 μm, 120 g, mobile phase A: water (0.1% trifluoroacetic acid), B: acetonitrile, gradient: 50%–55% B) to give title compound 1 (18.3 mg). 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),9.31(s,1H),8.54(s,1H),8.39(dd,J=7.8,2.0Hz,1H),7.36(dd,J=10.6,8.4Hz,1H),7. 30(d,J=6.4Hz,1H),7.20(d,J=6.0Hz,2H),6.32(s,1H),3.41(d,J=12.8Hz,2H),3.17(s,1H),2.79–2.64(m,2H),1.95(s,4H). MS(ESI,m / z):458.3[M+H] + .

[0165] Example 2: 3-(4-(6-amino-3-azabicyclo[4.1.0]heptane-3-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzyl nitrile

[0166]

[0167] a) Benzyl (3-(6-bromo-3-chloroquinoline-4-yl)-3-azabicyclo[4.1.0]heptane-6-yl)carbamate (2a)

[0168] 6-Bromo-3,4-dichloroquinoline (0.5 g) was dissolved in N-methylpyrrolidone (20 mL), followed by the addition of potassium carbonate (0.5 g) and benzyl (3-azabicyclo[4.1.0]heptane-6-yl)carbamate (0.9 g). After the addition was complete, the mixture was stirred at 130 °C for 3 hours. The mixture was purified by column chromatography (petroleum ether: ethyl acetate = 10:1, v / v) to give the title compound 2a (0.43 g).

[0169] b) Benzyl (3-(3-chloro-6-(3-cyano-2-(methoxymethoxy)phenyl)quinolin-4-yl)-3-azabicyclo[4.1.0]heptane-6-yl)carbamate (2b)

[0170] Compound 2a (0.2 g), M1 (0.3 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (10 mg), and cesium carbonate (0.78 mg) were dissolved in 5 mL of 1,4-dioxane and reacted at 80 °C for 3 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give the title compound 2b (78 mg).

[0171] c) Benzyl(3-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)-3-azabicyclo[4.1.0]heptane-6-yl)carbamate (2c)

[0172] Compound 2b (0.078 g), 3,5-difluorophenylboronic acid (0.065 g), bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium dichloride (10 mg), and cesium carbonate (0.18 g) were added to a reaction flask and dissolved in 5 mL of 1,4-dioxane. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 3 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated to prepare sand. Column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) yielded the title compound 2c (30 mg).

[0173] d) 3-(4-(6-amino-3-azabicyclo[4.1.0]heptane-3-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-(methoxymethoxy)benzylnitrile (2d)

[0174] Compound 2c (30 mg) was dissolved in methanol (3 mL), and then palladium on carbon (10 mg) was added. The mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The solution was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the title compound 2d (23 mg).

[0175] e) 3-(4-(6-amino-3-azabicyclo[4.1.0]heptane-3-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzylnitrile (Compound 2)

[0176] Compound 2d (23 mg) was dissolved in 2 mL of 1,4-dioxane solution, and 2 mL of 4.0 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 20%B to 40%B over 10 minutes; wavelength: UV 254nm; RT (min): 9.38, column temperature: 25℃) yielded title compound 2 (5.4mg). 1 H NMR (400MHz, DMSO-d6) δ8.83 (s, 1H), 8.57 (s, 1H), 8.10 (d, J = 8.8Hz, 1H), 7. 93(d,J=8.8Hz,1H),7.45(dd,J=7.2,1.9Hz,1H),7.33(t,J=9.4Hz,1H),7.28 –7.18(m,3H),6.29(t,J=7.5Hz,1H),2.85(d,J=12.2Hz,2H),1.86(s,1H),1. 53(d,J=14.3Hz,2H),1.23(s,2H),0.93–0.85(m,1H),0.67(d,J=9.2Hz,1H). MS(ES,m / z):468.9[M+H] + .

[0177] Example 3: 3-(4-((3-(aminomethyl)azacyclobutane-1-yl)methyl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzonitrile

[0178]

[0179] a) 6-Bromo-4-(bromomethyl)-3-chloroquinoline (3a)

[0180] Under nitrogen atmosphere, carbon tetrabromide (361 mg) was dissolved in dichloromethane (10 mL), and triphenylphosphine (456 mg) was added. The mixture was stirred at 20 °C for 1 hour, followed by the addition of (6-bromo-3-chloroquinoline-4-yl)methanol (250 mg). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1 (v / v)) to give the title compound 3a (120 mg).

[0181] b)(1-(6-bromo-3-chloroquinoline-4-yl)methyl)azacyclobutane-3-yl)methylcarbamate tert-butyl ester (3b)

[0182] Under nitrogen atmosphere, compound 3a (120 mg) was dissolved in N-methylpyrrolidone (10 mL), followed by the addition of tert-butyl carbamate (azacyclobutane-3-ylmethyl) (143 mg) and N,N-diisopropylethylamine (139 mg). The mixture was stirred at 120 °C for 2 hours. The reaction solution was extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1 (v / v)) to give the title compound 3b (70 mg).

[0183] c)(1-(3-chloro-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)methyl)azacyclobutane-3-yl)tert-butyl methylcarbamate (3c)

[0184] Under nitrogen atmosphere, compound 3b (70 mg) was dissolved in 1,4-dioxane (10 mL), and compound M1 (55 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11 mg), and cesium carbonate (155 mg) were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain the title compound 3c (50 mg).

[0185] d)(1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)methyl)azacyclobutane-3-yl)tert-butyl methylcarbamate (3d)

[0186] Compound 3c (40 mg), (3,5-difluorophenyl)boric acid (14 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (II) (5 mg), and cesium carbonate (74 mg) were added to a reaction flask and dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 3d (30 mg).

[0187] e)3-(4-((3-(aminomethyl)azacyclobutane-1-yl)methyl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzonitrile (compound 3)

[0188] Compound 3d (30 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 17%B to 37%B over 10 minutes; wavelength: UV 254nm; RT (min): 8.84, column temperature: 25℃) yielded the title compound 3 (3.5mg). 1 HNMR(400MHz, DMSO-d6)δ8.70(s,1H),8.28(s,2H),8.03–7.93(m,2H),7.53(dd,J=7.4,2.0Hz,1H),7.40(dd,J=7.2,2.8Hz,2H), 7.26(dd,J=7.7,1.9Hz,1H),6.38(t,J=7.5Hz,1H),3.94(s,2H),3.20(t,J=7.3Hz,4H),2.98(d,J=6.1Hz,2H),2.62–2.53(m,1H). MS(ES,m / z):457.1[M+H] + .

[0189] Example 4: (3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)phenyl)(imino)(methyl)-λ 6 -Aminosulfonone

[0190]

[0191] a)(3-bromophenyl)(imino)(methyl)-λ 6 -Aminosulfonone (4a)

[0192] (3-Bromophenyl)(methyl)thione (2 g), ammonium chloride (800 mg), and methanol (30 mL) were added at room temperature, followed by the addition of iodophenyl diacetic acid (6.4 g) in five portions, and the mixture was stirred for 1 hour. After the reaction was complete, the mixture was quenched with sodium sulfite solution, extracted with 200 mL of dichloromethane, and distilled under reduced pressure to dryness. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 1:1 (v / v)) to give the title compound 4a (1.2 g).

[0193] b) Imino(methyl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-λ 6 -Sulfamethoxazole (4b)

[0194] Compound 4a (936 mg), pinacol diborate (1270 mg), potassium acetate (836 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (146 mg), and anhydrous 1,4-dioxane (20 mL) were added under anhydrous and oxygen-free conditions. The mixture was then purged three times with nitrogen and stirred at 100°C for 5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness to obtain crude compound 4b.

[0195] c)(1-(3-chloro-6-(3-(S-methylsulfonylimino)phenyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (4c)

[0196] Compound 4b (200 mg), (1-(3-chloro-6-iodoquinoline-4-yl)piperidin-4-yl)carbamate tert-butyl ester (183 mg) (prepared according to the method for intermediate 5c in Example 5, by replacing thiomorpholine in step c) with piperidin-4-ylcarbamate tert-butyl ester), potassium carbonate (104 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (28 mg), 1,4-dioxane (20 mL), and water (1 mL) were added under anhydrous and oxygen-free conditions. The mixture was then purged with nitrogen three times and stirred at 90°C for 3 hours. The reaction solution was separated, and the organic phase was concentrated to dryness. Column chromatography (petroleum ether / ethyl acetate = 1:1 to 0:1 (v / v)) yielded the title compound 4c (260 mg).

[0197] d)(1-(3-(3,5-difluorophenyl)-6-(3-(S-methylsulfonylimino)phenyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (4d)

[0198] Compound 4c (260 mg), 3,5-difluorophenylboronic acid (96 mg), potassium carbonate (104 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (138 mg), and anhydrous 1,4-dioxane (15 mL) were added under anhydrous and oxygen-free conditions. The mixture was then purged three times with nitrogen and stirred at 110 °C for 3 hours. After the reaction was complete, the mixture was filtered, concentrated to dryness, and subjected to column chromatography (petroleum ether / ethyl acetate = 1:2 to 0:1 (v / v)) to give the title compound 4d (52 mg).

[0199] e)(3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)phenyl)(imino)(methyl)-λ 6 -Aminosulfonone (compound 4)

[0200] Compound 4d (52 mg), anhydrous 1,4-dioxane (5 mL), and 1,4-dioxane hydrochloride solution (4 mL) were added under anhydrous and oxygen-free conditions, and then stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was concentrated to dryness. Column chromatography (dichloromethane / methanol = 10:1 (v / v)) yielded the title compound 4 (20 mg). 1 H NMR (400MHz, CHCl3-d) δ8.57 (s, 1H), 8.51–8.35 (m, 3H), 8.19 (d, J = 8.7Hz, 1H), 8.05 (t, J = 7.4Hz, 3H), 7.75 (t, J = 7.9Hz, 1H), 6.92 (dd, J = 28.9, 7.7Hz,3H),3.48–3.35(m,2H),3.30(d,J=12.9Hz,1H),3.21(s,3H),,2. 79(dt,J=32.2,12.2Hz,2H),2.06(t,J=16.0Hz,2H),1.98–1.78(m,2H). MS(ESI,m / z):493.1[M+H] + .

[0201] Example 5: 3-(3-(3,5-difluorophenyl)-4-(1-imino-1-oxy-1λ) 6 -Thiomorpholino)quinoline-6-yl)-2-hydroxybenzyl nitrile

[0202]

[0203] a) 3-Chloro-6-iodoquinoline-4-ol (5a)

[0204] Under nitrogen atmosphere, 6-iodoquinoline-4-ol (5 g) was dissolved in acetic acid (50 mL), and N-chlorosuccinimide (3.7 g) was added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was filtered to obtain the crude product of the title compound 5a.

[0205] b) 3,4-Dichloro-6-iodoquinoline (5b)

[0206] Under nitrogen atmosphere, compound 5a (5g) was dissolved in phosphine oxychloride (10mL) and stirred at 90°C for 3 hours. The reaction mixture was then added to water (50mL) and stirred for 1 hour. Dichloromethane (50mL*2) was added for extraction. The organic phase was washed with saturated sodium chloride solution (50mL*2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give the title compound 5b (3g).

[0207] c) 4-(3-chloro-6-iodoquinoline-4-yl)thiomorpholine (5c)

[0208] Compound 5b (1 g), thiomorpholine (328 mg), and N,N-diisopropylethylamine (1.2 g) were dissolved in 20 mL of 1,4-dioxane. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to give the title compound 5c (0.7 g).

[0209] d)4-(3-chloro-6-iodoquinoline-4-yl)-1-imino-1λ 6 -Thiomorpholine-1-oxide (5d)

[0210] Under nitrogen atmosphere, compound 5c (700 mg) was dissolved in methanol (10 mL), and iodophenyl diacetic acid (1.2 g) and ammonium acetate (221 mg) were added. The mixture was stirred at 20 °C for 1 hour. Saturated sodium bicarbonate aqueous solution was added dropwise to the reaction mixture until pH = 9. Ethyl acetate (50 mL * 2) and water (50 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give the title compound 5d (350 mg).

[0211] e)3-(3-chloro-4-(1-imino-1-oxy-1λ) 6 -Thiomorpholino)quinoline-6-yl)-2-(methoxymethoxy)benzylnitrile(5e)

[0212] Compound 5d (350 mg), compound M1 (288 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (60 mg), and cesium carbonate (811 mg) were added to a reaction flask and dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 5e (160 mg).

[0213] f)3-(3-(3,5-difluorophenyl)-4-(1-imino-1-oxy-1λ) 6 -Thiomorpholino)quinoline-6-yl)-2-(methoxymethoxy)

[0214] Benzyl nitrile (5f)

[0215] Compound 5e (160 mg), (3,5-difluorophenyl)boric acid (66 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25 mg), and cesium carbonate (342 mg) were added to a reaction flask and dissolved in 10 mL of 1,4-dioxane. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 5f (80 mg).

[0216] g)3-(3-(3,5-difluorophenyl)-4-(1-imino-1-oxy-1λ) 6 -Thiomorpholino)quinoline-6-yl)-2-hydroxybenzyl nitrile (compound 5)

[0217] The crude compound 5f (80 mg) was dissolved in 1,4-dioxane (2 mL), and 1,4-dioxane hydrochloride (2 mL) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD 19 mm*250 mm, 10 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 30% B to 50% B over 10 min; wavelength: UV 254 nm; RT (min): 10.11, column temperature: 25 °C) yielded title compound 5 (49.6 mg). MS (ESI, m / z): 490.2 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ8.62–8.50(m,2H),7.97(s,1H),7.89(s,1H),7.67–7.56(m,1H),7.4 7–7.36(m,2H),7.29–7.21(m,2H),6.89–6.74(m,1H),3.76–3.34(m,4H),3.21–3.00(m,4H).

[0218] Example 6: 3-(3-(3,5-difluorophenyl)-4-(2-azaspiro[3.3]heptane-6-yl)quinoline-6-yl)-2-hydroxybenzyl nitrile

[0219]

[0220] a) 3-Bromo-6-methoxyquinoline-4-ol (6B)

[0221] Under nitrogen atmosphere, compound 6A (5g) was dissolved in acetic acid (50mL), and N-bromosuccinimide (6.1g) was added. The mixture was stirred at 60°C for 3 hours. The reaction solution was filtered to obtain crude compound 6B.

[0222] b) 3-Bromo-4-chloro-6-methoxyquinoline (6C)

[0223] Compound 6B (5 g) was dissolved in phosphine oxychloride (50 mL) under nitrogen atmosphere and stirred at 90 °C for 3 hours. The reaction solution was then added to water (50 mL) and stirred for 1 hour. Dichloromethane (50 mL * 2) was added for extraction. The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give the title compound 6C (3 g).

[0224] c) 4-Chloro-3-(3,5-difluorophenyl)-6-methoxyquinoline (6D)

[0225] Compound 6C (1 g), (3,5-difluorophenyl)boric acid (580 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (368 mg), and potassium carbonate (1.5 g) dissolved in 1,4-dioxane (20 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 h. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to give the title compound 6D (1 g).

[0226] d) 4-Chloro-3-(3,5-difluorophenyl)quinoline-6-ol (6-2)

[0227] Compound 6D (1g) was dissolved in acetic acid (8mL), and 33% hydrogen bromide in acetic acid solution (4mL) was added. The mixture was stirred in a sealed tube at 100℃ for 16 hours. The reaction solution was extracted with ethyl acetate (50mL*2) and water (50mL). The organic phase was washed with saturated sodium chloride solution (50mL*2), dried, and concentrated to dryness to obtain crude compound 6-2.

[0228] e)6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (6a)

[0229] Compound 6-1 (5 g) was dissolved in tetrahydrofuran (40 mL). Under nitrogen protection at -78 °C, bis(trimethylsilylaminolithium) (46 mL) was added and stirred for 1 hour. Then, a solution of N-phenylbis(trifluoromethanesulfonyl)imide (16 g) in tetrahydrofuran (40 mL) was slowly added. After the reaction was complete, 1 mL of water was added, and the mixture was concentrated to dryness. Extraction was then performed with water and ethyl acetate. The organic layer was dried, prepared as a slurry, and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to give the title compound 6a (1.6 g).

[0230] f) 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (6b)

[0231] Compound 6a (1.2 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (594 mg), potassium acetate (229 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (73 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and reacted for 4 hours. The reaction solution was concentrated to dryness and subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give the title compound 6b (800 mg).

[0232] g)6-(3-(3,5-difluorophenyl)-6-hydroxyquinoline-4-yl)-2-azaspiro[3.3]hept-5-ene-2-carboxylic acid tert-butyl ester (6c)

[0233] Compound 6b (488 mg), compound 6-2 (500 mg), cesium carbonate (600 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (52 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and reacted for 4 hours. The reaction solution was concentrated to dryness and subjected to column chromatography (ethyl acetate) to give the title compound 6c (500 mg).

[0234] h)6-(3-(3,5-difluorophenyl)-6-hydroxyquinoline-4-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6d)

[0235] Compound 6c (500 mg) was dissolved in methanol (5 mL), palladium on carbon (500 mg) was added, and the mixture was purged with hydrogen and reacted overnight. The reaction solution was filtered and concentrated, and column chromatography (ethyl acetate) was performed to give the title compound 6d (450 mg).

[0236] i) 6-(3-(3,5-difluorophenyl)-6-(((trifluoromethyl)sulfonyl)oxy)quinoline-4-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6e)

[0237] Compound 6d (440 mg) was dissolved in 2-methyltetrahydrofuran (40 mL) at -20 °C under nitrogen protection, and triethylamine (303 mg) and trifluoromethanesulfonic acid (423 mg) were added. The reaction was monitored every 10 minutes. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. Column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) gave the title compound 6e (68 mg).

[0238] j)6-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6f)

[0239] Compound 6e (68 mg), compound M1 (52 mg), cesium carbonate (117 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (10 mg), and 1,4-dioxane (15 mL) were added to a reaction flask. Under nitrogen protection, the temperature was raised to 100 °C, and the reaction was carried out for 3 hours. After the reactants had completely reacted, the reaction solution was filtered and concentrated to dryness, and column chromatography (petroleum ether: ethyl acetate = 2:1) was performed to give the title compound 6f (55 mg).

[0240] k)3-(3-(3,5-difluorophenyl)-4-(2-azaspiro[3.3]heptane-6-yl)quinoline-6-yl)-2-hydroxybenzylnitrile (Compound 6)

[0241] A solution of compound 6f (20 mg) in dichloromethane (2.5 mL) was added dropwise to trifluoroacetic acid (1 mL), and the mixture was stirred until the reactants had completely reacted. The reaction solution was concentrated, and the crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD 19 mm*250 mm, 10 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 25% B to 45% B over 10 min; wavelength: UV 254 nm; RT (min): 9.20, column temperature: 25 °C) yielded title compound 6 (5.4 mg). MS (ESI, m / z): 454.2 [M+H] + , 1H NMR(400MHz, DMSO-d6)δ8.61(s,1H),8.49(s,1H),8.04–7.92(m,2H),7.50(dd,J=7.5,1.9Hz,1H),7.42–7.33(m,2H),7.29–7.20 (m,2H),6.57(t,J=7.6Hz,1H),4.29(p,J=9.1Hz,1H),4.08(s,2H),3.65(s,2H),2.71–2.61(m,2H),2.04(dd,J=12.3,9.6Hz,2H).

[0242] Example 7: 3-(4-(3-aminopropyl-1-yn-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzonitrile

[0243]

[0244] a) 4-Bromo-3-chloro-6-iodoquinoline (7a)

[0245] Compound 7-1 (2 g) was dissolved in N,N-dimethylformamide (20 mL), and stirred at 100 °C for 16 h with phosphorus bromide (2.13 g) at 0 °C. The reaction solution was extracted with dichloromethane (50 mL * 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to give crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to give title compound 7a (1.2 g).

[0246] b) 3-(4-bromo-3-chloroquinoline-6-yl)-2-(methoxymethoxy)benzyl nitrile (7b)

[0247] Under nitrogen atmosphere, compound 7a (1 g) was dissolved in 1,4-dioxane (10 mL), and compound M1 (690 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (180 mg), and cesium carbonate (2.4 g) were added. The mixture was stirred at 20 °C for 1 h. The reaction solution was extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give the title compound 7b (500 mg).

[0248] c)(3-(3-chloro-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)prop-2-yn-1-yl)tert-butyl carbamate (7c)

[0249] Compound 7b (500 mg), tert-butyl propionate (3.84 g), (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (1.19 g), cuprous iodide (42.7 mg), and triethylamine (1 mL) were added to a reaction flask and dissolved in 10 mL of N,N-dimethylacetamide. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 1 hour. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to give the title compound 7c (400 mg).

[0250] d)(3-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)prop-2-yn-1-yl)tert-butyl carbamate (7d)

[0251] Compound 7c (400 mg), 3,5-difluorophenylboronic acid (158 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (59 mg), and potassium carbonate (347 mg) dissolved in 10 mL of 1,4-dioxane were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give the title compound 7d (150 mg).

[0252] e) 3-(4-(3-aminopropyl-1-yn-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzylnitrile (Compound 7)

[0253] The crude compound 7d (80 mg) was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was then subjected to preparative separation to obtain (column: X-Bridge Prep C). 18 OBD 19 mm*250 mm, 10 μm; Mobile phase A: water (0.1% HCOOH), Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Gradient: 25% B to 45% B over 10 min; Wavelength: UV 254 nm; RT (min): 9.09, Column temperature: 25℃) Compound 7 (9.2 mg). MS (ESI, m / z): 412.3 [M+H] + , 1HNMR(400MHz, DMSO-d6)δ9.07(s,1H),8.53–8.49(m,1H),8.20(d,J=8.6Hz,1H),8.02–7.98(m,1H), 7.76–7.68(m,2H),7.57–7.54(m,2H),7.45(td,J=9.4,2.4Hz,1H),7.18–7.13(m,1H),4.13(s,2H).

[0254] Example 8: 3-(3-(3,5-difluorophenyl)-4-(4-hydroxypiperidin-1-yl)quinolin-6-yl)-2-hydroxybenzyl nitrile

[0255]

[0256] a) 3-(3,4-dichloroquinoline-6-yl)-2-(methoxymethoxy)benzyl nitrile (8a)

[0257] Compound 8-1 (500 mg), compound M1 (447 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (125 mg), and potassium carbonate (427 mg) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), purged with nitrogen, and stirred overnight at 100 °C. The reaction mixture was concentrated to dry sand and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give title compound 8a (240 mg).

[0258] b) 3-(3-chloro-4-(4-hydroxypiperidin-1-yl)quinolin-6-yl)-2-(methoxymethoxy)benzylnitrile (8b)

[0259] Compound 8a (120 mg), piperidine-4-ol (41 mg), and potassium carbonate (93 mg) were dissolved in N,N-dimethylformamide (8 mL) and stirred overnight at room temperature. LCMS analysis showed that the starting material was consumed and product was present. The reaction solution was quenched with water, extracted with ethyl acetate, dried, concentrated to dry sand, and purified by column chromatography (petroleum ether:ethyl acetate = 3:7 (v / v)) to give title compound 8b (80 mg).

[0260] c) 3-(3-(3,5-difluorophenyl)-4-(4-hydroxypiperidin-1-yl)quinolin-6-yl)-2-hydroxybenzyl nitrile (Compound 8)

[0261] Compound 8b (160 mg), (3,5-difluorophenyl)boric acid (124 mg), potassium carbonate (163 mg), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (28 mg) were dissolved in 1,4-dioxane (10 mL), purged with nitrogen, and stirred overnight at 95 °C. The reaction mixture was concentrated to dryness, and the crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 25% B to 45% B over 10 min; wavelength: UV 254nm; RT (min): 9.73, column temperature: 25℃), yielded title compound 8 (6.8mg). MS (ESI, m / z): 458.0 [M+H] + , 1 H NMR (400MHz, MeOD) δ8.54–8.38(m,2H),8.07(d,J=8.8Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.63(ddd,J=30.6,7.6,1.6Hz ,2H),7.15–7.00(m,4H),3.85–3.70(m,1H),3.53–3.40(m,2H),2.92–2.79(m,2H),1.97–1.88(m,2H),1.75–1.61(m,2H).

[0262] Example 9: 3-((3-benzyl-7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl-1-amine

[0263]

[0264] a)(7-chloro-6-methoxyquinoline-3-yl)(phenyl)methyl ketone (9a)

[0265] 2-Chloro-4-methoxyaniline (5 g), 3-(dimethylamino)-1-phenylprop-2-en-1-one (8.3 g), and p-toluenesulfonic acid (12.1 g) were added to a reaction flask and dissolved in dimethyl sulfoxide (10 mL). Under nitrogen protection, the mixture was heated to 110 °C and reacted for 16 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL * 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 4:1 (v / v)) to give the title compound 9a (2 g).

[0266] b) 7-Chloro-3-(hydrazine(phenyl)methyl)-6-methoxyquinoline (9b)

[0267] Compound 9a (2g) was added to the reaction flask and dissolved in ethylene glycol (20mL). Under nitrogen protection, hydrazine hydrate (5mL) was added, and the mixture was heated to 100°C and sealed for 1 hour. The reaction solution was then concentrated to dryness to obtain the title compound 9b.

[0268] c) 3-Benzyl-7-chloro-6-methoxyquinoline (9c)

[0269] Compound 9b (2g) was added to the reaction flask and dissolved in ethylene glycol (20mL). Potassium hydroxide (1.08g) was added. Under nitrogen protection, the mixture was heated to 180°C and sealed for 3 hours. The pH of the reaction solution was adjusted to 7, extracted with dichloromethane, concentrated to dryness, and then isopropyl ether was added to slurry to obtain the title compound 9c (1g).

[0270] d) 3-Benzyl-5-bromo-7-chloro-6-methoxyquinoline (9d)

[0271] Compound 9c (1g) was added to the reaction flask and dissolved in acetic acid (10mL). N-bromosuccinimide (752mg) was added and the mixture was heated to 60℃ and reacted for 3 hours under nitrogen protection. The reaction solution was then concentrated to dryness to obtain the title compound 9d.

[0272] e) 3-Benzyl-7-chloro-6-methoxy-5-(4-(trifluoromethyl)phenyl)quinoline (9e)

[0273] Compound 9d (1 g), (4-(trifluoromethyl)phenyl)boronic acid (523 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (201 mg), and cesium carbonate (2.70 g) were added to a reaction flask and dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL * 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title compound 9e (650 mg).

[0274] f) 3-Benzyl-7-chloro-5-(4-(trifluoromethyl)phenyl)quinoline-6-ol (9f)

[0275] Compound 9e (500 mg) was added to the reaction flask and dissolved in 4 mL of acetic acid. Under nitrogen protection, 33% hydrogen bromide (2 mL) was added and the mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was then concentrated to dryness to obtain the title compound 9f.

[0276] g)(3-((3-benzyl-7-chloro-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl)tert-butyl carbamate (9g)

[0277] Compound 9f (500 mg), tert-butyl (3-bromopropyl)carbamate (345 mg), and cesium carbonate (472 mg) were added to a reaction flask and dissolved in N-methylpyrrolidone (10 mL). Under nitrogen protection, the mixture was heated to 100 °C and reacted for 1 hour. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to give 9 g (500 mg) of the title compound.

[0278] h)(3-(3-benzyl-7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl)tert-butyl carbamate (9h)

[0279] 9 g (400 mg) of compound, (3,5-dimethylphenyl)boric acid (157 mg), tetrakis(triphenylphosphine)palladium (80 mg), cesium carbonate (684 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title compound 9h (150 mg).

[0280] i) 3-((3-benzyl-7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl-1-amine (Compound 9)

[0281] The crude compound 9h (150 mg) was dissolved in 1,4-dioxane (1 mL), and 1,4-dioxane hydrochloride (1 mL) of 4M was added. The mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 40%B to 60%B over 10 minutes; wavelength: UV 254nm; RT (min): 8.46, column temperature: 25℃) yielded title compound 9 (42.5mg). 1H NMR (400MHz, DMSO-d6) δ8.77(d,1H),8.01(s,1H),7.89(d,2H),7.67(d,J=7.9Hz,2H),7.56(d,J=2.1Hz,1H),7.32(s,2H),7.29–7.23(m, 2H),7.21–7.14(m,3H),7.08(s,1H),4.10(s,2H),3.25(t,J=5.7Hz,2H),2.37(s,6H),2.19(t,J=7.5Hz,2H),1.28(q,J=6.7,5.9Hz,2H). MS(ESI,m / z):541.20[M+H] + .

[0282] Example 10: 4-(4-aminopiperidin-1-yl)-6-(3-cyano-2-hydroxyphenyl)-N-phenylquinoline-3-carboxamide

[0283]

[0284] a) Ethyl 6-bromo-4-chloroquinoline-3-carboxylic acid (10a)

[0285] A solution of ethyl 6-bromo-4-hydroxyquinoline-3-carboxylic acid (9.0 g) in phosphorus oxychloride (90 mL) was stirred for 2 hours at 110 °C. The reaction mixture was concentrated, the crude product was diluted with sodium bicarbonate (100 mL, saturated), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated to give title compound 10a (10.4 g).

[0286] b) Ethyl 6-bromo-4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)quinoline-3-carboxylic acid (10b)

[0287] To a solution of compound 10a (10.2 g) and N,N-diisopropylethylamine (20.96 g) in tetrahydrofuran (100 mL), tert-butyl piperidinium-4-ylcarbamate (16.24 g) was added. The mixture was stirred at 120 °C under N2 for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated and the crude product was purified by column chromatography (PE:EtOAc = 0 to 30% EtOAc) to give title compound 10b (11.6 g).

[0288] c) 4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-3-carboxylic acid ethyl ester (10c)

[0289] Under nitrogen atmosphere, tris(dibenzylacetone)dipalladium (230 mg) was added to a solution of compound 10b (1.2 g), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)benzyl nitrile (1.45 g), potassium phosphate (1.60 g), tricyclohexylphosphine (14 mg) in 1,4-dioxane (30 mL), and water (10 mL). The mixture was reacted in a microwave environment at 120 °C for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were concentrated and the crude product was purified by reverse-phase column chromatography (C18-I, conventional C18 20-40 μm, 120 g, acetonitrile / 0.1% ammonium bicarbonate aqueous solution, gradient: 45%–60% acetonitrile) to give title compound 10c (0.5 g).

[0290] d) 4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-3-carboxylic acid (10d)

[0291] At room temperature and under N2, a solution of lithium hydroxide (45 mg) in water (2 mL) was added to a mixture of compound 10c (350 mg), ethanol (2.0 mL), and tetrahydrofuran (2.0 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by reversed-phase column chromatography (C18-I, 120 g, mobile phase A: water (0.1% ammonium bicarbonate), B: acetonitrile, gradient: 45%–45% B) to give title compound 10d (190 mg).

[0292] e)(1-(6-(3-cyano-2-hydroxyphenyl)-3-(phenylcarbamoyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (10e)

[0293] Compound 10d (75 mg), aniline (65.7 mg), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (395.6 mg), and N-methylimidazole (115.8 mg) were dissolved in acetonitrile (4 mL) at room temperature. The reaction mixture was concentrated to give a crude product. The crude product was diluted with water (40 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were concentrated to give a crude product. The crude product was purified by reverse-phase column chromatography (WelFlash C18-I, Regular C18 20-40 μm, 80 g; mobile phase A: water (0.1% ammonium bicarbonate), B: acetonitrile; flow rate: 50 mL / min; isocratic ratio: 67% B) to give title compound 10e (40 mg).

[0294] f) 4-(4-aminopiperidin-1-yl)-6-(3-cyano-2-hydroxyphenyl)-N-phenylquinoline-3-carboxamide (Compound 10)

[0295] At 0 °C, trifluoroacetic acid (1 mL) was added to a solution of compound 10e (40 mg) in dichloromethane (5 mL). The mixture was stirred for 4 hours while slowly raising it to room temperature. The reaction mixture was concentrated to give a crude product. The crude product was purified by reverse-phase column chromatography (WelFlash C18-I, Regular C18 20-40 μm, 80 g; mobile phase A: water (0.1% ammonium bicarbonate), B: acetonitrile; flow rate: 50 mL / min; isocratic ratio: 39% B) to give title compound 10 (24.31 mg). 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.68(s,1H),8.63(s,1H),8.04(d,J=8.8Hz,1H),7.90(d,J=8.8Hz,1H),7.77(d,J=7.8Hz,2H),7.41 –7.35(m,3H),7.21–7.08(m,2H),6.23–6.19(m,1H),3.56(d,J=12.6Hz,2H),3.19–3.10(m,3H),2.00(d,J=10.0Hz,2H),1.93–1.82(m,2H). MS(ESI,m / z):464.0[M+H] + .

[0296] Example 11: 4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-N-phenylquinoline-6-carboxamide

[0297]

[0298] a)(1-(6-bromo-3-chloroquinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (11a)

[0299] Compound 6-bromo-3,4-dichloroquinoline (1.14 g) and piperidin-4-ylcarbamate tert-butyl ester (8.2 g) were dissolved in N,N-dimethylaniline (20 mL), purged with nitrogen, and N,N-diisopropylethylamine (5.3 g) was added. The reaction temperature was raised to 120 °C, and the reaction was carried out for 3 hours. The reaction solution was concentrated to dryness to obtain a crude product, which was then subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give the title compound 11a (1.2 g).

[0300] b) Methyl 4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-chloroquinoline-6-carboxylate (11b)

[0301] Compound 11a (2.92 g), triethylamine (10.01 g), methanol (100 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (970 mg) were added to a reaction flask. The mixture was stirred at 70 °C under CO2 conditions for 16 hours. The reaction mixture was concentrated and the crude product was diluted with water (100 mL) and extracted with ethyl acetate (100 × 3 mL). The combined organic layers were concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give title compound 11b (2.3 g).

[0302] b) Methyl 4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-carboxylate (11c)

[0303] Compound 11b (851 mg), (3,5-difluorophenyl)boric acid (800.2 mg), cyclohexylphosphine (113.7 mg), potassium phosphate (1.291 g), tris(dibenzylacetone)dipalladium (185.6 mg), and 1,4-dioxane / water (21 mL / 7 mL) were added to the reaction flask. The mixture was stirred at 120 °C under nitrogen for 2 hours. The reaction mixture was filtered. After completion, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (80 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 11c (860 mg).

[0304] c) 4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-carboxylic acid (11d)

[0305] Compound 11c (870 mg) was dissolved in methanol (18.0 mL) under nitrogen atmosphere at room temperature, and then a solution of lithium hydroxide (209 mg) in water (5 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by reversed-phase column chromatography (C18 20–40 μm, 120 g, acetonitrile / 0.1% ammonium bicarbonate aqueous solution, gradient: 45%–45% acetonitrile) to give title compound 11d (550 mg).

[0306] d)(1-(3-(3,5-difluorophenyl)-6-(phenylcarbamoyl)quinolin-4-yl)piperidin-4-yl)tert-butyl carbamate (11e)

[0307] Aniline (96 mg) was added to compound 11d (100 mg). Then, N,N,N',N'-tetramethylchloromethylammonium hexafluorophosphate (580 mg) and N-methylimidazole (168 mg) were added at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the crude product was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were concentrated, and the residue was slurried to provide the final product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 4:1 (v / v)) to give title compound 11e (50 mg).

[0308] e) 4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-N-phenylquinoline-6-carboxamide (Compound 11)

[0309] A solution of trifluoroacetic acid (1 mL) in dichloromethane (10 mL) was added to compound 11e (50 mg), and the mixture was stirred at 0 °C. The mixture was slowly brought to room temperature and stirred for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (WelFlash C18-I, Regular C18 20-40 μm, 80 g; mobile phase A: 10 mmol NH4HCO3 / H2O; B: MeCN; flow rate: 50 mL / min; isocratic rate: 61.3% B) to give title compound 11 (33.03 mg). 1 HNMR (400MHz, DMSO-d6) δ10.53(s,1H),8.72(d,J=1.6Hz,1H),8.61(s,1H),8.27(dd,J=8.8,2.0Hz,1H),8.10(d,J=8.6Hz,1H),7.84(d,J= 7.6Hz, 2H), 7.43–7.31 (m, 3H), 7.22–7.10 (m, 3H), 3.28–3.25 (m, 2H), 2.71 (t, J = 10.8Hz, 3H), 1.77 (d, J = 9.6Hz, 2H), 1.51 (d, J = 9.2Hz, 2H). MS(ESI,m / z):459.1[M+H] + .

[0310] Example 12: 3-Amino-N-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)propionamide

[0311]

[0312] a)(3-((3-chloro-6-methoxyquinoline-4-yl)amino)-3-oxopropyl)tert-butyl carbamate (12a)

[0313] 3-Chloro-6-methoxyquinoline-4-amine was dissolved in acetonitrile, and 3-((tert-butoxycarbonyl)amino)propionic acid, N-methylimidazolium, and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate were added and stirred at room temperature for 2 hours. LCMS analysis showed that the starting material was consumed and the product was detected. The reaction solution was quenched with water, extracted with ethyl acetate, concentrated, prepared into a granulated slurry, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 12a (2 g).

[0314] b)(3-((3,5-difluorophenyl)-6-methoxyquinoline-4-yl)amino)-3-oxopropyl)tert-butyl carbamate (12b)

[0315] Compound 12a (200 mg), (3,5-difluorophenyl)boronic acid (100 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (112 mg), and cesium carbonate (344 mg) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen, and heated to 100 °C with stirring for 3 hours. Four batches of the reaction solution were combined, quenched with water, extracted with ethyl acetate, dried, concentrated to dry sand, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1 (v / v)) to give title compound 12b (300 mg).

[0316] c) 3-Amino-N-(3-(3,5-difluorophenyl)-6-hydroxyquinoline-4-yl)propionamide (12c)

[0317] Compound 12b (600 mg) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and boron tribromide (493 mg) was added. The mixture was then purged with nitrogen and stirred at 0 °C for hours. The reaction solution was quenched with water, extracted, and purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the title compound 12c (500 mg).

[0318] d)(3-((3,5-difluorophenyl)-6-hydroxyquinoline-4-yl)amino)-3-oxopropyl)tert-butyl carbamate (12d)

[0319] Compound 12c (500 mg) was dissolved in tetrahydrofuran (10 mL), and triethylamine (29 mg) and di-tert-butyl dicarbonate (318 mg) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was extracted, concentrated to dryness, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to give the title compound 12d (300 mg).

[0320] e)4-(3-((tert-Butoxycarbonyl)amino)propamido)-3-(3,5-difluorophenyl)quinoline-6-yltrifluoromethanesulfonate (12e)

[0321] Compound 12d (120 mg) was dissolved in N,N-dimethylformamide (6 mL), and triethylamine (55 mg) and N-phenyl-O-((trifluoromethyl)sulfonyl)-N-(((trifluoromethyl)sulfonyl)oxy)hydroxylamine (105 mg) were added. The mixture was heated to 60 °C and stirred for 2 hours. The reaction solution was extracted, concentrated to dryness, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1 (v / v)) to give the title compound 12e (90 mg).

[0322] f)(3-((6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)amino)-3-oxopropyl)tert-butyl carbamate (12f)

[0323] Compound 12e (90 mg) was dissolved in 1,4-dioxane (5 mL), and potassium carbonate (45 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (18 mg), and compound M1 (54 mg) were added. The mixture was purged with nitrogen and stirred at 100 °C for 5 hours. LC-MS analysis showed that the reactants were consumed and products were present. The reaction solution was quenched with water, extracted with ethyl acetate, and concentrated to dryness to obtain the title compound 12f (110 mg).

[0324] g) 3-Amino-N-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)propionamide (Compound 12)

[0325] Compound 12f (110 mg) was dissolved in 1,4-dioxane (3 mL), and 1,4-dioxane hydrochloride (3 mL) was added. The mixture was stirred at room temperature for 2 hours. LCMS analysis showed that the reactants were consumed and products were present. The reaction solution was concentrated to dryness, and the crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 20%B to 40%B over 10 min; wavelength: UV 254nm; RT (min): 9.24, column temperature: 25℃) yielded the title compound 12 (19mg). 1 H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.85(s,1H),8.22(s,1H),8.15–7.95(m,2H),7.65(d, J=7.5Hz,1H),7.39–7.20(m,3H),6.32(t,J=7.6Hz,1H),3.12(d,J=6.7Hz,2H),2.80(s,2H). MS(ESI,m / z):445.2[M+H] + .

[0326] Example 13: N-(4-(4-aminopiperidin-1-yl)-6-(3-cyano-2-hydroxyphenyl)quinoline-3-yl)benzamide

[0327]

[0328] a)(1-(6-bromo-3-nitroquinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (13a)

[0329] 6-Bromo-4-chloro-3-nitro-4a,5-dihydroquinoline (900 mg) and piperidine-4-ylcarbamate tert-butyl ester (1.26 g) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (1.215 g) was added. The reaction was carried out at 120 °C under nitrogen protection for 2 hours. After the reaction was completed, 1 mL of water was added, and the mixture was concentrated to dryness. The mixture was extracted with water and ethyl acetate, the organic layer was dried, and the residue was prepared by column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give the title compound 13a.

[0330] b)(1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-nitroquinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (13b)

[0331] Compound 13a (1.3 g), borate ester (1.01 g), cesium carbonate (2.8 g), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (237 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and reacted for 2 hours. The reaction solution was concentrated to dryness and subjected to column chromatography (petroleum ether: ethyl acetate = 4:1 (v / v)) to give the title compound 13b (800 mg).

[0332] c)(1-(3-amino-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (13c)

[0333] Compound 13b (50 mg) was dissolved in ethanol (mL), palladium on carbon (50 mL) was added, hydrogen gas was displaced, and the reaction was carried out at room temperature for 2 hours. The mother liquor obtained by filtration was concentrated to dryness to give the title compound 13c.

[0334] d)(1-(3-benzylamino-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (13d)

[0335] Compound 13c (60 mg) was dissolved in acetonitrile at room temperature. Benzoic acid (43.9 mg), N,N,N',N'-tetramethylchloromethylammonium hexafluorophosphate (131 mg), N-methylimidazole (40 mg), and acetonitrile (4 mL) were added to the reaction flask. The mixture was reacted overnight under nitrogen protection. The reaction solution was concentrated to dryness to give the title compound 13d.

[0336] e)N-(4-(4-aminopiperidin-1-yl)-6-(3-cyano-2-hydroxyphenyl)quinoline-3-yl)benzamide (Compound 13)

[0337] A DCM solution of compound 13d (40 mg) was added dropwise to a DCM solution of trifluoroacetic acid (2.5 mL) (5 mL), and the mixture was stirred until the reactants reacted completely. The reaction solution was concentrated, and the crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: X-Bridge Prep C18OBD, 19 mm * 250 mm, 10 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 8% B to 28% B over 10 minutes; wavelength: UV 254 nm; RT (min): 9.75, column temperature: 25 °C) to give title compound 13 (20 mg). 1 H NMR (400MHz, DMSO-d6) δ10.26 (s, 1H), 8.59 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 8.11 –8.02(m,3H),7.83(dd,J=8.6,1.9Hz,1H),7.71(d,J=7.7Hz,2H),7.65(dd,J=8 .4,6.0Hz,1H),7.59(dd,J=8.3,6.6Hz,2H),7.16(t,J=7.7Hz,1H),3.50(s,2H) ,3.22(d,J=42.7Hz,3H), 1.97(d,J=10.2Hz,2H), 1.75(dt,J=12.2,5.9Hz,2H). MS(ESI, m / z): 464.2 [M+H] + .

[0338] Example 14: 4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-N-(3-hydroxyphenyl)quinoline-6-carboxamide

[0339]

[0340] a)(1-(3-(3,5-difluorophenyl)-6-((3-hydroxyphenyl)carbamoyl)quinoline-4-yl)piperidin-4-yl)tert-butyl carbamate (14a)

[0341] Compound 11d (50 mg), 3-aminophenol (23 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (120 mg), N,N-diisopropylethylamine (41 mg), and N,N-dimethylformamide (5.00 mL) were added to the reaction mixture at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography, eluting with acetonitrile / water (3:2) to give title compound 14a (20 mg).

[0342] b) 4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-N-(3-hydroxyphenyl)quinoline-6-carboxamide (Compound 14)

[0343] At 0 °C, trifluoroacetic acid (0.60 mL) was added dropwise to a stirred solution of compound 14a (15 mg) in dichloromethane (3.00 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to give a crude product. Purification was performed using a reversed-phase column (C18-I, conventional C18 20-40 μm, 120 g, mobile phase A: water (0.1% formic acid), B: acetonitrile, gradient: 50%–55% acetonitrile) to give title compound 14 (11.35 mg). 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.69(s,1H),8.61(s,1H),8.25(d,J=9.0Hz,1H),8.08(d,J=8.6Hz,1H),7.43(s,1H),7.35(t,J=9.6Hz, 1H),7.18(dq,J=15.8,8.0Hz,4H),6.54(d,J=8.0Hz,1H),3.26–3.24(m,3H),2.75-2.68(m,2H),1.77(d,J=13.0Hz,2H),1.50(d,J=8.2Hz,2H). MS(ESI,m / z):475.3[M+H] + .

[0344] Example 15: 3-(4-(4-(1-aminocyclopropyl)piperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzyl nitrile

[0345]

[0346] a) 3-Chloro-6-iodoquinoline-4-ol (15a)

[0347] Under nitrogen atmosphere, 6-iodoquinoline-4-ol (5g) was dissolved in acetic acid (50mL), and N-chlorosuccinimide (3.7g) was added. The mixture was stirred at 60°C for 3 hours. The reaction solution was filtered to obtain crude compound 15a.

[0348] b) 3,4-Dichloro-6-iodoquinoline (15b)

[0349] Compound 15a (2 g) was dissolved in phosphorus oxychloride (10 mL) under nitrogen atmosphere and stirred at 90 °C for 3 hours. The reaction solution was then added to water (50 mL) and stirred for 1 hour. Dichloromethane (50 mL * 2) was added for extraction. The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1 (v / v)) to give the title compound 15b (1.5 g).

[0350] c)(1-(1-(3-chloro-6-iodoquinoline-4-yl)piperidin-4-yl)cyclopropyl)tert-butyl carbamate (15c)

[0351] Compound 15b (161 mg) and (1-(piperidin-4-yl)cyclopropyl)carbamate tert-butyl ester (250 mg) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (193 mg) was added. The reaction was carried out at 120 °C under nitrogen protection for 6 hours. After the reaction was completed, 1 mL of water was added, and the mixture was concentrated to dryness. Then, water and ethyl acetate were added for extraction. The organic layer was dried, sand was prepared, and column chromatography was used to obtain compound 15c (240 mg).

[0352] d)(1-(1-(3-chloro-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)piperidin-4-yl)cyclopropyl)carbamate tert-butyl ester (15d)

[0353] Compound 15c (240 mg), compound M1 (160 mg), cesium carbonate (439 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (36 mg), and 1,4-dioxane (5 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and reacted for 2 hours. The reaction solution was concentrated to dryness, and compound 15d (120 mg) was obtained by column chromatography.

[0354] e)(1-(1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)piperidin-4-yl)cyclopropyl)tert-butyl carbamate (15e)

[0355] Compound 15d (120 mg) was dissolved in 1,4-dioxane (3 mL), and (3,5-difluorophenyl)boric acid (40 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (15 mg) and cesium carbonate (204 mg) were added. Nitrogen gas was purged, and the reaction was carried out at 100 °C for 2 hours. The reaction solution was filtered and concentrated to dryness to obtain compound 15e (60 mg).

[0356] f) 3-(4-(4-(1-aminocyclopropyl)piperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzyl nitrile (Compound 15)

[0357] At room temperature, 1,4-dioxane hydrochloride (4 mol / L, 3 mL) was added to compound 15e (60 mg), and the reaction was carried out for 1 hour at room temperature. The reaction solution was concentrated to dryness, and the crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 15%B to 35%B over 10 min; wavelength: UV 254nm; RT (min): 9.12, column temperature: 25℃) yielded compound 15 (24mg). 1 HNMR(400MHz,DMSO-d6)δ9.05(s,1H),8.51(s,1H),8.06–7.88(m,2H),7.62(d d,J=7.6,1.9Hz,1H),7.39–7.28(m,2H),7.23–7.11(m,2H),6.56(t,J=7.6Hz,1 H),3.60–3.45(m,1H),3.27(d,J=12.3Hz,2H),2.63(t,J=12.3Hz,2H),1.89(d ,J=12.2Hz,2H),1.58(d,J=12.2Hz,2H),1.24–1.08(m,1H),0.79–0.46(m,4H). MS(ES,m / z):497.2[M+H] + .

[0358] Example 16: 3-(4-(8-amino-5-azaspiro[2.5]oct-5-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzyl nitrile

[0359]

[0360] Referring to the preparation method of intermediate 11a in Example 11, replacing piperidine-4-ylcarbamate tert-butyl ester in step a) with (5-azaspiro[2.5]octane-8-yl)carbamate tert-butyl ester yields compound 16-1 (5-(6-bromo-3-chloroquinoline-4-yl)-5-azaspiro[2.5]octane-8-yl)carbamate tert-butyl ester).

[0361] a)(5-(3-chloro-6-(3-cyano-2-(methoxymethoxy)phenyl)quinoline-4-yl)-5-azaspiro[2.5]oct-8-yl)tert-butyl carbamate (16a)

[0362] Compound 16-1 (300 mg) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (450 mg), compound M1 (115 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (53 mg) were added. The mixture was purged with nitrogen and stirred at 90 °C for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, dried over an organic phase, prepared as sinter, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to give the title compound 16a (300 mg).

[0363] b)(5-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)-5-azaspiro[2.5]oct-8-yl)tert-butyl carbamate (16b)

[0364] Compound 16a (100 mg) was dissolved in 1,4-dioxane (10 mL) and water (0.1 mL), and cesium carbonate (120 mg), (3,5-difluorophenyl)boric acid (57 mg), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (13 mg) were added. The mixture was purged with nitrogen and stirred at 90 °C for 5 hours. The reaction solution was quenched with water, extracted with ethyl acetate, dried over an organic phase, prepared as sinter, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to give the title compound 16b (80 mg).

[0365] c) 3-(4-(8-amino-5-azaspiro[2.5]oct-5-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzylnitrile (Compound 16)

[0366] Compound 16b (80 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, concentrated to dryness, and the residue was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 7%B to 27%B over 10 min; wavelength: UV 254nm; RT (min): 9.08, column temperature: 25℃) yielded title compound 16 (11.24mg). 1 HNMR(400MHz,DMSO-d6)δ8.59(s,1H),8.44(s,1H),7.92(s,2H),7.45(dd,J=7.2 ,2.0Hz,1H),7.30(ddq,J=9.6,5.6,3.6,3.2Hz,2H),7.13(dd,J=8.0,2.4Hz,2H) ,6.50(t,J=7.6Hz,1H),3.50–3.30(m,3H),3.09(d,J=12.4Hz,1H),2.89(t,J=4. 4Hz,1H),2.33(s,1H),2.07(s,1H),1.86(s,1H),0.65–0.48(m,2H),0.24(s,2H). MS(ES,m / z):483.4[M+H] + .

[0367] Example 17: 7-(6-(4-aminopiperidin-1-yl)-7-(3,5-difluorophenyl)isoquinoline-4-yl)-1-hydroxy-2-naphthyl nitrile

[0368]

[0369]

[0370] a)(5-chloro-1H-inden-3-yl)oxy)triisopropylsilane (17B)

[0371] Compound 17A (10 g), triisopropylsilyl trifluoromethanesulfonate (20.2 g), and triethylamine (8.5 g) were dissolved in chloroform (100 mL) at room temperature, and the mixture was stirred for 1 hour at room temperature. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title compound 17B (12.7 g).

[0372] b)((2-bromo-7-chloronaphth-1-yl)oxy)triisopropylsilane(17C)

[0373] Compound 17B (10 g) was dissolved in n-hexane (31 mL), cooled to -78 °C, and a suspension of potassium tert-butoxide (15.6 g) in n-hexane (139 mL) was added at -78 °C. After 20 minutes, a solution of tribromomethane (15.7 g) in n-hexane (62 mL) was added dropwise at -78 °C, and the mixture was stirred at this temperature for one hour. The reaction mixture was then heated to 23 °C and stirred for another hour over one hour. The solvent was removed under reduced pressure to give crude product 17C (12.8 g).

[0374] c) 2-Bromo-7-chloronaphth-1-ol (17D)

[0375] Compound 17C was dissolved in N,N-dimethylformamide:water (20:1 (v / v), 13.44 mL), and potassium acetate (3.04 g) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ethyl acetate and brine, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 9:1 (v / v)) to give compound 17D (8.6 g).

[0376] d) 7-Chloro-1-hydroxy-2-naphthoonitrile (17E)

[0377] A solution of compound 17D (2 g), zinc cyanide (4.56 g), 1,1'-bis(diphenylphosphine)ferrocene (1.72 g), and tris(dibenzylacetone)palladium (1.42 g) in N,N-dimethylaniline (20 mL) was stirred at 135 °C for 4 hours. After cooling to ambient temperature, the reaction solution was adjusted to pH 5 with hydrochloric acid (1 N), then extracted with EA, and purified by preparative TLC on silica gel (oil ether: ethyl acetate = 3:1 (v / v)) to give compound 17D (180 mg).

[0378] e) 1-Hydroxy-7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-2-naphthonitrile (17-1)

[0379] A solution of compound 17D (180 mg), bis(pinarate)diboron (673 mg), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (37 mg), tris(dibenzylacetone)dipalladium (40 mg), and potassium acetate (260 mg) was prepared in 1,4-dioxane (5 mL). The mixture was then stirred at 135 °C for 4 hours under nitrogen. After cooling to ambient temperature, the reaction was extracted with ethyl acetate and water, followed by purification by thin-layer chromatography on silica gel (oil / ether:ethyl acetate = 5:1 (v / v)) to give compound 17-1 (100 mg).

[0380] f)(1-(4-bromo-7-chloroisoquinoline-6-yl)piperidin-4-yl)tert-butyl carbamate (17a)

[0381] Compound 4-bromo-7-chloro-6-fluoroisoquinoline (2 g), potassium carbonate (2.1 g), and piperidine-4-ylcarbamate tert-butyl ester (1.85 g) were dissolved in N,N-dimethylformamide and reacted under nitrogen atmosphere at 90 °C for 12 hours. The reaction solution was extracted with ethyl acetate and water, and the organic phase was washed with water. The crude product obtained by concentrating the organic phase was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to give title compound 17a (2.3 g).

[0382] g)1-(7-chloro-4-(7-cyano-8-hydroxynaphth-2-yl)isoquinoline-6-yl)piperidin-4-yl)tert-butyl carbamate (17b)

[0383] Compound 17a (67 mg), compound 17-1 (90 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (12.4 mg), and potassium carbonate (42 mg) were dissolved in 1,4-dioxane (0.9 mL) and water (0.1 mL). The mixture was then stirred at 100 °C for 2 hours under nitrogen. After cooling to ambient temperature, the mixture was extracted with ethyl acetate and water, followed by preparative TLC (petroleum ether:ethyl acetate = 5:1 (v / v)) purification to give title compound 17b (25 mg).

[0384] h)1-(4-(7-cyano-8-hydroxynaphth-2-yl)-7-(3,5-difluorophenyl)isoquinoline-6-yl)piperidin-4-yl)tert-butyl carbamate (17c)

[0385] Compound 17b (25 mg), (3,5-difluorophenyl)boronic acid (25 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (7 mg), and cesium carbonate (3.1 mg) were dissolved in 1,4-dioxane. The mixture was stirred at 120 °C for 16 hours. The mixture was extracted with ethyl acetate and water / salt solution, dried over anhydrous sodium sulfate, and concentrated to give the title compound 17c (25 mg).

[0386] i) 7-(6-(4-aminopiperidin-1-yl)-7-(3,5-difluorophenyl)isoquinoline-4-yl)-1-hydroxy-2-naphthonitrile (Compound 17)

[0387] Compound 17c (25 mg) was dissolved in 1,4-dioxane hydrochloric acid solution (1 mL, 4 M) and stirred at room temperature for 2 hours. The reaction solution was directly concentrated and dried by rotary evaporation to give 50 mg of crude product. Then, it was purified by preparative HPLC (Waters 2767 / Qda, column: XBridge C18, 10 μm, 19*250 mm; mobile phase A: water (0.05% ammonia) B: acetonitrile; flow rate: 20 mL / min; gradient: 29% B to 33% B over 10 min; RT: 9.25 min) to give title compound 17 (3.71 mg). 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.54(s,1H),8.48(s,1H),8.07(s,1H),7.80(d,J=8.2Hz,1H),7.71(d,J=9.6Hz,2H),7.35(d,J= 6.6Hz,2H),7.20(d,J=8.4Hz,2H),6.71(s,1H),3.16–3.01(m,3H),2.71(t,J=12.2Hz,2H),1.78–1.66(m,2H),1.57(d,J=9.4Hz,2H). MS(ESI,m / z):507.2[M+H] + .

[0388] Example 18: 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2-hydroxybenzyl nitrile

[0389]

[0390] Step 1-1: Lithium chloride (5.3 g), tris(dibenzylacetone)dipalladium (1.9 g), and tricyclohexylphosphine (1.2 g) were added to a solution of compound M1-1 (5.0 g) and hexabutyltin (14.3 g) in 1,4-dioxane (100 mL). The mixture was stirred at 100 °C for 4 hours. The reaction mixture was diluted with ammonium chloride (20 mL, saturated) and filtered. The combined reaction mixture was diluted with 50 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 50:1, (v / v)) gave 2-(methoxymethoxy)-3-(tributyltinyl)benzyl nitrile (compound 18-1, 750 mg).

[0391] a) Methyl 2-(3,5-difluorophenyl)-3-(dimethylamino)acrylate (18a)

[0392] 1,1-Dimethoxy-N,N-dimethylmethylamine (199.2 g) was added to a solution of 24.0 g of 2-(3,5-difluorophenyl)acetic acid in 240 mL of N,N-dimethylformamide at room temperature. The mixture was stirred at 120 °C under a nitrogen atmosphere for 4 hours. After completion, the reaction was quenched with ice water (300 mL), followed by extraction three times with ethyl acetate (400 mL). The organic phase was washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 18a (23 g).

[0393] b) 7-Bromo-3-(3,5-difluorophenyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (18b)

[0394] 1.69 g of 5-bromo-4-methoxypyridine-2-amine was added to a 40 mL acetic acid solution of compound 18a (2.0 g) at room temperature. The mixture was stirred at 140 °C under a nitrogen atmosphere for 5 hours. After completion, the reaction was cooled to room temperature and filtered. The filter cake was washed with n-hexane and concentrated to give title compound 18b (1.3 g).

[0395] c) 7-Bromo-3-(3,5-difluorophenyl)-4-hydroxy-8H-pyrido[1,2-a]pyrimidin-8-one (18c)

[0396] Compound 18b (1.0 g) was dissolved in a hydrobromic acid solution of acetic acid (250 mL) and stirred at 110 °C for 16 hours. After completion, the mixture was filtered and concentrated to give the title compound 18c (0.9 g).

[0397] d)(1-(7-bromo-3-(3,5-difluorophenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-4-yl)piperidin-4-yl)tert-butyl carbamate (18d)

[0398] To a solution of compound 18c (0.9 g) and piperidine-4-ylcarbamate tert-butyl ester (664 mg) in N,N-dimethylformamide (20 mL), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (1.988 g) and 1,8-diazacyclo[5,4,0]undecene-7 (319 mg) were added. The mixture was stirred at room temperature for 16 hours. The combined reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were concentrated to give a crude product. The crude product was subjected to reversed-phase column chromatography (C18-I, 20–40 μm, 80 g, acetonitrile / 0.1% formic acid aqueous solution, gradient: 55%–60% acetonitrile) to give title compound 18d (800 mg).

[0399] e)(1-(7-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-4-yl)piperidin-4-yl)tert-butyl carbamate (18e)

[0400] Compound 18d (100 mg), compound 18-1 (423 mg), cuprous iodide (356 mg), tetrakis(triphenylphosphine)palladium (22 mg), and lithium chloride (79 mg) were dissolved in N,N-dimethylformamide (4 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at 60 °C for 6 hours. The reaction mixture was quenched with ammonium chloride (saturated, 30 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol = 20:1, v / v) to give the title compound 18e (63 mg).

[0401] f) 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2-hydroxybenzyl nitrile (Compound 18)

[0402] Compound 18e (42 mg) was dissolved in 1,4-dioxane hydrochloride (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the crude product. The crude product was analyzed by preparative HPLC (C18 xbridge 21.2*250 mm, 10 μm, mobile phase A: water (0.05% ammonia), B: acetonitrile, gradient: 32% B to 33% B over 10 min, flow rate: 20 mL / min, RT: 8.25 min) to give title compound 18 (2.7 mg). MS (ESI, m / z): 474.2 [M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.67(s,1H),8.56(s,1H),7.68(d,J=9.2Hz,2H),7.32-7.20(m,2H),7.05(t, J=9.0Hz,1H),6.67(s,1H),6.25(s,1H),3.90(s,3H),3.09(d,J=11.2Hz,2H),2.11(s,2H),1.74(d,J=14.2Hz,2H).

[0403] Example 19: 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrimidino[1,2-b]pyridazine-7-yl)-2-hydroxybenzyl nitrile

[0404]

[0405] a)(6-chloro-5-methoxypyridazine-3-yl)tert-butyl carbamate (19a)

[0406] Under nitrogen atmosphere, cesium carbonate (26 g), palladium acetate (0.88 g), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (4.86 g) were added to a solution of 1,4-dioxane (100 mL) of 3,6-dichloro-4-methoxy-1,2-dihydropyridazine (10 g) and tert-butyl carbamate (8.6 g). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with ammonium chloride (30 mL, saturated) and filtered. The filtrate was extracted three times with ethyl acetate (200 mL). The organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) gave title compound 19a (2.5 g).

[0407] b) 6-Chloro-5-methoxypyridazine-3-amine (19b)

[0408] At 0 °C, trifluoroacetic acid (12.5 mL) was added to a solution of compound 19a (2.5 g) in dichloromethane (50 mL). The mixture was stirred at room temperature (0 °C) for 5 hours. The reaction mixture was then concentrated directly to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3 (v / v)) to give title compound 19b (1 g).

[0409] c) 7-Chloro-3-(3,5-difluorophenyl)-8-methoxy-4H-pyrimidino[1,2-b]pyridazin-4-one (19c)

[0410] Compound 19b (1 g) and methyl 2-(3,5-difluorophenyl)-3-(dimethylamino)acrylate (1.6 g) were dissolved in acetic acid (50 mL) and stirred at 140 °C for 16 hours. The reaction mixture was then concentrated and the crude product was purified by reverse-phase column chromatography (acetonitrile:water = 1:1 (v / v)) to give title compound 19c (0.5 g).

[0411] d) 7-Bromo-3-(3,5-difluorophenyl)-4-hydroxy-8H-pyrimidino[1,2-b]pyridazin-8-one (19d)

[0412] Compound 19c (400 mg) was dissolved in acetic acid solution of hydrogen bromide (125 mL) and stirred at 110 °C for 16 hours. The mixture was filtered and the filter cake was concentrated to give title compound 19d (0.6 g).

[0413] e)(1-(7-bromo-3-(3,5-difluorophenyl)-8-oxo-8H-pyrimidino[1,2-b]pyridazin-4-yl)piperidin-4-yl)tert-butyl carbamate (19e)

[0414] Hexachlorocyclotriphosphazene (258.4 mg) and potassium phosphate (404.4 mg) were added to a solution of compound 19d (270 mg) in acetonitrile (27 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Then, a solution of piperidine-4-ylcarbamate tert-butyl ester (167.9 mg) in acetonitrile (16 mL) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The pH of the crude product was adjusted to 12–13 with potassium carbonate (aqueous solution). The reaction mixture was concentrated to remove acetonitrile. After completion, the reaction mixture was diluted with water (80 mL) and extracted with dichloromethane (100 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol = 20:1 (v / v)) to give title compound 19e (78 mg).

[0415] f)(1-(7-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrimidino[1,2-b]pyridazin-4-yl)piperidin-4-yl)tert-butyl carbamate (19f)

[0416] Compound 19e (106 mg), compound 1-1 (447.7 mg), and cuprous iodide (377.1 mg) were mixed at room temperature under nitrogen atmosphere. The mixture was stirred at 60 °C for 6 hours. The reaction mixture was quenched with ammonium chloride (saturated, 40 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1 to 1:1 (v / v)) to give the title compound 19f (100 mg).

[0417] g)3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-8-oxo-8H-pyrimidino[1,2-b]pyridazine-7-yl)-2-hydroxybenzylnitrile (Compound 19)

[0418] 1,4-dioxane hydrochloride (4 mL) was added to a solution of compound 19f (80 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the crude product. The crude product was subjected to preparative HPLC (C18 xbridge 21.2*250 mm, 10 μm, mobile phase A: water (0.05% ammonia), B: acetonitrile, gradient: 22% B to 23% B over 10 min, flow rate: 20 mL / min, RT: 9.65 min) to give title compound 19 (3.91 mg). MS (ESI, m / z): 475.2 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.65(d,J=7.8Hz,2H),7.29(s,1H),7.25– 7.04(m,3H),6.18(s,1H),3.76(s,3H),2.92(s,2H),1.75(s,2H),1.47(s,2H).

[0419] Example 20: 3-((7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)prop-1-amine

[0420]

[0421] a) 5-Bromo-7-chloro-6-methoxyquinoline (20a)

[0422] 7-Chloro-6-methoxyquinoline (1g) was added to the reaction flask and dissolved in acetic acid (10mL). N-bromosuccinimide (1.1g) was added and the mixture was heated to 60°C and reacted for 3 hours under nitrogen protection. The reaction solution was then concentrated to dryness to obtain the title compound 20a.

[0423] b) 7-Chloro-6-methoxy-5-(4-(trifluoromethyl)phenyl)quinoline (20b)

[0424] Compound 20a (1 g), (4-(trifluoromethyl)phenyl)boronic acid (696 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (268 mg), and cesium carbonate (3.59 g) dissolved in 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 hours. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL * 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL * 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title compound 20b (650 mg).

[0425] c) 7-Chloro-5-(4-(trifluoromethyl)phenyl)quinoline-6-ol (20c)

[0426] Compound 20b (500 mg) was added to the reaction flask and dissolved in acetic acid (10 mL). 33% hydrobromic acid (2 mL) was added. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was then concentrated to dryness to obtain the title compound 20c.

[0427] d)(3-((7-chloro-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl)tert-butyl carbamate (20d)

[0428] Compound 20c (500 mg), tert-butyl (3-bromopropyl)carbamate (441 mg), cesium carbonate (603 mg), and N-methylpyrrolidone (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 1 hour. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to give the title compound 20d (400 mg).

[0429] e)(3-((7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl)tert-butyl carbamate (20e)

[0430] Compound 20d (400 mg), (3,5-dimethylphenyl)boric acid (187 mg), tetrakis(triphenylphosphine)palladium (96 mg), cesium carbonate (813 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and reacted for 3 h. The reaction solution was concentrated to dryness, and extracted with ethyl acetate (50 mL x 2) and water (50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried, and concentrated to dryness to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to give the title compound 20e (55 mg).

[0431] f)3-((7-(3,5-dimethylphenyl)-5-(4-(trifluoromethyl)phenyl)quinoline-6-yl)oxy)propyl-1-amine (Compound 20)

[0432] The crude compound 20e (55 mg) was dissolved in 1,4-dioxane (1 mL), and 1,4-dioxane hydrochloride (4 M) was added. The mixture was stirred at 20 °C for 2 h. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (column: X-Bridge Prep C). 18 OBD, 19mm*250mm, 10μm; mobile phase A: water (0.1% HCOOH), mobile phase B: acetonitrile; flow rate: 20mL / min; gradient: 30%B to 50%B over 10 minutes; wavelength: UV 254nm; RT (min): 8.75, column temperature: 25℃) yielded the title compound 20 (7mg). 1H NMR (400MHz, DMSO-d6) δ8.89(d,J=4.2Hz,1H),8.05(s,1H),7.92(d,J=7.9Hz,2H),7.79–7.66(m,3H),7.47(dd,J=8 .6, 4.1Hz, 1H), 7.34 (s, 2H), 7.10 (s, 1H), 3.29 (t, J = 5.8Hz, 2H), 2.38 (s, 6H), 2.26–2.16 (m, 2H), 1.34–1.26 (m, 2H). MS(ESI,m / z):451.2[M+H] + .

[0433] The compounds in Table 1 were prepared by modifying some of the raw materials, referring to the preparation methods in the above examples.

[0434] Table 1

[0435]

[0436]

[0437]

[0438] Test Example 1 uses cells expressing human SSTR2 to evaluate the agonistic activity of the compound against SSTR2.

[0439] 5000 stable human SSTR2-expressing CHO cells (purchased from Nanjing Kebai) were seeded in 384-well cell culture plates. Cells were diluted with 1× stimulation buffer (HTRF cAMP Gi Detection Kit, Revvity). The test compound was dissolved in DMSO (dimethyl sulfoxide) to prepare a 1 mM stock solution. The cell culture plates were placed on an automated liquid dispenser D300e (Tecan), with the dispensing program set to: a maximum compound concentration of 100 nM, using DMSO for a 4-fold serial dilution, for a total of 9 concentrations. After dispensing, the cell culture plates were incubated at 37°C in a 5% CO2 incubator for 30 min. Then, 10 μM Forskolin (MCE, catalog number HY-15371) was added using the automated liquid dispenser D300e (Tecan), setting up NC control wells (cells + 10 μM Forskolin) and NSC control wells (cells + stimulation buffer). The cell culture plate was incubated at 37°C in a 5% CO2 incubator for 45 min. The 384-well plate was then removed, and cAMP assay kits were added to detect antibodies. The plate was incubated at room temperature for 1 hour. Cells were detected using an Envision (PerkinElmer) microplate reader at excitation wavelengths of 320 nm, emission wavelengths of 620 nm and 665 nm. The ratio of receptor to donor emission signals in each well was calculated. A four-parameter logistic regression (4PL) model was used to fit the relationship between %Maxsignal cAMP Production (%cAMP maximum signal value) and analyte concentration to calculate the 50% effective concentration (EC50) of the compound for agonistic activity against human SSTR2 cells. 50 value).

[0440] %Maxsignal cAMP Production calculation formula:

[0441]

[0442] The experimental results are shown in Table 2.

[0443] Table 2

[0444]

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein X is N or CR a ; R a selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, or haloC1-C6alkoxy; R 1 selected from C2-C6alkenyl, C1-C6alkylamido, C1-C6alkoxyC1-C6alkyl, or 3-7 membered 1 optionally substituted with one or more R b substituents; Each R b They may be the same or different, and each is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, amino, aminoacyl, C1-C6 alkylaminoacyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 alkylamino, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; R 2 Selected from halogens, C6-C 10 Aryl, C6-C 10 Arylaminoyl, C3-C8 cycloalkylaminoyl or C6-C 10 Aryl amide group; wherein the C6-C 10 Aryl, C6-C 10 Arylaminoyl, C3-C8 cycloalkylaminoyl or C6-C 10 Each aryl amide group is independently and optionally surrounded by one or more R c replace; Each R c They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, sulfonylimide, C1-C6 alkylsulfonylimide, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group; R 3 is selected from the group consisting of aminoacyl, C6-C 10 aryl, 5-14 membered heteroaryl, C3-C8cycloalkylaminoacyl, 3-12 membered 10 heterocyclylaminoacyl, C6-C 10 aryl, 5-14 membered heteroaryl are each independently optionally substituted with one or more R d substituents; the C3-C8cycloalkylaminoacyl, 3-12 membered 10 heterocyclylaminoacyl, C6-C e aryl, 5-14 membered heteroaryl are each independently optionally substituted with one or more R Each R d They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, sulfonylimide, C1-C6 alkylsulfonylimide, 3-10 membered heterocyclic groups, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group; Each R e They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylamino, aminoacyl, C1-C6 alkylaminoacyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic, C3-C8 cycloalkyl, C6-C 10 aryl or 5-14 membered heteroaryl; wherein the 3-10 membered heterocyclic group, C3-C8 cycloalkyl group, C6-C 10 Each of the aryl or 5-14 heteroaryl groups is independently and optionally substituted with a halogen, cyano, nitro, hydroxyl, carboxyl or amino group; R 4 selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, or haloC1-C6alkoxy; R 5 selected from hydrogen, halogen, cyano, hydroxyl, amino, nitro, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, or haloC1-C6alkoxy; with the proviso that, When X is CR a R 1 for The R 1 Optionally by one or more R b When replacing, R 3 Selected from aminoacyl, C6-C substituted with sulfonylimide or C1-C6 alkylsulfonylimide 10 aryl, 5-14 membered heteroaryl substituted with sulfonylimide or C1-C6 alkylsulfonylimide, C3-C8 cycloalkylaminoyl, 3-12 membered heterocyclic aminoyl, C6-C 10 arylaminoyl or 5-14 heteroarylaminoyl; wherein the C6-C group is substituted with a sulfonylimide group or a C1-C6 alkylsulfonylimide group. 10 The aryl group, the 5-14 heteroaryl group substituted with a sulfonylimide group or a C1-C6 alkylsulfonylimide group, each independently and optionally substituted with one or more R groups f Substitution; the C3-C8 cycloalkyl aminoacyl group, 3-12 membered heterocyclic aminoacyl group, C6-C 10 The aryl aminoacyl group or the 5-14 heteroaryl aminoacyl group is independently and optionally surrounded by one or more R e Replace; the R f It is selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is N; Alternatively, X is CR a ; or R a is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkyl, or haloC1-C3 alkoxy; preferably, R a is hydrogen. or R 1 selected from said R 1 optionally substituted with one or more R b substituents; Preferably, R 1 selected from said R 1 optionally substituted with one or more R b substituents; Preferably, said R 1 optionally substituted by 1, 2 or 3 R b substituents; Preferably, each R b They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, carboxyl, amino, aminoacyl, C1-C3 alkylaminoacyl, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C1-C3 alkylamino, or aminoC1-C3 alkyl; more preferably, R b Selected from halogen, cyano, hydroxy, amino, aminoacyl, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl or halo-C1-C3 alkoxy; or R 1 is selected from Preferably, R 1 is selected from More preferably, R 1 is selected from 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C6-C 10 aryl, C6-C 10 arylaminoacyl, C3-C8cycloalkylaminoacyl, or C6-C 10 arylamido; wherein said R 2 is optionally substituted with one or more R c substituents; Preferably, R 2 is selected from phenyl, phenylaminoacyl, cyclopropylaminoacyl or phenylamido; wherein said R 2 is optionally substituted with one or more R c substituents; More preferably, R 2 is phenyl optionally substituted by one or more R c substituents; More preferably, R 2 is phenyl optionally substituted with 1-5 R c substituents; More preferably, R 2 is phenyl optionally substituted by 1, 2 or 3 R c substituents; Further preferably, R 2 is selected from the group consisting of: Further preferably, R 2 is selected from the group consisting of: Preferably, R c selected from halogen, cyano, nitro, hydroxyl, amino, carboxyl, Ci-C6-alkyl, Ci-C6-alkoxy, halogenated Ci-C6-alkyl, halogenated Ci-C6-alkoxy, amino Ci-C6-alkyl, hydroxy Ci-C6-alkyl or Ci-C6-alkylamino; More preferably, R c Selected from halogen, cyano, nitro, hydroxy, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, or halo-C1-C3 alkoxy; more preferably, R c Selected from halogen, cyano, hydroxy, C1-C3 alkyl, or C1-C3 alkoxy; more preferably, R c Selected from fluorine, cyano or methyl; or R 2 selected from preferably, R 2 selected from 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C6-C 10 aryl, 5-9 membered heteroaryl, C3-C8cycloalkylaminoacyl, or C6-C 10 arylaminoacyl; wherein the C6-C 10 aryl, 5-9 membered heteroaryl are each independently optionally substituted with one or more R d substituents; the C3-C8cycloalkylaminoacyl, or C6-C 10 arylaminoacyl are each independently optionally substituted with one or more R e substituents; Preferably, R 3 Selected from C6-C 10 Aryl, C3-C8 cycloalkylaminoyl or C6-C 10 Arylaminoacyl; wherein the C6-C 10 Aryl group is optionally bounded by one or more R d Substitution; the C3-C8 cycloalkylaminoyl or C6-C 10 Each aryl aminoacyl group is independently and optionally surrounded by one or more R groups. e replace; R is selected from the group consisting of hydrogen, C1-6alkyl, 3 C1-6alkyl, phenylaminoacyl or cyclopropylaminoacyl; wherein the phenyl, optionally substituted with one or more R d ; the phenylaminoacyl or cyclopropylaminoacyl are each independently optionally substituted with one or more R e ; Preferably, R 3 is selected from phenyl, phenylaminocarbonyl or cyclopropylaminocarbonyl; wherein said phenyl is optionally substituted with one or more R d ; said phenylaminocarbonyl or cyclopropylaminocarbonyl is each independently optionally substituted with one or more R e ; More preferably, R 3 is phenyl optionally substituted by 1, 2 or 3 R d substituents; More preferably, R 3 is phenyl optionally substituted by 1 or 2 R d substituents; Preferably, each R d They may be the same or different, and each is independently selected from halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, sulfonylimide or C1-C6 alkylsulfonylimide. Further preferably, each R d are the same or different and each is independently selected from halogen, cyano, hydroxy, amino, C1-C3alkyl, C1-C3alkoxy, haloC1-C3alkyl, haloC1-C3alkoxy, sulfonimidoyl, or C1-C3alkylsulfonimidoyl; Further preferably, R d is selected from fluoro, cyano, methylsulfonimidoyl or hydroxy; or said R 3 is selected from phenylaminoacyl or cyclopropylaminoacyl; said R 3 is optionally substituted with 1, 2, or 3 R e substituents; Preferably, selected from phenylaminoacyl; said R 3 optionally substituted by 1, 2 or 3 R e substituents; R is selected from halogen, cyano, hydroxy, amino, nitro, d-C6alkyl, d-C6alkoxy, halogenated d-C6alkyl or halogenated d-C6alkoxy; preferably, R e R is selected from halogen, cyano, hydroxy, amino, nitro, d-C6alkyl, d-C6alkoxy, halogenated d-C6alkyl or halogenated d-C6alkoxy; preferably, R e R is selected from halogen, cyano, hydroxy, amino, nitro, d-C6alkyl, d-C6alkoxy, halogenated d-C6alkyl or halogenated d-C6alkoxy; preferably, R e R is selected from halogen, cyano, hydroxy, amino, nitro, d-C6alkyl, d-C6alkoxy, halogenated d-C6alkyl or halogenated d-C6alkoxy; preferably, R or R 3 selected from Preferably, R 3 selected from More preferably, R 3 selected from 5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein when R 1 is R 3 is selected from said R d is selected from sulfoximine or C1-C6 alkylsulfoximine; said R f is selected from halogen, cyano, nitro, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, or halogenated C1-C6 alkoxy; said m is 0, 1, or 2; Preferably, when R 1 is R 3 is selected from Preferably, the m is 0 or 1; R is selected from halogen, cyano, hydroxy, amino, C1-C3alkyl, C1-C3alkoxy, haloC1-C3alkyl or haloC1-C3alkoxy. f R is selected from halogen, cyano, hydroxy, amino, C1-C3alkyl, C1-C3alkoxy, haloC1-C3alkyl or haloC1-C3alkoxy.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 4 is hydrogen, and / or, R 5 is hydrogen.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the compound or a pharmaceutically acceptable salt thereof has the Formula (II): wherein R 1 is selected from C2-C6alkynyl, amido, C1-C6alkoxyC1-C6alkyl, or 3-7 membered heterocyclylC1-C6alkyl; said R 1 is optionally substituted with one or more R b substituents; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; R 4 , R 5 , R a , R b , R c , R d each is defined as in Formula I; Preferably, the p is 0, 1 or 2; Preferably, the q is 0, 1 or 2; Preferably, R 1 selected from said R 1 optionally substituted with one or more R b substituents; or the compound or a pharmaceutically acceptable salt thereof has the Formula (III): wherein R 6 selected from hydrogen, halogen, cyano, hydroxyl, amino, Ci-C6alkylamino, aminoacyl, Ci-C6alkylaminoacyl, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, or haloCi-C6alkoxy; R 3 selected from the group consisting of said R d selected from the group consisting of sulfonimidoyl or C1-C6alkylsulfonimidoyl; said R f selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C6alkyl, C1-C6alkoxy, halogenated C1-C6alkyl or halogenated C1-C6alkoxy; said m is 0, 1 or 2; or R 3 is selected from aminoacyl, C3-C8cycloalkylaminoacyl, 3-12 membered 10 heterocyclylaminoacyl, C6-C10arylaminocyl, or 5-14 membered 10 heteroarylaminoacyl; wherein each of the C3-C8cycloalkylaminoacyl, 3-12 membered e heterocyclylaminoacyl, C6-C10arylaminocyl, or 5-14 membered R 2 , R 4 , R 5 , R a , R e each is defined as in formula I; R is selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkyl, or haloC1-C3 alkoxy; more preferably, R 6 R is selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, haloC1-C3 alkyl, or haloC1-C3 alkoxy; more preferably, R 6 is hydrogen; Preferably, R 3 for The R d Selected from sulfonamide or C1-C6 alkylsulfonamide, wherein R f Selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, or halo-C1-C3 alkoxy; wherein m is 0, 1, or 2; or R 3 is phenylaminocarbonyl or cyclopropylaminocarbonyl, each independently optionally substituted with one or more R e substituents; More preferably, R 3 is said R d is selected from C1-C6alkylsulfonylimino, said R f is selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl or halogenated C1-C3alkoxy; said m is 0 or 1; or R 3 is phenylaminoacyl, said R 3 is optionally substituted with 1, 2, or 3 R e substituents; More preferably, R 3 is Further preferably, R 3 is 8. The compound or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 and a pharmaceutically acceptable carrier.

10. Use of a compound of claims 1-8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the treatment and / or prevention of SSTR2 related diseases; Preferably, the SSTR2 related diseases include, but are not limited to, acromegaly, tumors, ophthalmic diseases, neuropathies, nephropathies, respiratory diseases, pain, neurodegenerative diseases, inflammatory diseases or psychiatric diseases; Preferably, the tumors are neuroendocrine tumors.

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