WO2022121914A1

WO2022121914A1 - Oxo-nitrogen ring derivative regulator, preparation method therefor, and application thereof

Info

Publication number: WO2022121914A1
Application number: PCT/CN2021/136249
Authority: WO
Inventors: 董加强; 邓欣贤; 龚珍; 肖华玲; 包如迪
Original assignee: 上海翰森生物医药科技有限公司; 江苏豪森药业集团有限公司
Priority date: 2020-12-10
Filing date: 2021-12-08
Publication date: 2022-06-16
Also published as: CN116134029A; TW202227413A

Abstract

An oxo-nitrogen ring derivative regulator, a preparation method therefor, and an application thereof, relating to an oxo-nitrogen ring derivative regulator, a preparation method therefor, and an application thereof and in particular to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and a use thereof as a regulator in the preparation of a related drug for the treatment of cancer, wherein each substituent in the general formula (I) is the same as the definition in the description.

Description

Oxonitrogen ring derivative regulator, its preparation method and application

technical field

The invention belongs to the field of biomedicine, in particular to an oxonitrogen ring derivative regulator and a preparation method and application thereof.

Background technique

CD73 is a type of cell surface glycosylphosphatidylinositol-fixed glycoprotein, encoded by the NT5E gene, also known as extracellular-5′-nucleotidase, expressed on the surface of many types of cells, including endothelial cells, lymphocytes, Stromal cells and various tumor cells. CD73 plays an important role in the conversion of intracellular AMP to adenosine. ATP (adenosine triphosphate) released by stressed or dying cells provides inflammatory signals that activate immunity. While extracellular ATP reacts with CD39 to generate ADP (adenosine diphosphate) or AMP (adenosine monophosphate), extracellular AMP is converted to adenosine by CD73, and adenosine passes through receptors (A1, A2 _A ) expressed on different cell surfaces. , A2 _B , A3) combined to exert physiological effects such as immunosuppression, induction of angiogenesis, and mucosal hydration.

Various studies have shown that CD73 is expressed on the surface of tumor cells such as rectal cancer, pancreatic cancer, non-small cell lung cancer, triple-negative breast cancer, and acute myeloid leukemia, and is expressed in regulatory T cells and macrophages in the tumor microenvironment. It is also expressed on the surface of dendritic cells, which promotes the increase of adenosine concentration in the tumor microenvironment. Adenosine binds to _A2A or _A2B on the surface of immune cells such as T cells, inhibits the proliferation and activation of T cells, and exerts immunity. inhibitory effect. Factors such as hypoxia and TGF-β in the tumor environment can increase the expression of CD73. Gene mutations such as TP53, KRAS, BRAF, and EGFR are also related to the high expression of CD73 in tumors. In addition, chemotherapy drugs, tyrosine kinase inhibitors, PD Both -1/PD-L1 inhibitors can up-regulate the expression of CD39 and CD73. Overexpression of CD73 is thought to be associated with poorer cancer prognosis and resistance to certain drugs. Targeting CD73 can reduce the production of adenosine in the tumor microenvironment, thereby achieving the effect of immune activation, and can be used in combination with PD-1/PD-L1 inhibitors or other target inhibitors of the adenosine pathway, such as _A2A inhibitors, It showed a good synergistic effect of immune activation in preclinical.

At present, a number of macromolecular and small molecule CD73 inhibitors have entered clinical research. CD73 antibody drugs such as BMS-986179 of BMS and MEDI-9447 of MedImmune/AstraZeneca have entered clinical phase II, single drug or combination therapy In a variety of solid tumors, early clinical results have shown a certain curative effect, and the safety is good. CD73 small-molecule inhibitors are progressing faster than Arcus' AB-680 and Eli Lilly's LY-3475070, both of which have entered clinical phase I and have launched clinical studies on a variety of solid tumors, but no efficacy data has been published yet. Several other companies are conducting preclinical studies.

To sum up, there is no approved targeted drug for CD73 target, clinical single drug or combination drug has the potential to treat a variety of solid tumors, and has broad market prospects.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound of general formula (I), its stereoisomer or its pharmaceutically acceptable salt:

in:

Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

Each R ¹ is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy radical, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 NR _AA R _BB , -CR _AA R _BB (CH ₂ ) _n1 NR _CC R _DD , -(CH ₂ ) _n1 R _AA , -CR _AA R _BB R _CC , -(CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 C(O)OR _AA , -(CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 SR _AA , -(CH ₂ ) _n1 NR _AA C(O)(CH ₂ ) _n2 R _BB , -(CH ₂ ) _n1 NR _AA C(O)OR _BB , -(CH ₂ ) _n1 NR _AA C(O)NR _BB R _CC or -NR _AA (CH ₂ ) _n1 R _BB , said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R _AA , R _BB , R _CC and R _DD are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy , haloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

Alternatively, any two of R _AA , R _BB , R _CC and R _DD and the nitrogen atom or carbon atom to which they are attached are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R ² is each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, deuterated alkoxy, haloalkyl, Hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n3 NR _A1 R _B1 , -CR _A1 R _B1 ( CH ₂ ) _n3 NR _C1 R _D1 , -(CH ₂ ) _n3 R _A1 , -CR _A1 R _B1 R _C1 , -(CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 C(O)OR _A1 , -( CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 SR _A1 , -(CH ₂ ) _n3 NR _A1 C(O)(CH ₂ ) _n4 R _B1 , -(CH ₂ ) _n3 NR _A1 C(O)OR _B1 , -(CH ₂ ) _n3 NR _A1 C(O)NR _B1 R _C1 or -NR _A1 (CH ₂ ) _n3 R _B1 , the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkane Oxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R _A1 , R _B1 , R _C1 and R _D1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy , haloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

Alternatively, any two of R _A1 , R _B1 , R _C1 and R _D1 and the nitrogen atom or carbon atom to which they are attached are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;

n1, n2, n3, n4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; and

Each of x, y is independently selected from 0, 1, 2, 3 or 4. In a further preferred embodiment of the present invention, Ring A is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

More preferably, a six-membered heterocyclic group containing nitrogen, oxygen or sulfur atoms;

Further preferably, oxo nitrogen-containing six-membered heterocyclic group;

more preferred

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (I-A):

in:

Ring C is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

More preferably C _3-6 cycloalkyl;

Further preference is given to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl;

R is each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1 -8} Deuterated alkoxy, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 Alkynyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, said amino, C _1-8 alkyl, C _1-8 Deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl , oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _{1 -8} haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl substituted by one or more of the substituents in;

Preferred are hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered Heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents;

y is selected from 0, 1, 2, 3 or 4;

z is selected from 0, 1, 2, 3, 4, 5 or 6; and

m is selected from 0 or 1.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II-A):

in:

--- is a single bond or a double bond;

m1 is selected from 0, 1, 2, 3 or 4;

In a further preferred embodiment of the present invention, Ring B is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

More preferably, a 5-10-membered monoheteroaryl or a 5-10-membered diheteroaryl;

Further preferably, a 5-10-membered monoheteroaryl group or a 5-10-membered di-heteroaryl group containing nitrogen, oxygen or sulfur atoms;

More preferably, 5-6 yuan nitrogen-containing monoheteroaryl or 8-10 yuan nitrogen-containing diheteroaryl;

Still further preferred,

Ring B is selected from

X ₁ is selected from -N- or -CH-, X ₂ and X ₃ are each independently selected from -N- or -C-, X ₄ and X ₅ are each independently selected from -N-, -NH- or -CH -,

is a single bond or a double bond;

Alternatively, Ring B is selected from

Y ₁ , Y ₂ , Y ₅ , Y ₆ are each independently selected from -N- or -CH-; Y ₃ is selected from -N-, -NH- or -CH-; Y ₄ is selected from -N-, -NH- , -CH- or -C(O)-,

is a single bond or a double bond;

Most preferably, ring B is selected from

In a further preferred embodiment of the present invention, the ring B is selected from

In a further preferred embodiment of the present invention, R ¹ is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 Alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n1 NR _AA R _BB , -CR _AA R _BB (CH ₂ ) _n1 NR _CC R _DD , -(CH ₂ ) _n1 R _AA , -CR _AA R _BB R _CC , -(CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 C(O)OR _AA , - (CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 SR _AA , -(CH ₂ ) _n1 NR _AA C(O)(CH ₂ ) _n2 R _BB , -(CH ₂ ) _n1 NR _AA C(O)OR _BB , -(CH ₂ ) _n1 NR _AA C(O)NR _BB R _CC or -NR _AA (CH ₂ ) _n1 R _BB , said amino, C _1-8 alkyl, C _1-8 deuterated alkyl , C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo , thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy one of C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl or replaced by multiple substituents,

Preferably, R ¹ is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, -(CH ₂ ) _n1 NR _AA R _BB , -CR _AA R _BB (CH ₂ ) _n1 NR _CC R _DD , -(CH ₂ ) _n1 R _AA , -CR _AA R _BB R _CC , -(CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 C(O)OR _AA , -(CH ₂ ) _n1 OR _AA , -(CH ₂ ) _n1 SR _AA , -(CH ₂ ) _n1 NR _AA C(O)(CH ₂ ) _n2 R _BB , -(CH ₂ ) _n1 NR _AA C(O)OR _BB , -(CH ₂ ) _n1 NR _AA C(O)NR _BB R _CC or -NR _AA (CH ₂ ) _n1 R _BB , said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _{1 -6} alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkene substituted by one or more substituents in base, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

R _AA , R _BB , R _CC and R _DD are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1 -8} haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C _6-14 aryl group or 5-14-membered heteroaryl group, said amino group, C _1-8 alkyl group, C _1-8 deuterated alkyl group, C _1-8 halogenated alkyl group, C _1-8 Hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2- 8} alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl substituted by one or more substituents,

Preferably, _RAA , _RBB , _RCC and _RDD are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, _C2-6 alkyl, _C2-6 deuterated alkyl , C _2-6 haloalkyl, C _2-6 hydroxyalkyl, C _2-6 alkoxy, C _2-6 haloalkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _2-6 alkyl group, C _2-6 deuterated alkyl group, C _2-6 halogenated alkyl group, C _2-6 hydroxyalkyl, C _2-6 alkoxy, C _2-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered hetero Cyclic, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _2-6 Alkyl, C _2-6 deuterated alkyl, C _2-6 haloalkyl, C _2-6 hydroxyalkyl, C _2-6 alkoxy, C _2-6 haloalkoxy, C _2-6 alkenyl, substituted by one or more substituents in C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

Alternatively, any two of R _AA , R _BB , R _CC and R _DD and the nitrogen or carbon atoms to which they are attached are linked to form C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium , halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, substituted by one or more substituents in C _6-14 aryl and 5-14-membered heteroaryl,

It is preferable to form a C _3-8 cycloalkyl group, a 3-8-membered heterocyclic group, a C _6-10 -membered aryl group or a 5-10-membered heteroaryl group, the C _3-8 cycloalkyl group, a 3-8 membered heterocyclic ring group, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkane base, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents.

In a further preferred embodiment of the present invention, R ² is each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 deuterated alkoxy, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n3 NR _A1 R _B1 , -CR _A1 R _B1 (CH ₂ ) _n3 NR _C1 R _D1 , -(CH ₂ ) _n3 R _A1 , -CR _A1 R _B1 R _C1 , -(CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 C(O)OR _A1 , -(CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 SR _A1 , -(CH ₂ ) _n3 NR _A1 C(O)(CH ₂ ) _n4 R _B1 , -( CH ₂ ) _n3 NR _A1 C(O)OR _B1 , -(CH ₂ ) _n3 NR _A1 C(O)NR _B1 R _C1 or -NR _A1 (CH ₂ ) _n3 R _B1 , the amino, hydroxyl, C _{1 -8} alkyl, C _1-8 deuterated alkyl, C _1-8 deuterated alkoxy, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _{1- 8} haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 deuterated Alkoxy, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C substituted by one or more substituents in _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl,

Preferably, R ² is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl , C _1-6 deuterated alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, -(CH ₂ ) _n3 NR _A1 R _B1 , -CR _A1 R _B1 (CH ₂ ) _n3 NR _C1 R _D1 , -(CH ₂ ) _n3 R _A1 , -CR _A1 R _B1 R _C1 , -(CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 C(O)OR _A1 , -(CH ₂ ) _n3 OR _A1 , -(CH ₂ ) _n3 SR _A1 , -(CH ₂ ) _n3 NR _A1 C(O)(CH ₂ ) _n4 R _B1 , -(CH ₂ ) _n3 NR _A1 C( O)OR _B1 , -(CH ₂ ) _n3 NR _A1 C(O)NR _B1 R _C1 or -NR _A1 (CH ₂ ) _n3 R _B1 , said amino, hydroxyl, C _1-6 alkyl, C _{1- 6} -deuterated alkyl, C _1-6 deuterated alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, Amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 deuterated alkoxy, C _1-6 Haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3 -Substituted by one or more substituents in the 8-membered heterocyclic group, the C _6-10 -membered aryl group or the 5-10-membered heteroaryl group;

R _A1 , R _B1 , R _C1 and R _D1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1 -8} haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C _6-14 aryl group or 5-14-membered heteroaryl group, said amino group, C _1-8 alkyl group, C _1-8 deuterated alkyl group, C _1-8 halogenated alkyl group, C _1-8 Hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _{2- 8} alkynyl, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl substituted by one or more substituents,

Preferably, R _A1 , R _B1 , R _C1 and R _D1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3- 8-membered heterocyclic group, C _6-10 -membered aryl group or 5-10-membered heteroaryl group, said amino group, C _1-6 alkyl group, C _1-6 deuterated alkyl group, C _1-6 halogenated alkyl group, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered hetero Cyclic, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 Alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, substituted by one or more substituents in C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

Alternatively, any two of R _A1 , R _B1 , R _C1 and R _D1 and the nitrogen atom or carbon atom to which they are attached are linked to form C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium , halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 Hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, substituted by one or more substituents in C _6-14 aryl or 5-14-membered heteroaryl,

It is preferable to form a C _3-8 cycloalkyl group, a 3-8-membered heterocyclic group, a C _6-10 -membered aryl group or a 5-10-membered heteroaryl group, the C _3-8 cycloalkyl group, a 3-8 membered heterocyclic ring group, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkane base, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl substituted with one or more substituents.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (II):

in:

^R3 and ^R4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, _C1-8 alkyl, _C1-8 deuterated alkyl base, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{3- 12} -cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, said amino, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkane base, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, sulfur substituted group, C _1-8 alkyl, C _1-8 deuterated alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, One or more of C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl substituted by a substituent;

Preferred are hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered Heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl, said amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _{2 -6} -alkynyl, C _3-8 cycloalkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl substituted with one or more substituents; more preferably hydrogen, Deuterium, halogen, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl or 5-10-membered heteroaryl, said C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkane oxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5- 10-membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Substituted by one or more substituents in alkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl;

More preferably hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, The C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, Oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1- Among ₆ haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl substituted by one or more substituents;

Further preferred is hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl or C _3-8 cycloalkyl; the C _1-6 alkyl or C _{3 -8} cycloalkyl, optionally further by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 ring Substituted by one or more substituents in alkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl

More preferably hydrogen, halogen, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl;

Still further preference is given to hydrogen, fluorine, chlorine, bromine, iodine, methyl, cyclopropyl, ethyl, propyl, isopropyl or trifluoromethyl.

In a further preferred embodiment of the present invention, R ² is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 deuterated alkoxy, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, _C6-10 aryl or 5-6 membered heteroaryl;

Preferred are hydrogen, deuterium, halogen, oxo, thio, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 deuterated alkoxy, C _1-3 haloalkyl, C _{1 -3} alkoxy, C _1-3 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl;

More preferably hydrogen, halogen, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl;

Further preferred are hydrogen, fluorine, chlorine, bromine, _-CD3 , methyl, ethyl, cyclopropyl;

y is selected from 1, 2 or 3, preferably 1.

In a further preferred embodiment of the present invention, the compound is further represented by general formula (II-1) or general formula (II-2):

When ring B is selected from

And when R ² is methyl, R ³ is not isopropyl.

In a further preferred embodiment of the present invention, the compound is further represented by general formula (IV), general formula (VI-1) or general formula (VI-2):

in:

Ring B is selected from 5-10 membered monoheteroaryl or 5-10 membered diheteroaryl;

Preferably 5-6 membered nitrogen-containing monoheteroaryl or 8-10 membered nitrogen-containing diheteroaryl;

More preferably,

Ring B is selected from

is a single bond or a double bond;

Alternatively, Ring B is selected from

Y ₁ , Y ₂ , Y ₅ , Y ₆ are each independently selected from -N- or -CH-; Y ₃ is selected from -N-, -NH-, -CH- or -CH ₂ -; Y ₄ is selected from -N -, -NH-, -CH-, _-CH2- or -C(O)-,

is a single bond or a double bond;

most preferred

Ring D is selected from C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

Preferably, Ring D is selected from cyclopropyl or cyclobutyl;

R ² is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1 -6} deuterated alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

Preferred are hydrogen, deuterium, halogen, amino, oxo, thio, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 deuterated alkoxy, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy;

More preferably hydrogen, halogen, amino, oxo, thio, methyl, methoxy or -CD3;

y is selected from 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (III-A), (III-B), (III-C), (III-D) or (III-E):

in:

R ⁵ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, said C _3-8 cycloalkyl, 3-8 membered heterocyclyl Cyclic, C _6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, C _1-6 alkyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, substituted by one or more substituents in C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

Preferably, R ⁵ is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclyl, the C _3-6 cycloalkyl and 3-6 membered heterocyclyl, optionally further deuterium, halogen, Amino, nitro, hydroxyl, cyano, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy and one or more substituents in C _3-6 cycloalkyl;

R ⁶ , R ⁷ _, R ⁸ are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 deuterium substituted alkoxy, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl or C _2-6 alkynyl; Preferably, R ⁶ , R ⁷ _, R ⁸ are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C _1-3 alkyl, C _1-3 deuterated alkyl, C _{1 -3} deuterated alkoxy, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (III-C):

R ⁵ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, optionally further by halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or _-CH2F is substituted with one or more substituents;

R ⁶ , R ⁷ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl, ethyl or trifluoromethyl.

In a further preferred embodiment of the present invention, the compound is further such as the general formula (IV-A-1), (IV-A-2), (IV-B-1), (IV-B-2), ( IV-C-1), (IV-C-2), (IV-D-1) or (IV-D-2):

in:

R ⁹ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 Haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3 -8-membered heterocyclyl, C _6-10 -membered aryl or 5-10-membered heteroaryl, the C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , C _6-10 aryl or 5-10 membered heteroaryl, optionally further by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C _1-6 alkane base, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C Substituted by one or more substituents in _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R ⁶ , R ⁷ and R ⁸ are as described above.

In a further preferred embodiment of the present invention, the specific structure of the compound is as follows:

The present invention further provides intermediates for synthesizing the compounds of the present invention, and the intermediates are shown in general formula (A):

wherein: Ring B, Ring C, R, R1, ^R2 , ^y , z, m and z are as defined above.

The present invention further provides intermediates for synthesizing the compounds of the present invention, and the intermediates are shown in general formula (B):

wherein: Ring B, R, R ¹ , R ² , m1 and z are all as defined above in general formula (II-A).

The present invention further provides intermediates for synthesizing the compounds of the present invention, and the intermediates are represented by general formula (C), general formula (C-1) or general formula (C-2):

wherein: ring B, ring D, R ² and y are all as defined in general formula (IV), general formula (IV-1) or general formula (IV-2) above.

The present invention further provides intermediates for synthesizing the compounds of the present invention, and the intermediates are shown in general formula (D):

wherein: R ⁵ , R ⁶ , and R ⁷ are as defined above in general formula (III-C).

The present invention further provides a method for preparing the compound of the present invention, comprising the steps of:

Wherein: the acid is selected from organic acid or inorganic acid, preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or phosphoric acid; organic acid is selected from 2,5- Dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetyl Aminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid , glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, Formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid , camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid acid, p-toluenesulfonic acid or L-malic acid;

Ring B, Ring C, R, R1, ^R2 , ^y , m and z are as defined above.

in:

Acid, Ring B, R, R1, ^R2 , ^y , m1 and z are as defined above.

in:

Acid, Ring B, Ring D, ^R2 and y are all as defined above.

in:

Acid, ^R5 , ^R6 , and ^R7 are as defined above.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds, a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

The present invention further relates to any one of the compounds of the general formula, stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical compositions in the preparation of CD73 inhibitor drugs.

The present invention further relates to the application of the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in preparing a medicine for treating cancer and related diseases.

The present invention also relates to a method of treating, preventing and/or treating cancer and related diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. pharmaceutical composition.

The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, conditions associated with CD73 inhibitors.

The present invention also relates to methods of treating cancer and related diseases in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrated substance or derivative.

The cancer described in the present invention is selected from solid tumors, gliomas or other tumors, preferably colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophagus cancer, head and neck cancer, brain cancer, glioblastoma, hepatocellular carcinoma, Lung cancer, melanoma, myeloma, pancreatic cancer, renal cell cancer, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms , more preferably an alkyl group of 1 to 4 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms; further preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydro Imidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably rolidine group, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl; more preferably rolidinyl, azetidinyl, Oxetanyl, oxanyl, piperidinyl, piperazinyl and pyranyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms above are further cyclo-linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, such as phenyl and naphthyl. More preferred is phenyl.

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10-membered, more preferably 5-8 membered, most preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazole base, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably An alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.

"Alkenyl" refers to an alkenyl group, also known as an alkenyl group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group of 2 to 6 carbon atoms, most preferably an alkyl group of 2 to 3 carbon atoms . The alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group of 2 to 6 carbon atoms, and most preferably an alkyl group of 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Fused ring group" refers to a polycyclic group formed by two or more carbocyclic or heterocyclic rings sharing a ring edge, and the fused ring group includes fused ring alkyl, fused ring heteroaryl, fused ring aryl and fused ring Cyclic heteroaryl group, wherein the fused cycloalkyl group refers to a polycyclic group formed by sharing a ring edge with a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; the fused ring heterocyclic group refers to a heterocyclic group. A polycyclic group formed by a ring group and a cycloalkyl group, an aryl group, and a heteroaryl group sharing a ring edge; the fused-ring aryl group refers to an aryl group, a cycloalkyl group, a heterocyclic group, and a heteroaryl group sharing a ring. The polycyclic group formed by the side of the ring; the fused ring heteroaryl group refers to the polycyclic group formed by the shared ring side of the heteroaryl group, the cycloalkyl group, the heterocyclic group and the hetero group; for example:

"Deuterated alkyl" refers to an alkyl group substituted with one or more deuteriums, wherein alkyl is as defined above.

"Deuterated alkoxy" refers to an alkoxy group substituted with one or more deuteriums, wherein alkoxy is as defined above.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carboxyl" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DEA" refers to diethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" means acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd2(dba ₎₃ _" refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" etc. all express the same Meaning, that means X can be any one or more of A, B, and C.

The hydrogen atom described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the embodiment compounds involved in the present invention can also be replaced by deuterium atom.

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

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have due biological activity.

Detailed ways

The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

Example

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or deuterated water (D ). ₂ O), the internal standard is tetramethylsilane (TMS).

An Agilent 1200 Infinity Series mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ~ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ~ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

The eluent system of silica gel column chromatography and the developing solvent system of thin layer chromatography used in the intermediates and purified compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: Dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Intermediate 1

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine

first step

3,6-Dichloropyridazine (1.0 g, 6.71 mmol) was suspended in 30 mL of deionized water, and (1R,2R)-2-isopropylcyclopropane-1-carboxylic acid (866 mg, 6.71 mmol) was added to prepare The method refers to WO2019168744A1) and concentrated sulfuric acid (1 mL), and heated to 70°C under nitrogen protection. Silver nitrate (228 mg, 1.34 mmol) solution (1 mL) was added, and then ammonium persulfate (4.5 g, 20.1 mmol) solution (15 mL) was added dropwise for about 30 minutes, and the reaction was continued at 70° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized with ammonia water to pH 8-9, and extracted with ethyl acetate (60 mL×2). The organic phases were combined, washed successively with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 1a (1.0 g), yield: 64.5%.

MS m/z(ESI): 230.8[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ6.87(s,1H), 2.03-1.98(m,1H), 1.32-1.29(m,1H), 1.27-1.23(m,1H), 1.18-1.13( m,1H),1.07-1.04(m,6H),1.02-0.98(m,1H).

second step

3,6-Dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 1a (740 mg, 3.20 mmol) was dissolved in 8 mL of 1,4-dioxane and 2 mL of water In the mixed solvent, 2,4-dimethoxypyrimidine-5-boronic acid (589 mg, 3.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (61 mg, 0.080 mmol) and cesium carbonate (1.25 g, 3.84 mmol), the mixture was replaced with nitrogen three times, and the reaction was microwaved at 70°C for 1 hour. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain The title product 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine intermediate 1 (455 mg) , Yield: 42.2%.

MS m/z(ESI): 335.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.76(s,1H), 7.58(s,1H), 3.99(s,3H), 3.98(s,3H), 2.02-1.97(m,1H) ,1.29-1.23(m,2H),1.13-1.07(m,2H),1.03-1.10(m,6H).

Intermediate 2

4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine

2,4-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrimidine (392 mg, 1.47 mmol), 4 , 6-dichloro-3-methylpyridazine (200 mg, 1.23 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (50 mg, 0.06 mmol) and Cesium carbonate (1.02 g, 3.07 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 5 mL), and the reaction solution was stirred at 70° C. for 3 hours under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, dried, and concentrated to obtain crude product, which was purified by silica gel column chromatography with eluent system B to obtain the title product 4-chloro -6-(2,4-Dimethoxypyrimidin-5-yl)-3-methylpyridazine Intermediate 2 (190 mg), yield: 58.1%.

MS m/z(ESI): 267.1[M+1] ⁺ .

Example 1

5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)- diketone

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (80 mg, 0.239 mmol) was dissolved in 3 mL of acetic acid, sodium acetate (98 mg, 1.19 mmol) was added, and the reaction was microwaved at 120° C. for 1 hour under nitrogen. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 6-(2,4-dimethoxypyrimidine- 5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3(2H)-one 1a (70 mg) was used directly in the next step.

MS m/z(ESI): 317.0[M+H] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3(2H)-one 1a (30 mg, 0.095 mmol) was dissolved in 3 mL of methanol, hydrochloric acid (2M, 1 mL) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-carbonyl-1,6- Dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 1 (16 mg), yield: 58.6%.

MS m/z(ESI): 289.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.87(s, 1H), 11.31(br s, 2H), 7.71(s, 1H), 7.23(s, 1H), 1.92-1.87(m, 1H) ),1.20-1.10(m,1H),0.99-0.94(m,7H),0.92-0.85(m,2H).

Example 2

5-(5-((1S,2R)-2-isopropylcyclopropyl)-1-methyl-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4( 1H,3H)-dione

first step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3(2H)-one 1a (30 mg, 0.095 mmol) was dissolved in 3 mL of acetonitrile, potassium carbonate (39 mg, 0.284 mmol) and methyl iodide (40 mg, 0.284 mmol) were added, and the reaction was carried out at room temperature for 6 hours. The reaction solution was poured into 30 mL of water, and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 6-(2,4-dimethoxypyrimidine- 5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-2-methylpyridazin-3(2H)-one 2a (30 mg) was used directly in the next step.

MS m/z(ESI): 331.0[M+H] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-2-methylpyridazine-3(2H)- Ketone 2a (30 mg, 0.091 mmol) was dissolved in 3 mL of methanol, hydrochloric acid (2M, 1 mL) was added, and the reaction was carried out at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-1-methyl-6-carbonyl -1,6-Dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 2 (22 mg), yield: 80.1%.

MS m/z(ESI): 303.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.27(br s, 2H), 7.75(s, 1H), 7.27(s, 1H), 3.67(s, 3H), 1.96-1.92(m, 1H) ),1.17-1.11(m,1H),1.00-0.94(m,7H),0.93-0.88(m,2H).

Example 3

5-(6-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,2-a]pyridin-8-yl)pyrimidine-2,4(1H,3H )-dione

first step

2-Bromo-1,1-diethoxyethane (1.67 g, 8.46 mmol) was dissolved in hydrobromic acid (48%, 3 mL), heated to 100° C. to react for 2 hours. The reaction solution was cooled to room temperature, 15 mL of ethanol was added, cooled to 0° C., and the pH was adjusted to alkaline by adding sodium bicarbonate. After filtration, 3,5-dibromo-6-methylpyridin-2-amine (1.5 g, 5.64 mmol) was added to the filtrate, and the reaction solution was refluxed for 5 hours. After cooling to room temperature, the reaction solution was poured into 50 mL of water, and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product 6,8-dibromo-5-methylimidazo[1,2-a]pyridine 3a (1.0 g), yield: 61.1%.

MS m/z(ESI): 288.8[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.11 (d, J=1.2 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 2.71 (s, 3H) ).

second step

6,8-Dibromo-5-methylimidazo[1,2-a]pyridine 3a (300 mg, 1.03 mmol) was dissolved in 6 mL of 1,4-dioxane and 1.5 mL of water, and 4,6-dioxane was added Chloro-3-methylpyridazine (190 mg, 1.03 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (38 mg, 0.052 mmol) and cesium carbonate (506 mg , 1.55 mmol), replaced with nitrogen three times, and reacted at 90 °C for 1 hour under microwave. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product 6-bromo-8-(2,4-dimethoxypyrimidin-5-yl)-5-methylimidazo[1,2-a]pyridine 3b (180 mg), yield: 49.8%.

MS m/z(ESI): 348.8[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.73 (s, 1H), 8.03 (d, J=1.2 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.58 (s, 1H) ),3.98(s,3H),3.92(s,3H),2.78(s,3H).

third step

6-Bromo-8-(2,4-dimethoxypyrimidin-5-yl)-5-methylimidazo[1,2-a]pyridine 3b (30 mg, 0.086 mmol) was dissolved in 1 mL of 1,4-bismuth Oxane and 0.3 mL of water, add [(1S,2S)-2-isopropylcyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxolane (18mg, 0.086mmol, its preparation method refers to WO2019168744A1), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (6mg, 0.0086mmol) and cesium carbonate (42mg, 0.129 mmol), replaced with nitrogen three times, and reacted at 100 °C for 1 hour under microwave. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product 8-(2,4-Dimethoxypyrimidin-5-yl)-6-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,2-a ] Pyridine 3c (25 mg), yield: 83.6%.

MS m/z(ESI): 353.0[M+H] ⁺ .

the fourth step

8-(2,4-Dimethoxypyrimidin-5-yl)-6-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1,2-a ] Pyridine 3c (25 mg, 0.071 mmol) was dissolved in 3 mL of methanol, hydrochloric acid (4 M, 1 mL) was added, and the reaction was carried out at 70° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-((1S,2R)-2-isopropylcyclopropyl)-5-methylimidazo[1] ,2-a]pyridin-8-yl)pyrimidine-2,4(1H,3H)-dione 3 (9.3 mg), yield: 40.4%.

MS m/z(ESI): 325.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.27(s, 2H), 9.14(s, 1H), 7.93(s, 1H), 7.84(d, J=1.2Hz, 1H), 7.60(d , J=1.2Hz, 1H), 2.68(s, 3H), 1.88-1.83(m, 1H), 1.22-1.18(m, 1H), 1.08(d, J=6.8Hz, 3H), 1.02(d, J=6.8Hz, 3H), 0.87-0.81(m, 2H), 0.80-0.75(m, 1H).

Example 4

5-(5-((1S,2R)-2-isopropylcyclopropyl)-1-ethyl-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4( 1H,3H)-dione

first step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3(2H)-one 1a ( 30 mg, 0.0946 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (65 mg, 0.474 mmol) was added with stirring, followed by dropwise addition of iodoethane (74 mg, 0.474 mmol). The reaction was stirred at room temperature for 20 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed sequentially with water (30 mL) and saturated sodium chloride (30 mL), dried and concentrated to give crude 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R )-2-isopropylcyclopropyl)-2-ethylpyridazin-3(2H)-one 4a (30 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 345.0[M+H] ⁺ .

second step

4a (30 mg, 0.0906 mmol) was dissolved in methanol (3 mL) with stirring at room temperature, and 6M hydrochloric acid solution (2 mL) was added to the reaction solution. The reaction solution was stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was prepared and separated by reverse-phase HPLC (formic acid system) to obtain the product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-1-ethyl -6-Carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 4 (14.3 mg), yield: 51.5%.

MS m/z(ESI): 317.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ7.77(s,1H), 7.24(s,1H), 4.15-4.05(m,2H), 1.98-1.93(m,1H), 1.28(t,J =7.2Hz,3H),1.19-1.10(m,1H),0.98-0.90(m,9H).

Example 5

5-(5-([1,1'-Bi(cyclopropane)]-2-yl)-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione

first step

N-methyl-N-nitrosourea (500 mg, 4.8 mmol) was added to a mixed solution of 20% potassium hydroxide aqueous solution (2 mL) and diethyl ether (2 mL) in an ice bath, and the mixture was stirred at this temperature for 1 hour. Under ice bath conditions, the organic phase of the above mixed solution was added to a solution of 5a (200 mg, 1.0 mmol) in ether (2 mL), and then palladium acetate (22 mg, 0.01 mmol) was added to the reaction solution, and the reaction was carried out under ice bath conditions. under stirring for 30 minutes. The reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL×3). The filtrate was concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to give the product 2-([[1,1'-bis(cyclopropane)]-2-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborane 5b (182 mg), yield: 84.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.21 (s, 12H), 1.02 (ddd, 1H), 0.85–0.72 (m, 1H), 0.57 (ddd, 1H), 0.45–0.24 (m, 3H) ,0.16–0.01(m,2H),-0.36(dt,1H).

second step

5b (92 mg, 0.44 mmol), 4-bromo-3,6-dichloropyridazine (100 mg, 0.44 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride palladium dichloromethane Compound (36 mg, 0.044 mmol) and potassium carbonate (121 mg, 0.88 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction was stirred at 80 °C under microwave conditions for 1 h under _N2 protection. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-bi(cyclopropane)]-2-yl)-3,6-dichloropyridazine 5c (79 mg), yield: 78%.

MS m/z(ESI): 228.8[M+1] ⁺ .

third step

Combine 5c (50 mg, 0.22 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (44 mg, 0.24 mmol), tetrakistriphenylphosphine palladium (26 mg, 0.022 mmol) and potassium carbonate (61 mg, 0.44 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). Under the protection of _N2 , the reaction solution was stirred at 80 °C under microwave condition for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-Bi(cyclopropane)]-2-yl)-3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine 5d (35 mg), Yield: 48%.

MS m/z(ESI): 333.1[M+1] ⁺ .

the fourth step

5d (100 mg, 0.31 mmol) and sodium acetate (381 mg, 4.65 mmol) were dissolved in acetic acid (2 mL). The reaction was heated to 120°C in the microwave and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated, and saturated sodium bicarbonate solution was added to the residue to neutralize pH to neutral. The aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed sequentially with water (20 mL) and saturated sodium chloride (20 mL), dried and concentrated to give crude 4-([1,1'-bi(cyclopropane)]-2-yl)-6-(2 ,4-Dimethoxypyrimidin-5-yl)pyridazin-3(2H)-one 5e (87 mg), yield: 82%. The product was used directly in the next reaction without purification.

MS m/z(ESI): 315.0[M+1] ⁺ .

the fifth step

5e (80 mg, 0.25 mmol) was dissolved in 1 M hydrochloric acid (4 mL), and the reaction solution was stirred at 70° C. for 12 hours. The reaction solution was concentrated, and the crude compound was separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-([1,1'-bi(cyclopropane)]-2-yl)-6-carbonyl-1,6 -Dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 5 (40.2 mg), yield: 57%.

MS m/z(ESI): 287.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.90(s,1H), 11.35(s,2H), 7.70(s,1H), 7.22(s,1H), 1.92-1.81(m,1H) ,0.99–0.91(m,2H),0.89–0.78(m,2H),0.49–0.32(m,2H),0.22–0.08(m,2H).

Example 5-1 and Example 5-2

5-(5-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione and 5-(5-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)-6-carbonyl-1,6-di Hydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Example 5 (40 mg, 0.14 mmol) was resolved by SFC to give Example 5-1 (10.7 mg, R.T=1.987 min, yield: 26.8%) and Example 5-2 (15 mg, R.T=1.601 min, yield: 26.8%) : 37.5%).

SFC: Chiral Preparation Conditions:

Chiral analysis method:

Example 5-1: MS m/z (ESI): 286.9 [M+1] ⁺ ;

Example 5-2: MS m/z (ESI): 287.0 [M+1] ⁺ .

Example 6

5-(5-([1,1'-Bi(cyclopropane)]-2-yl)-1-methyl-6-carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione

first step

5e (100 mg, 0.32 mmol) and potassium carbonate (110 mg, 0.8 mmol) were dissolved in anhydrous acetonitrile (8 mL) under ice bath and _N2 protected. At this temperature, iodomethane (68.16 mg, 0.48 mmol) was added dropwise with stirring. The reaction solution was transferred to room temperature and stirred for 12 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (3 mL×3), and the filtrate was concentrated to obtain the crude product 4-([1,1'-bi(cyclopropane)]-2-yl)-6-(2,4- Dimethoxypyrimidin-5-yl)-2-methylpyridazin-3(2H)-one 6a (83 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 329.0[M+1] ⁺ .

second step

6a (80 mg, 0.24 mmol) was dissolved in 1 M hydrochloric acid (4 mL), and the reaction solution was stirred at 70° C. for 12 hours. The reaction solution was concentrated, and the crude compound was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-([1,1'-bi(cyclopropane)]-2-yl)-1-methyl-6- Carbonyl-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 6 (48 mg), yield: 65%.

MS m/z(ESI): 300.8[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.31(brs,2H), 7.76(s,1H), 7.26(s,1H), 3.66(s,3H), 1.97–1.83(m,1H) ,1.30–1.13(m,1H),1.01–0.90(m,2H),0.89–0.80(m,1H),0.47–0.33(m,2H),0.22–0.09(m,2H).

Example 6-1 and Example 6-2

Example 6 (55 mg, 0.18 mmol) was resolved by SFC to obtain Example 6-1 (11.81 mg, R.T=1.381 min, yield: 21.5%) and Example 6-2 (17.44 mg, R.T=1.222 min, yield rate: 31.7%),

Example 6-1: MS m/z (ESI): 300.8 [M+1] ⁺ ;

Example 6-2: MS m/z (ESI): 300.8 [M+1] ⁺ .

Example 7

5-(6-Carbonyl-5-(2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

7a (1.5 g, 11.11 mmol) was dissolved in a mixed solution of methyl tert-butyl ether (5 mL) and water (2 mL) and stirred. The reaction solution was cooled with an ice bath, and an aqueous solution (2 mL) of sodium nitrite (0.843 g, 12.22 mmol) was added to the reaction solution. The reaction solution was warmed to room temperature and stirred for 3 hours. The aqueous phase of the reaction solution was separated, and the remaining organic phase (5 mL, according to document WO2015/52226, expected to contain 594 mg of product 2-diazo-1,1,1-trifluoroethane 7b, yield: 48.6%) was used directly for next reaction.

second step

Palladium acetate (120.9 mg, 0.54 mmol) was added to 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (748.4 mg, 4.86 mmol) at room temperature. methyl tert-butyl ether solution (5 mL), then 7b in methyl tert-butyl ether solution (5 mL, 594 mg, 5.4 mmol) was slowly added to the reaction. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the crude compound was purified by silica gel column chromatography (eluent system B) to obtain the product 4,4,5,5-tetramethyl-2-(2-(trifluoromethyl)cyclopropyl) )-1,3,2-dioxaborane intermediate 7c (0.7 g), yield: 60.9%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.83-1.63 (m, 1H), 1.24 (d, 12H), 1.11-0.95 (m, 1H), 0.85 (dd, 1H), 0.41-0.26 (m, 1H) ).

third step

4-Bromo-6-chloropyridazin-3-amine (1.0 g, 4.80 mmol), 7c (1.25 g, 5.28 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloride The methyl chloride complex (391.5 mg, 0.48 mmol) and cesium carbonate (4.69 g, 14.39 mmol) were dissolved in 1,4-dioxane/water (v/v=4:15 mL) with stirring. The reaction solution was heated to 110 °C and stirred for ₁₆ h under the protection of N Stir at 110°C for 16 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried and concentrated. The crude compound was isolated by silica gel column chromatography (eluent system B) to give the title product 6-chloro-4-(2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine 7d (450 mg) in yield : 39.5%.

MS m/z(ESI): 238.1[M+1] ⁺ .

the fourth step

Sodium nitrite (156.8 mg, 2.27 mmol) was dissolved in concentrated sulfuric acid (2.0 mL) and stirred. Compound 7d (450 mg, 1.89 mmol) dissolved in acetic acid (5 mL) was slowly added to the reaction solution under ice bath, and then the reaction solution was warmed to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction solution, and the reaction solution was continuously stirred at room temperature for 0.5 hours. Saturated NaCl (10 ml) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain crude 6-chloro-4-(2-(trifluoromethyl)cyclopropyl) ) pyridazin-3(2H)-one 7e (440 mg), and the product was used in the next reaction without purification.

MS m/z(ESI): 239.1[M+1] ⁺ .

the fifth step

7e (230.0 mg, 0.96 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (212.8 mg, 1.16 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium dichloromethane complex (78.7 mg, 0.096 mmol) and cesium carbonate (942.8 mg, 2.89 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2.5 mL) Stir. The reaction solution was microwave-heated to 100 °C under _N2 and stirred for 1 h. Saturated sodium chloride (10 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 6-(2,4-Dimethoxypyrimidin-5-yl)-4-(2-(trifluoromethyl)cyclopropyl)pyridazin-3(2H)-one 7f (260 mg), yield : 78.8%.

MS m/z(ESI): 342.8[M+1] ⁺ .

Step 6

7f (100 mg, 0.29 mmol) was dissolved in 1 M hydrochloric acid (2 mL), and the reaction solution was stirred at 70°C for 6 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(6-carbonyl-5-(2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazine) -3-yl)pyrimidine-2,4(1H,3H)-dione 7 (52 mg), yield: 65.2%.

MS m/z(ESI): 314.8[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.08(s, 1H), 11.32(s, 2H), 7.75(s, 1H), 7.57(s, 1H), 2.42(dd, J=9.4, 5.8 Hz, 2H), 1.53–1.41 (m, 1H), 1.40–1.29 (m, 1H).

Example 7-1 and Example 7-2

5-(6-Carbonyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H, 3H)-dione and 5-(6-carbonyl-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione

Example 7 (52 mg, 0.17 mmol) was resolved by SFC to obtain Example 7-1 (19.2 mg, R.T=2.870 min, yield: 36.8%) and Example 7-2 (15.6 mg, R.T=2.305 min, yield rate: 29.9%),

SFC: Chiral Preparation Conditions:

仪器instrument	Waters SFC 150Waters SFC 150
柱型Cylindrical	25025mm,10μm(REGIS(S,S)WHELK-O1)25025mm,10μm(REGIS(S,S)WHELK-O1)
柱压column pressure	100bar100bar
流动相mobile phase	Supercritical CO ₂/MeOH(0.1％7.0mol/L Ammonia in MeOH) Supercritical CO ₂ /MeOH (0.1% 7.0mol/L Ammonia in MeOH)
流速flow rate	80g/min80g/min
检测波长Detection wavelength	UV 214nmUV 214nm
柱温column temperature	室温room temperature

Chiral analysis method:

Example 7-1: MS m/z (ESI): 314.8 [M+1] ⁺ ;

Example 7-2: MS m/z (ESI): 314.8 [M+1] ⁺ .

Example 8

5-(1-Methyl-6-carbonyl-5-(2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione

first step

Compound 7f (120 mg, 0.35 mmol) and potassium carbonate (238.41 mg, 1.75 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature. Iodomethane (74.15 mg, 0.526 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 2 hours. Saturated sodium chloride (10 ml) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (10 ml×3). The organic phases were combined, dried and concentrated to give the crude product 6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-4-(2-(trifluoromethyl)cyclopropyl)pyridazine -3(2H)-one 8a (120 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 356.8[M+1] ⁺ .

second step

8a (120 mg, crude product) was dissolved in 1 M hydrochloric acid (2 mL), and the reaction solution was stirred at 70° C. for 6 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(1-methyl-6-carbonyl-5-(2-(trifluoromethyl)cyclopropyl)-1,6 -Dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (44 mg), yield: 39.6%.

MS m/z(ESI): 328.8[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.37(s, 2H), 7.79(s, 1H), 7.60(s, 1H), 3.68(s, 3H), 2.51–2.39(m, 2H), 1.60–1.29(m,2H).

Example 8-1 and Example 8-2

5-(1-Methyl-6-carbonyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione and 5-(1-methyl-6-carbonyl-5-(((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,6- Dihydropyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Example 8 (52 mg, 0.17 mmol) was resolved by SFC to obtain Example 8-1 (11.8 mg, R.T=3.114 min, yield: 22.7%) and Example 8-2 (15.4 mg, R.T=3.029 min, yield rate: 29.5%),

Example 8-1: MS m/z (ESI): 328.8 [M+1] ⁺ ;

Example 8-2: MS m/z (ESI): 328.8 [M+1] ⁺ .

Example 9

5-(8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Intermediate 1 (40 mg, 0.119 mmol) and tert-butyl carbamate (139.96 mg, 1.19 mmol) were dissolved in 1,4-dioxane (1 mL) and chloro(2-dicyclohexylphosphino-2 was added) ',4',6'-Triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9 mg, 0.012 mmol) and cesium carbonate (78 mg, 0.239 mmol). The mixture was replaced with nitrogen three times, and the reaction was microwaved at 100°C for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed successively with water (20 mL) and saturated sodium chloride (20 mL), dried and concentrated. The resulting residue was purified by silica gel column chromatography with eluent system B to give the product (6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropyl) tert-butylcyclopropyl)pyridazin-3-yl)carbamate 9a (25 mg), yield: 50.4%.

MS m/z(ESI): 416.2[M+H] ⁺ .

second step

9a (25 mg, 0.060 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (1 mL) was added dropwise with stirring. The reaction was stirred at room temperature for 2 hours. Dichloromethane (20 mL) was added to the reaction solution, and the organic phase was washed with saturated sodium bicarbonate (10 mL) and saturated sodium chloride (5 mL), dried and concentrated to obtain crude 6-(2,4-dimethoxypyrimidine) -5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-amine 9b (20 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 316.2[M+1] ⁺ .

third step

9b (20 mg, 0.063 mmol), 2-chloro-1,1-dimethoxy-ethane (79 mg, 0.634 mmol) and p-toluenesulfonic acid (22 mg, 0.127 mmol) were dissolved in isopropanol (3 mL) )middle. The reaction was heated to 100°C and stirred overnight. The reaction solution was concentrated, and the crude product was separated by reverse-phase HPLC (formic acid system) to obtain the title compound 5-(8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine -6-yl)pyrimidine-2,4(1H,3H)-dione 9 (2.3 mg), yield: 11.2%.

MS m/z(ESI): 311.9[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.16(s,1H), 8.16(s,1H), 8.03(s,1H), 7.65(s,1H), 7.32(s,1H), 1.50– 1.43(m, 2H), 1.41(s, 2H), 1.07(d, 1H), 1.00(dd, 6H).

Example 10

5-(8-(2-(Trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Compound 7d (410 mg, 1.73 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (317.42 mg, 1.73 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium dichloromethane complex (140.80 mg, 0.17 mmol) and cesium carbonate (1.69 g, 5.18 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 5 mL) mixture middle. The reaction was microwaved to 100°C under nitrogen and stirred for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried, and concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to give the product 6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-(tris). Fluoromethyl)cyclopropyl)pyridazin-3-amine 10a (320 mg), yield: 54.3%.

MS m/z(ESI): 341.8[M+1] ⁺ .

second step

Compound 10a (100 mg, 0.29 mmol), 2-chloro-1,1-dimethoxy-ethane (43.80 mg, 0.35 mmol) was dissolved in isopropanol (2 mL), followed by p-toluenesulfonic acid (60.2 mg, 0.35 mmol) was added to the reaction solution. The reaction was heated to 100°C under seal and stirred for 16 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine-6 -yl)pyrimidine-2,4(1H,3H)-dione 10 (35 mg), yield: 35.4%.

MS m/z(ESI): 337.8[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )) δ 11.39(s, 2H), 8.24(s, 1H), 8.01(s, 1H), 7.71(s, 1H), 7.60(s, 1H), 3.01 (s, 1H), 2.92–2.72 (m, 1H), 1.88 (dd, 1H), 1.67–1.47 (m, 1H).

Example 10-1 and Example 10-2

5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H) -diketone and 5-(8-((1R,2R)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4( 1H,3H)-dione

Example 10 (50 mg, 0.18 mmol) was resolved by SFC to give Example 10-1 (18 mg, R.T=3.98 min, yield: 36%) and Example 10-2 (15 mg, R.T=4.08 min, yield: 30%),

Example 10-1: MS m/z (ESI): 338.1 [M+1] ⁺ ;

Example 10-2: MS m/z (ESI): 338.1 [M+1] ⁺ .

Example 11

5-(2-Methyl-8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)- diketone

Compound 10a (50 mg, 0.15 mmol) and 1-bromo-2,2-dimethoxypropane (32.18 mg, 0.18 mmol) were dissolved in isopropanol (2 mL), followed by p-toluenesulfonic acid (30.9 mg, 0.18 mmol) was added to the reaction solution. The reaction solution was heated to 100°C under sealing and stirred for 16 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(2-methyl-8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b] ]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 11 (18 mg), 34.5% yield.

MS m/z(ESI): 351.8[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.36(s, 2H), 7.98(d, J=12.5Hz, 2H), 7.51(s, 1H), 2.97(s, 1H), 2.87-2.67( m, 1H), 2.38(s, 3H), 1.83(s, 1H), 1.69–1.46(m, 1H).

Example 12

5-(8-([1,1'-Bis(cyclopropane)]-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)- diketone

first step

12a (100 mg, 0.48 mmol), 4-bromo-6-chloropyridazin-3-amine (99 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane The complex (39 mg, 0.048 mmol) and potassium carbonate (132 mg, 0.96 mmol) were dissolved in a mixture of 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction was stirred at 80°C under microwave conditions for 1 hour under nitrogen. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 4-([1,1'-Bis(cyclopropane)]-2-yl)-6-chloropyridazin-3-amine 12b (64 mg), yield: 63%.

MS m/z(ESI): 210.1[M+1] ⁺ .

second step

12b (50 mg, 0.24 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (66 mg, 0.36 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride The dichloromethane complex (19 mg, 0.024 mmol) and cesium carbonate (156 mg, 0.48 mmol) were dissolved in a mixture of 1,4-dioxane/water (v/v=4:1,2 mL). The reaction was stirred at 100°C under microwave conditions for 1 hour under nitrogen. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 4-([1,1'-Bis(cyclopropane)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine 12c (46 mg), yielded Rate: 61%.

MS m/z(ESI): 314.2[M+1] ⁺ .

third step

12c (35 mg, 0.11 mmol), p-toluenesulfonic acid (22 mg, 0.13 mmol) and 2-chloro-1,1-dimethoxyethane (16 mg, 0.13 mmol) were dissolved in isopropanol (5 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-([1,1'-bis(cyclopropane)]-2-yl)imidazo[1,2-b] ]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 12 (15 mg), yield: 42%.

MS m/z(ESI): 309.9[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ11.31(s,1H), 8.17(d,1H), 7.99(s,1H), 7.66(d,1H), 7.28(s,1H), 2.28– 2.18 (m, 1H), 1.77–1.59 (m, 1H), 1.44–1.32 (m, 1H), 1.08–0.94 (m, 2H), 0.50–0.36 (m, 2H), 0.28–0.16 (m, 2H) ).

Example 12-1 and Example 12-2

5-(8-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidin-2,4 (1H,3H)-Dione and 5-(8-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)imidazo[1,2-b]pyridazine- 6-yl)pyrimidine-2,4(1H,3H)-dione

Example 12 (50 mg, 0.16 mmol) was chiral resolved by SFC to give Example 12-1 (12.87 mg, R.T=3.917 min, yield: 25.7%) and Example 12-2 (16.64 mg, R.T=3.483 min) , yield: 33.2%),

Example 12-1: MS m/z (ESI): 310.1 [M+1] ⁺ ;

Example 12-2: MS m/z (ESI): 310.1 [M+1] ⁺ .

SFC Chiral Resolution Conditions:

Chiral analysis method:

Example 13

5-(8-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine -2,4(1H,3H)-dione

12-1 (10 mg, 0.03 mmol) and N-chlorosuccinimide (5 mg, 0.03 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction was heated to 50°C and stirred for 4 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-3 - Chlorimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 13 (8 mg), yield: 74%.

MS m/z(ESI): 344.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.44(s, 2H), 8.02(s, 1H), 7.80(s, 1H), 7.37(s, 1H), 2.25(m, 1H), 1.87– 1.61(m,1H),1.39(m,1H),1.04(m,2H),0.61–0.40(m,2H),0.28–0.18(m,2H).

Example 14

5-(8-([1,1'-Bi(cyclopropane)]-2-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H ,3H)-dione

first step

Under nitrogen protection, 8-bromo-6-chloroimidazo[1,2-b]pyridazine 14a (5 g, 21.65 mmol) and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrakis fluoroborate) (9.2 g, 25.97 mmol) was dissolved in ethyl acetate (100 mL) and stirred. The reaction solution was heated to 50°C and stirred for 12 hours. The reaction solution was concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine 14b (862 mg), Yield: 16%.

MS m/z(ESI): 249.9[M+1] ⁺ .

second step

Under nitrogen protection, 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine 14b (800 mg, 3.21 mmol), 2-([[1,1'-bis(cyclopropane) ]-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.33 g, 6.42 mmol), 1,1-bis(diphenylphosphine)di Ferrocene dichloride palladium dichloromethane complex (261 mg, 0.32 mmol) and cesium carbonate (2.09 g, 6.42 mmol) were dissolved in 1,4-dioxane/water (v/v=20:1, 1 mL ) and stir. The reaction solution was heated to 120°C and stirred for 16 hours. Saturated sodium chloride (30 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×3 times). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 8-([1,1'-bi(cyclopropane)]-2-yl)-6- Chloro-3-fluoroimidazo[1,2-b]pyridazine 14c (129 mg), yield: 16%.

MS m/z(ESI): 252.0[M+1] ⁺ .

third step

8-([1,1'-Bi(cyclopropane)]-2-yl)-6-chloro-3-fluoroimidazo[1,2-b]pyridazine 14c (100 mg, 0.40 mmol) was added under nitrogen , (2,4-dimethoxypyrimidin-5-yl)boronic acid (88mg, 0.48mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (33mg , 0.040 mmol) and cesium carbonate (196 mg, 0.60 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL) with stirring. The reaction solution was heated to 100°C by microwave and stirred for 2 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 8-([1,1'-bi(cyclopropane)]-2-yl)-6-( 2,4-Dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine 14d (92 mg), yield: 65%.

MS m/z(ESI): 356.1[M+1] ⁺ .

the fourth step

8-([1,1'-Bi(cyclopropane)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2- b] Pyridazine 14d (50 mg, 0.14 mmol) was dissolved in a mixture of hydrochloric acid (1 M, 1 mL) and methanol (1 mL), heated to 70° C. and stirred for 3 hours. The reaction solution was concentrated, and the crude compound was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-([1,1'-bi(cyclopropane)]-2-yl)-3-fluoroimidazo[1] ,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 14 (24 mg), yield: 53%.

MS m/z(ESI): 326.9[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.37(s, 2H), 8.02(s, 1H), 7.50(d, J=7.1Hz, 1H), 7.29(s, 1H), 2.30-2.15( m, 1H), 1.76–1.63 (m, 1H), 1.45–1.34 (m, 1H), 1.11–0.95 (m, 2H), 0.51–0.35 (m, 2H), 0.27–0.15 (m, 2H).

Example 15

5-(3-Fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione

first step

Under nitrogen protection, 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine 14b (800 mg, 3.21 mmol) was added with (1S,2R)-2-isopropylcyclopropane- 1-Carboxylic acid (870 mg, 6.71 mmol, its preparation method refers to WO2019168744A1) (1.33 g, 6.42 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (261 mg , 0.32 mmol) and cesium carbonate (2.09 g, 6.42 mmol) were dissolved in 1,4-dioxane/water (v/v=20:1, 1 mL) with stirring. The reaction solution was heated to 120°C and stirred for 16 hours. Saturated sodium chloride (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system B) , the product 6-chloro-3-fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine 15a (82 mg), yield: 10% .

MS m/z(ESI): 254.0[M+1] ⁺ .

second step

6-Chloro-3-fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazine 15a (50 mg, 0.20 mmol), ( 2,4-Dimethoxypyrimidin-5-yl)boronic acid (44 mg, 0.24 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (17 mg, 0.02 mmol) and cesium carbonate (98 mg, 0.30 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL) with stirring. The reaction solution was heated to 100°C by microwave and stirred for 2 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system B) The product 6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b was obtained ] Pyridazine 15b (43 mg), yield: 60%.

MS m/z(ESI): 358.1[M+1] ⁺ .

third step

6-(2,4-Dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b] Pyridazine 15b (40 mg, 0.11 mmol) was dissolved in a mixture of hydrochloric acid (1 M, 1 mL) and methanol (1 mL), heated to 70°C and stirred for 3 hours. The reaction solution was concentrated, and the crude compound was separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(3-fluoro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2] -b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 15 (17 mg), yield: 47%.

MS m/z(ESI): 330.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δ 11.49(s, 2H), 7.99(s, 1H), 7.52(d, 1H), 7.26(s, 1H), 2.29–2.22(m, 1H), 1.47 –1.38(m,2H),1.32–1.22(m,1H),1.15–1.08(m,1H),0.99(dd,6H).

Example 16

5-(8-(2-Isobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Combine 16a (1.5 g, 11.72 mmol), 4-methyl-1-pentyne (1.06 g, 12.89 mmol) and zirconocene hydrochloride (302 mg, 1.17 mmol). The reaction was heated to 60°C in a sealed tube and stirred overnight. The reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product (E)-4,4,5,5-tetramethyl-2-(4-methylpentane-1- En-1-yl)-1,3,2-dioxaborolane 16b (1.75 g), yield: 72%.

¹ H NMR (400MHz, CDCl ₃ ) δ 6.68-6.55(m, 1H), 5.48-5.35(m, 1H), 2.09-2.01(m, 2H), 1.77-1.65(m, 1H), 1.27(s) ,12H),0.90(d,6H).

second step

Potassium hydroxide (2.72 g, 48.54 mmol) was dissolved in a mixture of methyl tert-butyl ether (10 mL) and water (10 mL) at 0°C. 1-Methyl-1-nitrosourea (4.17 g, 40.45 mmol) was added to the above alkali solution in batches, and after all the solids were dissolved, an ether solution of diazomethane was obtained. Under nitrogen protection, 16b (340 mg, 1.62 mmol) and palladium acetate (36 mg, 0.16 mmol) were dissolved in methyl tert-butyl ether (5 mL), and the reaction solution was cooled to 0°C and stirred. The diazomethane ether solution was dropped into the system using a syringe with stirring. After the dropwise addition, the reaction was returned to room temperature and stirring was continued for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 2-(2-isobutylcyclopropyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane 16c (257 mg), yield: 70%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.68 (m, 1H), 1.22 (s, 12H), 1.12-1.01 (m, 1H), 0.96-0.84 (m, 8H), 0.73-0.65 (m, 1H) ),0.43-0.34(m,1H),-0.39--0.49(m,1H).

third step

Under nitrogen, 16c (200 mg, 0.89 mmol), 3-amino-4-bromo-6-chloropyridazine (223 mg, 1.07 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium (65 mg, 0.089 mmol) and potassium carbonate (308 mg, 2.23 mmol) were dissolved in a mixture of 1,4-dioxane (3 mL) and water (1 mL). The reaction was microwaved to 90°C and stirred for 2.5 hours. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (5 mL×2), the organic phases were combined, dried, concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-chloro-4-(2- Isobutylcyclopropyl)pyridazin-3-amine 16d (102 mg), yield: 40%.

MS m/z(ESI): 226.1[M+1] ⁺ .

the fourth step

Under nitrogen protection, 16d (102 mg, 0.45 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (100 mg, 0.54 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (33 mg, 0.045 mmol) and potassium carbonate (187 mg, 1.36 mmol) were dissolved in a mixture of 1,4-dioxane (2.1 mL) and water (0.7 mL). The reaction was microwaved to 90°C and stirred for 2 hours. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL×2). The organic phases were combined, dried, concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to give the product 6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-isobutylcyclopropane) yl)pyridazin-3-amine 16e (135 mg), yield: 90.7%.

MS m/z(ESI): 330.0[M+1] ⁺ .

the fifth step

16e (135 mg, 0.41 mmol), 2-chloroacetaldehyde dimethyl acetal (102 mg, 0.82 mmol) and p-toluenesulfonic acid (85 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (2 mL) middle. The reaction was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-(2-isobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2 ,4(1H,3H)-dione 16 (31 mg), yield: 23.3%.

MS m/z(ESI): 326.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.30(s,1H), 8.42(s,1H), 8.17(d,1H), 8.00(s,1H), 7.67(s,1H), 7.30( s,1H),2.26-2.17(m,1H),1.79-1.67(m,1H),1.65-1.56(m,1H),1.51-1.26(m,3H),1.07-0.98(m,1H), 0.95-0.87(m,6H).

Example 16-1 and Example 16-2

5-(8-((1S,2S)-2-isobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione and 5 -(8-((1R,2R)-2-isobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 16 (20 mg, 0.061 mmol) was resolved on a chiral column (AS column) to give the title product 16-1 (2.4 mg, R.T=1.419 min), yield: 12.5%; 16-2 (4.9 mg, R.T=1.275 min), yield: 24.5%. AS column chiral resolution conditions:

Chiral analysis method:

Example 16-1, MS m/z (ESI): 326.2 [M+1] ⁺ ;

Example 16-2, MS m/z (ESI): 326.1 [M+1] ⁺ .

Example 17

5-(8-((1S,2S)-2-ethylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 17a (75 mg, 0.36 mmol), 2-((1S,2S)-2-ethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-di Oxaborolane (78mg, 0.40mmol, refer to WO2019168744A1 for the preparation method), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (26mg, 0.036mmol) and cesium carbonate (234.45mg, 0.72mmol) ), dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.5 mL). The reaction was heated to 120°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 6-chloro-4-((1S,2S)-2-ethylcyclopropyl)pyridazin-3-amine 17b (74mg ), yield: 55%.

MS m/z(ESI): 198.1[M+1] ⁺ .

second step

Under nitrogen protection, 17b (74 mg, 0.37 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (90 mg, 0.49 mmol), and 1,1-bis(diphenylphosphino)ferrocene were dichlorinated Palladium (27 mg, 0.037 mmol) and potassium carbonate (103 mg, 0.75 mmol) were dissolved in a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL). The reaction was heated to 90°C and stirred for 2 hours. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL x 2). The organic phases were combined, dried, concentrated, and the residue was separated by column chromatography on silica gel (eluent system B) to give the title product 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S )-2-ethylcyclopropyl)pyridazin-3-amine 17c (70 mg), yield: 62%.

MS m/z(ESI): 302.0[M+1] ⁺ .

third step

17c (70 mg, 0.23 mmol), 2-chloroacetaldehyde dimethyl acetal (58 mg, 0.46 mmol) and p-toluenesulfonic acid (100 mg, 0.58 mmol) were dissolved in isopropanol (1 mL). The reaction was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-((1S,2S)-2-ethylcyclopropyl)imidazo[1,2-b]pyridazine- 6-yl)pyrimidine-2,4(1H,3H)-dione 17 (35 mg), yield: 51%.

MS m/z(ESI): 298.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.46(s, 2H), 8.18(d, 1H), 7.96(s, 1H), 7.68(d, 1H), 7.25(s, 1H), 2.28- 2.19(m,1H),1.64-1.56(m,1H),1.51-1.40(m,3H),1.10-0.95(m,4H).

Example 18

5-(3-Chloro-8-((1S,2S)-2-ethylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H) -diketone

first step

Example 17 (28 mg, 0.094 mmol), N-chlorosuccinimide (12.58 mg, 0.94 mmol) was dissolved in N,N-dimethylformamide (0.8 mL) at room temperature and stirred for 72 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(3-chloro-8-((1S,2S)-2-ethylcyclopropyl)imidazo[1,2-b] ]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 18 (16 mg), 51.2% yield.

MS m/z(ESI): 332.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.42(s, 2H), 8.03(s, 1H), 7.81(s, 1H), 7.39(s, 1H), 2.25(m, 1H), 1.58( m,1H),1.51-1.40(m,3H),1.13-1.06(m,1H),0.98(t,J=7.2Hz,3H).

Example 19

first step

Example 10 (90 mg, 0.27 mmol) and 1-chloropyrrolidine-2,5-dione (36 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred. The reaction was stirred at 30°C for 48 hours. The reaction solution was filtered, and the filtrate was separated by reverse-phase HPLC preparative separation (formic acid system) to obtain the title product 5-(8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine-6 -yl)pyrimidine-2,4(1H,3H)-dione 19 (83 mg), yield: 83.7%.

MS m/z(ESI): 371.7[M+1] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.19(s,1H), 7.70(s,1H), 7.68(s,1H), 2.93–2.84(m,1H), 2.79–2.70(m,1H) ,1.81–1.72(m,1H),1.66–1.59(m,1H).

Example 19-1 and Example 19-2

5-(3-Chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4( 1H,3H)-dione and 5-(3-chloro-8-((1R,2R)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine-6- yl)pyrimidine-2,4(1H,3H)-dione

Example 19 (26 mg, 0.07 mmol) was resolved on a chiral column (GC7 column) to give Example 19-1 (10 mg, R.T=5.02 min, yield: 38.5%); and Example 19-2 (11 mg, R.T= 6.03 min, yield: 42.3%).

Chiral separation conditions:

Chiral analysis method:

Example 19-1, MS m/z (ESI): 371.7 [M+1] ⁺ ;

Example 19-2, MS m/z (ESI): 371.7 [M+1] ⁺ .

Example 20

5-(8-(Cyclopent-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 20a (100 mg, 0.48 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (93 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (39 mg, 0.048 mmol) and cesium carbonate (313 mg, 0.96 mmol) were dissolved in 1, 4-dioxane/water (v/v=4:1, 2 mL). The reaction solution was heated to 100°C by microwave and stirred for 2 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 6-chloro-4-(cyclopent-1-en-1-yl)pyridazine-3- Amine 20b (74 mg), yield: 78%.

MS m/z(ESI): 196.0[M+1] ⁺ .

second step

Under nitrogen protection, 4-([1,1'-bis(cyclopropane)]-2-yl)-6-chloropyridazin-3-amine 20b (60 mg, 0.31 mmol), (2,4-dimethoxy pyrimidin-5-yl)boronic acid (68 mg, 0.37 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (25 mg, 0.031 mmol) and cesium carbonate (202 mg) , 0.62 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction solution was heated to 100°C by microwave and stirred for 2 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 4-(cyclopent-1-en-1-yl)-6-(2,4-dimethylene) Oxypyrimidin-5-yl)pyridazin-3-amine 20c (62 mg), yield: 67%.

MS m/z(ESI): 300.1[M+1] ⁺ .

third step

20c (50 mg, 0.17 mmol), p-toluenesulfonic acid (29 mg, 0.51 mmol) and 2-chloro-1,1-dimethoxyethane (106 mg, 0.85 mmol) were dissolved in isopropanol (5 mL) under nitrogen )middle. The reaction solution was heated to 100°C and stirred for 12 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-(cyclopent-1-en-1-yl)imidazo[1,2-b]pyridazine-6- yl)pyrimidine-2,4(1H,3H)-dione 20 (19 mg), yield: 38%.

MS m/z(ESI): 296.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.50(s, 2H), 8.22(d, J=1.3Hz, 1H), 8.03(s, 1H), 7.78(t, J=2.3Hz, 1H) ,7.73(d,J=1.3Hz,1H),7.56(s,1H),2.83–2.70(m,2H),2.71–2.63(m,2H),2.13–1.94(m,2H).

Example 21

5-(8-(3,3-Dimethylcyclopent-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H) -diketone

first step

21a (987 mg, 8.80 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C and stirred for 5 min. Lithium bistrimethylsilylamide (1 M, 8 mL) was added dropwise to the above system, and the reaction was stirred at -78°C for 30 minutes. To the above reaction was added dropwise a solution of N-phenylbis(trifluoromethanesulfonyl)imide (3.14 g, 8.80 mmol) in tetrahydrofuran (10 mL). The reaction was slowly returned to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution (15 mL). The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (20 mL×2). The organic phases were combined, washed successively with 5% aqueous sodium carbonate solution and saturated sodium chloride solution, dried and concentrated to give crude product 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonic acid 21b (1.9 g), the product was directly used in the next reaction without purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.47 (s, 1H), 2.66-2.58 (m, 2H), 1.81 (t, J=7.8 Hz, 2H), 1.12 (s, 6H).

second step

Under nitrogen, 21b (500 mg, 2.05 mmol), pinacol diboronate (624 mg, 2.46 mmol), tris(dibenzylideneacetone)dipalladium (94 mg, 0.102 mmol), 2-dicyclohexylphosphine- 2',4',6'-Triisopropylbiphenyl (195 mg, 0.409 mmol) and potassium acetate (402 mg, 4.09 mmol) were dissolved in dry 1,4-dioxane (9 mL). The reaction was heated to 100°C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude title product 2-(3,3-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- Dioxaborolane 21c (454 mg), the product was used in the next reaction without purification.

third step

Under nitrogen, 3-amino-4-bromo-6-chloropyridazine (511 mg, 2.45 mmol), 21c (454 mg, 2.04 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium (150 mg, 0.204 mmol) and potassium carbonate (565 mg, 4.09 mmol) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL), and the reaction solution was heated to 100° C. and stirred for 2 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-chloro-4-(3,3-dimethylcyclopent-1-en-1-yl)pyridazine-3- Amine 21d (1 g), yield: 90%.

MS m/z(ESI): 224.1[M+1] ⁺ .

the fourth step

Under nitrogen protection, 21d (620 mg, 2.77 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (612 mg, 3.33 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride Palladium (203 mg, 0.277 mmol) and potassium carbonate (766 mg, 5.54 mmol) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (3 mL), and the reaction was microwaved to 90°C and stirred for 2 hours. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried, concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to give the product 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3,3-di Methylcyclopent-1-en-1-yl)pyridazin-3-amine 21e (107 mg), 11.8% yield.

MS m/z(ESI): 328.2[M+1] ⁺ .

the fifth step

21e (184 mg, 0.562 mmol), 2-chloroacetaldehyde dimethyl acetal (280 mg, 2.25 mmol) and p-toluenesulfonic acid (387 mg, 2.25 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). ), the reaction was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-(3,3-dimethylcyclopent-1-en-1-yl)imidazo[1,2-b] ]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 21 (97 mg), 53.4% yield.

MS m/z(ESI): 324.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.47(s, 2H), 8.21(s, 1H), 8.03(s, 1H), 7.72(s, 1H), 7.61-7.55(m, 2H), 2.83(t, 2H), 1.82(t, 2H), 1.18(s, 6H).

Example 22

5-(8-(2-(Cyclopropylmethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 2,2,6,6-tetramethylpiperidine lithium (525 mg, 3.57 mmol) was dissolved in dry tetrahydrofuran (1.4 mL) and stirred at 0°C. To the reaction solution was added dropwise a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (956 mg, 3.57 mmol) in tetrahydrofuran (2.8 mL) . The reaction was stirred at 0°C for 5 minutes. The reaction solution was cooled to -78°C, and 2-cyclopropylacetaldehyde (250 mg, 2.97 mmol) was added to the reaction solution. The reaction was stirred at -78°C for 4 hours. The reaction solution was concentrated, ethyl acetate (30 mL) was added to the residue, the organic phase was washed with saturated ammonium chloride, dried and concentrated, and the crude compound was separated by silica gel column chromatography (eluent system A) to obtain product (E)-2 -(3-Cyclopropylprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 22b (210 mg), yield: 33.9 %.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.70 (dt, 1H), 5.54 (dt, 1H), 2.10–1.98 (m, 2H), 1.27 (s, 12H), 0.69–0.54 (m, 1H), 0.45(dd,4H).

second step

Under nitrogen protection, 22b (210 mg, 1.01 mmol) and palladium acetate (23 mg, 0.1 mmol) were dissolved in methyl tert-butyl ether (5 mL) and stirred in an ice bath. Under ice bath, potassium hydroxide (1.13 g, 20.18 mmol) was dissolved in a mixture of water (10 mL) and methyl tert-butyl ether (10 mL). 1-Methyl-1-nitroso-urea (1.04 g, 10.09 mmol) was added portionwise with stirring. The reaction was stirred in and for 30 minutes. The bright yellow supernatant was added dropwise to the solution of 22b under an ice bath. After the dropwise addition was completed, the reaction solution was stirred under an ice bath for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2-[2-(cyclopropylmethyl)cyclopropyl]-4,4,5,5-tetra Methyl-1,3,2-dioxaborolane 22c (120 mg), yield: 53.5%.

¹ H NMR (400MHz, CDCl ₃ )δ1.22(s, 12H), 1.05-0.91(m, 2H), 0.87-0.70(m, 2H), 0.70-0.58(m, 2H), 0.50-0.35(m ,4H),-0.38(dt,1H).

third step

Under nitrogen protection, 22c (120 mg, 0.540 mmol), 4-bromo-6-chloro-pyridazin-3-amine (124 mg, 0.594 mmol), [1,1'-bis(diphenylphosphino)diocene Iron]palladium dichloride (91 mg, 0.054 mmol) and cesium carbonate (352 mg, 1.08 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.5 mL). The reaction solution was heated to 120°C and stirred for 12 hours. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated ammonium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-chloro-4-[ 2-(Cyclopropylmethyl)cyclopropyl]pyridazin-3-amine 22d (81.2 mg), yield: 67.2%.

MS m/z(ESI): 224.1[M+1] ⁺ .

the fourth step

Under nitrogen protection, 22d (80 mg, 0.358 mmol), 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)pyrimidine (105 mg, 0.393 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (60 mg, 0.036 mmol) and cesium carbonate (233 mg, 0.715 mmol) were dissolved in In a mixture of 1,4-dioxane (2 mL) and water (0.5 mL). The reaction solution was heated to 100°C by microwave and stirred for 1 hour. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 4-[2-(cyclopropylmethyl)cyclopropyl]-6-(2,4-dimethoxypyrimidine- 5-yl)pyridazin-3-amine 22e (60.7 mg), yield: 51.9%.

MS m/z(ESI): 328.1[M+1] ⁺ .

the fifth step

22e (61 mg, 0.185 mmol), 2-chloro-1,1-dimethoxy-ethane (115 mg, 0.927 mmol) and p-toluenesulfonic acid (32 mg, 0.185 mmol) were dissolved in DMF (3 mL). The reaction solution was heated to 100°C and stirred for 3 hours. The reaction solution was cooled and preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(8-(2-(cyclopropylmethyl)cyclopropyl)imidazo[1,2-b]pyridazine-6- yl)pyrimidine-2,4(1H,3H)-dione (33 mg), 55.0% yield.

MS m/z(ESI): 324.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s, 2H), 8.18(d, 1H), 7.95(d, 1H), 7.68(s, 1H), 7.26(s, 1H), 2.34– 2.24(m, 1H), 1.70(s, 1H), 1.51–1.42(m, 1H), 1.39(t, 2H), 1.15–1.04(m, 1H), 0.81(s, 1H), 0.38(d, 2H),0.09(d,2H).

Example 22-1 and Example 22-2

5-(8-((1S,2S)-2-(cyclopropylmethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione and 5-(8-((1R,2R)-2-(cyclopropylmethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2, 4(1H,3H)-dione

Example 22 (33 mg) was resolved on a chiral column (C4AS column) to give Example 22-1 (10.28 mg, R.T=3.739 min, yield: 31.2%); and Example 22-2 (6.2 mg, R.T=3.422 min, yield: 18.8%).

Chiral separation conditions:

Chiral analysis method:

Example 22-1, MS m/z (ESI): 324.2 [M+1] ⁺ ;

Example 22-2, MS m/z (ESI): 324.2 [M+1] ⁺ .

Example 23

5-(8-(2-Cyclobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 2,2,6,6-tetramethylpiperidine lithium (1.05 g, 7.13 mmol) was dissolved in dry tetrahydrofuran (10 mL) and stirred at 0°C. To the reaction solution was added dropwise a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)methane (1.91 g, 7.13 mmol) in tetrahydrofuran (3 mL) . The reaction was stirred at 0°C for 5 minutes. The reaction solution was cooled to -78°C, and cyclobutanecarbaldehyde (500 mg, 5.94 mmol) was added to the reaction solution. The reaction was stirred at -78°C for 4 hours. The reaction solution was concentrated, ethyl acetate (30 mL) was added to the residue, the organic phase was washed with saturated ammonium chloride, dried and concentrated, and the crude compound was separated by silica gel column chromatography (eluent system A) to obtain the title product (E)- 2-(2-Cyclobutylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 23b (710 mg), yield: 58%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.73 (dd, 1H), 5.34 (dd, 1H), 3.11–2.93 (m, 1H), 2.21–2.02 (m, 2H), 1.98–1.72 (m, 4H) ),1.26(s,12H).

second step

Under nitrogen protection, 23b (600 mg, 2.88 mmol) and palladium acetate (65 mg, 0.29 mmol) were dissolved in methyl tert-butyl ether (10 mL) with stirring under ice bath. Under ice bath, potassium hydroxide (3.24 g, 57.66 mmol) was dissolved in a mixture of water (10 mL) and methyl tert-butyl ether (10 mL). 1-Methyl-1-nitroso-urea (5.94 g, 57.66 mmol) was added portionwise with stirring. The reaction was stirred in and for 20 minutes. The bright yellow supernatant was added dropwise to the solution of 23b under an ice bath. After the dropwise addition was completed, the reaction solution was stirred under an ice bath for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the title product 2-(2-cyclobutylcyclopropyl)-4,4,5,5-tetramethyl-1, 3,2-Dioxaborolane 23c (410 mg), yield: 64%.

¹ H NMR (400MHz, CDCl ₃ )δ2.03-1.92(m,1H), 1.92-1.79(m,2H), 1.74-1.65(m,2H), 1.64-1.53(m,2H), 1.15(s) ,12H),1.05–0.94(m,1H),0.61–0.48(m,1H),0.44–0.30(m,1H),-0.36–-0.47(m,1H).

third step

Under nitrogen protection, 23c (384 mg, 1.73 mmol), 4-bromo-6-chloro-pyridazin-3-amine (300 mg, 1.44 mmol), [1,1'-bis(diphenylphosphino)diocene Iron]palladium dichloride (117 mg, 0.14 mmol) and cesium carbonate (937 mg, 2.88 mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (2 mL). The reaction solution was heated to 120°C and stirred for 12 hours. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated ammonium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-chloro-4-( 2-Cyclobutylcyclopropyl)pyridazin-3-amine 23d (322 mg), yield: 43%.

MS m/z(ESI): 224.0[M+1] ⁺ .

the fourth step

Under nitrogen protection, 23d (130 mg, 0.58 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (160 mg, 0.87 mmol), [1,1'-bis(diphenylphosphino) Ferrocene]palladium dichloride (47 mg, 0.058 mmol) and cesium carbonate (377 mg, 1.16 mmol) were dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.5 mL). The reaction solution was heated to 100°C by microwave and stirred for 1 hour. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 4-(2-cyclobutylcyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine -3-amine 23e (150 mg), yield: 78%.

MS m/z(ESI): 328.1[M+1] ⁺ .

the fifth step

23e (180 mg, 0.55 mmol), 2-chloro-1,1-dimethoxy-ethane (342 mg, 2.75 mmol) and trifluoroacetic acid (940 mg, 8.25 mmol) were dissolved in isopropanol (5 mL). The reaction solution was heated to 90°C and stirred for 10 hours. The reaction solution was cooled and separated by reverse phase HPLC (formic acid system) to obtain the product 5-(8-(2-cyclobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4 (1H,3H)-diketone 23 (120 mg), 67% yield.

MS m/z(ESI): 324.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s, 2H), 8.18(s, 1H), 7.95(s, 1H), 7.67(s, 1H), 7.26(s, 1H), 2.40– 2.22 (m, 2H), 1.99 (dq, 2H), 1.86–1.71 (m, 4H), 1.73–1.62 (m, 1H), 1.56–1.41 (m, 1H), 1.25–1.00 (m, 1H).

Example 23-1 and Example 23-2

5-(8-((1S,2R)-2-cyclobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione and 5 -(8-((1R,2S)-2-cyclobutylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 23 (120 mg) was resolved on a chiral column (C4AS column) to give Example 23-1 (17 mg, R.T=3.767 min, yield: 15%); and Example 23-2 (25 mg, R.T=3.477 min, Yield: 21%). Chiral separation conditions:

Chiral analysis method:

Example 23-1, MS m/z (ESI): 324.1 [M+1] ⁺ ;

Example 23-2, MS m/z (ESI): 324.1 [M+1] ⁺ .

Example 24

5-(5-Fluoro-4-(2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-di ketone

first step

Sodium hydride (183 mg, 7.64 mmol, 60% content in mineral oil) was dispersed in a mixture of tetrahydrofuran (20 mL) and N,N-dimethylformamide (20 mL) and stirred. To the reaction solution was added ethyl 3-fluoro-1H-pyrrole-2-carboxylate (1.00 g, 6.36 mmol) under nitrogen atmosphere. The reaction solution was stirred under an ice bath for 20 minutes. To the reaction solution was added O-diphenylphosphoryl hydroxylamine (1.93 g, 8.27 mmol). The reaction was stirred at room temperature for 3 hours. A saturated solution of sodium thiosulfate (50 mL) was added to the reaction solution, and the reaction was heated to 30° C. for 1 h. The reaction solution was diluted with ethyl acetate (120 mL), the organic phase was washed with water and saturated sodium chloride, dried and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product 1-amino-3-fluoro -lH-pyrrole-2-carboxylic acid ethyl ester 24b (1.10 g), yield: 100%.

MS m/z(ESI): 173.1[M+1] ⁺ .

second step

24b (4.25 g, 24.69 mmol) and triethylamine (4.99 g, 49.37 mmol) were dissolved in dichloromethane (50 mL) and stirred. 3-Chloro-3-carbonyl-propionic acid methyl ester (3.37 g, 24.69 mmol) was added dropwise to the reaction under an ice bath. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product 3-fluoro-1-(3-methoxy-3-carbonylpropionylamino)-1H-pyrrole-2-carboxylic acid Ethyl ester 24c (5.80 g), yield: 86.3%.

MS m/z(ESI): 273.1[M+1] ⁺ .

third step

Potassium tert-butoxide (4.23 g, 37.74 mmol) was added to a solution of 24c (5.14 g, 18.87 mmol) in tetrahydrofuran (200 mL) at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction solution was acidified with formic acid (5 mL), concentrated, and the crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 5-fluoro-2,4-dicarbonyl-1,2,3,4-tetrahydropyrrolo Methyl [1,2-b]pyridazine-3-carboxylate 24d (3.80 g), yield: 89.0%.

MS m/z(ESI): 227.0[M+1] ⁺ .

the fourth step

24d (2.00 g, 8.84 mmol) was dissolved in a mixture of acetic acid (10 mL) and water (10 mL) under nitrogen protection. The reaction was microwaved to 100°C and stirred for 1 hour. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (tetrahydrofuran/petroleum ether, from 0% to 80% v/v) to obtain 5-fluoropyrrolo[1,2-b]pyridazine-2,4-diol 24e (1.10 g), yield: 74.0%.

MS m/z(ESI): 169.0[M+1] ⁺ .

the fifth step

1,1,1-Trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (5.10 g, 14.28 mmol) was added to 24e (2.00 g, 11.90 mmol) and triethylamine (2.40 g g, 3.79 mmol) in tetrahydrofuran (36 mL). The reaction was stirred at room temperature for 16 hours. Formic acid (1 mL) was added to the reaction solution, concentrated, and the crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 5-fluoro-4-hydroxypyrrolo[1,2-b]pyridazin-2-yl Trifluoromethanesulfonic acid 24f (2.60 g), yield: 72.8%.

MS m/z(ESI): 301.0[M+1] ⁺ .

Step 6

Under nitrogen protection, 24f (600 mg, 2.00 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (441 mg, 2.4 mmol), cesium carbonate (974.39 mg, 3 mmol) and [1,1' -Bis(diphenylphosphino)ferrocene]palladium dichloride (293 mg, 0.4 mmol) was dissolved in a mixture of dioxane (6 mL) and water (1 mL). The reaction was microwaved to 100°C and stirred for 1 hour. The reaction solution was acidified with formic acid (1 mL), concentrated, and the crude product was separated by silica gel column chromatography (tetrahydrofuran/petroleum ether, from 0% to 40% v/v) to give the title product 2-(2,4-dimethoxypyrimidine) -5-yl)-5-fluoropyrrolo[1,2-b]pyridazin-4-ol 24 g (44 mg), yield: 82.0%.

MS m/z(ESI): 291.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.80(s,1H), 8.59(s,1H), 7.73-7.47(m,1H), 6.62(d,1H), 6.30(s,1H), 4.01(s, 3H), 3.98(s, 3H).

Step 7

1,1,1-Trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (2.22 g, 6.20 mmol) was added to 24 g (1.50 g, 5.17 mmol) and triethylamine (1.04 g g, 10.34 mmol) in tetrahydrofuran (30 mL). The reaction was stirred at room temperature for 16 hours. The reaction solution was neutralized with formic acid (6 mL), concentrated, and the crude product was purified with C18 reverse phase system (acetonitrile/water (containing formic acid 0.05%), from 0% to 90% v/v) to give the product 2-(2,4- Dimethoxypyrimidin-5-yl)-5-fluoropyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonic acid 24h (1.10 g), yield: 50.4%.

MS m/z(ESI): 423.0[M+1] ⁺ .

Step 8

Under nitrogen, 4,4,5,5-tetramethyl-2-[2-(trifluoromethyl)cyclopropyl]-1,3,2-dioxaborolane (252 mg, 1.07 mmol) , 24h (150mg, 0.355mmol), cesium carbonate (139mg, 0.426mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (26mg, 0.036mmol) were dissolved in dichloromethane In a mixture of oxane (3 mL) and water (0.2 mL), the reaction was microwaved to 100°C and stirred for 1 hour. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (tetrahydrofuran/petroleum ether, from 0% to 40% v/v) to obtain the product 2-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro -4-(2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazine 24i (110 mg), yield: 81.0%.

MS m/z(ESI): 383.1[M+1] ⁺ .

Step 9

24i (100 mg, 0.262 mmol) was dissolved in a mixture of hydrochloric acid (4M, 2 mL) and methanol (2 mL), heated to 70°C and stirred for 8 hours. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 2-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-4-(2-(trifluoromethyl) yl)cyclopropyl)pyrrolo[1,2-b]pyridazine 24 (78 mg), yield: 84.2%.

MS m/z(ESI): 354.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.32(s, 2H), 7.92(s, 1H), 7.78–7.55(m, 1H), 6.82(s, 1H), 6.77(d, 1H), 2.79–2.66 (m, 1H), 2.45–2.35 (m, 1H), 1.56–1.39 (m, 2H).

Example 24-1 and Example 24-2

5-(5-Fluoro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4( 1H,3H)-dione and 5-(5-fluoro-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazine-2- yl)pyrimidine-2,4(1H,3H)-dione

Example 24 (40 mg, 0.11 mmol) was resolved on a chiral column (C4AS column) to give Example 24-1 (10 mg, R.T=2.68 min, yield: 25.0%) and Example 24-2 (8 mg, R.T=2.90 min, yield: 20.0%). Chiral separation conditions:

Chiral analysis method:

Example 24-1, MS m/z (ESI): 355.1 [M+1] ⁺ ;

Example 24-2, MS m/z (ESI): 355.1 [M+1] ⁺ .

Example 25

5-(7-Chloro-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 3,6-dichloropyridazin-4-amine 25a (10 g, 61.35 mmol), trimethylsilyne (6.3 g, 64.42 mmol), bistriphenylphosphine palladium dichloride (1.3 g, 1.84 mmol), cuprous iodide (0.7 g, 3.68 mmol) and triethylamine (31 g, 306.75 mmol) were dissolved in acetonitrile (100 mL). The reaction was heated to 60°C and stirred for 5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 6-chloro-3-((trimethylsilyl)ethynyl)pyridazin-4-amine 25b (11.3g) , Yield: 81.9%.

MS m/z(ESI): 226.1[M+1] ⁺ .

second step

25b (5.9 g, 26.22 mmol) and cuprous iodide (1 g, 5.24 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction was heated to 120°C and stirred overnight. After cooling to room temperature, the reaction solution was poured into ice water, and the crude compound 3-chloro-5H-pyrrolo[3,2-c]pyridazine 25c (3.4 g) was obtained by filtration. The product was used in the next reaction without purification.

MS m/z(ESI): 154.1[M+1] ⁺ .

third step

Under nitrogen protection, 25c (1 g, 6.53 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (1.8 g, 9.80 mmol), 1,1'-bisdiphenylphosphinoferrocene Palladium dichloride (534 mg, 0.65 mmol) and potassium carbonate (3.6 g, 26.14 mmol) were dissolved in dioxane/water (v:v=8 mL/2 mL). The reaction was microwaved to 120°C and stirred for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-(2,4-dimethoxypyrimidin-5-yl)-5H-pyrrolo[3,2 -c]pyridazine 25d (500 mg), yield: 29.8%.

MS m/z(ESI): 258.1[M+1] ⁺ .

the fourth step

25d (300 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature and N-chlorosuccinimide (156 mg, 1.17 mmol) was added. The reaction was stirred at 50°C for 4 hours. The reaction solution was concentrated, dichloromethane (20 mL) was added to the residue to make a slurry, and the product was filtered to obtain 7-chloro-3-(2,4-dimethoxypyrimidin-5-yl)-5H-pyrrolo[3,2- c] Pyridazine 25e (210 mg), yield: 61.8%.

MS m/z(ESI): 292.0[M+1] ⁺ .

the fifth step

25e (200 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (5 mL). To the reaction solution were added iodoethane (259 mg, 2.06 mmol) and potassium carbonate (284 mg, 2.06 mmol) in this order. The reaction was stirred at 80°C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product 7-chloro-3-(2,4-dimethoxypyrimidin-5-yl)-5-ethyl-5H-pyrrolo[3,2-c ] Pyridazine 25f (230 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 320.1[M+1] ⁺ .

Step 6

25f (230 mg, 0.72 mmol) was dissolved in hydrochloric acid (1 M, 5 mL) at room temperature and stirred overnight. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(7-chloro-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione 25 (12.48 mg). Yield: 5.9%.

MS m/z(ESI): 292.1[M+1] ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ11.47(s,2H), 8.45(s,1H), 8.40(s,1H), 8.12(s,1H), 4.23(q,2H), 1.38(t , 3H).

Example 26

5-(7-Bromo-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

25d (1.0 g, 3.89 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature, and liquid bromine (620 mg, 3.89 mmol) was added dropwise. The reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated, and dichloromethane (100 mL) was added to the residue with stirring. The reaction solution was filtered, and the obtained solid was the product 7-bromo-3-(2,4-dimethoxypyrimidin-5-yl)-5H-pyrrolo[3,2-c]pyridazine 26a (1.2g), Yield: 91.8%.

MS m/z(ESI): 336.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ12.17(s,1H), 8.93(s,1H), 8.11(s,1H), 8.05(s,1H), 4.04(s,3H), 4.00( s, 3H).

second step

26a (150 mg, 0.45 mmol) and potassium carbonate (185 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (2.5 mL) at room temperature, and iodoethane (209 mg, 1.34 mmol) was added dropwise with stirring. The reaction was heated to 85°C and stirred for 3 hours. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated sodium chloride solution, dried, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 7-bromo-3-(2,4-dimethoxypyrimidine- 5-yl)-5-ethyl-5H-pyrrolo[3,2-c]pyridazine 26b (35 mg), yield: 21.5%.

MS m/z(ESI): 366.0[M+1] ⁺ .

third step

26b (35 mg, 0.096 mmol) was dissolved in a mixture of methanol (0.5 mL) and hydrochloric acid (2M, 1 mL). The reaction was heated to 75°C and stirred for 6 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(7-bromo-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-diketone 26 (11 mg), yield: 34%.

MS m/z(ESI): 336.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.55-11.32(m, 2H), 8.43(s, 1H), 8.39(s, 1H), 8.14(s, 1H), 4.24(q, 2H), 1.38(t,3H).

Example 27

5-(7-Chloro-5-isopropyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

25e (100 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (2 mL). To the reaction solution were added 2-iodopropane (175 mg, 1.03 mmol) and potassium carbonate (142 mg, 1.03 mmol) in this order. The reaction was stirred at 80°C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain the crude product 7-chloro-3-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-5H-pyrrolo[3,2- c] Pyridazine 27a (108 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 334.0[M+1] ⁺ .

second step

27a (108 mg, 0.32 mmol) was dissolved in hydrochloric acid (1 M, 5 mL) at room temperature and stirred overnight. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(7-chloro-5-isopropyl-5H-pyrrolo[3,2-c]pyridazin-3-yl) Pyrimidine-2,4(1H,3H)-dione 27 (17 mg). Yield: 17%

MS m/z(ESI): 306.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.47(s, 2H), 8.47(s, 1H), 8.39(s, 1H), 8.25(s, 1H), 4.83–4.74(m, 1H), 1.47(d,6H).

Example 28

5-(3-Bromo-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione

first step

Example 9 (60 mg, 0.19 mmol) and 1-bromopyrrolidine-2,5-dione (34 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred. The reaction was stirred at 30°C for 48 hours. The reaction solution was filtered, and the filtrate was separated by reverse-phase HPLC preparative separation (formic acid system) to obtain the title product 5-(3-bromo-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2] -b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 28 (55 mg), yield: 74.2%.

MS m/z(ESI): 390.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.45(s, 2H), 8.02(s, 1H), 7.83(s, 1H), 7.39(s, 1H), 2.31-2.27(m, 1H), 1.43-1.39(m,2H),1.26-1.22(m,1H),1.13-1.10(m,1H),1.02-0.98(m,6H).

Example 29

5-(3-Chloro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione

first step

Compound 9 (60 mg, 0.19 mmol) and 1-chloropyrrolidine-2,5-dione (25 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred. The reaction was stirred at 30°C for 48 hours. The reaction solution was filtered, and the filtrate was separated by reverse-phase HPLC preparative separation (formic acid system) to obtain the title product 5-(3-chloro-8-((1S,2R)-2-isopropylcyclopropyl)imidazo[1,2] -b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 29 (50 mg), yield: 76.0%.

MS m/z(ESI): 346.1[M+1] ⁺ .

1H NMR (400MHz, DMSO-d ₆ ) δ 11.42(s, 2H), 8.03(s, 1H), 7.81(s, 1H), 7.39(s, 1H), 2.32–2.23(m, 1H), 1.48 –1.37(m,2H),1.30–1.18(m,1H),1.16–1.07(m,1H),1.04–0.93(m,6H).

Example 30

5-(3-Chloro-8-(3,3-dimethylcyclopent-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4( 1H,3H)-dione

first step

21 (43 mg, 0.13 mmol), N-chlorosuccinimide (18 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL). The reaction was heated to 50°C and stirred for 3 hours. The reaction solution was filtered, and the filtrate was prepared and separated by reverse-phase HPLC (formic acid system) to obtain the product 5-(3-chloro-8-(3,3-dimethylcyclopent-1-en-1-yl)imidazo[1, 2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 30 (27.9 mg), yield: 58.6%.

MS m/z(ESI): 358.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.54(s, 2H), 8.07(s, 1H), 7.86(s, 1H), 7.68(s, 1H), 7.55(s, 1H), 2.84( t, 2H), 1.82(t, 2H), 1.18(s, 6H).

Example 31

5-(4-((1S,2R)-2-isopropylcyclopropyl)pyrazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-di ketone

first step

Under nitrogen, methyl-1H-pyrazole-3-carboxylate 31a (5 g, 39.65 mmol) was dissolved in dry tetrahydrofuran (200 mL) at 0°C with stirring. A solution of lithium bis(trimethylsilyl)amide (1 M, 47.58 mmol) was slowly added dropwise to the reaction solution. After dropping, (aminooxo)diphenylphosphine oxide (11 g, 47.58 mmol) was added to the reaction solution. The reaction solution was further stirred at room temperature for 12 hours. Dichloromethane (50 mL) was added to the reaction solution, the reaction solution was filtered, the filter residue was washed with dichloromethane, the organic phase was concentrated to obtain a crude product, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 1-amino-1H - Pyrazole-5-carboxylate methyl ester 31b (1.5 g), yield: 26%.

MS m/z(ESI): 142.0[M+1] ⁺ .

second step

31b (1.0 g, 7.08 mmol) and methyl-3-chloro-3-carbonylpropionate (1.0 g, 7.79 mmol) were dissolved in dichloromethane (10 mL) with stirring at room temperature. To the reaction solution was added triethylamine (2.2 g, 21.26 mmol). The reaction solution was further stirred at room temperature for 4 hours. Methanol (2 mL) was added to the reaction solution, the reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 1-(3-methoxy-3-carbonylpropionylamino)-1H-pyrazole -Methyl 5-carboxylate 31c (1.2 g), yield: 70%.

MS m/z(ESI): 242.0[M+1] ⁺ .

third step

31c (1.0 g, 4.14 mmol) and potassium tert-butoxide (1.4 g, 12.42 mmol) were dissolved in tetrahydrofuran (15 mL) at 0°C and stirred for 4 hours. The reaction solution was concentrated, and water (15 mL) and formic acid (2 mL) were added to neutrality. The reaction solution was filtered to obtain the product, methyl 4,6-dicarbonyl-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazine-5-carboxylate 31d (867mg), yield: 74%

MS m/z(ESI): 210.0[M+1] ⁺ .

the fourth step

31d (500 mg, 2.38 mmol) was dissolved in a solution of sodium hydroxide (382 mg, 9.56 mmol) in water (25 mL). The reaction solution was heated to 100°C and stirred for 12 hours. The reaction solution was cooled, and hydrochloric acid (1M) was added to make it neutral. The reaction solution was filtered to obtain the product pyrazolo[1,5-b]pyridazine-4,6-diol 31e (242 mg) with a yield of 67%.

MS m/z(ESI): 152.0[M+1] ⁺ .

the fifth step

31e (200 mg, 1.33 mmol), N-bis(trifluoromethanesulfonyl)aniline (520 mg, 1.46 mmol) and triethylamine (401 mg, 3.97 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature and stirred for 5 hours. Formic acid (1 mL) was added to the reaction solution, the reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 4-hydroxypyrazolo[1,5-b]pyridazin-6-yltris Fluoromethanesulfonic acid 31f (150 mg, white solid), yield: 40%.

MS m/z(ESI): 283.9[M+1] ⁺ .

Step 6

Under nitrogen protection, 31f (100 mg, 0.35 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (97 mg, 0.53 mmol), [1,1'-bis(diphenylphosphino) Ferrocene]palladium dichloride (29 mg, 0.035 mmol) and cesium carbonate (228 mg, 0.70 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The reaction solution was heated to 100°C by microwave and stirred for 1 hour. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-b]pyridazine- 4-ol 31 g (54 mg), yield: 56%.

MS m/z(ESI): 274.0[M+1] ⁺ .

Step 7

31 g (50 mg, 0.18 mmol), N-bis(trifluoromethanesulfonyl)aniline (72 mg, 0.2 mmol) and triethylamine (56 mg, 0.54 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature and stirred for 5 hours. Formic acid (0.1 mL) was added to the reaction solution, the reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-(2,4-dimethoxypyrimidin-5-yl)pyrazole [1,5-b]pyridazin-4-yltrifluoromethanesulfonic acid 31h (50 mg), yield: 67%.

MS m/z(ESI): 406.0[M+1] ⁺ .

Step 8

Under nitrogen protection, 31h (40 mg, 0.1 mmol), (1S, 2R)-2-isopropylcyclopropane-1-carboxylic acid (62 mg, 0.29 mmol, refer to WO2019168744A1 for its preparation method), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (8.16 mg, 0.01 mmol) and cesium carbonate (65 mg, 0.2 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.01 mL) ) in the mixture. The reaction solution was microwaved to 100°C and stirred for 1 hour. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated ammonium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-(2,4- Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyrazolo[1,5-b]pyridazine 31i (24 mg), yield: 72 %.

MS m/z(ESI): 340.1[M+1] ⁺ .

Step 9

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyrazolo[1,5-b]pyridazine 31i (20 mg, 0.06 mmol) was dissolved in hydrochloric acid (1 M, 2 mL) and stirred at 70°C overnight. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(4-((1S,2R)-2-isopropylcyclopropyl)pyrazolo[1,5-b] Pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 31 (12 mg). Yield: 64%

MS m/z(ESI): 312.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.42(s, 2H), 8.02(d, 2H), 7.18(s, 1H), 6.98(d, 1H), 2.18–2.07(m, 1H), 1.31–1.19 (m, 2H), 1.16–1.06 (m, 2H), 1.01 (t, 6H).

Example 32

5-(4-(3,3-Dimethylcyclopent-1-en-1-yl)pyrazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione

first step

Under nitrogen protection, 6-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-b]pyridazin-4-yltrifluoromethanesulfonic acid was added for 31h (30mg, 0.07mmol) , 2-(3,3-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6 mg, 0.007 mmol) and cesium carbonate (46 mg, 0.14 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.01 mL). The reaction solution was microwaved to 100°C and stirred for 1 hour. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated sodium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 6-(2,4- Dimethoxypyrimidin-5-yl)-4-(3,3-dimethylcyclopent-1-en-1-yl)pyrazolo[1,5-b]pyridazine 32a (24 mg), yielded Rate: 21%.

MS m/z(ESI): 352.1[M+1] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-(3,3-dimethylcyclopent-1-en-1-yl)pyrazolo[1,5-b]pyridin The oxazine 32a (21 mg, 0.06 mmol) was dissolved in hydrochloric acid (1 M, 2 mL) and stirred at 70°C overnight. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(4-(3,3-dimethylcyclopent-1-en-1-yl)pyrazolo[1,5] -b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 32 (13 mg). Yield: 67%.

MS m/z(ESI): 324.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.08(s, 2H), 7.61(s, 1H), 7.06(d, 1H), 6.71(s, 1H), 2.84(t, 2H), 1.83( t,2H),1.18(d,6H).

Example 33

5-(5-(Cyclopent-1-en-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, intermediate 2 (50 mg, 0.19 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane Borolane (73 mg, 0.38 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (16 mg, 0.019 mmol) and cesium carbonate (124 mg, 0.38 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction solution was heated to 100°C by microwave and stirred for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 4-(cyclopent-1-en-1-yl)-6-(2,4-dimethylene) Oxypyrimidin-5-yl)-3-methylpyridazine 19a (42 mg), yield: 74%.

MS m/z(ESI): 299.1[M+1] ⁺ .

second step

33a (30 mg, 0.10 mmol) was dissolved in hydrochloric acid (1 M, 2 mL). The reaction was heated to 70°C and stirred overnight. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-(cyclopent-1-en-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-diketone 33 (18 mg). Yield: 67%.

MS m/z(ESI): 271.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.41(s, 2H), 8.31(s, 1H), 8.07(s, 1H), 6.32(d, 1H), 2.75–2.65(m, 5H), 2.57(ddt, 2H), 1.97(p, 2H).

Example 34

5-(5-(3,3-Dimethylcyclopent-1-en-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

34a (987 mg, 8.80 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C and stirred for 5 min. Lithium bistrimethylsilylamide (1 M, 8 mL) was added dropwise to the above system, and the reaction was stirred at -78°C for 30 minutes. To the above reaction was added dropwise a solution of N-phenylbis(trifluoromethanesulfonyl)imide (3.14 g, 8.80 mmol) in tetrahydrofuran (10 mL). The reaction was slowly returned to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution (15 mL). The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (20 mL×2). The organic phases were combined, washed successively with 5% aqueous sodium carbonate solution and saturated sodium chloride solution, dried and concentrated to obtain crude product 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonic acid 34b (1.9 g), the product was directly used in the next reaction without purification.

second step

Under nitrogen, 34b (500 mg, 2.05 mmol), pinacol diboronate (624 mg, 2.46 mmol), tris(dibenzylideneacetone)dipalladium (93 mg, 0.102 mmol), 2-dicyclohexylphosphine- 2',4',6'-Triisopropylbiphenyl (195 mg, 0.409 mmol) and potassium acetate (402 mg, 4.09 mmol) were dissolved in dry 1,4-dioxane (9 mL). The reaction was heated to 100°C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product 2-(3,3-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-di Oxaborolane 34c (454 mg), the product was used in the next reaction without purification.

third step

Intermediate 2 (127 mg, 0.48 mmol), 34c (127 mg, 0.57 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (35 mg, 0.048 mmol), cesium carbonate ( 310 mg, 0.95 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5 mL). The reaction was heated to 100°C and stirred for 3 hours. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL×2). The organic phases were combined, dried, concentrated, and the crude product was separated by silica gel column chromatography (eluent system A) to give the product 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3,3-di Methylcyclopent-1-en-1-yl)-3-methylpyridazine 34d (140 mg), yield: 90%.

MS m/z(ESI): 327.2[M+1] ⁺ .

the fourth step

34d (140 mg, 0.43 mmol) was dissolved in a mixed solvent of hydrochloric acid (2M, 2.5 mL), methanol (1 mL) and tetrahydrofuran (1 mL), and the reaction was heated to 68°C and stirred for 3 hours. The reaction solution was filtered, and the filtrate was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-(3,3-dimethylcyclopent-1-en-1-yl)-6-methylpyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione 34 (50.8 mg), yield: 39.7%.

MS m/z(ESI): 299.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.46(s, 2H), 8.29(s, 1H), 8.05(s, 1H), 6.11(s, 1H), 2.78-2.71(m, 2H), 2.68(s, 3H), 1.79(t, 2H), 1.15(s, 6H).

Example 35

5-(8-(2-(Fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

Combine 35a (2 g, 11.74 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.65 g, 12.92 mmol), zirconocene hydride (303 mg, 1.77 mmol) ) and triethylamine (119 mg, 1.17 mmol) were placed in a reaction flask. Under nitrogen protection, the reaction solution was stirred at 60°C for 12 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with dichloromethane (10 mL), the filtrate was concentrated under reduced pressure, and the obtained crude compound was separated by silica gel column chromatography (eluent system A) to obtain the product tert-butyldimethyl ( (3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxo)silane 35b (2.2 g), yield: 63 %.

¹ H NMR (400MHz, CDCl ₃ ) δ 6.67(dt, 1H), 5.74(dt, 1H), 4.24(dd, 2H), 1.26(s, 12H), 0.90(s, 9H), 0.05(s, 6H).

second step

N-methyl-N-nitrosourea (500 mg, 4.8 mmol) was added to a mixed solution of a 20% aqueous potassium hydroxide solution (2 mL) and diethyl ether (2 mL) in an ice bath, and the mixture was stirred at this temperature for 1 hour. Under ice bath conditions, the organic phase of the above mixed solution was added to a solution of 35b (300 mg, 1.0 mmol) in ether (2 mL), and then palladium acetate (22 mg, 0.01 mmol) was added to the reaction solution, and the reaction was carried out under ice bath conditions. under stirring for 30 minutes. The reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL×3). The filtrate was concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system A) to obtain the product tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2) - Dioxaborolane-2-yl)cyclopropyl)methoxy)silane 35c (180 mg), yield: 57%.

¹ H NMR (400MHz, CDCl ₃ )δ3.59(dd,1H), 3.45(dd,1H), 1.25(m,1H), 1.21(s,12H), 0.88(s,9H), 0.68(ddd, 1H),0.54(ddd,1H),0.04(s,6H),-0.17–-0.30(m,1H).

third step

35c (150 mg, 0.48 mmol), 4-bromo-6-chloropyridazin-3-amine (99 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane The complex (39 mg, 0.048 mmol) and potassium carbonate (132 mg, 0.96 mmol) were dissolved in 1,4-dioxane/water (v:v=4:1, 2 mL), and the reaction solution was placed in a nitrogen atmosphere. Stir for 1 hour under microwave conditions at 80°C. Saturated sodium chloride (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 4- (2-(((tert-butyldimethylsilyl)oxo)methyl)cyclopropyl)-3,6-dichloropyridazine 35d (91 mg), yield: 57%.

MS m/z(ESI): 333.0[M+1] ⁺ .

the fourth step

35d (350 mg, 1.05 mmol) was dissolved in tetrahydrofuran and tetra-n-butylammonium fluoride (1 M in THF, 1.58 mmol) was added. The reaction solution was stirred at 25°C for 4 hours. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product (2-(3,6-dichloropyridazin-4-yl)cyclopropyl)methanol 35e (210 mg) , Yield: 90%.

MS m/z(ESI): 219.0[M+1] ⁺ .

the fifth step

35e (200 mg, 0.91 mmol) was dissolved in dry dichloromethane (3 mL), the reaction solution was stirred at -78°C under nitrogen protection, and then diethylaminosulfur trifluoride (221 mg, 1.37 mmol) was added, The reaction solution was continued to stir at -78°C for 4 hours. The reaction solution was quenched with saturated sodium bicarbonate solution until no bubbles were generated, extracted with dichloromethane (10 mL×3), the organic phases were combined, dried, and concentrated to obtain crude product, which was separated by silica gel column chromatography (eluent system A) to obtain Product 3,6-dichloro-4-(2-(fluoromethyl)cyclopropyl)pyridazine 35f (83 mg), yield: 41%.

MS m/z(ESI): 220.9[M+1]+.

Step 6

35f (53 mg, 0.24 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (66 mg, 0.36 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride Dichloromethane complex (19 mg, 0.024 mmol) and cesium carbonate (156 mg, 0.48 mol) were dissolved in 1,4-dioxane/water (4:1, 2 mL), and the reaction solution was added to 100 under nitrogen protection. Stir under microwave conditions for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product 3-chloro -6-(2,4-Dimethoxypyrimidin-5-yl)-4-(2-(fluoromethyl)cyclopropyl)pyridazine 35 g (53 mg), yield: 68%.

MS m/z(ESI): 325.0[M+1] ⁺ .

Step 7

35g (198mg, 0.61mmol), diphenylmethaneimide (331mg, 1.83mmol), tris(dibenzylideneacetone)dipalladium (56mg, 0.06mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (76 mg, 0.121 mmol) and cesium carbonate (396 mg, 1.22 mmol) were dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, the reaction solution was stirred at 120°C for 12 hours. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated sodium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product N-(6-(2 ,4-Dimethoxypyrimidin-5-yl)-4-(2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)-1,1-diphenylmethaneimine 35h (224mg) , Yield: 78%.

MS m/z(ESI): 470.1[M+1] ⁺ .

Step 8

35h (198 mg, 0.42 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL) and hydrochloric acid (1 M, 3 mL) was added. The reaction solution was heated to 70°C and stirred for 5 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 5-(6-amino-5-(2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-diketone 35i (72 mg). Yield: 60%

MS m/z(ESI): 278.0[M+1] ⁺ .

Step 9

35i (44 mg, 0.16 mmol), p-toluenesulfonic acid (32 mg, 0.19 mmol) and 2-chloro-1,1-dimethoxyethane (60 mg, 0.48 mmol) were dissolved in isopropanol (2 mL). The reaction solution was stirred at 100°C for 10 hours under nitrogen protection. The reaction solution was concentrated and separated by reverse-phase HPLC (formic acid system) to obtain the product 5-(8-(2-(fluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine- 2,4(1H,3H)-dione 35 (32 mg), yield: 66%.

MS m/z(ESI): 302.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.19(s,1H), 8.02(s,1H), 7.67(s,1H), 7.43(s,1H), 4.66–4.32(m,2H), 2.05–1.93 (m, 1H), 1.68–1.56 (m, 1H), 1.28–1.20 (m, 2H).

Example 36

5-(8-(2,2-Difluorocyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

3,6-Dichloropyridazine (1.0 g, 6.76 mmol) was suspended in 30 mL of deionized water, 2,2-difluorocyclopropane-1-carboxylic acid (824 mg, 6.76 mmol) and concentrated sulfuric acid (1 mL) were added, Heated to 70°C under nitrogen protection. A solution of silver nitrate (228 mg, 1.34 mmol) in water (1 mL) was added, and then a solution of ammonium persulfate (4.5 g, 20.1 mmol) in water (15 mL) was added dropwise for about 15 minutes, and the reaction was continued at 70° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized to pH 8-9 with ammonia water, and extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed successively with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude compound was separated by silica gel column chromatography (eluent system B), The product 3,6-dichloro-4-(2,2-difluorocyclopropyl)pyridazine 36b (400 mg) was obtained, yield: 26%.

MS m/z(ESI): 224.9[M+H] ⁺ .

second step

36b (400 mg, 1.78 mmol), 2,4-dimethoxypyrimidine-5-boronic acid (327 mg, 1.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (145 mg, 0.177 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were dissolved in 1,4-dioxane/water (v:v=4:1,2 mL). Under nitrogen protection, the reaction solution was stirred at 70°C under microwave condition for 1 hour. The reaction solution was cooled to room temperature, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed successively with water (25 mL) and saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude compound was separated by silica gel column chromatography (eluent system A), The product 3-chloro-4-(2,2-difluorocyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine 36c (300 mg) was obtained in 51% yield.

MS m/z(ESI): 329.0[M+H] ⁺ .

third step

36c (200 mg, 0.61 mmol), diphenylmethaneimide (331 mg, 1.83 mmol), tris(dibenzylideneacetone)dipalladium (56 mg, 0.06 mmol), 1,1'-binaphthyl-2,2 '-Bisdiphenylphosphine (76 mg, 0.121 mmol) and cesium carbonate (396 mg, 1.22 mmol) were dissolved in 1,4-dioxane (10 mL). Under nitrogen protection, the reaction solution was stirred at 120°C for 12 hours. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phase was washed with water, saturated sodium chloride, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system A) to obtain the product N-(4-(2 ,2-difluorocyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl)-1,1-diphenylmethaneimine 36d (210 mg), Yield: 72%.

MS m/z(ESI): 474.1[M+1] ⁺ .

the fourth step

36d (200 mg, 0.422 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL) and hydrochloric acid (1 M, 3 mL) was added. The reaction solution was heated to 70°C and stirred for 5 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 5-(6-amino-5-(2,2-difluorocyclopropyl)pyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-diketone 36e (72 mg). Yield: 60%

MS m/z(ESI): 282.0[M+1] ⁺ .

the fifth step

36e (45 mg, 0.16 mmol), p-toluenesulfonic acid (32 mg, 0.19 mmol) and 2-chloro-1,1-dimethoxyethane (60 mg, 0.48 mmol) were dissolved in isopropanol (2 mL). The reaction solution was stirred at 100°C for 10 hours under nitrogen protection. The reaction solution was concentrated and separated by reverse phase HPLC (formic acid system) to obtain the product 5-(8-(2,2-difluorocyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2 ,4(1H,3H)-dione 36 (30 mg), yield: 60%.

MS m/z(ESI): 306.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.55(s, 2H), 8.38(s, 1H), 8.04(d, 1H), 7.90(s, 1H), 7.64(s, 1H), 2.37( m,3H).

Example 37

5-(8-Cyclopentylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 36, compound 5-(8-cyclopentylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 37 was obtained.

MS m/z(ESI): 298.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.19(s,1H), 7.99(s,1H), 7.69(s,1H), 7.57(s,1H), 3.61-3.48(m,1H), 2.18–2.06 (m, 2H), 1.87–1.70 (m, 6H).

Example 38

5-(8-Cyclobutylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 36, compound 5-(8-cyclobutylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 38 was obtained.

MS m/z(ESI): 284.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.40(d,1H), 8.07(d,1H), 7.97(s,1H), 7.85(s,1H), 4.00(t,1H), 2.48– 2.40 (m, 2H), 2.36–2.29 (m, 2H), 2.19–2.06 (m, 1H), 2.00–1.84 (m, 1H).

Example 39

5-(8-(3,3-Dimethylcyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 36, the compound 5-(8-(3,3-dimethylcyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H, 3H)-diketone 39.

MS m/z(ESI): 312.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.37(s, 2H), 8.19(s, 1H), 8.02(s, 1H), 7.67(s, 1H), 7.59(s, 1H), 4.14– 3.81 (m, 1H), 2.26–2.17 (m, 2H), 2.18–2.09 (m, 2H), 1.30 (s, 3H), 1.13 (s, 3H).

Example 40

5-(8-(3,3-Difluorocyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 36, the compound 5-(8-(3,3-difluorocyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H was obtained )-diketone 40.

MS m/z(ESI): 320.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.38(s, 2H), 8.25(s, 1H), 8.04(s, 1H), 7.73(s, 1H), 7.66(s, 1H), 3.96– 3.76(m,1H),3.26–2.97(m,4H).

Example 41

5-(6-Amino-5-(3,3-difluorocyclobutyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 40, the compound 5-(6-amino-5-(3,3-difluorocyclobutyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 41 was obtained .

MS m/z(ESI): 296.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ7.98(s,1H), 7.76(s,1H), 6.26(s,2H), 3.42-3.23(m,1H), 3.21-3.01(m,2H) ),2.73–2.53(m,2H).

Example 42

5-(8-(Cyclohex-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

first step

42a (551 mg, 2.64 mmol), 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.40 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (176 mg, 0.24 mmol) and potassium carbonate (664 mg, 4.81 mmol) were dissolved in 1,4-dioxane (8 mL ) and water (2 mL) mixed solvent, nitrogen was replaced for 2 minutes. The reaction was heated to 100°C and stirred for 2 hours. The reaction was cooled to room temperature, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the product 6-chloro-4-(cyclohex-1-en-1-yl)pyridazin-3-amine 42b ( 490 mg), yield: 97%.

MS m/z(ESI): 210.1[M+1] ⁺ .

second step

42b (490 mg, 2.34 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (516 mg, 2.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (171 mg, 0.23 mmol), potassium carbonate (646 mg, 4.67 mmol) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (2 mL), nitrogen was replaced for 2 minutes, and the reaction was heated by microwave Stir to 100°C for 1 hour. The reaction was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give the product 4-(cyclohex-1-en-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin Azin-3-amine 42c (597 mg), yield: 81.5%.

MS m/z(ESI): 314.1[M+1] ⁺ .

third step

42c (120 mg, 0.38 mmol), 2-chloro-1,1-dimethoxy-ethane (95 mg, 0.77 mmol), p-toluenesulfonic acid (165 mg, 0.96 mmol) were dissolved in isopropanol (1 mL) ) and N,N-dimethylformamide (0.5 mL) in a mixed solvent. The reaction was heated to 100°C and stirred for 16 hours. The reaction was cooled to room temperature and filtered. The filter cake was preparatively separated by reverse phase HPLC (formic acid system) to obtain the product 5-(8-(cyclohex-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2 ,4(1H,3H)-dione 42 (20 mg), yield: 16.9%.

MS m/z(ESI): 310.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.41(s, 2H), 8.20(d, 1H), 8.04(s, 1H), 7.82-7.76(m, 1H), 7.70(d, 1H), 7.65(s, 1H), 2.51-2.49(m, 2H), 2.37-2.30(m, 2H), 1.85-1.74(m, 2H), 1.70-1.61(m, 2H).

Example 43

5-(7-Chloro-5-isobutyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 25, the title product 5-(7-chloro-5-isobutyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H was obtained )-diketone 43.

MS m/z(ESI): 320.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.52-11.48(m, 2H), 8.49(s, 1H), 8.37(d, 1H), 8.16(s, 1H), 4.04(d, 2H), 2.16-2.13(m,1H),0.85(d,6H).

Example 44

5-(5-ethyl-7-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 25, the title product 5-(5-ethyl-7-methyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H was obtained )-diketone 44.

MS m/z(ESI): 272.1[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ12.06(s,1H), 11.84(s,1H), 8.69(s,1H), 8.40(d,1H), 8.19(s,1H), 4.33(q,2H) ), 2.40(s, 3H), 1.40(t, 3H).

Example 45

5-(4-((1S,2R)-2-isopropylcyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 24, the title product 5-(4-((1S,2R)-2-isopropylcyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2 was obtained ,4(1H,3H)-diketone 45.

MS m/z(ESI): 311.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.29(s,2H), 7.90(s,1H), 7.78(s,1H), 6.83-6.79(m,1H), 6.75-6.71(m,1H) ), 6.67 (s, 1H), 2.08–1.99 (m, 1H), 1.30–1.16 (m, 1H), 1.16–1.09 (m, 1H), 1.09–0.95 (m, 8H).

Example 46

5-(4-([1,1'-Bi(cyclopropane)]-2-yl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)- diketone

Referring to the synthetic method of Example 24, the title product 5-(4-([1,1'-bi(cyclopropane)]-2-yl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine was obtained -2,4(1H,3H)-dione 46.

MS m/z(ESI): 309.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ7.88(s,1H), 7.78(s,1H), 6.81(dd,1H), 6.77-6.60(m,2H), 2.13-1.86(m,1H) ), 1.38–1.22 (m, 1H), 1.12–1.04 (m, 1H), 1.03–0.92 (m, 2H), 0.51–0.37 (m, 2H), 0.29–0.12 (m, 2H).

Examples 46-1 and 46-2

5-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4 (1H,3H)-dione and 5-(4-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)pyrrolo[1,2-b]pyridazine- 2-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the resolution method of Example 24, the title product 5-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)pyrrolo[1,2-b]pyridin was obtained Azin-2-yl)pyrimidine-2,4(1H,3H)-dione 46-1 and 5-(4-((1S,2R)-[1,1'-bi(cyclopropane)]-2- yl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione 46-2.

Example 46-1: MS m/z (ESI): 309.1 [M+1] ⁺ ;

Example 46-2: MS m/z (ESI): 309.1 [M+1] ⁺ .

Example 47

5-(4-(2-(Trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 24, the title product 5-(4-(2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4( 1H,3H)-diketone 47.

MS m/z (ESI): 337.1 [M+1] ⁺ .

Examples 47-1 and 47-2

5-(4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H) -diketone and 5-(4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4( 1H,3H)-dione

Referring to the synthetic method of Example 24, the title product 5-(4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1,2-b]pyridazine was obtained by chiral resolution -2-yl)pyrimidine-2,4(1H,3H)-dione 47-1 and 5-(4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyrrolo[1 ,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione 47-2.

Example 47-1: MS m/z (ESI): 337.1 [M+1] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD) δ8.00(s, 1H), 7.75(s, 1H), 6.94-6.90(m, 1H), 6.88-6.83(m, 1H), 6.72-6.66(m, 1H), 2.64–2.58 (m, 1H), 2.22–2.17 (m, 1H), 1.47 (m, 2H).

Example 47-2: MS m/z (ESI): 337.1 [M+1] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.02(s, 1H), 7.78(d, 1H), 6.94(s, 1H), 6.89(d, 1H), 6.71(d, 1H), 2.67–2.60 (m, 1H), 2.26–2.19 (s, 1H), 1.56–1.48 (m, 2H).

Example 48

5-(5-Fluoro-4-((1S,2R)-2-isopropylcyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H )-dione

Referring to the synthetic method of Example 24, the title product 5-(5-fluoro-4-((1S,2R)-2-isopropylcyclopropyl)pyrrolo[1,2-b]pyridazin-2-yl was obtained ) pyrimidine-2,4(1H,3H)-dione 48.

MS m/z(ESI): 329.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.37(s, 2H), 7.87(s, 1H), 7.69–7.52(m, 1H), 6.73(d, 1H), 6.56(s, 1H), 2.12(d, 1H), 1.29–1.11 (m, 3H), 1.08–0.96 (m, 7H).

Example 49

5-(4-([1,1'-Bi(cyclopropane)]-2-yl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H ,3H)-dione

Referring to the synthetic method of Example 24, the title product 5-(4-([1,1'-bi(cyclopropane)]-2-yl)-5-fluoropyrrolo[1,2-b]pyridazine-2 was obtained -yl)pyrimidine-2,4(1H,3H)-dione 49.

MS m/z(ESI): 327.1[M+1] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.45 (t, J=3.7 Hz, 1H), 6.65–6.46 (m, 2H), 2.22–2.12 (m, 1H), 1.38 –1.31(m,1H),1.17–1.08(m,1H),1.06–0.93(m,2H),0.54–0.39(m,2H),0.27–0.15(m,2H).

Examples 49-1 and 49-2

5-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine -2,4(1H,3H)-dione and 5-(4-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)-5-fluoropyrrolo[1 ,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the resolution methods of Example 24-1 and Example 24-2, the title product 5-(4-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-5 was obtained -Fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione 49-1 and 5-(4-((1S,2R)-[1, 1'-Bi(cyclopropane)]-2-yl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H)-dione 49-2 .

Example 49-1: MS m/z (ESI): 327.1 [M+1] ⁺ ;

Example 49-2, MS m/z (ESI): 327.1 [M+1] ⁺

Example 50

5-(4-((1S,2S)-2-ethylcyclopropyl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4(1H,3H) -diketone

Referring to the synthetic method of Example 24, the title product 5-(4-((1S,2S)-2-ethylcyclopropyl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl) was obtained Pyrimidine-2,4(1H,3H)-dione 50.

MS m/z(ESI): 315.1[M+1] ⁺ .

¹ H NMR (400MHz, CD ₃ OD)δ7.95(s,1H),7.50-7.41(m,1H),6.63-6.53(m,2H),2.18-2.08(m,1H),1.55-1.44( m, 2H), 1.27–1.15 (m, 2H), 1.05 (t, 3H), 0.99–0.94 (m, 1H).

Example 51

5-(4-(3,3-Dimethylcyclopent-1-en-1-yl)-5-fluoropyrrolo[1,2-b]pyridazin-2-yl)pyrimidine-2,4( 1H,3H)-dione

Referring to the synthetic method of Example 24, the title product 5-(4-(3,3-dimethylcyclopent-1-en-1-yl)-5-fluoropyrrolo[1,2-b]pyridazine- 2-yl)pyrimidine-2,4(1H,3H)-dione 51.

MS m/z(ESI): 341.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.41(s, 2H), 7.93(s, 1H), 7.69(t, 1H), 7.02(s, 1H), 6.75(d, 1H), 6.31– 6.25(m, 1H), 2.78(t, 2H), 1.81(t, 2H), 1.15(s, 6H).

Example 52

5-(4-((1R,2S)-[1,1'-bis(cyclopropane)]-2-yl)pyrazolo[1,5-b]pyridazin-6-yl)pyrimidine-2, 4(1H,3H)-dione

Referring to the synthetic method of Example 31, the title product 5-(4-((1R,2S)-[1,1'-bis(cyclopropane)]-2-yl)pyrazolo[1,5-b]pyridyl was obtained oxazin-6-yl)pyrimidine-2,4(1H,3H)-dione 52.

MS m/z(ESI): 310.1[M+1] ⁺

1H NMR (400MHz, DMSO-d6)δ11.47(s,2H), 8.02(d,1H), 8.01(s,1H), 7.19(s,1H), 6.94(d,1H), 2.12–2.03( m, 1H), 1.46–1.36 (m, 1H), 1.20–1.12 (m, 1H), 1.10–0.96 (m, 2H), 0.56–0.42 (m, 2H), 0.28–0.17 (m, 2H).

Example 53

5-(5-([[1,1'-Bis(cyclopropane)]-2-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

N-methyl-N-nitrosourea (500 mg, 4.8 mmol) was added to 2 mL of a mixed solution of 20% potassium hydroxide aqueous solution and 2 mL of diethyl ether in an ice bath, and the mixture was stirred at this temperature for 1 hour. Under ice bath conditions, the organic phase of the above mixed solution was added to 53a (200 mg, 1.0 mmol) dissolved in 2 mL of ether, and then palladium acetate (22 mg, 0.01 mmol) was added to the reaction solution, and the reaction solution was placed under ice bath conditions. under stirring for 30 minutes. The reaction solution was filtered, the filter cake was washed with dichloromethane (5mL×3), the filtrate was concentrated, and the product was separated by silica gel column chromatography (eluent system B) to obtain the product 2-([[1,1'-bis(cyclopropane) ]-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 53b (182 mg), yield: 84.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 1.21 (s, 12H), 1.02 (ddd, J=10.5, 8.6, 6.0 Hz, 1H), 0.85-0.72 (m, 1H), 0.57 (ddd, J= 7.9, 6.4, 3.5Hz, 1H), 0.45–0.24 (m, 3H), 0.16–0.01 (m, 2H), -0.36 (dt, J=9.6, 5.9Hz, 1H).

second step

Combine 53b (110 mg, 0.53 mmol), Intermediate 2 (100 mg, 0.035 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex (28 mg, 35 umol) and carbonic acid Cesium (285 mg, 0.88 mmol) was dissolved in 1,4-dioxane/water (v:v=4:1, 2 mL), and the reaction solution was stirred at 100°C under microwave conditions for 1 hour under the protection of N ₂ . Saturated sodium chloride (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 4-( [1,1'-Bis(cyclopropane)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine 53c (100 mg), yield: 85.3%.

MS m/z(ESI): 313.3[M+1] ⁺ .

third step

53c (100 mg, 0.32 mmol) was dissolved in 2 mL of a 1 M aqueous hydrochloric acid solution, and the reaction solution was stirred at 70° C. for 1 hour. The reaction solution was concentrated and separated by reverse-phase HPLC preparative separation (formic acid system) to obtain the title product 5-(5-([[1,1'-bis(cyclopropane)]-2-yl)-6-methylpyridazine-3- yl)pyrimidine-2,4(1H,3H)-dione 53 (38 mg), yield: 32.5%.

MS m/z(ESI): 285.3[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.03 (s, 1H), 7.49 (s, 1H), 2.40-2.10 (m, 3H), 1.57 (dd, J=12.0, 6.4Hz, 1H) ,0.87(dd,J＝8.5,3.5Hz,1H),0.83-0.75(m,1H),0.72(t,J＝7.1Hz,2H),0.35-0.16(m,2H),0.01(m,2H ).

Split of Example 53

5-(5-((1R,2S)-[1,1'-bis(cyclopropane)]-2-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione and 5-(5-((1S,2R)-[1,1'-bis(cyclopropane)]-2-yl)-6-methylpyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione

Example 53 (28 mg, 0.089 mmol) was resolved on a chiral column (OZ column) to give the title product 53-1 (6.54 mg, R.T=5.722 min), yield: 24.2%; 53-2 (5.4 mg, R.T. =3.934 min), yield: 22.4%.

MS m/z (ESI): 53-1, 285.3[M+1] ⁺ ; 53-2, 285.3[M+1] ⁺ .

Example 54

5-(5-(2-(tert-butyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

To a mixture of 3,3-dimethyl-1-butyne 54a (5 g, 60.87 mmol) and triethylamine (615 mg, 6.09 mmol) was added _Cp2Zr *HCl (1.57 g, 6.09 mmol) and pinacol Borane (7.79 g, 60.87 mmol), and the mixture was stirred at 60° C. for 12 hours under nitrogen protection. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the product (E)-2-(3,3-dimethyl-1-en-1-yl) )-4,4,5,5-tetramethyl-1,3,2-dioxolane 54b (8 g), yield: 63.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.64(d,1H), 5.35(d,1H), 1.27(s,12H), 1.02(s,9H).

second step

1-methyl-1-nitrosourea (1.55 g, 15 mmol) was slowly added to a mixture of 20% potassium hydroxide aqueous solution (10 mL) and dichloromethane (10 mL) at 0°C, and after stirring for 30 minutes, Take the lower layer of yellow solution and slowly add it dropwise to (E)-2-(3,3-dimethyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3 at 0°C , 2-dioxolane 54b (210 mg, 1 mmol) in dichloromethane (5 mL) and stirring was continued for 30 min at 25°C. The reaction solution was filtered, dried and concentrated to obtain the product 2-(2-(tert-butyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane 54c( 200 mg), yield: 80.1%.

¹ H NMR (400MHz, CDCl ₃ ): δ1.21(s, 12H), 0.93-0.90(m, 1H), 0.82(s, 9H), 0.52(dd, 2H), -0.23--0.30(m, 1H).

third step

To 2-(2-(tert-butyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane 54c (200 mg, 0.89 mmol) and 4- Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine Intermediate 2 (238 mg, 0.89 mmol) in 1,4-dioxane (3 mL) and water ( 0.6 mL) was added Pd(dppf)Cl ₂ *DCM (73 mg, 0.09 mmol) and cesium carbonate (582 mg, 1.78 mmol). The mixture was reacted in a microwave at 100°C for 1 hour under nitrogen. After the reaction was cooled, 10 mL of water was added to quench, extracted with ethyl acetate (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed with the eluent eluent system The resulting residue was purified by B to give the product 4-(2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine 54d (30 mg ), yield: 10.2%.

MS m/z(ESI): 329.0[M+1] ⁺ .

the fourth step

To a round bottom flask was added 4-(2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine 54d (30 mg, 0.09 mmol) and hydrochloric acid (1 M, 2 mL), and the mixture was stirred at 70 °C for 16 h. The reaction solution was cooled and concentrated, and the residue was purified by reverse preparative HPLC to give the title product 5-(5-(2-(tert-butyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-diketone 2 (13.5 mg), yield: 48.7%.

MS m/z(ESI): 301.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.74(s,1H), 11.62(s,1H), 8.34(d,1H), 7.90(s,1H), 2.76(s,3H), 2.01 (d,1H),1.19(d,2H),1.06(d,1H),0.92(s,9H).

Example 55

5-(6-Methyl-5-(2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

55a (1.5 g, 15.14 mmol) was dissolved in a mixed solution of 5 mL of methyl tert-butyl ether and 2 mL of water, and 2 mL of aqueous sodium nitrite (1.15 g, 16.66 mmol) was added to the reaction solution under ice bath conditions. The reaction solution was stirred at room temperature for 3 hours. The aqueous phase of the reaction solution was separated, and the organic phase was directly used for the next reaction. The product yield was estimated with reference to the literature (WO2015052226A1), and the estimated yield of the product 2-diazo-1,1,1-trifluoroethane 55b (700 mg): 48.6%.

second step

Palladium acetate (139.93 mg, 0.625 mmol) was added to a solution of 55b in methyl tert-butyl ether (10 mL, 700 mg, 6.25 mmol), followed by 4,4,5,5-tetramethyl-2-vinyl- 1,3,2-dioxaborane (865.91 mg, 5.62 mmol) was added to the reaction solution, and the reaction solution was stirred and reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluent system B) to obtain the product 4,4,5,5-tetramethyl-2-(2-(trifluoromethyl)cyclic) propyl)-1,3,2-dioxaborane 55c (0.7 g), yield: 47.5%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.83-1.63 (m, 1H), 1.24 (d, J=11.3 Hz, 12H), 1.11-0.95 (m, 1H), 0.85 (dd, J=11.2, 7.1 Hz,1H),0.41–0.26(m,1H).

third step

55c (133 mg, 0.55 mmol), Intermediate 2 (100 mg, 0.37 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex (28 mg, 0.035 mmol), Cesium carbonate (285 mg, 0.88 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL), and the reaction solution was stirred at 100°C under microwave conditions for 1 hour under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction, extracted with dichloromethane (10 mL×3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent system B) to obtain the product 6- (2,4-Dimethoxypyrimidin-5-yl)-3-methyl-4-(2-(trifluoromethyl)cyclopropyl)pyridazine 55d (70 mg), yield: 55.6%.

MS m/z(ESI): 342.8[M+1] ⁺ .

the fourth step

55d (70 mg, 0.21 mmol) was dissolved in 2.0 mL of 1 M aqueous hydrochloric acid, and the reaction was stirred at 70°C for 1 hour. The reaction solution was concentrated and separated by reverse-phase HPLC preparative separation (formic acid system) to obtain the title product 5-(6-methyl-5-(2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-diketone 55 (21 mg), yield: 55.6%.

MS m/z(ESI): 313.3[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.26 (s, 1H), 7.91 (s, 1H), 2.70 (s, 3H), 2.31 (dd, J=14.7, 6.3 Hz, 1H), 2.00 (dd, J=14.7, 7.1Hz, 1H), 1.55–1.42 (m, 1H), 1.35 (dd, J=14.8, 6.1Hz, 1H).

Split of Example 55

5-(6-Methyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione and 5-(6-Methyl-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Example 55 (20 mg, 0.064 mmol) was resolved on a chiral column (MIC column) to give 55-1 (4.48 mg, RT=4.640 min), yield: 22.6%; 55-2 (4.79 mg, RT=4.965 min) ), yield: 23.9%. MS m/z (ESI): 55-1, 313.3[M+1] ⁺ ; 55-2, 313.3[M+1] ⁺ .

Example 56

5-(5-(2-(Hydroxymethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

To a mixture of propargyl tert-butyldimethylsilyl ether 56a (5.64 g, 33.10 mmol) and triethylamine (352 mg, 3.48 mmol) was added pinacol borane (4.45 g, 34.80 mmol) and Cp ₂ Zr.HCl (897 mg, 3.48 mmol). The resulting solution was heated to 60°C and stirred under nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (eluent system B) to give (E)-tert-butyldimethyl((3-(4,4,5-trimethyl-1) ,3,2-dioxaboroboran-2-yl)allyl)oxy)silane 56b (9 g), yield: 90%.

¹ H NMR (CDCl ₃ ): δ 6.61 (dt, J=18.0, 3.5Hz, 1H), 5.68 (dd, J=18.0, 2.2Hz, 1H), 4.18 (dd, J=3.6, 2.4Hz, 2H) ),1.19(s,12H),0.85(s,9H),0.00(s,6H).

second step

56b (1 g, 3.35 mmol) was dissolved in dichloromethane (20 mL), diazomethane in ether (17 ml, 33.5 mmol) was added at zero degrees, followed by a catalytic amount of Pd(OAc) ₂ (65 mg, 0.30 mmol) , and stirred at room temperature for 1 hour. The reaction solution was directly suspended to dryness, and the crude product was purified by silica gel column chromatography (eluent system B) to obtain tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl)cyclopropyl)methoxy)silane 56c (0.8 g), yield: 80%.

¹ H NMR (CDCl ₃ ): δ 3.55 (dd, J=10.8, 5.6Hz, 1H), 3.42-3.38 (m, 1H), 1.17 (d, J=1.2Hz, 12H), 0.84 (s, 9H) ),0.65(ddd,J=9.9,7.9,4.3Hz,1H),0.51(ddd,J=9.0,5.2,3.5Hz,1H),0.08(dt,J=9.6,5.8Hz,2H).

third step

4-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine intermediate 2 (0.05 g, 0.19 mmol) and 56c (0.12 g, 0.38 mmol) were added To the reaction mixture was added potassium carbonate (52 mg, 0.38 mmol) and Pd(dppf)Cl2 ( ₁₅ mg, 0.019 mmol) in oxane (5 mL) and water (0.5 mL) under nitrogen. The resulting mixture was stirred at reflux for 5 hours. Water (20 mL) was added, extracted with ethyl acetate (30 mL), the organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the target compound 4-(2-((((tert-butyl Dimethylsilyl)oxy)methyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine 56d (0.05 g), yield : 68%.

MS m/z(ESI): 417.2[M+1] ⁺ .

the fourth step

56d (0.05 g, 0.12 mmol) was dissolved in hydrochloric acid solution (1 M, 10 mL) and reacted at 70°C overnight. The reaction solution was concentrated, and the residue was purified by reverse-phase preparative HPLC (formic acid) to give 5-(5-(2-(hydroxymethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4 (1H,3H)-diketone 56 (3 mg), yield: 10%.

MS m/z(ESI): 275.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ 11.41(s, 2H), 8.24(s, 1H), 7.73(s, 1H), 3.58(dd, J=11.4, 5.3Hz, 2H), 2.70( s, 3H), 2.02–1.94 (m, 1H), 1.87 (dt, J=8.7, 4.9Hz, 1H), 0.99 (ddt, J=31.5, 9.3, 4.9Hz, 2H).

Example 57

5-(5-(2-(1,3-Difluoropropan-2-yl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

Dimethyl sulfoxide (4.28 g, 54.73 mmol) was slowly added dropwise to a solution of oxalyl chloride (3.48 g, 27.36 mmol) in dichloromethane (30 mL) under nitrogen atmosphere at -78°C, stirred for 30 minutes, and then slowly added A solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol 57a (2 g, 13.68 mmol) in dichloromethane (10 mL). The reaction was stirred for two hours, then triethylamine (8.29 g, 82.09 mmol) was slowly added. After the stirring was continued for 30 minutes, the temperature was gradually raised to 25° C. under stirring, and the stirring was continued for about 30 minutes. The reaction solution was quenched by adding 50 mL of water, extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed with the eluent eluent system B The resulting residue was purified to give the product 2,2-dimethyl-1,3-dioxane-5-acetaldehyde 57b (1.2 g), yield: 61.5%.

¹ H NMR (400 MHz, CDCl ₃ ): 9.89(s,1H), 4.28-4.17(m,4H), 2.42-2.32(m,1H), 1.49(s,3H), 1.39(s,3H).

second step

To a solution of 2,2-dimethyl-1,3-dioxane-5-acetaldehyde 57b (1.2 g, 8.32 mmol) in methanol (40 mL) and tert-butyl methyl ether (20 mL) at 25 °C was added ( Dimethyl 1-diazo-2-oxopropyl)phosphonate (3.20 g, 16.65 mmol) and potassium carbonate (4.59 g, 33.29 mmol), the mixture was stirred at 25°C overnight for 16 hours. The reaction solution was quenched by adding 30 mL of water, extracted with tert-butyl methyl ether (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the product 5-ethynyl-2,2-dimethyl-1,3-dioxane 57c (750 mg), yield: 64.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.99-3.90 (m, 2H), 3.87-3.81 (m, 2H), 2.82 (dddq, 1H), 2.10 (d, 1H), 1.47 (s, 3H) ,1.38(s,3H).

third step

To a mixture of 5-ethynyl-2,2-dimethyl-1,3-dioxane 57c (700 mg, 4.99 mmol) and triethylamine (50 mg, 0.50 mmol) was added _Cp2Zr *HCl (129 mg , 0.50 mmol) and pinacol borane (639 mg, 4.99 mmol), the mixture was stirred overnight at 60°C under nitrogen protection for 12 hours. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography with eluent eluent system B to obtain the product (E)-2-(2-(2,2-dimethyl-1,3- Dioxan-5-yl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane 57d (750 mg), yield: 45.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.38 (dd, 1H), 5.54 (dd, 1H), 3.88–3.72 (m, 4H), 2.72–2.56 (m, 1H), 1.43 (s, 3H) ,1.39(s,3H),1.30–1.21(12H).

the fourth step

4-(2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine Intermediate 2 (150 mg, 0.56 mmol), (E)-2-(2-(2,2-Dimethyl-1,3-dioxan-5-yl)vinyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxolane 57d (150 mg, 0.56 mmol), Pd(dppf)Cl ₂ *CH ₂ Cl ₂ (46 mg, 0.06 mmol) and cesium carbonate (365 mg, 1.12 mmol) were added to 1,4-dioxane The reaction solution was replaced with nitrogen three times in a ring (2 mL) and water (0.5 mL), and then stirred under microwave at 100°C for 1 hour. 5 mL of water was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the eluent system B was used for silica gel column chromatography. The resulting residue was purified to give the product (E)-6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-(2,2-dimethyl-1,3-dioxane) -5-yl)vinyl)-3-methylpyridazine 57e (175 mg), yield: 84.5%.

MS m/z(ESI): 373.0[M+1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ9.02(s,1H), 7.90(s,1H), 6.64(d,1H), 6.43(dd,1H), 4.10(s,3H), 4.07(s ,3H),4.06–4.01(m,2H),3.85(dd,2H),2.77(s,3H),2.74–2.68(m,1H),1.48(s,3H),1.47(s,3H).

the fifth step

To a solution of trimethyl sulfoxide (207 mg, 0.94 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert-butoxide (105 mg, 0.94 mmol) at 0 °C under nitrogen atmosphere, and the mixture was stirred at 25 °C for 1 After 1 hour (E)-6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-(2,2-dimethyl-1,3-dioxan-5-yl) was added ) vinyl)-3-methylpyridazine 57e (175 mg, 0.47 mmol) and stirring was continued for 2 hours. 20 mL of ice water was added to the reaction solution, extracted with dichloromethane (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed with the eluent eluent system B The resulting residue was purified to give the product 6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-(2,2-dimethyl-1,3-dioxan-5-yl) )cyclopropyl)-3-methylpyridazine 57f (80 mg), yield: 44.1%.

MS m/z(ESI): 387.0[M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.00 (s, 1H), 7.43 (s, 1H), 4.08 (s, 3H), 4.07 (s, 3H), 4.04 (dd, 2H), 3.83-3.77 (m, 2H), 2.83(d, 4H), 1.79(s, 1H), 1.44(s, 6H), 1.08(t, 2H), 0.87(t, 1H).

Step 6

To 6-(2,4-dimethoxypyrimidin-5-yl)-4-(2-(2,2-dimethyl-1,3-dioxan-5-yl)cyclopropyl)- To a solution of 3-methylpyridazine 57f (55 mg, 0.14 mmol) in methanol (5 mL) was slowly added dropwise hydrochloric acid (2M, 0.5 mL), and the mixture was stirred at 25°C for 30 minutes. The pH of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 2-(2-(6- (2,4-Dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)cyclopropyl)propane-1,3-diol 57 g (45 mg), yield: 91%.

MS m/z(ESI): 347.0[M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96(s, 1H), 7.48(s, 1H), 4.07(s, 3H), 4.06(s, 3H), 3.97(d, 2H), 3.92-3.83 (m, 2H), 2.89(s, 3H), 2.01(d, 1H), 1.90(s, 1H), 1.62(d, 1H), 0.87(d, 2H).

Step 7

Add 2-(2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)cyclopropyl)propane to 2-(2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)cyclopropyl)propane at -78°C Diethylaminosulfur trifluoride (63 mg, 0.39 mmol) was slowly added dropwise to a solution of 57 g (45 mg, 0.13 mmol) of -1,3-diol in dichloromethane (6 mL), and the mixture was stirred at 30 °C overnight for 12 hours . 10 mL of saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 4-(2-(1,3 -Difluoropropan-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine 57h (20 mg, yellow solid), product without purification Proceed directly to the next reaction.

MS m/z(ESI): 351.0[M+1] ⁺ .

Step 8

To the round bottom flask was added 4-(2-(1,3-difluoropropan-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl pyridazine 57h (20 mg, 0.06 mmol) and hydrochloric acid (1 M, 2 mL), the mixture was stirred at 70 °C for 2 h. The reaction solution was cooled and concentrated, and the residue was purified by preparative HPLC to give the title product 5-(5-(2-(1,3-difluoropropan-2-yl)cyclopropyl)-6-methylpyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione 57 (3 mg), yield: 15.2%.

MS m/z(ESI): 323.0[M+1] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.28 (s, 1H), 7.83 (s, 1H), 4.58–4.54 (m, 4H), 2.78 (s, 3H), 2.11–2.03 (m, 1H) ), 1.60–1.56 (m, 1H), 1.18–1.13 (m, 1H), 0.93–0.85 (m, 2H).

Example 58

5-(5-(2-(1,3-Dihydroxypropyl-2-yl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-di ketone

first step

To a round-bottom flask were added 57 g of the compound in Example 57 (15 mg, 0.04 mmol) and hydrochloric acid (1 M, 2 mL), and the mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled and concentrated, and the residue was purified by preparative HPLC to give the title product 5-(5-(2-(1,3-dihydroxypropyl-2-yl)cyclopropyl)-6-methylpyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione 58 (3 mg), yield: 21.8%.

MS m/z(ESI): 319.0[M+1] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.13 (s, 1H), 7.58 (s, 1H), 3.68–3.58 (m, 4H), 2.70 (s, 3H), 1.92–1.88 (m, 1H) ), 1.55–1.46 (m, 1H), 1.15–1.11 (m, 1H), 1.06–1.01 (m, 1H), 0.81–0.76 (m, 1H).

Example 59

5-(6-Ethyl-5-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (60 mg, 0.179 mmol) was dissolved in a mixed solvent of 2 mL of 1,4-dioxane and 0.4 mL of water, added ethylboronic acid (39 mg, 0.537 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (15 mg, 0.0179 mmol) and cesium carbonate (117 mg, 0.358 mmol). The reaction solution was replaced with nitrogen three times, and the reaction was microwaved at 100° C. for 1 hour. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product crude 6-(2,4-Dimethoxypyrimidin-5-yl)-3-ethyl-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 59a (60 mg) , which was directly used in the next reaction.

MS m/z(ESI): 329.0[M+H] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-3-ethyl-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 59a (60 mg, 0.182 mmol ) was dissolved in 3 mL of methanol, hydrochloric acid (2M, 1 mL) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-ethyl-5-((1S,2R)-2-isopropylcyclopropyl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione 59 (24 mg), yield: 43.8%.

MS m/z(ESI): 301.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.42(s, 2H), 8.24(s, 1H), 7.64(s, 1H), 3.09(q, J=7.6Hz, 2H), 1.86-1.82 (m,1H),1.32(t,J=7.6Hz,3H),1.27-1.24(m,1H),1.03-0.98(m,7H),0.97-0.90(m,2H).

Example 60

5-(6-Cyclopropyl-5-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (60 mg, 0.179 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.4 mL of water, added cyclopropylboronic acid (23 mg, 0.269 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium (15 mg, 0.0179 mmol) and cesium carbonate (86 mg, 0.269 mmol). The reaction solution was replaced with nitrogen three times, and the reaction was microwaved at 100° C. for 1 hour. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Product 3-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 60a (60 mg), Yield: 98.4%.

MS m/z(ESI): 341.0[M+H] ⁺ .

second step

3-Cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 60a (60 mg, 0.178 mmol) was dissolved in 3 mL of methanol, hydrochloric acid (2M, 1 mL) was added, and the reaction was carried out at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-cyclopropyl-5-((1S,2R)-2-isopropylcyclopropyl)pyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione 60 (44 mg), yield: 80.0%.

MS m/z(ESI): 313.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.41(s, 2H), 8.21(s, 1H), 7.65(s, 1H), 2.09-2.05(m, 1H), 1.30-1.24(m, 1H), 1.18-1.15(m, 1H), 1.10-1.06(m, 3H), 1.03-0.98(m, 7H), 0.97-0.91(m, 3H).

Example 61

5-(6-(Hydroxymethyl)-5-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (80 mg, 0.239 mmol) was dissolved in 3 mL of 1,4-dioxane, (tributyltin) methanol (153 mg, 0.478 mmol) and tetrakis (triphenylphosphine) palladium (28 mg, 0.0239 mmol) were added, and the reaction solution was replaced with nitrogen 3 times , microwave reaction at 110 ℃ for 1 hour. The reaction solution was cooled to room temperature, 50 mL of water and a small amount of potassium fluoride were added to precipitate the tin reagent, filtered, and the filter cake was washed with ethyl acetate (40 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (40 mL). The organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain Crude product (6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanol 61a (50 mg ), which was directly used in the next step.

MS m/z(ESI): 331.0[M+H] ⁺ .

second step

(6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanol 61a (30 mg, 0.0908 mmol) was dissolved in 3 mL of methanol, hydrochloric acid (2M, 1 mL) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-(hydroxymethyl)-5-((1S,2R)-2-isopropylcyclopropyl)pyridine Azin-3-yl)pyrimidine-2,4(1H,3H)-dione 61 (9 mg), yield: 32.8%.

MS m/z(ESI): 303.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.39 (s, 1H), 7.76 (s, 1H), 5.43-5.39 (m, 1H), 4.86 (d, J=4.8Hz, 2H), 2.06 -2.03(m,1H),1.25-1.18(m,1H),1.02-0.98(m,6H),0.96-0.90(m,3H).

Example 62

5-(6-(Fluoromethyl)-5-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,

3H)-dione

first step

(6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)methanol 61a (30 mg, 0.091 mmol) was dissolved in 4 mL of tetrahydrofuran, triethylamine (44 mg, 0.272 mmol), triethylamine trihydrofluoride (46 mg, 0.454 mmol) and perfluorobutylsulfonyl fluoride (82 mg, 0.272 mmol) were added, room temperature React for 2 hours. Pour into 30 mL of saturated sodium bicarbonate solution, and extract with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 6-(2,4-dimethoxypyrimidine-5). -yl)-3-(fluoromethyl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 62a (20 mg), which was used directly in the next step.

MS m/z(ESI): 333.0[M+H] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-3-(fluoromethyl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 62a (20 mg , 0.0601 mmol) was dissolved in 3 mL of 1,4-dioxane, 1 mL of 2M hydrochloric acid was added, and the reaction was carried out at 70 °C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-(fluoromethyl)-5-((1S,2R)-2-isopropylcyclopropyl)pyridine Azin-3-yl)pyrimidine-2,4(1H,3H)-dione 62 (2.0 mg), yield: 10.9%.

MS m/z(ESI): 305.0[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.52 (s, 1H), 7.90 (s, 1H), 5.88 (dd, J=37.2 Hz, 10.4 Hz, 1H), 5.77 (dd, J=37.2 ,10.4Hz,1H),1.96-1.96(m,1H),1.09-1.04(m,1H),1.03-0.96(m,9H).

Example 63

5-(6-Amino-5-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (60 mg, 0.179 mmol) was dissolved in 2 mL of 1,4-dioxane, tert-butyl carbamate (63 mg, 0.537 mmol), tris(bisbenzylideneacetone)bispalladium(0) (16 mg, 0.0179 mmol), 2- Dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (8.5 mg, 0.0179 mmol) and cesium carbonate (88 mg, 0.269 mmol), the reaction solution was replaced with nitrogen three times, and the reaction was microwaved at 110° C. for 1 hour. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product tert-butyl (6-(2,4-dimethoxy) pyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)carbamate 63a (40 mg), which was used directly in the next step.

MS m/z(ESI): 416.0[M+H] ⁺ .

second step

tert-Butyl(6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazin-3-yl)aminomethane The acid ester 63a (40 mg, 0.096 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M hydrochloric acid was added, and the reaction was carried out at 70°C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(6-amino-5-((1S,2R)-2-isopropylcyclopropyl)pyridazine-3- yl)pyrimidine-2,4(1H,3H)-dione 63 (9.1 mg), yield: 32.8%.

MS m/z(ESI): 288.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.24(s, 2H), 7.94(s, 1H), 7.37(s, 1H), 6.25(s, 2H), 1.71-1.66(m, 1H) ,1.21-1.13(m,1H),1.00(dd,J=8.4,6.8Hz,6H),0.89-0.83(m,2H),0.78-0.74(m,1H).

Example 64

5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-methoxypyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (60 mg, 0.179 mmol) was dissolved in 3 mL of methanol, sodium methoxide (29 mg, 0.537 mmol) was added, and the reaction was heated to 70° C. for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 6-(2,4-dimethoxypyrimidine-5). -yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-methoxypyridazine 64a (55 mg), which was used directly in the next step.

MS m/z(ESI): 331.0[M+H] ⁺ .

second step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-methoxypyridazine 64a (55 mg, 0.0949 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M hydrochloric acid was added, and the reaction was carried out at 70° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-methoxypyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione 64 (37 mg), yield: 73.6%.

MS m/z(ESI): 303.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.37(br s, 2H), 8.08(s, 1H), 7.61(s, 1H), 4.07(s, 3H), 1.85-1.81(m, 1H) ),1.20-1.13(m,1H),1.02-0.89(m,9H).

Example 65

5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-ethoxypyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine Intermediate 1 (40 mg, 0.12 mmol) was dissolved in 5 mL of ethanol, sodium ethoxide (68 mg, 1 mmol) was added, and the reaction was heated to 60° C. for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, 20 mL of water was added, and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 6-(2,4-diethoxypyrimidine- 5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-ethoxypyridazine 65a (30 mg) was used directly in the next step.

MS m/z(ESI): 373.0[M+1] ⁺ .

second step

6-(2,4-diethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-ethoxypyridazine 65a (30 mg, 0.08 mmol) was dissolved in 1 mL of methanol, 1 mL of 2M hydrochloric acid was added, and the reaction was carried out at 70° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by reverse-phase HPLC to obtain the title product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-ethoxypyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione 65 (15 mg), yield: 55.3%.

MS m/z(ESI): 317.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.34(s, 2H), 8.08(s, 1H), 7.61(s, 1H), 4.51(p, 2H), 1.81(dt, 1H), 1.40 (t, 3H), 1.19–1.13 (m, 1H), 1.05–1.01 (m, 1H), 0.98 (dd, 6H), 0.94–0.91 (m, 1H), 0.88–0.84 (m, 1H).

Example 66

5-(8-((1R,2S)-(1,1'-bis(cyclopropane)]-2-yl)-3-methylimidazo[1,2-b]pyridazin-6-yl) Pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 13, the title product 5-(8-((1R,2S)-(1,1'-bis(cyclopropane)]-2-yl)-3-methylimidazo[1,2 -b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione 66.

MS m/z(ESI): 324.0[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.36(s, 2H), 8.03(s, 1H), 7.48(s, 1H), 7.24(s, 1H), 2.47(s, 3H), 2.25– 2.20 (m, 1H), 1.69–1.66 (m, 1H), 1.40–1.35 (m, 1H), 1.02

-0.97(m,2H),0.45-0.40(m,2H),0.20(s,2H).Example 675-(5-((1S,2R)-2-isopropylcyclopropyl)-6- (Methoxy-d3)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

Under nitrogen protection, 3,6-dichloropyridazine (1.0 g, 6.71 mmol) was suspended in 30 mL of deionized water, and (1R,2R)-2-isopropylcyclopropane-1-carboxylic acid (866 mg, 6.71 mmol) was added. mmol, and its preparation method refers to WO2019168744A1) and concentrated sulfuric acid (1 mL). After the reaction was heated to 70 °C, a solution of silver nitrate (228 mg, 1.34 mmol) in water (1 mL) was added dropwise to the reaction solution, and then a solution of ammonium persulfate (4.5 g, 20.1 mmol) in water (15 mL) was added dropwise, about 15 minutes to complete the dropwise addition. The reaction solution was stirred at 70°C for 1 hour. The reaction solution was cooled to room temperature and neutralized to pH 8-9 with ammonia water. The aqueous phase was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed successively with water (60 mL) and saturated sodium chloride solution (60 mL), dried and concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 3,6-dichloro- 4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 67b (1.0 g), yield: 64.5%.

MS m/z(ESI): 231.0[M+H] ⁺ .

second step

Under nitrogen protection, 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 67b (500 mg, 2.17 mmol), 2,4-dimethoxypyrimidine -5-boronic acid (400 mg, 2.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (179 mg, 0.22 mmol) and cesium carbonate (1.41 g, 4.34 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction solution was stirred under microwave conditions at 70°C for 1 hour. The reaction solution was cooled to room temperature, water (25 mL) was added, and the aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed successively with water (25 mL) and saturated sodium chloride solution (25 mL), dried and concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-6-( 2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 67c (306 mg), yield: 42.2%.

MS m/z(ESI): 335.1[M+H] ⁺ .

third step

Sodium hydride (288 mg, 12 mmol) was dissolved in deuterated methanol (3 mL) at room temperature and stirred for 10 minutes. 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine 67c (200 mg, 0.60 mmol) , added to the above mixed solution. The reaction solution was stirred at 65°C for 4 hours. The solution was cooled to room temperature, water (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed successively with water (5 mL) and saturated sodium chloride solution (5 mL), dried and concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to obtain the product 6-(2,4- Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(methoxy-d3)pyridazine 67d (156 mg), yield: 78 %.

MS m/z(ESI): 334.1[M+H] ⁺ .

the fourth step

6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(methoxy-d3)pyridazine 67d (100 mg, 0.30 mmol) was dissolved in a mixture of hydrochloric acid (1 M, 2 mL) and methanol (2 mL). The reaction was heated to 70°C and stirred for 3 hours. The reaction solution was concentrated to obtain crude product, and the crude product was separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-(methoxy- d3) Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 67 (59 mg), yield: 65%.

MS m/z(ESI): 306.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.37(br s, 2H), 8.08(s, 1H), 7.61(s, 1H), 1.85-1.81(m, 1H), 1.20-1.13(m, 1H),1.02-0.89(m,9H).

Example 68

5-(5-([1,1'-Bi(cyclopropane)]-2-yl)-6-methoxypyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

N-methyl-N-nitrosourea (500 mg, 4.8 mmol) was added to a mixed solution of 20% potassium hydroxide aqueous solution (2 mL) and diethyl ether (2 mL) in an ice bath, and the mixture was stirred at this temperature for 1 hour. Under ice bath conditions, the organic phase of the above mixed solution was added to a solution of 68a (200 mg, 1.0 mmol) in ether (2 mL), and then palladium acetate (22 mg, 0.01 mmol) was added to the reaction solution, and the reaction was carried out under ice bath conditions. under stirring for 30 minutes. The reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL×3). The filtrate was concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to give the product 2-([[1,1'-bis(cyclopropane)]-2-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborane 68b (182 mg), yield: 84.8%.

second step

68b (92 mg, 0.44 mmol), 4-bromo-3,6-dichloropyridazine (100 mg, 0.44 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloride palladium dichloromethane Compound (36 mg, 0.044 mmol) and potassium carbonate (121 mg, 0.88 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction was stirred at 80 °C under microwave conditions for 1 h under _N2 protection. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-bi(cyclopropane)]-2-yl)-3,6-dichloropyridazine 68c (79 mg), yield: 78%.

MS m/z(ESI): 228.8[M+1] ⁺ .

third step

Combine 68c (50 mg, 0.22 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (44 mg, 0.24 mmol), tetrakistriphenylphosphine palladium (26 mg, 0.022 mmol) and potassium carbonate (61 mg, 0.44 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). Under nitrogen protection, the reaction solution was stirred at 80°C under microwave conditions for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-Bi(cyclopropane)]-2-yl)-3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine 68d (35 mg), Yield: 48%.

MS m/z(ESI): 333.1[M+1] ⁺ .

the fourth step

Sodium metal (43 mg, 1.9 mmol) was added in portions to methanol (20 mL) under an ice bath and stirred until the sodium clumps were completely dissolved. To the reaction solution was added 68d (120 mg, 0.36 mmol). The reaction was heated to 65°C and stirred for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with saturated ammonium chloride and saturated sodium chloride, dried and concentrated to obtain the crude product 4-([1,1'-bi(cyclopropane)]-2 -yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methoxypyridazine 68e (118 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 329.0[M+1] ⁺ .

the fifth step

68e (118 mg, 0.359 mmol) was dissolved in a mixture of hydrochloric acid (2M, 5 mL) and methanol (5 mL), heated to 65°C and stirred for 3 hours. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-([1,1'-bi(cyclopropane)]-2-yl)-6-methoxyl Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 68 (45 mg), yield: 41.7%.

MS m/z(ESI): 300.9[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.38(s, 2H), 8.08(s, 1H), 7.59(s, 1H), 4.06(s, 3H), 1.80(dd, 1H), 1.23– 1.16 (m, 1H), 1.02–0.95 (m, 1H), 0.95–0.88 (m, 2H), 0.49–0.34 (m, 2H), 0.22–0.12 (m, 2H).

Example 68-1 and Example 68-2

5-(5-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-6-methoxypyridazin-3-yl)pyrimidine-2,4(1H, 3H)-dione and 5-(5-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)-6-methoxypyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione

Example 68 (47 mg, 0.16 mmol) was chiral resolved by SFC to give Example 68-1 (4.53 mg, R.T=1.899 min, yield: 9.6%) and Example 68-2 (5.21 mg, R.T=1.676 min) , yield: 11.1%),

Example 68-1: MS m/z (ESI): 300.9 [M+1] ⁺ ;

Example 68-2: MS m/z (ESI): 300.9 [M+1] ⁺ .

Chiral separation conditions:

Chiral analysis method:

Example 69

5-(6-(Methoxy-d ₃ )-5-(2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

first step

69a (1.5 g, 11.11 mmol) was dissolved in a mixed solution of methyl tert-butyl ether (5 mL) and water (2 mL) and stirred. The reaction solution was cooled with an ice bath, and an aqueous solution (2 mL) of sodium nitrite (0.843 g, 12.22 mmol) was added to the reaction solution. The reaction solution was warmed to room temperature and stirred for 3 hours. The aqueous phase of the reaction solution was separated, and the remaining organic phase (5 mL, according to document WO2015/52226, expected to contain 594 mg of product 2-diazo-1,1,1-trifluoroethane 69b, yield: 48.6%) was used directly for next reaction.

second step

Palladium acetate (121 mg, 0.54 mmol) was added to 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (748 mg, 4.86 mmol) methyl tert. butyl ether solution (5 mL), then a solution of 69b in methyl tert-butyl ether (5 mL, 594 mg, 5.4 mmol) was slowly added to the reaction. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the crude compound was purified by silica gel column chromatography (eluent system B) to obtain the product 4,4,5,5-tetramethyl-2-(2-(trifluoromethyl)cyclopropyl) )-1,3,2-dioxaborane intermediate 69c (0.7 g), yield: 60.9%.

third step

4-Bromo-6-chloropyridazin-3-amine (1.0 g, 4.80 mmol), 69c (1.25 g, 5.28 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloride The methyl chloride complex (392 mg, 0.48 mmol) and cesium carbonate (4.69 g, 14.39 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 5 mL) with stirring. The reaction solution was heated to 110 °C and stirred for 16 hours under nitrogen protection, and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (392 mg, 0.48 mmol) was added and continued at 110 Stir at °C for 16 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried and concentrated. The crude compound was isolated by silica gel column chromatography (eluent system B) to give the product 6-chloro-4-(2-(trifluoromethyl)cyclopropyl)pyridazin-3-amine 69d (450 mg), yield: 39.5%.

MS m/z(ESI): 238.1[M+1] ⁺ .

the fourth step

Sodium nitrite (157 mg, 2.27 mmol) was dissolved in concentrated sulfuric acid (2.0 mL) and stirred. Compound 69d (450 mg, 1.89 mmol) dissolved in acetic acid (5 mL) was slowly added to the reaction solution under ice bath, and then the reaction solution was warmed to room temperature and stirred for 1 hour. Water (5 mL) was added to the reaction solution, and the reaction solution was continuously stirred at room temperature for 0.5 hours. Saturated sodium chloride (10 ml) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain the crude product 6-chloro-4-(2-(trifluoromethyl)) Cyclopropyl)pyridazin-3(2H)-one 69e (440 mg), the product was used in the next reaction without purification.

MS m/z(ESI): 239.1[M+1] ⁺ .

the fifth step

69e (100 mg, 0.419 mmol) was dissolved in phosphorus oxychloride (64.26 mg, 0.419 mmol), and the reaction solution was heated to 100°C and stirred for 1 hour. The reaction solution was concentrated, saturated sodium bicarbonate (10ml) was added to the residue, the aqueous phase was extracted with dichloromethane (10ml×3), the organic phases were combined, dried and concentrated to obtain a crude product, which was subjected to silica gel column chromatography (eluent system B) The product 3,6-dichloro-4-(2-(trifluoromethyl)cyclopropyl)pyridazine 69f (100 mg) was isolated, yield: 92.82%.

MS: m/z (ESI): 258.3 [M+1] ⁺ ;

Step 6

Under nitrogen protection, 69f (250 mg, 0.98 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (180 mg, 0.98 mmol), 1,1-bis(diphenylphosphino)ferrocene Palladium dichloride dichloromethane complex (78mg, 0.098mmol), cesium carbonate (980mg, 2.94mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2ml) mixture During this time, the reaction was microwaved to 100°C and stirred for 1 hour. Saturated sodium chloride (10ml) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (10ml×3), the organic phases were combined, dried, and concentrated to obtain a crude product, which was obtained by silica gel column chromatography (eluent system B) Product 3-chloro-6-(2,4-dimethoxy-4,5-dihydropyrimidin-5-yl)-4-(2-(trifluoromethyl)cyclopropyl)pyridazine 69g (240mg ) yield: 68.6%.

MS: m/z (ESI): 361.3 [M+1] ⁺ ;

Step 7

Sodium hydride (166 mg, 6.93 mmol) was dissolved in deuterated methanol (1 mL) at room temperature, and the reaction solution was stirred at room temperature for 1 hour, and then 69 g (250 mg, 0.69 mmol) was added to the reaction solution. The reaction solution was further stirred at room temperature for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (10 ml×3), the organic phases were combined, dried, and concentrated to obtain the crude product 6-(2,4-dimethoxypyrimidine-5). -yl)-3-(methoxy- _d3 )-4-(2-(trifluoromethyl)cyclopropyl)pyridazine 69h (220 mg), the product was used in the next reaction without purification.

MS: m/z (ESI): 360.3 [M+1] ⁺ ;

Step 8

69h (200 mg, 0.55 mmol) was dissolved in hydrochloric acid solution (1 M, 2 mL) and the reaction was heated to 70°C and stirred for 1 hour. The reaction solution was concentrated, and the residue was preparatively separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(6-(methoxy-d ₃ )-5-(2-(trifluoromethyl)cyclopropyl)pyridazine) -3-yl)pyrimidine-2,4(1H,3H)-dione 69 (44 mg), yield: 23.6%.

MS: m/z (ESI): 332.3 [M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.43(s, 2H), 8.08(s, 1H), 7.84(s, 1H), 2.41(dt, 2H), 1.62–1.21(m, 2H).

Example 70

5-(5-([1,1'-Bi(cyclopropane)]-2-yl)-6-(methyl-d3)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- diketone

first step

N-methyl-N-nitrosourea (500 mg, 4.8 mmol) was added to a mixed solution of 20% potassium hydroxide aqueous solution (2 mL) and diethyl ether (2 mL) in an ice bath, and the mixture was stirred at this temperature for 1 hour. Under ice bath conditions, the organic phase of the above mixed solution was added to a solution of 70a (200 mg, 1.0 mmol) in ether (2 mL), then palladium acetate (22 mg, 0.01 mmol) was added to the reaction solution, and the reaction was carried out under ice bath conditions. under stirring for 30 minutes. The reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL×3). The filtrate was concentrated, and the obtained crude compound was separated by silica gel column chromatography (eluent system B) to give the product 2-([[1,1'-bis(cyclopropane)]-2-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborane 70b (182 mg), yield: 84.8%.

second step

70b (92 mg, 0.44 mmol), 4-bromo-3,6-dichloropyridazine (100 mg, 0.44 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane Compound (36 mg, 0.044 mmol) and potassium carbonate (121 mg, 0.88 mmol) were dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). The reaction was stirred at 80 °C under microwave conditions for 1 h under _N2 protection. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-Bi(cyclopropane)]-2-yl)-3,6-dichloropyridazine 70c (79 mg), yield: 78%.

MS m/z(ESI): 228.8[M+1] ⁺ .

third step

Combine 70c (50 mg, 0.22 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (44 mg, 0.24 mmol), palladium tetrakistriphenylphosphine (26 mg, 0.022 mmol) and potassium carbonate (61 mg, 0.44 mmol) was dissolved in 1,4-dioxane/water (v/v=4:1, 2 mL). Under nitrogen protection, the reaction solution was stirred at 80°C under microwave conditions for 1 hour. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-Bi(cyclopropane)]-2-yl)-3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine 70d (35 mg), Yield: 48%.

MS m/z(ESI): 333.1[M+1] ⁺ .

the fourth step

4-([1,1'-Bi(cyclopropane)]-2-yl)-3-chloro-6-(2,4-dimethoxypyrimidin-5-yl) under nitrogen protection at 0 °C ) pyridazine 70d (100 mg, 0.30 mmol), iron triacetylacetonate (11 mg, 0.03 mmol), N-methylpyrrolidone (one drop) were dissolved in tetrahydrofuran (5 mL) with stirring. Methyl-d3-magnesium iodide (1 M, 0.6 mL) was added dropwise to the reaction. After the dropwise addition was completed, the reaction solution was moved to room temperature and stirred for 4 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, concentrated, and the crude compound was separated by silica gel column chromatography (eluent system B) to obtain Product 4-([1,1'-Bi(cyclopropane)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(methyl-d3)pyridazine 70e (77 mg), yield: 82%.

MS m/z(ESI): 316.1[M+1] ⁺ .

the fifth step

4-([1,1'-Bi(cyclopropane)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(methyl-d3)pyridazine 70e (77 mg, 0.24 mmol) was dissolved in a mixture of hydrochloric acid (1 M, 2 mL) and methanol (2 mL), heated to 70°C and stirred for 4 hours. The reaction solution was concentrated to obtain crude product, and the crude product was separated by reverse-phase HPLC (formic acid system) to obtain the title product 5-(5-([1,1'-bi(cyclopropane)]-2-yl)-6-(methyl) -d3) Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione 70 (33 mg), yield: 47%.

MS m/z(ESI): 288.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.42(s,2H), 8.21(s,1H), 7.68(s,1H), 1.81-1.72(m,1H), 1.12-1.04(m,1H) ), 1.03–0.96 (m, 1H), 0.95–0.86 (m, 2H), 0.52–0.37 (m, 2H), 0.24–0.19 (m, 2H).

Example 70-1 and Example 70-2

5-(5-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-6-(methyl-d3)pyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione and 5-(5-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)-6-(methyl-d3)pyridazine- 3-yl)pyrimidine-2,4(1H,3H)-dione

Example 70 (33 mg, 0.11 mmol) was chiral resolved by SFC to give Example 70-1 (6.32 mg, R.T=1.653 min, yield: 19.2%) and Example 70-2 (8.80 mg, R.T=2.376 min) , yield: 26.7%),

Example 70-1: MS m/z (ESI): 288.1 [M+1] ⁺ ;

¹ H NMR(400MHz,DMSO-d6)δ12.00(s,1H),11.75(s,1H),8.41(s,1H),8.03(s,1H),1.95(s,1H),1.35(s ,1H),1.22(s,1H),1.13(s,1H),1.03(td,1H),0.60–0.37(m,2H),0.28–0.12(m,2H)

Example 70-2: MS m/z (ESI): 288.1 [M+1] ⁺ .

Chiral separation conditions:

Chiral analysis method:

Example 71

5-(8-(5,5-Dimethylcyclohex-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H) -diketone

Referring to the synthetic method of Example 12, the title product 5-(8-(5,5-dimethylcyclohex-1-en-1-yl)imidazo[1,2-b]pyridazin-6-yl) was obtained Pyrimidine-2,4(1H,3H)-dione 71.

MS m/z(ESI): 338.0[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ11.46(s, 2H), 8.20(d, 1H), 8.013(s, 1H), 7.79(d, 1H), 7.71(d, 1H), 7.61( s, 1H), 2.36(t, 2H), 2.30(d, 2H), 1.43(t, 2H), 1.00(s, 6H).

Example 72

5-(7-Cyclopropyl-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 25, the title product 5-(7-cyclopropyl-5-ethyl-5H-pyrrolo[3,2-c]pyridazin-3-yl)pyrimidine-2,4(1H, 3H)-diketone 72.

MS m/z(ESI): 298.1[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.41(s, 2H), 8.36(s, 1H), 8.28(s, 1H), 7.58(s, 1H), 4.13(q, 2H), 2.22- 2.11(m,1H),1.34(t,3H),1.01-0.91(m,4H).

Example 73

5-(8-(3-Methylcyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Referring to the synthetic method of Example 12, the title product 5-(8-(3-methylcyclobutyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H) was obtained -Diketone 73.

MS m/z(ESI): 298.1[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.52(s, 2H), 8.27(d, 1H), 8.02(dd, 1H), 7.79(s, 1H), 7.68(d, 1H), 3.87– 3.72 (m, 1H), 2.65–2.53 (m, 1H), 2.50–2.38 (m, 2H), 2.16–2.06 (m, 1H), 1.95–1.80 (m, 1H), 1.09 (d, 3H).

Example 74

5-(2,3-Dichloro-8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H )-dione

Referring to the synthetic method of Example 19, the title product 5-(2,3-dichloro-8-(2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl was obtained ) pyrimidine-2,4(1H,3H)-dione 74.

MS m/z(ESI): 405.8[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ11.32(s,2H), 8.11(s,1H), 7.82(s,1H), 2.88-2.81(m,2H), 1.81-1.76(m,1H) ),1.63–1.58(m,1H).

Biological Test Evaluation

The present invention is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

Test Example 1. Inhibition assay of the compounds of the present invention on the activity of free human CD73

1 The purpose of the experiment:

The inhibitory effect of the compounds of the present invention on the conversion of free human CD73 protein from AMP to adenosine was measured.

2 Experimental instruments and reagents:

2.1 Instruments:

Microplate reader (BioTek Synergy H1);

Pipette (Eppendorf &Rainin);

Centrifuge (Eppendorf).

2.2 Reagents:

Recombinant Human 5'-Nucleotidase/CD73Protein, CF protein was purchased from R&D Systems Company, the item number is 5795-EN-010;

AMP was purchased from Sigma Company, the item number is A1752;

Phosphate Assay Kit-PiColorLock ^TM was purchased from Abcam Company, the item number is ab270004;

UltraPure ^TM 1M Tris-HCI Buffer, pH 7.5, was purchased from Invitrogen Company, the item number is 15567027;

Magnesium chloride was purchased from Sigma Company, the item number is M1028-100ML;

The 384-well plate was purchased from Thermo, Cat. No. 464718.

3 Experimental methods:

This experiment is based on the principle that human CD73 protein converts AMP into adenosine and generates phosphate, and the enzyme activity of CD73 is characterized by detecting the content of phosphate generated. This experiment was carried out in a 384-well plate, and the buffer used in the experimental system was 25 mM Tris-HCl (pH 7.5), 5 mM MgCl ₂ , and 0.005% Tween 20. The CD73 protein was diluted with experimental buffer to 150pM, added to 384-well plate, 10 μL per well, centrifuged at 1000 rpm for 1 minute, and then compound solutions of different concentrations prepared in experimental buffer were added to 384-well plate, 10 μL per well, Centrifuge at 1000 rpm for 1 minute and mix well, add 50 μM AMP solution to the experimental well, 20 μL per well, centrifuge at 1000 rpm for 1 minute and mix well, seal the plate, and react at room temperature for 45 minutes. Add the mixed solution of PiColorLock ^TM and Accelerator (1:100) to the experimental wells, 10 μL per well, centrifuge at 1000 rpm for 1 minute and mix well, shake at room temperature for 5 minutes, then add Stabiliser, 4 μL per well, centrifuge at 1000 rpm for 1 minute and mix well, shake at room temperature for 5 minutes minute. Using the absorbance program in BioTek Synergy H1, the plate was read and absorbance at 635 nm was measured.

4 Experimental data processing methods:

Calculate the inhibition rate of each concentration according to the absorbance of each well, and use Graphpad Prism software to perform nonlinear regression curve fitting to obtain the IC ₅₀ value.

5 Experimental results:

According to the above scheme, the compounds shown in the present invention show biological activity of about 0.01 nM to 1000 nM (IC ₅₀ ) in the free human CD73 enzyme activity inhibition experiment. The specific experimental results are shown in Table 1:

Table 1

6 Experimental conclusions:

The above data show that the compounds of the examples of the present invention have strong inhibitory activity on the enzyme activity of free human CD73.

Test Example 2. Inhibitory assay of the compounds of the present invention on CD73 activity on the surface of tumor cells

1. Experimental purpose:

The inhibitory effect of the compounds of the present invention on the function of the surface CD73 protein of human breast cancer cells (MDA-MB-231, with high CD73 expression) from converting AMP to adenosine was measured.

2. Experimental instruments and reagents:

2.1 Instruments:

Microplate reader (BioTek Synergy H1);

Pipette (Eppendorf &Rainin);

Centrifuge (Eppendorf).

2.2 Reagents:

MDA-MB-231 was purchased from ATCC;

The Luminescent Cell Viability Assay was purchased from Promega, the product number is G7573;

The 96-well plate was purchased from Corning Company, the product number is 3610;

RPMI 1640 medium was purchased from Gibco Company, the article number is 22400089;

ATP Solution (10mM) was purchased from Life Technologies, the product number is PV3227;

AMP was purchased from Sigma, catalog number A1752;

FBS was purchased from Gibco Company, the article number is 10091148;

Pancreatin was purchased from Gibco Company, the product number is 25200056;

PBS was purchased from Gibco under the catalog number 10010023.

3. Experimental method:

In this experiment, CTG method was used to detect the inhibitory effect of compounds on the conversion of CD73 protein from AMP to adenosine on the surface of human breast cancer cells MDA-MB-231 with high CD73 expression.

When the MDA-MB-231 cells were cultured to an appropriate degree of confluency, the cells were collected, and the cells were adjusted to an appropriate density using complete medium (RPMI1640 medium containing 10% FBS), and the cell suspension was plated in a 96-well plate. Well 100 μL, put into 37°C, 5% _CO2 incubator overnight, remove supernatant, wash 3 times with serum-free 1640 medium, add 25 μL of serum-free 1640 medium and 25 μL of serum-free 1640 medium prepared Compound solutions of different concentrations, the vehicle control was serum-free 1640 medium containing DMSO, centrifuged at 1000 rpm for 1 minute to mix, and incubated at 37°C for 15 minutes. Add 1.2 mM AMP solution to the reaction wells, 25 μL per well, centrifuge at 1000 rpm for 1 minute to mix well, and incubate at 37°C for 2 hours. Transfer the supernatant into a new 96-well plate, 25 μL per well, then add 100 μM ATP solution, 25 μL per well, centrifuge at 1000 rpm for 1 minute and mix well, add CellTiter-Glo solution, shake and mix well, incubate in the dark for 10 minutes, and use The luminescence program in the BioTek Synergy H1 microplate reader reads and detects the luminescence signal value.

4. Experimental data processing method:

The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted to a nonlinear regression curve using Graphpad Prism software to obtain the _IC50 value.

5. Experimental results:

According to the above scheme, the compounds shown in the present invention show biological activity of about 0.01 nM to 1000 nM (IC ₅₀ ) in the inhibition experiment of CD73 enzyme activity on the surface of MDA-MB-231 cells. The specific experimental results are shown in Table 2:

Table 2

6. Experimental conclusion:

The above data show that the compounds of the examples of the present invention have strong inhibitory activity on CD73 enzymatic activity on the surface of MDA-MB-231 cells.

Test Example 3. Protocol for Stability Test of Liver Microsomes

1. Experimental purpose

The purpose of this experiment was to examine the stability of the compounds of the examples in liver microsomes.

2. Experimental instruments and reagents

2.1 Instruments

Liquid mass spectrometer (Shimadzu/AB SCIEX);

Centrifuge (Eppendorf);

Vortex (IKA);

Pipette (Eppendorf);

2.2 Reagents

96-well plate (Axycen, P-DW-11-C);

Methanol (Fisher, A452-4);

Acetonitrile (Fisher, A955-4);

Human liver microparticles (Xenotech, H0610);

Mouse liver microparticles (Xenotech, M1000);

NADPH(Bid, BD116582);

UDPGA (Sigma, U6751-500MG);

Alamethicin (Abcam, ab141893);

Phosphate buffer (Gibco, 10010-023);

DMSO (Sigma, 34869);

compound to be tested.

3. Experimental steps

3.1 Preparation of compound working solution

Compound working solution preparation: Compound stock solutions were added to phosphate buffer at a final concentration of 20 μM.

3.2 Preparation of liver microsome working solution

Dilute with 100 mM phosphate buffer to a final concentration of 0.625 mg/mL.

3.3 Prepare NADPH and UDPGA

Weigh NADPH and UDPGA, add 100 mM phosphate buffer, the final concentration is 20 mM.

3.4 Prepare the punch (Alamethicin)

Weigh 1 mg of Alamethicin and add 200 μL of DMSO to prepare a 5 mg/mL solution. Diluted with phosphate buffer to a final concentration of 50 μg/mL.

3.5 Preparation of reaction stop solution

Stop solution: cold acetonitrile containing 100 ng/mL labetalol hydrochloride and 400 ng/mL tolbutamide as internal standards.

3.6 Incubation process

400 μL of prepared liver microsomes, 25 μL of compound working solution and 25 μL of Alamethicin were sequentially added to the 96-well plate, and pre-incubated at 37°C for 10 min. Then add 50μL of prepared NADPH/UDPGA to start the reaction, incubate at 37°C, the total volume of the reaction system is 500μL, and the final contents of each component are as follows:

3.7 Sample Analysis

3.7.1 Chromatographic conditions

Instrument: Shimadzu LC-30AD

Column:

C18 (50*4.6mm, 5μm particle size);

Mobile phase: A: 0.1% formic acid solution, B: methanol

Wash gradient: 0.2～1.6min 5%A to 95%A, 3.0～3.1min 95%A to 5%A

Running time: 4.0min

3.7.2 Mass spectrometry conditions

Instrument: API5500 liquid chromatography mass spectrometer, AB Sciex company;

Ion source: Electrospray ionization source (ESI);

Drying gas: N ₂ , temperature 500°C;

Electrospray voltage: 5000V;

Detection method: positive ion detection;

Scanning mode: reaction monitoring (MRM) mode.

4. Experimental results:

Through the above scheme, the results of the stability test experiment of the compounds shown in the present invention in liver microsomes are shown in Table 3 below:

table 3

4. Experimental conclusion:

The above data show that the compounds of the examples of the present invention show good metabolic stability in the human and mouse liver microsome stability test experiments.

Test Example 4 Pharmacokinetic Determination in Mice

1. Research purposes:

Balb/C mice were used as test animals to study the pharmacokinetic behavior of the compounds of the examples of the present invention, orally administered at a dose of 50 mg/kg in the plasma of mice.

2. Experimental protocol

2.1 Test drug:

Compounds of the examples of the present invention, self-made;

Drug preparation:

Solvent: 20% HP-β-CD aqueous solution: Weigh 20 g of HP-β-CD, dissolve in 100 mL of purified water, vortex, mix and sonicate to obtain a clear solution.

The compound of the example of the present invention was weighed into a 4-mL glass bottle, 2.4 mL of solvent was added, and sonicated for 10 minutes to obtain a colorless and clear solution with a concentration of 5 mg/mL.

2.2 Experimental animals:

Balb/C Mouse 3 (3/example), male.

2.3 Administration:

There were 3 Balb/C mice, male; p.o. after overnight fasting, the dose was 50 mg/kg, and the administration volume was 10 mL/kg.

2.4 Sample collection:

Before administration of mice and 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, 0.04 mL of blood was collected from the orbit, placed in an EDTA-K ₂ test tube, centrifuged at 6000 rpm at 4°C for 6 min to separate the plasma, and the plasma was separated at -80 Store at ℃.

2.5 Sample processing:

1) Add 160uL of acetonitrile to 40uL of plasma sample for precipitation, and centrifuge at 3500×g for 5-20 minutes after mixing.

2) Take 100 uL of the supernatant solution after treatment for LC/MS/MS analysis of the concentration of the compound to be tested.

2.6 Liquid phase analysis

●Liquid phase condition: Shimadzu LC-20AD pump

Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

Column: phenomenex Gemiu 5um C18 50×4.6mm

●Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile

●Flow rate: 0.8mL/min

●Elution time: 0-4.0 minutes, the eluent is as follows:

3. Test results and analysis

The main parameters of pharmacokinetics are calculated with WinNonlin 6.1, and the results of the mice pharmacokinetic experiments are shown in Table 4 below:

Table 4: Pharmacokinetic parameters for oral administration of compounds of the present invention in mice

4. Experimental conclusion:

The data in the table shows that in the pharmacokinetic evaluation experiment of oral administration in mice, the compounds of the examples of the present invention showed higher exposure after oral administration.

Test Example 5: In vivo pharmacodynamic study of the compound on mouse breast cancer cell EMT-6 xenograft model

5.1 Experimental purpose:

The in vivo efficacy of the compounds on the mouse breast cancer cell EMT-6 xenograft model was evaluated.

5.2 Experimental instruments and reagents:

5.2.1 Instruments:

1. Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

2. Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.)

3. _CO2 incubator (Thermo-311, Thermo)

4. Centrifuge (Centrifuge 5720R, Eppendorf)

5. Automatic cell counter (Countess II, Life Technologies)

6. Vernier caliper (CD-6"AX, Mitutoyo, Japan)

7. Cell culture flask (T75/T225, Corning)

8. Electronic balance (CPA2202S, Sartorius)

9. Electronic balance (BSA2202S-CW, Sartorius)

5.2.2 Reagents:

1. Waymouth's MB 752/1 medium (11220-035, Gibco)

2. Fetal bovine serum (FBS) (10099-141C, Gibco)

3. Phosphate Buffered Saline (PBS) (10010-023, Gibco)

4. HP-β-CD (128446-35-5, Zibo Qianhui Biotechnology Co., Ltd.)

5.3 Experimental operation and data processing:

5.3.1 Animals

BALB/c mice, 6-8 weeks, female.

5.3.2 Cell culture and cell suspension preparation

a, Take out an EMT-6 cell from the cell bank, recover the cells with Waymouth's MB 752/1 medium (Waymouth's MB 752/1+15% FBS) containing 2mM L-glutamine, and place the recovered cells in a cell culture flask (mark the cell type, date, cultivator name, etc. on the bottle wall) and place it in a _CO2 incubator (incubator temperature is 37 °C, _CO2 concentration is 5%).

b, Passage after the cells cover 80-90% of the bottom of the culture flask, and continue to culture in a CO ₂ incubator after passage. This process is repeated until the number of cells meets the in vivo efficacy requirements.

c. Collect the cultured cells, count them with an automatic cell counter, and resuspend the cells with PBS according to the counting results to prepare a cell suspension (density 5×10 ⁶ /mL), which is placed in an ice box for use.

5.3.3 Cell seeding

a, Nude mice were labeled with disposable rat and mouse universal ear tags before inoculation.

b. Mix the cell suspension evenly during inoculation, draw 0.1-1mL of the cell suspension with a 1mL syringe, remove air bubbles, and then place the syringe on an ice pack for later use.

c, hold the nude mouse with the left hand, disinfect the position of the right back of the nude mouse against the right shoulder (inoculation site) with 75% alcohol, and start the inoculation after 30 seconds.

d, Inoculate the experimental nude mice in sequence (each mouse inoculates 0.1 mL of cell suspension).

5.3.4 Grouping, tumor measurement and administration of tumor-bearing mice

a, According to the body weight of the mice, grouping was carried out on the 2nd day after inoculation; and according to the grouping results, the test drug was started to be administered (administration method: oral administration; administration dose: 100 mg/kg; administration volume: 10 mL/kg; Dosing frequency: 2 times/day; dosing cycle: 18 days; vehicle: 20% HP-β-CD).

b, According to the tumor growth, the tumor was measured on the 4-7th day after inoculation, and the tumor size was calculated.

Calculation of tumor volume: tumor volume (mm ³ )=length (mm)×width (mm)×width (mm)/2

c, Tumors were measured and weighed twice a week.

d, Animals were euthanized after the experiment.

e, use software such as Excel to process data. Calculation of compound tumor inhibition rate TGI (%): when the tumor does not regress, TGI (%)=[1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/( The average tumor volume of the solvent control group at the end of treatment - the average tumor volume of the solvent control group at the beginning of treatment)] × 100%. When the tumor has regressed, TGI (%)=[1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/average tumor volume at the beginning of administration of this treatment group]× 100%.

5.4 Experimental conclusion:

The data in the table shows that in the pharmacodynamic evaluation experiment of oral administration in EMT-6 model mice, the compounds of the examples of the present invention showed a good tumor-inhibiting effect after oral administration, and the TGI of the compounds of the present invention was greater than 40%. The TGI of the compound is > 50%, more preferably the TGI of the compound is > 60%, and the TGI of the compound is more preferably > 70%.

Claims

A compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt:

in:

Ring A is selected from

Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R 1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, or thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy radical, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 NR AA R BB , -CR AA R BB (CH 2 ) n1 NR CC R DD , -(CH 2 ) n1 R AA , -CR AA R BB R CC , -(CH 2 ) n1 OR AA , -(CH 2 ) n1 C(O)OR AA , -(CH 2 ) n1 OR AA , -(CH 2 ) n1 SR AA , -(CH 2 ) n1 NR AA C(O)(CH 2 ) n2 R BB , -(CH 2 ) n1 NR AA C(O)OR BB , -(CH 2 ) n1 NR AA C(O)NR BB R CC or -NR AA (CH 2 ) n1 R BB , said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R AA , R BB , R CC and R DD are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy , haloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

Alternatively, any two of R AA , R BB , R CC and R DD and the nitrogen atom or carbon atom to which they are attached are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R2 is independently selected from hydrogen , deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, alkyl, deuterated alkyl, deuterated alkoxy, haloalkyl, hydroxy Alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n3 NR A1 R B1 , -CR A1 R B1 (CH 2 ) n3 NR C1 R D1 , -(CH 2 ) n3 R A1 , -CR A1 R B1 R C1 , -(CH 2 ) n3 OR A1 , -(CH 2 ) n3 C(O)OR A1 , -(CH 2 ) n3 OR A1 , -(CH 2 ) n3 SR A1 , -(CH 2 ) n3 NR A1 C(O)(CH 2 ) n4 R B1 , -(CH 2 ) n3 NR A1 C(O)OR B1 , -(CH 2 ) n3 NR A1 C(O)NR B1 R C1 or -NR A1 (CH 2 ) n3 R B1 , said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy alkenyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R A1 , R B1 , R C1 and R D1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy , haloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

Alternatively, any two of R A1 , R B1 , R C1 and R D1 and the nitrogen atom or carbon atom to which they are attached are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkane radicals, heterocyclyl, aryl and heteroaryl, optionally further substituted;

n1 is selected from 0, 1, 2, 3, 4, 5 or 6;

n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

n3 is selected from 0, 1, 2, 3, 4, 5 or 6;

n4 is selected from 0, 1, 2, 3, 4, 5 or 6;

x is selected from 0, 1, 2, 3 or 4; and

y is selected from 0, 1, 2, 3 or 4.
The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, the compound is further represented by general formula (I-A);

in:

Ring C is independently selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;

Preferably C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

More preferably C 3-6 cycloalkyl;

Further preferred is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl; R is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, Carboxyl, oxo, thio, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 deuterated alkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl , C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 -aryl or 5-14-membered heteroaryl, said amino, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 alkyl, C 1-8 deuterated Alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -Substituted by one or more substituents in 12 -cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl;

Preferred are hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl, C 6-10 aryl or 5-10-membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 -hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents; z is selected from 0 , 1, 2, 3, 4, 5 or 6; and

m is selected from 0 or 1;

When R 1 is hydrogen, ring B is
When ring C is C 3-6 saturated cycloalkyl, z is 1, and R 2 is hydrogen, methyl, chlorine, cyano or methoxy, R is not hydrogen, halogen, C 1-3 alkyl, iso- Butyl, C 1-2 alkyl substituted with 1 or 2 fluorine atoms.
The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt is characterized in that, the compound is further shown as general formula (II-A):

in:

is a single bond or a double bond;

m 1 is selected from 0, 1, 2, 3 or 4.
The compound according to any one of claims 1-3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-14 aryl or 5-14 membered heteroaryl;

Preferably C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

More preferably 5-10 membered monoheteroaryl or 5-10 membered diheteroaryl;

Further preferred is a 5-6 yuan nitrogen-containing monoheteroaryl group or an 8-10 yuan nitrogen-containing diheteroaryl group;

More preferably,

Ring B is selected from

X 1 is selected from -N- or -CH-, X 2 and X 3 are each independently selected from -N- or -C-, X 4 and X 5 are each independently selected from -N-, -NH- or -CH -,
is a single bond or a double bond;

Alternatively, Ring B is selected from
Y 1 , Y 2 , Y 5 , Y 6 are each independently selected from -N- or -CH-; Y 3 is selected from -N-, -NH-, -CH- or -CH 2 -; Y 4 is selected from -N -, -NH-, -CH-, -CH2- or -C(O)-,
is a single bond or a double bond;

most preferred
The compound according to any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo or thio.
The compound according to any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 deuterated alkoxy, C 1-8 haloalkyl, C 1-8 Hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14-membered heteroaryl, said amino, hydroxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 deuterated alkoxy, C 1 -8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl , 3-12-membered heterocyclyl, C 6-14 -membered aryl and 5-14-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio base, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 deuterated alkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy , C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered substituted with one or more substituents in the heteroaryl group;

Preferably, R 2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl , C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl or 5-10 membered heteroaryl, said amino, hydroxyl, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally further Deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Substituted with one or more substituents in alkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl.
The compound according to claim 4, its stereoisomer or its pharmaceutically acceptable salt is characterized in that, the compound is further shown as general formula (II):

in:

R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C1-8 alkyl, C1-8 deuterated alkyl base, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3- 12 -cycloalkyl, 3-12-membered heterocyclyl, C 6-14 -membered aryl or 5-14-membered heteroaryl, said amino, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkane base, 3-12 membered heterocyclyl, C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, sulfur substituted group, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, One or more of C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl substituted by a substituent;

Preferred are hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl, C 6-10 aryl or 5-10-membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 -hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl , C 6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl substituted with one or more substituents;

More preferably hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl or C 3-8 cycloalkyl; said C 1-6 alkyl or C 3 -8 cycloalkyl, optionally further by deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 ring Substituted by one or more substituents in alkyl, 3-8-membered heterocyclyl, C 6-10 -membered aryl and 5-10-membered heteroaryl;

Further preferred are hydrogen, halogen, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl;

Still more preferred are hydrogen, fluorine, chlorine, bromine, iodine, methyl, cyclopropyl, ethyl, propyl, isopropyl or trifluoromethyl.
The compound according to claim 6 or 7, its stereoisomer or its pharmaceutically acceptable salt, characterized in that,

R 2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1 -3 deuterated alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, 3-6 A membered heterocyclic group, a C 6-10 aryl group or a 5-6 membered heteroaryl group;

Preferred are hydrogen, deuterium, halogen, oxo, thio, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl, C 1 -3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;

More preferably hydrogen, halogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl;

Further preference is given to hydrogen, methyl, ethyl or cyclopropyl;

y is selected from 0, 1, 2 or 3.
The compound according to claim 7, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, the compound is further represented by general formula (II-1) or general formula (II-2):
The compound according to claim 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the compound is further such as general formula (IV), general formula (VI-1) or general formula (VI-2) shown:

in:

Ring D is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

Preferably, Ring D is selected from cyclopropyl or cyclobutyl;

R 2 is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, thio, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 deuterated alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

Preferred are hydrogen, deuterium, halogen, amino, oxo, thio, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;

More preferably hydrogen, halogen, amino, oxo, thio, methyl, methoxy or -CD3;

y is selected from 0, 1, 2 or 3.
The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, the compound is further such as general formula (III-A), (III-B), (III-C), ( III-D) or (III-E):

in:

R 5 is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said C 3-8 cycloalkyl, 3-8 membered heterocyclyl Cyclic, C 6-10 aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, substituted by one or more substituents in C 3-8 cycloalkyl, 3-8-membered heterocyclic group, C 6-10 -membered aryl or 5-10-membered heteroaryl;

Preferably, R 5 is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl, optionally further deuterium, halogen, Amino, nitro, hydroxyl, cyano, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy and one or more substituents in C 3-6 cycloalkyl;

R 6 , R 7 , R 8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 deuterium substituted alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;

Preferably, R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1 -3- deuterated alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy.
The compound according to claim 11, its stereoisomer or its pharmaceutically acceptable salt is characterized in that, the compound is further shown as general formula (III-C):

in:

R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl; the cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, optionally further by halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or -CH2F is substituted with one or more substituents;

R 6 , R 7 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl, ethyl or trifluoromethyl.
The compound according to any one of claims 1-12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the specific structure of the compound is as follows:
The compound represented by the general formula (A), its stereoisomer or its pharmaceutically acceptable salt:

in:

Ring B, Ring C, R, R 1 , R 2 , y, m and z are as defined in claim 2 .
The preparation method of the compound described in claim 2, its stereoisomer or its pharmaceutically acceptable salt, comprises the steps:

in:

The acid is selected from organic or inorganic acids,

Ring B, Ring C, R, R 1 , R 2 , y, m and z are as defined in claim 2 .
A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
Use of the compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a CD73 inhibitor medicine.
Use of the compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for treating cancer, preferably, The cancer is selected from the group consisting of colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, Cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.