Small molecule modulator of pantothenate kinase PANK, pharmaceutical composition and use thereof

Abstract

Provided in the present invention are a small molecule modulator of a pantothenate kinase PANK, a pharmaceutical composition and the use thereof. The compound can effectively modulate the activity of pantothenate kinase, can be used for treating or preventing conditions and diseases related to the activity of pantothenate kinase, and can be used in the preparation of a drug for such conditions or diseases.

Description

Pantothenic acid kinase (PANK) small molecule regulators, pharmaceutical compositions and their uses

[0001] This application claims priority to the following two earlier applications: Patent Application No. 202410916821.3, filed with the China National Intellectual Property Administration on July 9, 2024, entitled "Pantothenic Acid Kinase (PANK) Small Molecule Regulator, Pharmaceutical Composition and Use Thereof"; and Patent Application No. 202510740137.9, filed with the China National Intellectual Property Administration on June 4, 2025, also entitled "Pantothenic Acid Kinase (PANK) Small Molecule Regulator, Pharmaceutical Composition and Use Thereof". The entire contents of the aforementioned earlier applications are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical compounds, specifically relating to pantothenic acid kinase (PANK) small molecule regulators, pharmaceutical compositions, and their uses. Background Technology

[0003] Coenzyme A (CoA) is an essential cofactor in many metabolic reactions, including fatty acid synthesis and oxidation, complex lipid synthesis, and, most importantly, the oxidation of pyruvate in the citric acid cycle. CoA participates in over 100 biochemical reactions and provides a phosphopanthelthylethylamine cofactor for activating fatty acid synthases and carrier proteins. CoA exists primarily in its non-esterified form; CoA bound to an acyl group, called acyl-CoA, constitutes a small but important portion of the total CoA pool under normal healthy conditions. Some congenital metabolic disorders are caused by defects in enzymes that metabolize acyl-CoA, leading to abnormally high levels of acyl-CoA accumulation. "CASTOR" is the term for these disorders, representing abnormalities in the sequestration, toxicity, or redistribution of CoA. Acyl-CoA is a known feedback inhibitor of pantothenate kinase (PANK), a key enzyme in the first step of catalyzing the conversion of pantothenate to CoA.

[0004] CASTOR disorders are diverse, including organic acidemia, hydroxymethylglutaryl-CoA lyase deficiency, and fatty acid oxidase deficiency. Organic acidemia is a group of diseases primarily characterized by abnormalities in amino acid, fatty acid, and carbohydrate metabolism, leading to an increase in intermediate metabolites—organic acids—and causing a series of pathophysiological changes and clinical symptoms. Patients often have high levels of organic acids in their urine. Types of organic acidemia include, but are not limited to, propionic acidemia (PA), methylmalonic academia (MMA), and isovaleric acidemia (IVA). PA, for example, is a rare autosomal recessive metabolic disorder caused by a defect in the mitochondrial propionyl-CoA carboxylase (PCC) gene (subunit gene PCCA or PCCB). This gene produces an enzyme with reduced / lost catalytic activity, leading to the inability to properly metabolize propionyl-CoA (C3-CoA) to methylmalonyl-CoA. This, in turn, inhibits downstream metabolism and the production of non-esterified CoA and acetyl-CoA, thereby disrupting various metabolic processes, such as tricarboxylic acid (TCA) cycle disorders and abnormal urinary nitrogen metabolism. Reduced PCC activity can lead to the accumulation of intracellular C3-CoA, which can be metabolized via a bypass pathway to propionylcarnitine (C3). Because C3 consumes excessive carnitine, serum acetylcarnitine (C2) and free carnitine decrease. Therefore, the plasma C3:C2 ratio is a key biomarker for newborn screening and disease diagnosis. Currently, there are no effective drugs for treating PA (acute polyacrylamide). Acute treatment is mostly symptomatic, while stable treatment mainly involves dietary control, oral L-carnitine or betaine, or liver transplantation. Studies have shown that PANK agonists can regulate CoA by promoting the production of non-esterified CoA.

[0005] As described above, the present invention provides a small molecule PANK agonist that can increase non-esterified CoA, regulate the CoA pool, improve overall metabolism, and promote the elimination of toxic metabolites, and is expected to provide a new treatment for CASTOR diseases represented by organic acidosis. Summary of the Invention

[0006] To address the aforementioned technical problems, the present invention provides a compound of formula (I), its racemic mixture, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0007] in,

[0008] Q1 is selected from unsubstituted or arbitrarily assigned one, two or more R... a Replacement C 1-12 alkyl or

[0009] Ring A is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0010] Each R a They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. a1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R a2 C(=O)R a3 P(=O)R a4 R a5 Or, two R atoms attached to the same carbon atom a Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. a1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. a Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. a1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. a Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. a1 Replacement C 1-3 Alkylene; each R a1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R a6 ;R a2 R a3 R a4 R a5 R a6They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0011] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0012] L1 is absent or selected from unsubstituted or optionally selected from one, two or more of the following: oxo (=O), OH, NH2, CN, -COOH, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 The following groups are substituted by cycloalkyl or 3-6 membered heterocyclic groups: C 1-12 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 3-14 Cycloalkylene;

[0013] Y1 is absent or selected from carbonyl groups. No substitution or optional use by one, two or more R d The following groups are substituted: C 1-12 Alkylene, C 2-6 imidene group, C 2-6 Hypo-ynyl group, -O-(CH2) 0-6 -、-S-(CH2) 0-6 -、C 3-14 Cycloalkylene-(CH2) 0-6 -, 3-14 membered heterocyclic alkylene group -(CH2) 0-6 -、C 6-14 aryl-(CH2) 0-6 -, 5-14-membered heteroaryl-(CH2) 0-6 -、-NH-(CH2) 0-6 -、-NHCO-(CH2) 0-6 -、-CONH-(CH2) 0-6 -or X1 is selected from O or NR Y1 ;R Y1 Selected from H, CN, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; each R dThey may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. d1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1- 12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R d2 C(=O)R d3 ; Each R d1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d2 R d3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0014] Q2 does not exist or is selected from no substitution or is arbitrarily assigned by one, two or more Rs. b Replacement Or, when Q2 is selected from At that time, any position on ring B is connected to any position on ring A, together forming a non-substituted or arbitrarily substituted ring with one, two or more R's. b Replacement of multi-component fused ring systems;

[0015] Ring B is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0016] Each R b They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. b1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R b2 C(=O)R b3 P(=O)R b4 R b5 Or, two R atoms attached to the same carbon atom b Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. b1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. b Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. b1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. b Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. b1 Replacement C 1-3 Alkylene; each R b1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R b6 ;R b2 R b3 R b4 R b5 R b6 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0017] n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0018] Y2 either does not exist or is selected from -O-, -S-, or carbonyl groups. Unsubstituted or optionally substituted with one, two or more elements selected from oxo (=O), OH, NH2, CN, halogen, C 1-12Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 Alkylene, -OC 1-12 Alkylene, -SC 1-12 Alkylene, -NH-C 1-12 Alkylene, -C 1-12 Alkylene -O-, -C 1-12 Alkylene -S-, -C 1-12 Alkyl groups: -NH-, -CONH-, -NHCO-, -COO-, or -OCO-;

[0019] Ring C is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0020] Each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. c1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R c2 C(=O)R c3 P(=O)R c4 R c5 Or, two R atoms attached to the same carbon atom c Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. c Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. c1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. cConnected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. c1 Replacement C 1-3 Alkylene; each R c1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R c6 ;R c2 R c3 R c4 R c5 R c6 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0021] p is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0022] According to some implementation schemes, Q1 is selected from unsubstituted or optionally replaced by one, two or more Rs. a Substituted -CH(CH3)2 or Ring A is selected from C 3-6 Carbocyclic, 3-11 membered heterocyclic, phenyl or 5-11 membered heteroaryl.

[0023] According to some implementation schemes, Q1 is selected from unsubstituted or optionally replaced by one, two or more Rs. a Substituted -CH(CH3)2 or Ring A is selected from cyclopropyl ring, cyclobutyl ring, tetrahydrofuran ring, piperidine ring, benzene ring, thiophene ring, etc.

[0024] According to some implementation schemes, Q1 is selected from... Ring A is selected from the benzene ring.

[0025] According to some implementation schemes, each R a They may be identical or different, and are independently selected from CN, halogen, unsubstituted, or optionally composed of one, two, or more R. a1 The following groups are substituted: OH, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkynyl group, C 3-6Cycloalkyl, 3-6 membered heterocyclic groups, P(=O)(CH3)2; or, two R groups attached to adjacent carbon atoms. a Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. a1 The following ring systems are replaced: C 3-6 Carbon rings, 3-6 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings; or, two non-adjacent Rs a Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. a1 Replacement C 1-3 Alkylene; each R a1 They may be the same or different, and are independently selected from CN, halogens, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or -NHS(=O)2CH3.

[0026] According to some implementation schemes, each R a The same or different, independently selected from CN, F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, trifluoromethoxy, OH, -CH2OH, -CH2NH2, -NHSO2CH3, -PO(CH3)2.

[0027] According to some implementation schemes, m is selected from 0, 1, 2, 3, 4 or 5.

[0028] According to some implementation schemes, Q1 is selected from...

[0029] According to some implementation schemes, L1 is absent or selected from unsubstituted or optionally selected by one, two or more elements selected from -COOH, halogen, C 1-4 Alkyl, Halogenated C 1-4 The following groups are substituted by alkyl substituents: C 1-4 Alkylene or cyclopropane.

[0030] According to some implementation schemes, L1 is absent or selected from -CH2-, -CH2CH2-,

[0031] According to some implementation schemes, Y1 is absent or selected from carbonyl groups. No substitution or optional use by one, two or more R d The following groups are substituted: -O-(CH2) 0-6-, 3-14 membered heterocyclic alkylene group -(CH2) 0-6 -, 5-6 quinone heteroaryl-(CH2) 0-6 -、-NH-(CH2) 0-6 -、-NHCO-(CH2) 0-6 -、-CONH-(CH2) 0-6 -or X1 is selected from O or NH; each R d They may be the same or different, and are independently selected from 3-14 membered heterocyclic groups, -C(=O)CH3, and -C(=O)CH2CN.

[0032] According to some implementation schemes, Y1 is absent or selected from -C(O)-, -NHCO-, -CONH-, -OCH2-, -NHCOCH2-,

[0033] According to some implementation schemes, -L1-Y1- does not exist or is selected from -CH2CO-, -CH2-, -CH2CH2-, -NHCO-, -CH2CONH-, -CO-, -CONH-, -OCH2-, -NHCOCH2-,

[0034] According to some implementation schemes, Q2 does not exist or is selected from... Ring B is selected from 4-11 nitrogen-containing heterocyclic groups, phenyl groups, or 5-11 nitrogen-containing heteroaryl groups.

[0035] According to some implementation schemes, each R b They may be the same or different, and are independently selected from oxo (=O), -CH2CN, -CH2OH; or, two R atoms attached to the same carbon atom. b Together with the carbon atoms it is attached to, it forms the following ring system: C 3-6 Carbon rings or 3-6 membered heterocycles; or, two R atoms attached to adjacent carbon atoms. b Together with the carbon atoms they are attached to, they form the following ring system: C 3-6 Carbon rings, 3-6 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings; or, two non-adjacent Rs b Connected by their end groups, they together form C 1-3 Alkylene.

[0036] According to some implementation schemes, n is selected from 0, 1 or 2.

[0037] According to some implementation schemes, n is selected from 1 or 2.

[0038] Preferably, n is selected from 0.

[0039] According to some implementation schemes, Q2 does not exist or is selected from...

[0040] According to some implementation schemes, Y2 is absent or selected from -CH2-, -NH-, -O-, -CO-, or -SO2-.

[0041] According to some implementation schemes, the ring C is selected from phenyl or 5-11 heteroaryl groups.

[0042] According to some implementation schemes, each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. c1 The following groups are substituted: C 1-4 Alkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, -COOH, -CONH2, -SO2NH2; each R c1 Same or different, selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl; or, two R atoms attached to adjacent carbon atoms. c Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. c1 The following ring systems are replaced: 5-6 membered heteroaryl rings.

[0043] According to some implementation schemes, each R c They are either the same or different, and are independently selected from oxo (=O), CN, F, Cl, Br, CH3, COOH, CONH2, CON(CH3)2, SO2NH2.

[0044] According to some implementation schemes, p is selected from 0 or 1.

[0045] According to some implementation plans Selected from

[0046] According to some embodiments, the compound represented by formula (I) has the following structure:

[0047] Wherein, X1 is selected from CH2, NH, O or S; q1 is selected from 1 or 2; q2 is selected from 0 or 1;

[0048] Q1, Q2, L1, Y1, Y2, ring C, R b R c R d , n, and p have the definitions described in this paper.

[0049] According to some embodiments, the compound represented by formula (I) has the following structure:

[0050] Where q1 is selected from 1 or 2; q2 is selected from 0 or 1;

[0051] R1 is selected from unsubstituted or optionally selected from one of halogens (e.g., F, Cl, Br), C. 1-3 Alkyl (e.g., methyl, ethyl, isopropyl) or halogenated C 1-3 The following groups are substituted by alkyl groups (e.g., trifluoromethyl): C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, R1 is selected from cyclopropyl, );

[0052] R2 is selected from halogens (e.g., F, Cl, Br) or C. 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl);

[0053] Ring C, R a R b R c , m, n, p have the definitions described in this article.

[0054] According to some embodiments, the compound shown in formula (I) is selected from the following structures:

[0055] The present invention also provides a method for preparing the compound shown in formula (II-1), comprising step A or step B:

[0056] Step A:

[0057] Step B:

[0058] Wherein, R' is H or an alkali metal ion (e.g., Li). + K + Z represents a leaving group (e.g., Cl, Br);

[0059] Q1, Q2, Y2, ring C, R c p has the definition described in this article.

[0060] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0061] According to some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0062] According to some embodiments, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0063] The present invention also provides a method for treating or preventing diseases or conditions related to coenzyme A levels, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or a prodrug compound thereof, or a pharmaceutical composition thereof.

[0064] According to some implementation schemes, the patients include mammals, preferably humans.

[0065] According to some implementation schemes, the diseases or conditions associated with coenzyme A levels are selected from diseases of decreased, increased, isolated, toxic, or redistributed coenzyme A (CASTOR), metabolic diseases (e.g., fatty acid oxidase deficiency; phenylketonuria; glutaric acidemia), organic acidemia (methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (VA), and maple syrup urine disease (MSUD)), and neurological diseases (e.g., pantothenic acid kinase-related neurodegenerative diseases).

[0066] The present invention also provides at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt thereof, or a prodrug compound thereof, or a pharmaceutical composition thereof, for the treatment or prevention of diseases or conditions related to coenzyme A levels.

[0067] According to some implementation schemes, the diseases or conditions associated with coenzyme A levels are selected from diseases of decreased, increased, isolated, toxic, or redistributed coenzyme A (CASTOR), metabolic diseases (e.g., fatty acid oxidase deficiency; phenylketonuria; glutaric acidemia), organic acidemia (methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (VA), and maple syrup urine disease (MSUD)), and neurological diseases (e.g., pantothenic acid kinase-related neurodegenerative diseases).

[0068] The present invention also provides the use of at least one of the compounds of formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of pharmaceuticals.

[0069] According to some implementation schemes, the use may be in the preparation of medicaments for the treatment or prevention of diseases or conditions related to coenzyme A levels.

[0070] According to some implementation schemes, the diseases or conditions associated with coenzyme A levels are selected from diseases of decreased, increased, isolated, toxic, or redistributed coenzyme A (CASTOR), metabolic diseases (e.g., fatty acid oxidase deficiency; phenylketonuria; glutaric acidemia), organic acidemia (methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (VA), and maple syrup urine disease (MSUD)), and neurological diseases (e.g., pantothenic acid kinase-related neurodegenerative diseases). Beneficial effects

[0071] The compounds provided by this invention can effectively regulate the activity of pantothenic acid kinase and can be used to treat or prevent symptoms and diseases related to coenzyme A levels.

[0072] Terminology Definitions and Explanations

[0073] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0074] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0075] "More than" means three or more, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0076] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to describing each integer value in the numerical range "1-12", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0077] Term "C" 1-12 "alkyl" should be understood to refer to straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6"Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0078] Term "C" 2-12 "Alkenyl" should be understood as representing a monovalent hydrocarbon group with 1 to 12 carbon atoms, either linear or branched, containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C...). 2-8 Alkenyl), for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C64 ... 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0079] Term "C" 2-12 "Alkyne" should be understood as representing a monovalent hydrocarbon group with 1 to 12 carbon atoms, either directly linked or branched, containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0080] Term "C" 3-12 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon rings or tricyclic alkanes, having 3 to 12 carbon atoms, preferably "C". 3-10 "Cycloalkyl", more preferably "C" 3-8 cycloalkyl. The term "C" 3-12 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0081] Term "C" 6-14 "Aryl" should preferably be understood to represent a monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring), or tricyclic hydrocarbon ring having 6 to 14 carbon atoms and possessing monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C".6-10 "Aromatic". The term "C" 6- 14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0082] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-10-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo[a]fused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-... -, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthidyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cenolinyl, 2-, 4-, 6- or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6- 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbaolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- Phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenthiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazin[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furano[3,2-b]-pyranolyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-azolel, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazolo[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3] -c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiopheneyl, 2-, 4-, 5-, 6- or 7-benzozolyl, 2-, 4-, 5-, 6- or 7-benzimidazinyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atom on the 5-14-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-14-membered heteroaryl ring may be linked to other groups. When the 5-14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0083] The term "carbocyclic ring" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or bicyclic rings, including spirocyclic, fused, or bridged systems (such as bicyclic [11.1]pentane, bicyclic [2.2.1]heptane, bicyclic [3.2.1]octane, or bicyclic [5.2.0]nonane, tert-naphthalene, etc.), which may optionally be substituted with one or more (such as 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclic ring" refers to a carbocyclic ring containing 3, 4, 5, or 6 cyclic carbon atoms.

[0084] Unless otherwise defined, the term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2- states. For example, the "3-14 membered heterocyclic group" may be a 3-14 membered N-containing heterocyclic group (containing at least one N). Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-14-membered heterocyclic ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinium, the nitrogen atom on the piperidinium ring and the carbon atom at its para position can be attached to other groups.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0086] The term "nitrogen oxides" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds.

[0087] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0088] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0089] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0090] Unless otherwise stated, heterocyclic, hypocyclic, heteroaryl, or hypoaryl includes all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, it may include forms in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0091] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc.

[0092] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0093] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0094] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0095] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, where alkyl is defined as described above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0096] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. Non-limiting examples of hydroxyalkyl groups include: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, or dihydroxypropyl, etc.

[0097] The term "alkyloxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0098] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chain or branched saturated divalent hydrocarbon group. The definition of the number of carbon atoms in "alkylene" follows the definition of "alkyl" above. Those skilled in the art will understand that alkyleneoxy or oxyalkylene can be attached to the remainder of the molecule containing it in any orientation; that is, the two are used interchangeably.

[0099] Wavy lines intersecting chemical bonds Used to indicate the connection position of a group to other atoms in the molecular structure. For example... This indicates the 3-position connection with the pyridinium group. When the group connection position is not fixed, taking the pyridinium group as an example, it can be represented as follows: The method is shown to indicate that it can be connected to any connectable site on the pyridinyl group. For example... This indicates that it can be connected to any connectable position on the heteroaryl ring, for example, it can be connected to any of the four carbon atoms on the pyridine ring to the right of the heteroaryl group, or it can be connected to a carbon atom on the pyrazole ring to the left. Unless otherwise stated, similar expressions in this application are interpreted in the same way as above.

[0100] In the chemical structure of the compound described in this invention, the bond... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if stereoisomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations.

[0101] In this invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of H, C, N, O, S, F, and Cl, respectively such as 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H or D substitutions can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and are therefore preferred in some cases. The presence of hydrogen in the substituents of this invention, without the separate mention of the terms deuterium or tritium, does not imply the exclusion of deuterium or tritium, but rather may also include deuterium or tritium.

[0102] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0103] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0104] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0105] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0106] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0107] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Attached Figure Description

[0108] Figure 1. The relative fold change in CoA in cells.

[0109] Figure 2. Relative changes in MMA and C3:C2 ratio in mouse plasma. Detailed Implementation

[0110] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0111] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0112] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), or deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0113] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0114] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao Haiyang Chemical GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for TLC separation and purification is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0115] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is in degrees Celsius.

[0116] Example 1

[0117] 1-(5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 002

[0118] Synthesis of intermediate 002-3

[0119] Compound 002-1 (400 mg, 2.02 mmol) was dissolved in acetonitrile (10 mL), and compound 002-2 (301 mg, 2.02 mmol) and N,N-diisopropylethylamine (782 mg, 6.05 mmol) were added. The reaction was stirred at 90 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% petroleum ether: ethyl acetate) to obtain compound 002-3 (320 mg; yield 51%).

[0120] MS m / z(ESI): 311.1(M+1).

[0121] Synthesis of intermediate 002-4

[0122] Compound 002-3 (320 mg, 1.03 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 002-4 (217 mg; yield 100%).

[0123] MS m / z(ESI):211.1(M+1).

[0124] Synthesis of 1-(5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 002

[0125] Compound 002-4 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (46 mg, 0.24 mmol), N,N-diisopropylethylamine (93 mg, 0.72 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.29 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5u C18 100x21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 50%-100%, flow rate: 25mL / min) to obtain compound 002 (35mg; yield: 38%).

[0126] MS m / z(ESI): 387.1(M+1);

[0127] 1H NMR (400MHz, CD3OD) δ7.57(d,J=9.6Hz,1H),7.45(d,J=9.6Hz,1H),6.97(dd,J=8. 4,4.8Hz,2H),6.89(s,1H),4.13-4.10(m,1H),3.96(d,J=15.6Hz,1H),3.83(d,J=1 5.6Hz,1H),3.83-3.72(m,2H),3.62-3.52(m,1H),3.33-3.30(m,1H),3.16-3.09(m ,1H),2.05-2.01(m,1H),1.44-1.41(m,1H),0.98-0.92(m,2H),0.67-0.65(m,3H).

[0128] Compound 002 was chirally resolved (mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 50 / 50) to give compound 002a (10.13 mg, first peak, retention time: 2.074 min) and compound 002b (12.48 mg, last peak, retention time: 2.773 min).

[0129] Compound 002a

[0130] MS m / z (ESI): 387.1 (M+1).

[0131] 1 H NMR (400MHz, MeOD) δ7.52(t,J=6.4Hz,1H),7.39(d,J=9.5Hz,1H),7.02-6.87(m,3H),4.12(dt,J =13.3,5.3Hz,1H),3.97(d,J=15.5Hz,1H),3.85(d,J=13.3Hz,1H),3.79(dd,J=6.4,2.4Hz,1H),3 .62-3.53(m,1H),3.36-3.32(m,1H),3.31-3.26(m,1H),3.16-3.09(m,1H),2.07-2.00(m,1H),1. 42(q,J=6.4Hz,1H),0.96(dd,J=8.5,2.0Hz,2H),0.73-0.66(m,2H),0.62(dt,J=6.0,4.6Hz,1H).

[0132] Compound 002b

[0133] MS m / z (ESI): 387.1 (M+1).

[0134] 1H NMR(400MHz,MeOD)δ7.51(d,J=9.5Hz,1H),7.37(d,J=9.5Hz,1H),7.07-6.83(m,3H),4.10(dt, J=13.2,5.3Hz,1H),3.96(d,J=15.5Hz,1H),3.87-3.81(m,1H),3.78(dd,J=12.4,5.5Hz,1H),3. 60-3.51(m,1H),3.33(d,J=4.2Hz,1H),3.28(d,J=4.7Hz,1H),3.12(dt,J=12.0,5.9Hz,1H),2.0 7-1.96(m,1H),1.41(q,J=6.3Hz,1H),1.00-0.91(m,2H),0.76-0.66(m,2H),0.67-0.55(m,1H).

[0135] Example 2

[0136] 1-(7-(6-chloropyridazine-3-yl)-4,7-diazaspiro[2.5]octane-4-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 005

[0137] Synthesis of intermediate 005-2

[0138] Compound 005-1 (200 mg, 0.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 002-5 (184 mg, 0.95 mmol), N,N-diisopropylethylamine (368 mg, 2.85 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (397 mg, 1.05 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-100% / 25% petroleum ether / ethyl acetate) to obtain compound 005-2 (150 mg, yield 52%).

[0139] MS m / z(ESI): 333.1(M+1).

[0140] Synthesis of intermediate 005-3

[0141] Compound 005-2 (150 mg; 0.39 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 005-3 (130 mg, 100% yield).

[0142] MS m / z(ESI):289.1(M+1).

[0143] Synthesis of 1-(7-(6-chloropyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 005

[0144] Compound 005-3 (130 mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), and compound 002-2 (67 mg, 0.45 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added. The reaction was stirred at 90 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 55%-100%, flow rate: 20 mL / min) to obtain compound 005 (13 mg; yield 7%).

[0145] MS m / z(ESI): 401(M+1);

[0146] 1 H NMR (400MHz, MeOD) δ7.51(d,J=10.0Hz,1H),7.37(d,J=9.6Hz,1H),7.01-6.86(m,3H),3.92(s,2H),3.83(s,1H),3.73(s, 1H),3.64(m,2H),3.47(m,2H),1.33(s,2H),1.28(s,1H),1.22(s,1H),1.11(s,2H),0.98-0.93(m,2H),0.71-0.65(m,2H).

[0147] Example 3

[0148] 1-(6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 006

[0149] Synthesis of intermediate 006-2

[0150] Compound 006-1 (500 mg, 2.5 mmol) was dissolved in acetonitrile (10 mL), and compound 002-2 (370 mg, 2.5 mmol) and N,N-diisopropylethylamine (970 mg, 7.5 mmol) were added. The reaction was stirred at 90 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% / 5% dichloromethane / methanol) to obtain compound 006-2 (500 mg; yield 70%).

[0151] MS m / z(ESI): 311.1(M+1)

[0152] Synthesis of intermediate 006-3

[0153] Compound 006-2 (100 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 006-3 (67 mg; yield 100%).

[0154] MS m / z(ESI):211.1(M+1).

[0155] Synthesis of 1-(6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 006

[0156] Compound 006-3 (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (46 mg, 0.24 mmol), N,N-diisopropylethylamine (93 mg, 0.72 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (109 mg, 0.29 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini5u C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25mL / min) to obtain compound 006 (50mg; yield: 54%).

[0157] MS m / z(ESI): 387.1(M+1);

[0158] 1 H NMR(400MHz,MeOH)δ7.51(d,J=9.6Hz,1H),7.00(d,J=9.6Hz,1H),6.98-6.86(m,3H),4. 44(s,2H),4.32(s,4H),4.20(s,2H),3.47(s,2H),1.02-0.92(m,2H),0.72-0.65(m,2H).

[0159] Example 4

[0160] 1-(8-(6-chloropyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethyl-1-one 007

[0161] Synthesis of intermediate 007-2

[0162] Compound 007-1 (500 mg, 2.35 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 007-2 (355 mg, 2.35 mmol) and triethylamine (480 mg, 4.7 mmol) were added. The reaction was stirred at 120 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-100% / 35% petroleum ether / ethyl acetate) to give compound 007-2 (290 mg; yield 36%).

[0163] MS m / z(ESI): 325.1(M+1).

[0164] Synthesis of intermediate 007-3

[0165] Compound 007-2 (290 mg, 0.89 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give crude compound 007-3 (200 mg, 100% yield).

[0166] MS m / z(ESI):225.1(M+1).

[0167] Synthesis of 1-(8-(6-chloropyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethyl-1-one 007

[0168] Compound 007-3 (100 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (87 mg, 0.45 mmol), N,N-diisopropylethylamine (513 mg, 1.35 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (188 mg, 0.49 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 007 (37mg; yield: 13%).

[0169] MS m / z(ESI): 401(M+1);

[0170] 1 HNMR (400MHz, CDCl3) δ6.93-6.89 (m, 3H), 6.84 (t, J = 7.6Hz, 2H), 4.84 (s, 1H), 4. 40(d,J=10.4Hz,1H),3.65(d,J=4.4Hz,2H),3.54(d,J=14.6Hz,2H),2.95(d,J=1 1.2Hz,1H),2.06-2.01(m,2H),1.82(s,2H),1.44(s,1H),1.25(s,1H),0.98(d,J =6.0Hz,1H),0.95(d,J=4.4Hz,1H),0.71(d,J=5.6Hz,1H),0.68(d,J=4.8Hz,1H).

[0171] Example 5

[0172] 1-(6-(6-chloropyridazin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 010

[0173] Synthesis of intermediate 010-2

[0174] Compound 010-1 (500 mg, 2.51 mmol) was dissolved in acetonitrile (10 mL), and compound 002-2 (373.8 mg, 2.51 mmol) and cesium carbonate (1635 mg, 5.02 mmol) were added. The mixture was heated to 80°C and stirred for 16 hours. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to give compound 010-2 (160 mg; yield 21%).

[0175] MS m / z(ESI): 311.1(M+1).

[0176] Synthesis of intermediate 010-3

[0177] Compound 010-2 (150 mg, 0.48 mmol) was placed in a round-bottom flask, and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 010-3 (100 mg; yield 98%).

[0178] MS m / z(ESI):211.1(M+1).

[0179] Synthesis of 1-(6-(6-chloropyridazin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 010

[0180] Compound 010-3 (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (92 mg, 0.48 mmol), N,N-diisopropylethylamine (123 mg, 0.95 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (217 mg, 0.57 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 010 (89mg; yield: 48%).

[0181] MS m / z(ESI): 387.1(M+1);

[0182] 1H NMR (400MHz, DMSO) δ7.50(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),6.79(m,2H),6.66(d,J=8.0Hz,1H),4.51(d,J=4.0Hz,2H),3.94(m,2H),3. 69(m,1H),3.54(d,J=16Hz,2H),3.43(s,1H),2.75(m,1H),2.05-1.94(m,1H),1.61(d,J=8.80Hz,1H),0.98-0.92(m,2H),0.72-0.66(m,2H).

[0183] Example 6

[0184] 1-(2-(6-chloropyridazin-3-yl)-2,7-diazaspiro[3.5]nonane-7-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 012

[0185] Synthesis of intermediate 012-2

[0186] Compound 012-1 (500 mg; 2.20 mmol) was dissolved in acetonitrile (5 mL), and compound 002-2 (360 mg; 2.42 mmol) and N,N-diisopropylethylamine (568 mg, 4.40 mmol) were added. The reaction was stirred at 80 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% petroleum ether: ethyl acetate) to obtain compound 012-2 (780 mg; yield 87%).

[0187] MS m / z(ESI): 339.1(M+1)

[0188] Synthesis of intermediate 012-3

[0189] Compound 012-2 (300 mg, 0.89 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 012-3 (200 mg; yield 81%).

[0190] MS m / z(ESI):239.1(M+1).

[0191] Synthesis of 1-(2-(6-chloropyridazin-3-yl)-2,7-diazaspiro[3.5]nonane-7-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one O12

[0192] Compound 012-3 (100 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (89 mg, 0.46 mmol), N,N-diisopropylethylamine (108 mg, 0.84 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (239 mg, 0.63 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was directly filtered. The crude product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector; column: Xbridge 5u C18 150 x 19 mm).

[0193] The mobile phase was 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 50%-60%, flow rate: 20 mL / min) to purify compound 012 (42.82 mg; yield: 25%).

[0194] MS m / z(ESI): 415.2(M+1);

[0195] 1 H NMR(400MHz,cdcl3)δ7.24(s,1H),6.91(d,J=9.4Hz,2H),6.84(t,J=7.4Hz,1H),6.63(d,J=9.4Hz,1H),4.01-3.92(m,4H),3.68(s,2H) ,3.65-3.59(m,2H),3.45-3.38(m,2H),2.09-2.01(m,1H),1.85-1.79(m,2H),1.71-1.65(m,2H),1.00-0.93(m,2H),0.73-0.67(m,2H).

[0196] Example 7

[0197] 1-((1S,6R)-5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.2.0]octane-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 014a

[0198] Synthesis of intermediate 014a-2

[0199] Compound 014a-1 (343 mg, 1.61 mmol) was dissolved in acetonitrile (20 mL), and compound 002-2 (239.6 mg, 1.61 mmol) and DIEA (623.4 mg, 4.82 mmol) were added. The mixture was heated to 90°C and stirred for 1 hour. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to obtain compound 014a-2 (275 mg, 52%).

[0200] MS m / z(ESI): 325.2(M+1).

[0201] Synthesis of intermediate 014a-3

[0202] Compound 014a-2 (275 mg, 0.85 mmol) was dissolved in dichloromethane (2 mL), and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 014a-3 (175 mg, 92%).

[0203] MS m / z(ESI):225.1(M+1).

[0204] Synthesis of 1-((1S,6R)-5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 014a

[0205] Compound 014a-3 (175 mg, 0.78 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (151 mg, 0.78 mmol), N,N-diisopropylethylamine (202 mg, 1.56 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (355 mg, 0.94 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 014a (131mg, yield: 42%).

[0206] MS m / z(ESI): 401.2(M+1);

[0207] 1 H NMR (400MHz, DMSO) δ7.57(m,1H),7.12(m,1H),6.95m,3H),4.82(m,1H),4.32(m,1H),4.14(d,J=8.0Hz,1H),4.01(m,1H),3.8 5-3.60(m,3H),3.40(s,2H),3.17(m,1H),2.16(m,3H),2.04-1.95(m,1H),1.71(m,1H),0.98-0.91(m,2H),0.72-0.65(m,2H).

[0208] Example 8

[0209] 8-(6-chloropyridazine-3-yl)-2-(4-cyclopropyl-3-fluorobenzyl)-2,8-diazaspiro[4.5]decane-3-one 017

[0210] Synthesis of intermediate 017-2

[0211] PPh3 (4.91 g, 1.87 mmol) and CBr4 were placed in a three-necked flask under nitrogen protection. Dichloromethane (60 mL) was added in an ice-water bath, followed by compound 017-1 (2.4 g, 1.44 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reversed liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to give compound 017-2 (1.4 g; yield 42%).

[0212] 1 H NMR (400MHz, CDCl3) δ7.08-7.01(m,2H),6.84(m,1H),4.43(s,2H),2.13-2.01(m,1H),1.05-0.94(m,2H),0.77-0.69(m,2H).

[0213] Synthesis of intermediate 017-4

[0214] Compound 017-2 (334 mg, 1.31 mmol) was dissolved in DMF (5 mL) under nitrogen protection. NaH (63 mg, 2.62 mmol) was added under ice-water bath conditions. After stirring for 0.5 hours, a DMF (5 mL) solution of compound 017-3 (300 mg, 1.31 mmol) was added. After the reaction was completed, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate. The obtained organic phase was washed with water and then with saturated brine. It was dried over anhydrous sodium sulfate, filtered, and the concentrated organic phase residue was subjected to silica gel column chromatography (EA / PE = 0–100%) to obtain compound 017-4 (301 mg; yield 57%).

[0215] MS m / z(ESI): 403.2(M+1).

[0216] Synthesis of intermediate 017-5

[0217] Compound 017-4 (301 mg, 0.75 mmol) was added to HCl / 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 017-5 (210 mg; yield 93%).

[0218] MS m / z(ESI): 303.2(M+1).

[0219] Synthesis of 8-(6-chloropyridazin-3-yl)-2-(4-cyclopropyl-3-fluorobenzyl)-2,8-diazaspiro[4.5]decane-3-one 017

[0220] Compound 017-5 (200 mg, 0.66 mmol) was dissolved in acetonitrile (10 mL), and compound 002-2 (99 mg, 0.66 mmol) and DIEA (256 mg, 1.98 mmol) were added. The mixture was heated to 80 °C and stirred for 16 hours. After the reaction was completed, the reverse liquid was concentrated to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 017 (99.9 mg; yield: 36%).

[0221] MS m / z(ESI): 415.1(M+1);

[0222] 1H NMR (400MHz, CDCl3) δ7.24(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.86(m,3H),4.40(s,2H),3.75(s,2H),3.56 (s,2H),3.10(s,2H),2.43(s,2H),2.10-2.00(m,1H),1.77-1.65(m,4H),1.02-0.94(m,2H),0.74-0.67(m,2H).

[0223] Example 9

[0224] 1-(6-Chlorpyridazine-3-yl)-4-(4-cyclopropyl-3-fluorophenylethyl)-1,4-diazacycloheptane-5-one 019

[0225] Synthesis of intermediate 019-2

[0226] Compound 019-1 (1 g, 0.32 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (780 mg, 13.5 mmol) was added in portions under ice bath conditions. The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution under ice bath conditions, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-3% / 97% ethyl acetate / petroleum ether) to obtain compound 019-2 (400 mg, yield 49%).

[0227] MS m / z(ESI):163.1(M+1-18).

[0228] Synthesis of intermediate 019-3

[0229] Compound 019-2 (400 mg, 2.22 mmol) was dissolved in dichloromethane (10 mL), and triphenylphosphine (872 mg, 3.33 mmol) and carbon tetrabromide (1105 mg, 3.33 mmol) were added under ice bath conditions. The reaction was stirred under ice bath conditions for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: petroleum ether) to obtain compound 019-3 (400 mg, 74%).

[0230] Synthesis of intermediate 019-5

[0231] Compound 019-4 (500 mg, 2.34 mmol) was dissolved in 10 mL of dioxane in 4N hydrochloric acid. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 019-5 (380 mg, 100% yield).

[0232] MS m / z(ESI): 115.2(M+1)

[0233] Synthesis of intermediate 019-6

[0234] Compound 019-5 (300 mg, 2.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (389 mg, 2.6 mmol) and N,N-diisopropylethylamine (1.68 g, 13 mmol) were added. The reaction was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% / 5% dichloromethane / methanol) to obtain compound 019-6 (330 mg, yield 55%).

[0235] MS m / z(ESI): 227.1(M+1)

[0236] Synthesis of 1-(6-chloropyridazine-3-yl)-4-(4-cyclopropyl-3-fluorophenylethyl)-1,4-diazacycloheptane-5-one 019

[0237] Compound 019-6 (50 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydroxide (13 mg, 0.33 mmol) was added under ice bath conditions. After stirring for ten minutes, compound 019-3 (53 mg, 0.22 mmol) was added in portions every hour. The reaction was stirred at room temperature for 5 hours. After the reaction was complete, methanol was added to quench the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 50%-100%, flow rate: 20 mL / min) to obtain compound 019 (2.11 mg, yield: 2.4%).

[0238] MS m / z(ESI): 389.1(M+1);

[0239] 1H NMR (400MHz, MeOH) δ7.93(d,J=10.0Hz,1H),7.87(d,J=10.0Hz,1H),6.94(t,J=7.7Hz,2H),6.85(t,J=8.0Hz,1H),3.95-3.87( m,2H),3.80(d,J=4.5Hz,2H),3.74-3.63(m,4H),2.95-2.80(m,4H),2.06-1.95(m,1H),1.00-0.92(m,2H),0.70-0.64(m,2H).

[0240] Example 10

[0241] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethane-1-one 021

[0242] Synthesis of 1-(2-(6-chloropyridazin-3-yl)-2,7-diazaspiro[3.5]non-7-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 021

[0243] Compound 002-5 (100 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 021-1 (70 mg, 0.57 mmol), N,N-diisopropylethylamine (133 mg, 1.03 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (294 mg, 0.77 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm 10um; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 16-minute gradient, gradient ratio: acetonitrile phase 35%-45%, flow rate: 20mL / min) to obtain compound 021 (41mg; yield: 23%).

[0244] MS m / z(ESI): 301.2(M+1);

[0245] 1H NMR (400MHz, DMSO) δ8.61 (d, J = 8.8Hz, 1H), 7.05-6.89 (m, 3H), 4.95 (s, 1H), 4.81 (s, 2H), 4.13-4.04 (m ,2H),3.97-3.87(m,2H),3.83(s,2H),2.04-1.94(m,1H),0.94(d,J=8.2Hz,2H),0.69(d,J=4.8Hz,2H).

[0246] Example 11

[0247] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(6-(oxazol-5-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 022

[0248] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(6-(oxazol-5-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 022

[0249] Compound A (30 mg, 0.08 mmol) was dissolved in dioxane / water (4 / 1, 1 mL), and compound 022-1 (19 mg, 0.1 mmol), sodium carbonate (26 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (6 mg, 0.008 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatogram: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 47%-100%, flow rate: 20 mL / min) to obtain compound 022 (2.5 mg, yield: 8%).

[0250] MS m / z(ESI): 408.2(M+1);

[0251] 1H NMR (400MHz, MeOD) δ8.33(s,1H),7.79(d,J=9.6Hz,1H),7.68(s,1H),7.34(d,J=9.6Hz,1H),6.94-6. 91(m,3H),3.80(s,2H),3.78-3.65(m,8H),2.08-1.97(m,1H),1.00-0.93(m,2H),0.74-0.63(m,2H).

[0252] Example 12

[0253] 6-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 023

[0254] Synthesis of intermediate 023-3

[0255] Compound 023-1 (300 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), and compound 023-2 (345 mg, 1.5 mmol) and N,N-diisopropylethylamine (585 mg, 4.5 mmol) were added. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel column chromatography (eluent: 0%-5% / 95% petroleum ether / ethyl acetate) to obtain compound 023-3 (450 mg; yield 84.9%).

[0256] MS m / z(ESI):262.2(M-56).

[0257] Synthesis of intermediate 023-4

[0258] Compound 023-3 (100 mg, 0.31 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 023-4 (100 mg; yield 100%).

[0259] MS m / z(ESI):218.2(M+1).

[0260] Synthesis of 6-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one 023

[0261] Compound 023-4 (100 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (89 mg, 0.46 mmol), N,N-diisopropylethylamine (357 mg, 2.76 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (210 mg, 0.55 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 35%-100%, flow rate: 20mL / min) to obtain compound 023 (43mg; yield 23.51%).

[0262] MS m / z(ESI): 393.4(M+1);

[0263] 1 H NMR(400MHz,MeOD)δ8.72(d,J=4.4,1H),8.16-8.06(m,1H),7.67-7.59(m,1H),7 .04-6.87(m,3H),4.79-4.66(m,1H),4.56-4.37(m,3H),4.21-4.04(m,1H),3.79 (s,2H),3.27-3.13(m,1H),2.86-2.68(m,1H),2.11-2.01(m,1H),1.97-1.84(m, 2H),1.79-1.69(m,1H),1.66-1.49(m,1H),1.05-0.88(m,2H),0.80-0.62(m,2H).

[0264] Example 13

[0265] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one 024

[0266] Synthesis of intermediate 024-2

[0267] Compound 002-5 (200 mg, 1.03 mmol) was dissolved in DMF (2 mL), and compound 024-1 (211 mg, 1.13 mmol), N,N-diisopropylethylamine (266 mg, 2.06 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (258 mg, 1.54 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% petroleum ether: ethyl acetate) to obtain compound 024-2 (270 mg; yield 48%).

[0268] MS m / z(ESI): 385.2(M+23)

[0269] Synthesis of intermediate 024-3

[0270] Compound 024-2 (250 mg, 0.69 mmol) was dissolved in 3 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 024-3 (170 mg; yield 87%).

[0271] MS m / z(ESI): 263.2(M+1).

[0272] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(pyrido[2,3-d]pyrimidin-2-yl)piperazin-1-yl)ethane-1-one 024

[0273] Compound 024-3 (100 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 024-4 (69 mg, 0.42 mmol) and N,N-diisopropylethylamine (246 mg, 1.9 mmol) were added. The reaction was stirred at 100 °C for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16-minute gradient, gradient ratio: acetonitrile phase 36%-100%, flow rate: 20 mL / min) to obtain compound 024 (56.12 mg; yield: 38%).

[0274] MS m / z(ESI): 392.2(M+1);

[0275] 1H NMR(400MHz,dmso)δ9.35(s,1H),8.93(dd,J=4.4,1.9Hz,1H),8.39(dd,J=8.0,1.9Hz,1H),7.35(dd,J=8.0,4.6Hz,1H),7.05-6.97 (m,2H),6.95-6.90(m,1H),3.91(s,5H),3.77(s,2H),3.68-3.61(m,5H),2.04-1.96(m,1H),0.98-0.91(m,3H),0.72-0.67(m,3H).

[0276] Example 14

[0277] 4-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)-1-methylpyrimidin-2(1H)-one O25

[0278] Synthesis of 4-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)-1-methylpyrimidin-2(1H)-one O25

[0279] Compound 024-3 (100 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 025-1 (55 mg, 0.38 mmol) and N,N-diisopropylethylamine (296 mg, 2.3 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 025 (45 mg; yield: 31.56%).

[0280] MS m / z(ESI): 371.4(M+1);

[0281] 1 H NMR (400MHz, MeOD) δ7.63(d,J=7.2,1H),7.12-6.81(m,3H),6.13(d,J=7.2,1H),4.85(s,2H),3.77( s,2H),3.65(d,J=19.6,6H),3.37(s,3H),2.18-1.88(m,1H),1.12-0.85(m,2H),0.83-0.60(m,2H).

[0282] Example 15

[0283] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(oxazolo[4,5-b]pyridin-5-yl)piperazin-1-yl)ethane-1-one 026

[0284] Synthesis of intermediate 026-2

[0285] Compound 026-1 (2 g, 9.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and benzyl bromide (1.73 g, 10.1 mmol) and potassium carbonate (2.54 g, 18.4 mmol) were added. The reaction was stirred overnight at 60 °C. After the reaction was monitored by LC-MS to be complete, ethyl acetate (50 mL) was added to the reaction solution. The mixture was washed twice with water and then three times with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 026-2 (400 mg, yield 14%).

[0286] MS m / z(ESI): 308(M+H) + ).

[0287] Synthesis of intermediate 026-3

[0288] Compound 026-2 (400 mg, 1.29 mmol) was dissolved in 5 mL of 1,4-dioxane solution, and compound 024-3 (338 mg, 1.29 mmol), Pd2(dba)3 (108 mg, 0.13 mmol), and cesium carbonate (1.26 g, 3.87 mmol) were added. The mixture was stirred overnight at 85 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-100% / 50% petroleum ether / ethyl acetate) to obtain compound 026-3 (400 mg, yield 63%).

[0289] MS m / z(ESI): 491(M+H) + )

[0290] Synthesis of intermediate 026-4

[0291] Compound 026-3 (400 mg, 0.82 mmol) was dissolved in ethyl acetate solution (10 mL), and palladium on carbon (400 mg, 1.63 mmol) was slowly added to the reaction system. The reaction was stirred at room temperature for 2 hours under hydrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to give crude product 026-4 (300 mg, 99% yield).

[0292] MS m / z(ESI): 371(M+1).

[0293] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(oxazolo[4,5-b]pyridin-5-yl)piperazin-1-yl)ethane-1-one 026

[0294] Compound 026-4 (300 mg; 0.81 mmol) was dissolved in 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (5 mL), and triethyl orthoformate (144 mg; 0.97 mmol) was added. The reaction was stirred overnight at 85 °C. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25 mL / min) to obtain compound 026 (2 mg, yield: 0.5%).

[0295] MS m / z(ESI): 381(M+1);

[0296] 1 H NMR (400MHz, CDCl3) δ8.26(s,1H),7.84(d,J=8.8Hz,1H),7.16(d,J=8.0Hz,1H),6.93(d,J=8.0Hz,2H),6.86(t,J=8.0Hz,1H),3 .94(s,2H),3.73(s,2H),2.22(d,J=8.0Hz,1H),1.68-1.61(m,2H),0.99-0.94(m,2H),0.88(t,J=6.8Hz,3H),0.74-0.67(m,3H).

[0297] Example 16

[0298] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(5,8-dihydro-1,7-naphthidium-7(6H)-yl)piperidin-1-yl)ethane-1-one 027

[0299] Synthesis of intermediate 027-3

[0300] Compound 027-1 (300 mg, 1.5 mmol) was dissolved in dichloroethane (5 mL), and compound 027-2 (222 mg, 1.65 mmol) and sodium triacetoxyborohydride (957 mg, 4.50 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-20% petroleum ether: ethyl acetate) to obtain compound 027-3 (240 mg; yield 50%).

[0301] MS m / z(ESI): 318.2(M+1)

[0302] Synthesis of intermediate 027-4

[0303] Compound 027-3 (220 mg, 0.69 mmol) was dissolved in 2 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 027-4 (130 mg; yield 79%).

[0304] MS m / z(ESI): 218.2(M+1)

[0305] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(5,8-dihydro-1,7-naphthidium-7(6H)-yl)piperidin-1-yl)ethane-1-one 027

[0306] Compound 027-4 (100 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-5 (98 mg, 0.51 mmol), N,N-diisopropylethylamine (119 mg, 0.92 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (262 mg, 0.69 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was directly filtered. The crude product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150x 30 mm).

[0307] The mobile phase was 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 27%-100%, flow rate: 25 mL / min) to purify compound 027 (102.21 mg; yield: 56%).

[0308] MS m / z(ESI): 394.2(M+1);

[0309] 1 H NMR(400MHz,dmso)δ8.50-8.46(m,1H),7.74(d,J=7.2Hz,1H),7.37(dd,J=7.6,4.8Hz,1H),7.03 -6.89(m,3H),4.55(d,J=14Hz,2H),4.45-4.34(m,1H),4.14(d,J=13.2Hz,1H),3.71(s,2H),3.6 9-3.60(m,2H),3.45-3.24(m,2H),3.12(s,2H),3.04(t,J=12.8Hz,1H),2.59(t,J=12.4Hz,1H), 2.21-2.05(m,2H),2.03-1.95(m,1H),1.67-1.46(m,2H),0.98-0.90(m,2H),0.72-0.66(m,2H).

[0310] Example 17

[0311] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(pyrazolo[1,5-a]pyridin-2-yl)piperazin-1-yl)ethane-1-one 030

[0312] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(pyrazolo[1,5-a]pyridin-2-yl)piperazin-1-yl)ethane-1-one 030

[0313] Compound 024-3 (100 mg, 0.38 mmol) was dissolved in dioxane / water (10 / 1, 1.1 mL), and compound 030-1 (64 mg, 0.42 mmol), cesium carbonate (248 mg, 0.76 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (79 mg, 0.11 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 4 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatogram: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 17-minute gradient, gradient ratio: acetonitrile phase 80%-100%, flow rate: 20 mL / min) to give compound 030 (26.41 m; yield: 18%).

[0314] MS m / z(ESI): 379.2(M+1);

[0315] 1 H NMR(400MHz,dmso)δ8.40(d,J=6.8Hz,1H),7.37(d,J=8.8Hz,1H),7.12-7.05(m,1H),7.04-6.89(m,3H),6.62(td,J=6.8,1.2Hz ,1H),5.97(s,1H),3.75(s,2H),3.65-3.59(m,4H),3.26-3.18(m,4H),2.05-1.95(m,1H),0.97-0.90(m,2H),0.71-0.65(m,2H).

[0316] Example 18

[0317] N-(1-(6-chloropyridazin-3-yl)-1H-pyrazole-4-yl)-2-(4-cyclopropyl-3-fluorophenyl)acetamide 033

[0318] Synthesis of intermediate 033-2

[0319] Compound 033-1 (300 mg, 1.63 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 002-2 (244 mg, 1.63 mmol), cesium carbonate (1.59 g, 4.89 mmol), tris(dibenzylacetone)dipalladium (149 mg, 0.163 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (189 mg, 0.37 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-100% / 40% petroleum ether / ethyl acetate) to give compound 033-2 (200 mg; yield 36%).

[0320] MS m / z(ESI): 296.0(M+1)

[0321] Synthesis of intermediate 033-3

[0322] Compound 033-2 (200 mg, 0.68 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude compound 033-3 (170 mg, 99% yield).

[0323] MS m / z(ESI): 196(M+1)

[0324] Synthesis of N-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-2-(4-cyclopropyl-3-fluorophenyl)acetamide 033

[0325] Compound 033-3 (170 mg, 0.87 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (169 mg, 0.87 mmol), N,N-diisopropylethylamine (337 mg, 2.61 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (364 mg, 0.96 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20mL / min) to obtain compound 033 (8.23mg; yield: 3%).

[0326] MS m / z(ESI): 372(M+1);

[0327] 1 H NMR(400MHz,MeOD)δ8.91(s,1H),8.28(d,J=9.2Hz,1H),7.93(s,1H),7.88(m,1H),7.03(d,J=11.2Hz,2 H),6.92(t,J=8.4Hz,1H),5.34(s,1H),3.65(s,2H),3.34(s,1H),0.99-0.93(m,2H),0.90-0.86(m,2H).

[0328] Example 19

[0329] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 036

[0330] Synthesis of intermediate 036-3

[0331] Compound 036-1 (200 mg, 0.79 mmol) was dissolved in 1,4-dioxane (5 mL), and cyclopropionic acid 036-2 (83 mg, 0.95 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (66 mg; 0.07 mmol) and potassium phosphate (507 mg, 2.39 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 036-3 (120 mg, yield 67%).

[0332] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 036

[0333] Compound 036-3 (50 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 036-4 (47 mg, 0.23 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (179 mg, 0.47 mmol), and N,N-diisopropylethylamine (92 mg, 0.71 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with SQD2 detector (column: Xbridge 5u C18 150 x 19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 57%-67%, flow rate: 20 mL / min) to give compound 036 (36 mg; yield 36%).

[0334] MS m / z(ESI): 393(M+1) + ;

[0335] 1 H NMR (400MHz, CD3OD) δ7.53(d,J=9.6Hz,1H),7.43(d,J=9.6Hz,1H),6.69(d,J=8.8Hz ,2H),3.89-3.66(m,10H),1.96-1.87(m,1H),1.03-0.97(m,2H),0.73-0.67(m,2H).

[0336] Example 20

[0337] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)ethane-1-one 037

[0338] Synthesis of intermediate 037-2

[0339] Compound 037-1 (200 mg, 0.77 mmol) was dissolved in N,N-dimethylacetamide (5 mL) and water (0.2 mL). Copper iodide (29.18 mg, 0.16 mmol), bis(triphenylphosphine)palladium dichloride (27 mg, 0.04 mmol), trimethylsilylacetylene (103 mg, 0.92 mmol), and cesium carbonate (748.7 mg, 2.3 mmol) were added. The mixture was stirred at 100°C under nitrogen protection for 2 hours. After the reaction was complete, the mixture was diluted with water and ethyl acetate. The organic phase was collected, washed with saturated lithium bromide, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to give compound 037-1 (100 mg; yield 59.3%).

[0340] MS m / z(ESI):221.1(M+1).

[0341] Synthesis of intermediate 037-3

[0342] Compound 037-2 (190 mg; 0.86 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (61.98 mg, 2.59 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 1-2 with 4 mol / L hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was compound 037-3 (100 mg; yield 60%).

[0343] MS m / z(ESI):193.1(M+1).

[0344] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)ethane-1-one 037

[0345] Compound 037-3 (50 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 036-4 (51.7 mg, 0.26 mmol), N,N-diisopropylethylamine (100 mg, 0.78 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (118 mg, 0.31 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 037 (12mg; yield 12.4%).

[0346] MS m / z(ESI): 373.1(M+1) + ;

[0347] 1 H NMR (400MHz, CD3OD) δ7.58-7.55(m,1H),7.47-7.45(m,1H),7.34-7.30(m,1H),7.17-7.02(m,2H),3.85(s,2H),3.74-3.62(m,8H),2.05(s,3H).

[0348] Example 21

[0349] 1-(5-(6-chloropyridazin-3-yl)-5,8-diazaspiro[3.5]non-8-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 039

[0350] Synthesis of intermediate 039-1

[0351] Compound 005-1 (300 mg, 1.32 mmol) was dissolved in dioxane / water (10 / 1, 3.3 mL), and compound 002-2 (216 mg, 1.45 mmol), cesium carbonate (860 mg, 2.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (95 mg, 0.13 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-30% petroleum ether: ethyl acetate) to obtain compound 039-1 (150 mg, 33%).

[0352] MS m / z(ESI): 339.2(M+1)

[0353] Synthesis of intermediate 039-2

[0354] Compound 039-1 (150 mg, 0.44 mmol) was dissolved in 2 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 039-2 (90 mg; yield 90%). MS m / z (ESI): 239.2 (M+1).

[0355] Synthesis of 1-(5-(6-chloropyridazin-3-yl)-5,8-diazaspiro[3.5]non-8-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 039

[0356] Compound 039-2 (90 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 002-5 (95 mg, 0.49 mmol), N,N-diisopropylethylamine (97 mg, 0.75 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (215 mg, 0.57 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm10um; mobile phase 1: water (containing 0.1% NH3); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 50%-60%, flow rate: 25mL / min) to obtain compound 039 (12.05mg; yield 8%).

[0357] MS m / z(ESI): 415.2(M+1);

[0358] 1H NMR (400MHz, CD3OD) δ7.44(dd,J=9.2,5.6Hz,1H),7.25(dd,J=18.0,9.5Hz,1H),7.09-7.00( m,1H),6.98-6.87(m,2H),3.92(s,1H),3.82(s,1H),3.78(d,J=3.6Hz,2H),3.61-3.55(m,1H ),3.52-3.45(m,2H),3.44-3.39(m,1H),3.31(dt,J=3.2,1.6Hz,1H),2.21-2.16(m,2H),2.0 7-1.96(m,2H),1.42-1.30(m,2H),0.99-0.96(m,1H),0.96-0.93(m,1H),0.72-0.66(m,2H).

[0359] Example 22

[0360] Synthesis of 1-(8-(6-chloropyridazin-3-yl)-5,8-diazaspiro[3.5]non-5-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 041

[0361] Synthesis of intermediate 041-2

[0362] Compound 041-1 (200 mg; 0.87 mmol) was dissolved in acetonitrile (10 mL), and compound 002-2 (131.07 mg, 0.87 mmol) and potassium carbonate (243.19 mg, 1.75 mmol) were added. The reaction was stirred at 90 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give compound 041-2 (150 mg, yield 47%).

[0363] Synthesis of intermediate 041-3

[0364] Compound 041-2 (150 mg; 0.44 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the crude compound 041-3 was directly added to the next step of the reaction.

[0365] Synthesis of 1-(8-(6-chloropyridazin-3-yl)-5,8-diazaspiro[3.5]non-5-yl)-2-(4-cyclopropyl-3-fluorophenylethane-1-one) 041

[0366] Compound 041-3 (100 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 002-5 (89 mg; 0.41 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (238 mg; 0.62 mmol), and N,N-diisopropylethylamine (162 mg; 1.25 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with SQD2 detector. The chromatographic column was an Xbridge 5u C18 150x 19mm; mobile phase 1 was water (containing 0.1% FA); mobile phase 2 was acetonitrile; the gradient was 13 min, with a gradient ratio of 65%-75% acetonitrile phase and a flow rate of 20 mL / min to obtain compound 041 (24 mg, yield 13%).

[0367] MS m / z(ESI): 415(M+1) + ;

[0368] 1 H NMR (400MHz, DMSO) δ7.55(d,J=9.6Hz,1H),7.42(d,J=9.6Hz,1H),7.10-6.83(m,3H),3.77(s,2H),3.71(s,2H),3.6 5-3.56(m,4H),2.47(d,J=11.6Hz,2H),2.05-1.90(m,3H),1.90-1.64(m,2H),1.01-0.89(m,2H),0.76-0.65(m,2H).

[0369] Example 23

[0370] 1-(3-((6-chloropyridazin-3-yl)methyl)pyrrolidine-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 045

[0371] Synthesis of intermediate 045-2

[0372] Compound 045-1 (700 mg, 2.25 mmol) was dissolved in 1,4-dioxane (5 mL), and Zn powder (448 mg, 6.89 mmol) was added. Under nitrogen protection, the mixture was stirred at room temperature for 30 min. Compound 002-2 (336 mg, 2.25 mmol), Pd2(Dba)3 (336 mg, 2.25 mmol), and S-Phos (56 mg, 0.14 mmol) were then added. The reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate, and the resulting organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 0–10%) to obtain the target compound 045-2 (100 mg, yield 15%).

[0373] MS m / z(ESI): 320.1(M+23)

[0374] Synthesis of intermediate 045-3

[0375] Compound 045-2 (100 mg, 0.34 mmol) was added to HCl / 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 045-3 (65 mg; yield 98%).

[0376] MS m / z(ESI):198.2(M+1).

[0377] Synthesis of 1-(3-((6-chloropyridazin-3-yl)methyl)pyrrolidine-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 045

[0378] Compound 045-3 (65 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-5 (64 mg, 0.33 mmol), N,N-diisopropylethylamine (85 mg, 0.66 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (150 mg, 0.40 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 014 (2.5mg; yield 2%).

[0379] MS m / z(ESI): 374.1(M+1) + ;

[0380] 1 H NMR (400MHz, DMSO) δ7.86(m,1H),7.73(m,1H),7.01-6.86(m,3H),3.63-3.44(m,4H),3.25-3.16(m,1H),3. 06-2.94(m,3H),2.72-2.63(m,1H),2.07-1.85(m,2H),1.74-1.52(m,1H),0.94(m,2H),0.73-0.64(m,2H).

[0381] Example 24

[0382] (R)-1-(3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyrrolidine-7-yl)pyrrolidin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 046a

[0383] Synthesis of intermediate 046-3

[0384] Compound 046-1 (500 mg, 2.19 mmol) was dissolved in 1,4-dioxane (10 mL), followed by compound 046-2 (354 g, 2.30 mmol), Pd(dppf)Cl2 (180 mg, 0.22 mmol), and cesium carbonate (2160 mg, 6.66 mmol). Water (2 mL) was then added, and the mixture was heated to 50°C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reversed liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 0–10%) to obtain compound 046-3 (250 mg, 65%).

[0385] MS m / z(ESI): 175.1(M+1)

[0386] Synthesis of intermediate 046a-5

[0387] Compound 046-3 (100 mg, 0.57 mmol) was dissolved in 1,4-dioxane (5 mL), and compound 046a-4 (161 mg; 0.86 mmol) and DIEA (148 mg; 1.14 mmol) were added. The mixture was heated to 150 °C and stirred for 2 hours. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: eluent: DCM / MeOH = 0–10%) to obtain compound 046a-5 (160 mg; yield 86%).

[0388] MS m / z(ESI): 325.1(M+1)

[0389] Synthesis of intermediate 046a-6

[0390] Compound 046a-5 (150 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 046a-6 (100 mg; yield 97%).

[0391] MS m / z(ESI):225.1(M+1).

[0392] Synthesis of (R)-1-(3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)pyrrolidin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 046a

[0393] Compound 046a-6 (100 mg; 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (86 mg; 0.45 mmol), N,N-diisopropylethylamine (115 mg; 0.89 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (203 mg; 0.53 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 046a (47mg; yield 26%).

[0394] MS m / z(ESI): 401.2(M+1);

[0395] 1 H NMR (400MHz, DMSO) δ7.27(s,1H),6.93(m,3H),4.64-4.44(m,1H),3.77(m,1H),3.63-3.59(m,5H),3.44(m,1H),3.34(m, 1H),3.09-2.98(m,2H),2.24-2.16(m,1H),2.14-2.07(m,1H),2.03-1.95(m,1H),0.99-0.91(m,2H),0.72-0.65(m,2H).

[0396] Example 25

[0397] (S)-1-(3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyrrolidine-7-yl)pyrrolidin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 046b

[0398] Synthesis of intermediate 046-3

[0399] Compound 046-1 (500 mg, 2.19 mmol) was dissolved in 1,4-dioxane (10 mL), followed by compound 046-2 (354 g, 2.30 mmol), Pd(dppf)Cl2 (180 mg, 0.22 mmol), and cesium carbonate (2160 mg, 6.66 mmol). Water (2 mL) was then added, and the mixture was heated to 50°C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reversed liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: PE / EA = 0–10%) to give compound 046-3 (250 mg; yield 65%).

[0400] MS m / z(ESI): 175.1(M+1)

[0401] Synthesis of intermediate 046b-2

[0402] Compound 046-3 (100 mg, 0.57 mmol) was dissolved in 1,4-dioxane (5 mL), and compound 46b-1 (161 mg; 0.86 mmol) and DIEA (148 mg; 1.14 mmol) were added. The mixture was heated to 150 °C and stirred for 2 hours. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 0–10%) to obtain compound 046b-2 (160 mg; yield 86%).

[0403] MS m / z(ESI): 325.1(M+1).

[0404] Synthesis of intermediate 046b-3

[0405] Compound 046b-2 (150 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 046b-3 (100 mg; yield 99%).

[0406] MS m / z(ESI):225.1(M+1).

[0407] Synthesis of (S)-1-(3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)pyrrolidin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 046b

[0408] Compound 046b-3 (100 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (86 mg, 0.45 mmol), N,N-diisopropylethylamine (115 mg, 0.89 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (203 mg, 0.53 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 046b (45mg; yield 25%).

[0409] MS m / z(ESI): 401.1(M+1);

[0410] 1 H NMR(400MHz,DMSO)δ7.26(s,1H),7.04-6.87(m,3H),4.63-4.45(m,1H),3.8 6-3.74(m,1H),3.64(m,5H),3.44(m,1H),3.33(m,1H),3.03(m,2H),2.20(m 1H),2.10(m,1H),2.05-1.96(m,1H),1.01-0.92(m,2H),0.72-0.65(m,2H).

[0411] Example 26

[0412] 6-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)pyrrolidine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 047

[0413] Synthesis of intermediate 047-3

[0414] Compound 047-1 (300 mg; 1.6 mmol) was dissolved in tetrahydrofuran (10 mL), and compound 047-2 (369 mg; 1.6 mmol) and N,N-diisopropylethylamine (621 mg, 4.8 mmol) were added. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by rapid silica gel column chromatography (eluent: 0%-5% / 95% petroleum ether / ethyl acetate) to obtain compound 047-3 (400 mg; yield 73.83%).

[0415] MS m / z(ESI):248.1(M-56).

[0416] Synthesis of intermediate 047-4

[0417] Compound 047-3 (400 mg; 1.3 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 047-4 (300 mg; yield 100%). MS m / z (ESI): 204.2 (M+1).

[0418] Synthesis of 6-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)pyrrolidine-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 047

[0419] Compound 047-4 (100 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (6 mL), and compound 002-5 (96 mg, 0.49 mmol), N,N-diisopropylethylamine (191 mg, 1.5 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (224 mg, 0.59 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 047 (50 mg; yield 26.51%).

[0420] MS m / z(ESI): 380.4(M+1);

[0421] 1 H NMR(400MHz,MeOD)δ8.73(d,J=4.4,1H),8.18-8.03(m,1H),7.71-7.60(m,1H), 7.06-6.78(m,3H),5.10-4.88(m,1H),4.68-4.44(m,1H),4.44-4.28(m,1H),4. 03-3.74(m,3H),3.71(s,2H),3.68(s,2H),3.61-3.48(m,1H),2.56-2.19(m,2H ),2.15-1.88(m,1H),1.03-0.84(m,2H),0.77-0.67(m,1H),0.67-0.58(m,1H).

[0422] Compound 047 (50 mg) was purified by SFC chromatography (SFC 150 column: Daicel CHIRALPAK IG_3, 3.0*150 mm, 3 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.1% DEA, 7 M methanol solution); 6-minute gradient, gradient ratio of carbon dioxide:methanol phase = 70 / 30, flow rate: 1.5 mL / min) to obtain compound 047a (first peak, retention time = 2.137 min; 20 mg, yield 80%) and compound 047b (last peak, retention time = 2.974 min; 20 mg, yield 80%).

[0423] Compound 047a

[0424] 1 H NMR (400MHz, MeOD) δ8.71(d,J=4.8,1H),8.02(d,J=7.8,1H),7.69-7.52(m,1H),7.12-6.72(m,3H),4.63-4.28(m,2H),4.00-3.77(m,2H),3.77- 3.69(m,1H),3.69(s,1H),2.48-2.14(m,2H),2.15-1.91(m,1H),1.31(d ,J=18.2,2H),1.02-0.86(m,2H),0.77-0.67(m,1H),0.68-0.60(m,1H).

[0425] Compound 047b

[0426] 1 H NMR(400MHz,MeOD)δ8.71(d,J=4.4,1H),8.03(d,J=7.8,1H),7.73-7.53(m,1H ),7.14-6.77(m,3H),4.63-4.45(m,1H),4.35(d,J=17.6,1H),4.03-3.86(m,1H ),3.87-3.77(m,2H),3.79-3.70(m,1H),3.70-3.62(m,2H),2.54-2.20(m,1H) ,2.18-1.89(m,1H),1.31(d,2H),0.93(m,2H),0.79-0.68(m,1H),0.63(s,1H).

[0427] Example 27

[0428] 2-(5-chloropyridin-2-yl)-7-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-2,7-diazaspiro[4.4]nonane-3-one 049

[0429] Synthesis of intermediate 049-3

[0430] Compound 049-1 (300 mg, 1.24 mmol) was dissolved in 1,4-dioxane (15 mL), and compound 049-2 (298 mg, 1.24 mmol), cesium carbonate (1215 mg, 3.7 mmol), bis(dibenzylacetone)palladium (71 mg, 0.12 mmol), and 9,9-bis(trifluoromethyl)-2,3,6,7-oxanthracene tetracarboxylic dianhydride (72 mg, 0.12 mmol) were added. The reaction was stirred at 60°C for 2 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-5% / 95% petroleum ether / ethyl acetate) to obtain compound 049-3 (360 mg; yield 73.87%).

[0431] MS m / z(ESI): 353.4(M+1)

[0432] Synthesis of intermediate 049-4

[0433] Compound 049-3 (360 mg, 1.0 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 049-4 (360 mg; yield 100%).

[0434] MS m / z(ESI):252.1(M+1).

[0435] Synthesis of 2-(5-chloropyridin-2-yl)-7-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-2,7-diazaspiro[4.4]nonane-3-one 049

[0436] Compound 049-4 (100 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (77 mg, 0.40 mmol), N,N-diisopropylethylamine (154 mg, 1.2 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (181 mg, 0.48 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 62%-100%, flow rate: 25 mL / min) to obtain compound 049 (50 mg; yield 29.12%).

[0437] MS m / z(ESI): 428.8(M+1);

[0438] 1 H NMR (400MHz, DMSO) δ8.42(d,J=2.8,1H),8.32(d,J=7.6,1H),8.00-7.92(m,1H),7.28-6.76(m,3H),3.98-3.83(m,2H),3.72-3 .55(m,3H),3.54-3.39(m,2H),2.80-2.60(m,2H),2.11-1.85(m,3H),1.36-1.18(m,1H),1.02-0.88(m,2H),0.75-0.63(m,2H).

[0439] Example 28

[0440] 2-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-6-(pyridin-2-yl)-2,6-diazaspiro[3.4]octane-7-one 050

[0441] Synthesis of intermediate 050-3

[0442] Compound 050-1 (400 mg, 1.76 mmol), compound 050-2 (433 mg, 2.11 mmol), tris(dibenzylacetone)dipalladium (81 mg, 0.088 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (51 mg, 0.088 mmol), and cesium carbonate (1147 mg, 3.52 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction was stirred at 100°C under nitrogen protection for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-0% / 100% petroleum ether / ethyl acetate) to obtain compound 050-3 (190 mg, 35%).

[0443] MS m / z(ESI): 304.2(M+1)

[0444] Synthesis of intermediate 050-4

[0445] Compound 050-3 (180 mg, 0.59 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (6 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 050-4 (120 mg; yield 99%).

[0446] MS m / z(ESI):204.1(M+1).

[0447] Synthesis of 2-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-6-(pyridin-2-yl)-2,6-diazaspiro[3.4]octane-7-one 050

[0448] Compound 050-4 (110 mg, 0.54 mmol), compound 002-5 (158 mg, 0.81 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (309 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (140 mg, 1.08 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 50%-60%, flow rate: 20mL / min) to obtain compound 050 (13.29mg; yield: 6%).

[0449] MS m / z(ESI): 380.2(M+1);

[0450] 1 H NMR (400MHz, CDCl3) δ8.40-8.29(m,2H),7.79-7.69(m,1H),7.09(dd,J=6.8,5.2Hz,1H),6.94-6.92(m,2H),6.84(t,J=7.6Hz,1H),4.27(q,J= 11.6Hz,2H),4.18-4.03(m,4H),3.44(s,2H),2.98-2.83(m,1H),2.09- 2.02(m,1H),1.31-1.25(m,1H),1.02-0.93(m,1H),0.74-0.67(m,1H).

[0451] Example 29

[0452] 1-(6-((6-chloropyridazin-3-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 051

[0453] Synthesis of intermediate 051-2

[0454] Compound 051-1 (500 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 3,6-dichloropyridazine (411 mg; 2.7 mmol) and N,N-diisopropylethylamine (967.5 mg; 7.5 mmol) were added. The reaction was stirred at 90 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-5% / 95% petroleum ether / ethyl acetate) to obtain compound 051-2 (500 mg; yield 63.9%).

[0455] MS m / z(ESI): 311.1(M+1).

[0456] Synthesis of intermediate 051-3

[0457] Compound 051-2 (200 mg, 0.64 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane (5 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 051-3 (150 mg; yield 99%).

[0458] MS m / z(ESI):211.1(M+1).

[0459] Synthesis of 1-(6-((6-chloropyridazin-3-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 051

[0460] Compound 051-3 (80 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (73.7 mg; 0.38 mmol), N,N-diisopropylethylamine (147.2 mg; 1.14 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (173.3 mg; 0.46 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 20 mL / min) to obtain compound 051 (20 mg; yield 13.61%).

[0461] MS m / z(ESI): 387.1(M+1);

[0462] 1 H NMR (400MHz, DMSO) δ7.77(s,1H),7.49(d,J=9.2Hz,1H),7.03-6.90(m,4H),3.84(d,J=10.4Hz,1H),3.75(d,J=11.6Hz,1H),3.62 -3.58(m,4H),3.39-3.45(m,1H),2.03-1.96(m,1H),1.84-1.81(m,1H),1.77-1.73(m,1H),0.97-0.92(m,2H),0.71-0.67(m,2H).

[0463] Example 30

[0464] 1-(6-Chlorpyridazine-3-yl)-N-(4-Cyclopropyl-3-fluorophenyl)-1H-pyrazole-4-carboxamide 055

[0465] Synthesis of intermediate 055-2

[0466] Compound 055-2 (400 mg, 2.86 mmol) was dissolved in dioxane (5 mL), and compound 002-2 (423 mg, 2.86 mmol), cesium carbonate (2.8 g, 8.58 mmol), Xantphos (166 mg, 0.29 mmol), and Pd2dba3 (262 mg, 0.29 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-50% / 50% ethyl acetate / petroleum ether) to obtain compound 055-2 (200 mg, yield 28%).

[0467] MS m / z(ESI): 253.1(M+1)

[0468] Synthesis of intermediate 055-3

[0469] Compound 055-2 (200 mg, 0.79 mmol) was dissolved in tetrahydrofuran / water (1 / 1, 10 mL), and lithium hydroxide (154 mg, 2.37 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water was added for dilution, and the mixture was extracted with ethyl acetate. The aqueous phases were combined and the pH was adjusted to approximately 4 with 4N hydrochloric acid solution, followed by extraction with ethyl acetate. The organic phase was concentrated under reduced pressure to give compound 055-3 (100 mg, 56% yield).

[0470] MS m / z(ESI): 225.1(M+1)

[0471] Synthesis of 1-(6-chloropyridazine-3-yl)-N-(4-cyclopropyl-3-fluorophenyl)-1H-pyrazole-4-carboxamide 055

[0472] Compound 055-3 (80 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 055-4 (82 mg, 0.54 mmol), N,N-diisopropylethylamine (139 mg, 1.08 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (150 mg, 0.4 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Pre LC with QDA detector, column: Gemini 5u C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30mL / min) to obtain compound 055 (3.32mg, yield 2.6%).

[0473] MS m / z(ESI): 358.1(M+1);

[0474] 1 H NMR (400MHz, MeOH) δ10.25(s,1H),9.57(s,1H),8.41(s,1H),8.34(d,J=9.2Hz,1H),8.16(d,J=9.2Hz,1H),7.68(dd,J=12. 8,2.0Hz,1H),7.40(dd,J=8.4,1.6Hz,1H),7.00(t,J=8.8Hz,1H),2.06-1.94(m,1H),1.01-0.91(m,2H),0.76-0.63(m,2H).

[0475] Example 31

[0476] N-(4-(6-chloropyridazin-3-yl)phenyl)-2-(4-cyclopropyl-3-fluorophenyl)acetamide 056

[0477] Synthesis of intermediate 056-2

[0478] Compound 056-1 (500 mg, 0.59 mmol) was dissolved in dioxane / water (10 / 1, 5.5 mL), and compound 002-2 (344 mg, 2.3 mmol), potassium carbonate (581 mg, 4.2 mmol), and DPPF palladium dichloride (76 mg, 0.1 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-75% petroleum ether: ethyl acetate) to obtain compound 056-2 (550 mg, 87%).

[0479] MS m / z(ESI): 306.1(M+1).

[0480] Synthesis of intermediate 056-3

[0481] Compound 056-2 (550 mg, 1.80 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 056-3 (320 mg; yield 86%).

[0482] MS m / z(ESI): 206.1(M+1)

[0483] Synthesis of N-(4-(6-chloropyridazin-3-yl)phenyl)-2-(4-cyclopropyl-3-fluorophenyl)acetamide 056

[0484] Compound 056-3 (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-5 (104 mg, 0.53 mmol), N,N-diisopropylethylamine (126 mg, 0.97 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (277 mg, 0.73 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 72%-100%, flow rate: 20mL / min) to obtain compound 056 (20.27mg; yield 11%).

[0485] MS m / z(ESI): 382.1(M+1);

[0486] 1 H NMR(400MHz,dmso)δ10.44(s,1H),8.31(d,J=9.2Hz,1H),8.17-8.13(m,2H),7.99(d,J=9.2Hz,1H),7.83-7.78(m,2 H),7.16-7.07(m,2H),6.98(t,J=8.4Hz,1H),3.69(s,2H),2.07-1.99(m,1H),1.00-0.95(m,2H),0.74-0.70(m,2H).

[0487] Example 32

[0488] 1-(1-(6-chloropyridazin-3-yl)pyrrolidine-3-yl)-3-(4-cyclopropyl-3-fluorophenyl)tetrahydropyrimidine-2(1H)-one 057

[0489] Synthesis of intermediate 057-2

[0490] Compound 057-1 (700 mg, 4.63 mmol) and sodium carbonate (981 mg, 9.26 mmol) were dissolved in dioxane (10 mL) and water (10 mL), and di-tert-butyl dicarbonate (1.5 g, 6.94 mmol) was added. The reaction was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. After washing with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, compound 057-2 (1.2 g, 92% yield) was obtained.

[0491] MS m / z (ESI): 274.1 (M+Na)

[0492] Synthesis of intermediate 057-4

[0493] Compound 057-2 (700 mg, 2.78 mmol) was dissolved in N,N-dimethylformamide (30 mL), and stirred in an ice bath for 0.5 hours. Then, sodium hydroxide (223 mg, 5.57 mmol) was added. The reaction was stirred at 0°C for 0.5 hours, and then compound 057-3 (1.02 g, 5.57 mmol) was added. The reaction mixture was slowly heated to room temperature and stirred for 0.5 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was purified by rapid silica gel column chromatography (eluent: 0%-50% / 50% petroleum ether / ethyl acetate) to obtain compound 057-4 (980 mg, 99% yield).

[0494] MS m / z (ESI): 376.2 (M+Na).

[0495] Synthesis of intermediate 057-6

[0496] Compound 057-4 (300 mg, 0.845 mmol) was dissolved in tetrahydrofuran (15 mL), and hydrochloric acid (0.2 mL) was added. The reaction was stirred at 40 °C for 1 hour. Then, compound 057-5 (168 mg, 0.846 mmol) and methanol (10 mL) were added to the reaction solution. The reaction was stirred at room temperature for 0.5 hours. Then, sodium cyanoborohydride (80 mg, 1.27 mmol) was added to the reaction solution. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase column chromatography (eluent: 0%-40% / 60% water / acetonitrile) to obtain compound 057-6 (220 mg, yield 47%).

[0497] MS m / z(ESI): 490.2(M+1)

[0498] Synthesis of intermediate 057-7

[0499] Compound 057-6 (240 mg, 0.489 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and evaporated to dryness to give compound 057-7 (190 mg, 99% yield).

[0500] MS m / z(ESI): 390.2(M+1)

[0501] Synthesis of 1-(1-(6-chloropyridazin-3-yl)pyrrolidine-3-yl)-3-(4-cyclopropyl-3-fluorophenyl)tetrahydropyrimidine-2(1H)-one 057

[0502] Compound 057-7 (190 mg; 0.487 mmol) and diisopropylethylamine (63 mg, 0.487 mmol) were dissolved in dichloromethane (30 mL) and stirred in an ice bath for 0.5 hours. Then triphosgene (48 mg, 0.161 mmol) was added. The reaction was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-0% / 100% petroleum ether / ethyl acetate) and preparative high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 50%-60%, flow rate: 20mL / min) to obtain compound 057 (1.71mg, yield 1%).

[0503] MS m / z(ESI): 416.2(M+1);

[0504] 1 H NMR (400MHz, CDCl3) δ7.28(s,1H),7.00-6.92(m,2H),6.85(t,J=8.4Hz,1H),6.78(d,J=9.2Hz,1H),5.26-5.13(m,1H),3.89-3.75(m,2H),3.69-3 .62(m,2H),3.66-3.63(m,2H),3.45-3.35(m,2H),2.31-2.21(m,2H),2.1 7-2.08(m,2H),2.07-2.00(m,1H),0.99-0.91(m,2H),0.74-0.64(m,2H).

[0505] Example 33

[0506] 2-(1-(6-chloropyridazin-3-yl)pyrrolidine-3-yl)-5-(4-cyclopropyl-3-fluorobenzyl)-1,3,4-oxadiazole 060

[0507] Synthesis of intermediate 060-7

[0508] Compound 060-5 (500 mg, 3.87 mmol), compound 002-2 (692 mg, 4.64 mmol), and N,N-diisopropylethylamine (750 mg, 5.81 mmol) were dissolved in acetonitrile (30 mL). The reaction was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-0% / 100% petroleum ether / ethyl acetate) to obtain compound 060-7 (550 mg, yield 58%).

[0509] MS m / z(ESI): 242.1(M+1)

[0510] Synthesis of intermediate 060-3

[0511] Compound 060-7 (530 mg, 2.19 mmol) and lithium hydroxide (63 mg, 2.63 mmol) were dissolved in tetrahydrofuran (15 mL) and water (15 mL). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 060-3 (495 mg, 99% yield).

[0512] MS m / z(ESI): 228.1(M+1)

[0513] Synthesis of intermediate 060-2

[0514] Compound 060-1 (680 mg, 3.1 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrazine hydrate (20 mL) was added. The reaction was stirred at 65°C for 12 hours. After the reaction was completed, the reaction solution was concentrated and dried to obtain compound 060-2 (637 mg, 99% yield).

[0515] MS m / z(ESI): 209.1(M+1)

[0516] Synthesis of intermediate 060-4

[0517] Compound 060-3 (457 mg, 2.19 mmol), compound 060-2 (500 mg, 2.19 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1253 mg, 3.29 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (568 mg, 4.39 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-60% / 40% dichloromethane / methanol) to obtain compound 060-4 (900 mg, yield 48%). MS m / z (ESI): 180.1 (M+1).

[0518] Synthesis of 2-(1-(6-chloropyridazin-3-yl)pyrrolidine-3-yl)-5-(4-cyclopropyl-3-fluorobenzyl)-1,3,4-oxadiazole 060

[0519] Compound 060-4 (900 mg, 2.15 mmol) and triethylamine (240 mg, 2.4 mmol) were dissolved in dichloromethane (50 mL), and p-toluenesulfonyl chloride (460 mg, 2.4 mmol) was added. The reaction was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 50%-0% / 100% petroleum ether / ethyl acetate) to obtain compound 060 (70 mg, yield 8%).

[0520] MS m / z(ESI): 400.1(M+1).

[0521] Synthesis of 060a and 060b

[0522] Compound 060 (60 mg) was separated using an SFC (System: Waters SFC 80; Column: Daicel CHIRALCEL ID; Column size: 250 mm * 30 mm 10 μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (+0.2% 7.0 mol / L amine methanol solution); A:B = 55:45; Wavelength: 214 nm; Flow rate: 80 g / min; Column temperature: 35 ℃; Back pressure: 100 bar; Injection volume: 3.0 mL; Cycle time: 14.7 min; Solvent: MeOH: distillation grade, supercritical CO2: food grade) to obtain compounds 060a (first peak, retention time: 2.256 min, 20 mg, 28%) and 060b (last peak, retention time: 2.654 min, 20 mg, yield 28%).

[0523] Compound 060a

[0524] MS m / z(ESI): 400.1(M+1)

[0525] 1H NMR (400MHz, CDCl3) δ7.33-7.27(m,1H),6.99-6.92(m,1H),6.85(t,J=7.6Hz,1H),6.82-6.70(m,1H),4.2 0-3.94(m,4H),3.91-3.59(m,3H),2.54(s,2H),2.12-2.00(m,1H),1.04-0.91(m,2H),0.74-0.63(m,2H).-

[0526] Compound 060b

[0527] MS m / z(ESI): 400.1(M+1)

[0528] 1H NMR(400MHz, CDCl3)δ7.34(d,J=9.2Hz,1H),6.97-6.93(m,2H),6.86(t,J=8.0Hz,2H),4.15-4.03(m, 4H),3.91-3.76(m,3H),2.57-2.52(m,2H),2.08-2.03(m,1H),1.01-0.96(m,2H),0.73-0.69(m,2H).

[0529] Example 34

[0530] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(5,6,8,9-Tetrahydro-7H-pyrido[2,3-d]azacycloheptane-7-yl)ethane-1-one 061

[0531] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azacycloheptane-7-yl)ethane-1-one 061

[0532] Compound 061-1 (50 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-5 (65 mg, 0.33 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (192 mg, 0.51 mmol), and N,N-diisopropylethylamine (87 mg, 0.67 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with QDA detector. The chromatographic column was a Gemini 5u C18 100 x 21.2 mm column; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 25%-35%, flow rate: 25 mL / min) to obtain compound 061 (40 mg; yield 34%).

[0533] MS m / z(ESI): 325(M+1) + ;

[0534] 1 H NMR (400MHz, DMSO) δ8.60-8.51(m,1H),8.19-8.09(m,1H),7.65(dd,J=13.6,7.6Hz,1H),7.06-6.86(m,3H),3.82-3 .65(m,6H),3.21(d,J=9.6Hz,2H),3.00(d,J=4.0Hz,2H),2.04-1.93(m,1H),1.04-0.90(m,2H),0.77-0.63(m,2H).

[0535] Example 35

[0536] 1-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)pyrimidin-2(1H)-one O62

[0537] Synthesis of intermediate 062-3

[0538] Compound 062-1 (600 mg, 6.24 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 062-2 (1.94 g, 6.24 mmol) and cesium carbonate (6.09 g, 18.72 mmol) were added. The reaction was stirred at 80 °C for 1 hour. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to give crude compound 062-3 (1.2 g, yield 68%).

[0539] MS m / z(ESI):224.2(M-56).

[0540] Synthesis of intermediate 062-4

[0541] Compound 062-3 (1.2 g, 4.29 mmol) was dissolved in 5 mL of 4 M dioxane hydrochloride solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude 062-4 (770 mg, 100% yield).

[0542] MS m / z(ESI): 180.1(M+1).

[0543] Synthesis of 1-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)pyrimidin-2(1H)-one O62

[0544] Compound 062-4 (770 mg, 4.30 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 002-5 (835 mg, 4.30 mmol), HATU (1.80 g, 4.73 mmol), and DIEA (1.67 g, 12.9 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25 mL / min) to obtain compound 062 (16 mg, yield 7%).

[0545] MS m / z(ESI): 356.2(M+1);

[0546] 1H NMR (400MHz, CDCl3) δ8.49(d,J=4.0Hz,2H),6.92(dd,J=8.0,4.0Hz,3H),6.82(t,J=8.0Hz,1H),5.21(m,1H),3.91(s,1H),3.69( s,2H),3.60(s,1H),3.38(s,1H),2.06-1.97(m,2H),1.82-1.81(m,2H),1.37-1.23(m,2H),0.97-0.90(m,2H),0.72-0.65(m,2H).

[0547] Example 36

[0548] 2-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)pyridazine-3(2H)-one 063

[0549] Synthesis of intermediate 063-3

[0550] Compound 063-1 (1.5 g, 5.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 063-2 (660 mg, 6.84 mmol) and potassium carbonate (1.18 g, 8.55 mmol) were added. The reaction was stirred at 60 °C for 12 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-30% / 70% petroleum ether / ethyl acetate) to obtain compound 063-3 (500 mg, 28%).

[0551] MS m / z(ESI): 224.1(M-55)

[0552] Synthesis of intermediate 063-4

[0553] Compound 063-3 (250 mg, 0.89 mmol) was dissolved in 10 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 063-4 (159 mg, 99%).

[0554] MS m / z(ESI): 180.1(M+1)

[0555] Synthesis of 2-(1-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperidin-4-yl)pyridazine-3(2H)-one 063

[0556] Compound 063-4 (130 mg, 0.45 mmol), compound 002-5 (130 mg, 0.45 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (225 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (174 mg, 1.35 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 42%-100%, flow rate: 20mL / min) to obtain compound 063 (7.19mg; yield 4%).

[0557] MS m / z(ESI): 356.2(M+1);

[0558] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=2.4Hz,1H),7.17(dd,J=9.6,3.6Hz,1H),6.94(dd,J =11.2,5.6Hz,3H),6.85(t,J=7.6Hz,1H),5.20-5.03(m,1H),4.80(d,J=12.4Hz,1H), 3.98(d,J=12.4Hz,1H),3.72(s,2H),3.17(t,J=12.4Hz,1H),2.80-2.73(m,1H),2.09 -2.01(m,1H),1.91-1.76(m,4H),1.25(s,1H),0.99-0.92(m,2H),0.74-0.67(m,2H).

[0559] Example 37

[0560] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(6-(isoxazo-4-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 064

[0561] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(6-(isoxazo-4-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 064

[0562] Compound A (50 mg, 0.13 mmol) was dissolved in dioxane (2 mL), and compound 064-1 (18 mg, 0.16 mmol), sodium carbonate (42 mg, 0.39 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (9 mg, 0.013 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 3 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, chromatogram: Gemini 5u C18 100x 21.2 mm; mobile phase 1: water (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25 mL / min) to obtain compound 064 (2.15 mg, yield: 4%).

[0563] MS m / z(ESI): 408.2(M+1);

[0564] 1 H NMR (400MHz, MeOD) δ9.31(s,1H),8.96(s,1H),7.94(d,J=9.6Hz,1H),7.58(d,J=9.6Hz,1H),7.03-6. 87(m,3H),3.81(s,2H),3.80-3.66(m,8H),2.09-1.97(m,1H),1.00-0.92(m,2H),0.72-0.66(m,2H).

[0565] Example 38

[0566] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(6-(thiazolyl-5-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 066

[0567] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(6-(thiazol-5-yl)pyridazin-3-yl)piperazin-1-yl)ethane-1-one 066

[0568] Compound A (100 mg, 0.27 mmol) was dissolved in dioxane / water (10 / 1, 2.2 mL), and compound 066-2 (171 mg, 0.81 mmol), sodium carbonate (175 mg, 1.62 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (39 mg, 0.054 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, chromatogram: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 47%-100%, flow rate: 20 mL / min) to obtain compound 066 (3.54 mg; yield 3%).

[0569] MS m / z(ESI): 424.1(M+1);

[0570] 1 H NMR (400MHz, MeOD) δ9.10(s,1H),8.52(s,1H),8.09(d,J=9.6Hz,1H),7.46(d,J=9.6Hz,1H),7.04-6.96(m,2H),6.92(t,J=8.0Hz,1H),3.76( s,2H),2.69-2.64(m,1H),2.36-2.29(m,1H),2.03-1.91(m,2H),1.31- 1.18(m,4H),0.98-0.92(m,2H),0.90-0.79(m,1H),0.71-0.66(m,2H).

[0571] Example 39

[0572] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(1-cyclopropylpiperidin-4-yl)ethane-1-one 068

[0573] Synthesis of intermediate 068-3

[0574] Compound 068-1 (500 mg; 2.9 mmol) was dissolved in tetrahydrofuran / methanol (9 / 1; 10 mL), and compound 068-2 (1.5 g; 8.7 mmol), acetic acid (2 g; 35 mmol), and sodium cyanoborohydride (550 mg; 8.7 mmol) were added. The reaction was stirred at 65°C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: 0%-90% / 10% dichloromethane / methanol) to give compound 068-3 (300 mg; yield 48.6%).

[0575] MS m / z(ESI):212.1(M+1).

[0576] Synthesis of intermediate 068-4

[0577] Compound 068-3 (100 mg, 0.47 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (34 mg, 1.5 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 1-2 with 4 mol / L hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was compound 068-4 (50 mg; yield 57.6%).

[0578] MS m / z(ESI): 184.2(M+1).

[0579] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(1-cyclopropylpiperidin-4-yl)ethane-1-one 068

[0580] Compound 068-4 (50 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 036-4 (54 mg, 0.27 mmol), N,N-diisopropylethylamine (105.8 mg, 0.82 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (124.5 mg, 0.33 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C182 1.2*250mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25mL / min) to obtain compound 068 (10mg; yield 10%).

[0581] MS m / z(ESI): 364.2(M+1);

[0582] 1 H NMR (400MHz, CD3OD) δ7.47(d,J=9.6Hz,1H),7.34(d,J=9.6Hz,1H),3.75-3.62(m,8H),3.05(d,J=12Hz,2H),2.3 9(d,J=7.2Hz,2H),2.28-2.17(m,3H),2.04-1.73(m,4H),1.67-1.62(m,2H),0.51-0.41(m,4H)

[0583] Example 40

[0584] 1-(6-Chlorpyridazin-3-yl)-N-(4-Cyclopropyl-3-fluorobenzyl)-N-(Oxycyclobutane-3-yl)piperidine-4-amine 070

[0585] Synthesis of intermediate 070-2

[0586] Compound 070-1 (1.35 g, 6.75 mmol) was dissolved in acetonitrile (20 mL), and compound 002-2 (1.0 g, 6.75 mmol) and DIEA (2.85 g, 20.12 mmol) were added. The mixture was heated to 90 °C and stirred for 16 hours. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: DCM / MeOH = 0–10%) to give compound 070-2 (1.64 g; yield 78%).

[0587] MS m / z(ESI): 313.2(M+1).

[0588] Synthesis of intermediate 070-3

[0589] Compound 070-2 (300 mg, 0.96 mmol) was dissolved in dichloromethane (2 mL), and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 070-3 (192 mg; yield 94%).

[0590] MS m / z(ESI): 213.1(M+1)

[0591] Synthesis of intermediate 070-5

[0592] Compound 070-3 (200 mg, 0.94 mmol) and compound 070-4 (203 mg, 2.82 mmol) were dissolved in methanol (10 mL), and acetic acid (28 mg, 4.7 mmol) was added. After stirring at room temperature for 1 hour, NaBH(AcO)3 (996 mg, 4.70 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH = 0-10%) to obtain compound 070-5 (150 mg; yield 66%).

[0593] MS m / z(ESI):269.2(M+1).

[0594] Synthesis of 1-(6-chloropyridazin-3-yl)-N-(4-cyclopropyl-3-fluorobenzyl)-N-(oxetane-3-yl)piperidine-4-amine 070

[0595] Compound 070-5 (100 mg, 0.37 mmol) was dissolved in DMF (2 mL). NaH (18 mg, 0.74 mmol) was added under ice-water bath conditions. After stirring at room temperature for 0.5 hours, compound 070-6 (85 mg, 0.37 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was directly filtered. The crude product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 070 (19.9 mg; yield 13%).

[0596] MS m / z(ESI): 417.2(M+1);

[0597] 1 H NMR (400MHz, DMSO) δ7.47(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),7.09(m,2H),6.92(m,1H),4.43(m,5H),4.27-4.17(m,1H),3.7 6(s,2H),2.76(m,2H),4.00(s,1H),1.66(d,J=12.0Hz,2H),1.33(d,J=8.0Hz,2H),0.94(d,J=4.0Hz,2H),0.69(d,J=4.0Hz,2H).

[0598] Example 41

[0599] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(3,4-Dihydro-2,7-Naphthidin-2(1H)-yl)ethane-1-one 077

[0600] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(3,4-dihydro-2,7-naphthidium-2(1H)-yl)ethane-1-one 077

[0601] Compound 002-5 (114 mg, 0.586 mmol) was dissolved in NN-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (446 mg, 1.172 mmol) and NN-diisopropylethylamine (228 mg, 1.758 mmol). The reaction was stirred at room temperature for 0.5 hours, then compound 077-1 (100 mg, 0.586 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered. The crude product was purified by high performance liquid chromatography (HPLC) using a Waters MS-triggered Prep-LC with a QDA detector. The chromatographic column was an Xbridge 5u C18 150x 30mm. The mobile phase 1 was water (containing 0.1% FA), and the mobile phase 2 was acetonitrile. The gradient was 15 minutes, with a gradient ratio of 20%-100% acetonitrile phase and a flow rate of 25 mL / min. The result was compound 077 (20 mg; yield 10.44%).

[0602] MS m / z (ESI): 311.1 (M+1); HPLC: 99.59% (214nm), 95.06% (254nm);

[0603] 1H NMR (400MHz, MeOD) δ8.74(s,0.6H),8.58(d,J=6.2Hz,1.4H),7.88(d,J=6.2Hz,1H),7.00-6.81(m,3H),4.94(s,2H),3.89-3 .84(m,4H),3.14(dd,J=17.6,11.6Hz,1H),3.07(s,1H),2.08-1.96(m,1H),1.00-0.92(m,2H),0.69(dd,J=5.2,1.6Hz,2H).

[0604] Example 42

[0605] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(3,4-Dihydro-2,6-Naphthidin-2(1H)-yl)ethane-1-one 078

[0606] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(3,4-dihydro-2,6-naphthidium-2(1H)-yl)ethane-1-one 078

[0607] Compound 078-1 (70 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-5 (101 mg, 0.52 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (297 mg, 0.78 mmol), and N,N-diisopropylethylamine (168 mg, 1.31 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with QDA detector. The chromatographic column was a Welch Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 25%-55%, flow rate: 25mL / min) to obtain compound 078 (33mg, yield: 20%).

[0608] MS m / z(ESI): 311(M+1) + ;

[0609] 1H NMR (400MHz, DMSO) δ8.79(s,1H),8.70(d,J=6.0Hz,1H),7.94(d,J=5.6Hz,1H),7.08-6.84(m,3H),4.97(d,J=4 1.2Hz,2H),3.89-3.73(m,4H),2.93(d,J=4.0Hz,2H),2.07-1.95(m,1H),0.99-0.92(m,2H),0.72-0.64(m,2H).

[0610] Example 43

[0611] 1-(3-(6-chloropyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 080

[0612] Synthesis of intermediate 080-2

[0613] Compound 002-5 (100 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 080-1 (164 mg, 0.77 mmol), N,N-diisopropylethylamine (582 mg, 1.53 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (397 mg, 0.56 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-100% / 25% petroleum ether / ethyl acetate) to give compound 080-2 (80 mg; yield 38%).

[0614] MS m / z(ESI): 333(M-56)

[0615] Synthesis of intermediate 080-3

[0616] Compound 080-2 (80 mg; 0.21 mmol) was dissolved in 5 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 080-3 (70 mg; 99% yield).

[0617] MS m / z(ESI):289(M+1).

[0618] Synthesis of 1-(3-(6-chloropyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 080

[0619] Compound 080-3 (70 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (39 mg, 0.26 mmol) and N,N-diisopropylethylamine (93 mg, 0.72 mmol) were added. The reaction was stirred at 100 °C for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25 mL / min) to obtain compound 080 (24 mg, yield 17%).

[0620] MS m / z(ESI): 401(M+1);

[0621] 1 H NMR(400MHz, CDCl3)δ7.33(d,J=9.2Hz,1H),6.99-6.91(m,3H),6.84(t,J=7.6Hz, 1H),4.93(s,1H),4.40(d,J=11.6Hz,2H),3.78(d,J=11.2Hz,1H),3.68-3.64(m,2H ),3.30(d,J=10.8Hz,1H),3.01(d,J=9.2Hz,1H),2.29-2.21(m,1H),1.97-1.87(m, 3H),1.74(m,1H),1.64(m,1H),1.01-0.93(m,2H),0.87(m,1H),0.73-0.66(m,2H).

[0622] Example 44

[0623] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)propane-1-one 082

[0624] Synthesis of intermediate 082-2

[0625] Compound 082-1 ​​(1 g, 3.8 mmol) was dissolved in N,N-dimethylformamide (5 mL), and NaH (182 mg, 7.6 mmol) was added under ice bath conditions. After stirring for ten minutes, iodomethane (593 mg, 4.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-10% / 4% petroleum ether / ethyl acetate) to obtain compound 082-2 (800 mg, yield 77%).

[0626] MS m / z (ESI): 275.1 (M+H) + )

[0627] Synthesis of intermediate 082-3

[0628] Compound 082-2 (600 mg, 2.19 mmol) was dissolved in 5 mL of 1,4-dioxane solution and 0.5 mL of water. Compound 036-2 (226 mg, 2.63 mmol), Pd2(dppf)Cl (159 mg, 0.219 mmol), and cesium carbonate (4.28 g, 13.14 mmol) were added. The mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-10% / 5% petroleum ether / ethyl acetate) to obtain compound 082-3 (430 mg, yield 83%).

[0629] MS m / z (ESI): 237.2 (M+H) + ).

[0630] Synthesis of intermediate 082-4

[0631] Compound 082-3 (430 mg, 1.82 mmol) was dissolved in tetrahydrofuran solution (2 mL), and lithium hydroxide (131 mg, 5.46 mmol) was dissolved in water (2 mL) and added to the reaction system. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude product 082-4 (300 mg, yield 79%).

[0632] MS m / z(ESI):209.1(M+1).

[0633] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)prop-1-one 082

[0634] Compound 082-4 (300 mg, 1.44 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 036-4 (285 mg, 1.44 mmol), HATU (602 mg, 1.58 mmol), and DIEA (558 mg, 4.32 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 082. The crude compound 082 was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 25mL / min) to obtain compound 082a (first peak, RT=3.151min, 109mg, yield 21%) and compound 082b (last peak, RT=3.547min, 93mg, yield: 17%).

[0635] Compound 082a

[0636] MS m / z(ESI): 389.2(M+1);

[0637] 1 H NMR (400MHz, CDCl3) δ7.19(s,2H),6.84(d,J=8.0Hz,2H),6.76(t,J=8.0Hz,1H),3.90-3.88(m,1H),3.79-3.78(m,1H),3.72-3.69(m,1H ),3.59-3.57(m,2H),3.47(s,1H),3.35(s,1H),3.17(s,1H),1.37(d,J=4.0Hz,3H),1.18(s,1H),0.92-0.84(m,2H),0.66-0.59(m,2H).

[0638] Compound 082b

[0639] MS m / z(ESI): 389.2(M+1);

[0640] 1H NMR (400MHz, CDCl3) δ7.46 (d, J = 12.0Hz, 1H), 7.16-7.09 (m, 1H), 7.01 (m, 2 H),6.94(t,J=8.0Hz,1H),4.14-4.00(m,2H),3.98-3.93(m,1H),3.79(s,2 H),3.70(d,J=12.0Hz,2H),3.60(d,J=14.4Hz,1H),3.47(d,J=8.0Hz,1H), 1.55(d,J=4.0Hz,3H),1.07-1.03(m,2H),0.99(m,1H),0.84-0.77(m,2H).

[0641] Example 45

[0642] 1-(4-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 084

[0643] Synthesis of 1-(4-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 084

[0644] Compound 084-1 (50 mg, 0.33 mmol) was dissolved in dioxane (2 mL), and compound 024-3 (94 mg, 0.36 mmol), cesium carbonate (318 mg, 0.99 mmol), and Pd-PEPPSI-iPentCl-(o-picoline) (27 mg, 0.033 mmol) were added. The reaction was stirred at 85°C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5u C18 100x 21.2mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 48%-100%, flow rate: 25mL / min) to obtain compound 084 (62mg, yield: 50%).

[0645] MS m / z(ESI): 380.2(M+1);

[0646] 1H NMR (400MHz, MeOH) δ8.47(d,J=6.8Hz,1H),7.56-7.51(m,1H),7.42(d,J=8.8Hz,1H),7.01-6.95(m,3H),6.91(t,J=8.0Hz,1H),3.80(s,2 H),3.76-3.71(m,2H),3.71-3.66(m,2H),3.59-3.52(m,2H),3.48-3.43(m,2H),2.11-1.98(m,1H),0.98-0.92(m,2H),0.71-0.66(m,2H).

[0647] Example 46

[0648] 1-(4-(-chloropyridazin-3-yl)piperazin-1-yl)-2-(2,3-dihydro-1H-inden-5-yl)ethane-1-one 085

[0649] Synthesis of 1-(4-(-chloropyridazin-3-yl)piperazin-1-yl)-2-(2,3-dihydro-1H-inden-5-yl)ethane-1-one 085

[0650] Compound 085-1 (100 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (113 mg, 0.57 mmol), N,N-diisopropylethylamine (147 mg, 1.14 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (259 mg, 0.68 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 085 (116mg; yield 57%).

[0651] MS m / z(ESI): 357.1(M+1);

[0652] 1H NMR (400MHz, CDCl3) δ7.27(m,1H),7.17(d,J=8.0Hz,1H),7.13(s,1H),7.01(d,J=8.0Hz,1H),6.93(d,J=12 .0Hz,1H),3.83-3.77(m,2H),3.75(s,2H),3.62(s,4H),3.58-3.50(m,2H),2.88(m,4H),2.13-2.00(m,2H).

[0653] Example 47

[0654] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)ethane-1-one 089

[0655] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)ethane-1-one 089

[0656] Compound 089-1 (270 mg; 1.25 mmol), compound 002-2 (248 mg; 1.25 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (712 mg, 1.87 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (323 mg, 2.50 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. After washing with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was then purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 50%-80%, flow rate: 20mL / min). The purified product yielded compound 089 (21.20mg, yield 4%).

[0657] MS m / z(ESI): 397.1(M+1);

[0658] 1H NMR (400MHz, DMSO) δ7.57(d,J=9.6Hz,1H),7.41(d,J=9.6Hz,1H),7.33(d,J=8.4Hz,1H ),7.28(d,J=1.6Hz,1H),7.07(dd,J=8.4,1.6Hz,1H),3.82(s,2H),3.70-3.58(m,8H).

[0659] Example 48

[0660] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(naphth-2-yl)ethane-1-one 090

[0661] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(naphth-2-yl)ethane-1-one 090

[0662] Compound 090-1 (100 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 002-2 (117 mg, 0.59 mmol), N,N-diisopropylethylamine (139 mg, 1.07 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (306 mg, 0.81 mmol) were added. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C182 1.2*250mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 50%-100%, flow rate: 25mL / min) to obtain compound 090 (25.79mg; yield 13%).

[0663] MS m / z(ESI): 367.1(M+1);

[0664] 1 H NMR(400MHz,MeOD)δ7.86-7.80(m,3H),7.75(s,1H),7.48-7.40(m,4H),7.3 1(d,J=9.6Hz,1H),3.81-3.74(m,4H),3.67-3.63(m,2H),3.56-3.51(m,2H).

[0665] Example 49

[0666] 6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)pyridazin-3-carbamate 091

[0667] Synthesis of 6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)pyridazin-3-carbamate 091

[0668] Compound 024-3 (100 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 002-2 (58.5 mg, 0.42 mmol) and N,N-diisopropylethylamine (98.5 mg, 0.76 mmol) were added. The reaction was stirred at 100 °C for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5u C18 100x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 52%-62%, flow rate: 25 mL / min) to obtain compound 091 (33.62 mg; yield 24%).

[0669] MS m / z(ESI): 366.2(M+1);

[0670] 1 H NMR (400MHz, DMSO) δ7.90(d,J=9.6Hz,1H),7.35(d,J=9.6Hz,1H),7.03-6.89(m,3H),3.76(t,J=5.2Hz,6H),3.68-3 .60(m,4H),2.04-1.95(m,1H),0.97-0.91(m,2H),0.72-0.65(m,2H).(m,1H),0.97-0.91(m,2H),0.72-0.65(m,2H).

[0671] Example 50

[0672] 1-(6-(6-chloropyridazin-3-yl)-3-azabicyclo[4.1.0]heptane-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 092

[0673] Synthesis of intermediate 092-2

[0674] Compound 092-1 (120 mg, 0.39 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Compound 002-2 (58 mg, 0.39 mmol), potassium carbonate (110 mg, 0.78 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (43 mg, 0.58 mmol) were added to the nitrogen-purified system. The reaction was carried out under nitrogen protection at 100°C for 2 hours. After the reaction was completed, the mixture was filtered, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-100% petroleum ether / ethyl acetate) to obtain compound 092-2 (20 mg, yield 16%).

[0675] MS m / z(ESI): 254.2(M+1-56)

[0676] Synthesis of intermediate 092-3

[0677] Compound 092-2 (20 mg, 1.0 mmol) was dissolved in dichloromethane (1 mL), and then added to 4 M hydrochloric acid / dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was compound 092-3 (13 mg, 100% yield).

[0678] MS m / z(ESI):209.1(M+1).

[0679] Synthesis of 1-(6-(6-chloropyridazin-3-yl)-3-azabicyclo[4.1.0]hept-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 092

[0680] Compound 092-3 (13 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 002-5 (12 mg, 0.06 mmol), N,N-diisopropylethylamine (15 mg, 0.12 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (35 mg, 0.09 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x). The mobile phase was 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 55%-100%, flow rate: 20 mL / min) to purify, yielding compound 092 (2.33 mg, yield 10%).

[0681] MS m / z(ESI): 386.1(M+1);

[0682] 1 H NMR(400MHz,MeOD)δ7.75-7.47(m,2H),6.99-6.83(m,3H),4.00-3.95(m,1H),3.74-3.62(m,3H),3.50-3. 45(m,2H),2.65-2.51(m,1H),2.16-1.76(m,3H),1.42-1.36(m,1H),0.97-0.95(m,3H),0.75-0.61(m,2H).

[0683] Example 51

[0684] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-pyridin-2-carbonylpiperazin-1-yl)ethane-1-one 103

[0685] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-pyridin-2-carbonylpiperazin-1-yl)ethane-1-one 103

[0686] Compound 024-3 (100 mg; 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 103-1 (51 mg; 0.42 mmol), N,N-diisopropylethylamine (147 mg; 1.14 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (174 mg; 0.46 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 40%-100%, flow rate: 20mL / min) to obtain compound 103 (49mg, yield 35%).

[0687] MS m / z(ESI): 368.1(M+1);

[0688] 1H NMR(400MHz,MeOH)δ8.59(d,J=4.6Hz,1H),7.94-7.90(m,1H),7.61(d,J=7.6Hz,1H),7.49(dd,J=7.2,5.6Hz,1H),7.06-6.86(m,3H),3.7 4(s,1H),3.68(s,1H),3.63-3.54(m,4H),3.53-3.44(m,2H),3.42-3.36(m,2H),2.04-1.93(m,1H),0.99-0.88(m,2H),0.73-0.69(m,2H).

[0689] Example 52

[0690] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-nicotinylpiperazin-1-yl)ethane-1-one 104

[0691] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-nicotinylpiperazin-1-yl)ethane-1-one 104

[0692] Compound 104-1 (100 mg, 0.81 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 024-3 (193 mg, 0.74 mmol), N,N-diisopropylethylamine (287 mg, 2.22 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (308 mg, 0.81 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C182 1.2*250mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30mL / min) to obtain compound 104 (55mg, yield 32%).

[0693] MS m / z(ESI): 368.2(M+1);

[0694] 1H NMR (400MHz, CDCl3) δ8.68(s,2H),7.92(d,J=7.6Hz,1H),7.53(d,J=7.2Hz,1H),6.94-6.82(m,3H),3.71-3.67 (m,6H),3.50(m,4H),3.32(s,1H),2.08-2.01(m,1H),1.32-1.24(m,1H),1.01-0.94(m,2H),0.70-0.68(m,2H).

[0695] Example 53

[0696] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(pyrimidin-2-carbonyl)piperazin-1-yl)ethane-1-one 105

[0697] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(pyrimidin-2-carbonyl)piperazin-1-yl)ethane-1-one 105

[0698] Compound 105-1 (100 mg; 0.806 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (613 mg, 1.612 mmol) and N,N-diisopropylethylamine (313 mg, 2.417 mmol). The reaction was stirred at room temperature for 0.5 hours. Then, compound 024-3 (212 mg, 0.806 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with QDA detector. The chromatographic column was a Gemini 5u C18 100x 21.2mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 37%-100%, flow rate: 25mL / min) to obtain compound 105 (110mg; yield 36.68%).

[0699] MS m / z (ESI): 369.2 (M+1);

[0700] HPLC: 100.00% (214nm), 99.64% (254nm);

[0701] 1H NMR(400MHz,MeOD)δ8.88(s,2H),7.56-7.52(m,1H),7.00-6.87(m,3H),3.80(s,1H),3.75(d,J=4.8Hz,3H),3.69(s,2H),3.65- 3.61(m,1H),3.59-3.54(m,1H),3.37-3.33(m,1H),3.29-3.23(m,1H),2.11-1.97(m,1H),1.01-0.91(m,2H),0.74-0.64(m,2H).

[0702] Example 54

[0703] 2-(4-Cyclopropyl-3-fluorophenyl)-1-(4-(phenylsulfonyl)piperazin-1-yl)ethane-1-one 106

[0704] Synthesis of 2-(4-cyclopropyl-3-fluorophenyl)-1-(4-(phenylsulfonyl)piperazin-1-yl)ethane-1-one 106

[0705] Compound 106-1 (50 mg; 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 024-3 (82 mg; 0.32 mmol) and N,N-diisopropylethylamine (74 mg; 0.56 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with QDA detector. The chromatographic column was a Welch Ultimate C182 1.2*250 mm 10 μm column; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 55%-65%, flow rate: 25 mL / min) to obtain compound 106 (25 mg; yield 20%).

[0706] MS m / z(ESI): 403.2(M+1) + ;

[0707] 1 H NMR(400MHz,DMSO)δ7.82-7.59(m,5H),6.96-6.77(m,3H),3.69-3.47(m,6H) ,2.90-2.78(m,4H),2.05-1.89(m,1H),0.98-0.91(m,2H),0.74-0.61(m,2H).

[0708] Example 55

[0709] (1s,4s)-N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-4-methyl-2-oxabicyclo[2.1.1]hexane-1-carboxamide 108a

[0710] Synthesis of (1s,4s)-N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-4-methyl-2-oxabicyclo[2.1.1]hexane-1-carboxamide 108a

[0711] Compound 108a-1 (50 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 070-3 (82 mg, 0.39 mmol), N,N-diisopropylethylamine (135 mg, 1.05 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (160 mg, 0.42 mmol) were added. The reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C182 1.2*250mm 10um; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30mL / min) to obtain compound 108a (53mg, yield: 45%).

[0712] MS m / z(ESI): 337.1(M+1);

[0713] 1 H NMR (400MHz, MeOH) δ7.40(d,J=9.6Hz,1H),7.32(d,J=9.6Hz,1H),4.36(d,J=13.6Hz,2H),3.65(s,2H),3.14-3.02(m, 2H),1.97(dd,J=4.4,1.6Hz,2H),1.93(d,J=9.6Hz,2H),1.65(dd,J=4.6,1.6Hz,2H),1.63-1.51(m,2H),1.34(s,3H).

[0714] Example 56

[0715] (4-(6-chloropyridazin-3-yl)piperazin-1-yl)((1s,4s)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methyl ketone 109a

[0716] Synthesis of (4-(6-chloropyridazin-3-yl)piperazin-1-yl)((1s,4s)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methyl ketone 109a

[0717] Compound 109a-1 (50 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 070-3 (76 mg; 0.38 mmol), DIEA (146 mg; 0.38 mmol), and HATU (136 mg; 1.05 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30 mL / min) to obtain compound 109a (64 mg, yield 57%).

[0718] MS m / z(ESI): 323.2(M+1);

[0719] 1 H NMR (400MHz, CDCl3) δ7.33 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 3.91 (s, 2H), 3.80 (s, 4H), 3.64 (s, 4H), 2.01 (m, 2H), 1.95 (m, 2H), 1.47 (s, 3H).

[0720] Example 57

[0721] (1r,4r)-N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide 110a

[0722] Synthesis of (1r,4r)-N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide 110

[0723] Compound 110a-1 (50 mg; 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 070-3 (75 mg, 0.35 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (200 mg; 0.52 mmol) and N,N-diisopropylethylamine (114 mg, 0.87 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with QDA detector. The chromatographic column was a Welch Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile phase 20%-30%, flow rate: 30mL / min) to obtain compound 110a (85mg; yield 68%).

[0724] MS m / z(ESI): 337.2(M+1) + ;

[0725] 1 H NMR (400MHz, DMSO) δ7.62(d,J=8.0Hz,1H),7.52(d,J=9.6Hz,1H),7.42(d,J=9.6Hz,1H),4.29(d,J=13.6Hz,2H),3.92(d,J=7.6Hz, 1H),3.69(s,2H),3.07-2.97(m,2H),1.92-1.84(m,2H),1.76(d,J=9.6Hz,2H),1.65-1.58(m,2H),1.48-1.38(m,2H),1.32(s,3H).

[0726] Example 58

[0727] 2-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)-N,N-dimethyloxazol-5-carboxamide 112

[0728] Synthesis of intermediate 112-2

[0729] Compound 024-3 (180 mg, 0.684 mmol), compound 112-1 (100 mg, 0.570 mmol), and diisopropylethylamine (147 mg, 1.14 mmol) were dissolved in acetonitrile (15 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-90% / 10% dichloromethane / methanol) to obtain compound 112-2 (220 mg, 96%).

[0730] MS m / z(ESI): 402.2(M+H)

[0731] Synthesis of intermediate 112-3

[0732] Compound 112-2 (210 mg, 0.523 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide (19 mg, 0.785 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 112-3 (169 mg, 100%).

[0733] MS m / z(ESI): 374.1(M+H).

[0734] Synthesis of 2-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)-N,N-dimethyloxazol-5-carboxamide 112

[0735] Compound 112-3 (75 mg, 0.201 mmol) and diisopropylethylamine (78 mg, 0.603 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (115 mg, 0.301 mmol) were added. The reaction was stirred at room temperature for 0.5 hours. Then, dimethylamine hydrochloride (25 mg, 0.301 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 40%-50%, flow rate: 20mL / min) to obtain compound 112 (25.09mg, 31%).

[0736] MS m / z(ESI): 401.2(M+1);

[0737] 1 H NMR(400MHz,DMSO)δ7.44(s,1H),6.95-6.90(m,3H),3.73(s,2H),3.65-3.54(m,4H),3.4 5(d,J=2.8Hz,4H),3.04(s,6H),2.05-1.91(m,1H),0.99-0.89(m,2H),0.72-0.63(m,2H).

[0738] Example 59

[0739] 2-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)oxazol-5-carboxamide 114

[0740] Synthesis of 2-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)oxazol-5-carboxamide 114

[0741] Compound 112-3 (75 mg, 0.20 mmol) and diisopropylethylamine (78 mg, 0.603 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (115 mg, 0.30 mmol) were added. The reaction was stirred at room temperature for 0.5 hours. Then ammonium chloride (16 mg, 0.30 mmol) was added to the reaction solution. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% ammonia); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 15%-45%, flow rate: 25mL / min) to obtain compound 114 (36.65mg, yield 48%).

[0742] MS m / z(ESI): 373.2(M+1);

[0743] 1H NMR(400MHz,DMSO)δ7.58(s,1H),7.44(s,1H),7.24(s,1H),7.01-6.90(m,3H),3.74(s,2H),3 .62-3.56(m,4H),3.49-3.46(m,4H),2.10-1.92(m,1H),1.01-0.87(m,2H),0.75-0.63(m,2H).

[0744] Example 60

[0745] (3-(tert-butyl)bicyclo[1.1.1]pent-1-yl)(4-(6-chloropyridazin-3-yl)piperazin-1-yl)methyl ketone 118

[0746] Synthesis of (3-(tert-butyl)bicyclo[1.1.1]pent-1-yl)(4-(6-chloropyridazin-3-yl)piperazin-1-yl)methyl ketone 118

[0747] Compound 118-1 (90 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 002-2 (106 mg, 0.53 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (305 mg, 0.81 mmol) and N,N-diisopropylethylamine (173 mg, 1.33 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with SQD2 detector. The chromatographic column was an Xbridge 5u C18 150x 19mm column. The mobile phase 1 was water (containing 0.1% FA), and the mobile phase 2 was acetonitrile. The gradient was 13 min, with a gradient ratio of 55%-65% acetonitrile phase and a flow rate of 20 mL / min. Compound 118 (32 mg, yield 16%) was obtained.

[0748] MS m / z(ESI): 349(M+1) + ;

[0749] 1 H NMR (400MHz, DMSO) δ7.56(d,J=9.6Hz,1H),7.36(d,J=9.6Hz,1H),3.70(s,2H),3.58(d,J=21.6Hz,6H),1.85(s,6H),0.83(s,9H).

[0750] Example 61

[0751] (4-(6-Chlorpyridazin-3-yl)piperazin-1-yl)(cyclopropyl)methyl ketone 120

[0752] Synthesis of (4-(6-chloropyridazin-3-yl)piperazin-1-yl)(cyclopropyl)methyl ketone 120

[0753] Compound 002-2 (50 mg; 0.25 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (76 mg, 0.75 mmol) was added. Compound 120-1 (52 mg; 0.5 mmol) was added under ice bath conditions. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5uC18 100x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 23%-100%, flow rate: 25 mL / min) to obtain compound 120 (23 mg; yield 34%).

[0754] MS m / z(ESI): 267.1(M+1);

[0755] 1 H NMR (400MHz, MeOH) δ7.52-7.43(m,1H),7.40-7.28(m,1H),4.00-3.61(m,10H),2.08-1.95(m,1H),1.00-0.71(m,4H).

[0756] Example 62

[0757] N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)cyclopropaneformamide 121

[0758] Synthesis of N-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)cyclopropaneformamide 121

[0759] Compound 070-3 (50 mg; 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 120-1 (29 mg, 0.28 mmol), DIEA (97 mg, 0.75 mmol), and HATU (105 mg, 0.28 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250 mm 10 μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30 mL / min) to obtain compound 121 (21.7 mg; yield: 30%).

[0760] MS m / z(ESI): 281.2(M+1);

[0761] 1 H NMR (400MHz, CDCl3) δ7.21(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),5.66(d,J=8.0Hz,1H),4.30(d,J=16.0 Hz,2H),4.15-4.04(m,1H),3.12(m,2H),1.49(m,2H),1.32(m,2H),1.00-0.94(m,2H),0.77-0.69(m,2H).

[0762] Example 63

[0763] N-(2-((6-chloropyridazin-3-yl)(methyl)amino)ethyl)-N-methylcyclopropaneformamide 122

[0764] Synthesis of intermediate 122-1

[0765] Dissolve 3,6-dichloropyridazine 002-2 (100 mg, 0.6 mmol) in acetonitrile (3 mL), and add N... 1 N 2 -Dimethylethane-1,2-diamine (63 mg, 0.7 mmol), potassium carbonate (124 mg, 0.9 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography to obtain product N. 1 -(6-Chlorpyridazin-3-yl)-N,N ’ -Dimethylethane-1,2-diamine 122-1 (100 mg, yield 83%).

[0766] Synthesis of intermediate 122

[0767] N-(6-chloropyridazin-3-yl)-N,N-dimethylethane-1,2-diamine 122-1 (100 mg, 0.5 mmol) was dissolved in dichloroethane (3 mL), and cyclopropane carbonyl chloride (62 mg, 0.6 mmol) and triethylamine (75 mg, 0.7 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (HPLC) using Waters MS-triggered Prep-LC with SQD2 detector. The chromatographic column was an Xbridge 5u C18150 x 19 mm column; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20%-35%, flow rate: 20 mL / min) to obtain N-(2-((6-chloropyridazin-3-yl)(methyl)amino)ethyl)-N-methylcyclopropaneformamide 122 (3 mg, yield 2%).

[0768] MS m / z(ESI): 269.2(M+1) + ;

[0769] 1 H NMR (400MHz, DMSO) δ7.52-7.44(m,1H),7.20-7.11(m,1H),3.87-3.77(m,1H),3.76-3.63(m,2H),3.52 -3.45(m,1H),3.11(s,2H),3.05(d,J=7.2Hz,3H),2.86(s,1H),1.84-1.70(m,1H),0.65-0.51(m,4H).

[0770] Example 64

[0771] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(1-(hydroxymethyl)cyclopropyl)ethyl-1-one 124

[0772] Synthesis of intermediate 124-2

[0773] Compound 124-1 (200 mg; 1.8 mmol) was dissolved in water / ethanol (4 / 3; 7 mL), and potassium hydroxide (1.0 g, 18 mmol) was added. The reaction was stirred at 80 °C for 12 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was compound 124-2 (100 mg; yield 38.4%).

[0774] MS m / z(ESI): 129.0(M-1) - .

[0775] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(1-(hydroxymethyl)cyclopropyl)ethyl-1-one 124

[0776] Compound 124-2 (100 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (152.6 mg, 0.76 mmol), N,N-diisopropylethylamine (297.9 mg, 2.3 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (350.6 mg, 0.92 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 150x 30mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 124 (10 mg; yield 4.2%).

[0777] MS m / z(ESI): 311.1(M+1);

[0778] 1 H NMR (400MHz, DMSO) δ7.58 (d, J = 9.6 Hz, 1H), 7.42 (d, J = 9.6 Hz, 1H), 3.62-3.58 (m, 13H), 0.41-0.34 (m, 4H).

[0779] Example 65

[0780] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,3,6-trifluorophenyl)ethane-1-one 134

[0781] Synthesis of intermediate 134-2

[0782] At room temperature, 134-1 (500 mg, 1.86 mmol) was placed in a single-necked flask, and 4M hydrochloric acid-methanol solution (5.6 mL, 153.6 mmol) was added. The mixture was then reacted at 65°C for 16 hours. The reaction solution was evaporated to dryness to obtain crude product 134-2 (500 mg, yield 95.1%).

[0783] 1 H NMR (400MHz, CDCl3) δ7.19-7.09(m,1H),3.74(s,3H),3.71(s,2H).

[0784] Synthesis of intermediate 134-3

[0785] At room temperature, intermediates 134-2 (500 mg, 1.77 mmol), 036-2 (228.06 mg, 2.66 mmol), palladium acetate (41.7 mg, 0.19 mmol), tricyclohexylphosphine (99.2 mg, 0.35 mmol), and potassium phosphate (1690 mg, 7.96 mmol) were added to a microwave-safe tube, followed by the addition of toluene (10 mL) and water (2 mL). The reaction was carried out under nitrogen protection at 100°C for 4 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography to obtain compound 134-3 (280 mg, yield: 64.9%).

[0786] 1 H NMR (400MHz, CDCl3) δ6.38 (ddd, J = 10.0, 5.6, 2.4Hz, 1H), 3.72 (s, 3H), 3.68 (s, 2H), 2.16-2.06 (m, 1H), 1.10-1.02 (m, 2H), 0.76-0.69 (m, 2H).

[0787] Synthesis of intermediate 134-4

[0788] At room temperature, 134-3 (280 mg, 1.24 mmol) was placed in a single-necked flask, and THF (20 mL), lithium hydroxide (104.0 mg, 2.48 mmol%), and water (10 mL) were added. The mixture was then reacted at room temperature for 2 hours. The reaction solution was diluted with water, washed with ethyl acetate, and the pH of the aqueous phase was adjusted to approximately 3 with 2 M HCl. The solution was then washed three times with EA, and the organic phase was evaporated to dryness to obtain crude 134-4 (170 mg, yield: 64.7%).

[0789] 1 H NMR (400MHz, CDCl3) δ6.38 (ddd, J=10.0, 5.6, 2.4Hz, 1H), 3.72 (s, 2H), 2.17-2.03 (m, 1H), 1.10-1.00 (m, 2H), 0.77-0.67 (m, 2H).

[0790] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,3,6-trifluorophenyl)ethane-1-one 134

[0791] Diisopropylethylamine (333 mg, 2.58 mmol) was added to a DCM solution of 134-4 (170 mg, 0.86 mmol), 002-2 (257.3 mg, 1.12 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate (490.5 mg, 1.29 mmol) in 3 mL at room temperature. The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction mixture was diluted with water, extracted three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The crude product was purified by prep-HPLC. The product 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,3,6-difluorophenyl)ethane-1-one 134 (47.59 mg, yield 13%) was obtained.

[0792] LCMS calcld for C 19 H 19 ClF3N4O(M+H)+m / z=411.1, found: 411.1;

[0793] 1 H NMR (400MHz, CDCl3) δ7.28(d,J=9.6Hz,1H),6.95(d,J=9.6Hz,1H),6.39(ddd,J=10.0,5.6,2.0Hz,1H),3.90-3 .75(m,6H),3.74(s,2H),3.62-3.55(m,2H),2.09(dd,J=9.2,4.0Hz,1H),1.09-1.01(m,2H),0.77-0.68(m,2H).

[0794] Example 66

[0795] 1-[(3R)-4-(6-chloropyrazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 144a

[0796] Synthesis of intermediate 144a-2

[0797] 10 mL of tert-butanol was added to a mixture of 002-2 (500 mg, 3.36 mmol), 144a-1 (872.04 mg, 4.03 mmol), and potassium carbonate (1393 mg, 10.08 mmol), and the mixture was reacted in a microwave oven at 120 °C for 1.5 h. The reaction was confirmed by LCMS. The mixture was diluted with 30 mL of water, extracted three times with 30 mL of dichloromethane, dried and concentrated the organic phase, and purified by flash column chromatography to give compound 144a-2 (300 mg, yield 27.2%).

[0798] LCMS calcld for C 14 H 21 ClN4O3(M+H) + m / z = 329.1, found: 329.1

[0799] Synthesis of intermediate 144a-3

[0800] Trifluoroacetic acid (1.53 g, 13.4 mmol) was added to a solution of 144a-2 (100 mg, 0.30 mmol) in 2 mL of dichloromethane. The reaction was carried out at room temperature for 1 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated to obtain 144a-3 (100 mg crude product).

[0801] LCMS calcld for C9H 13 ClN4O(M+H) + m / z = 229.1, found: 229.1.

[0802] Synthesis of 1-[(3R)-4-(6-chloropyrazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 144a

[0803] Diisopropylethylamine (170.6 mg, 1.32 mmol) was added to a solution of 144-3 (100 mg, 0.44 mmol), 002-5 (93.3 mg, 0.44 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU) (0.17 g, 0.44 mmol) in N,N-dimethylformamide (3.0 mL). The reaction was carried out under nitrogen protection at room temperature for 2 h. The reaction was detected by LCMS. The reaction solution was purified by Prep-HPLC to give 1-[(3R)-4-(6-chloropyrazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 144a (50.07 mg, yield 27.08%).

[0804] LCMS calcld for C 20 H 21 ClF2N4O2(M+H) + m / z = 423.9, found: 423.9;

[0805] 1 H NMR (400MHz, CDCl3) δ7.43-7.26(m,1H),7.07-7.03(m,1H),6.63-6.60(m,2H),4.88-4.91(m,1H),4.57-4.80(m,2H),4.10-4. 24(m,1H),3.50-3.73(m,6H),3.25-3.30(m,1H),3.03-3.08(m,1H),1.83-1.90(m,1H),0.99-1.03(m,2H),0.67-0.71(m,2H).

[0806] Example 67

[0807] 1-[(3S)-4-(6-chloropyridazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 134

[0808] Synthesis of intermediate 145-2

[0809] Potassium carbonate (957.8 mg, 6.93 mmol) was added to a solution of 145-1 (500 mg; 2.31 mmol) and 3,6-dichloropyridazine (447.39 mg, 3.00 mmol) in tert-butanol (10 mL). The reaction mixture was stirred at 105 °C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (0–5% MeOH / DCM) to give 145-2 (140 mg; yield 18.4%).

[0810] LCMS(ESI)m / z = 329.1 [M+H] + .

[0811] Synthesis of intermediate 145-3

[0812] At room temperature, 1 mL of 4 M HCl / MeOH reaction solution was added to a 2 mL solution of dichloromethane containing 145-2 (140 mg, 0.43 mmol) and reacted for 30 minutes at room temperature. The reaction was monitored by LC-MS until completion. The reaction solution was filtered and concentrated to obtain a pale yellow solid, 145-3 (90 mg, yield 92.4%).

[0813] LCMS(ESI)m / z = 229.0 [M+H] + .

[0814] Synthesis of 1-[(3S)-4-(6-chloropyridazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 134

[0815] At room temperature, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (100.38 mg, 0.26 mmol) was added to a solution of 145-3 (50 mg, 0.22 mmol), 036-3 (51.35 mg, 0.24 mmol), and N,N-diisopropylethylamine (85.30 mg, 0.66 mmol) in tert-butanol (10 mL). The reaction mixture was reacted at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The residue was purified by high performance liquid chromatography (0.1% trifluoroacetic acid) to obtain 1-[(3S)-4-(6-chloropyridazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl]-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 145 (28.32 mg, yield 30.6%).

[0816] LCMS(ESI)m / z = 423.2[M+H] + ;

[0817] 1 H NMR (400MHz, CDCl3): δ7.29-7.27(m,1H),7.03-6.95(m,1H),6.64-6.62(m,2H),4.75-4.72(m,1H),4.55-4.34(m,1H),4.35-4.23(m,1H) ,4.12-4.07(m,1H),3.88-3.75(m,6H),3.51-3.35(m,1H),3.24-3.14(m,1H),3.12-3.09(m,1H),1.26(s,1H),1.00(s,2H),0.69(s,2H).

[0818] Example 68

[0819] (R)-2-(4-(6-chloropyrazin-3-yl)-1-(2-(4-cyclopropyl-2,6-difluorophenyl)acetyl)piperazin-2-yl)acetonitrile 155a

[0820] Synthesis of intermediate 155a-2

[0821] At room temperature, 002-2 (400 mg, 2.68 mmol) and 155a-1 (369 mg, 2.95 mmol) were added to a 50 mL single-necked flask, followed by the addition of dimethyl sulfoxide (10 mL). Diisopropylethylamine (0.69 g, 5.36 mmol) was then added dropwise with stirring. The reaction mixture was incubated at 120 °C for 5 h. The reaction was monitored by LC-MS to confirm completion. The crude product was purified by reverse-phase chromatography (eluted with CH3CN in H2O from 5.0% to 95%) to obtain compound 155a-2 (380 mg, yield 59.5%).

[0822] LCMS calcld for C 10 H 13 ClN5(M+H) + m / z = 238.1, found: 238.1.

[0823] Synthesis of (R)-2-(4-(6-chloropyrazin-3-yl)-1-(2-(4-cyclopropyl-2,6-difluorophenyl)acetyl)piperazin-2-yl)acetonitrile 155a

[0824] At room temperature, diisopropylethylamine (0.14 g, 1.05 mmol) was added to a solution of 155a-2 (50 mg, 0.21 mmol), 036-3 (53.47 mg, 0.25 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (119.7 mg, 0.32 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LCMS. The crude product was purified by high performance liquid chromatography (0.1% FA) to (R)-2-(4-(6-chloropyrazin-3-yl)-1-(2-(4-cyclopropyl-2,6-difluorophenyl)acetyl)piperazin-2-yl)acetonitrile (5.61 mg, yield 6.1%).

[0825] LCMS calcld for C 21 H 21 ClF2N5O(M+H) + m / z = 432.1, found: 432.1;

[0826] 1H NMR (400MHz, CDCl3) δ7.36-7.27(m,1H),7.06-6.98(m,1H),6.67-6.57(m,2H),5.00-4.32(m,2H),4.25-3.94(m,2H),3.83-3. 51(m,4H),3.38-3.20(m,1H),2.91-2.77(m,1H),2.69-2.59(m,1H),1.92-1.80(m,1H),1.06-0.95(m,2H),0.73-0.63(m,2H).

[0827] Example 69

[0828] 1-(3-chloro-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridazino[4,3-b][1,4]oxazin-8(6H)-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 013

[0829] Synthesis of intermediate 013-3

[0830] Compound 013-1 (500 mg, 1.48 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (118.5 mg, 2.9 mmol) was added at 0°C. The reaction was stirred at 0°C for 0.5 h. Compound 013-2 (337.7 mg, 1.48 mmol) was added, and the reaction was stirred at 25°C for 12 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: 0%-50% / 50% ethyl acetate / petroleum ether) to obtain compound 013-3 (500 mg; yield 62.7%).

[0831] MS m / z(ESI): 483.1(M+1)

[0832] Synthesis of intermediate 013-4

[0833] Compound 013-3 (500 mg, 1.0 mmol) was dissolved in 4 mol / L hydrochloric acid / dioxane (5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was compound 013-4 (350 mg; yield 88.4%).

[0834] MS m / z(ESI): 383.1(M+1)

[0835] Synthesis of intermediate 013-5

[0836] Compound 013-4 (80 mg; 0.21 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (108 mg, 0.83 mmol) was added. The reaction was stirred at 100 °C for 12 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: 0%-50% / 50% ethyl acetate / petroleum ether) to obtain compound 013-5 (80 mg; yield 55%).

[0837] MS m / z(ESI): 347.1(M+1)

[0838] Synthesis of intermediate 013-6

[0839] Compound 013-5 (80 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL), and 1-chloroethyl chloroformate (65.9 mg, 0.46 mmol) was added. The reaction was stirred at 70°C for 2 hours. After the reaction was completed, the crude product obtained by concentration under reduced pressure was dissolved in methanol (5 mL), and the mixture was stirred at 70°C for another hour. The reaction solution was then directly concentrated under reduced pressure to obtain the crude product 013-6 (40 mg), which was used directly in the next reaction without purification.

[0840] MS m / z(ESI): 227.1(M+1)

[0841] Synthesis of 1-(3-chloro-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridazino[4,3-b][1,4]oxazin-8(6H)-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethane-1-one 013

[0842] Compound 013-6 (50 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (42.8 mg, 0.22 mmol), N,N-diisopropylethylamine (85.5 mg, 0.66 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (100 mg, 0.26 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 013 (15mg).

[0843] Compound 013 (15 mg) was purified by SFC chromatography (SFC 150 column: CHIRALCEL AS, 250 mm × 30 mm ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.2% ammonia, 7 M methanol solution); 6-minute gradient, gradient ratio of carbon dioxide:methanol phase = 70 / 30, flow rate: 2.0 mL / min) to obtain compound 013a (3.76 mg, first peak, retention time: 2.339 min) and compound 013b (3.85 mg, last peak, retention time: Rt = 2.631 min).

[0844] Compound 013a

[0845] MS m / z(ESI): 403.1(M+1);

[0846] 1 H NMR(400MHz,MeOD)δ6.98-6.88(m,4H),4.69-4.62(m,1H),4.49-4.40(m,2H),4.20-4.05(m,2H),3.82(s,2H),3 .48-3.36(m,2H),3.04-2.85(m,1H),2.79-2.72(m,1H),2.07-1.99(m,1H),0.97-0.93(m,2H),0.70-0.66(m,2H)

[0847] Compound 013b

[0848] MS m / z(ESI): 403.1(M+1);

[0849] 1 H NMR(400MHz,MeOD)δ6.98-6.88(m,4H),4.66-4.62(m,1H),4.49-4.40(m,2H),4.20-4.05(m,2H),3.82(s,2H),3. 48-3.34(m,2H),3.01-2.86(m,1H),2.79-2.72(m,1H),2.05-2.01(m,1H),0.97-0.93(m,2H),0.70-0.66(m,2H).

[0850] Example 70

[0851] 1-(3-chloro-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridazino[4,3-b][1,4]oxazin-8(6H)-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 142

[0852] Synthesis of 1-(3-chloro-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridazino[4,3-b][1,4]oxazin-8(6H)-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 142

[0853] Compound 013-6 (70 mg, 0.309 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 036-3 (79 mg, 0.371 mmol), N,N-diisopropylethylamine (120 mg, 0.926 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (235 mg, 0.618 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 142 (36mg).

[0854] Compound 142 (36 mg) was prepared by SFC chromatography (SFC 150 column: Daicel CHIRALCEL AS, 250 mm × 30 mm ID, 10 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.2% ammonia, 7 M methanol solution); 6 min gradient, gradient ratio of carbon dioxide:methanol phase = 50 / 50, flow rate: 120 g / min) to obtain compound 142a (7 mg, first peak, Rt = 2.056 min) and compound 142b (5 mg, last peak, Rt = 2.491 min).

[0855] Compound 142a

[0856] MS m / z(ESI): 421.1(M+1);

[0857] 1H NMR (400MHz, CDCl3) δ6.68(s,1H),6.54(d,J=8.8Hz,2H),4.72-4.58(m,2H),4.30(dd,J=11.2,3.0Hz,1H),3.99(dd,J=23.2,14.2Hz,2 H), 3.66 (d, J = 9.6Hz, 2H), 3.52-3.23 (m, 2H), 2.91-2.82 (m, 1H), 2.45 (s, 1H), 1.84-1.72 (m, 1H), 0.97-0.90 (m, 2H), 0.64-0.57 (m, 2H).

[0858] Compound 142b

[0859] MS m / z(ESI): 421.1(M+1);

[0860] 1 H NMR (400MHz, CDCl3) δ6.68(s,1H),6.54(d,J=8.6Hz,2H),4.74-4.57(m,2H),4.30(dd,J=11.2,2.9Hz,1H),4.10-3.93(m,2H),3.65(t, J=12.6Hz,2H),3.44-3.22(m,2H),2.90-2.82(m,1H),2.45(t,J=12.2Hz,1H),1.86-1.73(m,1H),0.93-0.90(m,2H),0.67-0.57(m,2H).

[0861] Example 71

[0862] 1-(-5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 150

[0863] Synthesis of intermediate 150-2

[0864] Compound 150-1 (343 mg, 1.61 mmol) was dissolved in acetonitrile (20 mL), and compound 002-2 (239.6 mg, 1.61 mmol) and DIEA (623.4 mg, 4.82 mmol) were added. The mixture was heated to 90°C and stirred for 1 hour. After the reaction was completed, the reverse liquid was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to obtain compound 150-2 (275 mg, 52%).

[0865] MS m / z(ESI): 325.2(M+1)

[0866] Synthesis of intermediate 150-3

[0867] Compound 150-2 (275 mg, 0.85 mmol) was dissolved in dichloromethane (2 mL), and HCl / 1,4-dioxane (4 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain compound 150-3 (175 mg; yield 92%).

[0868] MS m / z(ESI):225.1(M+1).

[0869] Synthesis of 1-(5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 150

[0870] Compound 150-3 (175 mg, 0.78 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-5 (165 mg, 0.78 mmol), N,N-diisopropylethylamine (202 mg, 1.56 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (355 mg, 0.94 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 150 (34mg; yield 12%).

[0871] MS m / z(ESI): 419.1(M+1)

[0872] Compound 150 (34 mg) was purified by SFC chromatography (SFC 150 column: Daicel CHIRALPAK IG_3, 3.0*150 mm, 3 μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.1% DEA, 7 M methanol solution); 6-minute gradient, gradient ratio of carbon dioxide:methanol phase = 50 / 50, flow rate: 1.5 mL / min) to obtain compound 150a (10.34 mg, first peak, Rt = 3.798 min) and compound 150b (11.05 mg, last peak, Rt = 5.375 min).

[0873] Compound 150a

[0874] MS m / z(ESI): 419.1(M+1);

[0875] 1 H NMR (400MHz, DMSO) δ7.59(d,J=9.6,1H),7.16(d,J=9.6,1H),6.80(d,J=8.4,2H),4.50-4.30(m,1H),4.24-3.98(m,2H),3.94-3.67(m,2H ),3.60-3.39(m,2H),3.30-3.14(m,1H),2.34-2.13(m,1H),2.27-2.11(m,2H),2.03-1.78(m,2H),1.10-0.89(m,2H),0.80-0.68(m,2H).

[0876] Compound 150b

[0877] MS m / z(ESI): 419.1(M+1);

[0878] 1 H NMR (400MHz, DMSO) δ7.58(d,J=9.6,1H),7.16(d,J=9.6,1H),6.80(d,J=8.4,2H),4.54-4.25(m,1H),4.19-3.99(m,2H),3.97-3.64(m,2H ),3.59-3.41(m,2H),3.31-3.13(m,1H),2.42-2.27(m,1H),2.24-2.02(m,2H),2.02-1.69(m,2H),1.07-0.90(m,2H),0.81-0.61(m,2H).

[0879] Example 72

[0880] 2-(4-(azacyclobutan-1-yl)-2,6-difluorophenyl)-1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethane-1-one 161

[0881] Synthesis of intermediate 161-2

[0882] Compound 161-1 (160 mg, 0.64 mmol) was dissolved in dioxane (5 mL), and aziridine (62 mg, 0.76 mmol), cesium carbonate (623 mg, 1.91 mmol), and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (54 mg, 0.064 mmol) were added. The reaction was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0%-10% dichloromethane:methanol) to obtain compound 161-2 (140 mg; yield 96.67%).

[0883] MS m / z(ESI): 228.2(M+1)

[0884] Synthesis of 2-(4-(azacyclobutan-1-yl)-2,6-difluorophenyl)-1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethane-1-one 161

[0885] Compound 161-2 (140 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound 036-4 (135 mg, 0.68 mmol), N,N-diisopropylethylamine (160 mg, 1.23 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (352 mg, 0.92 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16-minute gradient, gradient ratio: acetonitrile phase 55%-65%, flow rate: 20mL / min) to obtain compound 161 (32.22mg; yield 12.82%).

[0886] MS m / z(ESI): 408.1(M+1);

[0887] 1H NMR(400MHz, CDCl3)δ7.25(s,1H),6.95-6.89(m,1H),6.00-5.86(m,2H),3.89-3.83(m,4H),3 .82-3.75(m,4H),3.75-3.70(m,2H),3.65-3.61(m,2H),3.60-3.52(m,2H),2.42-2.33(m,2H).

[0888] Example 73

[0889] 7-(6-chloropyridazin-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one 098

[0890] Synthesis of intermediate 098-3

[0891] Compound 098-1 (300 mg, 1.24 mmol) was dissolved in dioxane (15 mL), and compound 098-2 (372 mg, 1.24 mmol), cesium carbonate (1210 mg, 3.71 mmol), and bis(dibenzylacetone)palladium (113 mg, 0.12 mmol) and 9,9-bis(trifluoromethyl)-2,3,6,7-oxanthracene tetracarboxylic dianhydride (72 mg, 0.12 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 4 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% / 5% petroleum ether / ethyl acetate) to obtain compound 098-3 (150 mg, yield 26.25%).

[0892] MS m / z(ESI): 56(M-56)

[0893] Synthesis of intermediate 098-4

[0894] Compound 098-3 (150 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride solution (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solution was evaporated to dryness to give compound 098-4 (120 mg, yield: 78%).

[0895] MS m / z(ESI): 314.1(M+1).

[0896] Synthesis of intermediate 098-5

[0897] Compound 098-4 (120 mg, 0.38 mmol) was dissolved in dioxane / water (10 mL), and cyclopropylboronic acid (40 mg, 0.44 mmol), cesium carbonate (744 mg, 2.28 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (28 mg, 0.038 mmol) were added. The reaction was stirred at 100°C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-95% / 15% petroleum ether / ethyl acetate) to obtain compound 098-5 (100 mg, yield 65%).

[0898] MS m / z(ESI): 276(M+1)

[0899] Synthesis of 7-(6-chloropyridazin-3-yl)-2-(4-cyclopropyl-3-fluorophenyl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one 098

[0900] Compound 098-5 (100 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 002-2 (55 mg, 0.38 mmol) and N,N-diisopropylethylamine (402 mg, 3.12 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5u C18 250x21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 25 mL / min) to give compound 098 (10 mg; yield 30%); MS m / z (ESI): 388.1 (M+1).

[0901] Compound 098 (15 mg) was purified by SFC chromatography (SFC 150 column: Daicel CHIRALPAK IG_3, 3.0*150mm, 3um; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.1% DEA, 7M methanol solution); 12-minute gradient, gradient ratio of carbon dioxide:methanol phase = 50 / 50, flow rate: 1.5 mL / min) to obtain compound 098a (2.17 mg, first peak, retention time: 5.650 min) and compound 098b (2.18 mg, last peak, retention time: 6.605 min).

[0902] Compound 098a

[0903] 1H NMR (400MHz, DMSO) δ7.59(d,J=9.6,1H),7.57-7.50(m,1H),7.51-7.44(m,1H),7.24-7.16(m,1H),7.03-6.90(m,1H),4.56(d,J=12.8,1H) ,4.35(d,J=10.4,1H),4.08-3.74(m,3H),3.68-3.44(m,1H),3.13-2.85(m,3H),2.14-1.86(m,1H),1.04-0.81(m,2H),0.79-0.60(m,2H).

[0904] Compound 098b

[0905] 1 H NMR(400MHz,DMSO)δ7.59(d,J=9.6,1H),7.57-7.49(m,1H),7.51-7.43(m ,1H),7.27-7.14(m,1H),7.03-6.92(m,1H),4.56(d,J=13.2,1H),4.35(d ,J=10,1H),4.07-3.85(m,1H),3.91-3.71(m,2H),3.68-3.47(m,1H),3.1 3-2.83(m,3H),2.07-1.73(m,1H),1.04-0.80(m,2H),0.76-0.51(m,2H).

[0906] Example 74

[0907] 2-(3-chloro-4-cyclopropyl-2,6-difluorophenyl)-1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethane-1-one 139

[0908] Synthesis of intermediate 139-2

[0909] Compound 139-1 (2 g, 0.012 mol) was dissolved in dichloromethane (15 mL), and N-bromosuccinimide (2.39 g, 0.013 mol) was added. The reaction was stirred at 26 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to obtain compound 139-2 (2.3 g, yield 78%).

[0910] MS m / z(ESI):242.1(M+1).

[0911] Synthesis of intermediate 139-3

[0912] Compound 139-2 (2.3 g, 0.009 mol) was dissolved in dioxane:water 10:1 (11 mL), and cyclopropylboronic acid (0.98 g, 0.011 mol), potassium carbonate (3.9 g, 0.028 mol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (660 g, 0.9 mmol) were added. The reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure, and purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether:ethyl acetate) to obtain compound 139-3 (1.2 g, yield 62%).

[0913] MS m / z(ESI): 204.1(M+1)

[0914] Synthesis of intermediate 139-4

[0915] 139-3 (500 mg, 2.46 mmol) was dissolved in acetonitrile (15 mL), and cuprous bromide (423 mg, 2.95 mmol) and amyl nitrite (346 mg, 2.95 mmol) were added. The reaction was carried out under nitrogen protection at 70°C with stirring for 6 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The solution was then purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to obtain compound 139-4 (300 mg, yield 38%).

[0916] 1 H NMR (400MHz, MeOD) δ6.78(dd,J=9.7,2.0Hz,1H),2.24(d,J=5.2Hz,1H),1.10(ddd,J=8.8,5.3,2.1Hz,2H),0.78-0.73(m,2H).

[0917] Synthesis of intermediate 139-6

[0918] Compound 139-4 (300 mg, 1.12 mmol) was dissolved in dioxane / water = 10:1 (11 mL), followed by the sequential addition of compound 139-5 (266 mg, 1.35 mmol), potassium carbonate (464 mg, 3.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (82 mg, 0.11 mmol). The reaction mixture was stirred at 100°C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to give compound 139-6 (180 mg, yield 62%).

[0919] 1H NMR (400MHz, CDCl3) δ6.86(d,J=12.0Hz,1H),6.42(dd,J=11.8,1.8Hz,1H),5.74(d,J=13.1Hz,1H),3.94(q, J=7.0Hz,2H),2.21-2.13(m,1H),1.56(s,1H),1.35(t,J=7.0Hz,3H),1.07-1.00(m,2H),0.69-0.62(m,2H).

[0920] Synthesis of intermediate 139-7

[0921] Compound 139-6 (180 mg, 0.69 mmol) was dissolved in tetrahydrofuran (4 mL), and then 6 mol / L hydrochloric acid aqueous solution (4 mL) was added. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 6-7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was used directly in the next reaction without purification, and the crude product was compound 139-7 (120 mg).

[0922] Synthesis of intermediate 139-8

[0923] Compound 139-7 (60 mg, 0.26 mmol) was dissolved in tert-butanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Sodium dihydrogen phosphate (94 mg, 0.68 mmol), sodium chlorite (47 mg, 0.52 mmol), and 2-methyl-2-butene (182 mg, 2.60 mmol) were added sequentially at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, compound 139-8 (40 mg).

[0924] Synthesis of compound 2-(3-chloro-4-cyclopropyl-2,6-difluorophenyl)-1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethane-1-one 139

[0925] Compound 139-8 (40 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 036-4 (37 mg, 0.18 mmol), N,N-diisopropylethylamine (62 mg, 0.48 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77 mg, 0.19 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 139 (12mg; yield: 17%).

[0926] MS m / z(ESI): 427.1(M+1);

[0927] 1 H NMR (400MHz, MeOD) δ7.53(d,J=9.6Hz,1H),7.40(d,J=9.6Hz,1H),6.70(dd,J=10.5,1.8Hz,1H),3.94(s,2H),3.90(dd,J=6.6,2.8Hz,2H),3. 85(dd,J=6.8,2.8Hz,2H),3.80(dd,J=6.6,3.5Hz,2H),3.72(dd,J=6.5,3.6Hz,2H),2.35-2.23(m,1H),1.18-1.07(m,2H),0.84-0.74(m,2H).

[0928] Example 75

[0929] Synthesis of 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluoro-3-methoxyphenyl)ethane-1-one 140

[0930] Synthesis of intermediate 140-2

[0931] Compound 140-1 (2 g, 12.6 mmol) was dissolved in dichloromethane (20 mL), and N-bromosuccinimide (2.24 g, 12.6 mmol) was added at 0°C. The reaction was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by slurrying with petroleum ether to obtain compound 140-2 (2.5 g; yield 83.3%).

[0932] 1 H NMR (400MHz, DMSO) δ6.49-6.46(m,1H),5.76(s,2H),3.71(s,3H).

[0933] Synthesis of intermediate 140-3

[0934] Compound 140-2 (2.5 g, 10.5 mmol) was dissolved in dioxane / water = 10:1 (22 mL), followed by the addition of compound 139-5 (2.5 g, 12.6 mmol), potassium carbonate (4.38 g, 31.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (770 mg, 1.05 mmol). The reaction mixture was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: 0%-90% / 10% petroleum ether / ethyl acetate) to give compound 140-3 (2 g; yield 82.9%).

[0935] 1 H NMR (400MHz, CDCl3) δ7.12(d,J=13.2Hz,1H),6.25-6.22(m 1H),5.71(d,J=13.2Hz,1H),3.92(q,J=7.2Hz,2H),3.85(s,3H),1.33(t,J=6.8Hz,3H).

[0936] Synthesis of intermediate 140-4

[0937] Amyl nitrite (620 mg, 5.2 mmol) was dissolved in acetonitrile (10 mL), and cuprous bromide (1.18 g, 5.2 mmol) was added. After stirring for 0.5 hours, compound 140-3 (1 g, 4.4 mmol) was added, and the mixture was stirred for 2 hours under nitrogen protection at 25°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: 0%-95% / 5% petroleum ether / ethyl acetate) to give compound 140-4 (100 mg, yield 6.5%).

[0938] 1 H NMR (400MHz, CDCl3) δ7.30(d,J=13.2Hz,1H),7.06-7.03(m,1H),5.74(d,J=13.2Hz,1H),3.94(q,J=7.2Hz,2H),3.88(s,3H),1.36(t,J=7.2Hz,3H).

[0939] Synthesis of intermediate 140-5

[0940] Compound 140-4 (100 mg, 0.34 mmol) was dissolved in dioxane / water = 10:1 (5.5 mL), followed by the sequential addition of cyclopropylboronic acid (58.6 mg, 0.68 mmol), potassium carbonate (142 mg, 1.02 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (24.9 mg, 0.034 mmol). The reaction mixture was stirred at 100°C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: 0%-95% / 5% petroleum ether / ethyl acetate) to give compound 140-5 (50 mg, 57.6%).

[0941] 1 H NMR (400MHz, CDCl3) δ7.17 (d, J = 12.4Hz, 1H), 6.18-6.15 (m, 1H), 5.69 (d, J = 13.2Hz, 1H), 3.85 (q, J = 6. 8Hz,2H),3.80(s,3H),2.13-2.08(m,1H),1.27(t,J=7.2Hz,3H),0.94-0.89(m,2H),0.57-0.53(m,2H).

[0942] Synthesis of intermediate 140-6

[0943] Compound 140-5 (50 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), and then 6 mol / L hydrochloric acid aqueous solution (2 mL) was added. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 6-7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was used directly in the next reaction without purification, and the crude product was compound 140-6 (40 mg).

[0944] Synthesis of intermediate 140-7

[0945] Compound 140-6 (50 mg, 0.22 mmol) was dissolved in tert-butanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Sodium dihydrogen phosphate (79.5 mg, 0.66 mmol), sodium chlorite (39.9 mg, 0.44 mmol), and 2-methyl-2-butene (155 mg, 2.21 mmol) were added sequentially at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was compound 140-7 (30 mg).

[0946] MS m / z (ESI): 243.1 (M+1).

[0947] Synthesis of compound 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluoro-3-methoxyphenyl)ethane-1-one 140

[0948] Compound 140-7 (30 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 036-4 (29.5 mg, 0.14 mmol), N,N-diisopropylethylamine (48 mg, 0.37 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (56.5 mg, 0.14 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 140 (0.97mg; yield 3.6%).

[0949] MS m / z(ESI): 423.1(M+1);

[0950] 1 H NMR(400MHz,MeOD)δ7.50(d,J=9.6Hz,1H),7.39(d,J=9.6Hz,1H),6.42-6.39(m,1H),3.90(s,3H) ,3.85-3.75(m,8H),3.68-3.66(m,2H),2.28-2.16(m,1H),1.04-0.98(m,2H),0.69-0.66(m,2H).

[0951] Example 76

[0952] (1-(5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 149

[0953] Synthesis of 1-(5-(6-chloropyridazin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-2-(4-cyclopropyl-2,6-difluorophenyl)ethane-1-one 149

[0954] Compound 002-4 (100 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 036-3 (102 mg, 0.48 mmol), DIEA (186 mg, 1.44 mmol), and HATU (218 mg, 0.58 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5u C18 100x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 25 mL / min) to obtain compound 149 (35 mg, yield 18%).

[0955] MS m / z (ESI): 405.1 (M+1).

[0956] Compound 149 was chirally resolved (mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 75 / 25) to give compound 149a (first peak, retention time: 3.739 min, 13.85 mg) and compound 149b (last peak, retention time: 4.016 min, 17.32 mg).

[0957] Compound 149a

[0958] 1H NMR (400MHz, MeOD) δ7.53(d,J=9.6Hz,1H),7.41(d,J=9.6Hz,1H),6.69(d,J =8.8Hz,2H),4.10-4.02(m,1H),3.95(s,2H),3.84-3.75(m,1H),3.64-3.55 (m,1H),3.45-3.42(m,1H),3.35(dd,J=8.9,4.4Hz,1H),3.19-3.12(m,1H), 1.97-1.88(m,1H),1.48-1.42(m,1H),1.04-0.97(m,2H),0.76-0.60(m,3H)

[0959] Compound 149b

[0960] 1 H NMR (400MHz, MeOD) δ7.52(s,1H),7.41(d,J=9.6Hz,1H),6.69(d,J=8.8Hz,2H),4.10-4.02(m,1H),3.95(s,2H),3.83-3.76(m,1H),3.64-3.55(m,1 H),3.50-3.42(m,1H),3.35(dd,J=8.9,4.4Hz,1H),3.23-3.15(m,1H),1. 96-1.88(m,1H),1.48-1.42(m,1H),1.04-0.97(m,2H),0.75-0.63(m,3H)

[0961] Example 77

[0962] 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluoro-3-methylphenyl)ethane-1-one 152

[0963] Synthesis of intermediate 152-2

[0964] Compound 152-1 (3 g, 21 mmol) was dissolved in dichloromethane (15 mL), and N-bromosuccinimide (3.92 g, 22 mmol) was added. The reaction was stirred at 26 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to obtain compound 152-2 (3 g, 64%).

[0965] MS m / z(ESI): 222.0(M+1).

[0966] Synthesis of intermediate 152-3

[0967] Compound 152-2 (1.5 g, 6.8 mmol) was dissolved in dioxane:water 10:1 (11 mL), and cyclopropylboronic acid (0.88 g, 10.2 mmol), potassium carbonate (2.35 g, 17 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (0.99 g, 1.36 mmol) were added. The reaction was carried out under nitrogen protection at 100 °C for 16 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The solution was then purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether:ethyl acetate) to obtain compound 152-3 (0.8 g, yield 64%).

[0968] MS m / z(ESI): 184.2(M+1).

[0969] Synthesis of intermediate 152-4

[0970] Compound 152-3 (800 mg, 4.37 mmol) was dissolved in acetonitrile (15 mL), and cuprous bromide (1171 mg, 5.24 mmol) and amyl nitrite (615 mg, 5.24 mmol) were added. The reaction was carried out under nitrogen protection at 70°C for 6 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The solution was then purified by rapid silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to give compound 152-4 (500 mg, yield 46%).

[0971] 1 H NMR (400MHz, CDCl3) δ6.52-6.37(m,1H),2.26-2.16(m,3H),1.83-1.71(m,1H),0.93-0.85(m,2H),0.57-0.48(m,2H).

[0972] Synthesis of intermediate 152-5

[0973] Compound 152-4 (300 mg, 1.21 mmol) was dissolved in dioxane / water = 10:1 (11 mL), followed by the addition of compound 139-5 (361 mg, 1.82 mmol), potassium carbonate (420 mg, 3.04 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (89 mg, 0.12 mmol). The reaction mixture was stirred at 100°C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: 0%-5% petroleum ether: ethyl acetate) to give compound 152-5 (260 mg, 80%).

[0974] 1H NMR (400MHz, CDCl3) δ7.26(d,J=1.6Hz,1H),6.47(d,J=12.0Hz,1H),5.79(d,J=13.2Hz,1H),3.92-3.90(m, 2H),2.26(d,J=1.6Hz,3H),1.90-1.78(m,1H),1.34(t,J=7.0Hz,3H),0.97-0.89(m,2H),0.63-0.55(m,2H).

[0975] Synthesis of intermediate 152-6

[0976] Compound 152-5 (200 mg, 0.84 mmol) was dissolved in tetrahydrofuran (4 mL), and then 6 mol / L hydrochloric acid aqueous solution (4 mL) was added. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 6-7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was used directly in the next reaction without purification, and the crude product was compound 152-6 (150 mg).

[0977] Synthesis of intermediate 152-7

[0978] Compound 152-6 (100 mg, 0.48 mmol) was dissolved in tert-butanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Sodium dihydrogen phosphate (173 mg, 1.25 mmol), sodium chlorite (87 mg, 0.96 mmol), and 2-methyl-2-butene (510 mg, 0.48 mmol) were added sequentially at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was compound 152-7 (80 mg, 74% yield).

[0979] MS m / z(ESI): 227.1(M+1)

[0980] Synthesis of compound 1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-2,6-difluoro-3-methylphenyl)ethane-1-one 152

[0981] Compound 152-7 (50 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 036-4 (66 mg, 0.33 mmol), N,N-diisopropylethylamine (86 mg, 0.66 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (169 mg, 0.44 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly filtered. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150x 19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20mL / min) to obtain compound 152 (17.92mg; yield 19.9%).

[0982] MS m / z(ESI): 407.0(M+1);

[0983] 1 H NMR (400MHz, CDCl3) δ7.22(d,J=9.6Hz,1H),6.91(d,J=9.6Hz,1H),6.46(d,J=10.6Hz,1H),3.74-3.70(m,6H),3 .65(s,2H),3.55-3.52(m,2H),2.21(t,J=4.8Hz,3H),1.79-1.70(m,1H),0.94-0.83(m,2H),0.54-0.52(m,2H).

[0984] Using conditions similar to those in the above embodiments, the compounds listed in Table 1 below were prepared, and the structural characterization data of these compounds are listed together in Table A.

[0985] Table A

[0986] Biological evaluation

[0987] Test Example 1: Inhibitory Activity Test of PANK1 and PANK3

[0988] 1. Preparation of compounds.

[0989] The compound was diluted 5-fold (2 μL + 8 μL) in LDV plates, resulting in 8 dilution points. 5 nL of the compound was applied at each point, with a maximum final concentration of 10 μM and a final DMSO concentration of 0.1%.

[0990] 2. Composition of solutions and buffers

[0991] 1x Kinase Response Buffer A

[0992] 40mM Tris (pH 7.5)

[0993] 20mM MgCl2

[0994] 0.1 mg / ml BSA.

[0995] 3. Experimental Procedure

[0996] 1) Perform a kinase reaction (PANK1 / PANK3-substrate-ATP) with 5 μL of PANK1 or PANK3 kinase buffer (e.g., 1x reaction buffer a) and incubate at room temperature for 40 minutes.

[0997] 2) Add 5 μl of ADP-glot reagent to stop the kinase reaction, deplete the unused ATP, leaving only ADP and a very low ATP background;

[0998] 3) Incubate at room temperature for 40 minutes;

[0999] 4) Add 10 μL of kinase detection reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP;

[1000] 5) Incubate at room temperature for 30-60 minutes, depending on the ATP concentration used in the kinase reaction;

[1001] 6) Use a plate photometer or charge-coupled device (CCD) camera to measure luminescence details.

[1002] Data Analysis:

[1003] Inhibition rate (%) = 100 - (Compound well reading - Low-read control well reading) / (High-read control well reading - Low-read control well reading) × 100

[1004] High reading control well: 0.1% DMSO; Low reading control well: 10μM JNT-517.

[1005] Calculate IC using GraphPad Prism 9 software 50 (nM) and plot the effect-dose curve of the compound.

[1006] IC50 of the representative compounds in this article on the inhibitory activity of PANK1 and PANK3 50 The values ​​are shown in Table 1.

[1007] Table 1. Inhibitory activities of representative compounds in this paper against PANK1 and PANK3.

[1008] Experimental conclusion: The above representative compounds can effectively inhibit the kinase activity of PANK1 and PANK3.

[1009] Test Example 2: Activation activity test of PANK1 and PANK3

[1010] 1. Preparation of compounds.

[1011] The compound was diluted 3-fold (4 μL + 8 μL) in LDV plates at 11 dilution points, with the highest final concentration of the compound being 20 μM and the final concentration of DMSO being 0.2%.

[1012] 2. Composition of solutions and buffers

[1013] 1x Kinase Response Buffer A

[1014] 40mM Tris (pH 7.5)

[1015] 20mM MgCl2

[1016] 0.1 mg / ml BSA.

[1017] 3. Experimental Procedure

[1018] 1) Add 20 μM acetyl-CoA to 1X kinase buffer (e.g., 1X reaction buffer A); incubate PANK1 (50 ng / well) or PANK3 (25 ng / well) for 15 min;

[1019] 2) Add ATP to the above solution to a final concentration of 50 μM; continue incubation for 35 min;

[1020] 3) Add 3 μL of PANK1 / PANK3-acetyl-CoA-ATP mixture to the assay plate containing the compound to be tested, and incubate at room temperature for 40 minutes;

[1021] 4) Add 5μL LADP-Glo TM The reagent stops the kinase reaction, depletes the unused ATP, leaving only ADP and a very low ATP background.

[1022] 5) Incubate at room temperature for 40 minutes;

[1023] 6) Add 10 μL of kinase detection reagent to convert ADP into ATP, and introduce luciferase and luciferin to detect ATP;

[1024] 7) Incubate at room temperature for 30-60 minutes, depending on the ATP concentration used in the kinase reaction;

[1025] 8) Measure luminescence using a plate-reading photometer or a charge-coupled device (CCD) camera.

[1026] Data Analysis:

[1027] The effect-dose curve of the compound was plotted using XLfit software (the horizontal axis represents the compound concentration gradient, and the vertical axis represents the luminescence readings of the corresponding compound response).

[1028] EC50 of the representative compounds in this article on the activation activities of PANK1 and PANK3 in the presence of 20 μM acetyl-CoA 50 The values ​​are shown in Table 2.

[1029] Table 2 shows the activation activities of representative compounds in this paper on PANK1 and PANK3. Note: "--" indicates that it has not been tested.

[1030] Experimental conclusion: The above representative compounds can effectively activate the activities of PANK1 and PANK3 in the presence of 20 μM acetyl-CoA.

[1031] Test Example 3: The compound of the present invention increases the expression of CoA in cells.

[1032] HEK293 cells were transfected with human PANK1, PANK2β, PANK3, and the empty control plasmid pcDNA3.1, respectively. After treatment with the compound of this invention, BBP-671, or DMSO (blank control) at 10 μM for 24 hours, the cells were lysed, and the CoA content in the cells was detected by HPLC. The experimental steps are as follows, and the experimental results are shown in Figure 1.

[1033] Experimental procedure:

[1034] 1. Cell seeding: Seed 293T cells in 100mm culture dishes, add 10ml of complete growth medium (DMEM + 10% FBS + 1% PS), 3×10 6 Cells / plate (2 culture plates for each vector group, each culture plate is used to count the number of cells).

[1035] 2. Treatment: Transfect 3 μg of plasmid, add 10 μM of the compound or an isotropic amount of DMSO after 24 hours, and culture for another 24 hours. When the cell density approaches sub-confluence, collect the adherent cells in culture. For example, the growth density of HEK 293T cells is approximately 1.3 x 10⁶ cells per 100 mm culture dish. 7 Each cell.

[1036] 3. Cell lysis and sample preparation: Aspirate the culture medium from the culture dish. Quickly wash the cells in the culture dish with ice-cold phosphate-buffered saline (PBS) to remove residual culture medium, and aspirate the PBS from the culture dish. Quickly wash the cells with ice water to remove residual PBS, and aspirate the water from the culture dish. Add 1 mL of ice water to the culture dish. Scrape the cells into the cold water in the culture dish, and transfer the cell suspension to a glass tube containing 400 μL of 0.25 M KOH and 1.5 mL of water.

[1037] 4. Sample Preparation: Vortex the cell suspension at high speed for 10 seconds to mix vigorously. Then cover tightly with a paraffin membrane and incubate in a water bath at 55°C for 1 hour (without shaking). The sample pH should be ≥12. Add 160 μL of 1M Trizma-HCl and 10 μL of 100 mM mBBr, vortex at high speed for 10 seconds to bring the pH to approximately 8 to support the reaction of mBBr with free coenzyme A. Cover the sample and incubate at room temperature in the dark for 2 hours to allow the mBBr to react with the thiol of coenzyme A. Add 100 μL of acetic acid, vortex at high speed for 10 seconds to terminate the reaction. Centrifuge at 2,000 x g for 15 minutes to remove precipitated cell debris. Collect the supernatant in a glass tube for SPE column purification as described below.

[1038] 5. HPLC: Activate the Thermo SPE column with 1 ml methanol and equilibrate each column with 1 ml of water containing 1% formic acid. Add the sample supernatant to the column and collect the eluent. Wash the column with 1 ml of water to remove any unretained substances. Wash the column once with 1 ml methanol and once with 1 ml of methanol containing 1% ammonium hydroxide, and pour the eluent into another 8 ml glass tube to collect CoA-bimane. Dry the CoA-bimane sample in the tube to dryness under nitrogen. The dried sample is stable at room temperature until the next use. Seal and completely cover the tube and store. When ready for HPLC analysis, resuspend the sample in 500 μL of water and vortex vigorously for 10 seconds. Transfer the resuspended sample to a centrifuge tube filter (0.22 μm cellulose acetate, 2 ml size) and centrifuge at 5,000 x g for 10 minutes to remove any precipitate. Transfer 250 μl of the filtered sample to a suitable glass vial for HPLC analysis.

[1039] Experimental conclusion: Compared with the DMSO group, compound 134 and reference compound BBP-671 can enhance the expression of CoA in cells by activating the activity of three PANK proteins, especially PANK2β and PANK3 proteins.

[1040] Test Example 4: In vivo drug efficacy in an MMA mouse model

[1041] In methylmalonic acidemia Mut M698K The pharmacodynamics of the test substances (compounds BBP-671, 134, and 139) were evaluated in mouse models by detecting the levels of MMA and C3 / C2 in the plasma after drug administration.

[1042] Mut M698K Model mice were divided into four groups (half male and half female) based on baseline D0 MMA levels and body weight. They were treated according to the dosing regimen shown in Table 3. Animals were fasted for 12 hours prior to the last dose. Branched-chain amino acid stimulation was administered concurrently with the last QD (quick dose). Whole blood samples were collected 2 hours before and 3 hours after administration, as shown in Table 4. Samples were collected via tail vein, centrifuged at 4000g for 5 minutes, and plasma was collected to determine the levels of MMA and C3 / C2 in the plasma. The experimental results are shown in Figure 2.

[1043] Table 3 Dosing Regimen

[1044] Formulation: 0.5% MC 4000c.p

[1045] Table 4 Sample Collection Plan

[1046] Experimental conclusions: Compared with the untreated group, compound 134 of the present invention can significantly reduce the C3:C2 ratio and MMA level in the blood of mouse models of MMA disease; compounds 134 and 139 of the present invention and the positive reference compound BBP-671 can all significantly reduce the C3:C2 ratio in the blood of mouse models of MMA disease, suggesting the effectiveness of PANK agonists in mice with this disease, and the compounds of the present invention have better activity.

[1047] Unless otherwise stated, the structure of compound BBP-671 described in this invention is as follows:

[1048] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. The compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: in, Q1 is selected from unsubstituted or arbitrarily assigned one, two or more R... a Replacement C 1-12 alkyl or Ring A is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Each R a They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. a1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R a2 C(=O)R a3 P(=O)R a4 R a5 Or, two R atoms attached to the same carbon atom a Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. a1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. a Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. a1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. a Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. a1 Replacement C 1-3 Alkylene; each R a1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R a6 ;R a2 R a3 R a4 R a5 R a6 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; L1 is absent or selected from unsubstituted or optionally selected from one, two or more of the following: oxo (=O), OH, NH2, CN, -COOH, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 The following groups are substituted by cycloalkyl or 3-6 membered heterocyclic groups: C 1-12 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 3-14 Cycloalkylene; Y1 is absent or selected from carbonyl groups. No substitution or optional use by one, two or more R d The following groups are substituted: C 1-12 Alkylene, C 2-6 imidene group, C 2-6 Hypo-ynyl group, -O-(CH2) 0-6 -、-S-(CH2) 0-6 -、C 3-14 Cycloalkylene-(CH2) 0-6 -, 3-14 membered heterocyclic alkylene group -(CH2) 0-6 -、C 6-14 aryl-(CH2) 0-6 -, 5-14-membered heteroaryl-(CH2) 0-6 -、-NH-(CH2) 0-6 -、-NHCO-(CH2) 0-6 -、-CONH-(CH2) 0-6 -or X1 is selected from O or NR Y1 ;R Y1 Selected from H, CN, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; each R d They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. d1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1- 12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R d2 C(=O)R d3 ; Each R d1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d2 R d3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; Q2 does not exist or is selected from no substitution or is arbitrarily assigned by one, two or more Rs. b Replacement Or, when Q2 is selected from At that time, any position on ring B is connected to any position on ring A, together forming a non-substituted or arbitrarily substituted ring with one, two or more R's. b Replacement of multi-component fused ring systems; Ring B is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Each R b They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. b1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R b2 C(=O)R b3 P(=O)R b4 R b5 Or, two R atoms attached to the same carbon atom b Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. b1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. b Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. b1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. b Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. b1 Replacement C 1-3 Alkylene; each R b1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R b6 ;R b2 R b3 R b4 R b5 R b6 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; Y2 either does not exist or is selected from -O-, -S-, or carbonyl groups. Unsubstituted or optionally substituted with one, two or more elements selected from oxo (=O), OH, NH2, CN, halogen, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 Alkylene, -OC 1-12 Alkylene, -SC 1-12 Alkylene, -NH-C 1-12 Alkylene, -C 1-12 Alkylene -O-, -C 1-12 Alkylene -S-, -C 1-12 Alkyl groups: -NH-, -CONH-, -NHCO-, -COO-, or -OCO-; Ring C is selected from C 3-14 Carbocyclic rings, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. c1 The following groups are substituted: OH, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, Methylidene (=CH2), C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(=O)2R c2 C(=O)R c3 P(=O)R c4 R c5 Or, two R atoms attached to the same carbon atom c Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. c Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. c1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. c Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. c1 Replacement C 1-3 Alkylene; each R c1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or S(=O)2R c6 ;R c2 R c3 R c4 R c5 R c6 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; p is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, Q1 is selected from unsubstituted or arbitrarily assigned one, two or more R... a Substituted -CH(CH3)2 or Ring A is selected from C 3-6 Carbocyclic, 3-11 membered heterocyclic, phenyl or 5-11 membered heteroaryl; Preferably, Q1 is selected from unsubstituted or optionally substituted by one, two or more R. a Substituted -CH(CH3)2 or Ring A is selected from cyclopropyl ring, cyclobutyl ring, tetrahydrofuran ring, piperidine ring, benzene ring, thiophene ring, etc. Preferably, Q1 is selected from Ring A is selected from the benzene ring; Preferably, each R a They may be identical or different, and are independently selected from CN, halogen, unsubstituted, or optionally composed of one, two, or more R. a1 The following groups are substituted: OH, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, P(=O)(CH3)2; or, two R groups attached to adjacent carbon atoms. a Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. a1 The following ring systems are replaced: C 3-6 Carbon rings, 3-6 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings; or, two non-adjacent Rs a Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. a1 Replacement C 1-3 Alkylene; each R a1 They may be the same or different, and are independently selected from CN, halogens, OH, NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups or -NHS(=O)2CH3; Preferably, each R a The same or different, independently selected from CN, F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, ethynyl, methoxy, trifluoromethoxy, OH, -CH2OH, -CH2NH2, -NHSO2CH3, -PO(CH3)2. Preferably, m is selected from 0, 1, 2, 3, 4 or 5; Preferably, Q1 is selected from 3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, L1 is absent or selected from unsubstituted or optionally selected by one, two or more elements selected from -COOH, halogen, C 1-4 Alkyl, Halogenated C 1-4 The following groups are substituted by alkyl substituents: C 1-4 alkylene or cyclopropane; Preferably, L1 is absent or selected from -CH2-, -CH2CH2-, Preferably, Y1 is absent or selected from carbonyl groups. No substitution or optional use by one, two or more R d The following groups are substituted: -O-(CH2) 0-6 -, 3-14 membered heterocyclic alkylene group -(CH2) 0-6 -, 5-6 quinone heteroaryl-(CH2) 0-6 -、-NH-(CH2) 0-6 -、-NHCO-(CH2) 0- 6-, -CONH-(CH2) 0-6 -or X1 is selected from O or NH; each R d They may be the same or different, and are independently selected from 3-14 membered heterocyclic groups, -C(=O)CH3, and -C(=O)CH2CN; Preferably, Y1 is absent or selected from -C(O)-, -NHCO-, -CONH-, -OCH2-, -NHCOCH2-, Preferably, -L1-Y1- is absent or selected from -CH2CO-, -CH2-, -CH2CH2-, -NHCO-, -CH2CONH-, -CO-, -CONH-, -OCH2-, -NHCOCH2-, Preferably, Q2 is absent or selected from... Ring B is selected from 4-11 nitrogen-containing heterocyclic groups, phenyl groups, or 5-11 nitrogen-containing heteroaryl groups; Preferably, each R b They may be the same or different, and are independently selected from oxo (=O), -CH2CN, -CH2OH; or, two R atoms attached to the same carbon atom. b Together with the carbon atoms it is attached to, it forms the following ring system: C 3-6 Carbon rings or 3-6 membered heterocycles; or, two R atoms attached to adjacent carbon atoms. b Together with the carbon atoms they are attached to, they form the following ring system: C 3-6 Carbon rings, 3-6 membered heterocycles, benzene rings, or 5-6 membered heteroaromatic rings; or, two non-adjacent Rs b Connected by their end groups, they together form C 1-3 Alkylene; Preferably, n is selected from 0, 1, or 2; Preferably, n is selected from 1 or 2; Preferably, n is selected from 0; Preferably, Q2 is absent or selected from... Preferably, Y2 is absent or selected from -CH2-, -NH-, -O-, -CO- or -SO2-.

4. The compound according to any one of claims 1-3, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The ring C is selected from phenyl or 5-11 heteroaryl groups; Preferably, each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. c1 The following groups are substituted: C 1-4 Alkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, -COOH, -CONH2, -SO2NH2; each R c1 Same or different, selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl; or, two R atoms attached to adjacent carbon atoms. c Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. c1 The following ring systems are substituted: 5-6 membered heteroaryl rings; Preferably, each R c They are either the same or different, and are independently selected from oxo (=O), CN, F, Cl, Br, CH3, COOH, CONH2, CON(CH3)2, SO2NH2; Preferably, p is selected from 0 or 1; Preferably, Selected from 5. The compound according to any one of claims 1-4, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown in formula (I) has the following structure: Wherein, X1 is selected from CH2, NH, O or S; q1 is selected from 1 or 2; q2 is selected from 0 or 1; Q1, Q2, L1, Y1, Y2, ring C, R b R c R d , n, and p have the definitions of any one of claims 1-4; Preferably, the compound represented by formula (I) has the following structure: Where q1 is selected from 1 or 2; q2 is selected from 0 or 1; R1 is selected from unsubstituted or optionally selected from one of halogens (e.g., F, Cl, Br), C. 1-3 Alkyl (e.g., methyl, ethyl, isopropyl) or halogenated C 1-3 The following groups are substituted by alkyl groups (e.g., trifluoromethyl): C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, R1 is selected from cyclopropyl, )； R2 is selected from halogens (e.g., F, Cl, Br) or C. 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl); Ring C, R a R b R c m, n, and p have the definitions of any one of claims 1-4.

6. The compound according to any one of claims 1-5, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown in formula (I) is selected from the following structures:

7. A method for preparing the compound of formula (I) according to any one of claims 1-6, comprising the following step A or step B: Step A: Step B: in, R' is H or an alkali metal ion (e.g., Li). + K + Z represents a leaving group (e.g., Cl, Br); Q1, Q2, Y2, ring C, R c p has the definition of any one of claims 1-4.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of formula (I) according to any one of claims 1-6, a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof; Preferably, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition further contains one or more additional therapeutic agents.

9. A method of treating or preventing a disease or condition related to coenzyme A levels, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or a prodrug compound thereof, or a pharmaceutical composition thereof. Preferably, the patient includes a mammal, more preferably a human; Preferably, the diseases or conditions related to coenzyme a levels are selected from diseases of decreased, increased, isolated, toxic, or redistributed coenzyme a (CASTOR), metabolic diseases (e.g., fatty acid oxidase deficiency; phenylketonuria; glutaric acidemia), organic acidemia (methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (VA), and maple syrup urine disease (MSUD)), and neurological diseases (e.g., pantothenic acid kinase-related neurodegenerative diseases).

10. The use of at least one of the compounds of formula (I) according to any one of claims 1-6, their racemic mixtures, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds, or the use of the pharmaceutical composition according to claim 8 in the preparation of a medicament; Preferably, the use is in the preparation of a medicament for the treatment or prevention of diseases or conditions related to coenzyme A levels; Preferably, the diseases or conditions related to coenzyme a levels are selected from diseases of decreased, increased, isolated, toxic, or redistributed coenzyme a (CASTOR), metabolic diseases (e.g., fatty acid oxidase deficiency; phenylketonuria; glutaric acidemia), organic acidemia (methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (VA), and maple syrup urine disease (MSUD)), and neurological diseases (e.g., pantothenic acid kinase-related neurodegenerative diseases).

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