Pyridazinone derivatives and their applications in medicine

Abstract

Provided are pyridazinone derivatives and their applications in medicine. The derivatives are PARP inhibitors, such as PARP-7 inhibitors.

Description

Technical Field

[0001] The present invention relates to pyridazinone derivatives or their stereoisomers or pharmaceutically acceptable salts and their medical applications. Background Art

[0002] ADP-ribosylation is a post-translational modification process of proteins, which embeds single or multiple ADP-ribose groups into the amino acid residues of proteins. ADP-ribosylation is a reversible process and is involved in physiological regulations such as cell signal transduction, DNA damage repair, transcription, gene expression regulation, and apoptosis. ADP-ribose is derived from the redox cofactor: nicotinamide adenine dinucleotide (NAD+), and the enzyme mediating the embedding modification of ADP-ribose is ADP-ribosyltransferase. In the regulation of this physiological reaction, the N-glycosidic bond of NAD+ connecting the ADP-ribose molecule and the nicotinamide group is cleaved, and then it captures and forms a bond with the corresponding amino acid residue of the target protein. ADP-ribosyltransferase can perform two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are under stress, PARP will be activated, resulting in an increase in the amount of poly ADP-ribose and a decrease in the amount of NAD+. For more than a decade, it has been believed that PARP1 is the only poly-ADP-ribose polymerase in mammalian cells, so the most research has been done on this enzyme. So far, scientists have identified 17 different PARPs. MonoPARP occupies most of the PARP family and mediates important biological functions and various stress responses, such as: unfolded protein response, NF-KB signaling, antiviral response, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP-7) is one of the members of the MonoPARP family, and its expression is regulated by TCDD-activated aryl hydrocarbon receptor (AHR). AHR is a ligand-activated transcription factor that can mediate the toxic activities of many environmental xenobiotics. AHR upregulates the expression of PARP-7, and PARP-7 interacts with the kinase TBK1 and ADP-ribosylates it, resulting in the inhibition of TBK1 activity and the downregulation of the IFN-I (type I interferon) response, and further leading to the inhibition of the body's antiviral and tumor immune responses. Summary of the Invention

[0003] An object of one or more embodiments of the present application is to provide novel PARP inhibitors.

[0004] An object of one or more embodiments of the present application is to provide novel PARP-7 inhibitors.

[0005] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Wherein

[0008] R, R′, and R″ are each independently H or C 1-6 alkyl; or

[0009] R and R′ or R and R″ together with the attached atoms form a 4- to 8-membered heteroalkyl group;

[0010] R1 and R2 are each independently H or C 1-6 alkyl;

[0011] L1 is a bond or C═O;

[0012] L is a bond or NH;

[0013] C1 is a 6-, 7-, or 8-membered heterocyclic group;

[0014] R3 and R4 are each independently H, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH or CN;

[0015] C is a 6-membered heteroaryl group, and the 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from CN or C 1-6 alkyl optionally substituted by one or more halogens;

[0016] C2 is C 3-6 carbocycle;

[0017] R5 is each independently H, halogen, CN, or OH;

[0018] n is 1 or 2;

[0019] m is 0, 1, 2, 3, 4, or 5.

[0020] In one or more embodiments, C1 is a 6-, 7-, or 8-membered heterocyclic group containing 1, 2, or 3 N atoms.

[0021] In one or more embodiments, C1 is

[0022] In one or more embodiments, C is a 6-membered heteroaryl containing 1, 2, or 3 N atoms, and the 6-membered heteroaryl is optionally further substituted by 1 or more substituents selected from CN or C 1-6 alkyl optionally substituted by 1 or more halogens.

[0023] In one or more embodiments, C is optionally further substituted by 1 or more substituents selected from CN or C 1-6 alkyl optionally substituted by 1 or more halogens.

[0024] In one or more embodiments, the heterocycloalkyl is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 N atom.

[0025] In one or more embodiments, R is H.

[0026] In one or more embodiments, R′ and R″ are each independently H or C 1-6 alkyl;

[0027] In one or more embodiments, R1 and R2 are H.

[0028] In one or more embodiments, L1 is C═O.

[0029] In one or more embodiments, L is a bond.

[0030] In one or more embodiments, L1 is C═O and L is NH.

[0031] In one or more embodiments, L1 is C═O and L is a bond.

[0032] In one or more embodiments, C1 is

[0033] In one or more embodiments, R3 and R4 are each independently a halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by 1 or more OH groups.

[0034] In one or more embodiments, C is

[0035] In one or more embodiments, C2 is a C3 carbocycle.

[0036] In one or more embodiments, R5 is a halogen.

[0037] In one or more embodiments, n is 2.

[0038] In one or more embodiments, m is 0.

[0039] One or more embodiments of the present application provide a compound of general formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0040]

[0041] wherein

[0042] R1 and R2 are each independently selected from H or C 1-6 alkyl;

[0043] R3 and R4 are each independently selected from H, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH or CN;

[0044] R5 is each independently selected from H, halogen, CN or OH;

[0045] L is a bond or -NH-;

[0046] C1 is

[0047] C2 is C 3-5 carbocyclic ring;

[0048] n is 1 or 2;

[0049] m is 0, 1, 2, 3, 4 or 5.

[0050] In one or more embodiments, R1 and R2 are H.

[0051] In one or more embodiments, L is a bond.

[0052] In one or more embodiments, R3 and R4 are each independently halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more OH.

[0053] In one or more embodiments, C2 is a C3 carbocyclic ring.

[0054] In one or more embodiments, R5 is halogen.

[0055] In one or more embodiments, n is 2.

[0056] In one or more embodiments, m is 0.

[0057] One or more embodiments of the present application provide a compound or a stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following structures:

[0058]

[0059]

[0060]

[0061] One or more embodiments of the present application provide intermediate compounds or their stereoisomers or pharmaceutically acceptable salts for preparing compounds of general formula (I), (II) or their stereoisomers or pharmaceutically acceptable salts, which are compounds represented by general formula (III), (IV), (V) or (VI):

[0062]

[0063]

[0064] wherein

[0065] R, R′, and R″ are each independently H or C 1-6 alkyl; or

[0066] R and R′ or R and R″ together with the attached atoms form a 4- to 8-membered heteroalkyl group;

[0067] R1 and R2 are each independently H or C 1-6 alkyl;

[0068] L1 is a bond or C═O;

[0069] L is a bond or NH;

[0070] C1 is a 6- to 8-membered heteroaryl group;

[0071] R3 and R4 are each independently H, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH or CN;

[0072] C is a 6-membered heteroaryl group, and the 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from CN or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by one or more halogens;

[0073] C2 is C 3-6 carbocyclic ring;

[0074] R5 is each independently H, halogen, CN or OH;

[0075] C3 is a 6- to 8-membered heteroaryl group;

[0076] X1 is H or NH2;

[0077] n is 1 or 2;

[0078] m is 0, 1, 2, 3, 4 or 5.

[0079] In one or more embodiments, the heterocycloalkyl is a 4-, 5- or 6-membered heterocycloalkyl containing 1 N atom.

[0080] In one or more embodiments, C1 is a 6-, 7- or 8-membered heterocyclic group containing 1, 2 or 3 N atoms.

[0081] In one or more embodiments, C is a 6-membered heteroaryl containing 1, 2 or 3 N atoms.

[0082] In one or more embodiments, C1 is

[0083] In one or more embodiments, C is which is optionally further substituted by 1 or more substituents selected from CN or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 or more halogens.

[0084] In one or more embodiments, C3 is

[0085] In one or more embodiments, the intermediate compound or its stereoisomer or pharmaceutically acceptable salt has the following structure or its stereoisomer or pharmaceutically acceptable salt:

[0086]

[0087] One or more embodiments of the present application provide a pharmaceutical composition, which comprises:

[0088] (1) The compound of the present application, or its stereoisomer or pharmaceutically acceptable salt;

[0089] (2) Optionally one or more other active ingredients; and

[0090] (3) A pharmaceutically acceptable carrier and / or excipient.

[0091] One or more embodiments of the present application provide the use of the compound of the present application or its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition of the present application in the preparation of an anti-tumor drug.

[0092] In one or more embodiments, the formation of the tumor is related to PARP.

[0093] In one or more embodiments, the PARP is PARP-7.

[0094] One or more embodiments of the present application provide the use of the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application in the preparation of PARP inhibitors.

[0095] In one or more embodiments, the PARP is PARP-7.

[0096] One or more embodiments of the present application provide the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application for use as a medicine.

[0097] One or more embodiments of the present application provide the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application for use in a method of treating a tumor. In one or more embodiments, the formation of the tumor is related to PARP. In one or more embodiments, the PARP is PARP-7.

[0098] One or more embodiments of the present application provide the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application for use as a PARP inhibitor, such as a PARP-7 inhibitor.

[0099] One or more embodiments of the present application provide a method of treating a tumor, which comprises administering the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application to a subject in need thereof.

[0100] One or more embodiments of the present application provide a method of inhibiting PARP, which comprises administering the compounds of the present application or their stereoisomers or pharmaceutically acceptable salts or the pharmaceutical compositions of the present application. In one or more embodiments, the PARP is PARP-7. Detailed Description of the Invention

[0102] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0103] Carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further substituted by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), and oxygen isotopes include 16 O, 17 O and 18 O, and sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, bromine isotopes include 79 Br and 81 Br.

[0104] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms), preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and still more preferably an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when the alkyl group is a substituent, it may optionally be further substituted by one or more substituents.

[0105] "Aryl" refers to a substituted or unsubstituted aromatic ring, which may be a monocyclic ring having 5 to 8 members (e.g., 5, 6, 7, 8 members), a bicyclic ring having 5 to 12 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12 members), or a tricyclic system having 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members), which may be a bridged ring or a spiro ring. Non-limiting examples include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0106] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 5 to 8 members (such as 5, 6, 7, 8 members), a bicyclic ring of 5 to 12 members (such as 5, 6, 7, 8, 9, 10, 11, 12 members) or a tricyclic system of 10 to 15 members (such as 10, 11, 12, 13, 14, 15 members), and contains 1 to 6 (such as 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S. Preferably, it is a heterocyclic group of 3 to 8 members (such as 3, 4, 5, 6, 7, 8 members). Optionally substituted N and S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and the heterocyclic group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridinyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, pyrrolopyridinyl. When the heteroaryl is substituted, it can be optionally further substituted by one or more substituents.

[0107] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated heteroaromatic ring or non-heteroaromatic ring. When selected from heteroaromatic rings, its definition is the same as that of "heteroaryl" above; when selected from non-heteroaromatic rings, it can be a monocyclic ring with 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members), a bicyclic ring with 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or a tricyclic ring system with 10 to 15 members (such as 10, 11, 12, 13, 14, 15 members), and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a heterocyclic group with 3 to 8 members. The optionally substituted N and S in the ring of "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; "heterocyclic group" or "heterocycle" can be linked to a heteroatom or a carbon atom; "heterocyclic group" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclic group" or "heterocycle" include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuryl, dithiolanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl and oxaspiro[3.3]heptyl. The said "heterocyclic group" or "heterocycle" can be optionally further substituted by 0 or more substituents.

[0108] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a monocyclic ring of 3 to 8 members (such as 3, 4, 5, 6, 7 or 8 members), a bicyclic ring of 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or a tricyclic ring system of 10 to 15 members (such as 10, 11, 12, 13, 14, 15 members), and contains 1, 2 or 3 heteroatoms selected from N, O or S, such as a heterocyclic group of 3 to 8 members. The optionally substituted N and S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; "heterocycloalkyl" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl and oxaspiro[3.3]heptanyl.

[0109] "Carbocyclic group" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic cyclic ring. When selected from an aromatic ring, its definition is the same as that of "aryl" described above; when selected from a non-aromatic ring, it can be a monocyclic ring of 3 to 10 members, a bicyclic ring of 4 to 12 members or a tricyclic ring system of 10 to 15 members, and can be a bridged ring or a spiro ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The described "carbocyclic group" or "carbocycle" can optionally be further substituted by one or more substituents.

[0110] When the "alkyl", "aryl", "heteroaryl", "heterocycle", "heterocyclic group", "heterocycloalkyl", "carbocycle", "carbocyclic group" described above are substituted, they can optionally be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 、=NR q6, -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 substituted by a substituent of alkynyl, and wherein said substituent C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O)C 3-8 cycloalkyl is optionally further substituted by 1 to 3 substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O; R q1 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-10 aryl; R q2 , R q3Selected from H or C 1-6 alkyl; R q4 、R q5 selected from H, C 1-6 alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 and R q5 together with the N atom form a 3- to 8-membered heterocycle, and the said ring may contain one or more heteroatoms selected from N, O or S.

[0111] "Pharmaceutical composition" means a mixture formed by one or more compounds described in the present invention, their pharmaceutically acceptable salts or prodrugs and other active components, wherein "other active components" means pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0112] "Carrier" means a material that does not cause significant irritation to organisms and does not eliminate the biological activity and properties of the administered compound.

[0113] "Excipient" means an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.

[0114] "Stereoisomer" means an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0115] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt obtained by reacting the free acid of the compound of the present invention with a non-toxic inorganic base or organic base, or the free base with a non-toxic inorganic acid or organic acid, while maintaining the biological effectiveness and properties of the free acid or free base.

[0116] "Optional" or "optionally" or "selective" or "selectively" means that the subsequent described event or condition may but does not necessarily occur, and this description includes the cases where the event or condition occurs and the cases where it does not occur. For example, "heterocyclic group optionally substituted by alkyl" means that the alkyl may but does not necessarily exist, and this description includes the cases where the heterocyclic group is substituted by alkyl and the cases where the heterocyclic group is not substituted by alkyl. Detailed Description of the Invention

[0117] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0118] PMB: refers to p-methoxybenzyl.

[0119] Intermediate 1

[0120] (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid (Intermediate 1)

[0121] (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid

[0122]

[0123] The first step:

[0124] 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1b)

[0125] 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0126] At 0 - 10 °C, sodium hydride (11.82 g, 295.41 mmol, 1.5 equiv, 60%) was added portionwise to a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (1a, 50 g, 196.94 mmol, 1.0 equiv) in N,N-dimethylformamide (500 mL). 1-(Chloromethyl)-4-methoxybenzene (46.06 g, 294.11 mmol, 1.49 equiv) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was slowly poured into 1.0 L of ice-water mixture to quench, and extracted with 2 × 500 mL of dichloromethane. The organic layers were combined and concentrated. The solid was washed with methanol (500 mL × 2) to obtain compound 1b, a yellow solid (48.4 g, yield 66%).

[0127] LC-MS m / z (ESI) = 375.00 [M+1].

[0128] Step 2:

[0129] 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1c)

[0130] 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0131] Compound 1b (48.4 g, 129.40 mmol, 1.0 equiv) and potassium hydroxide (21.78 g, 388.30 mmol, 3.00 equiv) were dissolved in methanol (417 mL), and the reaction solution was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated to 80 mL and filtered to obtain the crude product. The obtained filter cake was slurried in water (160 mL) for 1 h and then filtered to obtain compound 1c as a white solid (38.72 g, yield 92%).

[0132] LC-MS m / z (ESI) = 326.30 [M+1].

[0133] Step 3:

[0134] 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1d)

[0135] 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0136] Compound 1c (14 g, 43.04 mmol, 1.0 equiv) and copper(I) iodide (4.10 g, 21.52 mmol, 0.50 equiv) were weighed into a 250 mL reaction flask, dissolved in N-methylpyrrolidone (72 mL), and then 2,2-difluoro-2-(fluorosulfonyl)ethyl acetate (16.4 mL, 129.11 mmol, 3.0 equiv) was slowly added. After addition, the reaction was stirred in an oil bath at 100 °C for 3 h. After the reaction was complete, 90 mL of water was added to the reaction solution to quench it. The resulting solution was extracted with 3 × 60 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 1d as a white solid (12.1 g, yield 89%).

[0137] LC-MS m / z (ESI) = 315.10 [M+1].

[0138] Step 4:

[0139] 5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1e)

[0140] 5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0141] At room temperature, trimethylsilyl iodide (9.97 g, 50.07 mmol, 1.3 equiv) was added dropwise to a solution of compound 1d (12.1 g, 38.52 mmol, 1.0 equiv) in N,N-dimethylformamide (60 mL). The resulting reaction mixture was stirred at 85 °C for 20 h. After completion of the reaction, 60 mL of water was added to the reaction mixture to quench the reaction, and then the resulting solution was extracted with dichloromethane (3 × 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 1e as a white solid (10.4 g, yield 90%).

[0142] LC-MS m / z (ESI) = 301.07 [M+1].

[0143] Step 5:

[0144] 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1f)

[0145] 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0146] At 0 °C, oxalyl dichloride (8.79 g, 69.32 mmol, 2.0 equiv) was slowly added dropwise to a solution of compound 1e (10.4 g, 34.66 mmol, 1.0 equiv) in DMF (52 mL). After addition, the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, 550 mL of water was added to the reaction solution to quench it. The mixture was filtered to give compound 1f as a white solid (11.04 g, 99%).

[0147] LC-MS m / z (ESI) = 319.68 [M+1].

[0148] Step 6:

[0149] (S)-5-((1-Hydroxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (1g)

[0150] (S)-5-((1-hydroxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0151] Weigh compound 1f (5.0 g, 15.69 mmol, 1.0 equiv) into a 100 mL reaction flask, and add ethanol (40 mL) to dissolve it. Subsequently, add triethylamine (4.4 mL, 31.38 mmol, 2.0 equiv) and (2S)-2-aminopropan-1-ol (1.19 g, 15.69 mmol, 1.0 equiv) in sequence, and stir the mixture at 60 °C for 4 h. After the reaction is complete, concentrate it under vacuum, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 1:1.5) to obtain compound 1g, a white solid (5.31 g, yield 95%).

[0152] LC-MS m / z (ESI) = 358.43 [M+1].

[0153] Step 7:

[0154] Methyl (S)-3-(2-(((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate (1h)

[0155] Methyl-(S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate

[0156] Weigh compound 1g (5.31 g, 14.86 mmol, 1.0 equiv) and cesium carbonate (4.73 g, 14.86 mmol, 1.0 equiv) into a 100 mL reaction flask. Subsequently, add acetonitrile (50 mL) to dissolve it, and add methyl prop-2-enoate (13.38 g, 148.6 mmol, 10 equiv) to the mixture. After addition, stir the reaction mixture at 30 °C for 4 h. After the reaction is complete, concentrate it under vacuum, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 1h, a white solid (3.40 g, yield 51%).

[0157] LC-MS m / z (ESI) = 444.50 [M+1].

[0158] Step 8:

[0159] (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate methyl ester (1i)

[0160] Methyl-(S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate

[0161] To a 25 mL reaction flask containing compound 1h (3.40 g, 7.67 mmol, 1.0 equiv), trifluoroacetic acid (21.42 mL) and trifluoromethanesulfonic acid (2.7 mL, 30.68 mmol, 4.0 equiv) were added successively. After addition, the reaction was stirred at 25 °C for 2 h. Subsequently, 85 mL of water was added to quench the reaction mixture. The resulting solution was extracted with 3 × 60 mL of ethyl acetate. The pH of the organic layer was adjusted to 8 - 9 with aqueous potassium carbonate solution. The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:3) to give compound 1i as a white solid (2.06 g, yield 83%).

[0162] LC-MS m / z (ESI) = 324.30 [M+1].

[0163] Step 9:

[0164] (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid (Intermediate 1)

[0165] (S)-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid

[0166] Weigh compound 1i (2.06 g, 6.37 mmol, 1.0 equiv) and lithium hydroxide monohydrate (1.34 g, 31.85 mmol, 5.0 equiv) separately and add them to a 100 mL reaction flask. Subsequently, add methanol (14 mL) and water (14 mL) in sequence, and stir the reaction solution at 25 °C for 1 h. After the reaction is complete, adjust the pH of the reaction mixture to 6 with trifluoroacetic acid. The reaction mixture is concentrated in vacuo, and the residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 6:1) to obtain intermediate 1, a pale yellow solid (1.32 g, yield 67%).

[0167] LC-MS m / z (ESI) = 310.32 [M+1].

[0168] Intermediate 2

[0169] 5-Cyclopropyl-2-(piperazin-1-yl)pyrimidine (Intermediate 2)

[0170] 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine

[0171]

[0172] First step:

[0173] tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (2b)

[0174] tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

[0175] Weigh 2-chloro-5-bromopyrimidine (2a, 12.0 g, 62.04 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (11.0 g, 59.08 mmol, 1.0 equiv) and potassium carbonate (16.33 g, 124.08 mmol, 2.0 equiv) into a 250 mL reaction flask. Subsequently, add N-methylpyrrolidone (90 mL) to the mixture to dissolve it, and heat and stir the reaction in an 80 °C oil bath for 1 h. After the reaction is complete, pour the reaction solution into 280 mL of ice-water mixture, filter the suspension to obtain compound 2b, a white solid (16.4 g, yield 81%).

[0176] LC-MS m / z (ESI) = 344.90 [M+1].

[0177] Second step:

[0178] 5-Bromo-2-(piperazin-1-yl)pyrimidine (2c)

[0179] 5-bromo-2-(piperazin-1-yl)pyrimidine

[0180] Weigh compound 2b (16.4 g, 47.78 mmol, 1.0 equiv) and dissolve it in a dioxane solution of hydrochloric acid (4 M, 67 mL). Stir the reaction solution at room temperature for 1 h. When the reaction is complete, filter the suspension, wash the filter cake with dioxane, and dry it to obtain compound 2c as a white solid (11.3 g, yield 97%).

[0181] LC-MS m / z (ESI) = 244.90 [M+1].

[0182] The third step:

[0183] 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine (Intermediate 2)

[0184] 5-cyclopropyl-2-(piperazin-1-yl)pyrimidine

[0185] Add the weighed compound 2c (1.0 g, 4.10 mmol, 1.0 equiv), potassium carbonate (2.83 g, 20.50 mmol, 5.0 equiv), cyclopropylboronic acid (1.06 g, 12.30 mmol, 3.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (344.8 mg, 0.41 mmol, 0.1 equiv) into a 25 mL reaction flask. Subsequently, add a THF / H2O (35.2 / 4.4 mL) mixture, protect it with N2, and heat and stir the reaction in an oil bath at 66 °C for 3 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate it under vacuum, and purify it by column chromatography (dichloromethane:methanol = 15:1) to obtain Intermediate 2 as a white solid (0.66 g, yield 78%).

[0186] LC-MS m / z (ESI) = 205.30 [M+1].

[0187] Intermediate 3

[0188] 5-cyclobutyl-2-(piperazin-1-yl)pyrimidine (Intermediate 3)

[0189] 5-cyclobutyl-2-(piperazin-1-yl)pyrimidine

[0190]

[0191] The first step:

[0192] tert-butyl 4-(5-(1-(hydroxycyclobutyl)pyrimidin-2-yl)piperazine-1-carboxylate (3a)

[0193] 4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0194] Compound 2b (7.8 g, 22.66 mmol, 1.0 equiv) was dissolved in anhydrous tetrahydrofuran (62 mL), and the temperature was lowered to -78 °C. Subsequently, 23.8 mL of n-butyllithium (1.0 M solution in n-hexane, 23.79 mmol, 1.05 equiv) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 10 min, then naturally warmed to ambient temperature and stirred for an additional 2 h. The reaction solution was cooled to -20 °C, and cyclobutanone (1.86 mL, 24.93 mmol, 1.1 equiv) was slowly added dropwise. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for 4 h. When the reaction was complete, the reaction was quenched with 10 mL of saturated ammonium chloride solution. The reaction mixture was extracted with 3 × 120 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude product 3a, a yellow oil (6.4 g). The crude product 3a was used directly in the next step without further purification.

[0195] LC-MS m / z (ESI) = 335.40 [M+1].

[0196] Second step:

[0197] 5-cyclobutyl-2-(piperazin-1-yl)pyrimidine (Intermediate 3)

[0198] 5-cyclobutyl-2-(piperazin-1-yl)pyrimidine

[0199] The dried compound 3a (ca. 5.7 mmol) was transferred to a 20 mL reaction flask and dissolved in dichloromethane (6 mL). Subsequently, triethylsilane (2.74 mL, 17.1 mmol, 3 equiv) and a dichloromethane solution of trifluoroacetic acid (3.0 mL, TFA:CH2Cl2 = 1:2, v / v) were added thereto. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated in vacuo to give an oil. The residue was purified by reverse-phase C18 column chromatography (water:acetonitrile = 1:3) to give Intermediate 3 as a white solid (1.35 g, 27%).

[0200] LC-MS m / z (ESI) = 219.20 [M+1].

[0201] Intermediate 4

[0202] 5-(1-Fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine (Intermediate 4)

[0203] 5-(1-fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

[0204]

[0205] Step 1:

[0206] Methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (4b)

[0207] methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0208] Weigh 2-chloro-5-carboxylate methyl ester 4a (17.2 g, 0.1 mol, 1.0 equiv), tert-butyl piperazine-1-carboxylate (21.0 g, 0.11 mol, 1.1 equiv) and potassium carbonate (28.0 g, 0.2 mol, 2.0 equiv) into a 250 mL reaction flask. Subsequently, add N-methylpyrrolidone (100 mL) to dissolve the mixture, and heat and stir the reaction in an 80 °C oil bath for 1 h. After the reaction is complete, pour the reaction solution into 280 mL of ice-water mixture, filter the suspension to obtain compound 4b as a white solid (26.2 g, yield 81%).

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 3.92 - 3.69 (m, 7H), 3.47 - 3.37 (m, 4H), 1.42 (s, 9H).

[0210] LC-MS m / z (ESI) = 323.20 [M+1].

[0211] Step 2:

[0212] tert-Butyl 4-(5-(1-hydroxycyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (4c)

[0213] tert-butyl 4-(5-(1-hydroxycyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0214] Weigh compound 4b (5.0 g, 15.5 mmol, 1.0 equiv), and dissolve it and titanium(IV) isopropoxide (6.4 g, 21.7 mmol, 1.4 equiv) in 50 mL of anhydrous tetrahydrofuran. While under ice-water bath and nitrogen protection, slowly add ethylmagnesium bromide solution (43.5 mL, 43.5 mmol, 2.8 equiv). After the addition is complete, stir the reaction mixture at room temperature for 2 h. After the reaction is complete, add 40 mL of ethyl acetate and 20 mL of water to the reaction solution, extract with ethyl acetate three times, and concentrate under reduced pressure to remove the solvent. The crude product is purified by column chromatography (n-hexane:ethyl acetate = 5:1) to obtain compound 4c as a white solid (1.5 g, yield 30%).

[0215] LC-MS m / z (ESI) = 321.20 [M+1].[[]END]]

[0216] The third step:

[0217] tert-butyl 4-(5-(1-(((trimethylsilyl)oxy)cyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (4d)

[0218] tert-butyl-4-(5-(1-((trimethylsilyl)oxy)cyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0219] Weigh compound 4c (500 mg, 1.5 mmol, 1.0 equiv) and dissolve it in 5 mL of dimethylformamide. Then, successively add imidazole (204 mg, 3 mmol, 2 equiv) and trimethylchlorosilane (285 μL, 2.25 mmol, 1.5 equiv), and stir the reaction mixture at room temperature for 1 h. After the reaction is complete, quench the reaction by adding 5 mL of water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 4d. The crude product is directly used in the next step of the reaction.

[0220] The fourth step:

[0221] tert-butyl 4-(5-(1-fluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (4e)

[0222] tert-butyl 4-(5-(1-fluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0223] Dissolve compound 4d (1.5 mmol, 1.0 equiv) in 5 mL of dichloromethane, add diethylaminosulfur trifluoride (396 μL, 3 mmol, 2.0 equiv), and react at room temperature for 1 h. After the reaction is complete, directly evaporate the solvent under reduced pressure and purify by column chromatography (n-hexane:ethyl acetate = 3:1) to obtain compound 4e as a white solid (290 mg, yield 60%).

[0224] 1 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, 2H), 3.77 - 3.71 (m, 4H), 3.40 (dd, 4H), 1.42 (s, 9H), 1.39 - 1.31 (m, 2H), 1.12 - 1.01 (m, 2H).

[0225] Step 5:

[0226] 5-(1-Fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine (Intermediate 4)

[0227] 5-(1-fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

[0228] Refer to the synthesis method of compound 2c to prepare Intermediate 4 as a white solid. Intermediate 4 can be directly used in the next step of the reaction without further purification.

[0229] LC-MS m / z (ESI) = 223.20 [M + 1]

[0230] Intermediate 5

[0231] 5-Cyclopropyl-2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine (Intermediate 5)

[0232] 5-cyclopropyl-2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine

[0233]

[0234] Step 1:

[0235] (2S,6R)-4-(5-Bromopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl ester (5b)

[0236] tert-butyl (2S,6R)-4-(5-bromopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate

[0237] Weigh 2-chloro-5-bromopyrimidine 2a (1.5 g, 7.7 mmol, 1.0 equiv), tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (2.0 g, 9.0 mmol, 1.2 equiv) and potassium carbonate (2.1 g, 15.4 mmol, 2.0 equiv) into a 100 mL reaction flask. Subsequently, add N-methylpyrrolidone (20 mL) to the mixture to dissolve it, and heat and stir the reaction in an 80 °C oil bath for 1 h. After the reaction is complete, pour the reaction solution into an 80 mL ice-water mixture, and filter the suspension to obtain compound 5b as a white solid (2.7 g, yield 98%).

[0238] LC-MS m / z (ESI) = 371.20 [M+1].

[0239] The second step:

[0240] (2S,6R)-4-(5-Cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (5c)

[0241] tert-butyl(2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxy-late

[0242] Refer to the synthesis method of intermediate 2 to prepare compound 5c as a white solid (1.8 g, yield 70%).

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 4.52 (s, 1H), 4.49 (s, 1H), 4.19 - 4.08 (m, 2H), 2.99 (dd, 2H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H), 1.09 (d, 6H), 0.89 - 0.83 (m, 2H), 0.67 - 0.59 (m, 2H).

[0244] LC-MS m / z (ESI) = 333.23 [M+1].

[0245] The third step:

[0246] 5-Cyclopropylpyrimidin-2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine (Intermediate 5)

[0247] 5-cyclopropyl-2-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine

[0248] Refer to the synthesis method of reference compound 2c to prepare intermediate 5, which is a white solid. Intermediate 5 is directly used in the next reaction without further purification.

[0249] Intermediate 6

[0250] 1-(5-cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-amine (Intermediate 6)

[0251] 1-(5-cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-amine

[0252]

[0253]

[0254] The first step:

[0255] (1-(5-bromopyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)carbamate (6b)

[0256] tert-butyl(1-(5-bromopyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)carbamate

[0257] Weigh 2-chloro-5-bromopyrimidine 2a (682 mg, 3.5 mmol, 1.0 equiv), tert-butyl (3,3-difluoropiperidin-4-yl)carbamate (1.0 g, 4.2 mmol, 1.2 equiv) and potassium carbonate (0.97 g, 7.0 mmol, 2.0 equiv) into a 50 mL reaction flask. Subsequently, add N-methylpyrrolidone (10 mL) to dissolve the mixture, and heat and stir the reaction in an 80 °C oil bath for 1 h. After the reaction is complete, pour the reaction solution into an 80 mL ice-water mixture, filter the suspension to obtain compound 6b, which is a white solid (1.02 g, yield 75%).

[0258] 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.24 (d, 1H), 4.76 - 4.68 (m, 1H), 4.45 (d, 1H), 4.23 - 4.04 (m, 1H), 3.56 (dd, 1H), 3.30 - 3.23 (m, 1H), 1.83 - 1.82 (m, 1H), 1.67 - 1.54 (m, 1H), 1.40 (s, 9H).

[0259] LC-MS m / z (ESI) = 394.25 [M+1].

[0260] Step 2:

[0261] (1-(5-Cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)carbamic acid tert-butyl ester (6c)

[0262] tert-butyl (1-(5-cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)carbamate

[0263] Referring to the synthetic method of Intermediate 2, Intermediate 6c was prepared as a white solid (770 mg, yield 87%).

[0264] 1 1H NMR (600 MHz, DMSO-d6) δ 8.19 (s, 2H), 7.20 (d, 1H), 4.78 - 4.72 (m, 1H), 4.47 (d, 1H), 4.16 - 4.02 (m, 1H), 3.50 - 3.43 (m, 1H), 3.21 - 3.16 (m, 1H), 1.79 - 1.74 (m, 2H), 1.62 - 1.56 (m, 1H), 1.40 (s, 9H), 0.93 - 0.83 (m, 2H), 0.68 - 0.61 (m, 2H).

[0265] LC-MS m / z (ESI) = 355.40 [M+1].

[0266] Step 3:

[0267] 1-(5-Cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-amine (Intermediate 6)

[0268] 1-(5-cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-amine

[0269] Referring to the synthesis method of reference compound 2c, intermediate 6 was prepared. It is a white solid and was directly used in the next step of the reaction without further purification.

[0270] Intermediate 7:

[0271] 7-(5-Cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (Intermediate 7)

[0272] 7-(5-cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octane

[0273]

[0274]

[0275] First step:

[0276] 2-Chloro-5-cyclopropylpyrimidine (7a)

[0277] 2-chloro-5-cyclopropylpyrimidine

[0278] Referring to the synthesis method of intermediate 2, compound 7a was prepared. It is a white solid (1.32 g, yield 83%).

[0279] 1 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 2H), 2.00 - 1.93 (m, 1H), 1.09 - 1.02 (m, 2H), 0.90 - 0.84 (m, 2H).

[0280] LC-MS m / z (ESI) = 155.03 [M + 1].

[0281] Second step:

[0282] tert-Butyl 7-(5-cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (7b)

[0283] tert-butyl 7-(5-cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0284] Weigh 2-chloro-5-cyclopropylpyrimidine 7a (300 mg, 2 mmol, 1.0 equiv), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (640 mg, 3 mmol, 1.2 equiv) and potassium carbonate (0.55 g, 4.0 mmol, 2.0 equiv) into a 50 mL reaction flask. Subsequently, add N-methylpyrrolidone (10 mL) to the mixture to dissolve it, and heat and stir the reaction in an 80 °C oil bath for 1 h. After the reaction is complete, pour the reaction solution into an 80 mL ice-water mixture, filter the suspension to obtain compound 7b as a white solid (350 mg, yield 53%).

[0285] LC-MS m / z (ESI) = 331.30 [M+1].

[0286] The third step:

[0287] Refer to the synthesis method of compound 2c to prepare intermediate 7 as a white solid; intermediate 7 can be directly used in the next step of the reaction without further purification.

[0288] Intermediate 8:

[0289] (1R,5S)-3-(5-cyclopropylpyrimidin-2-yl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (Intermediate 8)

[0290] (1R,5S)-3-(5-cyclopropylpyrimidin-2-yl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine

[0291]

[0292] Refer to the synthesis method of intermediate 7 to prepare intermediate 8 as a white solid (1.8 g, yield 70%).

[0293] LC-MS m / z (ESI) = 344.50 [M+1]

[0294] Intermediate 9:

[0295] (S)-2-(2-(((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (Intermediate 9)

[0296] (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid

[0297]

[0298] Step 1:

[0299] (S)-tert-butyl 2-(2-(((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetate (9a)

[0300] tert-butyl(S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro pyridazin-4-yl)amino)propoxy)acetate

[0301] Weigh 1 g (1.0 g, 2.79 mmol, 1.0 equiv) of the compound, tert-butyl bromoacetate (1.65 g, 8.37 mmol, 3.0 equiv) and potassium tert-butoxide (0.94 g, 8.37 mmol, 3.0 equiv) successively in 11.0 mL of dimethylformamide, react at room temperature for 3 h, quench the reaction with 30 mL of water, extract twice with 30 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and subject the residue to column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 9a as a yellow solid (0.33 g, yield 25%).

[0302] LC-MS m / z (ESI) = 472.48 [M+1].

[0303] Step 2:

[0304] (S)-2-(2-(((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid (Intermediate 9)

[0305] (S)-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid

[0306] In a 50 mL single-necked flask, dissolve compound 9a (330 mg, 0.7 mmol, 1 equiv) in 2.5 mL of dichloromethane, then add 2.5 mL of trifluoroacetic acid, react at room temperature for 2 h, rotary evaporate the reaction solution to obtain intermediate 9 (220 mg, yield 76%), and directly proceed to the next step of the reaction.

[0307] LC-MS m / z (ESI) = 416.37 [M + 1].

[0308] Intermediate 10

[0309] 1-(2-(Piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile (Intermediate 10)

[0310] 1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile

[0311]

[0312]

[0313] The first step:

[0314] tert-Butyl 4-(5-(1-(cyanocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (10a)

[0315] tert-butyl 4-(5-(1-cyanocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0316] Add 1,1′-Binaphthalene-2,2'-bis(diphenylphosphine) (124.5 mg, 0.2 mmol, 0.1 equiv), tris(dibenzylideneacetone)dipalladium(0):1,1′-Binaphthalene-2,2′-bis(diphenylphosphine) (91.6 mg, 0.1 mmol, 0.05 equiv) and tetrahydrofuran (2.0 ml) into the reaction flask, evacuate and backfill with nitrogen, and stir the suspension under nitrogen for 20 min. Take another reaction flask, add compound 2b (686 mg, 2.0 mmol, 1.0 equiv) and cyclopropanecarbonitrile (267 μL, 3.0 mmol, 1.5 equiv), dissolve with cyclopentyl methyl ether (4.0 mL), evacuate and backfill with nitrogen for protection after addition. Subsequently, add the prepared catalyst suspension to the reaction, and then dropwise add lithium bis(trimethylsilyl)amide (3.0 mL, 1 M in THF, 3.0 mmol, 1.5 euqiv). Heat the reaction mixture to 80 °C and stir for 3 h. After the reaction is complete, cool the reaction solution to room temperature and dilute with ethyl acetate and saturated ammonium chloride solution. Extract the reaction mixture with 3×60 mL of ethyl acetate. Combine the organic layers, dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 10a as a white solid (482 mg, yield 73%).

[0317] LC-MS m / z(ESI)=330.30[M + 1].

[0318] The second step:

[0319] 1-(2-(Piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile (Intermediate 10)

[0320] 1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile

[0321] Refer to the synthesis method of compound 2c to prepare the crude product of intermediate 10, which is 327 mg of white solid. Intermediate 10 can be directly used for the next reaction without further purification.

[0322] LC-MS m / z(ESI)=230.20[M + 1].

[0323] Intermediate 11

[0324] 5-(2,2-Difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine (Intermediate 11)

[0325] 5-(2,2-difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

[0326]

[0327] Step 1:

[0328] 4-(5-Vinylpyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11b)

[0329] tert-butyl 4-(5-vinylpyrimidin-2-yl)piperazine-1-carboxylate

[0330] Referring to the synthesis method of reference compound 2b, compound 11b was prepared as a white solid (1.2 g, yield 83%).

[0331] LC-MS m / z (ESI) = 290.4 [M+1].

[0332] Step 2:

[0333] 4-(5-(2,2-Difluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11c)

[0334] tert-butyl 4-(5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0335] Weigh 11b (634 mg, 2.18 mmol, 1.0 eq) and sodium iodide (729.7 mg, 4.87 mmol, 2.23 equiv) into a 15 mL high-pressure reaction tube, add dioxane (2.0 mL) and ethylene glycol dimethyl ether (30 μL) to dissolve. Evacuate and replace with nitrogen for protection, then successively add methyl fluorosulfonyldifluoroacetate (556 μL, 4.37 mmol, 2.0 equiv) and trimethylchlorosilane (474.3 mg, 4.37 mmol, 2.0 equiv). After addition, transfer the reaction to a 120 °C oil bath and stir for 3 h. After the reaction is complete, cool the reaction solution to room temperature, add 30 mL of ethyl acetate and 30 mL of water, and stir the mixture for 30 min. Separate the organic phase, concentrate in vacuo, and purify by column chromatography (ethyl acetate:petroleum ether = 1:15) to obtain compound 11c as a white solid (220 mg, yield 30%).

[0336] LC-MS m / z (ESI) = 341.30 [M+1].

[0337] Step 3:

[0338] 5-(2,2-Difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine (Intermediate 11)

[0339] 5-(2,2-difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

[0340] Referring to the synthesis method of reference compound 2c, a crude product of Intermediate 11 was prepared, which was 169 mg of a white solid. Intermediate 11 can be directly used in the next reaction without further purification.

[0341] LC-MS m / z (ESI) = 241.29 [M+1].

[0342] Intermediate 12

[0343] 2-(Piperazin-1-yl)-5-(2,2,3-trifluorocyclopropyl)pyrimidine (Intermediate 12)

[0344] 2-(piperazin-1-yl)-5-(2,2,3-trifluorocyclopropyl)pyrimidine

[0345]

[0346] First step:

[0347] tert-Butyl 4-(5-(2-bromo-1-fluoroethyl)pyrimidin-2-yl)piperazine-1-carboxylate (12a)

[0348] tert-butyl 4-(5-(2-bromo-1-fluoroethyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0349] Weigh compound 11b (420 mg, 1.4 mmol, 1.0 equiv) into a 25 mL reaction flask and dissolve it in 10 mL of dichloromethane. Cool the reaction to 0 °C, then dropwise add a solution of hydrogen fluoride in triethylamine (338 mg, 2.1 mmol, 1.5 equiv), and add N-bromosuccinimide (300 mg, 1.68 mmol, 1.2 equiv) to the reaction solution. The reaction is allowed to warm to room temperature naturally and stirred for 1 h. After the reaction is complete, pour the reaction into 20 mL of ice water, adjust the aqueous phase to alkaline with concentrated ammonia water, extract with dichloromethane (3 × 40 mL), separate the organic phase, concentrate in vacuo and dry to obtain compound 12a, which is 344 mg of a pale yellow oil. 12a can be directly used in the next reaction without further purification.

[0350] LC-MS m / z (ESI) = 390.20 [M+1].

[0351] Step 2:

[0352] 4-(5-(1-Fluorovinyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (12b)

[0353] tert-butyl 4-(5-(1-fluorovinyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0354] Weigh compound 12a (344 mg, 0.88 mmol, 1.0 equiv) and potassium tert-butoxide (188 mg, 1.68 mmol, 1.2 equiv) separately into a 25 mL reaction flask, add tetrahydrofuran (10 mL) to dissolve, and then stir the reaction at 50 °C. After the reaction is complete, let the reaction solution cool to room temperature naturally, and then slowly add it to 30 mL of ice-water mixture. Extract with dichloromethane (3 × 40 mL), separate the organic phase, concentrate in vacuo, and purify by column chromatography (ethyl acetate: petroleum ether = 1:20) to obtain compound 12b as a white solid (128 mg, yield 47%).

[0355] 1 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 5.25 (dd, 1H), 4.82 (dd, 1H), 3.87 - 3.72 (m, 4H), 3.41 (t, 4H), 1.42 (s, 9H).

[0356] LC-MS m / z (ESI) = 309.30 [M+1].

[0357] Step 3:

[0358] 4-(5-(2,2,3-Trifluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (12c)

[0359] tert-butyl 4-(5-(2,2,3-trifluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0360] Weigh compound 12b (64 mg, 0.2 mmol, 1.0 equiv), anhydrous sodium iodide (6 mg, 0.04 mmol, 0.2 eq), and dissolve them in 5 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add (trifluoromethyl)trimethylsilane (74 μL, 0.5 mmol, 2.5 equiv) to the reaction. After addition, stir the reaction at 65 °C for 2 h. When the reaction is complete, concentrate the reaction solution under vacuum and purify it by column chromatography (ethyl acetate:petroleum ether = 1:15) to obtain compound 12c as a colorless oil (54 mg, yield 75%).

[0361] LC-MS m / z (ESI) = 359.33 [M+1].

[0362] Step 4:

[0363] 2-(Piperazin-1-yl)-5-(2,2,3-trifluorocyclopropyl)pyrimidine (Intermediate 12)

[0364] 2-(piperazin-1-yl)-5-(2,2,3-trifluorocyclopropyl)pyrimidine

[0365] Refer to the synthesis method of compound 2c to prepare a crude product of Intermediate 12, which is 47 mg of a white solid. Intermediate 12 can be directly used in the next reaction without further purification.

[0366] LC-MS m / z (ESI) = 259.30 [M+1].

[0367] Intermediate 13

[0368] 3-(5-Cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (Intermediate 13)

[0369] 3-(5-cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0370]

[0371] Step 1:

[0372] tert-Butyl 3-(5-cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (13a)

[0373] tert-butyl 3-(5-cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0374] 2-Chloro-5-cyclopropylpyrimidine 7a (300 mg, 2 mmol, 1.0 equiv) was weighed and dissolved in N,N-dimethylformamide (10 mL). tert-Butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (460 mg, 2.3 mmol, 1.2 equiv) and DIPEA (1.6 mL, 9.7 mmol, 5.0 equiv) were added successively, and the reaction was heated and stirred in an oil bath at 120 °C for 1 h. The reaction solution was cooled to room temperature and distilled under reduced pressure. Compound 13a was obtained by column chromatography (petroleum ether:ethyl acetate = 3:1) as a yellow oil (400 mg, yield 65%).

[0375] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 4.21 - 4.11 (m, 2H), 4.12 - 3.96 (m, 2H), 3.44 (d, 2H), 2.56 - 2.51 (m, 1H), 1.78 - 1.76 (m, 1H), 1.43 (d, 1H), 1.25 (s, 9H), 0.91 - 0.79 (m, 2H), 0.69 - 0.57 (m, 2H).

[0376] LC-MS m / z (ESI) = 317.20 [M+1].

[0377] Step 2:

[0378] 3-(5-Cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (Intermediate 13)

[0379] 3-(5-cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[0380] Referring to the synthesis method of Compound 2c, Intermediate 13 was prepared as a white solid. Intermediate 13 can be directly used in the next step of the reaction without further purification.

[0381] LC-MS m / z (ESI) = 217.20 [M+1].

[0382] Intermediate 14

[0383] 8-(5-Cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane (Intermediate 14)

[0384] 8-(5-cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane

[0385]

[0386] Refer to the synthesis method of Intermediate 13 to prepare the crude product of Intermediate 14, which is a white solid. Intermediate 14 can be directly used in the next reaction without further purification.

[0387] LC-MS m / z (ESI) = 231.20 [M+1].

[0388] Intermediate 15

[0389] 5-((2S)-1-(3-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Intermediate 15)

[0390] 5-(((2S)-1-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0391]

[0392]

[0393] First step:

[0394] tert-butyl 8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (15b)

[0395] tert-butyl 8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-propoxy)-propanoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0396] Weigh 15a (212 mg, 1.0 mmol, 1.0 equiv), intermediate 1 (401 mg, 1.3 mmol, 1.3 equiv), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (380 mg, 1.0 mmol, 1.0 equiv) into a 10 mL reaction flask, and dissolve them in N,N-dimethylformamide (4.0 mL). Add N,N-diisopropylethylamine (0.65 mL, 4.0 mmol, 4 equiv) to the mixture, and stir the reaction at 25 °C for 1 h. After the reaction is complete, concentrate the reaction mixture under vacuum. The residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 1:5) to obtain 15b, a white solid (307 mg, yield 61%).

[0397] LC-MS m / z (ESI) = 505.20 [M+1].

[0398] Step 2:

[0399] 5-((2S)-1-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (intermediate 15)

[0400] 5-(((2S)-1-(3-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0401] Refer to the synthesis method of reference compound 2c to prepare the crude product of intermediate 15, which is 100 mg of white solid. Intermediate 15 can be directly used for the next reaction without further purification.

[0402] LC-MS m / z (ESI) = 405.20 [M+1].

[0403] Intermediate 16

[0404] 5-cyclopropyl-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidine (intermediate 16)

[0405] 5-cyclopropyl-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidine

[0406]

[0407] Refer to the synthesis method of intermediate 13, and the crude product of intermediate 16 was prepared, which is a white solid. Intermediate 16 can be directly used in the next reaction without further purification.

[0408] LC-MS m / z(ESI) = 233.20[M+1].

[0409] Intermediate 17

[0410] 5-cyclopropyl-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidine (Intermediate 17)

[0411] 5-cyclopropyl-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidine

[0412]

[0413] Refer to the synthesis method of intermediate 13, and the crude product of intermediate 17 was prepared, which is a white solid. Intermediate 17 can be directly used in the next reaction without further purification.

[0414] LC-MS m / z(ESI) = 217.20[M+1].

[0415] Intermediate 18:

[0416] 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid (Intermediate 18)

[0417] 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid

[0418]

[0419] The first step:

[0420] tert-butyl 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate (18a)

[0421] tert-butyl 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate

[0422] Weigh compound 1g (550mg, 1.539mmol, 1.0equiv), tert-butyl 2-bromopropionate (479mg, 2.309mmol, 1.5equiv) and potassium tert-butoxide (259mg, 2.309mmol, 1.5equiv) successively in 11.0 mL of DMF, react at room temperature for 3 h, quench the reaction with 30 mL of water, then extract twice with 30 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 18a, which is a yellow solid (360mg, yield 48%).

[0423] LC-MS m / z (ESI) = 486.5 [M+1].

[0424] The second step:

[0425] 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid (Intermediate 18)

[0426] 2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoic acid

[0427] In a 20 mL single-necked flask, dissolve compound 18a (300mg, 0.618mmol, 1equiv) in 5 mL of DCM, then add 2 mL of trifluoroacetic acid, react at room temperature for 2 h. After the reaction is complete, concentrate the reaction mixture under vacuum. The residue is purified by C18 reversed-phase chromatography (water:acetonitrile = 3:2) to obtain Intermediate 18, which is a white solid (250mg, yield 94%).

[0428] LC-MS m / z (ESI) = 430.4 [M+1].

[0429] Intermediate 19

[0430] 3-((1-(1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid (Intermediate 19)

[0431] 3-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid

[0432]

[0433] Step 1:

[0434] 5-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (19a)

[0435] 5-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0436] Weigh 1f (1.5 g, 4.72 mmol, 1.0 equiv) into a 100 mL reaction flask, and dissolve it in N,N-dimethylformamide (15 mL). Subsequently, add diisopropylethylamine (3.3 mL, 18.87 mmol, 4.0 equiv) and pyrrol-2-ylmethanol (0.53 g, 5.19 mmol, 1.1 equiv) successively. Stir the mixture at 100 °C for 2 h. After the reaction is complete, concentrate it under vacuum, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Compound 19a, a white solid (1.59 g, yield 88%).

[0437] LC-MS m / z (ESI) = 384.15 [M+1].

[0438] Step 2:

[0439] Methyl 3-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoate (19b)

[0440] Methyl 3-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoate

[0441] Weigh compound 19a (1.59 g, 4.16 mmol, 1.0 equiv) and cesium carbonate (1.35 g, 4.16 mmol, 1.0 equiv) into a 50 mL reaction flask, and add acetonitrile (14 mL) to dissolve. Slowly add methyl prop-2-enoate (3.6 g, 41.55 mmol, 10.0 equiv) dropwise to the mixture. After addition, stir the reaction mixture at 30 °C for 4 h. After the reaction is complete, concentrate under vacuum, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 19b, a white solid (1.04 g, yield 53%).

[0442] LC-MS m / z (ESI) = 470.18 [M+1].

[0443] The third step:

[0444] 3-((1-(1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid (Intermediate 19)

[0445] 3-((1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoic acid

[0446] Weigh compound 19b (1.04 g, 2.217 mmol, 1.0 equiv) and lithium hydroxide monohydrate (265 mg, 11.09 mmol, 5.0 equiv) into a 50 mL reaction flask respectively. Subsequently, add methanol (5 mL) and water (5 mL) in sequence, and stir the reaction solution at 25 °C for 1 h. After the reaction is complete, adjust the pH value of the reaction mixture to 6 with trifluoroacetic acid. Concentrate the reaction mixture under vacuum, and purify the residue by C18 reversed-phase chromatography (water:acetonitrile = 5:1) to obtain Intermediate 19, a pale yellow solid (830 mg, yield 82%).

[0447] LC-MS m / z (ESI) = 456.17 [M+1].

[0448] Intermediate 20

[0449] 1-(5-Cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine (Intermediate 20)

[0450] 1-(5-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine

[0451]

[0452] Step 1:

[0453] tert-butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (20b)

[0454] tert-butyl 4-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0455] Weigh 20a (3.9 g, 15.00 mmol, 1.0 equiv), tert-butyl piperazine-1-carboxylate (5.54 g, 22.5 mmol, 1.5 equiv) and potassium carbonate (7.3 g, 52.5 mmol, 3.5 equiv) into a 250 mL reaction flask. Subsequently, add acetonitrile (40 mL) to dissolve the mixture, and heat and stir the reaction in an 80 °C oil bath for 2 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate it under vacuum, and purify it by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 20b as a white solid (1.4 g, yield 22.67%).

[0456] LC-MS m / z (ESI) = 409.06 [M+1].

[0457] Step 2:

[0458] tert-butyl-4-(5-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (20c)

[0459] tert-butyl-4-(5-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate

[0460] Into a 25 mL reaction flask, the weighed intermediate 20b (1.4 g, 3.40 mmol, 1.0 equiv), cesium carbonate (2.78 g, 8.50 mmol, 2.5 equiv), cyclopropylboronic acid (442 mg, 5.1 mmol, 1.5 equiv) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (277 mg, 0.34 mmol, 0.1 equiv) were added respectively. Subsequently, a Toulune / H2O (20 / 2 mL) mixture was added, the reaction system was evacuated and replaced with nitrogen for protection, and the reaction was heated and stirred in an oil bath at 95 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under vacuum, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 20c as a white solid (1.02 g, yield 79.41%).

[0461] LC-MS m / z(ESI) = 371.18[M+1]

[0462] The third step:

[0463] 1-(5-Cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine (intermediate 20)

[0464] 1-(5-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)piperazine

[0465] Referring to the synthesis method of reference compound 2c, intermediate 20 was prepared as a white solid (800 mg, yield 97%).

[0466] LC-MS m / z(ESI) = 271.18[M+1].

[0467] Intermediate 21

[0468] 5-Cyclopropyl-2-(piperazin-1-yl)nicotinonitrile (intermediate 21)

[0469] 5-cyclopropyl-2-(piperazin-1-yl)nicotinonitrile

[0470]

[0471] The first step:

[0472] 2-Chloro-5-cyclopropylnicotinonitrile (21b)

[0473] 2-chloro-5-cyclopropylnicotinonitrile

[0474] Into a 25 mL reaction flask, the weighed compound 21a (2.17 g, 10 mmol, 1.0 equiv), cesium carbonate (8.2 g, 25 mmol, 2.5 equiv), cyclopropylboronic acid (1.72 g, 20 mmol, 2.0 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (816 mg, 1 mmol, 0.1 equiv) were added respectively. Subsequently, a Toulune / H2O (20 / 2 mL) mixture was added, the reaction system was evacuated and filled with nitrogen for protection, and the reaction was heated and stirred in an oil bath at 95 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under vacuum, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 21b as a white solid (670 mg, yield 38.40%).

[0475] LC-MS m / z(ESI) = 178.03[M+1]

[0476] Step 2:

[0477] tert-butyl 4-(3-cyano-5-cyclopropylpyridin-2-yl)piperazine-1-carboxylate (21c)

[0478] tert-butyl 4-(3-cyano-5-cyclopropylpyridin-2-yl)piperazine-1-carboxylate

[0479] Refer to the synthesis method of intermediate 2b, and intermediate 21c was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a white solid (0.8 g, yield 63.80%).

[0480] LC-MS m / z(ESI) = 328.19[M+1].

[0481] Step 3:

[0482] 5-cyclopropyl-2-(piperazin-1-yl)nicotinonitrile (intermediate 21)

[0483] 5-cyclopropyl-2-(piperazin-1-yl)nicotinonitrile

[0484] Refer to the synthesis method of compound 2c, and intermediate 21 was prepared as a white solid. Intermediate 21 can be directly used in the next step of the reaction without further purification.

[0485] LC-MS m / z(ESI) = 228.19[M+1].

[0486] Intermediate 22

[0487] 2-cyclopropyl-5-(piperazin-1-yl)pyrazine (Intermediate 22)

[0488] 2-cyclopropyl-5-(piperazin-1-yl)pyrazine

[0489]

[0490] Step 1:

[0491] tert-butyl 4-(5-chloropyrazin-2-yl)piperazine-1-carboxylate (22b)

[0492] tert-butyl 4-(5-chloropyrazin-2-yl)piperazine-1-carboxylate

[0493] Refer to the synthesis method of Intermediate 2b, and purify it by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain Intermediate 22b, a pale yellow solid (2.0 g, yield 50%).

[0494] LC-MS m / z (ESI) = 298.12 [M+1].

[0495] Step 2:

[0496] tert-butyl 4-(5-cyclopropylpyrazin-2-yl)piperazine-1-carboxylate (22c)

[0497] tert-butyl 4-(5-cyclopropylpyrazin-2-yl)piperazine-1-carboxylate

[0498] Refer to the synthesis method of Intermediate 2, and purify it by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain Intermediate 22c, a white solid (0.9 g, yield 44%).

[0499] LC-MS m / z (ESI) = 304.19 [M+1]

[0500] Step 3:

[0501] 2-cyclopropyl-5-(piperazin-1-yl)pyrazine (Intermediate 22)

[0502] 2-cyclopropyl-5-(piperazin-1-yl)pyrazine

[0503] Refer to the synthesis method of Compound 2c to prepare Intermediate 22, a white solid. Intermediate 22 can be directly used in the next step of the reaction without further purification.

[0504] LC-MS m / z (ESI) = 204.19 [M+1].

[0505] Intermediate 23

[0506] 3-((S)-2-aminopropoxy)-1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)butan-1-one (Intermediate 23)

[0507] 3-((S)-2-aminopropoxy)-1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)butan-1-one

[0508]

[0509] The first step:

[0510] 1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-hydroxybutan-1-one (23a)

[0511] 1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-hydroxybutan-1-one

[0512] Weigh Intermediate 2 (139 mg, 0.50 mmol, 1.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol, 1.5 equiv), and 1-hydroxybenzotriazole (101 mg, 0.75 mmol, 1.5 equiv) into a 10 mL reaction flask and dissolve them with N,N-dimethylformamide (2.0 mL). Then, add N,N-diisopropylethylamine (331 μL, 2.0 mmol, 4 equiv) and 3-hydroxybutyric acid (57 mg, 0.55 mmol, 1.1 equiv) dropwise to the mixture in sequence. The reaction is stirred at 25 °C for 12 h. After the reaction is complete, the reaction mixture is concentrated under vacuum. The residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 1:5) to obtain Intermediate 23a as a pale yellow oil (135 mg, yield 60%).

[0513] LC-MS m / z (ESI) = 290.3 [M+1].

[0514] The second step:

[0515] tert-butyl ((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)carbamate (23b)

[0516] tert-butyl((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)carbamate

[0517] In a 50 mL reaction flask, weigh intermediate 23a (130 mg, 0.45 mmol, 1.0 equiv), and dissolve it in anhydrous N,N-dimethylformamide (4 mL). Under nitrogen protection, add sodium hydride (54 mg, 1.35 mmol, 3.0 equiv) portionwise at 0 °C. After addition, continue stirring at this temperature for 10 min. Subsequently, slowly dropwise add a solution of tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (160 mg, 0.68 mmol, 1.5 equiv) in N,N-dimethylformamide (7 mL) to the reaction system, maintaining the temperature at 0 °C during the addition process and continue stirring for 2 h. After the reaction is complete, adjust the reaction system to pH = 3 with hydrochloric acid solution (2 M) and stir at room temperature for 0.5 h. Extract the reaction mixture with ethyl acetate (3 × 120 mL). Combine the organic layers, dry over anhydrous sodium sulfate, concentrate in vacuo to obtain the crude product, and purify it by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 23b as a colorless oil (40 mg, yield 40%).

[0518] LC-MS m / z (ESI) = 448.6 [M+1].

[0519] The third step:

[0520] 3-((S)-2-aminopropoxy)-1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)butan-1-one (intermediate 23)

[0521] 3-((S)-2-aminopropoxy)-1-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)butan-1-one

[0522] Referring to the synthesis method of reference compound 2c, prepare the crude product of intermediate 23, which is a white solid. Intermediate 23 can be directly used in the next step of the reaction without further purification.

[0523] LC-MS m / z (ESI) = 348.5 [M+1].

[0524] Intermediate 24

[0525] 2-(Piperazin-1-yl)-5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidine (Intermediate 24)

[0526] 2-(piperazin-1-yl)-5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidine

[0527]

[0528] Step 1:

[0529] tert-butyl 4-(5-formylpyrimidin-2-yl)piperazine-1-carboxylate (24c)

[0530] tert-butyl 4-(5-formylpyrimidin-2-yl)piperazine-1-carboxylate

[0531] Referring to the synthesis method of Intermediate 2b, the crude product of Intermediate 24c was obtained, which was a white solid. Intermediate 24c could be directly used for the next reaction without further purification.

[0532] LC-MS m / z (ESI) = 293.40 [M+1].

[0533] Step 2:

[0534] tert-butyl 4-(5-(2,2-difluorovinyl)pyrimidin-2-yl)piperazine-1-carboxylate (24d)

[0535] tert-butyl 4-(5-(2,2-difluorovinyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0536] Weigh Intermediate 24c (2.83 g, 12 mmol, 1.0 equiv) and triphenylphosphine (4.72 g, 18.0 mmol, 1.5 equiv) into a 250 mL reaction flask, dissolve them with N,N-dimethylformamide (70 mL), and add sodium bromodifluoroacetate in batches under nitrogen protection (added within 10 min); after addition, the reaction was stirred at 90 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature and distilled under reduced pressure. Intermediate 24d was obtained by column chromatography (petroleum ether:ethyl acetate = 3:1), which was a yellow solid (2.1 g, yield 73%).

[0537] LC-MS m / z (ESI) = 327.40 [M+1].

[0538] Step 3:

[0539] 4-(5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (24e)

[0540] tert-butyl 4-(5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

[0541] Weigh the intermediate 24d (1.0 g, 3.1 mmol, 1.0 equiv) into a 100 mL reaction bottle, dissolve it in diethylene glycol dimethyl ether, and heat the reaction solution to 180°C under nitrogen protection. When the temperature rises to the specified temperature, add sodium chlorodifluoroacetate (1.65 g, 10.8 mmol, 3.5 equiv) in batches under nitrogen blowing; after the addition, stir and react for 4 h. After the reaction is complete, the residue is purified by C18 reverse phase chromatography (water: acetonitrile = 1:5) to obtain the intermediate 24e as a white solid (354.4 mg, yield 30%).

[0542] LC-MS m / z(ESI)=377.4[M+1].

[0543] Step 4:

[0544] 2-(Piperazin-1-yl)-5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidine (Intermediate 24)

[0545] 2-(piperazin-1-yl)-5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidine

[0546] Referring to the synthesis method of compound 2c, intermediate 24 was prepared as a white solid. Intermediate 24 can be directly used in the next reaction without further purification.

[0547] LC-MS m / z(ESI)=277.4[M+1].

[0548] Example 1

[0549] (S)-5-((1-(3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 1)

[0550] (S)-5-((1-(3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0551]

[0552] Weigh intermediate 1 (303 mg, 0.979 mmol, 1.0 equiv), intermediate 2 (200 mg, 0.979 mmol, 1.0 equiv), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (372 mg, 0.979 mmol, 1.0 equiv) into a 10 mL reaction flask and dissolve them in N,N-dimethylformamide (4.0 mL). Add N,N-diisopropylethylamine (0.65 mL, 3.916 mmol, 4 equiv) to the mixture. After addition, stir the reaction at 25 °C for 1 h. After the reaction is complete, concentrate it under vacuum. The residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 1:5) to obtain compound 1 as a white solid (125 mg, yield 25%).

[0553] 1 H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.21 (s, 2H), 7.66 (s, 1H), 5.78 (s, 1H), 3.97 - 3.80 (m, 6H), 3.72 - 3.71 (m, 2H), 3.64 (dd, 1H), 3.61 - 3.44 (m, 3H), 2.62 (t, 2H), 1.79 - 1.73 (m, 1H), 1.31 - 1.25 (m, 3H), 0.98 - 0.95 (m, 2H), 0.66 - 0.63 (m, 2H).

[0554] LCMS m / z = 496.5 [M+1].

[0555] Example 2

[0556] (S)-5-((1-(3-(4-(5-cyclobutylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 2)

[0557] (S)-5-((1-(3-(4-(5-cyclobutylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0558]

[0559] Referring to the synthesis method of reference compound 1, compound 2 was prepared as a white solid (157 mg, yield 34%).

[0560] 1 H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1H), 8.29 (s, 2H), 7.66 (s, 1H), 5.78 (d, 1H), 3.99 - 3.79 (m, 6H), 3.78 - 3.68 (m, 2H), 3.68 - 3.54 (m, 3H), 3.52 - 3.35 (m, 2H), 2.62 (t, 2H), 2.42 - 2.28 (m, 2H), 2.17 - 1.86 (m, 5H), 1.31 - 1.25 (m, 3H).

[0561] LCMS m / z = 510.6 [M+1].

[0562] Example 3

[0563] (S)-5-((1-(3-(4-(5-(1-fluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 3)

[0564] (S)-5-((1-(3-(4-(5-(1-fluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0565]

[0566] Referring to the synthesis method of reference compound 1, compound 3 was prepared as a white solid (70 mg, yield 42%).

[0567] 11H NMR (600 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.45 (d, 2H), 7.91 (s, 1H), 6.30 - 6.26 (m, 1H), 4.17 - 4.13 (m, 1H), 3.76 (t, 2H), 3.72 - 3.65 (m, 4H), 3.53 - 3.50 (m, 4H), 3.48 (d, 2H), 2.59 (t, 2H), 1.40 - 1.32 (m, 2H), 1.15 (d, 3H), 1.09 - 1.05 (m, 2H).

[0568] LCMS m / z = 514.4 [M+1].

[0569] Example 4

[0570] (S)-5-((1-(3-(4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 4)

[0571] (S)-5-((1-(3-(4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0572]

[0573] First step:

[0574] 1-(2-(Piperazin-1-yl)pyrimidin-5-yl)cyclobutanol (4A)

[0575] 1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclobutan-1-ol

[0576] Referring to the synthetic method of Intermediate 2c, the crude product of Compound 4A was obtained as a white solid. Compound 4A can be directly used in the next step reaction without further purification.

[0577] LCMS m / z = 235.2 [M+1].

[0578] Second step:

[0579] (S)-5-((1-(3-(4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 4)

[0580] (S)-5-((1-(3-(4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0581] Referring to the synthesis method of Reference Compound 1, Compound 4 was prepared as a white solid (70 mg, yield 26%).

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.47 (s, 2H), 7.91 (s, 1H), 6.31 - 6.27 (m, 1H), 5.59 (s, 1H), 4.23 - 4.03 (m, 1H), 3.74 - 3.64 (m, 6H), 3.52 - 3.47 (m, 6H), 2.58 (t, 2H), 2.40 - 2.34 (m, 2H), 2.27 - 2.20 (m, 2H), 1.86 - 1.77 (m, 1H), 1.61 - 1.49 (m, 1H), 1.14 (d, 3H).

[0583] LCMS m / z = 526.3 [M+1].

[0584] Example 5

[0585] 5-(((S)-1-(3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 5)

[0586] 5-(((S)-1-(3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0587]

[0588] Referring to the synthesis method of reference compound 1, compound 5 was prepared as a white solid (280 mg, yield 53%).

[0589] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.18 (s, 2H), 7.91 (s, 1H), 6.28 (dd, 1H), 4.50 (d, 3H), 4.23 - 4.06 (m, 2H), 3.69 (s, 2H), 3.48 (d, 2H), 3.03 - 2.85 (m, 2H), 2.72 - 2.57 (m, 1H), 2.42 (s, 2H), 1.80 - 1.72 (m, 1H), 1.18 - 1.00 (m, 8H), 0.96 - 0.76 (m, 2H), 0.71 - 0.53 (m, 2H).

[0590] LCMS m / z = 524.3 [M+1].

[0591] Example 6

[0592] 5 - (((S)-1-(3-((2R,6S)-2,6-dimethyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)cyclobutoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 6)

[0593] N-(1-(5-cyclopropylpyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)-3-((S)-3-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)butoxy)propanamide

[0594]

[0595] Referring to the synthesis method of reference compound 1, compound 6 was prepared as a white solid (60 mg, yield 82%).

[0596] 11H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.20 (s, 2H), 8.13 (d, 1H), 7.90 (s, 1H), 6.26 (d, 1H), 4.84 - 4.74 (m, 1H), 4.47 (dd, 3H), 4.12 (s, 2H), 3.68 - 3.56 (m, 2H), 3.48 - 3.42 (m, 2H), 3.16 (t, 1H), 2.40 - 2.37 (m, 2H), 1.80 - 1.73 (m, 2H), 1.60 - 1.49 (m, 1H), 1.15 (s, 1H), 1.13 (s, 1H), 0.93 - 0.83 (m, 2H), 0.67 - 0.61 (m, 2H).

[0597] LCMS m / z = 560.54 [M+1].

[0598] Example 7

[0599] (S)-5-((1-(3-(4-(5-(1-Hydroxycyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 7)

[0600] (S)-5-((1-(3-(4-(5-(1-hydroxycyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0601]

[0602] The first step:

[0603] 1-(2-(Piperazin-1-yl)pyrimidin-5-yl)cyclopropan-1-ol (7A)

[0604] 1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropan-1-ol

[0605] Referring to the synthesis method of Intermediate 2c, the crude product of Compound 7A was prepared. Compound 7A can be directly used in the next step of the reaction without further purification.

[0606] LCMS m / z = 221.3 [M+1].

[0607] The second step:

[0608] (S)-5-((1-(3-(4-(5-(1-hydroxycyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 7)

[0609] (S)-5-((1-(3-(4-(5-(1-hydroxycyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0610] Referring to the synthetic method of Reference Compound 1, Compound 7 was prepared as a white solid (16 mg, yield 6%).

[0611] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.29 (s, 2H), 7.91 (s, 1H), 6.31 - 6.26 (m 1H), 5.96 (s, 1H), 4.20 - 4.11 (m, 1H), 3.85 (d, 1H), 3.71 - 3.64 (m, 5H), 3.54 (d, 1H), 3.51 - 3.46 (m, 5H), 2.58 (t, 2H), 1.14 (d, 3H), 1.02 - 0.96 (m, 2H), 0.90 - 0.85 (m, 2H).

[0612] LCMS m / z = 512.3 [M+1].

[0613] Example 8

[0614] (S)-5-((1-(3-(7-(5-cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 8)

[0615] (S)-5-((1-(3-(7-(5-cyclopropylpyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0616]

[0617] Referring to the synthetic method of Reference Compound 1, Compound 8 was prepared as a white solid (40 mg, yield 25%).

[0618] 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.14 (s, 2H), 7.89 (s, 1H), 6.26 - 6.23 (m, 1H), 4.13 (t, 1H), 3.81 - 3.40 (m, 9H), 2.71 (t, 2H), 2.52 (s, 1H), 1.78 - 1.71 (m, 1H), 1.11 (d, 3H), 1.06 - 0.70 (m, 6H), 0.65 - 0.57 (m, 2H).

[0619] LCMS m / z = 522.3 [M+1].

[0620] Example 9

[0621] N-((1R,5S)-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide (Compound 9)

[0622] N-((1R,5S)-3-(5-cyclopropylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide

[0623]

[0624] Referring to the synthetic method of Reference Compound 1, Compound 9 was prepared as a white solid (76 mg, yield 50%).

[0625] 11H NMR (600 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.13 (s, 2H), 8.02 (d, 1H), 7.90 (s, 1H), 6.27 (dd, 1H), 4.13 (t, 1H), 3.75 (dd, 2H), 3.68 - 3.56 (m, 2H), 3.45 - 3.41 (m, 4H), 2.52 (d, 1H), 2.33 - 2.31 (m, 1H), 2.25 (t, 2H), 1.80 - 1.66 (m, 3H), 1.14 (d, 3H), 0.92 - 0.80 (m, 2H), 0.65 - 0.54 (m, 2H).

[0626] LCMS m / z = 508.3 [M+1].

[0627] Example 10

[0628] (S)-5-((1-(2-(4-(5-Cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 10)

[0629] (S)-5-((1-(2-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0630]

[0631] The first step:

[0632] (S)-5-((1-(2-(4-(5-Cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (10A)

[0633] (S)-5-((1-(2-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0634] Referring to the synthesis method of Compound 1, Compound 10A was prepared as a white solid product (200 mg, yield 63%).

[0635] LC-MS m / z (ESI) = 602.6 [M+1].

[0636] Step 2:

[0637] (S)-5-((1-(2-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 10)

[0638] (S)-5-((1-(2-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0639] To a 25 mL reaction flask containing Compound 10A (200 mg, 0.33 mmol, 1.0 equiv), trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL, 2.64 mmol, 8.0 equiv) were added successively. After addition, the reaction was stirred at 25 °C for 2 h. Subsequently, 15 mL of water was added to the reaction solution to quench it. Extraction was carried out with ethyl acetate (3 × 20 mL), and the pH of the organic layer was adjusted to 8 - 9 with an aqueous potassium carbonate solution. The organic layers were combined and concentrated in vacuo, and the residue was purified by reverse phase (water:acetonitrile = 3:2) to obtain Compound 10, a white solid (105 mg, yield 62%).

[0640] 1 1H NMR (600 MHz, DMSO) δ 12.47 (s, 1H), 8.19 (s, 2H), 7.94 (s, 1H), 6.66 (dd, 1H), 4.41 - 4.09 (m, 3H), 3.76 - 3.61 (m, 4H), 3.54 (d, 2H), 3.50 (dd, 2H), 3.40 (t, 2H), 1.82 - 1.71 (m, 1H), 1.17 (d, 3H), 0.93 - 0.81 (m, 2H), 0.68 - 0.59 (m, 2H).

[0641] LC-MS m / z (ESI) = 482.2 [M+1].

[0642] Example 11

[0643] 5-((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 11)

[0644] 5-(((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0645]

[0646] Step 1:

[0647] (S)-3-(hydroxymethyl)-4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazine-1-carboxylic acid tert-butyl ester (11B)

[0648] tert-butyl (S)-3-(hydroxymethyl)-4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazine-1-carboxylate

[0649] Referring to the synthesis method of Compound 1, Compound 11B was prepared as a white solid (320 mg, 97%).

[0650] LC-MS m / z (ESI) = 508.3 [M+1].

[0651] Step 2:

[0652] 5-((S)-1-(3-((S)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (11C)

[0653] 5-(((S)-1-(3-((S)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0654] Refer to the synthetic method of Intermediate 2c to prepare the crude product of Compound 11C. 11C can be directly applied to the next reaction without further purification.

[0655] LC-MS m / z (ESI) = 408.3 [M+1].

[0656] The third step:

[0657] 5-((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 11)

[0658] 5-(((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0659] Dissolve Compound 11C (200 mg, 0.416 mmol, 1.0 equiv) in N,N-dimethylacetamide (2.0 mL), and successively add Intermediate 7a (70.7 mg, 0.46 mmol, 1.1 equiv) and N,N-diisopropylethylamine (0.36 mL, 2.08 mmol, 5.0 equiv). After addition, the reaction is stirred at 120 °C for 5 h. After the reaction is complete, the reaction mixture is concentrated in vacuo. The residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 1:1.5) to obtain Compound 11 as a white solid (30 mg, 14%).

[0660] 11H NMR (600 MHz, DMSO-d6) δ 12.47 (d, 1H), 8.18 (d, 2H), 7.92 (s, 1H), 6.29 - 6.27 (m, 1H), 4.63 - 4.42 (m, 2H), 4.32 - 4.25 (m, 1H), 4.17 - 4.12 (m, 1H), 4.03 (d, J = 9.6 Hz, 1H), 3.67 (t, 2H), 3.49 (d, 1H), 3.44 - 3.34 (m, 4H), 3.30 - 3.20 (m, 1H), 3.01 - 2.99 (m, 1H), 2.80 - 2.69 (m, 2H), 2.65 - 2.57 (m, 1H), 1.78 - 1.74 (m, 1H), 1.15 (d, 3H), 0.95 - 0.79 (m, 2H), 0.69 - 0.57 (m, 2H).

[0661] LC-MS m / z (ESI) = 526.23 [M+1].

[0662] Example 12

[0663] (S)-1-(2-(4-(3-(2-(((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile (Compound 12)

[0664] (S)-1-(2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile

[0665]

[0666] Referring to the synthetic method of Reference Compound 1, Compound 12 was prepared as a white solid (98 mg, yield 34%).

[0667] 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.30 (s, 2H), 7.90 (s, 1H), 6.34 - 6.28 (m 1H), 5.96 (s, 1H), 4.19 - 4.10 (m, 1H), 3.87 (d, 1H), 3.73 - 3.62 (m, 5H), 3.54 - 3.52 (m, 2H), 3.50 - 3.44 (m, 4H), 2.44 (t, 2H), 1.20 (d, 3H), 1.00 - 0.95 (m, 2H), 0.90 - 0.87 (m, 2H).

[0668] LC-MS m / z = 521.50 [M+1].

[0669] Example 13

[0670] 5-(((S)-1-(3-(4-(5-((R)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13-1)

[0671] 5-(((S)-1-(3-(4-(5-((R)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0672] 5-(((S)-1-(3-(4-(5-((S)-2,2-difluorocyclopropyl))pyrimidin-2-yl)piperidin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13-2)

[0673] 5-(((S)-1-(3-(4-(5-((S)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0674]

[0675] The first step:

[0676] 5-(((S)-1-(3-(4-(5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13)

[0677] 5-(((S)-1-(3-(4-(5-(2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0678] Referring to the synthetic method of Compound 1, Compound 13 was prepared as a white solid (98 mg, yield 34%).

[0679] LCMS m / z = 521.50 [M+1].

[0680] Second step:

[0681] 5-(((S)-1-(3-(4-(5-((R)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13-1)

[0682] 5-(((S)-1-(3-(4-(5-((R)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0683] 5-(((S)-1-(3-(4-(5-((S)-2,2-difluorocyclopropyl))pyrimidin-2-yl)piperidin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 13-2)

[0684] 5-(((S)-1-(3-(4-(5-((S)-2,2-difluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0685] The racemate 13 was resolved by SFC to give Compound 13-1 (27 mg, ee%: 100%, chiral HPLC (OX-3); mobile phase: n-hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 11.738 min) and Compound 13-2 (24 mg, ee%: 97.18%, chiral HPLC (OX-3); mobile phase: n-hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 18.869 min).

[0686] Compound 13-1: 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 7.87 (s, 1H), 6.23 (dd, 1H), 6.05 (s, 1H), 5.00 (s, 2H), 4.45 (dd, 1H), 4.36 - 4.26 (m, 2H), 4.15 - 4.09 (m, 2H), 3.33 - 3.18 (m, 2H), 1.33 (d, 3H), 1.12 (d, 3H).

[0687] Compound 13-2: 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 7.86 (s, 1H), 6.25 (dd, 1H), 6.10 (s, 1H), 5.08 (s, 2H), 4.43 (dd, 1H), 4.31 - 4.24 (m, 2H), 4.14 - 4.06 (m, 2H), 3.39 - 3.24 (m, 2H), 1.31 (d, 3H), 1.13 (d, 3H).

[0688] Example 14

[0689] 5-(((S)-1-(3-oxo-3-(4-(5-((R)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14-1)

[0690] 5-(((S)-1-(3-oxo-3-(4-(5-((S)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0691] 5-(((S)-1-(3-oxo-3-(4-(5-((S)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14-2)

[0692] 5-(((S)-1-(3-oxo-3-(4-(5-((R)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0693]

[0694] Step 1:

[0695] 5-(((S)-1-(3-oxo-3-(4-(5-(1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14)

[0696] 5-(((2S)-1-(3-oxo-3-(4-(5-(1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0697] Referring to the synthetic method of Compound 1, Compound 14 was prepared as a white solid (51 mg, yield 46%).

[0698] LCMS m / z = 550.40 [M+1].

[0699] Step 2:

[0700] 5-(((S)-1-(3-oxo-3-(4-(5-((R)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14-1)

[0701] 5-(((S)-1-(3-oxo-3-(4-(5-((S)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0702] 5-(((S)-1-(3-oxo-3-(4-(5-((S)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 14-2)

[0703] 5-(((S)-1-(3-oxo-3-(4-(5-((R)-1,2,2-trifluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0704] The racemate 14 was resolved by SFC to give Compound 14-1 (30 mg, ee%: 100%, chiral HPLC (OX-3); mobile phase: hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm @ 4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 15.850 min) and Compound 14-2 (29 mg, ee%: 100%, chiral HPLC (OX-3); mobile phase: hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm @ 4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 16.936 min).

[0705] Compound 14-1: 11H NMR (600 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.59 (d, 2H), 7.92 (s, 1H), 6.28 (dd, 1H), 4.17 - 4.13 (m, 1H), 3.80 (t, 2H), 3.76 (dd, 2H), 3.71 - 3.64 (m, 2H), 3.53 (t, 4H), 3.49 (d, 2H), 2.59 (t, 3H), 2.47 - 2.38 (m, 1H), 1.15 (d, 3H).

[0706] Compound 14-2: 1 1H NMR (600 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.59 (d, 2H), 7.91 (s, 1H), 6.28 (dd, 1H), 4.15 (t, 1H), 3.80 (t, 2H), 3.76 (t, 2H), 3.72 - 3.63 (m, 2H), 3.57 - 3.46 (m, 6H), 2.67 - 2.57 (m, 3H), 2.47 - 2.37 (m, 1H), 1.15 (d, 3H).

[0707] Example 15

[0708] 5-((2S)-1-(3-(3-(5-Cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 15)

[0709] 5-(((2S)-1-(3-(3-(5-cyclopropylpyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0710]

[0711]

[0712] Referring to the synthetic method of Compound 1, Compound 15 was prepared as a white solid (270 mg, yield 44%).

[0713] 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.18 - 8.14 (m, 2H), 7.81 (d, 1H), 6.20 (s, 1H), 4.61 (s, 1H), 4.38 - 4.36 (m, 1H), 4.00 - 3.96 (m, 1H), 3.90 - 3.79 (m, 2H), 3.70 - 3.65 (m, 1H), 3.61 - 3.56 (m, 3H), 3.41 - 3.73 (m, 1H), 2.59 (d, 1H), 2.42 - 2.31 (m, 1H), 2.29 - 2.20 (m, 1H), 1.77 - 1.79 (m, 1H), 1.53 (d, 1H), 1.03 - 1.01 (m, 3H), 0.87 - 0.82 (m, 2H), 0.61 - 0.55 (m, 2H).

[0714] LCMS m / z = 508.10 [M+1].

[0715] Example 16

[0716] 5 - ((2S)-1-(3-(8-(5-cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 16)

[0717] 5 - (((2S)-1-(3-(8-(5-cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0718]

[0719] Compound 16 was prepared according to the synthetic method of Reference Compound 1 as a white solid (128 mg, yield 20%).

[0720] 11H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.17 (d, 2H), 7.91 (s, 1H), 6.28 (s, 1H), 4.99 - 4.55 (m, 2H), 4.34 - 4.06 (m, 3H), 3.68 (t, 2H), 3.48 (t, 2H), 3.20 - 3.08 (m, 1H), 2.95 (dd, 1H), 2.78 - 2.64 (m, 1H), 1.81 - 1.70 (m, 1H), 1.14 (d, 3H), 1.10 (d, 1H), 1.02 (dd, 3H), 0.96 (d, 1H), 0.89 - 0.82 (m, 2H), 0.65 - 0.59 (m, 2H).

[0721] LCMS m / z = 522.10 [M+1].

[0722] Example 17

[0723] 5 - ((2S)-1-(3-(3-(5-cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 17)

[0724] 5 - (((2S)-1-(3-(3-(5-cyclopropylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0725]

[0726] Weigh 2-chloro-5-cyclopropylpyrimidine 7a (92 mg, 0.6 mmol, 1.0 equiv) and dissolve it in N,N-dimethylformamide (10 mL). Then add intermediate 15 (240 mg, 0.6 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.5 mL, 3 mmol, 5.0 equiv) in sequence, and heat and stir the reaction in an oil bath at 120 °C for 1 h. Cool the reaction solution to room temperature and distill it under reduced pressure. The residue is purified by C18 reverse-phase chromatography (water:acetonitrile = 1:5) to obtain Compound 17 as a white solid (78 mg, yield 25%).

[0727] 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.15 (d, 2H), 7.89 (d, 1H), 6.26 (dd, 1H), 4.59 (d, 1H), 4.46 - 4.08 (m, 6H), 3.71 - 3.63 (m, 2H), 3.48 (d, 2H), 2.98 (dd, 1H), 2.94 - 2.82 (m, 1H), 2.62 - 2.52 (m, 1H), 1.90 - 1.81 (m, 1H), 1.67 (d, 1H), 1.65 - 1.45 (m, 2H), 1.12 (dd, 3H), 0.90 - 0.79 (m, 2H), 0.68 - 0.54 (m, 2H).

[0728] LC-MS m / z (ESI) = 522.20 [M+1].

[0729] Example 18

[0730] 5 - ((S)-1-(3-((2R,5S)-4-(5-cyclopropylpyrimidin-2-yl)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 18)

[0731] 5 - (((S)-1-(3-((2R,5S)-4-(5-cyclopropylpyrimidin-2-yl)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0732]

[0733]

[0734] Referring to the synthetic method of Compound 1, Compound 18 was prepared as a white solid (40 mg, yield 50%).

[0735] 11H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.17 (d, 2H), 7.91 (s, 1H), 6.28 (s, 1H), 4.89 - 4.59 (m, 2H), 4.26 (d, 1H), 4.24 - 4.06 (m, 2H), 3.68 (t, 2H), 3.48 (t, 2H), 3.44 - 3.40 (m, 1H), 3.20 - 3.16 (m, 1H), 3.12 - 3.01 (m, 1H), 2.98 - 2.93 (m, 1H), 1.85 - 1.67 (m, 1H), 1.14 (d, 3H), δ 1.12 - 0.94 (m, 6H), 0.90 - 0.82 (m, 2H), 0.67 - 0.56 (m, 2H).

[0736] LC-MS m / z (ESI) = 524.20 [M+1].

[0737] Example 19

[0738] 5 - ((2S)-1-(3-(5-(5-cyclopropylpyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 19)

[0739] 5 - (((2S)-1-(3-(5-(5-cyclopropylpyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0740]

[0741] Compound 19 was prepared according to the synthetic method of Reference Compound 1 as a white solid (80 mg, yield 31%).

[0742] 11H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.13 (s, 2H), 7.85 (d, 1H), 6.28 - 6.21 (m, 1H), 4.86 - 4.69 (m, 2H), 4.06 (d, 1H), 3.69 - 3.56 (m, 2H), 3.53 (d, 1H), 3.49 - 3.44 (m, 2H), 3.39 (d, 2H), 3.31 - 3.27 (m, 1H), 2.65 - 2.53 (m, 2H), 2.36 - 2.25 (m, 1H), 1.89 (d, 1H), 1.77 - 1.70 (m, 1H), 1.13 - 1.01 (m, 3H), 0.86 - 0.83 (m, 2H), 0.63 - 0.51 (m, 2H).

[0743] LC-MS m / z (ESI) = 508.20 [M+1].

[0744] Example 20

[0745] 5 - ((S)-1-(3 - ((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20-1)

[0746] 5 - (((S)-1-(3 - ((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0747] 5 - ((S)-1-(3 - ((R)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20-2)

[0748] 5 - (((S)-1-(3 - ((R)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0749]

[0750] The first step:

[0751] Tert-butyl 3-methyl-4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)piperazine-1-carboxylate (20B)

[0752] tert-butyl 3-methyl-4-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazine-1-carboxylate

[0753] Referring to the synthesis method of compound 1, compound 20B was prepared as a white solid (230 mg, yield 72%).

[0754] LC-MS m / z(ESI)=492.51[M+1].

[0755] Step 2:

[0756] 5-((2S)-1-(3-(2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (20C)

[0757] 5-(((2S)-1-(3-(2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0758] Referring to the synthesis method of intermediate 2c, a crude compound 20C was prepared as a white solid. Compound 20C can be directly used in the next reaction without further purification.

[0759] LC-MS m / z(ESI)=392.40[M+1].

[0760] Step 3:

[0761] 5-((2S)-1-(3-(4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20)

[0762] 5-(((2S)-1-(3-(4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0763] Refer to the synthetic method of reference compound 19 to prepare compound 20, which is a white solid (140 mg, yield 40%).

[0764] LC-MS m / z (ESI) = 510.53 [M+1].

[0765] Fourth step:

[0766] 5-((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20-1)

[0767] 5-(((S)-1-(3-((S)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0768] 5-((S)-1-(3-((R)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 20-2)

[0769] 5-(((S)-1-(3-((R)-4-(5-cyclopropylpyrimidin-2-yl)-2-methylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0770] The racemic compound 20 was resolved by SFC to give compound 20-1 (35 mg, ee%: 99.74%, chiral HPLC (OX-3); mobile phase: n-hexane: isopropanol = 80:20; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 8.157 min) and compound 20-2 (29 mg, ee%: 98.80%, chiral HPLC (OX-3); mobile phase: n-hexane: isopropanol = 80:20; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 6.596 min).

[0771] Compound 20-1: 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.17 (s, 2H), 7.91 (s, 1H), 6.29 - 6.26 (m, 1H), 4.61 (s, 1H), 4.48 (d, 1H), 4.35 (d, 2H), 4.23 (d, 1H), 4.15 (t, 2H), 3.76 (d, 1H), 3.66 (t, 2H), 3.47 (d, 2H), 3.05 (t, 1H), 3.00 - 2.89 (m, 1H), 2.83 (q, 1H), 1.79 - 1.72 (m, 1H), 1.14 (d, 3H), 1.07 (d, 1H), 0.98 (d, 1H), 0.89 - 0.83 (m, 2H), 0.65 - 0.60 (m, 2H).

[0772] LC-MS m / z (ESI) = 510.60 [M+1].

[0773] Compound 20-2: 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.17 (s, 2H), 7.91 (s, 1H), 6.29 - 6.26 (m, 1H), 4.62 (s, 1H), 4.48 (d, 1H), 4.37 (t,, 2H), 4.23 (d,, 1H), 4.14 (t, 2H), 3.75 (d, 1H), 3.66 (d, 2H), 3.47 (d, 2H), 3.04 (s, 1H), 2.94 (s, 1H), 2.81 (t, 1H), 1.79 - 1.72 (m, 1H), 1.14 (d, 3H), 1.07 (d, 1H), 0.98 (d, 1H), 0.89 - 0.83 (m, 2H), 0.66 - 0.60 (m, 2H).

[0774] Example 21

[0775] 5 - ((S)-1-(3 - ((2S,5R)-4-(5 - cyclopropylpyrimidin - 2 - yl)-2,5 - dimethylpiperazin - 1 - yl)-3 - oxopropoxy)propan - 2 - yl)amino)-4-(trifluoromethyl)pyridazin - 3(2H)-one (Compound 21)

[0776] 5 - (((S)-1-(3 - ((2S,5R)-4-(5 - cyclopropylpyrimidin - 2 - yl)-2,5 - dimethylpiperazin - 1 - yl)-3 - oxopropoxy)propan - 2 - yl)amino)-4-(trifluoromethyl)pyridazin - 3(2H)-one

[0777]

[0778] The first step:

[0779] tert - butyl (2R,5S)-2,5 - dimethyl - 4-(3 - ((S)-2 - ((6 - oxo - 5 - (trifluoromethyl)-1,6 - dihydropyridazin - 4 - yl)amino)propoxy)propanoyl)piperazine - 1 - carboxylate (21B)

[0780] tert - butyl (2R,5S)-2,5 - dimethyl - 4-(3 - ((S)-2 - ((6 - oxo - 5 - (trifluoromethyl)-1,6 - dihydropyridazin - 4 - yl)amino)propoxy)propanoyl)piperazine - 1 - carboxylate

[0781] Referring to the synthetic method of Compound 1, Compound 21B was prepared as a white solid (120 mg, yield 61%).

[0782] LC-MS m / z (ESI) = 506.54 [M+1].

[0783] Second step:

[0784] 5-((S)-1-(3-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (21C)

[0785] 5-(((S)-1-(3-((2S,5R)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0786] Referring to the synthetic method of Intermediate 2c, the crude product of Compound 21C was prepared as a white solid. Compound 21C can be directly applied to the next reaction without further purification.

[0787] LC-MS m / z (ESI) = 406.42 [M+1].

[0788] Third step:

[0789] 5-((S)-1-(3-((2S,5R)-4-(5-cyclopropylpyrimidin-2-yl)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 21)

[0790] 5-(((S)-1-(3-((2S,5R)-4-(5-cyclopropylpyrimidin-2-yl)-2,5-dimethylpiperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0791] Referring to the synthetic method of Compound 19, Compound 21 was prepared as a white solid (40 mg, yield 23%).

[0792] 11H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.17 (d, 2H), 7.91 (s, 1H), 6.32 - 6.25 (m, 1H), 4.85 - 4.66 (m, 2H), 4.25 (s, 1H), 4.24 - 4.11 (m, 2H), 3.74 - 3.63 (m, 2H), 3.48 (t, 2H), 3.41 (m, 1H), 3.22 - 3.15 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 1.74 (m, 1H), 1.14 (m, 3H), 1.11 - 0.94 (m, 6H), 0.86 (m, 2H), 0.66 - 0.59 (m, 2H).

[0793] LC-MS m / z (ESI) = 524.56 [M+1].

[0794] Example 22

[0795] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide (Compound 22)

[0796] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide

[0797]

[0798] The first step:

[0799] tert-Butyl (3R,4R)-3-hydroxy-4-(2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide)piperidine-1-carboxylate (22B)

[0800] tert-butyl(3R,4R)-3-hydroxy-4-(2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamido)piperidine-1-carboxylate

[0801] Referring to the synthetic method of reference compound 1, compound 22B was prepared as a white solid (220 mg, yield 60%).

[0802] LC-MS m / z (ESI) = 628.66 [M+1].

[0803] Second step:

[0804] N-((3R,4R)-3-hydroxypiperidin-4-yl)-2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide (22C)

[0805] N-((3R,4R)-3-hydroxypiperidin-4-yl)-2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide

[0806] Referring to the synthetic method of reference compound 2c, the crude product of compound 22C was prepared as a white solid. Compound 22C can be directly applied to the next reaction without further purification.

[0807] LC-MS m / z (ESI) = 528.55 [M+1].

[0808] Third step:

[0809] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propylamine (22D)

[0810] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide

[0811] Referring to the synthesis method of reference compound 19, compound 22D was prepared as a white solid (110 mg, yield 45%).

[0812] LC-MS m / z (ESI) = 646.68 [M+1].

[0813] Fourth step:

[0814] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propionamide (compound 22)

[0815] N-((3R,4R)-1-(5-cyclopropylpyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanamide

[0816] Referring to the synthesis method of intermediate 1i, compound 22 was prepared as a white solid (41 mg, yield 45%).

[0817] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (d, J = 24.8 Hz, 1H), 8.16 (s, 2H), 7.95 (d, 1H), 7.55 - 7.52 (m, 1H), 6.49 - 6.29 (m, 1H), 4.68 - 4.43 (m, 2H), 4.16 (s, 1H), 3.85 - 3.78 (m, 1H), 3.72 - 3.64 (m, 1H), 3.46 - 3.29 (m, 5H), 2.78 (d, 2H), 1.79 - 1.73 (m, 2H), 1.20 - 1.14 (m, 6H), 0.90 - 0.81 (m, 2H), 0.65 - 0.57 (m, 2H).

[0818] LC-MS m / z (ESI) = 526.53 [M+1].

[0819] Example 23

[0820] (R)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 23-1)

[0821] (R)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0822] (S)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 23-2)

[0823] (S)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0824]

[0825]

[0826] The first step:

[0827] 2-(4-methoxybenzyl)-5-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (23A)

[0828] 2-(4-methoxybenzyl)-5-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0829] Referring to the synthesis method of reference compound 1, compound 23A was prepared as a white solid (810 mg, yield 66%).

[0830] LC-MS m / z (ESI) = 670.25 [M+1].

[0831] Second step:

[0832] 5-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 23)

[0833] 5-(2-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0834] Referring to the synthesis method of reference intermediate 1i, compound 23 was prepared as a white solid (485 mg, yield 73%).

[0835] LC-MS m / z (ESI) = 550.19 [M+1].

[0836] Third step:

[0837] (R)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 23-1)

[0838] (R)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0839] (S)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 23-2)

[0840] (S)-5-(2-((3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0841] The racemic compound 23 was resolved by SFC to give compound 23-1 (54 mg, ee%: 100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol = 70: 30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm @ 4.8 nm; diode array detector starting wavelength: 200 nm; diode array detector end wavelength: 400 nm; RT = 11.738 min) and compound 23-2 (56 mg, ee%: 97.18%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol = 70: 30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm @ 4.8 nm; diode array detector starting wavelength: 200 nm; diode array detector end wavelength: 400 nm; RT = 18.869 min).

[0842] Compound 23-1: 11H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.19 (s, 2H), 8.01 (s, 1H), 4.56 - 4.47 (m, 1H), 3.69 - 3.58 (m, 6H), 3.52 - 3.44 (m, 7H), 3.22 - 3.16 (m, 1H), 2.55 - 2.52 (m, 2H), 2.06 (q, J = 6.4 Hz, 1H), 1.87 (d, J = 5.1 Hz, 1H), 1.76 (d, J = 5.2 Hz, 1H), 1.62 (d, J = 3.8 Hz, 2H), 0.90 - 0.83 (m, 2H), 0.66 - 0.60 (m, 2H).

[0843] LC-MS m / z (ESI) = 550.19 [M+1].[

[0844] Compound 23-2: 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.19 (s, 2H), 8.01 (s, 1H), 4.53 - 4.50 (m, 1H), 3.70 - 3.57 (m, 6H), 3.52 - 3.44 (m, 7H), 3.22 - 3.18 (m, 1H), 2.55 - 2.51 (m, 2H), 2.10 - 2.03 (m, 1H), 1.87 (d, J = 5.0 Hz, 1H), 1.82 - 1.72 (m, 1H), 1.62 (t, J = 5.2 Hz, 2H), 0.90 - 0.83 (m, 2H), 0.66 - 0.60 (m, 2H).

[0845] LC-MS m / z (ESI) = 550.19 [M+1].[

[0846] Example 24

[0847] 5-((R)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24-1)

[0848] 5-((E)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0849] 5-((S)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24-2)

[0850] 5-((S)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0851]

[0852]

[0853] Step 1:

[0854] 5-(2-((3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (24A)

[0855] 5-(2-((3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0856] Referring to the synthesis method of Compound 1, Compound 24A was prepared as a yellow oil (300 mg, yield 45%).

[0857] LCMS m / z = 670.33 [M+1].

[0858] Step 2:

[0859] 5-(2-((3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24)

[0860] 5-(2-((3-((2R,6S)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0861] Referring to the synthesis method of Intermediate 1i, Compound 24 was prepared as a white solid (180 mg, yield 73%).

[0862] LC-MS m / z (ESI) = 550.27 [M+1].

[0863] Step 3:

[0864] 5-((R)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24-1)

[0865] 5-((R)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0866] 5-((S)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 24-2)

[0867] 5-((S)-2-((3-((2S,6R)-4-(5-cyclopropylpyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0868] The racemic compound 24 was resolved by SFC to obtain compound 24-1 (54 mg, ee%: 100%, chiral HPLC (OX-3); mobile phase: n-hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 5.05 min) and compound 24-2 (56 mg, ee%: 97.18%, chiral HPLC (OX-3); mobile phase: n-hexane:ethanol = 70:30; column temperature: 35; column pressure: 80 bar; flow rate: 2 mL / min; detector signal channel: 214 nm@4.8 nm; starting wavelength of diode array detector: 200 nm; ending wavelength of diode array detector: 400 nm; RT = 7.49 min).

[0869] Compound 24-1: 1 H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.17 (s, 2H), 8.01 (s, 1H), 4.50 (d, 3H), 4.19 - 4.03 (m, 1H), 3.67 (s, 2H), 3.52 - 3.49 (m, 2H), 3.40 - 3.54 (m, 2H), 3.21 (s, 1H), 2.95 (s, 2H), 2.45 - 2.37 (m, 2H), 2.07 (s, 1H), 1.87 (s, 1H), 1.79 - 1.72 (m, 1H), 1.63 (d, 2H), 1.08 (d, 6H), 0.90 - 0.83 (m, 2H), 0.66 - 0.58 (m, 2H).

[0870] Compound 24-1: 1 H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.17 (s, 2H), 8.01 (s, 1H), 4.50 (d, 3H), 4.09 (s, 1H), 3.66 (s, 2H), 3.51 (d, 2H), 3.43 - 3.34 (m, 2H), 3.20 (s, 1H), 2.96 (s, 2H), 2.45 - 2.34 (m, 2H), 2.07 (s, 1H), 1.87 (s, 1H), 1.81 - 1.70 (m, 1H), 1.62 (s, 2H), 1.08 (d, 6H), 0.90 - 0.82 (m, 2H), 0.66 - 0.62 (m, 2H).

[0871] Example 25

[0872] (S)-5-((1-(3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 25)

[0873] (S)-5-((1-(3-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-3-oXopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0874]

[0875] Referring to the synthesis method of Reference Compound 1, Compound 25 was prepared as a white solid (120 mg, yield 43%).

[0876] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 6.27 (dd, 1H), 3.70 - 3.65 (m, 2H), 3.56 - 353 (m, 4H), 3.48 (d, 2H), 3.01 - 2.98 (m, 4H), 2.58 (t, 2H), 2.07 - 1.95 (m, 1H), 1.15 (d, 3H), 0.98 - 0.90 (m, 2H), 0.84 - 0.73 (m, 2H).

[0877] LC-MS m / z (ESI) = 563.20 [M+1].

[0878] Example 26

[0879] (S)-5-cyclopropyl-2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile (Compound 26)

[0880] (S)-5-cyclopropyl-2-(4-(3-(2-((6-oXo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

[0881]

[0882] Referring to the synthesis method of reference compound 1, compound 26 was prepared as a white solid (68 mg, yield 26%).

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.29 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 6.28 (dd, 1H), 4.21 - 4.09 (m, 2H), 3.68 - 3.61 (m, 4H), 3.58 (d, 2H), 3.49 - 3.37 (m, 4H), 2.59 (t, 2H), 1.96 - 1.92 (m, 1H), 1.15 (d, 3H), 0.98 - 0.88 (m, 2H), 0.77 - 0.66 (m, 2H).

[0884] LC-MS m / z (ESI) = 520.22 [M+1].

[0885] Example 27

[0886] (S)-5-((1-(3-(4-(5-cyclopropylpyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 27)

[0887] (S)-5-((1-(3-(4-(5-cyclopropylpyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0888]

[0889]

[0890] Referring to the synthesis method of reference compound 1, compound 27 was prepared as a white solid (76 mg, yield 32%).

[0891] 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.26 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.24 (dd, 1H), 4.33 - 4.26 (m, 2H), 3.74 - 3.63 (m, 4H), 3.52 (d, 2H), 3.55 - 3.46 (m, 4H), 2.59 (t, 2H), 1.99 - 1.90 (m, 1H), 1.15 (d, 3H), 0.96 - 0.84 (m, 2H), 0.79 - 0.63 (m, 2H).

[0892] LC-MS m / z (ESI) = 496.20 [M+1].

[0893] Example 28

[0894] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 28)

[0895] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0896]

[0897] Step 1:

[0898] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (28A)

[0899] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0900] Referring to the synthesis method of intermediate 1g, compound 28A was prepared as a white solid (34 mg, yield 64%).

[0901] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.18 (d, 2H), 7.92 (s, 1H), 6.29 (s, 1H), 4.90 - 4.57 (m, 2H), 4.26 (t, 1H), 4.24 - 4.11 (m, 2H), 3.65 (t, 2H), 3.43 (t, 2H), 3.44 - 3.40 (m, 1H), 3.20 - 3.16 (m, 1H), 3.12 - 3.01 (m, 1H), 2.88 - 2.73 (m, 1H), 1.84 - 1.66 (m, 1H), 1.12 (d, 3H), 61.10 - 0.94 (m, 3H), 0.91 - 0.80 (m, 2H), 0.62 - 0.55 (m, 2H).

[0902] LC-MS m / z (ESI) = 630.70 [M+1].

[0903] Second step:

[0904] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 28)

[0905] 5-(((2S)-1-((4-(4-(5-cyclopropylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutan-2-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0906] Referring to the synthesis method of compound 15, compound 28 was prepared as a white solid (22 mg, 80% yield).

[0907] 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.26 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 6.24 (dd, 1H), 4.33 - 4.26 (m, 2H), 3.74 - 3.63 (m, 4H), 3.52 (d, 2H), 3.55 - 3.46 (m, 4H), 2.59 - 2.55 (m, 2H), 1.99 - 1.90 (m, 1H), 1.15 (d, 3H), 0.96 - 0.84 (m, 2H), 0.79 - 0.63 (m, 2H).

[0908] LC-MS m / z (ESI) = 510.20 [M+1].

[0909] Example 29

[0910] (S)-5-((1-(3-oxo-3-(4-(5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29)

[0911] (S)-5-((1-(3-oxo-3-(4-(5-(2,2,3,3-tetrafluorocyclopropyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0912]

[0913] Compound 29 was prepared according to the synthetic method of Reference Compound 1, as a white solid (66 mg, yield 43%).

[0914] 1 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 6.30 - 6.26 (m, 1H), 4.17 - 4.12 (m, 1H), 3.85 - 3.65 (m, 6H), 3.64 - 3.46 (m, 7H), 2.59 (t, 3H), 1.15 (d, 3H).

[0915] LC-MS m / z (ESI) = 568.20 [M+1].

[0916] Biological assays

[0917] PARP enzyme biochemical assay protocol:

[0918] 1. Coating: Coat overnight with 1×histone mixture (25 μL / well).

[0919] 2. Blocking: Add 100 μL / well of Blocking buffer and block for 90 min.

[0920] 3. Compound dilution: Dilute the compound at 8 concentrations in a 1:3 ratio, with the starting concentration of 1000 nM.

[0921] 4. Add 2.5 μL of compounds at different concentrations and 10 μL of enzyme (1 - 2 ng / μL) to a 12.5 μL mixture containing 10×PARP buffer, 10×PARP Assay mixture, 5×Activated DNA, and distilled water, and incubate at room temperature for 1 h.

[0922] 5. Add diluted Streptavidin-HRP and incubate for 30 min, then add the chromogenic solution for color development.

[0923] 6. Read the chemiluminescence with an enzyme-labeled instrument.

[0924] IC 50 : Refers to the compound concentration when the PARP enzyme activity is inhibited by 50%.

[0925] Table 1. Inhibitory activity of compounds against PARP-7 enzyme

[0926]

[0927] Conclusion: The compounds of the present invention have significant biological inhibitory activity against the PARP-7 target protein.

[0928] Table 2. Selectivity of compounds for PARP-1 and PARP-7 subtypes

[0929]

[0930] Conclusion: The compounds of the present invention have stronger selectivity for PARP-7 compared to the control.

[0931] Experimental protocol for inhibiting the proliferation of NCI-H1373 cells

[0932] 1. Seed NCI-H1373 cells in a 96-well cell culture plate (1500 cells / well), with a volume of 80 μL per well. Incubate overnight in an incubator at 37°C and 5% CO2.

[0933] 2. Prepare a 10 mM stock solution of the compound in DMSO and dilute it 8-fold (1:5) with 1640 medium to final concentrations of 10000, 2000, 400, 80, 16, 3.2, 0.64, and 0.128 nM.

[0934] 3. Use cells without drug treatment as the control group, and the remaining cells are treated with each drug concentration. At the same time, set up cell-free culture wells as the blank zeroing group. Each group has 2 parallel wells and is placed in a 37 °C, 5% CO2 incubator for culture.

[0935] 4. After 6 days of culture, take out the 96-well plate from the incubator, add 100 μL of Cell Titer Blue working solution to each well, shake for 2 min, and incubate for 10 min.

[0936] 5. Read the chemiluminescence with a microplate reader.

[0937] 6. Calculate the cell survival rate = (fluorescence intensity of the treatment group / fluorescence intensity of the control group) × 100%, and calculate the half maximal inhibitory concentration (IC 50 ) by curve fitting.

[0938] IC 50 : Refers to the compound concentration when cell proliferation is inhibited by 50%.

[0939] Table 3. Compound inhibition of NCI-H1373 cell proliferation activity

[0940]

[0941] Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of NCI-H1373 cells.

[0942] Induction of drug-metabolizing enzyme CYP450

[0943] 1. Incubate adherent primary human hepatocytes (3 donors) under the following experimental conditions: cell density is 0.7×10 6 cell / mL, temperature 37.0 °C, 5% CO2.

[0944] 2. After incubating the compound with the cells for 2 - 3 days, test the enzyme activity of CYP450.

[0945] 3. Test data processing: % relative positive control activity (% of PC) = (activity of the sample in the compound-treated group - activity of the sample in the blank control group) / (activity of the sample in the positive control group - activity of the sample in the blank control group) × 100%

[0946] Positive control group: Hepatocytes were incubated with inducers of CYP450 (for CYP2B6 subtype, corresponding to 1000 μM phenobarbital; for CYP3A4 subtype, corresponding to 25 μM rifampicin).

[0947] Blank control group: Cells were incubated with a medium containing the same content (v / v) of organic solvent.

[0948] Table 4. Induction experiment of compound on metabolic enzyme CYP450

[0949]

[0950] Conclusion: The compound of the present invention has no potential induction effect on the activity of metabolic enzyme CYP450, while the control product has obvious induction activity.

[0951] The specification of the present invention has described the specific implementation manners in detail. Those skilled in the art should recognize that the above implementation manners are exemplary and should not be construed as limitations on the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound of general formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof: wherein R, R', and R'' are each independently H or C 1-6 an alkyl group; or R and R′ or R and R″ together with the attached atoms form a 4-, 5- or 6-membered heteroalkyl group containing 1 N atom; R1 and R2 are each independently H or C 1-6 alkyl group; L1 is a bond or C═O; L is a bond or NH; C1 is R3 and R4 are each independently H, halogen or C 1-6 alkyl, where the C 1-6 alkyl is optionally further substituted by 1 or more substituents selected from OH or CN; C is a 6-membered heteroaryl containing 1, 2 or 3 N atoms, and the 6-membered heteroaryl is optionally further substituted by 1 or more substituents selected from CN or C alkyl optionally substituted by 1 or more halogens; 1-6 alkyl; C2 is cyclopropyl, cyclobutyl or cyclopentyl; R5 are each independently H, halogen, CN or OH; n is 1 or 2; m is 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R and R′ or R and R″ together with the atoms to which they are attached form a 5-membered heteroalkyl group containing 1 nitrogen atom, L1 is C═O, L is a bond, and C1 is R3 and R4 are each independently H or C 1-6 alkyl, C is a 6-membered heteroaryl group containing 2 nitrogen atoms, C2 is cyclopropyl, cyclobutyl or cyclopentyl, and R5 is H.

3. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is H; L1 is C═O; L is a bond; C1 is C is a 6-membered heteroaryl containing 2 N atoms; R5 is H or OH.

4. The compound according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each of R′ and R″ is independently H or C 1-6 alkyl; L1 is C═O; C1 is C is a 6-membered heteroaryl containing 2 N atoms.

5. The compound according to claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are H; n is 2; C1 is C is 6. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L1 is C═O; R is H; R′ and R″ are each independently H or C 1-6 alkyl; C1 is C is R3 is H; R4 is C1-6 alkyl, which is optionally further substituted by one OH or CN; C2 is cyclopropyl; R5 is H.

7. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond; R is H; R' and R'' are each independently H or C 1-6 alkyl; both R1 and R2 are H; n is 2; C1 is C is C2 is cyclopropyl; R3, R4 and R5 are all H.

8. The compound according to claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein when L1 is C═O and L is NH, C1 is and both R3 and R4 are halogen, and C2 is cyclopropyl.

9. The compound according to claim 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein when L1 is C═O and L is a bond, C1 is and both R3 and R4 are each halogen or both are H.

10. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally further substituted by 1 or more OH.

11. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C is 12. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C2 is cyclopropyl.

13. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R5 is halogen.

14. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.

15. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.

16. A compound of general formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof: wherein R1 and R2 are each independently selected from H or C 1-6 alkyl group; R3 and R4 are each independently selected from H, halogen or C 1-6 alkyl, where said C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH or CN; R5 are each independently selected from H, halogen, CN or OH; L is a bond or —NH—; C1 is C2 is cyclopropyl, cyclobutyl or cyclopentyl; n is 1 or 2; m is 0, 1, 2, 3, 4 or 5.

17. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R1 and R2 are H.

18. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond.

19. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is independently halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally further substituted by 1 or more OH.

20. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C2 is cyclopropyl.

21. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R5 is halogen.

22. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.

23. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.

24. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from the following structures:

25. An intermediate compound, or a stereoisomer or pharmaceutically acceptable salt thereof, for preparing a compound of general formula (I), (II) or a stereoisomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VI): wherein R, R′, and R″ are each independently H or C 1-6 an alkyl group; or R and R′ or R and R″ together with the attached atoms form a 4-, 5- or 6-membered heteroalkyl group containing 1 N atom; R1 and R2 are each independently H or C 1-6 alkyl group; L1 is a bond or C═O; L is a bond or NH; C1 is R3 and R4 are each independently H, halogen or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally further substituted by 1 or more substituents selected from OH or CN; C is a 6-membered heteroaryl containing 1, 2 or 3 N atoms, which 6-membered heteroaryl is optionally further substituted by 1 or more substituents selected from CN or C 1-6 alkyl, and the C 1-6 alkyl is optionally further substituted by 1 or more halogens; C2 is cyclopropyl, cyclobutyl or cyclopentyl; R5 are each independently H, halogen, CN or OH; n is 1 or 2; m is 0, 1, 2, 3, 4 or 5.

26. The compound according to claim 25, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C is 27. The compound according to claim 25, or a stereoisomer or pharmaceutically acceptable salt thereof, having the following structure:

28. A pharmaceutical composition comprising: (1) A compound according to any one of claims 1 to 24, or a stereoisomer or pharmaceutically acceptable salt thereof; (2) Optionally one or more other active ingredients; and (3) A pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1 to 24, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28, in the preparation of an anti-tumor drug; wherein the formation of the tumor is related to PARP, and the PARP is PARP-7. Use of a compound according to any one of claims 1 to 24, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28, in the preparation of a PARP inhibitor; wherein the PARP is PARP-7.

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