CN116023367A

CN116023367A - Tetrahydrofuran-containing polycyclic derivative, pharmaceutically acceptable salt thereof, and preparation method and application thereof

Info

Publication number: CN116023367A
Application number: CN202211313911.0A
Authority: CN
Inventors: 周国强; 魏毅; 袁宏斌; 刘康志
Original assignee: Unilink Pharmaceutical Technology Hong Kong Co ltd
Current assignee: Unilink Pharmaceutical Technology Hong Kong Co ltd
Priority date: 2021-10-25
Filing date: 2022-10-25
Publication date: 2023-04-28
Also published as: WO2023072096A1; TW202320750A

Abstract

The invention relates to a polycyclic derivative containing tetrahydrofuran, a pharmaceutically acceptable salt thereof, a preparation method and application thereof. In particular, the invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds, and their use as CDK2 inhibitors in the treatment of cancer. Wherein each substituent in the general formula (I) is as defined in the specification.

Description

Tetrahydrofuran-containing polycyclic derivative, pharmaceutically acceptable salt thereof, and preparation method and application thereof

Technical Field

The invention belongs to the field of medicine synthesis. In particular to a tetrahydrofuran-containing polycyclic derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof and application of the tetrahydrofuran-containing polycyclic derivative serving as a CDK2 inhibitor in preparing medicaments for treating cancers.

Background

Uncontrolled sustained proliferation is a hallmark of cancer and other proliferative disorders, and thus induction of cell cycle arrest is effective in inhibiting tumor growth. The cell cycle is the period of time between successive divisions of a cell during which the cell achieves precise replication and division of the cell through precise control of various enzymatic reactions. In eukaryotes, there are 4 major phases of the cell cycle, G1, S, G, M phases, with cell cycle switching being regulated primarily by CDKs family kinases.

Cyclin Dependent Kinases (CDKs), which belong to the serine/threonine protein kinase family, are heterodimeric complexes consisting of a cyclin catalyzing kinase subunit and a regulatory subunit, are key kinases involved in cell cycle regulation, and 11 CDK members have been found. CDK functions can be largely divided into two major classes. One class of CDKs is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; another broad class of CDKs are involved in transcriptional regulation, including predominantly CDK7, CDK8, CDK9, CDK10, CDK11, and the like. CDK1 is involved in M-phase activity; CDK2 is involved in G1, S, M phase activity; CDK4/6 is involved in G1 phase activity. The remaining CDK 5/7/8/9/19 has also recently been found to play an important role in the regulation of cyclical activity.

Cyclin Dependent Kinases (CDKs) constitute a heterodimeric family of serine/threonine protein kinases involved in the cell cycle and transcription. They include two broad categories: cell cycle CDK and transcriptional CDK. The function of CDKs depends on specific interactions with the regulatory protein cyclin (cyclin) which forms heterodimers with CDKs to activate the regulatory cell cycle process.

Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. Cyclin E/CDK2 complexes play an important role in regulating G1/S conversion, histone biosynthesis and centrosome replication. Cyclin D/CDK4/6 and cyclin E/CDK2 progressively phosphorylate retinoblastoma (Rb), releasing the G1 transcription factor E2F, facilitating entry into S phase. Activation of cyclin A/CDK2 promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F early in S phase to complete S phase.

Cyclin E is a regulated Cyclin of CDK2, often overexpressed in cancer. Amplification or overexpression of Cyclin E has long been associated with adverse consequences of breast cancer. Over-expression of cyclin E2 (CCNE 2) is associated with the following factors. Amplification or overexpression of cyclin E1 (CCNE 1) has also been associated with adverse consequences of ovarian, gastric, endometrial and other cancers. The overexpression or amplification of Cyclin E also causes breast cancer to be resistant to inhibitors of CDK 4/6. Inhibition of CDK2 can inhibit cancer cell growth of Cyclin E overexpression, and in addition, inhibition of CDK2 can also inhibit MYCN-related cancers, and CDK2 inhibitors have good cancer treatment prospects.

CDK1 plays a key role in the M phase transition of cells, and inhibition of CDK1 activity leads to relatively large toxicity. CDK1 and CDK2 are very similar in the kinase domain, and therefore development of highly selective CDK2 inhibitors is extremely difficult. Various CDK inhibitors have been found to include CDK4/6 inhibitors, CDK7 inhibitors, CDK9 inhibitors, CDK2/4/6 inhibitors and CDK2/9 inhibitors, but CDK 2-specific inhibitors with better selectivity still have potential advantages.

Disclosure of Invention

The present invention discovers a series of novel CDK2 kinase inhibitor compounds, and has good selectivity for CDK2 specific inhibition.

The invention aims to provide a compound shown in a general formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure shown in the general formula (I) is as follows:

wherein ,

represents the cis configuration (i.e., two substituents on the tetrahydrofuran ring are on the same side);

l is selected from the group consisting of bond, -C (O) -, -S (O) _m -、-C(O)(CH ₂ ) _n -or- (CH) ₂ ) _n -；

R is selected from hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n OR _a 、-(CH ₂ ) _n SR _a 、-(CH ₂ ) _n NR _b R _a 、-(CH ₂ ) _n C(O)R _a 、-(CH ₂ ) _n C(O)NR _b R _a 、-(CH ₂ ) _n NR _b C(O)R _a 、-(CH ₂ ) _n S(O) _m R _a 、-(CH ₂ ) _n S(O) _m NR _b R _a 、-(CH ₂ ) _n S(O)(＝NR _b )R _a 、-(CH ₂ ) _n N＝S(＝O)R _a R _b Or- (CH) ₂ ) _n NR _b S(O) _m R _a The C is _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroarylA radical, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R _x Selected from the group consisting of

Or R is _y ；

Ring A is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R ₁ independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy, 5-14 membered heteroAryloxy, - (CH) ₂ ) _n OR _c 、-(CH ₂ ) _n SR _d 、-(CH ₂ ) _n NR _d R _c 、-O(CH ₂ ) _n NR _d R _c 、-(CH ₂ ) _n C(O)R _c 、-(CH ₂ ) _n C(O)NR _d R _c 、-(CH ₂ ) _n NR _b C(O)R _c 、-(CH ₂ ) _n S(O) _m R _c 、-(CH ₂ ) _n S(O) _m NR _d R _c 、-(CH ₂ ) _n S(O)(＝NR _d )R _c 、-(CH ₂ ) _n N＝S(＝O)R _c R _d Or- (CH) ₂ ) _n NR _d S(O) _m R _c The amino group, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy and 5-14 membered heteroaryloxy, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

alternatively, any two R ₁ Together the atoms to which they are attached form C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto,Nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R _y Selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl or C _2-6 Alkynyl, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl and C _2-6 Alkynyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R _a 、R _b 、R _c and R_d Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy or 5-14 membered heteroaryloxy, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy and 5-14 membered heteroaryloxy, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

or ,R_a and R_b And the atoms at which they are located together form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, said 3-12 membered heterocyclyl and 5-14 membered heteroaryl optionally being further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group; and is also provided with

x is an integer of 0 to 10;

n is an integer of 0 to 10;

m is 0, 1 or 2.

The invention also provides a preferable scheme, wherein the compound shown in the general formula (I), a prodrug, a stereoisomer or a pharmacy thereofAcceptable salts, some of which may be defined as described below, others of which may be defined as in any of the embodiments of the invention (hereinafter "the invention also provides a preferred embodiment"), R, where C is defined as _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, wherein in R, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F.

The invention also provides a preferable scheme, wherein in R, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, wherein in R, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl is, for example, ethenyl, propenyl or butenyl.

The invention also provides a preferable scheme, wherein in R, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl is, for example, ethynyl, propynyl or butynyl.

The invention also provides a preferable scheme, wherein in R, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]Pentanyl or cyclohexyl, also for example cyclopropyl, cyclobutyl or

The present invention also provides a preferred embodiment wherein R, the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 7 membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, wherein in R, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl.

The invention also provides a preferred embodiment, wherein R, the 5-14 membered heteroaryl groups are independently 5-6 membered heteroaryl groups (e.g., 6 membered), wherein the number of heteroatoms in the 5-6 membered heteroaryl groups independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, wherein in the ring A, the C _3-12 Cycloalkyl radicals are C _3-6 Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The invention also provides a preferable scheme, wherein in the ring A, the 3-12 membered heterocyclic group is C _3-8 A membered heterocyclic group; wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, wherein in the ring A, the C _6-14 Aryl is C _6-10 Aryl groups such as phenyl or naphthyl.

The present invention also provides a preferred embodiment, in ring a, the 5-14 membered heteroaryl is independently a 5-10 membered heteroaryl (e.g., 5-, 6-, 9-membered), the 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl or a 5-and 6-membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl is independently 1 or 2 (e.g., 2), and the number of heteroatoms in the 5-and 6-membered heteroaryl is independently 1 or 4 (e.g., 4); wherein the heteroatoms in the 5-6 membered heteroaryl and the 5-and 6-membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, wherein in the ring A, the C _1-6 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl, ethyl or propyl.

The invention also provides a preferable scheme, wherein in the ring A, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F.

The invention also provides a preferable scheme, wherein in the ring A, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The invention also provides a preferable scheme, wherein in the ring A, the C _1-6 Alkylthio groups are independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.

The invention also provides a preferable scheme, wherein in the ring A, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, wherein in the ring A, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl is, for example, ethenyl, propenyl or butenyl.

The invention also provides a preferable scheme, wherein in the ring A, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl is, for example, ethynyl, propynyl or butynyl.

The invention also provides a preferable scheme, a ring R ₁ Wherein the halogen is independently F, cl, br or I, e.g., F.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _1-6 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, preferably methyl, ethylA group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl is, for example, ethenyl, propenyl or butenyl.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl is, for example, ethynyl, propynyl or butynyl.

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]Pentanyl or cyclohexyl, and also for example cyclopropyl.

The invention also provides a preferable scheme, a ring R ₁ Wherein the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 7 membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl.

The invention also provides a preferable scheme, a ring R ₁ In which the 5-14 membered heteroaryl is in the form of a 5-6 membered heteroarylAryl or 5-and 6-membered heteroaryl, wherein the number of heteroatoms in the 5-to 6-membered heteroaryl and the 5-and 6-membered heteroaryl independently can be 1 or 2; wherein the heteroatoms in the 5-6 membered heteroaryl and the 5-and 6-membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, a ring R ₁ In the above, the C _3-12 Cycloalkyl oxy is independently C _3-6 Cycloalkyloxy, for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy, and also for example cyclopropyloxy.

The invention also provides a preferable scheme, a ring R _y In the above, the C _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, a ring R _y In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, C _1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F.

The invention also provides a preferable scheme, a ring R _y In the above, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The invention also provides a preferable scheme, a ring R _y In the above, the C _1-6 Alkylthio groups are independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.

The invention also provides a preferable scheme, a ring R _y In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention is thatAlso provided is a preferred embodiment, ring R _y In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl is, for example, ethenyl, propenyl or butenyl.

The invention also provides a preferable scheme, a ring R _y In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl is, for example, ethynyl, propynyl or butynyl.

The invention also provides a preferable scheme, a ring R _y In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1 ]Pentanyl or cyclohexyl, and also for example cyclopropyl.

The invention also provides a preferable scheme, a ring R _y Wherein the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl; wherein the number of heteroatoms in the 3-8 membered heterocyclic group independently can be 1 or 2; wherein the heteroatoms in the 3-8 membered heterocyclic groups may be independently selected from one or both of N and O.

The invention also provides a preferable scheme, a ring R _y In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl.

The invention also provides a preferable scheme, a ring R _y Wherein the 5-14 membered heteroaryl is in the form of a 5-6 membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl independently can be 1 or 2; wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl A group, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkylthio groups are independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl is, for example, ethenyl, propenyl or butenyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl is, for example, ethynyl, propynyl or butynyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]Pentanyl or cyclohexyl, and also for example cyclopropyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In said 3-12The membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 4-membered, 7-membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl.

The invention also provides a preferable scheme, R _a 、R _b 、R _c and R_d Wherein the 5-14 membered heteroaryl is independently a 5-6 membered heteroaryl (e.g., 6 membered), wherein the number of heteroatoms in the 5-6 membered heteroaryl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N).

The invention also provides a preferable scheme, wherein the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as the general formula (I-A) or the general formula (I-B):

wherein ：

L、R and R_x As defined by formula (I).

In a preferred embodiment of the invention, said R is selected from the group consisting of 3-10 membered nitrogen containing heterocyclyl, 5-10 membered nitrogen containing heteroaryl, -C (O) R _a or-C (O) NR _b R _a Said 3-10 membered nitrogen containing heterocyclyl and 5-10 membered nitrogen containing heteroaryl optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl oxy3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy group and the 5-10 membered heteroaryloxy group;

R _a and R_b Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy or 5-14 membered heteroaryloxy, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 Aryloxy and 5-14 membered heteroaryloxy, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

or ,R_a and R_b And the atoms at which they are located together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, said 3-10 membered heterocyclyl and 5-10 membered heteroaryl optionally being further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group.

The invention also provides a preferable scheme, wherein the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as the general formula (II):

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in formula (I).

The invention also provides a preferable scheme, wherein the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as the general formula (II-A) or the general formula (II-B):

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as previously described.

In a preferred embodiment of the invention, the ring A is selected from 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic fused heterocyclyl or 8-10 membered bicyclic fused heteroaryl.

In a further preferred embodiment of the invention, the ring a is selected from pyrazolyl, pyridinyl or pyrazolo 5-6 membered heteroaryl.

In a further preferred embodiment of the invention, the ring a is selected from pyrazolyl, pyridinyl or pyrazolopyrimidinyl.

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

In a preferred embodiment of the invention, L is a bond, -C (O) -or-C (O) CH ₂ 。

The invention also provides a preferable scheme, wherein the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as the general formula (III):

wherein ：

R _x 、R _a and R_b As defined by formula (I).

The invention also provides a preferable scheme, wherein the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as a general formula (IV):

wherein ：

R ₁ 、R _a 、R _b and x is as defined in formula (I).

The invention also provides a preferable scheme, wherein R is _a Selected from hydrogen or methyl;

the R is _b Selected from methyl, ethyl, t-butyl, isobutyl, cyclopropyl, cyclobutyl or bicyclo [1.1.1]Pentanyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl and bicyclo [1.1.1]A pentylalkyl group optionally further substituted with one or more substituents of methyl, ethyl, isopropyl or tert-butyl;

or ,R_a and R_b Together the atoms at which they are located form an azetidinyl or 7-azabicyclo [2.2.1 ]]A heptyl group, a methyl group,said azetidinyl and 7-azabicyclo [2.2.1 ]]Heptane, optionally further substituted with one or more methyl groups.

The present invention also provides a preferred embodiment of the present invention,

is->

is->

The invention also provides a preferable scheme, R ₁ Independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _3-12 Cycloalkyl, said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-8 Cycloalkyl, further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in the cycloalkyl group.

The invention also provides a preferable scheme, R ₁ Independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _3-8 Cycloalkyl, said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-8 Cycloalkyl, further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-8 One or more substituents in the cycloalkyl group.

The invention also disclosesProvides a preferred scheme, R ₁ Independently selected from C _1-6 Alkyl, said C _1-6 Alkyl is optionally further C _1-6 Alkyl and C _1-6 One or more substituents in the alkoxy group.

The invention also provides Sup>A preferable scheme, and the specific structure of the compound, the prodrug, the stereoisomer or the pharmaceutically acceptable salt thereof is shown as the general formulSup>A (IV-A) and the general formulSup>A (IV-B):

wherein ：

R ₁ 、R _a 、R _b and x is as defined in formula (I).

In a preferred embodiment of the invention, the R _a and R_b Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy or 5-to 10-membered heteroaryloxy, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy and 5-to 10-membered heteroaryloxy, optionally further substituted with hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy group and the 5-10 membered heteroaryloxy group;

or ,R_a and R_b And the atoms at which they are located together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl, said 3-10 membered heterocyclyl and 5-10 membered heteroaryl optionally being further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents in the aryloxy group and the 5-to 10-membered heteroaryloxy group.

In a further preferred embodiment of the invention, said R _a Selected from hydrogen or methyl;

the R is _b Selected from methyl, ethyl, isopropyl, t-butyl, isobutyl, cyclopropyl, cyclobutyl, or bicyclo [1.1.1]Pentanyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl and bicyclo [1.1.1]A pentylalkyl group optionally further substituted with one or more substituents of methyl, ethyl, isopropyl, cyclopropyl, or tert-butyl;

or ,R_a and R_b Together the atoms at which they are located form an azetidinyl or 7-azabicyclo [2.2.1 ]]Heptyl, said azetidinyl and 7-azabicyclo [2.2.1]Heptane, optionally further substituted with one or more methyl groups.

In a further preferred embodiment of the invention, the

Selected from->

In a preferred embodiment of the invention, the R ₁ Independently selected from hydrogen, deuterium, cyano, amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Hydroxyalkyl, -CH ₂ OR _c 、-(CH ₂ ) ₂ OR _c 、-CH ₂ NR _d R _c 、-(CH ₂ ) ₂ NR _d R _c 、-O(CH ₂ ) ₂ NR _d R _c 、-CH ₂ S(O)(＝NR _d )R _c 、-S(O)(＝NR _d )R _c 、-CH ₂ N＝S(＝O)R _c R _d or-C (O) NR _d R _c The amino group, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy and C _1-3 Hydroxyalkyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy group and the 5-10 membered heteroaryloxy group;

R _c and R_d Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy,C _6-10 Aryloxy or 5-to 10-membered heteroaryloxy, said amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy and 5-to 10-membered heteroaryloxy, optionally further substituted with hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents in the aryloxy group and the 5-to 10-membered heteroaryloxy group.

In a further preferred embodiment of the invention, said R ₁ Independently selected from-CN, -NH ₂ 、-OH、-CH ₃ 、-CF ₃ 、-OCH ₃ 、-CH ₂ OCH ₃ 、-CH ₂ NH ₂ 、-CH(OH)CH ₃ 、-C(O)NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-C(O)N(CH ₃ ) ₂ 、-(CH ₂ ) ₂ OCH ₃ 、-OCH(CH ₃ ) ₂ 、-O(CH ₂ ) ₂ OCH ₃ or-O (CH) ₂ ) ₂ N(CH ₃ ) ₂ 。

In a further preferred embodiment of the invention, said R ₁ Independently selected from H, D, F, cl, -CN, -NH ₂ 、-OH、-CH ₃ 、-CF ₃ 、-CD ₃ 、-OCH ₃ 、-OCF ₃ 、-CH ₂ OCH ₃ 、-(CH ₂ ) ₂ OCH ₃ 、

In a further preferred embodiment of the invention, R is

L is-C (O) -, R _x Is selected from

Or R is _y The method comprises the steps of carrying out a first treatment on the surface of the Ring A is selected from 5-14 membered heteroaryl, said 5-14 membered heteroaryl optionally being substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in cycloalkyl are substituted; r is R ₁ Independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy or C _3-12 Cycloalkyl, said C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 Cycloalkyl optionally further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in cycloalkyl are substituted;

R _y selected from C _1-6 Alkyl, said C _1-6 Alkyl is substituted with one or more substituents in a 5-14 membered heteroaryl; the 5-14 membered heteroaryl is further substituted with one or more C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Alkoxy groups are substituted.

In a further preferred embodiment of the invention, R is

-L-R _x Is->

In a further preferred embodiment of the invention, -L-R _x Is that

R is->

5-to 10-membered nitrogen containing heteroaryl or- (CH) ₂ ) _n C(O)NR _b R _a The method comprises the steps of carrying out a first treatment on the surface of the n is 0, R _a Is hydrogen, R _b Is quilt C _3-12 Cycloalkyl-substituted C _1-6 Alkyl, C _3-12 Cycloalkyl or quilt C _1-6 Alkyl substituted C _3-12 Cycloalkyl; or, together with the atoms to which they are attached, form an azetidinyl or 7-azabicyclo [2.2.1]Heptyl, said azetidinyl and 7-azabicyclo [2.2.1]Heptane, optionally further substituted with one or more methyl groups; the 5-to 10-membered nitrogen containing heteroaryl group is optionally further substituted with deuterium, halogen and C _1-3 One or more substituents in the alkyl group.

In a further preferred embodiment of the invention, -L-R _x Is that

R is->

In a further preferred embodiment of the invention, R is

/>

In a further preferred embodiment of the invention, -L-R _x Is that

R is->

In a further preferred embodiment of the invention, R is

In a further preferred embodiment of the invention, -L-R _x Is that

The present invention also provides a preferred embodiment which is generally understood to be unsubstituted when the present invention does not specifically describe whether it is substituted or unsubstituted.

The present invention also provides a preferred embodiment of the compounds of the general formula as shown above, their prodrugs, stereoisomers or pharmaceutically acceptable salts thereof, in particular selected from the following compounds:

/>

/>

the invention also relates to a method for preparing the compound shown in the general formula (I), the prodrug or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:

introducing R groups into the compound shown in the formula (Ia) and the formula (Ib) through single-step or multi-step nucleophilic substitution, coupling reaction, mitsunobu reaction, esterification reaction and other common organic reactions to obtain a compound shown in the formula (Ic) or a stereoisomer and pharmaceutically acceptable salts thereof;

the compound shown in the formula (Ic) is subjected to reduction reaction to obtain a compound shown in the formula (Id) or a stereoisomer and pharmaceutically acceptable salts thereof;

The compound shown in the formula (If) or stereoisomer thereof is obtained by common organic reactions such as amidation reaction, nucleophilic substitution or coupling reaction and the like of the formula (Id) and the formula (Ie);

removing protecting group R from compound represented by formula (If) _1a Obtaining a compound represented by formula (Ig), a prodrug or stereoisomer thereof, and a pharmaceutically acceptable salt thereof;

the compound shown in the formula (I), a prodrug or a stereoisomer thereof and a pharmaceutically acceptable salt thereof are obtained by separating and purifying the formula (Ig);

optionally, the compound shown in the formula (I) is further subjected to chiral resolution to obtain a single-configuration compound, a prodrug or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

wherein ：

X ₁ selected from, but not limited to, hydroxyl, halogen, or triflate (OTf), etc.;

X ₂ selected from, but not limited to, hydroxyl, halogen, or triflate (OTf), etc.;

R _1a is a protecting group on the pyrazole nitrogen selected from, but not limited to, t-butyl (t-Bu), tetrahydro-2H-pyran-2-yl (THP), (trimethylsilyl) ethoxymethyl (SEM), p-methoxybenzyl (PMB), and the like;

L、R and R_x As defined by formula (I).

The invention also relates to a method for preparing the compound shown in the general formula (II), the prodrug or the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps:

Reacting the formula (IIa) with the formula (IIb) to obtain a compound shown in the formula (IIc), a prodrug or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

the compound shown in the formula (II), a prodrug or a stereoisomer thereof and a pharmaceutically acceptable salt thereof are obtained through separation and purification of the formula (IIc);

optionally, the compound shown in the formula (II) is subjected to chiral resolution to obtain a single-configuration compound, a prodrug or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in formula (II).

The invention relates to an intermediate compound shown in a formula (IIa) or a stereoisomer and salt thereof, which has the following specific structure:

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in formula (II).

The invention relates to an intermediate compound shown in a formula (IIa) or a stereoisomer and a pharmaceutically acceptable salt thereof, which has the following specific structure:

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in formula (II).

In a preferred embodiment of the invention, the compound of formula (IIa) is selected from the following compounds:

/>

the present invention further relates to a process for preparing the intermediate compound represented by the formula (IIa) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized by comprising the steps of:

The compound shown in the formula (IIa-3) or stereoisomer and pharmaceutically acceptable salt thereof are obtained by common organic reactions such as amidation reaction, nucleophilic substitution or coupling reaction and the like of the formula (IIa-1) and the formula (IIa-2);

reacting formula (IIa-3) with phenyl p-nitrochloroformate to form a compound represented by formula (IIa-4) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof;

deprotection of a protecting group R of formula (IIa-4) _1a Obtaining a compound represented by formula (IIa) or a stereoisomer thereof, and a pharmaceutically acceptable salt thereof;

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in formula (II).

The invention relates to an intermediate compound shown in a formula (IIa-1) or a stereoisomer and salt thereof, which has the following specific structure:

wherein ：

R _1a is a protecting group on the pyrazole nitrogen selected from, but not limited to, t-butyl (t-Bu), tetrahydro-2H-pyran-2-yl (THP), (trimethylsilyl) ethoxymethyl (SEM), p-methoxybenzyl (PMB); the salt may be a pharmaceutically acceptable salt or the like.

In a preferred embodiment of the invention, the compound of formula (IIa-1) is selected from the following compounds:

the present invention further relates to a process for preparing the intermediate compound represented by the formula (IIa-1) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized by comprising the steps of:

reacting a compound represented by the formula (IIa-1 a) with the formula (IIa-1 b) to obtain a compound represented by the formula (IIa-1 c);

the compound shown in the formula (IIa-1 c) is subjected to a reduction reaction to obtain a compound shown in the formula (IIa-1 d), and the compound shown in the formula (IIa-1 d) is subjected to an oxidation reaction to obtain a compound shown in the formula (IIa-1 e);

the compound shown in the formula (IIa-1 e) and allyl potassium trifluoroborate are subjected to an addition reaction to obtain a compound shown in the formula (IIa-1 f);

the compound represented by the formula (IIa-1 f) is subjected to epoxidation reaction with m-chloroperoxybenzoic acid (mCPBA) to obtain a compound represented by the formula (IIa-1 g);

closing a ring of a compound shown in the formula (IIa-1 g) under an acidic condition to obtain an intermediate compound shown in the formula (Ia) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

the compound shown in the formula (Ia) can be subjected to a reduction reaction to obtain a compound shown in the formula (IIa-1) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof;

wherein ：

X ₄ Selected from, but not limited to, halogen, triflate (OTf), hydroxyl, etc.;

R _1a as defined by formula (IIa-1).

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of each compound of formula (I) as described above, a prodrug, stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

The invention further relates to a compound shown in a general formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, and application of the pharmaceutical composition in preparation of medicines for treating CDK2 mediated diseases.

The invention further relates to a compound shown in the general formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, and application of the pharmaceutical composition in preparing a medicament for treating abnormal growth of cells.

The invention further relates to a compound shown in the general formula (I), a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, and application of the pharmaceutical composition in preparing a medicament for treating cancer.

In a further aspect, the invention relates to a method of treating a disease mediated by CDK2 using a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.

In another aspect, the present invention further relates to methods of treating abnormal cell growth using compounds of formula (I), prodrugs, stereoisomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.

In another aspect, the present invention further relates to the use of a compound of formula (I), a prodrug, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, for the treatment of cancer.

In a preferred embodiment of the present invention, the cancer may be ovarian cancer.

In a further aspect, the invention relates to the use of a compound of formula (I), a prodrug, stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, for the treatment of a disease mediated by CDK 2.

In another aspect, the present invention further relates to the use of a compound of formula (I), a prodrug, stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, for the treatment of abnormal cell growth.

Detailed description of the invention

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

The term "alkyl" refers to a hydrocarbon group lacking one hydrogen in a saturated aliphatic hydrocarbon, 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 an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.

The term "alkylene" refers to a group of an alkyl group in which one hydrogen is further substituted, i.e. a hydrocarbon group of a saturated aliphatic hydrocarbon lacking two hydrogens, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkylene group containing from 1 to 8 carbon atoms, more preferably an alkylene group containing from 1 to 6 carbon atoms, most preferably an alkylene group containing from 1 to 3 carbon atoms. Non-limiting examples include "methylene" (-CH) ₂ (-), "ethylene" (- (CH) ₂ ) ₂ (-), "n-propylene" (- (CH) ₂ ) ₃ (-), "isopropylidene" (- (CH) ₃ )(CH ₂ ) (-), "n-butylene" (- (CH) ₂ ) ₄ (-), etc.

The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched chain group containing from 2 to 20 carbon atoms, preferably an alkenyl group containing from 2 to 8 carbon atoms, more preferably an alkenyl group containing from 2 to 6 carbon atoms, and most preferably an alkenyl group containing from 2 to 4 carbon atoms. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" refers to an unsaturated aliphatic alkynyl group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group containing 2 to 6 carbon atoms, most preferably an alkynyl group containing 2 to 4 carbon atoms. Such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent, the cycloalkyl ring atom containing from 3 to 20 carbon atoms, preferably containing from 3 to 12 carbon atoms, more preferably containing from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl being preferred; polycyclic cycloalkyl includes spirocycloalkyl, fused ring alkyl, bridged cycloalkyl, and the like.

The term "spirocycloalkyl" refers to a polycyclic group containing from 5 to 20 carbon atoms, with a single ring sharing one carbon atom (referred to as a spiro atom), which may contain one or more double bonds, which are not aromatic in their entirety (i.e., do not form a conjugated pi-electron system in their entirety), but may have a ring or rings with conjugated pi-electron systems. The spirocycloalkyl ring atom is preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

etc.; />

The term "fused ring alkyl" refers to an all-carbon polycyclic group containing from 5 to 20 carbon atoms, each ring in the system sharing an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds which are wholly non-aromatic (i.e., are wholly incapable of forming a conjugated pi-electron system), but may have one or more rings with a conjugated pi-electron system. The fused ring alkyl ring atoms are preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:

Etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group containing from 5 to 20 carbon atoms, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds, which are not aromatic in their entirety (i.e., do not form a conjugated pi-electron system in their entirety), but may have one or more rings with a conjugated pi-electron system. The bridged cycloalkyl ring atoms are preferably 6 to 14 carbon atoms, more preferably 7 to 10 carbon atoms. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

etc.

The cycloalkyl ring may be fused to a cycloalkyl or aryl ring, wherein the ring attached to the parent structure may be a cycloalkyl or aryl ring, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen, phosphorus, boron or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. The heterocyclyl preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; further preferred contain 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetane, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, pyridonyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetane, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, piperidinyl, pyridonyl, and piperazinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups and the like; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.

The term'Spiroheterocyclyl "refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, with one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen, phosphorus, boron or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, which are wholly non-aromatic (i.e. wholly incapable of forming conjugated pi-electron systems), but may have a ring or rings with conjugated pi-electron systems. The spiroheterocyclyl ring atom is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

etc.

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, each ring in the system sharing an adjacent pair of atoms with the other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, phosphorus, boron or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. One or more of the rings may contain one or more double bonds, which are wholly non-aromatic (i.e., wholly incapable of forming conjugated pi-electron systems), but may have one or more rings with conjugated pi-electron systems. The fused heterocyclyl ring atoms are preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group containing 5 to 20 ring atoms, any two rings sharing two atoms not directly attached, wherein one or more of the ring atoms is selected from nitrogen, oxygen, phosphorus, boron or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, which are wholly non-aromatic (i.e. wholly incapable of forming conjugated pi-electron systems), but may have a ring or rings with conjugated pi-electron systems. The bridged heterocyclyl ring atoms are preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

etc.

The heterocyclyl ring may be fused to a cycloalkyl, heterocyclyl, aryl or heteroaryl ring, wherein the ring attached to the parent structure may be a cycloalkyl, heterocyclyl, aryl or heteroaryl ring, non-limiting examples of which include:

etc.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from oxo (=o), thioxo (=s), alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

The term "aryl" refers to a 6 to 20 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, the aryl ring atoms preferably being 6 to 14 membered, more preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl.

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

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen, or the like. Heteroaryl groups are divided into monocyclic heteroaryl groups and polycyclic heteroaryl groups; the heteroaryl ring atoms are preferably 5 to 14 membered, more preferably 5 to 10 membered; the monocyclic heteroaryl ring atom is preferably 5-or 6-membered, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, pyridazinyl, oxadiazolyl and the like, preferably pyridyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl and oxadiazolyl. Polycyclic heteroaryl generally refers to the heteroaryl ring fused to an aryl or heteroaryl group to form a polycyclic fused heteroaryl, wherein the ring attached to the parent structure may be an aryl or heteroaryl ring, polycyclic fused heteroaryl is preferably a bicyclic fused heteroaryl, non-limiting examples of which include:

Etc.

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

The term "haloalkyl" refers to a group in which the hydrogen in the alkyl group is replaced with one or more halogens, wherein the alkyl group is defined above. Non-limiting examples of haloalkyl groups include: the haloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"hydroxyalkyl" refers to a group in which the hydrogen in the alkyl group is substituted with one or more hydroxyl groups, wherein alkyl is as defined above. Non-limiting examples of hydroxyalkyl groups include: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, and the like, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy or butoxy, the alkoxy group being optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkylthio" refers to-S- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propylthio, butylthio, alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "cycloalkyloxy" refers to-O- (cycloalkyl), wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to-O- (heterocyclyl) wherein heterocyclyl is as defined above.

The term "C _6-14 Aryloxy "means-O- (C) _6-14 Aryl), wherein C _6-14 Aryl is as defined above.

The term "5-14 membered heteroaryloxy" refers to-O- (5-14 membered heteroaryloxy), wherein 5-14 membered heteroaryloxy is as defined above.

"hydroxy" refers to-OH.

"halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"carboxy" means-C (O) OH.

"THF" refers to tetrahydrofuran.

"PE" refers to petroleum ether.

"EA" refers to ethyl acetate.

"IPA" refers to isopropanol.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"TFA" refers to trifluoroacetic acid.

"ACN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et ₂ O "refers to diethyl ether.

"DCM" refers to dichloromethane.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd ₂ (dba) ₃ "means tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.

"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.

"KHMDS" refers to potassium bistrimethyldisilyl amino.

"LiHMDS" refers to lithium bis (trimethylsilyl) amide.

"MeLi" refers to lithium-based.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "means sodium triacetoxyborohydride.

The terms "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 is, X may be any one or several of A, B, C.

The hydrogen in the invention can be replaced by the isotope deuterium, and any hydrogen in the compound of the embodiment of the invention can be replaced by deuterium.

All compounds of the invention, as shown, have a structure that conflicts with the name given, subject to structural representation.

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

"substituted" means that one or more hydrogens, preferably 5, more preferably 1 to 3 hydrogens, in the group are replaced with a corresponding number of substituents independently of each other. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the compound provided by the embodiment of the invention has good inhibitory activity on CDK2/CycE1 kinase and good selectivity on CDK2/CDK1 kinase inhibition. The compound provided by the embodiment of the invention has good inhibition activity on OVCAR-3 cell proliferation. The compounds of the examples of the present invention showed better permeability and lower efflux activity on the Caco-2 cell model. The embodiment of the invention obviously optimizes the pharmacokinetic properties of the product.

Detailed Description

The chemical synthesis method comprises the following steps:

the compounds described herein can be synthesized by a variety of methods known to those skilled in the art of organic synthesis using starting materials that are commercially available or can be prepared by known experimental methods. The compounds of the present invention may be synthesized by the following methods, or by synthetic methods known in the art of synthetic organic chemistry, in combination with variations of the methods known to those skilled in the art. Preferred synthetic methods include, but are not limited to, the following description. For a more detailed description of the various reaction steps, refer to the "examples" section below.

The starting materials in the synthesis step may be synthesized using or according to methods known in the art, or may be purchased from Sigma Aldrich co.ltd, pichia medicine (Bide Pharmatech ltd.), shao far chemistry (Accela ChemBio co.ltd), or the like, unless otherwise specified.

All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.

Analytical method and instrument device:

LCMS data for the example characterization were obtained by the Agilent 1260-6120/6125MSD system with DAD detector. The testing method comprises the following steps:

LCMS method a:

column: HALO C18 4.6X105 mm,2.7 μm

Column temperature: 45 DEG C

Mobile phase: solvent a was 0.025% trifluoroacetic acid +99.975% water; solvent B was 0.025% trifluoroacetic acid+99.975% acetonitrile

Flow rate: 1.8mL/min

Gradient: solvent B was linearly increased from 5% to 95% over 0.8 min, then held at 95% for 0.8 min, and finally held at 5% for 2.0 min

LCMS method B:

column: HALO C18 4.6X105 mm,2.7 μm

Column temperature: 45 DEG C

Mobile phase: solvent a was 0.1% formic acid +99.9% water; solvent B was 0.1% formic acid+99.9% acetonitrile

Flow rate: 1.8mL/min

LCMS method C:

column:

C18 4.6×50mm,2.5μm

column temperature: 40 DEG C

Mobile phase: solvent a is 0.05% ammonia +99.5% water; solvent B is 100% acetonitrile

Flow rate: 1.8mL/min

Gradient: solvent B was linearly increased from 5% to 95% to 1 minute over 2.5 minutes, then held at 95% for 2 minutes, and finally held for 5% to 2.5 minutes starting from 2.05 minutes

The NMR data used for the characterization of the examples were obtained by Bruker Fourier transform Spectroscopy @ ¹ H NMR:400 MHz). The data are given in terms of chemical shifts (multiplicity, number of hydrogen atoms). Chemical shift by internal standard tetramethylsilane (delta) _{Tetramethylsilane} =0 ppm) and/or a reference solvent peak, which is at ¹ For deuterated dimethyl sulfoxide (DMSO-d) in the H NMR spectrum ₆ ) 2.49ppm for deuterated methanol (CD ₃ OD) was 3.30ppm for deuterated acetonitrile (CD ₃ CN) of 1.94ppm, for deuterated chloroform (CDCl) ₃ ) 7.24ppm.

The purification method comprises the following steps:

the purification of the examples and intermediates was performed by silica gel chromatography, reverse phase silica gel chromatography and/or Supercritical Fluid Chromatography (SFC). Silicon (Si)Gel chromatography generally uses silica gel or preloaded silica gel column as carrier, and petroleum ether/ethyl acetate or dichloromethane/methanol system as eluent; reverse phase silica gel chromatography is typically carried out using a C18 silica gel column, using a UV detector (214 nm and 254 nm) and preparative LCMS, with mobile phases including acetonitrile/water (0.1% formic acid), acetonitrile/water (0.1% trifluoroacetic acid), and acetonitrile/water (0.1% ammonia) systems. Supercritical Fluid Chromatography (SFC) generally employs different types of columns as carriers, with CO ₂ Containing 0.2% NH ₃ The system such as methanol (7M ammonia methanol solution) is a mobile phase.

Preparation of the intermediate:

intermediate a:5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (4-nitrophenyl) carbonate

The synthetic route is as follows:

step 1: 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (A-2)

Thionyl chloride (98.5 g,0.83 mol) was added to a methanol solution (500 mL) of 5-nitro-1-hydro-pyrazole-3-carboxylic acid (50.0 g,0.32 mol) at 0deg.C, and the reaction solution was stirred at 70deg.C for 16 hours. After the reaction was completed, the solvent was removed by vacuum concentration. The organic phase was concentrated in vacuo and dried to give compound a-2 (crude, white solid, 48.0 g). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝170.1

¹ H NMR(400MHz,DMSO-d ₆ )δ15.23(s,1H),7.53(s,1H),3.90(s,3H).

Step 2:1- (tert-butyl) -3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (A-3)

5-nitro-1H-pyrazolesMethyl 3-carboxylate (15.0 g,87.7 mmol), triphenylphosphine (69.1 g,263 mmol) and tert-butanol (19.5 g,263 mmol) were dissolved in tetrahydrofuran (150 mL). Diethyl azodicarboxylate (45.8 g,263 mmol) was added dropwise to the above solution at 0℃and the mixture was stirred at 70℃for 16 hours. The mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated in vacuo and dried, and the resulting crude product was purified by silica gel chromatography (PE: dcm=3:1) to give compound a-3 (pink oil, 10.0g, yield: 50%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝227.2

Step 3: (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) methanol (A-4)

To a solution of methyl 1- (tert-butyl) -3-nitro-1H-pyrazole-5-carboxylate (11.0 g,48.4 mmol) in tetrahydrofuran (55.0 mL) was added lithium borohydride (3.20 g,31.7 mmol) in portions at 0deg.C, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate, and the organic phase was concentrated in vacuo and dried after washing with saturated brine. The crude product was purified by silica gel chromatography (PE: ea=4:1) to give compound a-4 (yellow oil, 7.3g, yield: 72%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝199.2

Step 4:1- (tert-butyl) -3-nitro-1H-pyrazole-5-carbaldehyde (A-5)

To a solution of (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) methanol (6.0 g,30.1 mmol) in ethyl acetate (55.0 mL) was added manganese dioxide (78.5 g,903 mmol) in portions, and the reaction mixture was stirred at 80℃for 16 hours. The filter cake was filtered and washed with ethyl acetate and the organic phase was concentrated in vacuo. The crude product was purified by silica gel chromatography (PE: ea=10:1) to give compound a-5 (pale yellow oil, 4.0g, yield: 67%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝197.2.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.04(s,1H),7.94(s,1H),1.69(s,9H).

Step 5:1- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) but-3-en-1-ol (A-6)

To a mixed solution of 1- (tert-butyl) -3-nitro-1H-pyrazole-5-carbaldehyde (1.80 g,9.1 mmol) and tetrabutylammonium iodide (0.34 g,0.91 mmol) in methylene chloride and water (36.0 mL) at room temperature was added allyl group Potassium trifluoroborate (2.69 g,18.2 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane, washed with saturated brine, concentrated in vacuo and dried, and the resulting residue was purified by silica gel chromatography (PE: ea=3:1) to give compound a-6 (yellow oil, 1.60g, yield: 74%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝239.3.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.09(s,1H),5.82(ddt,J＝17.2,10.2,6.8Hz,1H),5.69(s,1H),5.19–5.02(m,2H),5.00(s,1H),2.59(td,J＝6.8,4.0Hz,2H),1.65(s,9H).

Step 6:1- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) -2- (oxaprozin-2-yl) ethan-1-ol (A-7)

To a solution of 1- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) but-3-en-1-ol (4.50 g,18.8 mmol) in methylene chloride (50.0 mL) was added 3-chloroperoxybenzoic acid (9.75 g,56.5 mmol) in portions at room temperature, and the mixture was stirred at 40℃for 16 hours. The mixture was extracted with dichloromethane, washed with saturated brine, and the organic phase was concentrated in vacuo and dried, and the resulting residue was purified by silica gel chromatography (PE: ea=3:2) to give compound a-7 (colorless oil, 4.00g, yield: 83%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝255.3.

Step 7:5- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) tetrahydrofuran-3-ol (A-8)

To a solution of 1- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) -2- (oxaprozin-2-yl) ethan-1-ol (1.00 g,3.90 mmol) in 1, 4-dioxane (50.0 mL) was added dropwise concentrated sulfuric acid (380 mg,3.90 mmol) at room temperature, and the mixture was stirred at 50 ℃ for 16 hours. The reaction system was diluted with water in ice bath and adjusted to pH 8 with saturated aqueous sodium hydrogencarbonate, then extracted with ethyl acetate, washed with saturated brine, concentrated in vacuo and dried, and the resulting crude product was purified by silica gel chromatography (PE: EA=1:1) to give compound A-8 (colorless oil, 400mg, yield: 41%).

LC-MS(ESI),m/z:[M+H] ⁺ ＝255.3.

Step 8:5- (3-amino-1- (tert-butyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-ol (A-9)

To 5- (1- (tert-butyl) -3 at room temperatureTo a solution of nitro-1H-pyrazol-5-yl) in tetrahydrofuran-3-ol (600 mg,2.35 mmol) in tetrahydrofuran (15.0 mL) was added palladium on carbon (300 mg), and the mixture was stirred under hydrogen atmosphere at 50℃for 16 hours. After the reaction was completed, the reaction mixture was extracted with methylene chloride, washed with saturated brine, concentrated in vacuo and dried, and the obtained crude product was purified by silica gel chromatography (PE: ea=20:1) to give compound a-9 (pale yellow oil, 300mg, yield: 57%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝226.1.

Step 9: n- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (A-10)

3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxylic acid (230 mg,1.35 mmol) was dissolved in N, N-dimethylformamide solution (10.0 mL), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (668 mg,1.76 mmol) was added to the above solution at room temperature, and the mixture was stirred at room temperature for 30 minutes. N, N-diisopropylethylamine (349 mg,2.70 mmol), 5- (3-amino-1- (tert-butyl) -1-hydro-pyrazol-5-yl) tetrahydrofuran-3-ol (335 mg,1.49 mmol) was then added separately to the above solution, and the reaction mixture was stirred at 70℃for 16 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated in vacuo and dried, and the resulting crude product was purified by silica gel chromatography (DCM: meoh=20:1) to give compound a-10 (yellow solid, 280mg, yield: 55%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝378.2.

Step 10:5- (1- (tert-butyl) -3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (A-11)

N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (300 mg,0.79 mmol), 4-dimethylaminopyridine (10 mg,0.082 mmol) and pyridine (189 mg,2.38 mmol) were dissolved in tetrahydrofuran solution (150 mL), and 4-nitrophenyloxyformyl chloride (104 mg,0.52 mmol) was added to the above solution at 0℃and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetateAfter washing with saturated brine, concentration in vacuo and drying, the crude product obtained was purified by silica gel chromatography (PE: ea=1:2) to give compound a-11 (white oil, 300mg, yield: 70%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝543.20.

Step 11:5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (intermediate A)

A solution of 5- (1- (tert-butyl) -3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (600 mg,2.35 mmol) in formic acid (5.0 mL) was stirred at 75deg.C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give intermediate a (pale yellow oil, crude product, 600 mg) which was used directly in the next step. LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝487.1.

Intermediate B cis-5- (3-amino-1- (4-tert-butyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-ol

The synthetic route is as follows:

step 1:5- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) tetrahydrofuran-3-one (B-1)

To a solution of 5- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) tetrahydrofuran-3-ol (3.30 g,12.9 mmol) in dichloromethane (50 mL) under nitrogen at room temperature was added pyridine chlorochromate (2.80 g,25.9 mmol) in portions, and the reaction mixture was stirred at room temperature overnight. Pyridine chlorochromate (1.40 g,12.9 mmol) was then added to the reaction and stirring was continued for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1-1:1) to give compound B-1 (2.0 g, yield: 61%). LC-MS (ESI), M/z: [ M+H ] +=254.1

Step 2: cis-5- (1- (tert-butyl) -3-nitro-1H-pyrazol-5-yl) tetrahydrofuran-3-ol (B-2)

To a solution of compound B-1 (3.7 g,15 mmol) in tetrahydrofuran (20 mL) was slowly added lithium triethylborohydride (1M in tetrahydrofuran, 18.3mL,36.5 mmol) at-60℃under nitrogen. After the completion of the dropwise addition, the reaction mixture was stirred under nitrogen at-60℃for 2 hours. After the reaction was completed, the reaction system was quenched with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the solid and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give compound B-2 (2.8 g, yield 68%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝256.0

Step 3: cis-5- (3-amino-1- (4-tert-butyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-ol (intermediate B)

Palladium on carbon (300 mg) was added to a tetrahydrofuran solution (15 mL) of Compound B-2 (600 mg,2.35 mmol) under a hydrogen atmosphere, and the reaction mixture was stirred at 50℃for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with a dichloromethane/methanol mixed solution (dichloromethane: methanol=10:1). The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane: methanol=20:1) to give intermediate B (300 mg, yield: 57%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝226.1

¹ H NMR(400M,DMSO-d ₆ )δ7.15–7.13(m,1H),5.39–5.28(m,1H),4.48–4.40(m,1H),4.05–3.99(m,1H),3.77–3.75(m,1H),3.66–3.62(m,1H),3.52–3.38(m,1H),1.66–1.62(m,9H).

Intermediate C: cis-5- (3-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-ol

The synthetic route is as follows:

step 1: 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (C-1)

To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (100 g,0.637 mol) in methanol (1000 mL) at 0deg.C was slowly added dropwise thionyl chloride (348 g,2.93 mol) under nitrogen. After completion of the dropwise addition, the reaction mixture was stirred at 0℃for 10 minutes, then warmed to 70℃and stirred at this temperature for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1000 mL), and then washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and then filtered to remove the solid. The filtrate was concentrated under reduced pressure to give crude compound C-1 (107 g) which was used directly in the next step. LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝172.0

Step 2:1- (4-methoxybenzyl) -3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (C-2)

To a solution of compound C-1 (30 g,0.18 mol) in N, N-dimethylformamide (300 mL) were added p-methoxybenzyl bromide (52 g,0.26 mol) and anhydrous potassium carbonate (48 g,0.35 mol) under nitrogen atmosphere. The reaction mixture was stirred at 50℃for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the solids were removed by filtration and the filtrate was concentrated under reduced pressure, and the resulting residue was slurried (petroleum ether: ethyl acetate=10:1) to collect the solids. The solid was dried to give compound C-2 (36 g, 71%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝309.0

Step 3:1- (4-methoxybenzyl) -3-nitro-1H-pyrazole-5-methanol (C-3)

Sodium borohydride (39 g,1.8 mol) was added portionwise to a solution of compound C-2 (130 g, 0.426 mol) in tetrahydrofuran (1.3L) at 0℃under nitrogen. After the completion of the addition, the reaction mixture was allowed to return to room temperature naturally and stirred at room temperature for 15 hours. After the reaction was completed, an ice-water mixture (1L) was slowly added to the reaction mixture and stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (700 mL. Times.3), the organic phases were combined and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and filtered to remove solids . The resulting filtrate was concentrated under reduced pressure to give crude compound C-3 (120 g) which was directly used in the next reaction. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝285.9

Step 4:1- (4-methoxybenzyl) -3-nitro-1H-pyrazole-5-carbaldehyde (C-4)

A solution of oxalyl chloride (32 mL,0.38 mol) in dichloromethane (500 mL) was cooled to-78deg.C under nitrogen, and dimethyl sulfoxide (34 mL,0.48 mol) was slowly added to the reaction, and the reaction mixture was stirred at-78deg.C for 1 hour. A solution of Compound C-3 (50 g,0.19 mol) in methylene chloride (200 mL) was added dropwise to the reaction, and the reaction mixture was stirred at-78℃for 2 hours after completion of the addition. Triethylamine (131 g,1.30 mol) was slowly added dropwise to the reaction, and after completion of the addition, the temperature of the reaction system was naturally returned to-20℃and the reaction mixture was stirred at this temperature for 1 hour. After the reaction was completed, water (300 mL) was added to the reaction mixture to quench it, and extracted with methylene chloride (200 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered to remove the solid. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound C-4 (40 g, yield: 81%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.96(s,1H),7.85(s,1H),7.30–7.22(m,3H),6.96–6.88(m,3H),5.73(s,2H),3.73(s,3H).

Step 5:1- (1- (4-methoxybenzyl) -3-nitro-1H-pyrazol-5-yl) but-3-yn-1-ol (C-5)

A suspension of zinc powder (18 g,0.28 mol) in tetrahydrofuran (240 mL) was cooled to 0℃under nitrogen, and propargyl bromide (16 g,0.14 mol) was slowly added dropwise to the above suspension. After completion of the dropwise addition, the reaction mixture was stirred at 0℃for 1 hour. Subsequently, a solution of Compound C-4 (24 g,0.92 mol) in tetrahydrofuran (100 mL) was added to the reaction system. After completion of the dropwise addition, the temperature of the reaction system was slowly returned to room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (300 mL) was added to the reaction mixture to quench, the solid was removed by filtration, and the filter cake was washed with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (300 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfateThe solids were removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound C-5 (20 g, yield: 74%). LC-MS (ESI), M/z: [ M+Na ]] ⁺ ＝324.1

Step 6:5- (1- ((4-methoxyphenyl) methyl) -3-nitropyrazol-5-yl) tetrahydrofuran-3-one (C-6)

To a solution of compound C-5 (50 g,0.17 mol) in 1, 2-dichloroethane (500 mL) was slowly added a solution of dibromopyridine nitroxide (57 g,0.33 mol) in 1, 2-dichloroethane (500 mL), methanesulfonic acid (19 g,0.20 mol) in 1, 2-dichloroethane (0.2 mol/L,1000 mL) and triphenylphosphine gold (I) bistrifluoromethane sulphonimide (3.68 g,4.98 mmol) in 1, 2-dichloroethane (36 mL) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (1000 mL) was added to the reaction mixture to dilute, and extracted with methylene chloride (200 ml×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound C-6 (29.0 g, yield: 55%). LC-MS (ESI), M/z: [ M+Na ] ] ⁺ ＝340.1

Step 7: cis-5- (1- ((4-methoxyphenyl) methyl) -3-nitropyrazol-5-yl) tetrahydrofuran-3-ol (C-7)

A solution of Compound C-6 (16.7 g,52.7 mmol) in tetrahydrofuran (170 mL) was cooled to-70℃under nitrogen, and lithium triethylborohydride (1.0 mol/L,130mL,130 mmol) was slowly added to the reaction, and the reaction mixture was stirred at-60℃for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (300 mL) was added to the reaction mixture to quench it, and extracted with ethyl acetate (200 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound C-7 (12.4 g, yield: 78%). LC-MS (ESI), M/z: [ M+Na ]] ⁺ ＝342.0

¹ H NMR(400M,DMSO-d ₆ )δ7.23(d,J＝8.7Hz,2H),7.06(s,1H),6.92(d,J＝8.7Hz,2H),5.43(s,2H),5.15–5.04(m,2H),4.44–4.39(m,1H),3.78–3.74(m,1H),3.73(s,3H),3.48–3.42(m,1H),1.92–1.85(m,1H).

Step 8: cis-5- (1- (4-methoxybenzyl) -3-aminopyrazol-5-yl) tetrahydrofuran-3-ol (intermediate C)

Palladium on carbon (10 g) was added to a tetrahydrofuran solution (500 mL) of Compound C-7 (50 g,0.16 mol) under a hydrogen atmosphere, and the reaction mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound intermediate C (40 g) which was directly used for the next reaction. LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝290.1

Intermediate D: cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate

The synthetic route is as follows:

step 1: n- (1-tert-butyl-5- (4-oxotetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (D-1)

To a solution of compound A-10 (25.80 g,68.25 mmol) in methylene chloride (387 mL) was added pyridinium chlorochromate (22.00 g,102.4 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After the completion of the reaction, water (400 mL) was added to the reaction system, and the mixture was extracted with methylene chloride (400 mL. Times.2). The organic phases were combined, washed with saturated brine (400 mL. Times.2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. Concentrating the filtrate under reduced pressure, and collecting residuePurification by silica gel chromatography (dichloromethane: methanol=50:1) afforded compound D-1 (15.0 g, 58%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝376.1

Step 2: cis-N- (1-tert-butyl-5- ((2R, 4R) -4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (D-2)

To a tetrahydrofuran solution (440 mL) of compound D-1 (11.00 g,29.26 mmol) was added lithium triethylboron (58.5 mL,1.0mol/L tetrahydrofuran solution, 58.5 mmol) at-65℃and the reaction mixture was stirred at-65℃for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction system at 0℃to quench the reaction. Then, water (300 mL) was added to the reaction system for dilution, and the mixture was extracted with ethyl acetate (400 mL. Times.2). The organic phases were combined, washed with saturated brine (400 mL. Times.2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (dichloromethane: methanol=100:1 to 1:1) to give compound D-2 (10.0 g, 90%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝378.2

Step 3: cis-5- (1- (tert-butyl) -3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (intermediate D)

Compound D-2 (10.00 g,26.46 mmol) and 4-dimethylaminopyridine (323 mg,2.64 mmol) were dissolved in dichloromethane (200 mL) and pyridine (6.28 g,79.4 mmol) and 4-nitrophenyloxy formyl chloride (7.98 mg,39.7 mmol) were added to the above solution at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine, concentrated in vacuo and dried, and the resulting crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=100:1 to 3:7) to give intermediate D (11.20 g, 78%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝543.20

Preparation of examples:

example 1: cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

to a solution of 5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazol-5-ylamino) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (600 mg,1.23 mmol) in tetrahydrofuran (20 mL) was added dropwise t-butylamine (902 mg,12.3 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phases were combined. After washing with saturated saline, concentration in vacuo and drying, the residue obtained was purified by preparative HPLC (column: gemini 5u C18.times.21.2 mm; mobile phase: acetonitrile (30-40%)/water (0.1% formic acid); flow rate: 20 mL/min) to give cis-product example 1 (HPLC front, t) _R ＝4.43min,150mg，LC-MS(ESI),m/z:[M+H] ⁺ = 421.20) and trans-product example 1' (HPLC post peak, t _R =4.581min, 140mg, yield: 33%, LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝421.20)。

Example 1A and example 1B:

(3R, 5R) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 1A) and (3S, 5S) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 1B)

Cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 1) chiral preparation HPLC (column: CHIRALPAK AD-H250 mm 20mm,5 μm, mobile phase: 35% IPA (NH) ₄ OH 0.2%), flow rate: 40 mL/min) to give example 1A (62.1 mg, yield: 11%) and example 1B (66.4 mg, yield: 12%).

Example 1A:

t _R ＝2.35min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝421.2.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.49(s,1H),10.81(s,1H),7.13(s,1H),6.95(s,1H),6.58(s,1H),5.15(br,1H),4.85(br,1H),4.34(s,2H),4.06(s,3H),3.86(br,2H),3.27(s,3H),2.75–2.64(m,1H),1.93(br,1H),1.22(s,9H).

example 1B:

t _R ＝4.64min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝421.2.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.49(s,1H),10.81(s,1H),7.13(s,1H),6.95(s,1H),6.58(s,1H),5.15(br,1H),4.85(br,1H),4.34(s,2H),4.05(s,3H),3.85(br,2H),3.27(s,3H),2.75–2.64(m,1H),1.93(br,1H),1.22(s,9H).

examples 3-11 were prepared by the synthetic methods of reference examples 1, 1A and 1B, and specific characterization data are as follows:

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examples 3 to 7 and 9 to 10 in the above Table were prepared by chiral preparation (CHIRALPAK IC mm. Times.20 mm,5 μm,40% MeOH (0.2% NH) ₄ OH), flow rate: 40 g/min) to obtain the corresponding single-configuration compound; example 11 preparation by chiral (CHIRALPAK OJ-H250 mm. Times.20 mm,5 μm,40% MeOH (0.2% NH) ₄ OH), flow rate: 40 g/min) to obtain the corresponding compound with single configuration.

Example 12: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: cis-N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -1-methyl-1H-pyrazole-5-carboxamide (12-2)

To a solution of compound 12-1 (0.135 g,1.07 mmol) in N, N-dimethylformamide (5 mL) under nitrogen was added HATU (0.4476 g,1.17 mmol) and the reaction mixture was stirred at 25℃for 0.5 h. N, N-diisopropylethylamine (0.252 g,1.95 mmol) and intermediate B (0.22 g,0.98 mmol) were then added to the system. The reaction system was warmed to 50 ℃ and stirred for 2 hours. After completion of the reaction, water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfateDrying, filtering, and concentrating under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 12-2 (0.24 g, yield: 73%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝333.9

Step 2: cis-5- (1- (tert-butyl) -3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (12-3)

To a mixed solution of compound 12-2 (0.24 g,0.72 mmol) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) under nitrogen atmosphere were added 4-nitrophenyl chloroformate (0.218 g,1.08 mmol), pyridine (0.171 g,2.16 mmol) and 4-dimethylaminopyridine (9.0 mg,0.070 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the completion of the reaction, water (20 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the solid and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 12-3 (0.20 g, yield: 55%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝499.2

Step 3: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (12-4)

Compound 12-3 (0.20 g,0.40 mmol) was dissolved in formic acid (4 mL) and the reaction mixture was warmed to 85deg.C and then stirred for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was crude compound 12-4 (0.15 g) which was directly used for the next reaction. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝442.8

Step 4: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 12)

To a solution of compound 12-4 (0.15 g,0.34 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (0.248 g,3.39 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: gemini-C18X121.2 mm,5 μm; mobile phase: acetonitrile)Water (0.1% trifluoroacetic acid); gradient: 30% -40%) to give example 12.LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝376.9

Example 12A and example 12B:

(3S, 5S) -5- (3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 12A) and (3R, 5R) -5- (3- (1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 12B)

Example 12 resolution by chiral preparative HPLC (column: CHIRALPAK WHELK-01 250 mm. Times.20 mm,5 μm; mobile phase: 40% isopropyl alcohol (0.2% ammonia; flow rate: 50 mL/min) gave example 12A (11.5 mg, yield: 16%) and example 12B (14.2 mg, yield: 20%).

Example 12A:

t _R ＝3.08min

LC-MS(ESI),m/z:[M+H] ⁺ ＝376.9

¹ H NMR(400MHz,CD ₃ OD)δ7.54(d,J＝2.1Hz,1H),6.98(d,J＝2.1Hz,1H),6.55(s,1H),5.25–5.19(m,1H),5.08–5.01(m,1H),4.19(s,3H),4.08–4.04(m,1H),3.98–3.94(m,1H),2.79–2.70(m,1H),2.20–2.12(m,1H),1.30(s,9H).

example 12B:

t _R ＝3.31min

LC-MS(ESI),m/z:[M+H] ⁺ ＝376.9

¹ H NMR(400MHz,CD ₃ OD)δ7.48(d,J＝2.1Hz,1H),6.92(d,J＝2.1Hz,1H),6.51(s,1H),5.21–5.14(m,1H),5.02–4.95(m,1H),4.13(s,3H),4.01(d,J＝10.2Hz,1H),3.91(dd,J＝10.3,4.5Hz,1H),2.75–2.63(m,1H),2.16–2.06(m,1H),1.25(s,9H).

examples 14-15 were prepared by the synthetic methods of reference examples 1, 1A and 1B, and specific characterization data are as follows:

Example 14 in the above Table was isolated by chiral preparation (CHIRALPAK WHELK-01 250 mm. Times.20 mm, 5. Mu. m m, mobile phase: 40% isopropyl alcohol (0.2% ammonia; flow rate: 50 mL/min) to give the corresponding single configuration compound; example 15 the corresponding single configuration compound was isolated by chiral preparation (CHIRALPAK AD-H250 mm 20mm,5 μm, mobile phase: 35% isopropyl alcohol (0.2% ammonia), flow rate: 40 g/min).

Example 18: cis-N- (5- (4- ((4-isopropylpyridin-2-yl) tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide

The synthetic route is as follows:

step 1: 2-fluoro-4- (prop-1-en-2-yl) pyridine (18-2)

To a solution of compound 18-1 (3.35 g,19.0 mmol) and 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3-dioxaborane (9.58 g,56.9 mmol) in 1, 4-dioxane/water (24 mL) was added potassium carbonate (7.88 g,56.9 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (0.70 g,0.95 mmol) at room temperature. The reaction mixture was stirred at 70 ℃ for 16 hours under argon atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (150 mL) and extracted with ethyl acetate (150 ml×2). The organic phases were combined, washed with saturated brine (200 ml×2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: petroleum ether=1:9) to give compound 18-2 (1.1 g, yield: 42%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝138.1

Step 2:2- ((5- (1- (tert-butyl) -5-nitro-1H-pyrazol-3-yl) tetrahydrofuran-3-yl) oxy) -4- (prop-1-en-2-yl) pyridine (18-3)

To a solution of compound 18-2 (250 mg,1.82 mmol) and 5- (1-tert-butyl-5-nitropyrazol-3-yl) tetrahydrofuran-3-ol (A-8, 512mg,2.00 mmol) in N, N-dimethylformamide (10 mL) was added sodium hydride (60%, 1.83g,4.56 mmol) at 0deg.C. The reaction mixture was stirred at 80℃for 16 hours. After the reaction was completed, the reaction was quenched with water at 0 ℃. The quenched mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 ml×2). The organic phases were combined, washed with water (100 ml×2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to give compound 18-3 (284 mg, yield: 42%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝373.2

Step 3:1- (tert-butyl) -3- (-4- ((isopropylpyridin-2-yl) oxy) tetrahydrofuran-2-yl) -1H-pyrrol-5-amine (Compound 18-4)

To a solution of compound 18-3 (300 mg, 0.264 mmol) in tetrahydrofuran/water (5 mL) under a hydrogen atmosphere were added palladium on carbon (300 mg,2.82 mmol) and palladium hydroxide on carbon (300 mg,2.09 mmol). The reaction mixture was stirred at 100℃for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with a dichloromethane/methanol mixed solution (dichloromethane: methanol=10:1). The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:9) to give compound 18-4 (220 mg, yield: 79%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝345.3

Step 4: cis-N- (1- (tert-butyl) -5- (4- ((4-isopropylpyridin-2-yl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (18-5)

To a solution of 5- (methoxymethyl) -2-methylpyrazole-3-carboxylic acid (50 mg,0.29 mmol) in N, N-dimethylformamide (5 mL) was added 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (145 mg,0.382 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. N, N-diisopropylethylamine (76 mg,0.59 mmol) and compound 18-4 (111 mg,0.322 mmol) were added to the reaction system, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is completed, the reaction mixture isCooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 ml×2). The organic phases were combined, washed with saturated brine (150 ml×2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=3:2) to give compound 18-5 (90 mg, yield: 62%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝497.2

Step 5: cis-N- (5- (4- ((4-isopropylpyridin-2-yl) tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (example 18)

Compound 18-5 (80 mg,0.16 mmol) was added to formic acid (3 mL) and the reaction mixture was stirred at 40℃for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 ml×2). The organic phases were combined, washed with saturated brine (150 ml×2), dried over anhydrous sodium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: gemini-C18.times.21.2 mm,5 μm; mobile phase: acetonitrile/water (0.1% formic acid; gradient: 0-35%) to give compound example 18.LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝441.2

Example 18A and example 18B:

n- (5- ((2R, 4R) -4- ((4-isopropylpyridin-2-yl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazol-5-carbamate and N- (5- ((2S, 4S) -4- ((4-isopropylpyridin-2-yl) oxy) tetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (methoxymethyl) -1-methyl-1H-pyrazol-5-carbamate

Example 18 was further resolved by chiral preparative HPLC (column: CHIRALPAK OJ-H250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol/0.2% ammonia; flow rate: 50 mL/min) to give example 18A (27 mg, yield: 36%) and example 18B (25 mg, yield: 34%).

Example 18A:

t _R ＝2.22min

LC-MS(ESI),m/z:[M+H] ⁺ ＝441.2

¹ H NMR(400MHz,DMSO-d ₆ )δ12.55(s,1H),10.80(s,1H),8.05(d,J＝5.3Hz,1H),7.13(s,1H),6.90(dd,J＝5.3,1.2Hz,1H),6.69(s,1H),6.63(s,1H),5.56(s,1H),4.98(t,J＝6.8Hz,1H),4.34(s,2H),4.06(s,3H),4.03–3.96(m,2H),3.27(s,3H),2.89–2.75(m,2H),2.15–2.05(m,1H),1.17(d,J＝6.9Hz,6H).

example 18B:

t _R ＝2.90min

LC-MS(ESI),m/z:[M+H] ⁺ ＝441.2

¹ H NMR(400MHz,DMSO-d ₆ )δ12.55(s,1H),10.80(s,1H),8.05(d,J＝5.3Hz,1H),7.13(s,1H),6.90(dd,J＝5.3,1.2Hz,1H),6.69(s,1H),6.63(s,1H),5.56(s,1H),4.98(t,J＝6.8Hz,1H),4.34(s,2H),4.06(s,3H),4.03–3.96(m,2H),3.27(s,3H),2.88–2.74(m,2H),2.15–2.06(m,1H),1.17(d,J＝6.9Hz,6H).

EXAMPLE 20 cis-5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl (4-nitrophenyl) carbonate

The synthetic route is as follows:

step 1:2, 2-difluoro-2- ((5- (methoxycarbonyl) -1-methyl-1H-pyrazol-3-yl) oxy) acetic acid (20-3)

To a solution of compound 20-1 (1.0 g,6.4 mmol) in 1, 4-dioxane (20 mL) was added sodium hydride (0.284 g,9.61 mmol) at room temperature. After the reaction mixture was stirred at 25℃for 30 minutes, sodium 2-bromo-2, 2-difluoroacetate (1.89 g,9.61 mmol) was added and the mixture was heated to 80℃and stirred for 16 hours. After the reaction is completed, 1, 4-dioxane is addedRing (50 mL) dilution. The mixture was filtered off with suction, and the filtrate was concentrated under reduced pressure. To the resulting solid was added dioxane hydrochloride solution (4.0 mol/L), stirred at room temperature for 2 minutes, then the solvent was removed by concentration under reduced pressure, the resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL. Times.2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was separated by preparative HPLC to give the product compound 20-3 (1.10 g, yield: 68%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝251.1

Step 2: 1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid methyl ester (20-4)

To a solution of compound 20-3 (0.50 g,2.0 mol) in deuterated chloroform (10 mL) under nitrogen at room temperature was added xenon difluoride (1.0 g,6.0 mol). The reaction was allowed to react at room temperature under ultrasound for 2 minutes, then stirred at 25℃for 20 minutes. After completion of the reaction, water (50 mL) was added to the reaction system to dilute, and the mixture was extracted with chloroform (50 ml×2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 20-4 (0.30 g, yield: 67%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝225.0

Step 3: 1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxylic acid (20-5)

To a mixed solution of compound 20-4 (0.30 g,1.34 mmol) in methanol (5 mL) and water (5 mL) at 25℃was added sodium hydroxide (0.16 g,4.0 mmol). The reaction mixture was stirred at 25 ℃ for 2 hours. After completion of the reaction, diluted hydrochloric acid (1.0 mol/L) was added to the system to adjust ph=5, and the mixture was extracted with ethyl acetate (20 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product compound 20-5 (0.25 g). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝211.1

Step 4: cis-N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide (20-6)

To a solution of compound 20-5 (0.25 g,1.2 mmol) in N, N-dimethylformamide (5 mL) under nitrogen was added HATU (0.547 g,1.44 mmol)) The reaction mixture was stirred at 25℃for 0.5 h. Then, N-diisopropylethylamine (0.460 g,3.60 mmol) and intermediate B (0.268 g,1.19 mmol) were added to the reaction system. Heat to 50 ℃ and stir for 2 hours. After the completion of the reaction, water (20 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 20-6 (0.35 g, yield: 71%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝418.2

Step 5: cis-5- (1- (tert-butyl) -3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl)) carbonate (20-7)

To a mixed solution of compound 20-6 (0.30 g,0.72 mmol) in dichloromethane (5 mL) and tetrahydrofuran (5 mL) under nitrogen was added 4-nitrobenzoate (0.29 g,1.44 mmol), pyridine (0.17 g,2.16 mmol) and 4-dimethylaminopyridine (9.0 mg,0.07 mmol), and the reaction mixture was stirred at 25℃for 16 hours. After the completion of the reaction, water (20 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (15 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 20-7 (0.30 g, yield: 68%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝583.2

Step 6: cis-5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (20-8)

Compound 20-7 (0.28 g,0.48 mmol) was dissolved in formic acid (10 mL), warmed to 90℃and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 20-8 (0.30 g) as a crude product, which was directly used for the next reaction. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝527.1

Step 7: cis-5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 20)

To a solution of compound 20-8 (0.10 g,0.20 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (0.16 mg,2.0 mmol) at room temperature. The reaction mixture was stirred for a further 16 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC (column: gemini-C18,150 ×21.2mm,5 μm; mobile phase: acetonitrile/water (0.1% formic acid; gradient: 30% -34%), to give example 20.LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝460.9

Example 20A and example 20B:

(3R, 5R) -5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazol-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3, S5S) -5- (3- (1-methyl-3- (trifluoromethoxy) -1H-pyrazol-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 20 was further purified by chiral separation (column type: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% isopropyl alcohol (0.2% ammonia water); flow rate: 40 mL/min) to give example 20A (28.1 mg, yield: 31%) and example 20B (25.8 mg, yield: 28%).

Example 20A:

t _R ＝1.57min

LC-MS(ESI),m/z:[M+H] ⁺ ＝460.9

¹ H NMR(400MHz,CD ₃ OD)δ6.80(s,1H),6.55(s,1H),5.20–5.14(m,1H),5.01–4.95(m,1H),4.11(s,3H),4.06–4.01(m,1H),3.97–3.91(m,1H),2.76–2.67(m,1H),2.16–2.10(m,1H),1.28(s,9H).

example 20B:

t _R ＝2.62min

LC-MS(ESI),m/z:[M+H] ⁺ ＝460.8

¹ H NMR(400MHz,CD ₃ OD)δ6.77(s,1H),6.53(s,1H),5.20–5.14(m,1H),5.01–4.95(m,1H),4.08(s,3H),4.01(d,J＝10.3Hz,1H),3.91(dd,J＝10.4,4.3Hz,1H),2.75–2.63(m,1H),2.14–2.06(m,1H),1.26(s,9H).

example 21: cis-5- (3- (6-methoxymethyl-4-methylnicotinamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

/>

step 1: 5-bromo-4-methylpyridine-2-methanol (21-2)

Borane-tetrahydrofuran complex (0.074L, 0.074 mol) was added dropwise to a tetrahydrofuran solution (30 mL) of compound 21-1 (4.0 g,0.019 mol) under nitrogen. After stirring at room temperature for 12 hours, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (100 mL), extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-2 (2.0 g, yield: 52%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝202.1,204.1

Step 2: 5-bromo-2-methoxymethyl-4-methylpyridine (21-3)

Sodium hydride (0.48 g,0.012 mol) was added in portions to a tetrahydrofuran solution (30 mL) of compound 21-2 (2.00 g,9.90 mmol) under nitrogen protection at 0deg.C, and after the reaction mixture was stirred at 0deg.C for 0.5 hours, methyl iodide (2.81 g,0.012 mol) was added to the reaction solution, followed by removal of the cold bath, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (100 mL), extracted with methylene chloride (30 mL. Times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-3 (0.50 g, yield: 23%). LC-MS(ESI),m/z:[M+H] ⁺ ＝216.1,218.1.

Step 3: 6-methoxymethyl-4-methylnicotinic acid tert-butyl ester (21-4)

A solution of compound 21-3 (0.30 g,1.39 mmol) in tetrahydrofuran (10 mL) was cooled to-78deg.C under nitrogen and butyllithium (1.20 mL,2.78 mmol) was added dropwise. The reaction mixture was stirred at-78℃for 0.5 hours, then a solution of di-tert-butyl carbonate (0.606 g,2.78 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the reaction was continued at-78℃for 2 hours after the completion of the addition. After completion of the reaction, a saturated aqueous ammonium chloride solution (15 mL) was added to the reaction system, the mixture was extracted with methylene chloride (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-4 (0.130 g, yield: 39%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝238.1

Step 4: 6-methoxymethyl-4-methylnicotinic acid (21-5)

Compound 21-4 (0.13 g,0.55 mmol) was dissolved in dichloromethane (2.0 mL) at room temperature, cooled to 0deg.C, and hydrochloric acid/dioxane solution (4 mol/L,5.0 mL) was added dropwise. The reaction solution was kept at 0℃and stirred for 3 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added to the reaction system, and the reaction mixture was extracted with dichloromethane (10 ml×3), the organic phases were combined, washed with saturated brine, and the aqueous phase was adjusted to ph=5 with addition of hydrochloric acid (2 mol/L) and extracted with dichloromethane (10 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 21-5 (95.0 mg, yield: 95%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝182.0

Step 5: cis-N- (1-tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -6-methoxymethyl-4-methylnicotinamide (21-6)

Dicyclohexylcarbodiimide (0.18 g,0.87 mmol) and 4-dimethylaminopyridine (81 mg,0.67 mmol) were added to a solution of compound 21-5 (0.301 g,1.33 mmol) in N, N dimethylformamide (8 mL) under nitrogen. Stirring was continued for 0.5 h at ambient temperature, followed by addition of intermediate B (0.15 g,0.67 mmol) and stirring was continued for 2 h after the addition was complete. After the reaction is finished, the reaction is reversedThe reaction system was quenched with water (30 mL), extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:9) to give compound 21-6 (0.14 g, yield: 54%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝389.0

Step 6: cis-5- (1-tert-butyl) -3- (6-methoxymethyl) -4-methylnicotinamide-1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (21-7)

Compound 21-6 (0.15 g,0.77 mmol), pyridine (0.122 g,1.54 mmol), p-nitrophenyl chloroformate (0.19 mg,0.93 mmol) and 4-dimethylaminopyridine (9.44 mg,0.0774 mmol) were dissolved in dichloromethane (10 mL) under nitrogen and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, water (10 mL) was added to the reaction system to quench the reaction. The reaction mixture was extracted with dichloromethane (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 21-7 (0.115 g, yield: 27%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝553.8

Step 7: cis-5- (3- (6-methoxymethyl) -4-methylnicotinamide-1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (21-8)

Compound 21-7 (0.11 g,0.20 mmol) was dissolved in formic acid (3 mL) at room temperature, warmed to 90℃and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude product compound 21-8 (80 mg). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝497.8

Step 8: cis-5- (3- (6-methoxymethyl-4-methylnicotinamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 21)

To a solution of compounds 21-8 (80 mg,0.16 mmol) in tetrahydrofuran (5 mL) under nitrogen was added N, N-diisopropylethylamine (21 mg,0.16 mmol) and tert-butylamine (59 mg,0.80 mmol). The reaction mixture was stirred at room temperature for 5 hours. After the completion of the reaction, the reaction was quenched by addition of water (10 mL) and extracted with dichloromethane (5 mL. Times.3)) The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: gemini-C18.times.21.2 mm,5 μm; mobile phase: acetonitrile/water (0.1% formic acid; gradient: 30-95%) to give example 21 (41.0 mg). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝432.0

Example 21A and example 21B:

(3R, 5R) -5- (3- (6-methoxymethyl-4-methylnicotinamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (6-methoxymethyl-4-methylnicotinamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 21 SFC (apparatus: SFC Thar prep 80; column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia water); flow rate: 40 g/min) was isolated and purified by chiral preparation to give example 21A (20.0 mg, yield: 29%) and example 21B (19.5 mg, yield: 28%).

Example 21A:

t _R ＝5.04min

LC-MS(ESI),m/z:[M+H] ⁺ ＝431.9

¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(s,1H),10.91(s,1H),8.52(s,1H),7.34(s,1H),6.96(s,1H),6.62(brs,1H),5.18–5.10(m,1H),4.90–4.79(m,1H),4.50(s,2H),91–3.83(m,2H),3.36(s,3H),2.74–2.67(m,1H),2.41(s,3H),2.01–1.94(m,1H),1.22(s,9H).

example 21B:

t _R ＝7.14min

LC-MS(ESI),m/z:[M+H] ⁺ ＝432.0

¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(s,1H),10.91(s,1H),8.52(s,1H),7.35(s,1H),6.94(s,1H),6.62(s,1H),5.20–5.09(m,1H),4.91–4.81(s,1H),4.50(s,2H),3.90–3.76(m,2H),3.38(s,3H),2.76–2.65(m,1H),2.41(s,3H),2.01–1.93(m,1H),1.22(s,9H).

example 22: cis-5- (3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-tert-butylcarbamate

The synthetic route is as follows:

step 1: cis-N- (1-tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -2- (2-methoxypyridin-4-yl) acetamide (22-2)

To compound 22-1 (0.10 g,0.60 mmol) in dichloromethane (8 mL) under nitrogen was added triethylamine (61 mg,0.60 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14 g,0.60 mmol) and 4-dimethylaminopyridine (73 mg,0.60 mmol). After the reaction solution was stirred at room temperature for 0.5 hours, intermediate B (0.14 g,0.60 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. After the completion of the reaction, the reaction was quenched by adding water (15 mL) to the reaction system, and the reaction mixture was extracted with methylene chloride (5 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:9) to give compound 22-2 (0.12 g, yield: 53%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝375.1

Step 2: cis-5- (1-tert-butyl) -3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (22-3)

Compound 22-2 (0.27 g,0.72 mmol), pyridine (0.114 g,1.44 mmol), p-nitrophenyl chloroformate (0.17 g,0.86 mmol) and 4-dimethylaminopyridine (10 mg,0.070 mmol) were dissolved in dichloromethane (10 mL) under nitrogen and stirred at room temperature for 5 hours. After the reaction was completed, the reaction system was quenched by adding water (10 mL), the reaction mixture was extracted with methylene chloride (10 mL. Times.3), and the mixture was combinedThe organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give the product compound 22-3 (0.180 g, yield: 46%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝539.8

Step 3: cis-5- (3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (22-4)

Compound 22-3 (0.16 g,0.30 mmol) was dissolved in formic acid (3 mL) at room temperature, warmed to 90℃and then stirred for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 22-4 (0.120 g) as a crude product, which was directly used in the next reaction. LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝484.1

Step 4: cis-5- (3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-tert-butylcarbamate (example 22)

To a solution of compound 22-4 (90 mg,0.19 mmol) in tetrahydrofuran (5 mL) was added N, N-diisopropylethylamine (48 mg,0.37 mmol) and tert-butylamine (68 mg,0.93 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After the completion of the reaction, the reaction was quenched by adding water (10 mL) to the reaction system, and the mixture was extracted with methylene chloride (5 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: gemini-C18.X121.2 mm,5 μm; mobile phase: acetonitrile-water (0.1% formic acid; gradient: 10-95%) to give example 22 (16.0 mg, yield: 20%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝418.2.

Example 22A and example 22B:

(3R, 5R) -5- (3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-tert-butylcarbamate and (3S, 5S) -5- (3- (2- (2-methoxypyridin-4-yl) acetamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-tert-butylcarbamate

Example 22 SFC (apparatus: SFC Thar prep 80; column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia water); flow rate: 40 g/min) was isolated and purified by chiral preparation to give example 22A (6.3 mg, yield: 8%) and example 22B (8.9 mg, yield: 11%).

Example 22A:

t _R ＝3.17min

LC-MS(ESI),m/z:[M+H] ⁺ ＝418.2

¹ H NMR(400MHz,CD ₃ OD)δ7.95(d,J＝5.3Hz,1H),6.85(dd,J＝5.3,1.3Hz,1H),6.70(s,1H),6.34(brs,1H),5.07(s,1H),4.94–4.83(m,1H),3.94–3.89(m,1H),3.83(d,J＝4.5Hz,1H),3.79(s,3H),3.58(s,2H),2.62–2.52(m,1H),2.04–1.96(m,1H),1.14(s,9H).

example 22B:

t _R ＝5.82min

LC-MS(ESI),m/z:[M+H] ⁺ ＝418.2

¹ H NMR(400MHz,CD ₃ OD)δ8.03(d,J＝5.3Hz,1H),6.92(dd,J＝5.3,0.9Hz,1H),6.77(s,1H),6.43(brs,1H),5.14(s,1H),5.00–4.91(m,1H),3.98(d,J＝10.3Hz,1H),3.90(d,J＝3.6Hz,1H),3.87(s,3H),3.65(s,2H),2.70–2.59(m,1H),2.07(d,J＝9.0Hz,1H),1.22(s,9H).

example 23: cis-5- (3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydro-furan-3-yl tert-butylcarbamic acid

The synthetic route is as follows:

step 1:3- (hydroxymethyl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (23-2)

Under the protection of nitrogen, compound 23-1(5.0 g,0.029 mol), methyl iodide (8.35 g,5.90 mmol) and potassium carbonate (8.13 g,5.90 mmol) were dissolved in acetonitrile (50 mL). The reaction system was warmed to 80 ℃ and stirred for 10 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the cake was rinsed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 23-2 (1.30 g, yield: 20%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝185.1

Step 2: 3-bromomethyl-1-methylpyrazole-5-carboxylic acid ethyl ester (23-3)

Compound 23-2 (0.750 g,4.07 mmol) was dissolved in acetonitrile (25 mL) under nitrogen, followed by addition of phosphorus tribromide (1.65 g,6.01 mmol) and stirring of the reaction system at 80℃for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and quenched with water (100 mL). After stirring was continued for 5 minutes, ethyl acetate (100 mL) was added to the reaction system. The reaction mixture was separated and the aqueous phase was extracted with ethyl acetate (50 mL. Times.2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=2:1) to give compound 23-3 (0.83 g, yield: 78%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝247.1,249.1

Step 3: 3-Cyclopropoxymethyl-1-methylpyrazole-5-carboxylic acid ethyl ester (23-4)

Cyclopropyl alcohol (0.390 g,6.71 mol) was dissolved in tetrahydrofuran (30 mL) at room temperature. Sodium hydride (269 mg,60%,6.71 mol) was added in portions after the reaction system was cooled to 0℃and stirring was continued for 0.5 hours after the addition was completed. To the reaction was added compound 23-3 (0.830 g,3.35 mol) and stirred at room temperature for 10 hours. After the completion of the reaction, the reaction was quenched by addition of water (100 mL). After stirring for 5 min, the reaction mixture was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give the product compound 23-5 (0.468 g, yield: 55%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝225.0

Step 4: 3-Cyclopropoxymethyl-1-methylpyrazole-5-carboxylic acid (23-5)

Compound 23-4 (0.20 g,0.89 mmol) and lithium hydroxide monohydrate (74.8 mg,1.78 mmol) were dissolved in tetrahydrofuran and water (10:1, 20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (50 mL) was added to the reaction system, followed by adjusting the pH of the system to 3-4 with dilute hydrochloric acid (1 mol/L), the reaction mixture was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give compound 23-5 (0.130 g, yield: 67%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝197.1

Step 5: cis-N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide (23-6)

To a solution of compound 23-5 (0.218 g,1.11 mmol) in N, N-dimethylformamide (5 mL) under nitrogen was added HATU (0.586 g,1.33 mmol) and the reaction mixture was stirred for 0.5 h. N, N-diisopropylethylamine (0.287 g,2.22 mmol) and intermediate B (0.250 g,1.11 mmol) were then added to the system. The reaction system was warmed to 50 ℃ and stirred for 2 hours. After completion of the reaction, the reaction system was diluted with water (30 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 23-6 (0.250 g, yield: 56%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝404.1

Step 6: cis-5- (1- (tert-butyl) -3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (23-7)

To a solution of compound 23-6 (0.25 g,0.62 mmol) in dichloromethane (5 mL) and tetrahydrofuran (5 mL) under nitrogen was added 4-nitrobenzoate (0.19 g,0.93 mmol), pyridine (0.147 g,1.86 mmol) and 4-dimethylaminopyridine (8.0 mg,0.066 mmol). The reaction mixture was stirred at 25℃for 16 hours. After completion of the reaction, water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL. Times.3) . The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give product 23-7 (0.280 g, yield: 79%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝569.2.

Step 7: cis-5- (3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydro-furan-3-yl (4-nitrophenyl) carbonate (23-8)

Compound 23-7 (0.28 g,0.49 mmol) was dissolved in tetrahydrofuran (3 mL) and formic acid (3 mL), and the reaction mixture was stirred at 70℃for 72 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give compound 23-8 (0.100 g, yield: 40%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝523.1

Step 8: cis-5- (3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydro-furan-3-yl tert-butylcarbamate (example 23)

To a solution of compound 23-8 (0.10 g,0.20 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (0.143 g,1.96 mmol) at room temperature, and the reaction mixture was stirred for an additional 16 hours. After completion of the reaction, the reaction system was concentrated, and the resulting residue was purified by preparative HPLC (column: gemini-C18,150X 21.2mm,5 μm; mobile phase: acetonitrile/water (0.1% trifluoroacetic acid; gradient: 30% -32%), to give example 23 (30.0 mg, yield: 34%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝446.9.

Example 23A and example 23B:

(3S, 5S) -5- (3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3R, 5R) -5- (3- (3- (cyclopropoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 23 SFC (column: CHIRALPAK IC,250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia; flow rate: 40 mL/min)) was further purified by chiral preparation to give example 23A (6.4 mg, yield: 7%) and example 23B (7.1 mg, yield: 8%).

Example 23A:

t _R ＝2.18min

LC-MS(ESI),m/z:[M+H] ⁺ ＝446.9

¹ H NMR(400MHz,CD ₃ OD)δ6.96(s,1H),6.71–6.54(m,1H),5.27–5.17(m,1H),5.08–5.00(m,1H),4.56(s,2H),4.15(s,3H),4.08–4.04(m,1H),3.98–3.94(m,1H),3.46–3.42(m,1H),2.80–2.70(m,1H),2.20–2.10(m,1H),1.30(s,9H),0.64–0.58(m,2H),0.56–0.50(m,2H).

example 23B:

t _R ＝2.35min

LC-MS(ESI),m/z:[M+H] ⁺ ＝446.9

¹ H NMR(400MHz,CD ₃ OD)δ6.96(s,1H),6.63(s,1H),5.25–5.20(m,1H),5.10–5.00(m,1H),4.56(s,2H),4.15(s,3H),4.08–4.04(m,1H),3.98–3.94(m,1H),3.46–3.40(m,1H),2.79–2.69(m,1H),2.20–2.10(m,1H),1.30(s,9H),0.64–0.58(m,2H),0.56–0.50(m,2H).

example 24: cis-5- (3- (4-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: 1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (24-2)

To a solution of compound 24-1 (2.5 g, 0.020mol) in N, N dimethylformamide (30 mL) was added potassium carbonate (5.5 g,0.040 mol) and methyl iodide (3.4) at room temperatureg,0.020 mol) and then reacted at room temperature for 6 hours. After the reaction was completed, water (80 mL) was added to quench the reaction. The reaction mixture was extracted with dichloromethane (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 24-2 (1.80 g, yield: 58%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝141.1

Step 2: 4-fluoro-1-methylpyrazole-5-carboxylic acid methyl ester (24-3)

To a solution of compound 24-2 (1.8 g,0.013 mol) in nitromethane (20 mL) at room temperature was added sodium carbonate (0.551 g,5.20 mmol) and 1-chloromethyl-4-fluoro-1, 4-nitrogen

Bicyclo [2.2.2]Octanedi (tetrafluoroborate) (5.1 g,0.014 mol). The reaction system was warmed to 80 ℃ and stirred for 12 hours. After the reaction was completed, water (30 mL) was added to quench the reaction. The reaction mixture was extracted with dichloromethane (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 24-3 (0.30 g, yield: 15%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝159.1

Step 3: 4-fluoro-1-methyl-1H-pyrazole-5-carboxylic acid (24-4)

Compound 24-3 (0.460 g,2.91 mmol) and lithium hydroxide monohydrate (0.244 g,5.82 mmol) were dissolved in a mixture of tetrahydrofuran and water (10:1, 15 mL) at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction, 50mL of water was added, followed by pH adjustment to 3-4 with dilute hydrochloric acid (1 mol/L), and the mixture was extracted with ethyl acetate (50 mL. Times.2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give compound 24-4 (0.230 g, yield: 49%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝145.1

Step 4: cis-N- (1-tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -4-fluoro-1-methyl-1H-pyrazole-5-carboxamide (24-5)

To a solution of compound 24-4 (96 mg,0.66 mmol) in N, N-dimethylformamide (8 mL) under nitrogen was added HATU (0.38 g,0.99 mmol) and N, N-diisopropylethylamine (0.172 g,1.33 mmol). Intermediate B (0.15 g,0.66 mmol) was added to the system after stirring the reaction mixture for 0.5 hours. The reaction system was stirred for 2 hours. After completion of the reaction, water (30 mL) was added to the reaction system to dilute, and the reaction mixture was extracted with methylene chloride (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give product compound 24-5 (54 mg, yield: 23%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝517.2

Step 5: cis-5- (1-tert-butyl) -3- (4-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (24-6)

Compound 24-5 (40 mg,0.11 mmol), pyridine (27 mg,0.34 mmol), p-nitrophenyl chloroformate (28 mg,0.13 mmol) and 4-dimethylaminopyridine (2.0 mg,0.016 mmol) were dissolved in dichloromethane (5 mL) under nitrogen and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was quenched by addition of water (10 mL) and extracted with dichloromethane (10 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give the product compound 24-6 (46 mg, yield: 78%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝517.2

Step 6: cis-5- (4-fluoro-1-methylpyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (24-7)

Compound 24-6 (46 mg,0.089 mmol) was dissolved in formic acid (3 mL) at room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude 24-7 (50 mg) which was used directly in the next reaction. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝461.1.

Step 7: cis-5- (3- (4-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 24)

To a tetrahydrofuran solution (5 mL) of compound 24-7 (50 mg,0.11 mmol) were added tert-butylamine (40 mg,0.54 mmol) and N, N-diisopropylethylamine (28 mg,0.21 mmol) at room temperature, and stirred for 5 hours. After completion of the reaction, the reaction was quenched by adding water (10 mL), and the reaction mixture was extracted with methylene chloride (5 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (dichloromethane: methanol=20:1) to give example 24 (7.0 mg). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝395.1.

Example 24A and example 24B:

(3R, 5R) -5- (3- (4-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (4-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 24 was further purified by chiral SFC (column: CHIRALPAK AD-H,250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia; flow rate: 40 g/min)) to give example 24A (3.3 mg, yield: 9%) and example 24B (3.3 mg, yield: 9%).

Example 24A:

t _R ＝2.76min

LC-MS(ESI),m/z:[M+H] ⁺ ＝395.1

¹ H NMR(400MHz,CD ₃ OD)δ7.50–7.43(m,1H),6.58–6.49(m,1H),5.21(s,1H),5.06–4.96(m,1H),4.08(s,3H),4.05(s,1H),3.98–3.92(m,1H),2.75–2.65(m,1H),2.20-2.10(m,1H),1.30(s,9H).

example 24B:

t _R ＝6.23min

LC-MS(ESI),m/z:[M+H] ⁺ ＝395.1

example 25: cis-5- (3- (3-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: 3-fluoro-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (25-2)

To a solution of compound 25-1 (1.00 g,6.30 mmol) in N, N-dimethylformamide (15 mL) was added potassium carbonate (1.74 g,12.6 mmol) and methyl iodide (1.34 g,9.50 mmol) at room temperature, and the reaction mixture was stirred for 2 hours. After completion of the reaction, water (150 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (100 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1) to give compound 25-2 (0.65 g, yield: 60%).

¹ H NMR(400MHz,CDCl ₃ )δ6.29(d,J＝6.0Hz,1H),4.32(q,J＝7.2Hz,2H),4.04(s,3H),1.35(t,J＝7.2Hz,3H).

Step 2: 3-fluoro-1-methyl-1H-pyrazole-5-carboxylic acid (25-3)

To a mixed solution of compound 25-2 (0.65 g,38 mmol) in tetrahydrofuran (5 mL) and water (5 mL) at room temperature was added lithium hydroxide monohydrate (0.48 g,11 mmol), and the reaction mixture was stirred for 1 hour. After the completion of the reaction, diluted hydrochloric acid (1 mol/L) was added to the system to adjust the pH to 5, and then the mixture was extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was crude product compound 25-3 (0.48 g).

¹ H NMR(400MHz,DMSO-d ₆ )δ13.7(brs,1H),6.50(d,J＝6.0Hz,1H),3.98(s,3H).

Step 3: cis-N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -3-fluoro-1-methyl-1H-pyrazole-5-carboxamide (25-4)

To a solution of compound 25-3 (0.12 g,0.83 mmol) in N, N-dimethylformamide (3 mL) was added HATU (0.380 g,1.00 mmol) at room temperature and the reaction mixture was stirred for 0.5 h. N, N-diisopropylethylamine (0.323 g,2.50 mmol) and intermediate B (0.19 g,0.83 mmol) were then added to the system. After the addition was completed, the reaction system was warmed to 50℃and stirred for 2 hours. After the completion of the reaction, water (20 mL) was added to the reaction to dilute, and the mixture was extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give the product compound 25-4 (0.15 g, yield: 51%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝352.2

Step 4: cis-5- (1- (tert-butyl) -3- (3-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (25-5)

To a mixed solution of compound 25-4 (0.15 g,0.43 mmol) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) at room temperature were added 4-nitrobenzoate (0.17 g,0.85 mmol), pyridine (0.101 g,1.28 mmol) and 4-dimethylaminopyridine (5.0 mg,0.041 mmol), and the reaction mixture was stirred for an additional 16 hours. After the completion of the reaction, water (20 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 25-5 (0.120 g, yield: 54%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝516.8

Step 5: cis-5- (3- (3-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (25-6)

Compound 25-5 (0.12 g,0.23 mmol) was dissolved in formic acid (4 mL) at room temperature, the reaction was then warmed to 90℃and stirring continued for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was crude product compound 25-6 (0.100 g) and was used directly in the next step. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝460.7

Step 6: cis-5- (3- (3-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 25)

To a solution of compound 25-6 (0.10 g,0.22 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (0.158 g,2.17 mmol) at room temperature, and the reaction mixture was stirred for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: gemini-C18,150 ×21.2mm,5 μm; mobile phase: acetonitrile/water (0.1% formic acid; gradient: 30% -34%), to give example 25 (50.0 mg). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝394.9

Example 25A and example 25B:

(3R, 5R) -5- (3- (3-fluoro) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (3-fluoro-1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 25 was further purified by chiral SFC separation (column: CHIRALPAK AD-H,250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia; flow rate: 40 mL/min) to give example 25A (19.4 mg, yield: 23%) and example 25B (19.3 mg, yield: 23%).

Example 25A:

t _R ＝2.88min

LC-MS(ESI),m/z:[M+H] ⁺ ＝394.9

¹ H NMR(400MHz,CD ₃ OD)δ6.62(brs,1H),6.53(d,J＝5.8Hz,1H),5.25–5.20(m,1H),5.10–5.00(m,1H),4.06(s,3H),4.05–4.03(m,1H),3.98–3.93(m,1H),2.80–2.70(m,1H),2.20–2.10(m,1H),1.30(s,9H).

example 25B:

t _R ＝7.10min

LC-MS(ESI),m/z:[M+H] ⁺ ＝394.9

¹ H NMR(400MHz,CD ₃ OD)δ6.62(brs,1H),6.53(d,J＝5.8Hz,1H),5.25–5.20(m,1H),5.10–5.00(m,1H),4.06(s,3H),4.05–4.03(s,1H),3.98–3.93(m,1H),2.80–2.70(m,1H),2.20–2.10(m,1H),1.30(s,9H).

example 26: cis-5- (3- (1-cyclopropyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: 1-cyclopropyl-1H-pyrazole-5-carboxylic acid ethyl ester (26-2)

To a solution of compound 26-1 (1.00 g,7.10 mmol) in 1, 2-dichloroethane (15 mL) under nitrogen was added cyclopropylboronic acid (1.22 g,14.2 mmol), 2-bipyridine (1.29 g,7.10 mmol), copper acetate (1.29 g,7.10 mmol) and sodium carbonate (1.51 g,14.20 mmol). The reaction mixture was then warmed to 70 ℃ and stirred for 16 hours. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), the reaction mixture was filtered, the filtrate was extracted with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1) to give compound 26-2 (0.28 g, yield: 22%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝181.0

Step 2: 1-cyclopropyl-1H-pyrazole-5-carboxylic acid (26-3)

To a mixed solution of compound 26-2 (0.20 g,1.1 mmol) in tetrahydrofuran (5 mL) and water (5 mL) at room temperature was added lithium hydroxide monohydrate (0.14 g,3.3 mmol), and the reaction mixture was stirred for 1 hour. After the completion of the reaction, diluted hydrochloric acid (1 mol/L) was added to the system to adjust the pH to 5, and then the mixture was extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was crude product compound 26-3 (0.13 g). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝153.1

Step 3: cis-N- (1- (tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -1-cyclopropyl-1H-pyrazole-5-carboxamide (26-4)

To a solution of compound 26-3 (0.12 g,0.79 mmol) in N, N-dimethylformamide (3 mL) was added HATU (0.36 g,0.95 mmol) at room temperature and the reaction mixture was stirred for an additional 0.5 h. N, N-diisopropylethylamine (0.306 g,2.37 mmol) and intermediate B (0.18 g,0.79 mmol) were then added to the system. After the addition was completed, the reaction system was warmed to 50℃and stirred for 2 hours. After completion of the reaction, water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=10:1) to give the product compound 26-4 (0.15 g, yield: 53%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝360.2

Step 4: cis-5- (1- (tert-butyl) -3- (1-cyclopropyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (26-5)

To a mixture of compound 26-4 (0.15 g,0.42 mmol) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was added 4-nitrobenzoate (0.17 g,0.83 mmol), pyridine (0.099 g,1.2 mmol) and 4-dimethylaminopyridine (5.0 mg,0.041 mmol) at room temperature, and the reaction mixture was stirred for an additional 16 hours. After completion of the reaction, water (20 mL) was added to the reaction system to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL. Times.3), and the mixture was combinedThe organic phase of (2) was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give the product compound 26-5 (0.160 g, yield: 73%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝525.1

Step 5: cis-5- (3- (1-cyclopropyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (26-6)

Compound 26-5 (0.16 g,0.31 mmol) was dissolved in formic acid (4 mL) at room temperature, and the reaction was then warmed to 85deg.C and stirred for an additional 1 hour. After the completion of the reaction, the reaction system was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure, and the obtained residue was crude product compound 26-6 (0.120 g) and was used directly in the next step. LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝469.1

Step 6: cis-5- (3- (1-cyclopropyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 26)

To a solution of compound 26-6 (0.10 g,0.21 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (0.156 g,2.14 mmol) at room temperature and stirred for 16 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid chromatography (column type: gemini-C18,150×21.2mm,5 μm, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 29% -31%), to give example 26 (50.0 mg). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝402.9.

Example 26A and example 26B:

(3R, 5R) -5- (3- (1-cyclopropyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (1-cyclopropyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 26 was further purified by SFC chiral separation (column model: CHIRALPAK AD-H,250 mm. Times.20 mm,5 μm; mobile phase: 40% isopropyl alcohol (0.2% ammonia water; flow rate: 40 g/min) to give example 26A (21.8 mg, yield: 25%) and example 26B (20.4 mg, yield: 24%).

Example 26A:

t _R ＝2.51min

LC-MS(ESI),m/z:[M+H] ⁺ ＝402.9

¹ H NMR(400MHz,CD ₃ OD)δ7.42(d,J＝2.1Hz,1H),6.83(d,J＝1.7Hz,1H),6.61(brs,1H),5.25–5.12(m,1H),5.05–4.95(m,1H),4.31–4.19(m,1H),4.04–3.99(m,1H),3.94–3.89(m,1H),2.75–2.65(m,1H),2.17–2.05(m,1H),1.25(s,9H),1.15–1.10(m,2H),1.04–0.98(m,2H).

Example 26B:

t _R ＝5.34min

LC-MS(ESI),m/z:[M+H] ⁺ ＝402.9

¹ H NMR(400MHz,CD ₃ OD)δ7.42(d,J＝2.1Hz,1H),6.83(d,J＝1.7Hz,1H),6.61(brs,1H),5.25–5.20(m,1H),5.05–4.95(m,1H),4.31–4.19(m,1H),4.04–3.99(m,1H),3.94–3.89(m,1H),2.75–2.65(m,1H),2.15–2.05(m,1H),1.25(s,9H),1.15–1.10(m,2H),1.04–0.98(m,2H).

example 27: cis-5- (3- (1- (cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: 1-Cyclopropylmethylpyrazole-5-carboxylic acid methyl ester (27-2)

Cesium carbonate (10 g,0.032 mol) and bromomethylcyclopropane (2.58 g,0.019 mol) were added to a solution of compound 27-1 (2.0 g,0.016 mol) in N, N dimethylformamide (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was extracted with methylene chloride (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give the product compound 27-2 (0.850 g, yield: 29%).

¹ H NMR(400MHz,CDCl ₃ )δ7.49(d,J＝2.0Hz,1H),6.84(d,J＝2.0Hz,1H),4.44(d,J＝7.2Hz,2H),3.88(s,3H),1.42–1.31(m,1H),0.53–0.48(m,2H),0.43–0.39(m,2H).

Step 2: 1-Cyclopropylmethylpyrazole-5-carboxylic acid (27-3)

To a mixed solution of compound 27-2 (0.85 g,4.7 mmol) in tetrahydrofuran (20 mL) and water (14 mL) at room temperature was added lithium hydroxide monohydrate (0.594 g,14.2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, diluted hydrochloric acid (1 mol/L) was added to the system to adjust the pH to 5, and then the mixture was extracted with methylene chloride (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was crude product compound 27-3 (0.58 g). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝167.1

Step 3: cis-N- (1-tert-butyl) -5- (4-hydroxytetrahydrofuran-2-yl) -1H-pyrazol-3-yl) -1-cyclopropylmethyl-1H-pyrazole-5-carboxamide (27-4)

N, N-diisopropylethylamine (0.778 g,6.02 mmol) and HATU (1.70 g,4.52 mmol) were added to a solution of compound 27-3 (0.50 g,3.1 mmol) in N, N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was stirred for 0.5 h, then intermediate B (0.678 g,3.09 mmol) was added to the system. After the addition was completed, the reaction was stirred for 2 hours. After the completion of the reaction, water (30 mL) was added to the reaction system to dilute, and the mixture was extracted with dichloromethane (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:9) to give the product compound 27-4 (0.40 g, yield: 35%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝374.2

Step 4: cis-5- (1-tert-butyl) -3- (1-cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (27-5)

To a solution of compound 27-4 (0.40 g,1.07 mmol) in dichloromethane (10 mL) was added 4-nitrobenzoate (0.258 g,1.29 mmol), pyridine (0.170 g,2.14 mmol) and 4-dimethylaminopyridine (13.1 mg,0.11 mmol) at room temperature, and the reaction mixture was stirred for 5 hours. After the completion of the reaction, water (10 mL) was added to dilute the mixture, and the mixture was extracted with dichloromethane (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give the product compound 27-5 (0.33 g, yield: 61%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝538.8

Step 5: cis-5- (3- (1-cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (27-6)

Compound 27-5 (0.24 g,0.45 mmol) was dissolved in formic acid (3 mL) at room temperature, warmed to 90℃and stirred for 2 hours. After the completion of the reaction, the reaction system was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was crude product compound 27-6 (0.180 g) and was used directly in the next step. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝483.0

Step 6: cis (5- (3- (1- (cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 27)

To a solution of compound 27-6 (0.15 g,0.31 mmol) in tetrahydrofuran (5 mL) under nitrogen was added N, N-diisopropylethylamine (60 mg,0.47 mmol) and tert-butylamine (0.40 g,0.78 mmol). Stirred at room temperature for 5 hours. After the completion of the reaction, the reaction was quenched by adding water (10 mL). The reaction mixture was extracted with dichloromethane (5 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: gemini-C18.times.21.2 mm,5 μm; mobile phase: acetonitrile/water (0.1% formic acid; gradient: 10-95%) to give example 27 (80.0 mg). LC-MS (ESI), m- z:[M+H] ⁺ ＝417.1.

Example 27A and example 27B:

(3R, 5R) -5- (3- (1- (cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (1- (cyclopropylmethyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 27 was isolated and purified by chiral SFC (instrument: SFC tharprep 80; column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2% ammonia water); flow rate: 40 g/min) to give example 27A (37.7 mg, yield: 29%) and example 27B (30.5 mg, yield: 24%).

Example 27A:

t _R ＝2.61min

LC-MS(ESI),m/z:[M+H] ⁺ ＝417.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.50(s,1H),10.81(s,1H),7.47(d,J＝1.6Hz,1H),7.12(s,1H),6.89(s,1H),6.55(s,1H),5.16–5.06(m,1H),4.87–4.76(m,1H),4.35(d,J＝7.1Hz,2H),3.86–3.73(m,2H),2.72–2.63(m,1H),1.97–1.88(m,1H),1.28–1.20(m,1H),1.18(s,9H),0.47–0.35(m,2H),0.33–0.26(m,2H).

example 27B:

t _R ＝4.75min

LC-MS(ESI),m/z:[M+H] ⁺ ＝417.2

EXAMPLE 28 cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl-7-azabicyclo [2.2.1] heptane-7-carboxylic acid ester

The synthetic route is as follows:

step 1: cis-5- (1-tert-butyl-3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl-7-azabicyclo [2.2.1] heptane-7-carboxylic acid ester (28-1)

Intermediate D (150 mg,0.276 mmol), 7-azabicyclo [2.2.1] at room temperature]Heptane hydrochloride (111 mg,0.830 mmol) and DIEA (214 mg,1.66 mmol) were added to THF (2 mL). The mixture was stirred at 40 ℃ for 2 hours and then cooled to room temperature. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered to remove solids. The filtrate was concentrated in vacuo and dried, and the resulting crude product was purified by silica gel chromatography (dichloromethane: methanol=15:1) to give compound 28-1 (110 mg, yield: 80%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝501.3

Step 2: cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl-7-azabicyclo [2.2.1] heptane-7-carboxylic acid ester (example 28)

Compound 28-1 (110 mg,0.220 mmol) was added to formic acid (2 mL) at room temperature. The mixture was stirred at 75 ℃ for 12 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo and dried, and the resulting residue was purified by preparative HPLC (column: gemini 5u C18.times.21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid; gradient: 40-60%; flow rate: 20 mL/min) to give example 28 (45 mg, yield: 46%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝445.1.

Example 28A and example 28B:

(3R, 5R) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl-7-azabicyclo [2.2.1] heptane-7-carboxylic acid ester and (3S, 5S) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl-7-azabicyclo [2.2.1] heptane-7-carboxylic acid ester

Example 28 chiral preparation SFC (column: CHIRALPAK-OJ, mobile phase: carbon dioxide/methanol (triethylamine), flow rate: 12.5 mL/min) resolved example 28A (19.7 mg, yield: 88%) and example 28B (23.0 mg, yield: 98%)

Example 28A:

t _R ＝2.09min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝445.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.48(s,1H),10.80(s,1H),7.13(s,1H),6.61(s,1H),5.19(s,1H),5.04–5.00(m,1H),4.33(s,2H),4.08(s,2H),4.05(s,3H),3.94–3.86(m,2H),3.27(s,2H),2.69–2.57(m,1H),2.16–2.02(m,1H),1.60–1.57(m,4H),1.34(d,J＝6.7Hz,4H).

example 28B:

t _R ＝2.73min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝445.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.47(s,1H),10.81(s,1H),7.12(s,1H),6.60(s,1H),5.24–5.13(m,1H),5.01(s,1H),4.34(s,2H),4.08(s,2H),4.05(s,3H),3.94–3.86(m,2H),3.27(s,3H),2.61(dd,J＝14.2,6.4Hz,1H),2.08(dd,J＝13.6,3.4Hz,1H),1.60–1.58(m,4H),1.34(d,J＝6.8Hz,4H).

example 29: cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-ylbicyclo [1.1.1] pentan-1-ylcarbamate

The synthetic route is as follows:

step 1: cis-5- (1-tert-butyl-3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-ylbicyclo [1.1.1] pentan-1-ylcarbamate (29-1)

Intermediate D (100 mg,0.184 mmol) and N, N-diisopropylethylamine (71 mg,0.55 mmol) were added to THF (5 mL) at room temperature. After stirring the mixture at room temperature for 0.5 hours, bicyclo [1.1.1] is added]Pentane-1-amine hydrochloride (33 mg,0.28 mmol). The mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered to remove solids. The filtrate was concentrated in vacuo and dried, and the resulting crude product was purified by preparative thin layer chromatography (dichloromethane: methanol=20:1) to give compound 29-1 (80 mg, yield: 89%). LC-MS (ESI), M/z: [ m+h] ⁺ ＝487.2

Step 2: cis-5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-ylbicyclo [1.1.1] pentan-1-ylcarbamate (example 29)

Compound 29-1 (60 mg,0.087 mmol) was added to formic acid (5 mL) at room temperature. The mixture was stirred at 75 ℃ for 2 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo and dried, and the resulting residue was purified by preparative HPLC (column: gemini 5u C18.times.21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid; gradient: 40-60%; flow rate: 20 mL/min) to give example 29 (28 mg, yield: 44%). LC-MS (ESI), M/z: [ M+H)] ⁺ ＝431.2

Example 29A and example 29B:

(3R, 5R) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-ylbicyclo [1.1.1] pentan-1-ylcarbamate and (3S, 5S) -5- (3- (3- (methoxymethyl) -1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-ylbicyclo [1.1.1] pentan-1-ylcarbamate

Example 29 was resolved by chiral preparative HPLC (column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% isopropyl alcohol (0.2% ammonia; flow rate: 40 mL/min) to give example 29A (9.1 mg, yield: 65%) and example 29B (9.9 mg, yield: 71%).

Example 29A:

t _R ＝1.61min

LC-MS(ESI),m/z:[M+H] ⁺ ＝431.2

¹ H NMR(400MHz,DMSO-d ₆ )δ12.51(s,1H),10.79(s,1H),7.93(s,1H),7.13(s,1H),6.57(s,1H),5.16(dd,J＝6.8,3.4Hz,1H),4.87(s,1H),4.35(s,2H),4.06(s,3H),3.86(s,2H),3.28(s,3H),2.76–2.67(m,1H),2.36(s,1H),1.91(m,7H).

example 29B:

t _R ＝2.81min

LC-MS(ESI),m/z:[M+H] ⁺ ＝431.2

example 30: cis-5- (3- (1- (S) -methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl- (1- (S) -1-methyl-1-cyclopropylmethyl) carbamate

The synthetic route is as follows:

step 1: cis-N- (5- (4-hydroxytetrahydrofuran-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) -1-methyl-1H-pyrazole-5-carboxamide (30-2)

2-methylpyrazole-3-carboxylic acid (140 mg,1.11 mmol) and intermediate C (321 mg,1.11 mmol) were dissolved in dichloroethane, and triethylamine (337 mg,3.33 mmol) and 1-propylphosphoric anhydride (706 mg,2.22 mmol) were added to the stirred reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the mixture was extracted with methylene chloride, and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: methanol=92:8) to give compound 30-2 (170 mg, yield: 38%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝398.1

Step 2: cis-5- (1- (4-methoxybenzyl) -3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl- (4-nitrophenyl) carbonate (30-3)

To a suspension of compound 30-2 (160 mg,0.403 mmol) and 4-dimethylaminopyridine (4.0 mg,0.033 mmol) in dichloromethane (5 mL) was added pyridine (96 mg,1.2 mmol) and p-nitrophenyl chloroformate (162 mg,0.806 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was directly dried by spin-drying, and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=0 to 3:7) to give compound 30-3 (200 mg, yield: 88%). LC-MS (ESI), M/z: [ M+H ] ] ⁺ ＝563.0

Step three: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (30-4)

Compound 30-3 (200 mg,0.357 mmol) was dissolved in trifluoroacetic acid (3 mL) and the reaction mixture was stirred at 75deg.C for 16 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give compound 30-4 (120 mg, yield: 76%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝443.1

Step four: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (1- (S) -methylcyclobutyl) carbamate (example 30)

(1S) -1-cyclopropylethylamine (58 mg,0.68 mmol) was dissolved in tetrahydrofuran, and N, N-diisopropylethylamine (175 mg,1.36 mmol) was added. After stirring the reaction at room temperature for half an hour, compound 30-4 (60 mg,0.14 mmol) was added and stirring was continued for 16 hours. After the completion of the reaction, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give example 30 (15 mg, 29%) by purification of the residue by preparative HPLC. LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝389.1.

Example 30A and example 30B:

(3R, 5R) -5- (3- (1- (S) -methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuranyl-3-yl- (1- (S) -1-methyl-1-cyclopropylmethyl) carbamate and (3S, 5S) -5- (3- (1- (S) -methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuranyl-3-yl- (1- (S) -1-methyl-1-cyclopropylmethyl) carbamate

Example 30 SFC (column: CHIRALPAK-AD; mobile phase: carbon dioxide/isopropanol (formic acid); flow rate: 1.8 mL/min) was resolved to give example 30A (5.0 mg, yield: 67%) and example 30B (4.9 mg, yield: 65%).

Example 30A:

t _R ＝11.61min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝389.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.53(s,1H),10.81(s,1H),7.50(s,1H),7.17(d,J＝13.8Hz,2H),6.56(s,1H),5.16(s,1H),4.84(s,1H),4.09(s,3H),3.86(s,2H),3.03–2.94(m,1H),2.74–2.66(m,1H),1.97(s,1H),1.10(d,J＝6.6Hz,3H),0.86–0.79(m,1H),0.41–0.29(m,2H),0.28–0.21(m,1H),0.14–0.06(m,1H).

example 30B:

t _R ＝14.13min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝389.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.52(s,1H),10.81(s,1H),7.49(d,J＝1.8Hz,1H),7.17(d,J＝11.3Hz,2H),6.58(s,1H),5.16(s,1H),4.85(s,1H),4.09(s,3H),3.86(s,2H),3.03–2.94(m,1H),2.75–2.66(m,1H),2.01–1.91(m,1H),1.10(d,J＝6.6Hz,3H),0.87–0.77(m,1H),0.41–0.28(m,2H),0.28–0.21(m,1H),0.14–0.06(m,1H).

example 31: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofurane-3-yl- (1-methylcyclobutyl) carbamate

The synthetic route is as follows:

1-methylcyclobutane-1-amine (115 mg,1.36 mmol) was dissolved in tetrahydrofuran, and N, N-diisopropylethylamine (263 mg,2.03 mmol) was added. After stirring the reaction at room temperature for half an hour, compound 12-4 (60 mg,0.14 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction system and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to the compound example 31 (10 mg, 19%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝389.1.

Example 31A and example 31B:

(3R, 5R) -5- (3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuranyl-3-yl- (1-methylcyclobutyl) carbamate and (3S, 5S) -5- (3- (1-methyl-1H-pyrazole-5-carboxamido) -1H-pyrazol-5-yl) tetrahydrofuranyl- (1-methylcyclobutyl) carbamate

Example 31 SFC (column: CHIRALPAK-AD; mobile phase: carbon dioxide/isopropanol (diethylamine); flow rate: 0.8 mL/min) was resolved to give example 31A (3.5 mg, yield: 70%) and example 31B (3.5 mg, yield: 70%).

Example 31A:

t _R ＝3.44min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝389.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.52(s,1H),10.81(s,1H),7.49(s,1H),7.34(s,1H),7.16(s,1H),6.59(s,1H),5.16(s,1H),4.86(s,1H),4.09(s,3H),3.85(s,2H),2.74–2.65(m,1H),2.27–2.18(m,2H),1.95(s,1H),1.85–1.77(m,2H),1.75–1.67(m,2H),1.32(s,3H).

example 31B:

t _R ＝14.65min.

LC-MS(ESI),m/z:[M+H] ⁺ ＝389.1

¹ H NMR(400MHz,DMSO-d ₆ )δ12.52(s,1H),10.81(s,1H),7.49(s,1H),7.34(s,1H),7.16(s,1H),6.59(s,1H),5.16(s,1H),4.85(s,1H),4.09(s,3H),3.86(s,2H),2.74–2.65(m,1H),2.28–2.17(m,2H),1.95(s,1H),1.85–1.76(m,2H),1.75–1.65(m,2H),1.32(s,3H).

example 32: cis (3-methyl-1H-pyrazole-5-carboxamide-3, 4-dideuterio) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1: 1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (32-2)

The compound 1H-pyrazole-5-carboxylic acid ethyl ester (1.1 g,7.9 mmol) was dissolved in N, N-dimethylformamide (10 mL) at room temperature. To the reaction were added potassium carbonate (2.1 g,16 mmol) and methyl iodide (1.4 g,9.4 mmol) and the reaction mixture was stirred at room temperature for 12 hours. After completion of the liquid quality test reaction, water (30 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 32-2 (560 mg, yield: 46%). LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝155.1

Step 2:3, 4-diiodo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (32-3)

Compound 32-2 (500 mg,3.24 mmol) was dissolved in carbon tetrachloride (8 mL) at room temperature. Iodine (1.65 g,6.48 mmol), iodic acid (570 mg,3.24 mmol), acetic acid (19 mg,0.32 mmol) and sulfuric acid (106 mg,0.32 mmol) were added to the reaction, and the reaction mixture was stirred at 80℃for 2 hours. After completion of the reaction, water (30 mL) was added to the reaction system to dilute, and the mixture was extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were washed with saturated brine (10 mL) and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 32-3 (1.3 g, yield: 98%). LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝406.8

Step 3: 1-methylpyrazole-3, 4-dideuterium-5-carboxylic acid (32-4)

Compound 32-3 (300 mg,0.739 mmol) was dissolved in an aqueous solution of deuterated sodium hydroxide (99.5% deuterated) in deuterium (40% strength, 5 mL) at room temperature, zinc powder (4.7 mg,0.073 mmol) was added, and the mixture was stirred at 80℃for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude compound 32-4 (80 mg).

¹ H NMR(400MHz,CDCl ₃ )δ4.21(s,3H).

Step 4: cis-N- (5-hydroxytetrahydrofuran-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) -1-methyl-1H-pyrazole-3, 4-dideuterium-5-carboxamide (32-5)

N, N-diisopropylethylamine (181 mg,1.40 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (53 mg,1.40 mmol) were added to a solution of compound 32-4 (80 mg,0.70 mmol) in N, N-dimethylformamide (5 mL) at room temperature under nitrogen, and after stirring the reaction solution at room temperature for 0.5 hour, cis-5- (3-amino-1- (4-methoxybenzyl) -1H-pyrazol-5-yl) tetrahydrofuran-3-ol (intermediate C,203mg,0.702 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the liquid quality test, water (15 mL) was added to the reaction system and the mixture was diluted, and the mixture was extracted with methylene chloride (10 mL. Times.3), and the combined organic phases were washed with saturated brine (10 mL) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 32-5 (120 mg, yield: 43%). LC-MS (ESI) M/z: [ M+H ] ] ⁺ ＝400.0

Step 5: cis-5- (1- (4-methoxybenzyl) -3- (1-methyl-1H-pyrazole-5-carboxamide-3, 4-dideuterio) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl- (4-nitrophenyl) carbonate (32-6)

Compound 32-5 (120 mg,0.30 mmol), pyridine (72 mg,0.65 mmol), p-nitrophenyl chloroformate (74 mg,0.39 mmol) and 4-dimethylaminopyridine (4.0 mg,0.033 mmol) were dissolved in dichloromethane (10 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 5 hours. After completion of the liquid monitoring reaction, water (10 mL) was added for dilution, and extracted with dichloromethane (10 ml×3), and the combined organic phases were washed with saturated brine (10 mL), concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=2:1) to give compound 32-6 (150 mg, yield: 89%). LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝565.0

Step 6: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamide-3, 4-dideutero) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (32-7)

Compound 32-6 (150 mg,0.266 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature, stirred at 90℃for 2 hours, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude compound 32-7 (100 mg). LC-MS (ESI) M/z: [ M+H ] ] ⁺ ＝445.0

Step 7: cis-5- (3- (1-methyl-1H-pyrazole-5-carboxamide-3, 4-dideuterium) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 32)

To a tetrahydrofuran solution (5 mL) of compound 32-7 (100 mg,0.225 mmol) was added N, N-diisopropylethylamine (60 mg,0.47 mmol) and tert-butylamine (82.3 mg,1.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with dichloromethane (5 ml×3), washed with saturated brine (5 mL), and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: gemini-C18X 21.2mm,5 μm; mobile phase: 10-95% acetonitrile-water (0.1% formic acid; flow rate: 20 mL/min) to give example 32 (30 mg, yield: 34%). LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝379.1.

Example 32A and example 32B:

(3R, 5R) - (3-methyl-1H-pyrazole-5-carboxamide-3, 4-dideuterium) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl-tert-butylcarbamate and (3S, 5S) - (3-methyl-1H-pyrazole-5-carboxamide-3, 4-dideuterium) -1H-pyrazol-5-yl-tetrahydrofuran-3-yl-tert-butylcarbamate

Example 32 (30 mg,0.079 mmol) was resolved by chiral SFC (column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% ethanol (0.2%) ammonia; flow rate: 40 g/min) to give example 32A (9.4 mg, yield: 31%) and example 32B (10 mg, yield: 33%).

Example 32A:

t _R ＝2.7min

LC-MS(ESI),m/z:[M+H] ⁺ ＝379.1

¹ H NMR(400MHz,MeOD)δ6.52(s,1H),5.10(s,1H),4.93(s,1H),4.06(s,3H),3.94(d,J＝10.2Hz,1H),3.87–3.81(m,1H),2.62(dt,J＝14.5,7.6Hz,1H),2.08–1.98(m,1H),1.18(s,9H).

example 32B:

t _R ＝6.1min

LC-MS(ESI),m/z:[M+H] ⁺ ＝379.1

¹ H NMR(400MHz,MeOD)δ6.64(s,1H),5.22(s,1H),5.05(s,1H),4.18(s,3H),4.06(d,J＝10.2Hz,1H),3.98–3.94(m,1H),2.74(dt,J＝14.5,7.6Hz,1H),2.19–2.11(m,1H),1.30(s,9H).

example 33: cis-5- (3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

The synthetic route is as follows:

step 1:1- (Trideuteromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester (33-2)

To a solution of ethyl 1H-pyrazole-5-carboxylate (2.00 g,14.3 mmol) in N, N-dimethylformamide (20 mL) was added deuterated iodomethane (4.15 g,28.6 mmol) and potassium carbonate (3.95 g,28.6 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and filtered. The filtrate was extracted with ethyl acetate (100 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=5:1) to give compound 33-2 (1.00 g, yield: 45%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝158.1

Step 2:1- (Trideuteromethyl) -1H-pyrazole-5-carboxylic acid (33-3)

To a mixed solution of tetrahydrofuran (5 mL) and water (5 mL) at room temperature was added compound 33-2 (500 mg,3.18 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, diluted hydrochloric acid (1 mol/L) was added to the system to adjust ph=5, and the acidified mixture was washed with ethyl acetate (20 ml×) 3) And (5) extracting. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 33-3 (0.36 g, yield: 87%). LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝130.1

Step 3: cis-N- (5- (4-hydroxytetrahydrofuran-2-yl) -1- (4-methoxybenzyl) -1H-pyrazol-3-yl) -1- (tridentate methyl) -1H-pyrazole-5-carboxamide (33-4)

To a solution of compound 33-3 (100 mg,0.769 mmol) in N, N-dimethylformamide (3 mL) was added 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (354 mg,0.931 mmol) under nitrogen at room temperature. After stirring the mixture at room temperature for 0.5 hours, N-diisopropylethylamine (301 mg,2.32 mmol) and intermediate C (224 mg,0.775 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 ml×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 33-4 (220 mg, yield: 70%).

LC-MS(ESI)m/z:[M+H] ⁺ ＝401.1

Step 4: cis-5- (1- (4-methoxybenzyl) -3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (33-5)

To a mixed solution of compound 33-4 (220 mg,0.549 mmol) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was added 4-nitrobenzoate (167 mg,0.829 mmol), pyridine (131 mg,1.65 mmol) and 4-dimethylaminopyridine (7 mg,0.06 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate=1:1) to give compound 33-5 (150 mg, yield: 50%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝566.1

Step 5: cis-5- (3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl (4-nitrophenyl) carbonate (33-6)

Compound 33-5 (150 mg,0.265 mmol) was dissolved in formic acid (3 mL) at room temperature and the reaction mixture was stirred at 85℃for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue obtained by the concentration was crude compound 33-6 (100 mg). The crude product was used directly in the next reaction. LC-MS (ESI) M/z: [ M+H ]] ⁺ ＝445.8

Step 6: cis-5- (3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate (example 33)

To a solution of compound 33-6 (100 mg,0.225 mmol) in tetrahydrofuran (3 mL) was added tert-butylamine (164 mg,2.25 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the residue obtained by the concentration was purified by preparative HPLC (column: gemini-C18X121.2mm, 5 μm; mobile phase: acetonitrile/water (0.1% trifluoroacetic acid); gradient: 30% -34%; flow rate: 20 mL/min), to give example 33 (50 mg, yield: 58%). LC-MS (ESI), M/z: [ M+H ]] ⁺ ＝380.2.

Example 33A and example 33B:

(3R, 5R) -5- (3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate and (3S, 5S) -5- (3- (1- (tridentate methyl) -1H-pyrazole-5-carboxamide) -1H-pyrazol-5-yl) tetrahydrofuran-3-yl tert-butylcarbamate

Example 33 (50 mg,0.13 mmol) was separated by chiral SFC chromatography (column: CHIRALPAK AD-H250 mm. Times.20 mm,5 μm; mobile phase: 40% isopropyl alcohol (0.2% ammonia); flow rate: 40 g/min) to give example 33A (24.1 mg, yield: 48%) and example 33B (22.8 mg, yield: 46%).

Example 33A:

t _R ＝2.38min

LC-MS(ESI)m/z:[M+H] ⁺ ＝380.1

¹ H NMR(400MHz,CD ₃ OD)δ7.53(d,J＝2.1Hz,1H),6.97(d,J＝2.1Hz,1H),6.60(d,J＝16.6Hz,1H),5.22(s,1H),5.03(t,J＝6.3Hz,1H),4.06(d,J＝10.2Hz,1H),3.98–3.94(m,1H),2.77–2.70(m,1H),2.16(dd,J＝6.1,5.0Hz,1H),1.30(s,9H).

example 33B:

t _R ＝5.39min

LC-MS(ESI)m/z:[M+H] ⁺ ＝380.1

¹ H NMR(400MHz,CD ₃ OD)δ7.53(d,J＝2.1Hz,1H),6.96(d,J＝2.1Hz,1H),6.58(d,J＝16.6Hz,1H),5.22(s,1H),5.03(t,J＝6.3Hz,1H),4.06(d,J＝10.2Hz,1H),3.98–3.94(m,1H),2.77–2.70(m,1H),2.16(dd,J＝6.1,5.0Hz,1H),1.30(s,9H).

biological evaluation

The following further description explains the invention in connection with testing, but these examples are not meant to limit the scope of the invention.

1. Enzyme activity assay

(one) CDK1/CDK2 enzyme Activity test

1. The purpose of the experiment is as follows:

the compounds of the invention CDK2/CycE1 and CDK1/CyclinB were tested for their enzymatic activity in vitro.

2. Laboratory instruments and reagents:

3. the experimental method comprises the following steps:

all compounds were initially prepared as 10mM stock in DMSO, then diluted to 50 x their final concentration in DMSO, and 10 μl of each DMSO dilution was transferred to a buffer containing 90 μl of 1 x kinase (50mM HEPES pH7.5,10mM MgCl ₂ 2mM DTT and 0.01% Brij-35) in one well of the new 96 Kong Jishu plate, followed by 10 minutes of mixing. mu.L of each compound dilution was then added to 384 well plates. mu.L of an enzyme solution containing CDK2/CycE1 or CDK1/cyclinB (final concentration 3 nM) was added to each well, and incubated at room temperature for 10 minutes after mixing. Then 10. Mu.L of peptide solution containing FAM-labeled peptide (final concentration of 3000nM FAM-P18 (5-FAM-QSPKG-CONH 2)), ATP (final concentration of 77. Mu.M or 20. Mu.M, respectively) in 1 Xkinase buffer was added to each well. All reactions were incubated at 20-30℃for 30 min, then quenched by the addition of 25. Mu.L of stop buffer (100mM HEPES pH7.5, 50mM EDTA,0.2%Coating Reagent#3 and 0.015% Brij-35).

4. The data processing method comprises the following steps:

after the reaction, the reaction mixture was subjected to detection with Caliper EZ Reader II, and the inhibition ratio was = [ (MA-X)/(MA-MI) ]X100%, where MA = DMSO control only value, MI = no enzyme control value, X = value at any particular compound dose. IC was then calculated using XLfit by plotting the dose-response curve ₅₀ Values.

5. Experimental results:

as can be seen from the above protocol, the compounds of the present invention show an IC of about 0.01nM to 10nM in CDK2/CycE1 enzymatic activity assay ₅₀ Inhibitory activity; the compounds of the invention show IC of about 1nM to 1000nM in CDK1/cyclinB enzymatic activity assay ₅₀ Inhibiting activity.

The selectivity multiple of the CDK2/CDK1 inhibitory activity of the compound disclosed by the embodiment of the invention is 2-1000 times; some example compounds have a selectivity multiple of 10 to 30; some example compounds have a selectivity multiple of 30 to 50; some example compounds have a selectivity factor of even greater than 50.

TABLE 1 inhibitory Activity and fold selectivity of Compounds of the invention against CDK2/CycE1 and CDK 1/CycinB

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In the above tables, "A", "B", "C", "D", "E" and "+", "++", "+++", "+++", "+++". Plus "+":

"A" means IC ₅₀ Less than or equal to 10nM; "B" means greater than 10nM < IC ₅₀ Less than or equal to 50nM; "C" means 50nM < IC ₅₀ Less than or equal to 250nM; "D" means 250nM < IC ₅₀ Less than or equal to 1000nM; "E" means IC ₅₀ ＞1000nM；

"+" indicates that 1 < N is less than or equal to 3; "++" indicates that N is more than 3 and less than or equal to 10; "+". ++'s representation of N is more than 10 and less than or equal to 30; "+". ++ + "means N is more than 30 and less than or equal to 50; "+ ++ + ++'s N > 50.

6. Conclusion of experiment:

the above data shows that the compounds of the present invention have good inhibitory activity against CDK2/CycE1 kinase and good selectivity for CDK2/CDK1 kinase inhibition.

(II) CDK4/CDK6/CDK7 enzyme Activity test

1. The purpose of the experiment is as follows:

compounds of the invention CDK4/CycD1, CDK6/cycD3 and CDK7/cycH/MAT1 were tested for enzymatic activity in vitro.

2. Laboratory instruments and reagents:

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3. the experimental method comprises the following steps:

the inhibition of CDK4/CycD1, CDK6/cycD3 and CDK7/cyclinH/MAT1 kinases by small molecule inhibitors is tested in this experiment by using fluorescence microfluidic Mobility detection technology (Mobility-Shift Assay). Kinase catalyzes ATP to remove a phosphate group to generate ADP, and transfers the phosphate group to a substrate peptide, wherein the substrate peptide is provided with a fluorescent label, the product is added with a phosphate group, the charge is changed, and during electrophoresis, the substrate and the phosphorylated product are separated due to different mobilities and are respectively detected, and the quantity of the substrate and the phosphorylated product is proportional to a fluorescent signal. And measuring the amount of the substrate and the product by using a Caliper instrument, and calculating the conversion rate of the product, thereby calculating the inhibition rate.

All compounds were formulated at 50-fold of initial concentration with 100% dmso and transferred to 50 μl to 384 well Echo plates; dilutions were made with 100% dmso as required by the customer, transferring 50 μl of 100% dmso into two empty wells as controls without compound and without enzyme. 400nL of compound was transferred to 384 well reaction plates using Echo 550. Transfer 10. Mu.L of the sample with 1-fold kinase buffer (50mM HEPES pH 7.5,10mM MgCl) ₂ 2mM DTT and 0.01%Brij-35) of CDK4/CycD1, CDK6/cycD 3and CDK7/cyclinH/MAT1 2-fold kinase solution into 384-well plates, negative control wells were added with 1-fold kinase buffer. Incubating for 10 minutes at room temperature after uniformly mixing; FAM-labeled polypeptide (final concentration of 3000nM FAM-P8 on CDK4/CycD1, final concentration of 3000nM FAM-P8 on CDK6/CycD3, final concentration of 3000nM FAM-CTD3 on CDK 7/CyinH/MAT 1), ATP (final concentrations of 672. Mu.M, 800. Mu.M and 70. Mu.M on CDK4/CycD1, CDK6/CycD 3and CDK 7/CyinH/MAT 1, respectively) was added to a 1-fold kinase buffer to form a 2-fold substrate solution; transferring 10 mu L of the 2-fold substrate solution to a 384-well plate reaction plate to initiate reaction; incubation was carried out at 28℃for 60 min, and 25. Mu.L of stop solution (100mM HEPES pH 7.5,50mM EDTA,0.2%Coating Reagent#3and 0.015%Brij-35) was added to the 384-well plate to stop the reaction.

4. The data processing method comprises the following steps:

the conversion data were read at CaliperEZ Reader II (downstream voltage: -500V, upstream voltage: -2250V, reference pressure: -0.5PSI, screening pressure: -1.2 PSI). Conversion was converted to inhibition data. Percent inhibition = [ (MA-X)/(MA-MI)]X 100%. "MI" is the control well reading for the reaction without enzyme; "MA" is a control well reading with DMSO addedThe method comprises the steps of carrying out a first treatment on the surface of the "X" is the compound's reading from different wells. Calculation of IC using XLFIT (Excel add-in version 5.4.0.8) fit in Excel software ₅₀ Values.

5. Experimental results:

from the above scheme, it was found that the compounds of the present invention inhibit kinase of CDK4/CycD1, CDK6/CycD3 and CDK7/cycH/MAT1 ₅₀ The values are shown in table 2.

TABLE 2 inhibitory Activity of the inventive Compounds against CDK4/CycD1, CDK6/CycD3 and CDK7/cycH/MAT1

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"NA" means untested.

6. Conclusion of experiment:

the above data shows that the compounds of the examples of the present invention have weak kinase inhibitory activity against CDK4/CycD1, CDK6/cycD3 and CDK7/cycH/MAT 1; the compounds of the embodiments of the invention have good selectivity for CDK2/CDK4, CDK2/CDK6 and CDK2/CDK7 kinase inhibition.

2. Cell Activity assay

1. The purpose of the experiment is as follows:

Compounds of the invention were tested for their proliferation inhibitory activity on OVCAR-3 cells.

2. Laboratory instrument and reagent

Enzyme-labeled instrument: TECAN Spark 10M (TECAN)

Name of the name	Source	Numbering device
			OVCAR-3	ATCC	HTB-161
FBS	Gibco	10099141
			RPMI1640	ATCC	302001
Penicillin/Streptomycin(100×)	Gibco	15140122
			Insulin from bovine pancreas	MNCGENE	CC101
celltiter-glo luminescent cell viability assay kit	Fisher scientific	G7573

3. Experimental method

OVCAR-3 culture conditions: RPMI1640,20% FBS,1% penicillin and streptomycin, 0.01mg/mL bovine insulin.

Day 0: cells were seeded in 96-well plates and cultured overnight with 120 μl of medium.

Day 1: the compound was dissolved in DMSO to a stock solution of 10 mM. The reference and test compounds were diluted to 200-fold final concentration in DMSO. Compounds in DMSO were 3-fold diluted in 96-well platesTo 8 different concentrations, test compounds were then diluted 40-fold with cell culture medium and 30 μl (5×) of compound solution was added to each well of cells. The cell plates were centrifuged at 1000rpm for 1 min, then at 37℃and 5% CO ₂ Cell plates were incubated for 7 days. 0.5% DMSO medium was used as a blank control and cells incubated with 0.5% DMSO medium solution were used as 100% controls.

Day 8: cell use

And (5) detecting the reagent.

4. And (3) data processing:

the inhibition ratio is calculated according to the following formula:

inhibition = 100-100 (compound drug treated reading-low control reading)/(high control reading-low control reading), IC was calculated according to the formula ₅₀ 。

5. Experimental results:

from the scheme, the IC with the proliferation inhibition of the OVCAR-3 cells by the compound of the embodiment of the invention ₅₀ As shown in table 3.

TABLE 3 proliferation inhibiting Activity of the inventive Compounds against OVCAR-3 cells

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6. Conclusion of experiment:

the data show that the compounds of the embodiments of the present invention have good inhibitory activity on OVCAR-3 cell proliferation.

3. Caco-2 cell permeability experiments

1. The purpose of the experiment is as follows:

the permeability of the compounds of the invention at the concentration administered was studied by means of a Caco-2 cell model.

2. Experimental instrument:

instrument name	Model number	Manufacturer(s)
			Centrifugal machine	Heraeus MULTIFUGE X3R	Thermo Fisher
Electronic analytical balance	DENVER TB-25	Danver instruments (Beijing) Limited
			Mass spectrometer	4000Q TRAP	AB SCIEX
High performance liquid chromatograph	LC-20AD	Shimadzu
			Automatic sample injector	RACK CHANGER II	Shimadzu

3. Experimental reagent:

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4. experimental method

The first step: caco-2 cells (ATCC) were cultured with DMEM medium supplemented with 10% FBS, 1% PS and 1% NEAA at 37℃with 5% CO ₂ Culturing in culture flask under the condition. The cells are grown and fused to 70 to 80 percent, the cells are digested by 0.25 percent EDTA-pancreatin, counted, diluted to 80,000 cells/hole by DMEM culture solution, the cells are inoculated in a Transwell-24 pore plate and placed in CO ₂ Culturing in incubator, discarding the culture medium every two to three days, adding fresh culture medium, and continuing at 37deg.C and 5% CO ₂ Culturing under the condition, and continuously culturing for 18-22 days.

And a second step of: the TC stock solution is diluted by 1000 times of transport buffer solution preheated to 37 ℃ and is uniformly mixed, and the solution is the compound administration solution with the administration concentration of 10 mu M. The cell culture broth was discarded, rinsed with transport buffer preheated to 37℃and for the transport study from the top membrane side to the substrate side (transport direction A. Fwdarw.B), 500. Mu.L of dosing solution containing the control compound or test compound was added to the A side and 1300. Mu.L of transport buffer was added to the B side. For the substrate side to top membrane side transport study (transport direction b→a), 500 μl of transport buffer was added to the a side and 1300 μl of dosing solution containing control or test compounds was added to the B side. The cell plates were incubated for 90min. After incubation, the sample is added with a volume of precipitant. Mix well with shaking 1min and centrifuge at 4000 rpm/min for 15min. Taking supernatant, redissolving, and detecting and analyzing by LC-MS/MS.

And a third step of: the integrity of the cell monolayer is assessed by measuring the transmembrane resistance (TEER) of the cell monolayer, requiring a transmembrane resistance of not less than 600Ohms per cell well.

Fourth step: detection of the concentration of test Compound TC and positive control naldolol, propranolol, P-gp substrate paclitaxel in samples by LC/MS/MS method

5. And (3) data processing:

the apparent permeability coefficient (Papp) of TC and positive compounds and the ratio of apparent permeability coefficients, efflux Ratio (ER), were calculated using the following formulas.

Outflow ratio (Efflux ratio) =papp _(B→A) /Papp _(A→B)

Note that: v is the volume of the receiving tank; a is the area of the transport membrane; c is the initial concentration of incubation;

is the medicine delivery quantity per unit time

6. Experimental results:

from the above protocol, the permeability test data of the compounds of the examples of the present invention are shown in Table 4:

TABLE 4 Table 4

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7. Conclusion of experiment:

the above data shows that the compounds of the examples of the present invention exhibit better permeability and lower efflux activity on the Caco-2 cell model.

4. Determination of metabolic stability

1. The purpose of the experiment is as follows:

test compounds for stability in hepatocytes.

Species of genus	Sex (sex)	Suppliers (suppliers)	Goods number
				Human liver cell	Male and female mixture	BioIVT	X008001

Viability of cryopreserved hepatocytes was determined using trypan blue and cell concentration was adjusted to 10 with buffer ⁶ Individual cells/mL. In a 24-well plate, 400. Mu.L of positive control/test compound solution (2. Mu.M compound in culture medium) was incubated with 400. Mu.L of hepatocytes (200 ten thousand cells per ml). At various time points (0, 15, 30, 60, 90 and 120 minutes), the reaction was stopped by adding 300. Mu.L of human Indoxyl Sulfate (IS) to 30. Mu.L of the reaction mixture and centrifuging at 4000rpm for 15 minutes at 4 ℃. 100. Mu.L of the supernatant was analyzed by LC-MS/MS. In vitro hepatocyte clearance is based on the elimination half-life (t _1/2 ) To estimate. The peak area ratio of each compound (test or control) to IS was calculated. Drug elimination rate constants k (min-1), t _1/2 (min) and in vitro intrinsic clearance CL _int (microliters/minute/million cells) is calculated according to the following equation:

k= -slope

t _1/2 ＝0.693/k

CL _int ＝(0.693/t _1/2 ) X (culture volume (. Mu.L)/cell count (million))

CL _in =in vitro CL _int X (liver weight (g)/body weight (Kg))X (number of cells (million)/liver weight (g))

CL _hepatic ＝(Q _hep ×F _u ×CL _int )/(Q _hep +F _u ×CL _int )

Extraction ratio=cl _hepatic /Q _hep

4. Experimental results:

the results of the test experiments of the compounds of the present invention in human liver stability are shown in the following Table 5:

TABLE 5

5. Conclusion of experiment:

the data show that the compound of the embodiment of the invention has better metabolic stability in human liver cell stability test experiments.

5. Pharmacokinetic studies

The purpose of the experiment is as follows: pharmacokinetic of test Compounds in beagle in vivo experiments

Experimental materials: beagle dog (Male, marshall Bio)

Experimental operation:

3 male beagle dogs, crospover. The beagle dogs were fasted at 17 pm 30 minutes prior to dosing and fed was resumed 4 hours after dosing. The first period of administration, single anterior cephalic vein injection of the compound to be tested, the administration dosage is 1mg/kg; after 7 days of elution, a second cycle was performed, and the test compound was orally administered at a single dose of 10mg/kg. The anterior cephalic intravenous group was given 5min,15min,30min,1h,2h,4h,8h,12h and 24h after the end of administration, and blood was taken through the jugular vein. The single oral groups were given 15min,30min,1h,2h,4h,8h,12h and 24h after the end of dosing before dosing, and blood was taken through the jugular vein. Blood was taken in EDTA-K2 anticoagulant tubes and 800. Mu.L of whole blood was taken at each time point. Immediately after blood sample collection, the sample is placed on wet ice and centrifuged. The sample will be centrifuged (set at 4 degrees for 10 minutes, 3000 rpm) within 30 minutes to obtain plasma. Plasma samples were placed in 2 tubes (target 150. Mu.L/tube) respectively. 50. Mu.L of plasma was taken and added to 5. Mu.L of MeOH/ACN solution containing 5ng/mL ISTD (Terfenadine), and after shaking and mixing uniformly, the mixture was centrifuged at 4000rpm for 15min, the supernatant was diluted 5-fold with MeOH/r water (1:1, v/v,0.1% FA), and the plasma concentration was quantitatively analyzed by an analytical method using LC-MS/MS sample injection, and drug substitution parameters such as peak reaching concentration, peak reaching time, clearance, half life, area under the drug time curve, bioavailability, etc. were calculated.

Experimental results:

from the above protocol, the pharmacokinetic data of the compounds of the examples of the present invention are shown in table 6:

TABLE 6

Conclusion of experiment:

the compounds of the invention have good pharmacokinetic parameters in dogs; in particular, example 12B, showed a 9-fold lower clearance, approximately 24-fold higher exposure and 1-fold higher bioavailability than the reference compound PF-07104091.

6. In vivo efficacy study

Purpose of experiment

The in vivo efficacy of the compounds on OVCAR-3 tumor mouse transplantation models was evaluated.

Animal and model

Animal information

Balb/c nude mice, 6-9 weeks, females, purchased from Jiangsu Ji Yikang Biotech Co. Mice were kept in a 12 hour light 12 hour dark environment. Mice were labeled with mouse ear tags prior to inoculation.

Cell information

Model	Accession ID	Tumor type
			OVCAR-3	CVCL_0465	Human ovarian cancer

Experimental operation

Cell culture

OVCAR-3 tumor cells were cultured in RPMI1640 medium containing 20% bovine serum and 10. Mu.l insulin. Placing the cells in an incubator at 37deg.C, CO ₂ The concentration was 5%. Cells were collected and counted as they grew into the log phase.

Cell seeding

Collection of 1X10 ⁷ OVCAR-3 cells were resuspended in 0.2 ml of a suspension of PBS and Matrigel (1:1) and inoculated in the right shoulder position on the right back of each mouse.

Grouping

When the average tumor volume of tumor-bearing mice reaches 150-200mm ³ At this time, mice were organically grouped and dosing was started.

Mice were observed for data acquisition

Following cell inoculation, mice were checked daily for morbidity and mortality. Tumors and mouse body weights were measured twice weekly.

Tumor volume was calculated according to the following formula:

tumor volume (mm) ³ ) =length (mm) x width (mm)/2.

The administration mode is as follows: the preparation is taken orally, and is taken twice daily for 28 days.

Animals were euthanized after the end of the experiment.

The data were processed with Excel et al software and the compound tumor inhibition rate TGI (%) was calculated.

TGI (%) = (1-drug treated mean tumor volume/control mean tumor volume) x100%

The test results are shown in the following table

Transplantation tumor pharmacodynamic parameters of the compounds of Table 7

Experimental results

The above results show that example 12B shows good tumor growth inhibition at a dose of 75mg/kg in the OVCAR-3 mouse engraftment tumor model; and, it showed a better tumor growth inhibitory effect than PF-07104091 at a dose of 175 mg/kg.

Claims

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

wherein ,

R is selected from hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, - (CH) ₂ ) _n OR _a 、-(CH ₂ ) _n SR _a 、-(CH ₂ ) _n NR _b R _a 、-(CH ₂ ) _n C(O)R _a 、-(CH ₂ ) _n C(O)NR _b R _a 、-(CH ₂ ) _n NR _b C(O)R _a 、-(CH ₂ ) _n S(O) _m R _a 、-(CH ₂ ) _n S(O) _m NR _b R _a 、-(CH ₂ ) _n S(O)(＝NR _b )R _a 、-(CH ₂ ) _n N＝S(＝O)R _a R _b Or- (CH) ₂ ) _n NR _b S(O) _m R _a The C is _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R _x selected from the group consisting of

Or R is _y ；

Ring A is selected from C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more of the aryloxy groups and 5-14 membered heteroaryloxy groupsSubstituted by substituents;

alternatively, any two R ₁ Together the atoms to which they are attached form C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl or 5-14 membered heteroaryl, said C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group;

R _y selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl or C _2-6 Alkynyl, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl and C _2-6 Alkynyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy and 5-14 membered heteroaryloxy groupsSubstituted;

or ,R_a and R_b And the atoms at which they are located together form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, said 3-12 membered heterocyclyl and 5-14 membered heteroaryl optionally being further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 memberedHeterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group; and is also provided with

x is an integer of 0 to 10;

n is an integer of 0 to 10;

m is 0, 1 or 2.

2. The compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from 3-10 membered nitrogen containing heterocyclyl, 5-10 membered nitrogen containing heteroaryl, -C (O) R _a or-C (O) NR _b R _a Said 3-10 membered nitrogen containing heterocyclyl and 5-10 membered nitrogen containing heteroaryl optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy group and the 5-10 membered heteroaryloxy group;

or ,R_a and R_b And the atoms at which they are located together form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said 3-8 membered heterocyclyl and 5-10 membered heteroaryl optionally being further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, C _3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C _6-14 One or more substituents in the aryloxy group and the 5-14 membered heteroaryloxy group.

3. The compound, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein formula (I) is further represented by formula (II):

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in1, a part of the material is described in the specification;

preferably, the general formula (I) is further represented by the general formula (II-A) and the general formula (II-B):

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as claimed in claim 1.

4. A compound according to any one of claims 1 to 3, a prodrug, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound meets one or more of the following conditions:

(1) Ring a is selected from 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic fused heterocyclyl or 8-10 membered bicyclic fused heteroaryl; preferably, the ring a is selected from pyrazolyl or pyrazolo 5-6 membered heteroaryl; more preferably, the ring a is selected from pyrazolyl, pyridinyl or pyrazolopyrimidinyl; for example, the number of the cells to be processed,

(2) L is a bond, -C (O) -or-C (O) CH ₂ -；

(3) The R is _a Selected from hydrogen or methyl; the R is _b Selected from methyl, ethyl, t-butyl, isobutyl, cyclopropyl, cyclobutyl or bicyclo [1.1.1]Pentanyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl and bicyclo [1.1.1]A pentylalkyl group optionally further substituted with one or more substituents of methyl, ethyl, cyclopropyl, isopropyl, or tert-butyl;

or ,R_a and R_b Together the atoms at which they are located form an azetidinyl or 7-azabicyclo [2.2.1 ]]Heptyl, said azetidinyl and 7-azabicyclo [2.2.1 ]Heptane, optionally further substituted with one or more methyl groups; preferably, the method comprises the steps of,

is->

For example->

Is->

(4)R ₁ Independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 Cycloalkyl, further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in cycloalkyl are substituted; preferably, R ₁ Independently selected from deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-8 Cycloalkyl, further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-8 One or more substituents in cycloalkyl are substituted; more preferably, R ₁ Independently select C _1-6 Alkyl, further C _1-6 Alkyl and C _1-6 One or more substituents in the alkoxy group.

5. The compound of any one of claims 1-4, a prodrug, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein formula (I) is further represented by formula (III):

wherein ：

R _x 、R _a and R_b The claims 1-4; preferably, the general formula (I) is further represented by the general formula (IV):

wherein ：

R ₁ 、R _a 、R _b and x is as defined in claims 1-4; more preferably, the general formulSup>A (I) is further represented by the general formulSup>A (IV-A) and the general formulSup>A (IV-B):

wherein ：

R ₁ 、R _a 、R _b And x is as defined in claims 1-4.

6. The compound, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R _a and R_b Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy or 5-to 10-membered heteroaryloxy, said amino, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy and 5-10 memberedHeteroaryloxy, optionally further substituted with hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Hydroxyalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy group and the 5-10 membered heteroaryloxy group;

7. The compound, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R _a Selected from hydrogen or methyl;

R _b selected from methyl, ethyl, isopropyl, t-butyl, isobutyl, cyclopropyl, cyclobutyl, or bicyclo [1.1.1]Pentanyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl and bicyclo [1.1.1]A pentylalkyl group optionally further substituted with one or more substituents of methyl, ethyl, isopropyl or tert-butyl;

or ,R_a and R_b Together the atoms at which they are located form an azetidinyl or 7-azabicyclo ring[2.2.1]Heptyl, said azetidinyl and 7-azabicyclo [2.2.1]Heptane, optionally further substituted with one or more methyl groups; preferably, the method comprises the steps of,

selected from->

8. The compound, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ₁ Independently selected from hydrogen, deuterium, cyano, amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Hydroxyalkyl, -CH ₂ OR _c 、-(CH ₂ ) ₂ OR _c 、-CH ₂ NR _d R _c 、-(CH ₂ ) ₂ NR _d R _c 、-O(CH ₂ ) ₂ NR _d R _c 、-CH ₂ S(O)(＝NR _d )R _c 、-S(O)(＝NR _d )R _c 、-N＝S(＝O)R _c R _d 、-CH ₂ N＝S(＝O)R _c R _d or-C (O) NR _d R _c The amino group, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy and C _1-3 Hydroxyalkyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy, 5-to 10-membered heteroarylOne or more substituents in the oxy group are substituted;

R _c and R_d Each independently selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy or 5-to 10-membered heteroaryloxy, said amino, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 Aryloxy and 5-to 10-membered heteroaryloxy, optionally further substituted with hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, oxo, thio, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Hydroxyalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, C _3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C _6-10 One or more substituents of the aryloxy and 5-to 10-membered heteroaryloxy groups are substituted, preferably R ₁ Independently selected from H, D, F, cl, -CN, -NH ₂ 、-OH、-CH ₃ 、-CF ₃ 、-CD ₃ 、-OCH ₃ 、-OCF ₃ 、-CH ₂ OCH ₃ 、-(CH ₂ ) ₂ OCH ₃ 、

9. The compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R is

L is-C (O) -, R _x Is selected from->

Or R is _y The method comprises the steps of carrying out a first treatment on the surface of the Ring A is selected from 5-14 membered heteroaryl, said 5-14 membered heteroaryl being substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in cycloalkyl are substituted; r is R ₁ Independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 Cycloalkyl, further substituted with deuterium, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy and C _3-12 One or more substituents in cycloalkyl are substituted; r is R _y Selected from C _1-6 Alkyl, said C _1-6 Alkyl is substituted with one or more substituents in a 5-14 membered heteroaryl; the 5-14 membered heteroaryl is further substituted with one or more C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Alkoxy substituted;

preferably, R is

-L-R _x Is->

10. The compound according to claim 1,A prodrug, stereoisomer or pharmaceutically acceptable salt thereof, characterized by, -L-R _x Is that

R is->

5-to 10-membered nitrogen containing heteroaryl or- (CH) ₂ ) _n C(O)NR _b R _a The method comprises the steps of carrying out a first treatment on the surface of the n is 0, R _a Is hydrogen, R _b Is quilt C _3-12 Cycloalkyl-substituted C _1-6 Alkyl, C _3-12 Cycloalkyl or quilt C _1-6 Alkyl substituted C _3-12 Cycloalkyl; or, together with the atoms to which they are attached, form an azetidinyl or 7-azabicyclo [2.2.1]Heptyl, said azetidinyl and 7-azabicyclo [2.2.1 ]Heptane, optionally further substituted with one or more methyl groups; the 5-to 10-membered nitrogen containing heteroaryl group is optionally further substituted with deuterium, halogen and C _1-3 One or more substituents in the alkyl group; preferably, -L-R _x Is->

R is

11. The compound, prodrug, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R is

Preferably, R is->

and/or-L-R _x Is that

/>

12. The compound of claim 1, a prodrug, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is not

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/>

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/>

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13. The compound of claim 1, a prodrug, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound satisfies one or more of the following conditions:

(1) In R, the C _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(2) In R, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F;

(3) In R, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl preferably being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(4) In R, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl groups such as ethenyl, propenyl, or butenyl;

(5) In R, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl, for example, ethynyl, propynyl or butynyl;

(6) In R, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]Pentanyl or cyclohexyl, also for example cyclopropyl, cyclobutyl or

(7) In R, the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 7 membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N);

(8) In R, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl;

(9) In R, the 5-14 membered heteroaryl groups are independently 5-6 membered heteroaryl groups (e.g., 6 membered), wherein the number of heteroatoms in the 5-6 membered heteroaryl groups independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N);

(10) In ring A, the C _3-12 Cycloalkyl radicals are C _3-6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(11) In ring A, the 3-12 membered heterocyclic group is C _3-8 A membered heterocyclic group; wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N);

(12) In ring A, the C _6-14 Aryl is C _6-10 Aryl groups such as phenyl or naphthyl;

(13) In ring a, the 5-14 membered heteroaryl is 5-10 membered heteroaryl, independently 5-10 membered heteroaryl (e.g., 6-, 5-, 9-membered), 5-10 membered heteroaryl is independently 5-6 membered heteroaryl or 5-and 6-membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl independently can be 1 or 2 (e.g., 2); wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N);

(14) In ring A, the C _1-6 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl, ethyl or propyl;

(15) In ring A, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F;

(16) In ring A, the C _1-6 Alkoxy is independently C _1-4 Alkoxy groups, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxyA group, a sec-butoxy group or a tert-butoxy group;

(17) In ring A, the C _1-6 Alkylthio groups are independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio;

(18) In ring A, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl preferably being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(19) In ring A, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl groups such as ethenyl, propenyl, or butenyl;

(20) In ring A, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl, for example, ethynyl, propynyl or butynyl;

(21) Ring R ₁ Wherein the halogen is independently F, cl, br or I, such as F;

(22) Ring R ₁ In the above, the C _1-6 Alkyl is independently C _1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl;

(23) Ring R ₁ In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F;

(24) Ring R ₁ In the above, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(25) Ring R ₁ In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl preferably being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(26) Ring R ₁ In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl groups such as ethenyl, propenyl, or butenyl;

(27) Ring R ₁ In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl, for example, ethynyl, propynyl or butynyl;

(28) Ring R ₁ In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]A pentyl or cyclohexyl group, such as also cyclopropyl;

(29) Ring R ₁ Wherein the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 7 membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N);

(30) Ring R ₁ In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl;

(31) Ring R ₁ Wherein the 5-14 membered heteroaryl is in the form of a 5-6 membered heteroaryl or a 5-6 membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl and the 5-6 membered heteroaryl independently can be 1 or 2; wherein the heteroatoms in the 5-6 membered heteroaryl and the 5-and 6-membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N);

(32) Ring R ₁ In the above, the C _3-12 Cycloalkyl oxy is independently C _3-6 Cycloalkyloxy, for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy, also for example cyclopropyloxy;

(33) Ring R _y In the above, the C _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(34) Ring R _y In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, C _1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I,such as F;

(35) Ring R _y In the above, the C _1-6 Alkoxy is independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio;

(36) Ring R _y In the above, the C _1-6 Alkylthio groups are independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(37) Ring R _y In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl preferably being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(38) Ring R _y In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl groups such as ethenyl, propenyl, or butenyl;

(39) Ring R _y In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl, for example, ethynyl, propynyl or butynyl;

(40) Ring R _y In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl and bicyclo [1.1.1]A pentyl or cyclohexyl group, such as also cyclopropyl;

(41) Ring R _y Wherein the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl; wherein the number of heteroatoms in the 3-8 membered heterocyclic group independently can be 1 or 2; wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O;

(42) Ring R _y In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl;

(43) Ring R _y Wherein the 5-14 membered heteroaryl is in the form of a 5-6 membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl independently can be 1 or 2; wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O;

(44)R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkyl is independently C _1-4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(45)R _a 、R _b 、R _c and R_d In the above, the C _1-6 Haloalkyl is independently C _1-4 Haloalkyl, said alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halo may be F, cl, br or I, such as F;

(46)R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkoxy is independently C _1-4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(47)R _a 、R _b 、R _c and R_d In the above, the C _1-6 Alkylthio groups are independently C _1-4 Alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio;

(48)R _a 、R _b 、R _c and R_d In the above, the C _1-6 Hydroxyalkyl is independently C _1-4 Hydroxyalkyl, said alkyl preferably being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(49)R _a 、R _b 、R _c and R_d In the above, the C _2-6 Alkenyl groups are independently C _2-4 Alkenyl groups such as ethenyl, propenyl, or butenyl;

(50)R _a 、R _b 、R _c and R_d In the above, the C _2-6 Alkynyl groups are independently C _2-4 Alkynyl, for example, ethynyl, propynyl or butynyl;

(51)R _a 、R _b 、R _c and R_d In the above, the C _3-12 Cycloalkyl is independently C _3-6 Cycloalkyl radicals, e.g. cyclopropyl, cycloButyl, cyclopentyl, bicyclo [1.1.1]A pentyl or cyclohexyl group, such as also cyclopropyl;

(52)R _a 、R _b 、R _c and R_d Wherein the 3-12 membered heterocyclyl is independently a 3-8 membered heterocyclyl (e.g., 4-membered, 7-membered); wherein the number of heteroatoms in the 3-8 membered heterocyclyl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 3-8 membered heterocyclyl may be independently selected from one or both of N and O (e.g., N);

(53)R _a 、R _b 、R _c and R_d In the above, the C _6-14 Aryl is independently C _6-10 Aryl groups such as phenyl or naphthyl;

and (54)R_a 、R _b 、R _c and R_d Wherein the 5-14 membered heteroaryl is independently a 5-6 membered heteroaryl (e.g., 6 membered), wherein the number of heteroatoms in the 5-6 membered heteroaryl independently can be 1 or 2 (e.g., 1); wherein the heteroatoms in the 5-6 membered heteroaryl groups can be independently selected from one or both of N and O (e.g., N).

14. The compound, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

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15. a process for preparing a compound of general formula (I), a prodrug or stereoisomer thereof, and a pharmaceutically acceptable salt thereof, as defined in claim 1, comprising the steps of:

Introducing R groups into the compound shown in the formula (Ia) and the formula (Ib) through single-step or multi-step nucleophilic substitution, coupling reaction, mitsunobu reaction and common organic reaction of esterification reaction to obtain a compound shown in the formula (Ic) or a stereoisomer and pharmaceutically acceptable salts thereof;

the compound shown in the formula (If) or stereoisomer thereof is obtained by common organic reaction of amidation reaction, nucleophilic substitution or coupling reaction of the formula (Id) and the formula (Ie);

wherein ：

X ₁ selected from but not limited to hydroxyl, halogen or triflate (OTf);

X ₂ selected from but not limited to hydroxyl, halogen or triflate (OTf);

R _1a is a protecting group on the pyrazole nitrogen selected from, but not limited to, t-butyl (t-Bu), tetrahydro-2H-pyran-2-yl (THP), (trimethylsilyl) ethoxymethyl (SEM);

L、R and R_x The method of any one of claims 1-14.

16. A process for preparing a compound of formula (II), a prodrug or stereoisomer thereof, and a pharmaceutically acceptable salt thereof, as defined in claim 3, comprising the steps of:

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in claims 1-14.

17. An intermediate compound represented by formula (IIa) or stereoisomers and salts thereof, having the specific structure:

wherein ：

ring A, L, R ₁ 、R _a 、R _b And x is as defined in claims 1-8;

preferably, the salt is a pharmaceutically acceptable salt;

more preferably, said formula (IIa) is selected from the following compounds:

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18. a process for preparing an intermediate compound of formula (IIa) as defined in claim 17 or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound shown in the formula (IIa-3) or stereoisomer and pharmaceutically acceptable salt thereof are obtained by common organic reaction of amidation reaction, nucleophilic substitution or coupling reaction of the formula (IIa-1) and the formula (IIa-2);

wherein ：

X ₃ selected from but not limited to hydroxyl, halogen or triflate (OTf);

ring A, L, R ₁ 、R _a 、R _b And x is as defined in claims 1-14.

19. An intermediate compound represented by the formula (IIa-1) or a stereoisomer thereof and a salt thereof, which has the following specific structure:

/>

wherein ：

R _1a is a protecting group on the pyrazole nitrogen selected from, but not limited to, t-butyl (t-Bu), tetrahydro-2H-pyran-2-yl(THP), (trimethylsilyl) ethoxymethyl (SEM), p-methoxybenzyl (PMB); the salt may be a pharmaceutically acceptable salt;

preferably, the formula (IIa-1) is selected from the following compounds:

20. A process for preparing an intermediate compound of formula (IIa-1) as defined in claim 19 or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the steps of:

wherein ：

X ₄ selected from, but not limited to, halogen, triflate (OTf) or hydroxy;

R _1a such as weightClaim 6.

21. A pharmaceutical composition comprising a therapeutically effective dose of a compound of any one of claims 1-14, a prodrug, stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

22. Use of a compound according to any one of claims 1 to 14, a prodrug, stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for the treatment of a disease mediated by CDK 2.

23. Use of a compound according to any one of claims 1 to 14, a prodrug, stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, in the manufacture of a medicament for the treatment of abnormal cell growth, preferably in the manufacture of a medicament for the treatment of cancer, more preferably the cancer is ovarian cancer.