CN116157396A

CN116157396A - Pyridazinone derivatives and their use in medicine

Info

Publication number: CN116157396A
Application number: CN202180054567.5A
Authority: CN
Inventors: 魏用刚; 朱钰沁; 楚洪柱; 孙毅
Original assignee: Chengdu Baiyu Pharmaceutical Co Ltd
Current assignee: Chengdu Baiyu Pharmaceutical Co Ltd
Priority date: 2020-11-27
Filing date: 2021-11-29
Publication date: 2023-05-23
Also published as: WO2022111700A1

Abstract

Pyridazinone derivatives are provided, as are PARP inhibitors, such as PARP-7 inhibitors, and their use in medicine.

Description

Pyridazinone derivatives and their use in medicine

Technical Field

The invention relates to a pyridazinone derivative or a stereoisomer or a pharmaceutically acceptable salt thereof and a medical application thereof.

Background

Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-transcriptional modification of proteins by inserting single or multiple adenosine diphosphate ribose (ADP-ribose) groups into amino acid residues of the protein. ADP-ribosylation is a reversible process involving physiological regulation of cell signaling, DNA damage repair, transcription, gene expression regulation, apoptosis, etc. ADP-ribose is derived from a redox cofactor: nicotinamide adenine dinucleotide (Nicotinamide adenine dinucleotide, NAD+), the enzyme mediating the ADP-ribose intercalating modification is ADP-ribosylase. In this regulation of the physiological response, the N-glycosidic bond of NAD+ linking the ADP-ribose molecule and the nicotinamide group is cleaved and subsequently captured to the corresponding amino acid residue of the target protein. ADP-ribosyl enzymes can undergo two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation. When DNA damage or cells are stressed by pressure, PARP is activated, resulting in an increase in poly ADP-ribose and a decrease in nad+. PARP1 has been considered for over a decade to be the only poly ADP-ribose polymerase in mammalian cells and therefore the enzyme has been the most studied. To date, scientists have identified 17 different PARPs. MonoPARP occupies a large part of the PARP family and mediates important biological functions and various stress responses, such as: unfolded protein response, NF- κb signaling, antiviral response, and cytokine signaling. 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced poly (ADP-ribose) polymerase (PARP-7) is one of the monoprop family members whose expression is regulated by TCDD-activated Aromatic Hydrocarbon Receptors (AHR), a ligand-activated transcription factor, that mediates the toxic activity of many environmental heterologous organisms. AHR up-regulates the expression of PARP-7, which causes inhibition of TBK1 activity and down-regulation of IFN-I (type I interferon) response by interaction with and ADP-ribosylation of kinase TBK1, thereby resulting in inhibition of antiviral and tumor immune responses in the body.

Disclosure of Invention

It is an object of one or more embodiments of the present application to provide novel PARP inhibitors.

It is an object of one or more embodiments of the present application to provide novel PARP-7 inhibitors.

One or more embodiments of the present application provide compounds of formula (I), or stereoisomers or pharmaceutically acceptable salts thereof:

wherein the method comprises the steps of

R, R ', R' are each independently H or C _1-6 An alkyl group; or alternatively

R and R 'or R and R' form, with the atom to which they are attached, a 4-to 8-membered heterocycloalkyl group;

R ₁ 、R ₂ each independently is H or C _1-6 An alkyl group;

L ₁ is a bond or c=o;

l is a bond or NH;

C ₁ is a 6-membered, 7-membered or 8-membered heterocyclic group;

R ₃ 、R ₄ each independently is H, halogen or C _1-6 Alkyl, wherein the C _1-6 Alkyl is optionally further substituted1 or more substituents selected from OH or CN;

c is a 6 membered heteroaryl, said 6 membered heteroaryl optionally being further substituted with 1 or more C selected from CN or optionally with 1 or more halogen _1-6 Substituted by alkyl;

C ₂ is C _3-6 A carbocycle;

R ₅ each independently is H, halogen, CN or OH;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.

In one or more embodiments, C ₁ Is a 6-, 7-or 8-membered heterocyclic group containing 1, 2 or 3N atoms.

In one or more embodiments, C ₁ Is that

In one or more embodiments, C is a 6 membered heteroaryl containing 1, 2, or 3N atoms, optionally further substituted with 1 or more C selected from CN or optionally substituted with 1 or more halo groups _1-6 The substituent of the alkyl group is substituted.

In one or more embodiments, C is

Optionally further substituted with 1 or more C selected from CN or optionally substituted with 1 or more halogen _1-6 The substituent of the alkyl group is substituted.

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

In one or more embodiments, R is H.

In one or more embodiments, R' are each independently H or C _1-6 An alkyl group;

in one or more embodiments, R ₁ And R is ₂ H.

In one or more embodiments, L ₁ C=o.

In one or more embodiments, L is a bond.

In one or more embodiments, L ₁ C=o, L is NH.

In one or more embodiments, L ₁ C=o, L is a bond.

In one or more embodiments, C ₁ Is that

In one or more embodiments, R ₃ 、R ₄ Each independently is halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more OH groups.

In one or more embodiments, C is

In one or more embodiments, C ₂ Is C ₃ Carbocycles.

In one or more embodiments, R ₅ Is halogen.

In one or more embodiments, n is 2.

In one or more embodiments, m is 0.

One or more embodiments of the present application provide compounds of formula (II), or stereoisomers or pharmaceutically acceptable salts thereof:

wherein the method comprises the steps of

R ₁ 、R ₂ Each independently selected from H or C _1-6 An alkyl group;

R ₃ 、R ₄ each independently selected from H, halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from OH or CN;

R ₅ each independently selected from H, halogen, CN or OH;

l is a bond or-NH-;

C ₁ is that

C ₂ Is C _3-5 A carbocycle;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.

In one or more embodiments, R ₁ And R is ₂ H.

In one or more embodiments, L is a bond.

In one or more embodiments, C ₂ Is C ₃ Carbocycles.

In one or more embodiments, R ₅ Is halogen.

In one or more embodiments, n is 2.

In one or more embodiments, m is 0.

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

one or more embodiments of the present application provide intermediate compounds or stereoisomers or pharmaceutically acceptable salts thereof useful in the preparation of compounds of formula (I), (II), or stereoisomers or pharmaceutically acceptable salts thereof, having the formula (III), (IV), (V), or (VI):

wherein the method comprises the steps of

R, R ', R' are each independently H or C _1-6 An alkyl group; or alternatively

R ₁ 、R ₂ each independently is H or C _1-6 An alkyl group;

L ₁ is a bond or c=o;

l is a bond or NH;

C ₁ is a 6 to 8 membered heterocyclyl;

R ₃ 、R ₄ each independently is H, halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from OH or CN;

c is a 6 membered heteroaryl, optionally further substituted with 1 or more groups selected from CN or C _1-6 Substituted by substituents of alkyl groups, said C _1-6 Alkyl is optionally further substituted with 1 or more halogens;

C ₂ is C _3-6 A carbocycle;

R ₅ each independently is H, halogen, CN or OH;

C ₃ is a 6 to 8 membered heterocyclyl;

X ₁ is H or NH ₂ ；

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.

In one or more embodiments, C is a 6 membered heteroaryl group comprising 1, 2, or 3N atoms.

In one or more embodiments, C ₁ Is that

In one or more embodiments, C is

Optionally further coated with 1 or more components selected from CN or C _1-6 Substituted by substituents of alkyl groups, said C _1-6 The alkyl group is optionally further substituted with 1 or more halogens.

In one or more embodiments, C ₃ Is that

In one or more embodiments, the intermediate compound or a stereoisomer or pharmaceutically acceptable salt thereof has the structure:

one or more embodiments of the present application provide a pharmaceutical composition comprising:

(1) A compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof;

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

(3) Pharmaceutically acceptable carriers and/or excipients.

One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application in the preparation of an antitumor drug.

In one or more embodiments, the tumor formation is related to PARP.

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

One or more embodiments of the present application provide for the use of a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, in the preparation of a PARP inhibitor.

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

One or more embodiments of the present application provide a compound of the present application or a stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application for use as a medicament.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application for use in a method of treating a tumor. In one or more embodiments, the tumor formation is related to PARP. In one or more embodiments, the PARP is PARP-7.

One or more embodiments of the present application provide compounds of the present application or stereoisomers or pharmaceutically acceptable salts thereof or pharmaceutical compositions of the present application, which are useful as PARP inhibitors, e.g. PARP-7 inhibitors.

One or more embodiments of the present application provide a method of treating a tumor comprising administering a compound of the present application or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application to a subject in need thereof.

One or more embodiments of the present application provide a method of inhibiting PARP comprising administering a compound of the present application or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present application. In one or more embodiments, the PARP is PARP-7.

Detailed Description

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include ¹² C、 ¹³ C and C ¹⁴ Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include ¹⁶ O、 ¹⁷ O and ¹⁸ isotopes of O, sulfur include ³² S、 ³³ S、 ³⁴ S and ³⁶ isotopes of S, nitrogen include ¹⁴ N and ¹⁵ isotopes of N, fluorine include ¹⁷ F and F ¹⁹ Isotopes of F, chlorine include ³⁵ Cl and Cl ³⁷ Isotopes of Cl, bromine include ⁷⁹ Br and ⁸¹ Br。

"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 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 of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 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 substituted, it may optionally be further substituted with 1 or more substituents.

"aryl" refers to a substituted or unsubstituted aromatic ring that may be a 5 to 8 membered (e.g., 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system that may be a bridged or spiro ring, non-limiting examples include phenyl, naphthyl. The aryl group may optionally be further substituted with 1 or more substituents.

"heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 5 to 8 membered (e.g., 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) heterocyclic groups, the N, S optionally substituted in the ring of the heterocyclic group being oxidizable to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom and the heterocyclic group may be a bridged or spiro ring, non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridinyl. When heteroaryl is substituted, it may optionally be further substituted with 1 or more substituents.

"heterocyclyl" or "heterocycle" refers to a saturated or unsaturated heteroaromatic or non-heteroaromatic ring, the definition of which is the same as that of "heteroaryl" above when selected from heteroaromatic rings; when selected from non-heteroaromatic rings, it may be a 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. Optionally substituted N, S in the ring of a "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or carbon atom; "heterocyclyl" or "heterocycle" may be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" include epoxy ethyl, cyclopropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, oxy Cycloheptyl, thiepinyl, oxazepinyl, diazapinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazalkyl, 1, 3-dithianyl, dihydrofuranyl, dithianyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxapentyl, pyrazolinyl, dithianyl, dithidienyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, 1,2, 3-isoquinolinyl, 1, 3-tetrahydroisoquinolinyl, 1, 3-pyrrolyl, 1, 3-bicycloquinolinyl]Hexyl, 3-azabicyclo [4.1.0]Heptyl and azabicyclo [2.2.2]Hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1 ]Octyl group,

Azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1]]Dodecyl, azaadamantyl and oxaspiro [3.3]]A heptyl group. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 0 or more substituents.

"heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring radical which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7 or 8 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1, 2 or 3 heteroatoms selected from N, O or S, e.g., 3 to 8 membered heterocyclyl. Optionally substituted N, S in the ring of the "heterocycloalkyl" group can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or carbon atom; "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxy ethyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, piperidinyl, piperdinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo [3.2.1] octanyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl, and oxaspiro [3.3] heptanyl.

"carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When selected from aromatic rings, the definition is the same as for "aryl" above; when selected from the group consisting of non-aromatic rings, it may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system, which may be bridged or spiro, 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 "carbocyclyl" or "carbocycle" may be optionally further substituted with 1 or more substituents.

When "alkyl", "aryl", "heteroaryl", "heterocycle", "heterocyclyl", "heterocycloalkyl", "carbocycle", "carbocyclyl" described above is substituted, it may optionally be further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups 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 alkynyl groups, and wherein said substituents 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 with 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 is R ^q1 Selected from C _1-6 Alkyl, C _1-6 Alkoxy or C _6-10 An aryl group; r is R ^q2 、R ^q3 Selected from H orPerson C _1-6 An alkyl group; r is R ^q4 、R ^q5 Selected from H, C _1-6 Alkyl, -NH (c=nr ^q1 )NR ^q2 R ^q3 、-S(＝O) ₂ NR ^q2 R ^q3 、-C(＝O)R ^q1 or-C (=O) NR ^q2 R ^q3 Wherein said C _1-6 The alkyl group optionally being further substituted by 1 or more groups 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 Substituted by a substituent of heterocycloalkyl; or R is ^q4 And R is R ^q5 And the N atom forms a 3 to 8 membered heterocyclic ring, which may contain 1 or more heteroatoms selected from N, O or S.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other active ingredients, wherein "other active ingredients" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate 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 disintegrating agents.

"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.

Detailed Description

The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.

PMB: refers to p-methoxybenzyl.

Intermediate 1

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

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

The first step:

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

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

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

LC-MS m/z(ESI)＝375.00[M+1]。

And a second step of:

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

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

Compound 1b (48.4 g,129.40mmol,1.0 equiv) was dissolved in methanol (417 mL) and the reaction stirred at room temperature for 2h. The resulting reaction mixture was concentrated to 80mL and filtered to give crude product. The resulting filter cake was slurried in water (160 mL) for 1h and filtered to give compound 1c as a white solid (38.72 g, 92% yield).

LC-MS m/z(ESI)＝326.30[M+1]。

And a third step of:

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

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

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

LC-MS m/z(ESI)＝315.10[M+1]。

Fourth step:

5-hydroxy-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 e)

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

To a solution of compound 1d (12.1 g,38.52mmol,1.0 equiv.) in N, N-dimethylformamide (60 mL) was added dropwise trimethyliodosilane (9.97 g,50.07mmol,1.3 equiv.) at room temperature. The resulting reaction solution was stirred at 85℃for 20h. After the reaction was completed, 60mL of water was added to the reaction mixture to quench the reaction, followed by extraction of the resulting solution with 3×60mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, and 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%).

LC-MS m/z(ESI)＝301.07[M+1]。

Fifth step:

5-chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 f)

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

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

LC-MS m/z(ESI)＝319.68[M+1]。

Sixth step:

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

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

Compound 1f (5.0 g,15.69mmol,1.0 equiv) was weighed into a 100mL reaction flask and dissolved in ethanol (40 mL). Subsequently, triethylamine (4.4 mL,31.38mmol,2.0 equiv) and (2S) -2-aminopropan-1-ol (1.19 g,15.69mmol,1.0 equiv) were added in this order, and the mixture was stirred at 60℃for 4h. After completion of the reaction, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1.5) to give compound 1g, white solid (5.31 g, yield 95%).

LC-MS m/z(ESI)＝358.43[M+1]。

Seventh step:

(S) -3- (2- (((1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoic acid methyl ester (1 h)

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

1g (5.31 g,14.86mmol,1.0 equiv) of compound was weighed into a 100mL reaction flask, cesium carbonate (4.73 g,14.86mmol,1.0 equiv). Subsequently, acetonitrile (50 mL) was added for dissolution, and methyl prop-2-enoate (13.38 g,148.6mmol,10 equiv) was added to the mixture. After the addition, the reaction mixture was stirred at 30℃for 4h. After completion of the reaction, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 1h as a white solid (3.40 g, yield 51%).

LC-MS m/z(ESI)＝444.50[M+1]。

Eighth step:

(S) -3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoic acid methyl ester (1 i)

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

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

LC-MS m/z(ESI)＝324.30[M+1]。

Ninth step:

Compound 1i (2.06 g,6.37mmol,1.0 equiv) and lithium hydroxide monohydrate (1.34 g,31.85mmol,5.0 equiv) were weighed separately and added to a 100mL reaction flask. Subsequently, methanol (14 mL) and water (14 mL) were added in this order, and the reaction solution was stirred at 25℃for 1h. After the reaction was completed, the pH of the reaction mixture was adjusted to 6 with trifluoroacetic acid. The reaction mixture was concentrated in vacuo and the residue purified by C18 reverse phase chromatography (water: acetonitrile=6:1) to give intermediate 1 as a pale yellow solid (1.32 g, 67% yield).

LC-MS m/z(ESI)＝310.32[M+1]。

Intermediate 2

5-cyclopropyl-2- (piperazin-1-yl) pyrimidine (intermediate 2)

5-cyclopropyl-2-(piperazin-1-yl)pyrimidine

The first step:

4- (5-bromopyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (2 b)

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

2-chloro-5-bromopyrimidine (2 a,12.0g,62.04mmol,1.05 equiv.) was weighed out, piperazine-1-carboxylic acid tert-butyl ester (11.0 g,59.08mmol,1.0 equiv.) and potassium carbonate (16.33 g,124.08mmol,2.0 equiv.) in a 250mL reaction flask. Subsequently, N-methylpyrrolidone (90 mL) was added to the mixture to dissolve, and the reaction was heated under an oil bath at 80℃and stirred for 1h. After the reaction was completed, the reaction solution was poured into 280mL of an ice-water mixture, and the suspension was filtered to obtain compound 2b as a white solid (16.4 g, yield 81%).

LC-MS m/z(ESI)＝344.90[M+1]。

And a second step of:

5-bromo-2- (piperazin-1-yl) pyrimidine (2 c)

5-bromo-2-(piperazin-1-yl)pyrimidine

Compound 2b (16.4 g,47.78mmol,1.0 equiv) was weighed and dissolved in dioxane solution of hydrochloric acid (4M, 67 mL). The reaction solution was stirred at room temperature for 1h. When the reaction was complete, the suspension was filtered, the filter cake was washed with dioxane, and dried to give compound 2c as a white solid (11.3 g, 97% yield).

LC-MS m/z(ESI)＝244.90[M+1]。

And a third step of:

5-cyclopropyl-2- (piperazin-1-yl) pyrimidine (intermediate 2)

5-cyclopropyl-2-(piperazin-1-yl)pyrimidine

Into a 25mL reaction flask, weighed compound 2c (1.0 g,4.10mmol,1.0 equiv), potassium carbonate (2.83 g,20.50mmol,5.0 equiv), cyclopropylboronic acid (1.06 g,12.30mmol,3.0 equiv) and [1,1' -bis (diphenylphosphine) ferrocene were added separately ]Palladium dichloride dichloromethane complex (344.8 mg,0.41mmol,0.1 equiv). Subsequent addition of THF/H ₂ O (35.2/4.4 mL) mixture, N ₂ The reaction was protected and placed under heating at 66 ℃ in an oil bath with stirring for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by column chromatography (dichloromethane: methanol=15:1) to give intermediate 2 as a white solid (0.66 g, yield 78%).

LC-MS m/z(ESI)＝205.30[M+1]。

Intermediate 3

5-cyclobutyl-2- (piperazin-1-yl) pyrimidine (intermediate 3)

5-cyclobutyl-2-(piperazin-1-yl)pyrimidine

The first step:

4- (5- (1- (hydroxycyclobutyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3 a)

tert-butyl 4-(5-(1-hydroxycyclobutyl)pyrimidin-2-yl)piperazine-1-carboxylate

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

LC-MS m/z(ESI)＝335.40[M+1]。

And a second step of:

5-cyclobutyl-2- (piperazin-1-yl) pyrimidine (intermediate 3)

5-cyclobutyl-2-(piperazin-1-yl)pyrimidine

The dried compound 3a (about 5.7 mmol) was transferred to a 20mL reaction flask and dichloromethane (6 mL) was dissolved. Subsequently, a solution of triethylsilane (2.74 mL,17.1mmol,3 equiv) and trifluoroacetic acid in dichloromethane (3.0 mL, TFA: CH) was added thereto ₂ Cl ₂ =1:2, volume ratio). After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo to give an oil. The residue was purified by reverse phase C18 chromatography (water: acetonitrile=1:3) to give intermediate 3 as a white solid (1.35 g, 27%).

LC-MS m/z(ESI)＝219.20[M+1]。

Intermediate 4

5- (1-fluorocyclopropyl) -2- (piperazin-1-yl) pyrimidine (intermediate 4)

5-(1-fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

The first step:

2- (4- (tert-Butoxycarbonyl) piperazin-1-yl) pyrimidine-5-carboxylic acid methyl ester (4 b)

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

Methyl 2-chloro-5-carboxylate 4a (17.2 g,0.1mol,1.0 equiv) piperazine-1-carboxylate (21.0 g,0.11mol,1.1 equiv) and potassium carbonate (28.0 g,0.2mol,2.0 equiv) were weighed into a 250mL reaction flask. Subsequently, N-methylpyrrolidone (100 mL) was added to the mixture to dissolve, and the reaction was heated and stirred for 1h at 80℃in an oil bath. After the reaction was completed, the reaction solution was poured into 280mL of an ice-water mixture, and the suspension was filtered to obtain compound 4b as a white solid (26.2 g, yield 81%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,2H),3.92–3.69(m,7H),3.47–3.37(m,4H),1.42(s,9H)。

LC-MS m/z(ESI)＝323.20[M+1]。

And a second step of:

4- (5- (1- (hydroxycyclopropyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (4 c)

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

Compound 4b (5.0 g,15.5mmol,1.0 equiv.) and tetraisopropyl titanate (6.4 g,21.7mmol,1.4 equiv.) are weighed into 50mL anhydrous tetrahydrofuran, and ethyl magnesium bromide solution (43.5 mL,43.5mol,2.8 equiv.) is added dropwise under the protection of nitrogen in an ice-water bath, and the reaction is carried out at room temperature for 2h. After the reaction was completed, 40mL of ethyl acetate and 20mL of water were added to the reaction solution, extraction was performed three times with ethyl acetate, the solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (n-hexane: ethyl acetate=5:1) to give compound 4c as a white solid (1.5 g, yield 30%).

LC-MS m/z(ESI)＝321.20[M+1]。

And a third step of:

4- (5- (1- (((trimethylsilyl) oxy) cyclopropyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (4 d)

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

Compound 4c (500 mg,1.5mmol,1.0 equiv) was weighed in 5mL dimethylformamide, imidazole (204 mg,3mol,2 equiv) and trimethylchlorosilane (285. Mu.L, 2.25mmol,1.5 equiv) were added sequentially and reacted at room temperature for 1h. After the reaction was completed, 5mL of water was added to quench, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4d, and the crude product was directly used for the next reaction.

Fourth step:

4- (5- (1-fluorocyclopropyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (4 e)

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

Compound 4d (1.5 mmol,1.0 equiv) was dissolved in 5mL of dichloromethane, and diethylaminosulfur trifluoride (396. Mu.L, 3mol,2.0 equiv) was added and reacted at room temperature for 1h. After completion of the reaction, the mixture was directly dried by spin-drying (n-hexane: ethyl acetate=3:1) to give compound 4e as a white solid (290 mg, yield 60%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.44(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)。

Fifth step:

5- (1-fluorocyclopropyl) -2- (piperazin-1-yl) pyrimidine (intermediate 4)

5-(1-fluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

Referring to the synthetic procedure for compound 2c, intermediate 4 was prepared as a white solid, intermediate 4 was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝223.20[M+1]

Intermediate 5

5-cyclopropyl-pyrimidin-2- ((3S, 5R) -3, 5-dimethylpiperazin-1-yl) pyrimidine (intermediate 5)

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

The first step:

(2S, 6R) -4- (5-bromopyrimidin-2-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (5 b)

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

2-chloro-5-bromopyrimidine 2a (1.5 g,7.7mmol,1.0 equiv), (2S, 6R) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (2.0 g,9.0mmol,1.2 equiv) and potassium carbonate (2.1 g,15.4mmol,2.0 equiv) were weighed into a 100mL reaction flask. Subsequently, nitrogen methyl pyrrolidone (20 mL) was added to the mixture to dissolve, and the reaction was heated and stirred for 1h at 80 ℃ in an oil bath. After the reaction was completed, the reaction solution was poured into 80mL of an ice-water mixture, and the suspension was filtered to obtain compound 5b as a white solid (2.7 g, yield 98%).

LC-MS m/z(ESI)＝371.20[M+1]。

And a second step of:

(2S, 6R) -4- (5-Cyclopropylpyrimidin-2-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (5 c)

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

Referring to the synthetic procedure for intermediate 2, compound 5c was prepared as a white solid (1.8 g, 70% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.17(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)。

LC-MS m/z(ESI)＝333.23[M+1]。

And a third step of:

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

The synthesis of reference compound 2c afforded intermediate 5 as a white solid, intermediate 5 was used directly in the next reaction without further purification.

Intermediate 6

1- (5-Cyclopropylpyrimidin-2-yl) -3, 3-difluoropiperidin-4-amine (intermediate 6)

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

The first step:

(1- (5-bromopyrimidin-2-yl) -3, 3-difluoropiperidin-4-yl) carbamic acid tert-butyl ester (6 b)

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

2-chloro-5-bromopyrimidine 2a (682 mg,3.5mmol,1.0 equiv), (3, 3-difluoropiperidin-4-yl) carbamic acid tert-butyl ester (1.0 g,4.2mmol,1.2 equiv) and potassium carbonate (0.97 g,7.0mmol,2.0 equiv) were weighed into a 50mL reaction flask. Subsequently, nitrogen methyl pyrrolidone (10 mL) was added to the mixture to dissolve, and the reaction was heated and stirred for 1h at 80 ℃ in an oil bath. After the reaction was completed, the reaction solution was poured into 80mL of an ice-water mixture, and the suspension was filtered to obtain compound 6b as a white solid (1.02 g, yield 75%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.50(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)。

LC-MS m/z(ESI)＝394.25[M+1]。

And a second step of:

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

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

Referring to the synthetic procedure for intermediate 2, intermediate 6c was prepared as a white solid (770 mg, 87% yield).

¹ H NMR(600MHz,DMSO-d ₆ )δ8.19(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)。

LC-MS m/z(ESI)＝355.40[M+1]。

And a third step of:

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

The synthesis of reference compound 2c afforded intermediate 6 as a white solid, intermediate 6 was used directly in the next reaction without further purification.

Intermediate 7:

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

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

The first step:

2-chloro-5-cyclopropylpyrimidine (7 a)

2-chloro-5-cyclopropylpyrimidine

Referring to the synthetic procedure for intermediate 2, compound 7a was prepared as a white solid (1.32 g, 83% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.55(s,2H),2.00–1.93(m,1H),1.09–1.02(m,2H),0.90–0.84(m,2H)。

LC-MS m/z(ESI)＝155.03[M+1]。

And a second step of:

7- (5-Cyclopropylpyrimidin-2-yl) -4, 7-diazaspiro [2.5] octane-4-carboxylic acid tert-butyl ester (7 b)

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

2-chloro-5-cyclopropylpyrimidine 7a (300 mg,2mmol,1.0 equiv), tert-butyl 4, 7-diazaspiro [2.5] octane-4-carboxylate (640 mg,3mmol,1.2 equiv) and potassium carbonate (0.55 g,4.0mmol,2.0 equiv) were weighed into a 50mL reaction flask. Subsequently, nitrogen methyl pyrrolidone (10 mL) was added to the mixture to dissolve, and the reaction was heated and stirred for 1h at 80 ℃ in an oil bath. After the reaction was completed, the reaction solution was poured into 80mL of an ice-water mixture, and the suspension was filtered to obtain compound 7b as a white solid (350 mg, yield 53%).

LC-MS m/z(ESI)＝331.30[M+1]。

And a third step of:

the synthesis method of the reference compound 2c is used for preparing an intermediate 7 which is white solid; intermediate 7 was used directly in the next reaction without further purification.

Intermediate 8:

(1R, 5S) -3- (5-cyclopropyl-pyrimidin-2-yl) -1, 5-dimethyl-3-azabicyclo [3.1.0] hex-6-amine (intermediate 8)

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

Referring to the synthetic procedure for intermediate 7, intermediate 8 was prepared as a white solid (1.8 g, 70% yield).

LC-MS m/z(ESI)＝344.50[M+1]

Intermediate 9:

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

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

The first step:

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

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

1g (1.0 g,2.79mmol,1.0 equiv.) of the compound, tert-butyl bromoacetate (1.65 g,8.37mmol,3.0 equiv.) and potassium tert-butoxide (0.94 g,8.37mmol,3.0 equiv.) are sequentially weighed, reacted in 11.0mL of dimethylformamide at room temperature for 3h, quenched with 30mL of water, extracted twice with 30mL of ethyl acetate, and the organic phase dried over anhydrous sodium sulfate and concentrated to give the compound 9a as a yellow solid (0.33 g, 25% yield) by column chromatography of the residue (petroleum ether: ethyl acetate=2:1).

LC-MS m/z(ESI)＝472.48[M+1]。

And a second step of:

In a 50mL single-port bottle, compound 9a (330 mg,0.7mmol,1 equiv) was dissolved in 2.5mL of dichloromethane, then 2.5mL of trifluoroacetic acid was added, the reaction was reacted at room temperature for 2 hours, and the reaction solution was dried by spin to obtain intermediate 9 (220 mg, yield 76%) which was directly subjected to the next reaction.

LC-MS m/z(ESI)＝416.37[M+1]。

Intermediate 10

1- (2- (piperazin-1-yl) pyrimidin-5-yl) cyclopropane-1-carbonitrile (intermediate 10)

1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile

The first step:

4- (5- (1- (cyanocyclopropyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (10 a)

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

1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (124.5 mg,0.2mmol,0.1 equiv), tris (dibenzylideneacetone) dipalladium (0): 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (91.6 mg,0.1mmol,0.05 equiv) and tetrahydrofuran (2.0 ml) were charged into the reaction flask, nitrogen was purged, and the suspension was stirred under nitrogen for 20min. Another flask was charged with compound 2b (686 mg,2.0mmol,1.0 equiv) and cyclopropanecarbonitrile (267. Mu.L, 3.0mmol,1.5 equiv), dissolved in cyclopentylmethyl ether (4.0 mL) and blanketed with nitrogen by Bi Chouhuan. Subsequently, the prepared catalyst suspension was added to the reaction, followed by dropwise addition of lithium bis (trimethylsilylamide) (3.0mL,1M in THF,3.0mmol,1.5euqiv). The reaction mixture was heated to 80 ℃ and stirred for 3h. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with ethyl acetate and saturated ammonium chloride solution. The reaction mixture was extracted with 3X 60mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether=1:10) to give compound 10a as a white solid (482 mg, 73% yield).

LC-MS m/z(ESI)＝330.30[M+1]。

And a second step of:

1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropane-1-carbonitrile

The crude intermediate 10 was prepared as a white solid 327mg by the synthetic method of reference compound 2 c. Intermediate 10 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝230.20[M+1]。

Intermediate 11

5- (2, 2-Difluorocyclopropyl) -2- (piperazin-1-yl) pyrimidine (intermediate 11)

5-(2,2-difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

The first step:

4- (5-vinyl-pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (11 b)

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

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

LC-MS m/z(ESI)＝290.4[M+1]。

And a second step of:

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

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

11b (634 mg,2.18mmol,1.0 eq) was weighed out separately, and sodium iodide (729.7 mg,4.87mmol,2.23 eq) was dissolved in 15mL high pressure reaction tube, followed by addition of dioxane (2.0 mL) and ethylene glycol dimethyl ether (30. Mu.L). Nitrogen protection was exchanged, followed by dropwise addition of fluorosulfonyldifluoromethyl acetate (556. Mu.L, 4.37mmol,2.0 equiv.) and trimethylchlorosilane (474.3 mg,4.37mmol,2.0 equiv.) in this order, and after the addition, the reaction was moved to 120℃under an oil bath and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 30mL of ethyl acetate and 30mL of water were added, and the mixture was stirred for 30min. The organic phase was separated, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether=1:15) to give compound 11c as a white solid (220 mg, yield 30%).

LC-MS m/z(ESI)＝341.30[M+1]。

And a third step of:

5- (2, 2-Difluorocyclopropyl) -2- (piperazin-1-yl) pyrimidine (intermediate 11)

5-(2,2-difluorocyclopropyl)-2-(piperazin-1-yl)pyrimidine

The crude intermediate 11 was prepared as a white solid 169mg by the synthetic method of reference compound 2 c. Intermediate 11 was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝241.29[M+1]。

Intermediate 12

2- (piperazin-1-yl) -5- (2, 3-trifluorocyclopropyl) pyrimidine (intermediate 12)

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

The first step:

4- (5- (2-bromo-1-fluoroethyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (12 a)

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

Compound 11b (420 mg,1.4mmol,1.0 equiv) was weighed into a 25mL reaction flask and dissolved by adding 10mL dichloromethane. The reaction was cooled to 0℃and then a solution of triethylamine in hydrogen trifluoride (338 mg,2.1mmol,1.5 equiv.) was added dropwise, and bromosuccinimide (300 mg,1.68mmol,1.2 equiv.) was added to the reaction solution. The reaction naturally warmed to room temperature and stirring was continued for 1h. After the reaction was completed, the reaction was poured into 20mL of ice water, the aqueous phase was adjusted to be alkaline with concentrated aqueous ammonia, the organic phase was extracted with methylene chloride (3×40 mL), and concentrated in vacuo, and dried to give compound 12a as a pale yellow oily substance 344mg.12a was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝390.20[M+1]。

And a second step of:

4- (5- (1-fluorovinyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (12 b)

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

Compound 12a (344 mg,0.88mmol,1.0 equiv) and potassium tert-butoxide (188 mg,1.68mmol,1.2 equiv) were weighed into a 25mL reaction flask, dissolved in tetrahydrofuran (10 mL) and the reaction was stirred at 50deg.C. After the reaction was completed, the reaction solution was naturally cooled to room temperature, and then slowly added to 30mL of an ice-water mixture, dichloromethane (3×40 mL) was extracted, and the organic phase was separated, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether=1:20) to give compound 12b as a white solid (128 mg, yield 47%).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.62(s,2H),5.25(dd,1H),4.82(dd,1H),3.87–3.72(m,4H),3.41(t,4H),1.42(s,9H)。

LC-MS m/z(ESI)＝309.30[M+1]。

And a third step of:

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

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

Compound 12b (64 mg,0.2mmol,1.0 eq.) is weighed out, anhydrous sodium iodide (6 mg,0.04mmol,0.2 eq.) is dissolved by adding 5mL anhydrous tetrahydrofuran. (trifluoromethyl) trimethylsilane (74. Mu.L, 0.5mmol,2.5 equiv) was added to the reaction under nitrogen. After the addition, the reaction was allowed to react at 65℃with stirring for 2h. After the reaction was completed, the reaction mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether=1:15) to give compound 12c as a colorless oil (54 mg, yield 75%).

LC-MS m/z(ESI)＝359.33[M+1]。

Fourth step:

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

The synthesis of reference compound 2c afforded crude intermediate 12 as a white solid, 47mg. Intermediate 12 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝259.30[M+1]。

Intermediate 13

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

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

The first step:

3- (5-Cyclopropylpyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (13 a)

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

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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.20(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)。

LC-MS m/z(ESI)＝317.20[M+1]。

And a second step of:

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

The synthesis of reference compound 2c afforded intermediate 13 as a white solid. Intermediate 13 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝217.20[M+1]。

Intermediate 14

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

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

Referring to the synthesis of intermediate 13, crude intermediate 14 was prepared as a white solid. Intermediate 14 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝231.20[M+1]。

Intermediate 15

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

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

The first step:

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 (15 b)

tert-butyl8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-propoxy)-propanoyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

15a (212 mg,1.0mmol,1.0 equiv.) is weighed separately, intermediate 1 (401 mg,1.3mmol,1.3 equiv.) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (380 mg,1.0mmol,1.0 equiv.) is dissolved in a 10mL reaction flask and taken up in N, N-dimethylformamide (4.0 mL). N, N-diisopropylethylamine (0.65 mL,4.0mmol,4 equiv) was added to the mixture and the reaction was stirred at 25℃for 1h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give 15b as a white solid (307 mg, yield 61%).

LC-MS m/z(ESI)＝505.20[M+1]。

And a second step of:

The synthesis of reference compound 2c afforded crude intermediate 15 as a white solid, 100mg. Intermediate 15 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝405.20[M+1]。

Intermediate 16

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

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

Referring to the synthesis of intermediate 13, crude intermediate 16 was prepared as a white solid. Intermediate 16 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝233.20[M+1]。

Intermediate 17

5-cyclopropyl-2- ((2S, 5R) -2, 5-dimethylpiperazin-1-yl) pyrimidine (intermediate 17)

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

Referring to the synthesis of intermediate 13, crude intermediate 17 was prepared as a white solid. Intermediate 17 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝217.20[M+1]。

Intermediate 18:

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

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

The first step:

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

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

1g (550 mg,1.539mmol,1.0 equiv) of the compound, tert-butyl 2-bromopropionate (479 mg,2.309mmol,1.5 equiv) and potassium tert-butoxide (319 mg,2.309mmol,1.5 equiv) were sequentially weighed out, reacted in 11.0mL of DMF at room temperature for 3h, quenched with water by the addition of 30mL of water, extracted twice with 30mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate=3:1) to give the compound 18a as a yellow solid (360 mg, yield 48%).

LC-MS m/z(ESI)＝486.5[M+1]。

And a second step of:

In a 20mL single-port flask, compound 18a (300 mg,0.618mmol,1 equiv) was dissolved in 5mL DCM, then 2mL trifluoroacetic acid was added and reacted at room temperature for 2h, after the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=3:2) to give intermediate 18 as a white solid (250 mg, 94% yield).

LC-MS m/z(ESI)＝430.4[M+1]。

Intermediate 19

3- ((1- (1- (1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionic acid (intermediate 19)

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

The first step:

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

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

1f (1.5 g,4.72mmol,1.0 equiv) was weighed into a 100mL reaction flask and dissolved in N, N-dimethylformamide (15 mL). Subsequently, diisopropylethylamine (3.3 mL,18.87mmol,4.0 equiv) and pyrrol-2-ylmethanol (0.53 g,5.19mmol,1.1 equiv) were added sequentially. The mixture was stirred at 100℃for 2h. After completion of the reaction, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 19a as a white solid (1.59 g, yield 88%).

LC-MS m/z(ESI)＝384.15[M+1]。

And a second step of:

pyrrolidin-2-ylmethoxymethyl 3- ((1- (1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionate (19 b)

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

Compound 19a (1.59 g,4.16mmol,1.0 equiv) was weighed into a 50mL reaction flask and dissolved by adding acetonitrile (14 mL). To the mixture was slowly added dropwise methyl prop-2-enoate (3.6 g,41.55mmol,10.0 equiv). After the addition, the reaction mixture was stirred at 30℃for 4h. After completion of the reaction, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 19b as a white solid (1.04 g, yield 53%).

LC-MS m/z(ESI)＝470.18[M+1]。

And a third step of:

3- ((1- (1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionic acid (intermediate 19)

Compound 19b (1.04 g,2.21 mmol,1.0 equiv) and lithium hydroxide monohydrate (265 mg,11.09mmol,5.0 equiv) were weighed separately into a 50mL reaction flask. Subsequently, methanol (5 mL) and water (5 mL) were added in this order, and the reaction solution was stirred at 25℃for 1h. After the reaction was completed, the pH of the reaction mixture was adjusted to 6 with trifluoroacetic acid. The reaction mixture was concentrated in vacuo and the residue was purified by C18 reverse phase chromatography (water: acetonitrile=5:1) to give intermediate 19 as a pale yellow solid (830 mg, 82% yield).

LC-MS m/z(ESI)＝456.17[M+1]。

Intermediate 20

1- (5-cyclopropyl-3- (trifluoromethyl) pyridin-2-yl) piperazine (intermediate 20)

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

The first step:

4- (5-bromo-3- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (20 b)

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

20a (3.9 g,15.00mmol,1.0 equiv) piperazine-1-carboxylic acid tert-butyl ester (5.54 g,22.5mmol,1.5 equiv) and potassium carbonate (7.3 g,52.5mmol,3.5 equiv) were weighed into a 250mL reaction flask. Subsequently, acetonitrile (40 mL) was added to the mixture to dissolve, and the reaction was heated under an oil bath at 80 ℃ and stirred for 2h. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give intermediate 20b as a white solid (1.4 g, yield 22.67%).

LC-MS m/z(ESI)＝409.06[M+1]。

And a second step of:

4- (5-cyclopropyl-3- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (20 c)

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

To a 25mL reaction flask, weighed intermediate 20b (1.4 g,3.40mmol,1.0 equiv), cesium carbonate (2.78 g,8.50mmol,2.5 equiv), cyclopropylboronic acid (442 mg,5.1mmol,1.5 equiv) and [1,1' -bis (diphenylphosphine) ferrocene were added separately]Palladium dichloride dichloromethane complex (277 mg,0.34mmol,0.1 equiv). Subsequent addition of Toulune/H ₂ O (20/2 mL) mixture, pumping nitrogen for protection, and heating the reaction in an oil bath at 95deg.C Stirring for 2h. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated in vacuo, and chromatographed on a column (petroleum ether: ethyl acetate=5:1) to give intermediate 20c as a white solid (1.02 g, yield 79.41%).

LC-MS m/z(ESI)＝371.18[M+1]

And a third step of:

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

Referring to the synthetic procedure for compound 2c, intermediate 20 was prepared as a white solid (800 mg, 97% yield).

LC-MS m/z(ESI)＝271.18[M+1]。

Intermediate 21

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

5-cyclopropyl-2-(piperazin-1-yl)nicotinonitrile

The first step:

2-chloro-5-cyclopropylnicotinonitrile (21 b)

2-chloro-5-cyclopropylnicotinonitrile

Into a 25mL reaction flask, weighed compound 21a (2.17 g,10mmol,1.0 equiv), cesium carbonate (8.2 g,25mmol,2.5 equiv), cyclopropylboronic acid (1.72 g,20mmol,2.0 equiv) and [1,1' -bis (diphenylphosphine) ferrocene were added, respectively]Palladium dichloride dichloromethane complex (816 mg,1mmol,0.1 equiv). Subsequent addition of Toulune/H ₂ O (20/2 mL) and nitrogen were purged, and the reaction was heated in an oil bath at 95deg.C and stirred for 2h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated in vacuo, and chromatographed on a column (petroleum ether: ethyl acetate=5:1) to give intermediate 21b as a white solid (670 mg, yield 38.40%).

LC-MS m/z(ESI)＝178.03[M+1]

And a second step of:

4- (3-cyano-5-cyclopropylpyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (21 c)

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

Referring to the synthetic method of intermediate 2b, intermediate 21c was purified via column chromatography (petroleum ether: ethyl acetate=3:1) as a white solid (0.8 g, yield 63.80%).

LC-MS m/z(ESI)＝328.19[M+1]。

And a third step of:

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

5-cyclopropyl-2-(piperazin-1-yl)nicotinonitrile

The synthesis of reference compound 2c afforded intermediate 21 as a white solid. Intermediate 21 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝228.19[M+1]。

Intermediate 22

2-cyclopropyl-5- (piperazin-1-yl) pyrazine (intermediate 22)

2-cyclopropyl-5-(piperazin-1-yl)pyrazine

The first step:

4- (5-Chloropyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (22 b)

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

Referring to the synthetic method of intermediate 2b, intermediate 22b was purified via column chromatography (petroleum ether: ethyl acetate=3:1) as a pale yellow solid (2.0 g, yield 50%).

LC-MS m/z(ESI)＝298.12[M+1]。

And a second step of:

4- (5-Cyclopropylpyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (22 c)

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

Referring to the synthetic procedure for intermediate 2, purification via column chromatography (petroleum ether: ethyl acetate=3:1) afforded intermediate 22c as a white solid (0.9 g, 44% yield).

LC-MS m/z(ESI)＝304.19[M+1]

And a third step of:

2-cyclopropyl-5- (piperazin-1-yl) pyrazine (intermediate 22)

2-cyclopropyl-5-(piperazin-1-yl)pyrazine

The synthesis of reference compound 2c produced intermediate 22 as a white solid. Intermediate 22 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝204.19[M+1]。

Intermediate 23

3- ((S) -2-aminopropoxy) -1- (4- (5-cyclopropylpyrimidin-2-yl) piperazin-1-yl) butanone (intermediate 23)

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

The first step:

1- (4- (5-Cyclopropylpyrimidin-2-yl) piperazin-1-yl) -3-hydroxybutan-1-one (23 a)

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

Intermediate 2 (139 mg,0.50mmol,1.0 equiv.) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (144 mg,0.75mmol,1.5 equiv.) 1-hydroxybenzotriazole (101 mg,0.75mmol,1.5 equiv.) is weighed separately into a 10mL reaction flask and dissolved in N, N-dimethylformamide (2.0 mL). N, N-diisopropylethylamine (331. Mu.L, 2.0mmol,4 equiv.) and 3-hydroxybutyric acid (57 mg,0.55mmol,1.1 equiv.) are added dropwise to the mixture in this order, and the reaction is stirred at 25℃for 12h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give intermediate 23a as a pale yellow oil (135 mg, yield 60%).

LC-MS m/z(ESI)＝290.3[M+1]。

And a second step of:

((2S) -1- ((4- (4- (5-cyclopropylpyrimidin-2-yl) piperazin-1-yl) -4-oxobutan-2-yl) oxy) propan-2-yl) carbamic acid tert-butyl ester (23 b)

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

In a 50mL reaction flask, intermediate 23a (130 mg,0.45mmol,1.0 equiv) was weighed and dissolved in anhydrous N, N-dimethylformamide (4 mL). Sodium hydride (54 mg,1.35mmol,3.0 equiv.) was added in portions at 0deg.C under nitrogen, and stirring was continued at that temperature for 10min. Subsequently, a solution of (S) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (160 mg,0.68mmol,1.5 equiv.) in N, N-dimethylformamide (7 mL) was slowly added dropwise to the reaction system, the temperature during the dropwise addition was kept at 0℃and stirring was continued for 2 hours. After the reaction was complete, the reaction was adjusted to ph=3 with hydrochloric acid solution (2M) and stirred at room temperature for 0.5h. The reaction mixture was extracted with ethyl acetate (3X 120 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product which was purified by column chromatography (dichloromethane: methanol=20:1) to give intermediate 23b as a colorless oil (40 mg, 40% yield).

LC-MS m/z(ESI)＝448.6[M+1]。

And a third step of:

The crude product of intermediate 23 was prepared as a white solid by the synthetic method of reference compound 2 c. Intermediate 23 can be used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝348.5[M+1]。

Intermediate 24

2- (piperazin-1-yl) -5- (2, 3-tetrafluorocyclopropyl) pyrimidine (intermediate 24)

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

The first step:

4- (5-formyl-pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (24 c)

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

Referring to the synthesis of intermediate 2b, crude intermediate 24c was obtained as a white solid. Intermediate 24c was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝293.40[M+1]。

And a second step of:

4- (5- (2, 2-Difluorovinyl) pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (24 d)

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

Intermediate 24c (2.83 g,12mmol,1.0 equiv) was weighed into a 250mL reaction flask, triphenylphosphine (4.72 g,18.0mmol,1.5 equiv) dissolved in N, N-dimethylformamide (70 mL) and added in portions with nitrogen blanket to sodium difluorobromoacetate (completed in 10 min); after the addition, the reaction was stirred at 90℃for 2h. After the reaction was completed, the reaction solution was cooled to room temperature and distilled under reduced pressure. Column chromatography (petroleum ether: ethyl acetate=3:1) afforded intermediate 24d as a yellow solid (2.1 g, 73% yield).

LC-MS m/z(ESI)＝327.40[M+1]。

And a third step of:

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

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

Intermediate 24d (1.0 g,3.1mmol,1.0 equiv) was weighed into a 100mL reaction flask, dissolved in diethylene glycol dimethyl ether, and the reaction was heated to 180deg.C under nitrogen. After the temperature was raised to the specified temperature, sodium chlorodifluoroacetate (1.65 g,10.8mmol,3.5 equiv) was added in portions under nitrogen bubbling; after the addition, the reaction was stirred for 4 hours. After the reaction was complete, the residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give intermediate 24e as a white solid (354.4 mg, yield 30%).

LC-MS m/z(ESI)＝377.4[M+1]。

Fourth step:

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

The synthesis of reference compound 2c produced intermediate 24 as a white solid. Intermediate 24 was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝277.4[M+1]。

Example 1

(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)

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

Intermediate 1 (303 mg,0.979mmol,1.0 equiv.) and intermediate 2 (200 mg,0.979mmol,1.0 equiv.) are weighed out separately, and urea hexafluorophosphate (372 mg,0.979mmol,1.0 equiv.) is dissolved in a 10mL reaction flask as N, N-dimethylformamide (4.0 mL). N, N-diisopropylethylamine (0.65 mL,3.916mmol,4 equiv) was added to the mixture, and the reaction was stirred at 25℃for 1h. After the reaction was complete, concentrated in vacuo and the residue purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give compound 1 as a white solid (125 mg, yield 25%).

¹ H NMR(400MHz,Chloroform-d)δ10.33(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)。

LCMS m/z＝496.5[M+l]。

Example 2

(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)

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

Referring to the synthetic method for compound 1, compound 2 was prepared as a white solid (157 mg, 34% yield).

¹ H NMR(400MHz,Chloroform-d)δ10.36(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)。

LCMS m/z＝510.6[M+l]。

Example 3

(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)

(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

Referring to the synthetic method for compound 1, compound 3 was prepared as a white solid (70 mg, 42% yield).

¹ H NMR(600MHz,DMSO-d ₆ )δ12.46(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)。

LCMS m/z＝514.4[M+l]。

Example 4

(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)

(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

The first step:

1- (2- (piperazin-1-yl) pyrimidin-5-yl) cyclobutanol (4A)

1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclobutan-1-ol

Referring to the synthesis of intermediate 2c, crude compound 4A was obtained as a white solid. Compound 4A was used directly in the next reaction without further purification.

LCMS m/z＝235.2[M+1]。

And a second step of:

Referring to the synthetic method for compound 1, compound 4 was prepared as a white solid (70 mg, 26% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(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)。

LCMS m/z＝526.3[M+1]。

Example 5

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)

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

Referring to the synthetic method for compound 1, compound 5 was prepared as a white solid (280 mg, 53% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.45(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)。

LCMS m/z＝524.3[M+l]。

Example 6

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)

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

Referring to the synthetic method for compound 1, compound 6 was prepared as a white solid (60 mg, 82% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.47(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)。

LCMS m/z＝560.54[M+l]。

Example 7

(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)

(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

The first step:

1- (2- (piperazin-1-yl) pyrimidin-5-yl) cyclopropan-1-ol (7A)

1-(2-(piperazin-1-yl)pyrimidin-5-yl)cyclopropan-1-ol

Referring to the synthetic procedure for intermediate 2c, crude compound 7A was prepared and compound 7A was used directly in the next reaction without further purification.

LCMS m/z＝221.3[M+l]。

And a second step of:

Referring to the synthetic method for compound 1, compound 7 was prepared as a white solid (16 mg, yield 6%).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(s,1H),8.29(s,2H),7.91(s,1H),6.31–6.26(m1H),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)。

LCMS m/z＝512.3[M+l]。

Example 8

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

(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

Referring to the synthetic method for compound 1, compound 8 was prepared as a white solid (40 mg, yield 25%).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.44(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)。

LCMS m/z＝522.3[M+l]。

Example 9

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

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

Referring to the synthetic method for compound 1, compound 9 was prepared as a white solid (76 mg, 50% yield).

¹ H NMR(600MHz,DMSO-d ₆ )δ12.47(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)。

LCMS m/z＝508.3[M+l]。

Example 10

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

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

The first step:

(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)

(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

Referring to the synthetic method for compound 1, compound 10A was prepared as a white solid product (200 mg, 63% yield).

LC-MS m/z(ESI)＝602.6[M+1]。

And a second step of:

To a 25mL reaction flask weighed compound 10A (200 mg,0.33mmol,1.0 equiv) was added trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL,2.64mmol,8.0 equiv) in sequence. After the addition, the reaction was stirred at 25℃for 2h. Subsequently, 15mL of water was added to the reaction solution for quenching. Ethyl acetate extraction (3×20 mL), the pH of the organic layer was adjusted to 8 to 9 with aqueous potassium carbonate. The organic layers were combined, concentrated in vacuo and the residue was purified by reverse phase (water: acetonitrile=3:2) to give compound 10 as a white solid (105 mg, 62% yield).

¹ H NMR(600MHz,DMSO)δ12.47(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)。

LC-MS m/z(ESI)＝482.2[M+1]。

Example 11

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

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

The first step:

(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)

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

Referring to the synthetic method for compound 1, compound 11B was prepared as a white solid (320 mg, 97%).

LC-MS m/z(ESI)＝508.3[M+1]。

And a second step of:

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

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

Referring to the synthesis method of the intermediate 2C, a crude product of the compound 11C is prepared. 11C was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝408.3[M+1]。

And a third step of:

Compound 11C (200 mg,0.416mmol,1.0 equiv.) is dissolved in N' N-dimethylacetamide (2.0 mL) and intermediate 7a (70.7 mg,0.46mmol,1.1 equiv.) is added sequentially, N, N-diisopropylethylamine (0.36 mL,2.08mmol,5.0 equiv.). After the addition, the reaction was stirred at 120℃for 5h, and the reaction mixture was concentrated in vacuo after the reaction was complete. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:1.5) to give compound 11 as a white solid (30 mg, 14%).

¹ H NMR(600MHz,DMSO-d6)δ12.47(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＝9.6Hz,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)。

LC-MS m/z(ESI)＝526.23[M+1]。

Example 12

(S) -1- (2- (4- (3- (2- (((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) piperazin ] -1-yl) pyrimidin-5-yl) cyclopropane-1-carbonitrile (compound 12)

(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

Referring to the synthetic method for compound 1, compound 12 was prepared as a white solid (98 mg, 34% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(s,1H),8.30(s,2H),7.90(s,1H),6.34–6.28(m1H),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)。

LC-MS m/z＝521.50[M+l]。

Example 13

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)

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

5- (((S) -1- (3- (4- (5- ((S) -2, 2-difluorocyclopropyl)) pyrimidin-2-yl) piperidin-1-yl) -3-ylpropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 13-2)

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

The first step:

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)

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

Referring to the synthetic method for compound 1, compound 13 was prepared as a white solid (98 mg, 34% yield).

LCMS m/z＝521.50[M+l]。

And a second step of:

Resolution of racemate 13 by SFC gave compound 13-1 (27 mg, ee%:100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol=70:30; column temperature: 35; column pressure: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; 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: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; RT= 18.869 min).

Compound 13-1: ¹ H NMR(400MHz,DMSO-d ₆ )δ8.80(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)。

compound 13-2: ¹ H NMR(400MHz,DMSO-d6)δ8.79(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)。

example 14

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

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

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

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

The first step:

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

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

Referring to the synthetic method for compound 1, compound 14 was prepared as a white solid (51 mg, 46% yield).

LCMS m/z＝550.40[M+l]。

And a second step of:

Resolution of racemate 14 by SFC gave compound 14-1 (30 mg, ee%:100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol=70:30; column temperature: 35; column pressure: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; RT= 15.850 min) and compound 14-2 (29 mg, ee%:100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol=70:30; column temperature: 35; column pressure: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; RT= 16.936 min).

Compound 14-1: ¹ H NMR(600MHz,DMSO-d ₆ )δ12.46(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)。

compound 14-2: ¹ H NMR(600MHz,DMSO-d ₆ )δ12.46(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)。

example 15

5- ((2S) -1- (3- (3- (5-cyclopropylpyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) -3-oxypropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 15)

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

Referring to the synthetic method for compound 1, compound 15 was prepared as a white solid (270 mg, 44% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.48(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)。

LCMS m/z＝508.10[M+l]。

Example 16

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

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

Referring to the synthetic method for compound 1, compound 16 was prepared as a white solid (128 mg, 20% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.44(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)。

LCMS m/z＝522.10[M+l]。

Example 17

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

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

2-chloro-5-cyclopropylpyrimidine 7a (92 mg,0.6mmol,1.0 equiv) was weighed out and dissolved in N, N-dimethylformamide (10 mL), intermediate 15 (240 mg,0.6mmol,1.0 equiv) and N, N-diisopropylethylamine (0.5 mL,3mmol,5.0 equiv) were added in this order, and the reaction was heated and stirred at 120℃in an oil bath for 1h. The reaction solution was cooled to room temperature and distilled under reduced pressure. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give compound 17 as a white solid (78 mg, yield 25%).

¹ H NMR(400MHz,DMSO-d6)δ12.46(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)。

LC-MS m/z(ESI)＝522.20[M+1]。

Example 18

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

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

Referring to the synthetic procedure for compound 1, compound 18 was prepared as a white solid (40 mg, 50% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.44(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),δ1.12–0.94(m,6H),0.90–0.82(m,2H),0.67–0.56(m,2H)。

LC-MS m/z(ESI)＝524.20[M+1]。

Example 19

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

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

Referring to the synthetic method for compound 1, compound 19 was prepared as a white solid (80 mg, 31% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.47(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)。

LC-MS m/z(ESI)＝508.20[M+1]。

Example 20

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

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

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

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

The first step:

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

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

Referring to the synthetic method for compound 1, compound 20B was prepared as a white solid (230 mg, 72% yield).

LC-MS m/z(ESI)＝492.51[M+1]。

And a second step of:

5- ((2S) -1- (3- (2-methylpiperazin-1-yl) -3-oxypropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (20C)

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

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

LC-MS m/z(ESI)＝392.40[M+1]。

And a third step of:

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

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

Referring to the synthesis of compound 19, compound 20 was prepared as a white solid (140 mg, 40% yield).

LC-MS m/z(ESI)＝510.53[M+1]。

Fourth step:

Resolution of racemate compound 20 by SFC gave compound 20-1 (35 mg, ee%:99.74%, chiral HPLC (OX-3), mobile phase: n-hexane: isopropanol=80:20, column temperature: 35, column pressure: 80bar, flow rate: 2mL/min, detector signal path: 214nm@4.8nm, diode array detector start wavelength: 200nm, diode array detector end wavelength: 400nm, 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: 80bar, flow rate: 2mL/min, detector signal path: 214nm@4.8nm, diode array detector start wavelength: 200nm, diode array detector end wavelength: 400nm, rt= 6.596 min).

Compound 20-1: ¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(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)。

LC-MS m/z(ESI)＝510.60[M+1]。

compound 20-2: ¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(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)。

example 21

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

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

The first step:

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

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

Referring to the synthetic method for compound 1, compound 21B was prepared as a white solid (120 mg, 61% yield).

LC-MS m/z(ESI)＝506.54[M+1]。

And a second step of:

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

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

Referring to the synthesis of intermediate 2C, crude compound 21C was prepared as a white solid. Compound 21C was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝406.42[M+1]。

And a third step of:

Referring to the synthesis of compound 19, compound 21 was prepared as a white solid (40 mg, 23% yield).

¹ H NMR(400MHz,DMSO-d6)δ12.45(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)。

LC-MS m/z(ESI)＝524.56[M+1]。

Example 22

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) propanamide (Compound 22)

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

The first step:

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)

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

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

LC-MS m/z(ESI)＝628.66[M+1]。

And a second step of:

n- ((3R, 4R) -3-hydroxypiperidin-4-yl) -2- ((S) -2- ((1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) amide (22C)

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

The synthesis method of the reference compound 2C is used for preparing a crude product of the compound 22C, which is a white solid. Compound 22C was used directly in the next reaction without further purification.

LC-MS m/z(ESI)＝528.55[M+1]。

And a third step of:

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) propanamine (22D)

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

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

LC-MS m/z(ESI)＝646.68[M+1]。

Fourth step:

Referring to the synthetic procedure for intermediate 1i, compound 22 was prepared as a white solid (41 mg, 45% yield).

¹ H NMR(400MHz,DMSO-d6)δ12.45(d,J＝24.8Hz,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)。

LC-MS m/z(ESI)＝526.53[M+1]。

Example 23

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

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

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

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

The first step:

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)

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

Referring to the synthetic method for compound 1, compound 23A was prepared as a white solid (810 mg, 66% yield).

LC-MS m/z(ESI)＝670.25[M+1]。

And a second step of:

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)

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

Referring to the synthetic method for intermediate 1i, compound 23 was prepared as a white solid (485 mg, 73% yield).

LC-MS m/z(ESI)＝550.19[M+1]。

And a third step of:

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

Resolution of racemate compound 23 by SFC gave compound 23-1 (54 mg, ee%:100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol=70:30; column temperature: 35; column pressure: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; 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: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; rt= 18.869 min).

Compound 23-1: ¹ H NMR(400MHz,DMSO-d6)δ12.36(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＝6.4Hz,1H),1.87(d,J＝5.1Hz,1H),1.76(d,J＝5.2Hz,1H),1.62(d,J＝3.8Hz,2H),0.90–0.83(m,2H),0.66–0.60(m,2H)。

LC-MS m/z(ESI)＝550.19[M+1]。

compound 23-2: ¹ H NMR(400MHz,DMSO-d6)δ12.36(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＝5.0Hz,1H),1.82–1.72(m,1H),1.62(t,J＝5.2Hz,2H),0.90–0.83(m,2H),0.66–0.60(m,2H)。

LC-MS m/z(ESI)＝550.19[M+1]。

example 24

5- ((R) -2- ((3- ((2S, 6R) -4- (5-cyclopropyl-pyrimidin-2-yl) -2, 6-dimethylpiperazin-1-yl) -3-oxypropoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 24-1)

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

5- ((S) -2- ((3- ((2S, 6R) -4- (5-cyclopropyl-pyrimidin-2-yl) -2, 6-dimethylpiperazin-1-yl) -3-oxypropoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 24-2)

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

The first step:

5- (2- ((3- ((2 r,6 s) -4- (5-cyclopropylpyrimidin-2-yl) -2, 6-dimethylpiperazin-1-yl) -3-oxypropoxy) methyl) pyrrolidin-1-yl) -2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (24A)

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

Referring to the synthetic procedure for compound 1, compound 24A was prepared as a yellow oil (300 mg, 45% yield).

LCMS m/z＝670.33[M+l]。

And a second step of:

5- (2- ((3- ((2R, 6S) -4- (5-cyclopropyl-pyrimidin-2-yl) -2, 6-dimethylpiperazin-1-yl) -3-oxypropoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 24)

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

Referring to the synthetic method for intermediate 1i, compound 24 was prepared as a white solid (180 mg, 73% yield).

LC-MS m/z(ESI)＝550.27[M+1]。

And a third step of:

Resolution of racemate compound 24 by SFC gave compound 24-1 (54 mg, ee%:100%, chiral HPLC (OX-3); mobile phase: n-hexane: ethanol=70:30; column temperature: 35; column pressure: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; 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: 80bar; flow rate: 2mL/min; detector signal path: 214nm@4.8nm; diode array detector start wavelength: 200nm; diode array detector end wavelength: 400nm; RT=7.49 min).

Compound 24-1: ¹ H NMR(400MHz,DMSO-d ₆ )δ12.34(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)。

compound 24-1: ¹ H NMR(400MHz,DMSO-d ₆ )δ12.34(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)。

example 25

(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)

Referring to the synthetic method for compound 1, compound 25 was prepared as a white solid (120 mg, 43% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(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)。

LC-MS m/z(ESI)＝563.20[M+1]。

Example 26

(S) -5-cyclopropyl-2- (4- (3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propyl) piperazin-1-yl) nicotinonitrile (compound 26)

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

Referring to the synthetic method for compound 1, compound 26 was prepared as a white solid (68 mg, 26% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.45(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)。

LC-MS m/z(ESI)＝520.22[M+1]。

Example 27

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

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

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

¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(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)。

LC-MS m/z(ESI)＝496.20[M+1]。

Example 28

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)

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

The first step:

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)

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

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

¹ H NMR(400MHz,DMSO-d ₆ )δ12.46(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),δ1.10–0.94(m,3H),0.91–0.80(m,2H),0.62–0.55(m,2H)。

LC-MS m/z(ESI)＝630.70[M+1]。

And a second step of:

Reference compound 15 was prepared as a white solid (22 mg,80% yield) by the synthetic method of compound 28

¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(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)。

LC-MS m/z(ESI)＝510.20[M+1]。

Example 29

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

(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

Referring to the synthesis of compound 1, compound 29 was prepared as a white solid (66 mg, 43% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.45(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)。

LC-MS m/z(ESI)＝568.20[M+1]。

Biological assay

PARP enzymatic biochemical assay protocol:

1. coating: 1 Xhistory media (25. Mu.L/well) overnight coated.

2. Closing: blocking buffer 100. Mu.L/well was added and blocked for 90min.

3. Compound dilution: the compounds were diluted in a 1:3 ratio at 8 concentrations, starting at 1000nM.

4. To 12.5. Mu.L of a mixture containing 10 XPAR buffer, 10 XP PARP Assay mixture, 5 XPivated DNA, distilled water, 2.5. Mu.L of different concentrations of compound, 10. Mu.L of enzyme (1-2 ng/. Mu.L) were added and incubated for 1h at room temperature.

5. Dilute strepitavidin-HRP was added and incubated for 30min, and the color development was performed by adding a color development solution.

6. Chemiluminescent readings were performed with a microplate reader.

IC ₅₀ : refers to the concentration of the compound at which PARP enzyme activity is 50% inhibited.

TABLE 1 PARP-7 enzyme inhibitory Activity of Compounds

Conclusion: the compound has remarkable biological inhibition activity on PARP-7 target protein.

TABLE 2 Selectivity of Compounds for PARP-1, PARP-7 subtype

Conclusion: compared with a control, the compound provided by the invention has stronger PARP-7 selectivity.

NCI-H1373 cell proliferation inhibition protocol

1. NCI-H1373 cells were seeded into 96-well cell culture plates (1500 per well) with a volume of 80 μl per well. Placing at 37deg.C and 5% CO ₂ Incubators were incubated overnight.

2. Compounds were made up in 10mM stock solution in DMSO and diluted in 1640 medium at 8 concentrations (1:5) with final concentrations of 10000, 2000, 400, 80, 16,3.2,0.64,0.128nm, respectively.

3. Taking cells without drug treatment as control group, respectively treating other cells with each drug concentration, setting cell-free culture holes as blank zeroing group, setting 2 parallel holes each, placing into 37 deg.C and 5% CO ₂ Culturing in an incubator.

4. After 6 days of culture, the 96-well plates were removed from the incubator, 100 μ L Cell Titer Blue working fluid was added to each well, shaken for 2min, and incubated for 10min.

5. Chemiluminescent readings were performed with a microplate reader.

6. Calculate cell viability = (treatment group fluorescence intensity/control group fluorescence intensity) ×100%, calculate half-inhibitory concentration by curve fitting (half maximal inhibitory concentration, IC) ₅₀ )。

IC ₅₀ : meaning that the cell proliferation is subject to 50%Concentration of compound at the time of inhibition.

TABLE 3 Compounds inhibit NCI-H1373 cell proliferation Activity

Conclusion: the compound has remarkable inhibition effect on NCI-H1373 cell proliferation.

CYP450 induction by drug metabolizing enzyme

1. Adherent primary human hepatocytes (3 donors) were incubated under the following experimental conditions: cell density of 0.7X10 ⁶ cell/mL, temperature 37.0deg.C, 5% CO ₂ 。

2. After 2-3 days of incubation of the compounds with cells, the enzymatic activity of CYP450 is tested.

3. Test data processing: % relative positive control activity (% of PC) = (compound-panel sample activity-blank sample activity)/(positive control sample activity-blank sample activity) ×100%

Positive control group: hepatocytes were incubated with an inducer of CYP450 (CYP 2B6 subtype corresponding to phenobarbital 1000. Mu.M, CYP3A4 subtype corresponding to rifampin 25. Mu.M).

Blank control group: cells were incubated with medium containing the same amount (v/v) of organic solvent.

TABLE 4 Induction experiments of the compounds on the Metabolic enzyme CYP450

Conclusion: the compound has no potential induction effect on the CYP450 activity of the metabolic enzyme, and the reference substance has obvious induction activity.

While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims

A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

R, R ', R' are each independently H or C _1-6 An alkyl group; or alternatively

R and R 'or R and R' form, with the atom to which they are attached, a 4-to 8-membered heterocycloalkyl group;

R ₁ 、R ₂ each independently is H or C _1-6 An alkyl group;

L ₁ is a bond or c=o;

l is a bond or NH;

C ₁ is a 6-, 7-or 8-membered heterocyclic group, preferably a 6-, 7-or 8-membered heterocyclic group containing 1, 2 or 3N atoms, more preferably

R ₃ 、R ₄ Each independently is H, halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from OH or CN;

c is a 6 membered heteroaryl, preferably a 6 membered heteroaryl containing 1, 2 or 3N atoms, more preferably

The 6 membered heteroaryl optionally being further substituted with 1 or more C selected from CN or optionally with 1 or more halogen _1-6 Substituted by alkyl;

C ₂ is C _3-6 A carbocycle;

R ₅ each independently is H, halogen, CN or OH;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is a 4-, 5-, or 6-membered heterocycloalkyl containing 1N atom.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R is H.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R', R "are each independently H or C _1-6 An alkyl group;
the compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₁ And R is ₂ H.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L ₁ C=o.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L ₁ C=o, L is NH.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L ₁ C=o, L is a bond.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C ₁ Is that
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₃ 、R ₄ Each independently is halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more OH groups.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C is
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C ₂ Is C ₃ Carbocycles.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₅ Is halogen.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
A compound of formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

R ₁ 、R ₂ Each independently selected from H or C _1-6 An alkyl group;

R ₃ 、R ₄ each independently selected from H, halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from OH or CN;

R ₅ each independently selected from H, halogen, CN or OH;

l is a bond or-NH-;

C ₁ is that

C ₂ Is C _3-5 A carbocycle;

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₁ And R is ₂ H.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₃ 、R ₄ Each independently is halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more OH groups.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C ₂ Is C ₃ Carbocycles.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₅ Is halogen.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.
The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein m is 0.
A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from the following structures:
an intermediate compound for preparing a compound of general formula (I), (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, having a compound of general formula (III), (IV), (V) or (VI):

Wherein the method comprises the steps of

R, R ', R' are each independently H or C _1-6 An alkyl group; or alternatively

R and R 'or R and R' form, with the atom to which they are attached, a 4-to 8-membered heterocycloalkyl group;

R ₁ 、R ₂ each independently is H or C _1-6 An alkyl group;

L ₁ is a bond or c=o;

l is a bond or NH;

C ₁ is a 6-to 8-membered heterocyclic group, preferably

R ₃ 、R ₄ Each independently is H, halogen or C _1-6 Alkyl, wherein the C _1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from OH or CN;

c is a 6 membered heteroaryl, preferably
The 6 membered heteroaryl is optionally further substituted with 1 or more groups selected from CN or C _1-6 Substituted by substituents of alkyl groups, said C _1-6 Alkyl is optionally further substituted with 1 or more halogens;

C ₂ is C _3-6 A carbocycle;

R ₅ each independently is H, halogen, CN or OH;

C ₃ is a 6-to 8-membered heterocyclic group, preferably

X ₁ Is H or NH ₂ ；

n is 1 or 2;

m is 0, 1, 2, 3, 4 or 5.
The compound of claim 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is a 4-, 5-, or 6-membered heterocycloalkyl containing 1N atom.
The compound of claim 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C ₁ Is a 6-, 7-or 8-membered heterocyclic group containing 1, 2 or 3N atoms.
The compound of claim 26, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein C is a 6 membered heteroaryl comprising 1, 2 or 3N atoms.
An intermediate compound according to claim 26, or a stereoisomer or pharmaceutically acceptable salt thereof, which is of the structure:
a pharmaceutical composition comprising:

(1) A compound of any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof;

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

(3) Pharmaceutically acceptable carriers and/or excipients.
Use of a compound according to any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, in the manufacture of an anti-tumour medicament; preferably, the tumor formation is related to PARP; more preferably, the PARP is PARP-7.
Use of a compound according to any one of claims 1 to 25, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, for the preparation of a PARP inhibitor; preferably, the PARP is PARP-7.