Cyclic compound as well as preparation method and medical application thereof

Abstract

The invention relates to a cyclic compound as well as a preparation method and medical application thereof. Specifically, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound to inhibition of CDK2 enzyme activity, especially treatment of diseases related to CDK2 kinase activity. Wherein the definition of each group in the general formula (I) is the same as that in the specification.

Description

Technical Field

[0001] The present invention relates to a macrocyclic compound containing a heterocycle and use thereof in preventing and / or treating diseases related to CDK2 kinase activity. Background Art

[0002] Members of the cyclin-dependent kinase (CDK) family specifically bind to corresponding cyclins to form CDK-cyclin complexes, regulating the progression of the cell cycle, such as CDK1-cyclinB, CDK2-cyclinA, CDK2-cyclinE, CDK4-cyclinD, CDK6-cyclinD, etc. Currently, CDK4 / 6 inhibitors (Palbociclib, Ribociclib, and Abemaciclib) are used in combination with endocrine therapy for the first-line treatment of ER+HER2-type breast cancer, and have brought significant clinical benefits to this population. However, some patients still fail to respond to treatment (10-20%), and 70-80% of tumor patients will develop drug resistance after 12-36 months of treatment (Tripathy et al., Lancet Oncol, 2018: 19(7), 904-915). Factors contributing to resistance to CDK4 / 6 therapy include Rb loss, CCND1 overexpression, p16 amplification, and CCNE1 amplification-mediated CDK2 bypass activation (Pandey et al., Int J Cancer, 2019: 145(5), 1179-1188).

[0003] CDK2 is a key regulator of the cell cycle, remaining active from late G1 phase throughout S phase. CDK2 primarily regulates the transition from G1 to S phase and promotes S phase progression by binding to cyclin E and cyclin A, respectively, to form complexes. CDK2 has a classic kinase-like protein structure, folding into a "bilobate" shape. The smaller N-terminus is composed of five antiparallel β-strands and a C-helix. The C-helix contains the sequence PSTAIRE, which is required for cyclin binding. The larger C-terminal region is rich in α-helices and contains the activation segment T-loop (Asp145-Glu172) and the activation phosphorylation site Thr160. The T-loop binds to the Ser / Thr (phospho-receptor) region of the substrate, undergoing phosphorylation activation and exerting its cell cycle regulatory role. The N-terminus and C-terminus are connected by a flexible hinge region (Glu81-His84), which forms a deep cleft, the ATP binding site (Pavletich et al., J Mol Biol, 1999: 287(5), 821-828; Malumbres et al., Genome Biol, 2014: 15(6)). The activation and inhibition of CDK2 are regulated by the following mechanisms: in the absence of mitogen signals, CDK2 is in an inactive state; in the late G1 phase, CDK2 activity begins to increase; E2F mediates CCNE gene transcription, and its protein product binds to and activates CDK2; full activation of the CDK2-cyclin E or A complex requires CAK phosphorylation of the Thr160 site; Wee1 and Myt1 kinases can inhibit phosphorylation of Thr14 and Tyr15 sites, respectively, and dephosphorylation of these residues by the CDC25 protein phosphatase family can reactivate CDK2; in addition, the CDK inhibitory protein family Cip and Kip can bind to CDK2 and inactivate it, and CyclinE and CyclinA can be degraded by ubiquitin ligase-mediated ubiquitination (Tadesse et al., J Med Chem, 2019: 62(9), 4233-4251).

[0004] Dysregulation of CDK2 and its cell cycle protein partners has been observed in a range of tumor types. For example, Cyclin E1, encoded by CCNE1, is highly expressed in a variety of malignancies, and CCNE1 amplification or overexpression is associated with poor prognosis in a variety of tumors, including endometrial cancer, gastric cancer, and ovarian cancer (Au Yeung et al., Clin Cancer Res, 2017: 23(7), 1862-1874; Nakayama et al., Cancer, 2010: 116(11), 2621-2634; Ooi et al., Hum Pathol, 2017: 6158-67). Cyclin E1 amplification / overexpression-mediated CDK2 bypass activation is a common factor in the development of resistance to CDK4 / 6 inhibitors (Turner et al., J Clin Oncol, 2019: 37(14), 1169-1178; Herrera-Abreu et al., Cancer Res, 2016: 76(8), 2301-2313). In addition, studies have shown that tumor cells with CCNE1 amplification or overexpression are dependent on CDK2 activity for proliferation, suggesting that CDK2 may be an attractive therapeutic target for CCNE1 amplified tumors (Au Yeung et al., Clin Cancer Res, 2017: 23(7), 1862-1874; McDonald et al., Cell, 2017: 170(3), 577-592; Choi et al., AACR, 2021).

[0005] Early pan-CDK inhibitors lacked selectivity and were active against CDK2 while also inhibiting other CDKs. Clinical side effects manifested as severe blood and gastrointestinal toxicity, which may be related to the inhibition of CDK1 and CDK9 (Kumar et al., Blood, 2015: 125(3), 443-448; Otto et al., Nat Rev Cancer, 2017: 17(2), 93-115). CDK1 is essential for the normal development of cells, especially for highly proliferative intestinal and hematopoietic system cells (Lu et al., Toxicol Sci, 2020: 177(1), 226-234; Santamaria et al., Nature, 2007: 448(7155), 811-815; Jayapal et al., Haematologica, 2015: 100). Therefore, the subsequent development of selective CDK2 inhibitors needs to consider retaining the activity of CDK1 / 9 to reduce drug toxicity.

[0006] In order to achieve better cancer treatment effects and better meet clinical needs, it is still necessary to develop CDK inhibitors with excellent selectivity, especially selective CDK2 inhibitors. Summary of the Invention

[0007] After intensive research, the present inventors have designed and synthesized a series of novel compounds, which can be used to prevent and / or treat diseases associated with CDK2 kinase activity.

[0008] Therefore, an object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in:

[0011] Ring A is selected from heteroaryl, aryl, heterocyclyl or cycloalkyl;

[0012] X is selected from -C(O)-, -S(O)-, -S(O)2-;

[0013] U is: -L 1 -L 2 -L 3 -;

[0014] in:

[0015] L 1 , L 2 , L 3 Each is independently selected from a single bond, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a -NR c -, -O-, -S-, -NHC(O)-, -C(O)NH-, -NHS(O) p -、-S(O) p NH-、-(CR d R e ) m O-、-(CR d R e ) m NH-、-(CR d R e ) m NHC(O)-、-(CR d R e ) m C(O)NH-、-O(CR d R e ) m -、-NH(CR d R e ) m -、-NHC(O)-(CR d R e ) m-、-C(O)NH(CR d R e ) m -, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, provided that L 1 , L 2 , L 3 Not all are single bonds;

[0016] R 1 is selected from hydrogen and alkyl;

[0017] R 2 is selected from hydrogen and alkyl;

[0018] Each R 3 Each is independently selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR d R e ) v OR c 、-OR c 、-C(O)R c 、-OC(O)R c 、-C(O)OR c 、-C(O)NR a R b 、-NHC(O)R c 、-S(O) p R c 、-S(O) p NR a R b 、-NHS(O) p R c wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0019] Two adjacent R 3The atoms to which it is attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] R a and R b each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0021] R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0022] R c selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0023] R d and R e each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or

[0024] Rd and R e Together with the nitrogen atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0025] p is 1 or 2;

[0026] n is an integer from 0 to 3;

[0027] m is an integer from 1 to 10;

[0028] v is an integer from 1 to 6.

[0029] In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0030]

[0031] Among them: Ring A, U, R 1 、R 2 、R 3 , n are as defined in the general formula (I).

[0032] In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is a 5-10 membered heteroaryl or C6-C 10 Aryl.

[0033] In another preferred embodiment, according to the compound represented by general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from 5-6 membered heteroaryl or phenyl, preferably pyrazolyl, pyridyl, imidazolyl, pyrrolyl, thiazolyl or phenyl.

[0034] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IVA) or (IVB), or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0035]

[0036] in,

[0037] Z1 is selected from CH or N;

[0038] Z2 is selected from CH or N;

[0039] R 1 、R 2 、R 3 , L 1 , L 2 , L 3 , n are as defined in the general formula (I).

[0040] In another preferred embodiment, the compound represented by the general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R 3 Each independently selected from halogen, cyano, C 1-6 Alkyl, -(CR d R e ) v OR c , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from halogen;

[0041] R d and R e are each independently selected from hydrogen and C 1-6 alkyl;

[0042] R c Selected from C 1-6 alkyl;

[0043] v is an integer from 1 to 4, preferably 1 or 2; more preferably 1;

[0044] n is 0 or 1.

[0045] In another preferred embodiment, the compound represented by the general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein -L 1 -L 2 -L 3 -Selected from C 1-10 Alkylene, preferably C 4-10 Alkylene.

[0046] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0047] L 1 Selected from single bond, C 1-6 Alkylene, -NR c -、-O-、-S-、-(CR d R e ) m O-、-(CR d R e ) m NH-、-NH(CR d R e ) m -、-(CR d R e ) m NHC(O)-、-(CR d R e ) m C(O)NH-, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl, C 3-6 One or more groups are substituted on the cycloalkyl group;

[0048] L 2 Selected from C 1-6 Alkylene, -O-, -S-, -NHC(O)-, -C(O)NH-, -(CR d R e ) m O-、-O(CR d R e ) m -、C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl, C 3-6 One or more groups of the cycloalkyl group are substituted;

[0049] L 3 Selected from single bond, C 1-6 Alkylene, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group, wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group may be further selected from halogen, C 1-6 Alkyl, C 3-6 One or more groups of the cycloalkyl group are substituted;

[0050] R c Selected from hydrogen or C 1-6 alkyl;

[0051] R d and R e Each independently selected from hydrogen or C 1-6 alkyl;

[0052] m is an integer of 1 to 6.

[0053] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0054] L 1 Selected from -O-;

[0055] L 2 Selected from C 1-6 Alkylene, wherein the C 1-6 The alkylene group is optionally replaced by C 1-6 Alkyl substitution;

[0056] L 3 Selected from single bond, C 1-6 Alkylene, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl substitution.

[0057] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0058] L 1 Selected from-NR c -;

[0059] L 2 Selected from C 1-6Alkylene, -(CR d R e ) m O-;

[0060] L 3 Selected from C 1-6 Alkylene, C 3-6 Cycloalkyl, wherein the C 1-6 The alkylene group is optionally replaced by C 1-6 Alkyl substitution;

[0061] R c Selected from hydrogen or C 1-6 alkyl;

[0062] R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen;

[0063] m is an integer of 1 to 6.

[0064] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0065] L 1 Selected from -NH(CR d R e ) m -;

[0066] L 2 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably C 3-6 Cycloalkyl;

[0067] L 3 Selected from C 1-6 alkylene;

[0068] R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen;

[0069] m is an integer of 1 to 6.

[0070] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0071] L 1Selected from -(CR d R e ) m NHC(O)-;

[0072] L 2 Selected from C 1-6 Alkylene, -O-, -(CR d R e ) m O-;

[0073] L 3 Selected from C 1-6 alkylene;

[0074] R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen;

[0075] m is an integer of 1 to 6, preferably an integer of 1 to 4, more preferably 1 or 2.

[0076] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0077] L 1 Selected from-NR c -;

[0078] L 2 Selected from C 1-6 alkylene;

[0079] L 3 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably 5-6 membered heterocyclic group.

[0080] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0081] L 1 Selected from -NH(CR d R e ) m -;

[0082] L 2 Selected from -O(CR d R e ) m -;

[0083] L 3 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably C 3-6 Cycloalkyl;

[0084] R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen.

[0085] In another preferred embodiment, the compound represented by general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0086] L 1 Selected from C 1-6 Alkylene, preferably C 1-4 alkylene;

[0087] L 2 is selected from 5-6 membered heterocyclic groups;

[0088] L 3 Selected from C 3-6 Cycloalkyl.

[0089] In another preferred embodiment, the compound represented by the general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen and C 1-6 alkyl.

[0090] In another preferred embodiment, the compound represented by the general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen and C 1-6 alkyl.

[0091] In another preferred embodiment, the compound represented by the general formula (I), (II), (IVA), (IVB) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein m is an integer from 1 to 4, for example, 1, 2, 3, 4.

[0092] Typical compounds of the present invention include, but are not limited to:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] or its tautomers, meso racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts.

[0103] The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0104]

[0105] Compound Ig is heated in an acidic solvent to react and remove the protecting group to obtain a compound of formula (I), wherein the acidic solvent is preferably formic acid or trifluoroacetic acid;

[0106] Among them, X, ring A, U, R 1 、R 2 、R 3 , n are as defined in the general formula (I).

[0107] The present invention further provides a pharmaceutical composition comprising a compound represented by the general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0108] The present invention further provides the use of the compounds represented by the general formula (I), (II), (IVA), (IVB) according to the present invention, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same, in the preparation of medicaments for preventing and / or treating diseases associated with CDK2 kinase activity.

[0109] The present invention further provides the use of the compounds represented by the general formula (I), (II), (IVA), (IVB) according to the present invention, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same, in the preparation of drugs for preventing and / or treating diseases related to protein-dependent kinase or cyclin signaling pathways, wherein the diseases are preferably cancer-related diseases such as endometrial cancer, ovarian cancer, breast cancer, primary peritoneal cancer, gastric cancer, and lung cancer.

[0110] Another aspect of the present invention provides a compound represented by the general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used as a selective CDK2 inhibitor.

[0111] Another aspect of the present invention provides a compound represented by the general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use as a drug; preferably, the drug is used to prevent and / or treat diseases related to protein-dependent kinase or cyclin signaling pathways.

[0112] Another aspect of the present invention provides a compound represented by the general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use in preventing and / or treating diseases associated with CDK2 kinase activity.

[0113] Another aspect of the present invention provides a compound represented by the general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for preventing and / or treating diseases related to protein-dependent kinase or cyclin signaling pathways, preferably cancer-related diseases such as endometrial cancer, ovarian cancer, breast cancer, primary peritoneal cancer, gastric cancer, and lung cancer.

[0114] A method for preventing and / or treating diseases associated with protein-dependent kinase or cyclin signaling pathways, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound represented by general formula (I), (II), (IVA), or (IVB) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The disease is preferably a cancer-related disease such as endometrial cancer, ovarian cancer, breast cancer, primary peritoneal cancer, gastric cancer, or lung cancer.

[0115] A method for preventing and / or treating diseases associated with CDK2 kinase activity, comprising administering to a patient in need thereof a preventively or therapeutically effective amount of a compound represented by general formula (I), (II), (IVA), or (IVB) according to the present invention, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0116] A method for selectively inhibiting CDK2, comprising administering to a subject in need thereof an effective inhibitory amount of a compound represented by general formula (I), (II), (IVA), or (IVB) according to the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0117] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0118] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0119] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0120] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavorings can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0121] Dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient by adding water and a dispersant or wetting agent for mixing, a suspending agent, or one or more preservatives. Suitable dispersants, wetting agents, and suspending agents are described above. Other excipients such as sweeteners, flavorings, and coloring agents may also be added. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0122] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0123] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0124] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants, wetting agents, and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0125] The pharmaceutical compositions of the present invention may be in the form of topical administration, such as creams, suspensions, emulsions, ointments, gels, drops, oils, lotions, films, patches, tapes, inhalants, and sprays. Intraocular administration may be in the form of subconjunctival or subfascial capsules; retrobulbar or intravitreal injections, depot injections, or implants. Compounds administered by these routes may be in the form of solutions or suspensions. Compounds administered by depot injection may contain pharmaceutically acceptable carriers or excipients. These pharmaceutically acceptable carriers or excipients may be natural or synthetic, and may be biodegradable or non-biodegradable, and promote controlled drug release. Implants for controlled release of compounds may be composed of natural or synthetic, biodegradable or non-biodegradable materials. Carriers are acceptable because they are compatible with the other components of the composition and are not harmful to the patient. Some examples of carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose; and cyclodextrins.

[0126] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment protocols.

[0127] The present invention can contain the compound shown in general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as active ingredient, mixed with pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivative of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compound of the present invention can be used as the sole active ingredient or in combination with other therapeutic agents. Combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0128] Terminology

[0129] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0130] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0131] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is 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, carboxyl or carboxylate.

[0132] The term "alkylene" refers to a divalent alkyl group of straight and branched chains, and alkyl is as defined above. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene. Alkylene can be substituted or unsubstituted. When substituted, the substituent can be substituted on any available point of attachment, and the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate. When the number of substituents in the alkylene is greater than or equal to 2, the substituents can be linked together to form a ring structure.

[0133] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is 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.

[0134] The term "alkenylene" refers to straight and branched divalent alkenyl groups, wherein alkenyl is as defined above.

[0135] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0136] The term "alkynylene" refers to straight and branched divalent alkynyl groups, wherein alkynyl is as defined above.

[0137] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0138] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0139] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0140]

[0141] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-12 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0142]

[0143] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0144] The term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 10 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0145] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 5 to 12 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0146]

[0147] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0148] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 5 to 12-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0149]

[0150] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

[0151] The heterocyclyl group may be optionally substituted or unsubstituted. 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.

[0152] The term "aryl" or "aromatic ring" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0153]

[0154] The aryl group may be substituted or unsubstituted. 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.

[0155] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0156] The heteroaryl group 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.

[0157] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0158] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0159] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0160] The term "hydroxy" refers to an -OH group.

[0161] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0162] The term "amino" refers to -NH2.

[0163] The term "cyano" refers to -CN.

[0164] The term "nitro" refers to -NO2.

[0165] The term "oxo" or "oxo" refers to =0.

[0166] The term "carboxy" refers to -C(O)OH.

[0167] The term "mercapto" refers to -SH.

[0168] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0169] The term "acyl" refers to a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0170] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0171] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0172] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0173] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0174] "Carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. DETAILED DESCRIPTION

[0175] The compounds of the present invention and their preparation will be further understood by way of the examples, which illustrate some methods of preparing or using the compounds. However, it will be appreciated that these examples do not limit the scope of the present invention. Variations of the present invention as now known or further developed are considered to fall within the scope of the invention as described herein and as claimed.

[0176] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0177] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0178] The separation and purification of compounds and intermediates can be carried out using appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize them.

[0179] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Brukerdps 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0180] Mass spectra were measured using LC (Waters 2695) / MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).

[0181] The preparative liquid chromatography method used an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).

[0182] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.20 mm to 0.25 mm, and the specification used in preparative thin layer chromatography (Prep-TLC) to separate and purify the product was 0.5 mm.

[0183] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0184] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, etc.

[0185] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0186] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0187] The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0188] The chemical reactions described herein are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0189] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0190] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0191] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0192] Example

[0193] Preparation Example 1: Preparation of 1-(tert-butyl)-5-((rac,cis)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-3-amine (INT-1)

[0194]

[0195] Step 1: Preparation of methyl 3,3-dimethoxycyclopentane-1-carboxylate (INT-1a)

[0196] 3-Oxocyclopentane-1-carboxylic acid (10.0 g, 78.1 mmol), p-toluenesulfonic acid (269 mg, 1.56 mmol), and trimethyl orthoformate (49.7 g, 469 mmol) were dissolved in methanol (300 mL) at room temperature and stirred at room temperature for 16 hours. The reaction mixture was quenched by adding 400 mL of saturated sodium bicarbonate solution and concentrated in vacuo to remove the methanol. The mixture was then extracted with 1000 mL of ethyl acetate, and the aqueous phase was extracted once more with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1) to obtain 11.0 g of the title product as a yellow oily liquid in a yield of 75.0%.

[0197] Step 2: Preparation of 3-(3,3-dimethoxycyclopentyl)-3-oxopropionitrile (INT-1b)

[0198] Anhydrous acetonitrile (4.80 g, 117 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) at room temperature and cooled to -65°C. Under a nitrogen atmosphere, n-butyllithium (2.5 M) (117 mL, 117 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was allowed to react at -65°C for 1 h. Methyl 3,3-dimethoxycyclopentane-1-carboxylate (11.0 g, 58.5 mmol) was slowly added, and the mixture was stirred at -65°C for 1 h. The reaction mixture was quenched with methanol, and a saturated solution of NH4Cl was added to adjust the pH to ~7. The mixture was extracted with 1000 mL of ethyl acetate, and the aqueous phase was extracted once more with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 6.00 g of the title product as a yellow solid in a 54.5% yield.

[0199] Step 3: Preparation of 1-(tert-butyl)-5-(3,3-dimethoxycyclopentyl)-1H-pyrazol-3-amine (INT-1c)

[0200] Dissolve sodium hydroxide (1.46 g, 36.5 mmol) and tert-butylhydrazine hydrochloride (4.53 g, 36.5 mmol) in ethanol (200 mL) at room temperature and stir for 1 hour. Add 3-(3,3-dimethoxycyclopentyl)-3-oxopropionitrile (6.00 g, 18.3 mmol) and stir at 75°C for 16 hours. Filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 3.00 g of the title product as a white solid, in a yield of 62.5%.

[0201] Step 4: Preparation of benzyl (1-(tert-butyl)-5-(3,3-dimethoxycyclopentyl)-1H-pyrazol-3-yl)carbamate (INT-1d)

[0202] Dissolve 1-(tert-Butyl)-5-(3,3-dimethoxycyclopentyl)-1H-pyrazol-3-amine (3.00 g, 11.2 mmol) in acetonitrile (50 mL). Add benzyl chloroformate (3.84 g, 22.5 mmol) at 0°C and stir at room temperature for 2 hours. Add NaHCO₃ (3.02 g, 36.0 mmol) and stir at room temperature for 16 hours. The reaction mixture is concentrated directly, and the residue is purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:2) to obtain 3.00 g of the title product as a yellow oil in a yield of 67.8%.

[0203] Step 5: Preparation of benzyl (1-(tert-butyl)-5-(3-oxocyclopentyl)-1H-pyrazol-3-yl)carbamate (INT-1e)

[0204] Benzyl (1-(tert-butyl)-5-(3,3-dimethoxycyclopentyl)-1H-pyrazol-3-yl)carbamate (3.00 g, 7.48 mmol) was dissolved in acetone (20 mL) and water (20 mL) at room temperature. p-Toluenesulfonic acid (167 mg, 0.973 mmol) was added and stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the acetone and extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted once with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:2) to obtain 2.20 g of the title product as a yellow oil in an 83.7% yield.

[0205] Step 6: Preparation of benzyl (1-(tert-butyl)-5-((rac,cis)-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamate (INT-1f)

[0206] Benzyl (1-(tert-butyl)-5-(3-oxocyclopentyl)-1H-pyrazol-3-yl)carbamate (2.20 g, 6.20 mmol) was dissolved in THF (300 mL) at room temperature. Under a nitrogen atmosphere, the temperature was lowered to -65°C, and lithium triethylborohydride (1.28 g, 12.4 mmol) was added dropwise. The mixture was stirred at -65°C for 1.5 hours. The temperature was raised to -10°C to 0°C, and sodium bicarbonate solution was added to adjust the pH to 8. H₂O₂ (30 mL) was added at 10°C, and the mixture was stirred for 1 hour. The mixture was then quenched by adding 100 mL of saturated aqueous Na₂SO₃. The mixture was extracted with 300 mL of ethyl acetate, and the aqueous phase was extracted once more with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane:ethyl acetate = 1:1) to obtain 1.50 g of the title product as a yellow oily liquid.

[0207] Step 7: Preparation of benzyl (1-(tert-butyl)-5-((rac,cis)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (INT-1g)

[0208] At room temperature, compound 1f (30.0 g, 84.0 mmol) and imidazole (8.56 g, 126 mmol) were dissolved in DMF (100 mL). t-Butyldimethylsilyl chloride (16.4 g, 109 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used directly in the next reaction.

[0209] LCMS: m / z 472 [M+H] + .

[0210] Step 8: Preparation of 1-(tert-butyl)-5-((rac,cis)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-3-amine (INT-1)

[0211] At room temperature, compound INT-1g (40g) was dissolved in tetrahydrofuran (100mL), and palladium on carbon (10% wet) (8g) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, the mixture was filtered through celite and concentrated to obtain 29g of a yellow oily liquid.

[0212] LCMS: m / z 338 [M+H]+ .

[0213] Preparation Example 2: Preparation of benzyl (1-(tert-butyl)-5-((rac,cis)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclohexyl)-1H-pyrazol-3-yl)carbamate (INT-2)

[0214]

[0215] Step 1: Preparation of benzyl (1-(tert-butyl)-5-((rac,cis)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclohexyl)-1H-pyrazol-3-yl)carbamate (INT-2)

[0216] Compound INT-1f (1.50 g, 4.20 mmol), pyridine (996 mg, 12.6 mmol), and DMAP (51.3 mg, 0.42 mmol) were dissolved in DCM (15 mL) at room temperature. 4-Nitrophenylcarbonyl chloride (1.27 g, 6.30 mmol) was added under a nitrogen atmosphere and stirred at room temperature for 16 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted once with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 2.00 g of the title product as a yellow oily liquid in a 90.0% yield.

[0217] Example 1: (rac, cis, Z)-2 1 Preparation of H-6,12-dioxa-3,10-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentaneheterocyclododecane-4,11-dione (1)

[0218]

[0219] Step 1: Preparation of methyl 3-(3-((tert-butoxycarbonyl)amino)propoxy)benzoate (1a)

[0220] Methyl 3-hydroxybenzoate (580 g, 3.82 mmol), tert-butyl (3-bromopropyl)carbamate (1.00 g, 4.20 mmol), and potassium carbonate (2.60 g, 19.1 mmol) were dissolved in DMF (10 mL) at room temperature. The mixture was reacted at 75°C for 16 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.40 g of the crude title compound as a yellow oil.

[0221] LC-MS: m / z 310.0 [M+H] + .

[0222] Step 2: Preparation of methyl 3-(3-aminopropoxy)benzoate (1b)

[0223] Methyl 3-(3-((tert-butoxycarbonyl)amino)propoxy)benzoate (500.0 mg, 1.61 mmol) and trifluoroacetic acid (3 mL) were dissolved in DCM (5 mL) at room temperature. The mixture was reacted at room temperature for 2 hours and concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next step.

[0224] LC-MS: m / z 210.0 [M+H] + .

[0225] Step 3: Preparation of methyl 3-(3-(((((rac,cis)-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoate (1c)

[0226] Methyl 3-(3-aminopropoxy)benzoate (338 mg, 1.61 mmol), compound INT-2 (844 mg, 1.61 mmol), and DIEA (1.03 g, 8.05 mmol) were dissolved in THF (5 mL) at room temperature and stirred at room temperature for 2 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted once more with 200 mL of ethyl acetate. The organic phases were combined, washed with sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 700 mg of a yellow oily liquid, with a yield of 73.1%.

[0227] LC-MS: m / z 593.0 [M+H] + .

[0228] Step 4: Preparation of methyl 3-(3-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoate (1d)

[0229] Methyl 3-(3-(((((rac,cis)-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoate (1c) (680 mg, 1.14 mmol) was dissolved in THF (5 mL) at room temperature. Pd / C (10% wet) (136 mg) was added and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give the crude product as a yellow oil, which was used directly in the next step.

[0230] LC-MS: m / z 459.0 [M+H] + .

[0231] Step 5: Preparation of 3-(3-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoic acid (1e)

[0232] Methyl 3-(3-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoate (1d) (526 mg, 1.14 mmol) and lithium hydroxide monohydrate (96.0 mg, 2.28 mmol) were dissolved in methanol / water (2 / 1 mL) at room temperature and stirred at 50°C overnight. The mixture was concentrated under reduced pressure to give a crude yellow oil, which was used directly in the next step.

[0233] LC-MS: m / z 445.0 [M+H] + .

[0234] Step 6: (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 Preparation of H-6,12-dioxa-3,10-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentaneheterocyclododecane-4,11-dione (1f)

[0235] 3-(3-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)propoxy)benzoic acid (1e) (480 mg, 1.08 mmol), N,N-diisopropylethylamine (696 mg, 5.40 mmol) and T3P (6.80 g, 10.8 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure to give a crude yellow oil, which was used directly in the next step.

[0236] LC-MS: m / z 427.0 [M+H]+ .

[0237] Step 7: (rac,cis,Z)-2 1 Preparation of H-6,12-dioxa-3,10-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentaneheterocyclododecane-4,11-dione (1)

[0238] =(rac,cis,Z)-2 1 -(tert-butyl)-2- 1 H-6,12-dioxa-3,10-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentacyclododecane-4,11-dione (1f) (460 mg, 1.08 mmol) was dissolved in formic acid (5 mL), stirred at 75°C overnight, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column type: C18, mobile phase: acetonitrile / water, gradient: 0%-100%) to obtain 20.0 mg of the title product as a white solid, with a yield of 5.80%.

[0239] LC-MS: m / z 371.0 [M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),9.68(d,J=27.7Hz,1H),7.25(t,J=7.8Hz,1 H),7.03(d,J=7.5Hz,1H),6.91(dd,J=22.8,8.4Hz,1H),6.85-6.60(m,2H),5.37(d ,J=57.5Hz,1H),5.10-4.69(m,1H),3.84(d,J=48.6Hz,2H),2.92(s,2H),2.32(d,J =59.5Hz,1H),2.22-2.10(m,2H),1.73(dd,J=48.0,7.6Hz,4H),1.60-1.35(m,2H).

[0241] Example 2: (rac, cis, Z)-2 1 Preparation of H-6,15-dioxa-3,13-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (2)

[0242]

[0243] Compound 2 was prepared according to the synthetic method of Example 1, except that tert-butyl (6-bromohexyl)carbamate was used instead of tert-butyl (3-bromopropyl)carbamate, to obtain 120.0 mg of the title product as a white solid.

[0244] LC-MS: m / z=413[M+H] + .

[0245] 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.52(s,1H),7.74-7.25(m,3H),7.08-6.93(m,1H),6.53(d,J= 83.2Hz, 2H), 4.97 (s, 1H), 4.15 (t, J = 23.5Hz, 2H), 3.30-3.08 (m, 2H), 2.91 (s, 1H), 2.30-1.21 (m, 14H).

[0246] Example 3: (rac, cis, Z)-2 1 Preparation of H-6,16-dioxa-3,14-diaza-2(5,3)-pyrazolo-5(1,3)-benzo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (3)

[0247]

[0248] Compound 3 was prepared according to the synthetic method of Example 1, except that tert-butyl (7-bromoheptyl)carbamate was used instead of tert-butyl (3-bromopropyl)carbamate, to obtain 20.0 mg of the title product as a white solid.

[0249] LC-MS: m / z 427.2[M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),10.68(s,1H),7.59(d,J=29.0Hz,2H),7.34(t,J=7.9Hz,1H),7.03(s,1H),6.52(d,J=57.4Hz,2H),4.9 4(s,1H),4.28-4.05(s,2H),3.27(s,1H),2.99(d,J=71.4Hz,2H),2.15(s,1H),1.87(d,J=47.6Hz,4H),1.68(s,2H),1.32(d,J=69.5Hz,9H).

[0251] Example 4: (rac, cis, Z)-2 1Preparation of H-6,13-dioxa-3,11-diaza-5(2,6)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclotridecane-4,12-dione (4)

[0252]

[0253] Step 1: Preparation of methyl 6-(4-((tert-butoxycarbonyl)amino)butoxy)picolinate (4a): Sodium hydride (335 mg, 8.38 mmol) was added to a solution of tert-butyl (4-hydroxybutyl)carbamate (1.46 g, 7.74 mmol) in tetrahydrofuran (20 mL) at 0°C. The mixture was stirred for 1 hour, and methyl 6-fluoropicolinate (1.00 g, 6.45 mmol) was added. The mixture was allowed to react for 2 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added for extraction. The organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 900 mg of the title product as a brown oil.

[0254] LC-MS: m / z=325[M+H] + .

[0255] Step 2: Preparation of methyl 6-(4-aminobutoxy)picolinate (4b)

[0256] Trifluoroacetic acid (1.58 g, 13.9 mmol) and methyl 6-(4-((tert-butoxycarbonyl)amino)butoxy)picolinate (4a) (900 mg, 2.77 mmol) were dissolved in dichloromethane (10 mL) and reacted at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and used directly in the next reaction.

[0257] LC-MS: m / z = 225 [M+H] + .

[0258] Step 3: Preparation of methyl 6-(4-(((((rac,cis)-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)picolinate (4c)

[0259] Methyl 6-(4-aminobutoxy)picolinate (4b) (624 mg, 2.77 mmol), compound INT-2 (966 mg, 1.85 mmol), and N,N-diisopropylethylamine (717 mg, 5.55 mmol) were dissolved in tetrahydrofuran (10 mL) and allowed to react at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 930 mg of the title product as a brown oil.

[0260] LC-MS: m / z=608[M+H] + .

[0261] Step 4: Preparation of methyl 6-(4-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)picolinate (4d)

[0262] Compound 4c (930 mg) was dissolved in ethyl acetate (10 mL) at room temperature, and palladium carbon (150 mg) was added. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through celite and concentrated to obtain 710 mg of a red oily liquid.

[0263] LC-MS: m / z=474[M+H] + .

[0264] Step 5: Preparation of 6-(4-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)picolinic acid (4e)

[0265] Lithium hydroxide (157 mg, 3.75 mmol) and compound 4d (710 mg, 1.50 mmol) were dissolved in methanol (10 mL) and water (3 mL) at room temperature and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and used directly in the next step.

[0266] LC-MS: m / z=460[M+H] + .

[0267] Step 6: (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 Preparation of H-6,13-dioxa-3,11-diaza-5(2,6)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclotridecane-4,12-dione (4f)

[0268] T3P (9.55 g, 15.0 mmol), compound 4e (690 mg, 1.50 mmol), and DIEA (969 mg, 7.50 mmol) were dissolved in dichloromethane (10 mL) at room temperature and heated to 60°C for 16 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 100 mg of the title product as a white solid.

[0269] LC-MS: m / z=442[M+H] + .

[0270] Step 7: (rac,cis,Z)-2 1 Preparation of H-6,13-dioxa-3,11-diaza-5(2,6)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclotridecane-4,12-dione (4)

[0271] At room temperature, (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 H-6,13-Dioxa-3,11-diaza-5(2,6)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclotridecan-4,12-dione (4f) (100 mg) was dissolved in formic acid (5 mL) and the temperature was raised to 70°C for 16 hours. After concentration, the residue was separated by preparative liquid chromatography (column model: Daisogei 30 mm × 250 mm, C18, 10 μm, 100A, mobile phase: acetonitrile / water, gradient: 10%-50%) to obtain 8.00 mg of a white solid.

[0272] LC-MS: m / z=386[M+H] + .

[0273] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.01(s,1H),7.90(t,J=7.7Hz,1H),7.63(d,J=7.3Hz,1H),7.23(s,1H),7.02(d,J=8.3Hz,1H), 5.83(s,1H),4.94(s,1H),4.79(s,1H),4.09(s,1H),3.41(s,1H),2.67(s,1H),2.09(dd,J=51.7,22.6Hz,4H),1.65(d,J=109.5Hz,7H).

[0274] Example 5: (rac, cis, Z)-2 1 Preparation of H-9,16-dioxa-3,7,14-triaza-5(3,2)-pyridinyl-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (5)

[0275]

[0276] Step 1: Preparation of tert-butyl (4-(((4-nitrophenoxy)carbonyl)oxy)butyl)carbamate (5a)

[0277] At room temperature, tert-butyl (4-hydroxybutyl)carbamate (500 mg, 2.64 mmol), 4-nitrophenyl chloroformate (795 mg, 3.96 mmol), pyridine (626 mg, 7.93 mmol), and DMAP (32.2 mg, 0.264 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 16 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.00 g of the crude title compound as a yellow solid.

[0278] LC-MS: m / z 355.1[M+H] + .

[0279] Step 2: Preparation of 2-(12,12-dimethyl-3,10-dioxo-4,11-dioxa-2,9-diazatridecyl)nicotinate (5b)

[0280] At room temperature, tert-butyl (4-(((4-nitrophenoxy)carbonyl)oxy)butyl)carbamate (5a) (1.00 g, 2.82 mmol), methyl 2-(aminomethyl)nicotinate (468 mg, 2.82 mmol), and DIEA (1.09 g, 8.46 mmol) were dissolved in THF (10 mL) and stirred at room temperature overnight. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 680 mg of the title product as a red oil. Yield: 63.5%

[0281] LC-MS: m / z 382.1[M+H] + .

[0282] Step 3: Preparation of methyl 2-((((4-aminobutyloxy)carbonyl)amino)methyl)nicotinate (5c)

[0283] Methyl 2-(12,12-dimethyl-3,10-dioxo-4,11-dioxa-2,9-diazatridecyl)nicotinate (5b) (660 mg, 1.73 mmol) and trifluoroacetic acid (3 mL) were dissolved in dichloromethane (5 mL) at room temperature and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product which was used directly in the next step.

[0284] LC-MS: m / z 282.1[M+H] + .

[0285] Step 4: Preparation of methyl 2-((((4-(((((rac,cis)-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)carbonyl)amino)methyl)nicotinate (5d)

[0286] Methyl 2-((((4-aminobutyloxy)carbonyl)amino)methyl)nicotinate (5c) (480 mg, 1.70 mmol), compound INT-2 (887 mg, 1.70 mmol), and N,N-diisopropylethylamine (1.10 g, 8.54 mmol) were dissolved in THF (10 mL) at room temperature and stirred overnight at room temperature. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to afford 980 mg of the title product as a red oil in an 86.6% yield.

[0287] LC-MS: m / z 665.3 [M+H] + .

[0288] Step 5: Preparation of methyl 2-((((4-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)carbonyl)amino)methyl)nicotinate (5e)

[0289] Compound 5d (960 mg, 1.44 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, and Pd / C (10% wet) (192 mg) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered through celite, and concentrated under reduced pressure to give a crude yellow oil, which was used directly in the next step.

[0290] LC-MS: m / z 531.2 [M+H] + .

[0291] Step 6: Preparation of 2-((((4-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)butoxy)carbonyl)amino)methyl)nicotinic acid (5f)

[0292] Compound 5e (800 mg, 1.50 mmol) and trimethyltin hydroxide (1.30 g, 7.54 mmol) were dissolved in 1.2-dichloroethane (5 mL) at room temperature and stirred at 90°C overnight. The pH was adjusted to ~3 with citric acid. 200 mL of water was added to the reaction mixture, and the mixture was extracted with 300 mL of dichloromethanol / 30 mL of methanol. The aqueous phase was then extracted twice with 100 mL of dichloromethanol / 10 mL of methanol. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to obtain 270 mg of the title product as a red oil in a 34.7% yield.

[0293] LC-MS: m / z 517.2 [M+H] + .

[0294] Step 7: (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 Preparation of H-9,16-dioxa-3,7,14-triaza-5(3,2)-pyridinyl-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (5 g)

[0295] Compound 5f (260 mg, 0.503 mmol), T3P (1.60 g, 2.51 mmol), and DIEA (259 mg, 2.01 mmol) were dissolved in dichloromethane (5 mL) at room temperature, stirred at 60°C overnight, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to give 100 mg of the title product as a yellow oil in a 40.0% yield.

[0296] LC-MS: m / z 499.2 [M+H] + .

[0297] Step 8: (rac,cis,Z)-2 1 Preparation of H-9,16-dioxa-3,7,14-triaza-5(3,2)-pyridinyl-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (5)

[0298] =(rac,cis,Z)-2 1 -(tert-butyl)-2- 1H-9,16-dioxa-3,7,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (5 g) (100 mg, 0.200 mmol) was dissolved in formic acid (5 mL), stirred at 75°C for 5 hours, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (column type: C18-4, mobile phase: acetonitrile / water, gradient: 0%-100%) to obtain 20.0 mg of the title product as a white solid, with a yield of 22.7%.

[0299] LC-MS: m / z 443.2 [M+H] + .

[0300] 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.58(s,1H),8.75-8.42(m,1H),7.88(s ,1H),7.37(s,1H),7.16(s,1H),6.99-6.63(m,1H),6.56-6.18(m,1H),4.97(d, J=65.5Hz,1H),4.51(d,J=63.1Hz,2H),3.86(s,2H),3.08(d,J=102.5Hz,2H),2 .75(d,J=13.5Hz,1H),2.07(s,1H),2.01-1.63(m,4H),1.41(d,J=40.0Hz,4H).

[0301] Example 6: (rac, cis, Z)-2 1 Preparation of H-11,16-dioxa-3,7,14-triaza-5(3,2)-pyridinyl-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (6)

[0302]

[0303] Step 1: Preparation of 2-(12,12-dimethyl-3,10-dioxo-6,11-dioxa-2,9-diazatridecyl)nicotinate (6a)

[0304] Methyl 2-(aminomethyl)nicotinate (355 mg, 2.14 mmol), 3-(2-((tert-butoxycarbonyl)amino)ethoxy)propanoic acid (500 mg, 2.14 mmol), HATU (1.22 g, 3.21 mmol), and DIEA (830 mg, 6.43 mmol) were dissolved in DCM (5 mL) at room temperature and stirred at room temperature for 2 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to afford 720 mg of the title product as a yellow oil in a 93.5% yield.

[0305] LC-MS: m / z 382.1[M+H] + .

[0306] Step 2: Preparation of methyl 2-((3-(2-aminoethoxy)propionamido)methyl)nicotinate (6b)

[0307] Methyl 2-(12,12-dimethyl-3,10-dioxo-6,11-dioxa-2,9-diazatridecyl)nicotinate (6a) (720 mg, 1.88 mmol) and trifluoroacetic acid (4 mL) were dissolved in dichloromethane (3 mL) at room temperature and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude title compound for the next step.

[0308] LC-MS: m / z 282.1[M+H] + .

[0309] Step 3: Preparation of methyl 2-((3-(2-(((((rac,cis)--3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)ethoxy)propionamido)methyl)nicotinate (6c)

[0310] Methyl 2-((3-(2-aminoethoxy)propionamido)methyl)nicotinate (6b) (530 mg, 1.88 mmol), compound INT-2 (980 mg, 1.88 mmol), and N,N-diisopropylethylamine (1.2 g, 9.40 mmol) were dissolved in THF (10 mL) at room temperature and stirred overnight at room temperature. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to afford 760 mg of the title product as a yellow oil in a 60.8% yield.

[0311] LC-MS: m / z 665.3 [M+H] + .

[0312] Step 4: Preparation of methyl 2-((3-(2-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)ethoxy)propionamido)methyl)nicotinate (6d)

[0313] At room temperature, compound 6c (740 mg, 1.11 mmol) was dissolved in tetrahydrofuran (3 mL), and Pd / C (10% wet) (148 mg) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered through celite, and concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next step.

[0314] LC-MS: m / z 531.2 [M+H] + .

[0315] Step 5: Preparation of 2-((3-(2-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)ethoxy)propionamido)methyl)nicotinic acid (6e)

[0316] Compound 6d (600 mg, 1.13 mmol) and trimethyltin hydroxide (1.01 g, 5.66 mmol) were dissolved in 1.2-dichloroethane (5 mL) at room temperature and stirred at 90°C overnight. The pH was adjusted to ~3 with citric acid. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of dichloromethanol / 30 mL of methanol. The aqueous phase was then extracted twice with 100 mL of dichloromethanol / 10 mL of methanol. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to afford 60.0 mg of the title product as a red oil in a 10.2% yield.

[0317] LC-MS: m / z 517.2 [M+H] + .

[0318] Step 6: (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 Preparation of H-11,16-dioxa-3,7,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-8,15-dione (6f)

[0319] Compound 6e (60.0 mg, 0.116 mmol), T3P (369 mg, 0.581 mmol) and DIEA (60.0 mg, 0.464 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred at 60°C overnight. The mixture was concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next step.

[0320] LC-MS: m / z 499.2 [M+H] + .

[0321] Step 7: (rac,cis,Z)-2 1 Preparation of H-11,16-dioxa-3,7,14-triaza-5(3,2)-pyridinyl-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,8,15-trione (6)

[0322] Compound 6f (60 mg, 0.116 mmol) was dissolved in formic acid (3 mL) at room temperature, stirred at 75°C for 3 hours, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (C18 column, mobile phase: acetonitrile / water, gradient: 0%-100%) to give 20.0 mg of the title product as a white solid, in a 37.7% yield.

[0323] LC-MS: m / z 443.2[M+H] + .

[0324] 1H NMR (400MHz, DMSO-d6) δ12.13(s,1H),10.92(s,1H),8.58(t,J=7.5Hz,1H),8.39-8.00(m,1 H),7.86(d,J=7.6Hz,1H),7.40(dd,J=7.7,4.8Hz,1H),6.68(d,J=33.1Hz,1H),6.43(d,J=5 1.0Hz,1H),5.04(d,J=23.1Hz,1H),4.46(d,J=6.3Hz,2H),3.54(t,J=6.0Hz,3H),3.39-3.2 8(m,3H),3.01(s,1H),2.44-2.22(m,3H),2.17-2.03(m,1H),1.83(td,J=12.1,8.0Hz,4H).

[0325] Example 7: (rac, cis, Z)-2 1 Preparation of H-16-oxa-3,6,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (7)

[0326]

[0327]

[0328] Step 1: Preparation of methyl 2-((7-((tert-butoxycarbonyl)amino)heptyl)amino)nicotinate (7a)

[0329] Methyl 2-fluoronicotinate (674 mg, 4.34 mmol), tert-butyl (7-aminoheptyl)carbamate (1.00 g, 4.34 mmol), and triethylamine (1.32 g, 13.0 mmol) were dissolved in NMP (15 mL) at room temperature and heated to 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE) to obtain 1.66 g of the title compound as a yellow oily liquid.

[0330] LCMS: m / z 366 [M+H] + .

[0331] Step 2: Preparation of methyl 2-((7-aminoheptyl)amino)nicotinate (7b)

[0332] Trifluoroacetic acid (4 ml) was added to a solution of methyl 2-((7-((tert-butoxycarbonyl)amino)heptyl)amino)nicotinate (7a) (1.66 g) in dichloromethane (10 mL) at room temperature and allowed to react for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and used directly in the next reaction.

[0333] LC-MS: m / z=266[M+H] + .

[0334] Step 3: Preparation of methyl 2-((7-(((((rac,cis)-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)heptyl)aminonicotinate (7c)

[0335] Methyl 2-((7-aminoheptyl)amino)nicotinate (7b) (609 mg, 2.30 mmol), compound INT-2 (800 mg, 1.53 mmol), and N,N-diisopropylethylamine (989 mg, 7.65 mmol) were dissolved in tetrahydrofuran (10 mL) and reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 1.08 g of the title product as a brown oil.

[0336] LC-MS: m / z=649[M+H] + .

[0337] Step 4: Preparation of methyl 2-((7-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)heptyl)amino)nicotinate (7d)

[0338] Compound 7c (1.08 g) was dissolved in ethyl acetate (10 mL) at room temperature, and palladium on carbon (200 mg) was added. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through celite and concentrated to obtain 840 mg of a yellow oily liquid.

[0339] LC-MS: m / z=515[M+H] + .

[0340] Step 5: Preparation of 2-((7-(((((rac,cis)-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)oxy)carbonyl)amino)heptyl)amino)nicotinic acid (7e)

[0341] Lithium hydroxide (161 mg, 3.84 mmol) and compound 7d (790 mg, 1.53 mmol) were dissolved in methanol (10 mL) and water (3 mL) at room temperature and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and used directly in the next reaction.

[0342] LC-MS: m / z=501[M+H] + .

[0343] Step 6: (rac,cis,Z)-2 1 -(tert-butyl)-2- 1 Preparation of H-16-oxa-3,6,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (7f)

[0344] T3P (9.76 g, 15.3 mmol), compound 7e (768 mg, 1.53 mmol), and DIEA (991 mg, 7.67 mmol) were added to a dichloromethane (15 mL) solution at room temperature and heated to 60°C for 16 hours. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to obtain 27 mg of the title product as a white solid.

[0345] LC-MS: m / z=483[M+H] + .

[0346] Step 7: (rac,cis,Z)-2 1 Preparation of H-16-oxa-3,6,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (7)

[0347] Compound 7f (27 mg) was dissolved in formic acid (3 mL) at room temperature and the reaction mixture was heated to 70°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (Daisogei 30 mm x 250 mm, C18, 10 μm, 100 Å column, mobile phase: acetonitrile / water, gradient: 10%-50%) to yield 6.00 mg of a white solid.

[0348] LC-MS: m / z=427[M+H] + .

[0349] 1H NMR (400MHz, DMSO-d6) δ12.16(s,1H),10.65(s,1H),8.60(t,J=5.0Hz,1H),6.96(dd,J=7.7,3.8Hz,1H),6.54(dd,J=7.6,4.9 Hz,1H),6.46(s,1H),4.92(t,J=4.3Hz,1H),3.56-3.44(m,1H),3.20(d,J=7.4Hz,2H),2.78-2.64(m,1H),2.46-1.13(m,18H).

[0350] Example 8: (rac, cis, Z)-2 1 Preparation of H-6,15-dioxa-3,13-diaza-5(2,6)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (8)

[0351]

[0352] Compound 8 was prepared according to the synthetic method of Example 4, except that tert-butyl (6-hydroxyhexyl)carbamate was used instead of tert-butyl (4-hydroxybutyl)carbamate, to obtain 2.00 mg of the title product as a white solid.

[0353] LC-MS: m / z = 414.1 [M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),9.99(s,1H),7.91(t,J=7.8Hz,1H),7.74-7.51(m,2H),6.98(dd,J=37.6,7.0Hz,2H),6.03( s,1H),4.99(s,1H),4.70-4.56(m,1H),3.15(s,1H),2.82(s,1H),2.16(s,2H),1.95-1.81(m,5H),1.68(s,1H),1.50-1.39(m,5H).

[0355] Example 9: (rac, cis, Z)-2 1 Preparation of H-15-oxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (9)

[0356]

[0357] Compound 9 was prepared according to the synthetic method of Example 7, except that tert-butyl (6-bromohexyl)carbamate was used instead of tert-butyl (7-aminoheptyl)carbamate in step 1, to give 20.0 mg of the title product as a white solid.

[0358] LC-MS: m / z 413 [M+H] + .

[0359] 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),10.68(s,1H),8.57(s,1H),8.27-8. 08(m,2H),6.82(s,1H),6.64-6.50(m,2H),5.01(d,J=65.3Hz,1H),3.39(s, 2H),3.21(d,J=21.5Hz,2H),2.91(s,1H),2.20(d,J=59.4Hz,1H),1.95(d,J =15.3Hz, 1H), 1.81 (t, J = 14.6Hz, 4H), 1.47 (d, J = 19.7Hz, 7H), 1.24 (s, 1H).

[0360] Example 10: (rac, cis, Z)-2 1 Preparation of H-9,14-dioxa-3,6,12-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclotetradecane-4,13-dione (10)

[0361]

[0362] Compound 10 was prepared according to the synthetic method of Example 7, except that tert-butyl (2-(2-aminoethoxy)ethyl)carbamate was used instead of tert-butyl (7-aminoheptyl)carbamate in step 1, to give 75 mg of the title product as a white solid.

[0363] LC-MS: m / z=401[M+H] + .

[0364] 1 HNMR(400MHz,DMSO-d6)δ12.12(s,1H),10.78(s,1H),9.05(t,J=4.5Hz,1H),8.28-8.07(m,2H),6.88(s,1H),6.57 (dd,J=7.3,5.1Hz,1H),6.04(t,J=5.3Hz,1H),5.18(td,J=5.9,2.3Hz,1H),3.70-3.32(m,9H),2.24-1.65(m,6H).

[0365] Example 11: (rac, cis, Z)-2 1 H-1 2 Preparation of -oxa-3,6,10-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-8(1,4)-cyclohexane-1(1,3)-cyclopentaneheterocyclododecane-4,11-dione (11)

[0366]

[0367] Step 1: Preparation of 2-fluoronicotinic acid (11a)

[0368] Methyl 2-fluoronicotinate (526 mg, 3.39 mmol) and lithium hydroxide monohydrate (285 mg, 6.79 mmol) were dissolved in methanol / water (10 / 3 mL) at room temperature and stirred overnight at room temperature. The mixture was concentrated under reduced pressure to obtain a crude yellow oil, which was used directly in the next step.

[0369] LC-MS: m / z 142[M+H] + .

[0370] According to the synthesis method of Example 7, except that compound 11a was used instead of compound 7b, and tert-butyl (((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)carbamate was used instead of tert-butyl 4-aminobutyrate, 50 mg of the title product was obtained as a white solid.

[0371] LC-MS: m / z=439[M+H] + .

[0372] 1 HNMR(400MHz,DMSO-d6)δ12.21(s,1H),10.52(d,J=46.5Hz,1H),8.42-7.76(m,3H),7.30-6.91(m,1H),6.56(dd,J=7.6,4.9Hz,1 H), 6.27 (d, J = 28.2Hz, 1H), 4.86 (d, J = 60.0Hz, 1H), 3.44 (s, 2H), 3.10 (d, J = 41.5Hz, 2H), 2.70-2.53 (m, 1H), 2.39-0.68 (m, 16H).

[0373] Example 12: (rac, cis, Z)-6 1 Preparation of H-8-oxa-5,10-diaza-3(2,3)-pyridin-1(1,4)-piperidin-6(3,5)-pyrazolo-7(1,3)-cyclopenta-11(1,3)-cyclobutaneheterocycloundecane-4,9-dione (12)

[0374]

[0375] Step 1: Preparation of methyl 2-((2-((tert-Butoxycarbonyl)amino)-7-azaspiro[3.5]non-7-yl)methyl)nicotinate (12a).

[0376] Methyl 2-(bromomethyl)nicotinate (1.0 g, 4.38 mmol), tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate (1.05 g, 4.38 mmol), and potassium carbonate (1.28 g, 8.76 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The mixture was reacted at 80°C for 4 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 1.67 g of the title compound as a yellow oil in a 98.2% yield.

[0377] Step 2: Preparation of 2-((2-((tert-Butyloxycarbonyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)nicotinic acid (12b)

[0378] Compound 12a (1.67 g, 4.29 mmol) and lithium hydroxide (360 mg, 8.58 mmol) were dissolved in tetrahydrofuran / water (10 / 5 mL) at room temperature and reacted at room temperature for 16 hours. The filtrate was concentrated under reduced pressure and used directly in the next step.

[0379] Step 3: Preparation of tert-butyl (7-((3-(1-(tert-butyl)-5-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamoyl)pyridin-2-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (12c)

[0380] Compound 12b (1.6 g, 4.26 mmol), compound INT-2 (1.43 g, 4.26 mmol), N,N-diisopropylethylamine (1.63 g, 12.7 mmol), and T3P (13.5 g, 21.3 mmol) were dissolved in acetonitrile (10 mL) at room temperature and reacted at 60°C for 16 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phases were combined, dried, and concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 750 mg of a yellow oily liquid, a yield of 25.3%.

[0381] LCMS: m / z 695 [M+H] + .

[0382] Step 4: Preparation of tert-butyl (7-((3-(1-(tert-butyl)-5-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamoyl)pyridin-2-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (12d)

[0383] Compound 12c (750 mg, 1.08 mmol) was dissolved in TBAF (1 M in THF) (3 mL) at room temperature and reacted for 16 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phases were combined, dried, concentrated, and used directly in the next reaction.

[0384] LCMS: m / z 581 [M+H] + .

[0385] Step 5: Preparation of tert-butyl (7-((3-(1-(tert-butyl)-5-((1S,3R)-3-((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamoyl)pyridin-2-yl)methyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (12e)

[0386] Compound 12d (660 mg, 1.13 mmol), pyridine (267 mg, 3.39 mmol), and DMAP (27.5 mg, 0.226 mmol) were dissolved in dichloromethane (10 mL) at room temperature. 4-Nitrophenyl chloroformate (339 mg, 1.69 mmol) was slowly added and allowed to react at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:1) to afford 496 mg of the title product as a brown oil in a 58.9% yield.

[0387] LCMS: m / z 746 [M+H]+.

[0388] Step 6: Preparation of (1R,3S)-3-(3-(2-((2-amino-7-azaspiro[3.5]nonan-7-yl)methyl)nicotinamide)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (12f)

[0389] Compound 12e (496 mg, 0.664 mmol) and trifluoroacetic acid (1 ml) were dissolved in dichloromethane (4 mL) at room temperature, stirred at room temperature for 3 hours, concentrated under reduced pressure, and used directly in the next reaction.

[0390] LCMS: m / z 646 [M+H] + .

[0391] Step 7: (rac,cis,7 1S,7 3 R,Z)-6 1 -(tert-butyl)-6- 1 Preparation of H-8-oxa-5,10-diaza-3(2,3)-pyridine-1(1,4)-piperidine-6(3,5)-pyrazole-7(1,3)-cyclopentane-11(1,3)-cyclobutanone-4,9-dione (12 g)

[0392] Compound 12f (420 mg, 0.651 mmol) and N,N-diisopropylethylamine (420 mg, 3.25 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature and allowed to react for 16 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 300 mL of ethyl acetate. The aqueous phase was then extracted once more with 200 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 300 mg of a yellow oily liquid in a yield of 90.9%.

[0393] LCMS: m / z 507 [M+H] + .

[0394] Step 8: (rac,cis,Z)-6 1 Preparation of H-8-oxa-5,10-diaza-3(2,3)-pyridin-1(1,4)-piperidin-6(3,5)-pyrazolo-7(1,3)-cyclopenta-11(1,3)-cyclobutaneheterocycloundecane-4,9-dione (12)

[0395] Compound 12 g (300 mg, 0.591 mmol) was dissolved in formic acid (3 mL) at room temperature, stirred at 80°C for 16 hours, and concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (C18 column, mobile phase: acetonitrile / water, gradient: 0%-100%) to obtain 35.0 mg of the title compound as a white solid, in a yield of 13.1%.

[0396] LC-MS: m / z 451[M+H] + .

[0397] 1H NMR (400MHz, DMSO-d6) δ13.26(s,1H),12.01(s,1H),8.70–8.42(m,1H),8.08(d,J=8.0Hz,1H),7.44(dd,J=7.8,4.7Hz,1H),6.86(s ,1H),6.57(s,1H),5.05(s,1H),3.58(d,J=102.8Hz,4H),2.06(d,J=44.0Hz,5H),1.71(d,J=62.6Hz,7H),1.30(d,J=118.7Hz,6H).

[0398] Example 13: (rac, cis, Z)-4,15-dioxo-2 1 H-10,16-dioxa-3,6,14-triaza-2(5,3)-pyrazolo-5(1,2)-benzo-1(1,3)-cyclopentaneheterocyclohexadecane-5-nitropropane 3 Preparation of -carbonitrile (13)

[0399]

[0400] Compound 13 was prepared according to the synthetic method of Example 7, except that tert-butyl (3-(3-aminopropoxy)propyl)carbamate was used instead of tert-butyl (7-aminoheptyl)carbamate in step 1, and methyl 3-cyano-2-fluorobenzoate was used instead of methyl 2-fluoronicotinate in step 1, to give 33 mg of the title product as a white solid.

[0401] LC-MS: m / z 453 [M+H] + .

[0402] 1 HNMR (400MHz, DMSO-d6) δ12.26-12.11(m,1H),10.82(d,J=18.3Hz,1H),8.28(s,1H),8.03(s,0H),7.89(d,J=7.8Hz,1H),7.62(dd,J=7.7, 1.5Hz,1H),6.88-6.67(m,2H),6.55(d,J=53.4Hz,1H),5.03(d,J=58.0Hz,1H),3.82-3.36(m,6H),3.28-2.81(m,3H),2.41-1.18(m,12H).

[0403] Example 14: (rac, cis, 10 1 S,10 3 R,Z)-2 1Preparation of H-9,13-dioxa-3,6,11-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopenta-10(1,3)-cyclobutaneheterocyclotridecane-4,12-dione (14)

[0404]

[0405] According to the synthesis method of Example 12, except that tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate in step 1 was replaced with tert-butyl ((1s,3s)-3-(2-aminoethoxy)cyclobutyl)carbamate, 94.0 mg of the title product was obtained as a white solid.

[0406] LC-MS: m / z 427 [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),10.66(s,1H),8.77(d,J=4.6Hz,1H),8.3 0–8.09(m,2H),7.19(d,J=6.3Hz,1H),6.69–6.49(m,2H),4.91(t,J=4.0Hz,1H), 3.79(p,J=6.8Hz,1H),3.69–3.53(m,2H),3.45(s,1H),2.80(dd,J=10.7,4.8Hz, 1H), 2.26 (ddd, J=15.3, 11.4, 4.4Hz, 1H), 2.21–2.02 (m, 3H), 1.98–1.63 (m, 4H).

[0408] Example 15: (rac, cis, 10 1 R,10 3 S,Z)-2 1 Preparation of H-9,13-dioxa-3,6,11-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopenta-10(1,3)-cyclobutaneheterocyclotridecane-4,12-dione (15)

[0409]

[0410] Compound 15 was prepared according to the synthetic method of Example 12, except that tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate in step 1 was replaced with tert-butyl ((1r,3r)-3-(2-aminoethoxy)cyclobutyl)carbamate, to give 80.0 mg of the title product as a white solid.

[0411] LC-MS: m / z 427 [M+H] + .

[0412] 1 H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.73(s,1H),8.95(s,1H),8.32-8.10(m,2H),7.13(s,1H),6.92-6.39(m,2H), 5.15(s,1H),4.55(s,1H),4.00(s,1H),3.45(d,J=32.5Hz,4H),3.26(s,1H),2.39(s,2H),2.19(d,J=8.8Hz,3H),2.03 -1.58(m,5H).

[0413] Example 16: (rac, cis, Z)-5 6 -Trifluoromethyl-2 1 Preparation of H-9,13-dioxa-3,6,11-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopenta-10(1,3)-cyclobutaneheterocyclotridecane-4,12-dione (16)

[0414]

[0415] Compound 16 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate was used instead of tert-butyl ((1r,3r)-3-(2-aminoethoxy)cyclobutyl)carbamate, to give 13.0 mg of the title product as a white solid.

[0416] LC-MS: m / z 495.1 [M+H] + .

[0417] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),11.07(s,1H),9.01(s,1H),8.34(d,J=7.8Hz,1H),7.14(s,1H),7.00(d,J=7.7Hz,2H),6.78 (s,1H),5.16(s,1H),4.55(s,1H),4.01(s,1H),3.51(s,2H),2.38(s,2H),2.20(d,J=6.5Hz,2H),1.93–1.70(m,6H),1.24(s,2H).

[0418] Example 17: (rac, cis, Z)-5 6 -Trifluoromethyl-2 1 Preparation of H-10,16-dioxa-3,6,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (17)

[0419]

[0420] Compound 17 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (7-azaspiro[3.5]non-2-yl)carbamate was used instead of tert-butyl (3-(3-aminopropoxy)propyl)carbamate, to give 27.0 mg of the title product as a white solid.

[0421] LC-MS: m / z 497.10 [M+H] + .

[0422] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.71-8.57(m,1H),8.30-8.13(m,1H),6.9 6(d,J=7.7Hz,1H),6.89-6.76(m,1H),6.57(d,J=63.1Hz,1H),4.94(t,J=4.0Hz, 1H),3.63-3.47(m,6H),3.29-3.19(m,2H),2.93-2.83(m,1H),2.26(ddd,J=15.1 ,11.0,4.7Hz,1H),2.18-2.05(m,1H),1.94(d,J=15.0Hz,1H),1.87-1.71(m,8H).

[0423] Example 18: (rac, cis, Z)-5 6 -methyl-2 1 Preparation of H-10,16-dioxo-3,6,14-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclohexadecane-4,15-dione (18)

[0424]

[0425] Compound 18 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-methylnicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (3-(3-aminopropoxy)propyl)carbamate was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 37.0 mg of the title product as a white solid.

[0426] LC-MS: m / z 443.20 [M+H] + .

[0427] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.66(t,J=5.6Hz,1H),8.04(d,J=7.9Hz,1H),6.80( s,1H),6.46(s,1H),6.39(d,J=7.8Hz,1H),4.95(t,J=4.2Hz,1H),3.50(ddt,J=21.9,11.4, 6.3Hz, 6H), 3.22 (d, J=6.5Hz, 2H), 2.90 (dd, J=13.3, 5.9Hz, 1H), 2.30 (s, 3H), 2.23 (td, J=1 0.4, 5.3Hz, 1H), 2.12 (s, 1H), 1.93 (d, J = 15.1Hz, 1H), 1.77 (tdd, J = 14.6, 11.6, 7.7Hz, 8H).

[0428] Example 19: (rac, cis, Z)-12,12-dimethyl-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (19)

[0429]

[0430] Step 1: Preparation of ethyl 2-(3-((tert-butoxycarbonyl)amino)-3-methylbutoxy)acetate (19a)

[0431] At 0°C under a nitrogen atmosphere, tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate (4.00 g, 19.7 mmol) and rhodium diacetate (435 mg, 0.98 mmol) were dissolved in dichloromethane (60 mL). Ethyl diazoacetate (4.49 g, 39.4 mmol) dissolved in dichloromethane (40 mL) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 8 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA = 10:1) to obtain 2.82 g of the title compound as a yellow oily liquid.

[0432] LCMS: m / z 300 [M+H] + .

[0433] Step 2: Preparation of tert-butyl (4-(2-hydroxyethoxy)-2-methylbutan-2-yl)carbamate (19b)

[0434] Compound 19a (2.82 g, 9.76 mmol) was dissolved in tetrahydrofuran (100 mL) at 0°C, and lithium aluminum hydride (556 mg, 14.6 mmol) was added portionwise. The mixture was allowed to react at 0°C for 1.5 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next step.

[0435] LC-MS: m / z=248[M+H] + .

[0436] Step 3: Preparation of 2-(3-((tert-Butoxycarbonyl)amino)-3-methylbutoxy)ethyl methanesulfonate (19c)

[0437] Compound 19b (930 mg, 3.77 mmol), methanesulfonic anhydride (983 mg, 5.65 mmol), and triethylamine (951 mg, 9.41 mmol) were dissolved in dichloromethane (20 mL) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next step.

[0438] LC-MS: m / z=326[M+H] + .

[0439] Step 4: Preparation of tert-butyl (4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-2-methylbutan-2-yl)carbamate (19d)

[0440] Compound 19c (1.22 g, 3.75 mmol) and potassium phthalimide (1.04 g, 5.63 mmol) were dissolved in N,N-dimethylformamide (60 mL) at room temperature and heated to 60°C for 16 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA = 5:1) to obtain 1.15 g of the title compound as a yellow oily liquid.

[0441] LC-MS: m / z=377[M+H] + .

[0442] Step 5: Preparation of tert-butyl (4-(2-aminoethoxy)-2-methylbutan-2-yl)carbamate (19e)

[0443] Compound 19d (1.15 g, 3.06 mmol) and hydrazine hydrate (612 mg, 12.2 mmol) were dissolved in ethanol (60 mL) at room temperature and heated to 50°C for 8 hours. After completion of the reaction, the white solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a yellow oil, which was used directly in the next reaction.

[0444] LC-MS: m / z=247[M+H] + .

[0445] The remaining steps were the same as the synthetic method of Example 12, except that tert-butyl (4-(2-aminoethoxy)-2-methylbutan-2-yl)carbamate (19e) was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, and methyl 2-fluoronicotinate was used instead of methyl 2-(bromomethyl)nicotinate, to give 28.0 mg of the title product as a white solid.

[0446] LC-MS: m / z 443.20 [M+H] + .

[0447] 1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.67(s,1H),8.73(s,1H),8.18-8.11(m,2 H),6.66-6.60(m,1H),6.56(dd,J=7.5,4.9Hz,1H),6.33(s,1H),4.94(s,1H),3.5 6(d,J=6.6Hz,4H),3.46(s,2H),3.25(s,2H),2.28(s,1H),2.16-2.07(m,1H),1.9 5(d,J=15.8Hz,1H),1.80(td,J=13.0,11.3,6.8Hz,4H),1.34(s,3H),1.25(s,3H).

[0448] Example 20: Preparation of (rac,cis,Z)-spiro[cyclopropane-1,12'-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecane]-4',14'-dione (20)

[0449]

[0450] Compound 20 was prepared according to the synthetic method of Example 19, except that tert-butyl (1-(2-hydroxyethyl)cyclopropyl)carbamate was used instead of tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate, to give 75.0 mg of the title product as a white solid.

[0451] LC-MS: m / z 441.10 [M+H] + .

[0452] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.72(s,1H),8.75(d,J=4.5Hz,1H),8.20 –8.11(m,2H),6.88(s,1H),6.57(dd,J=7.7,4.8Hz,1H),6.53(s,1H),4.99(t,J=4 .7Hz,1H),3.73–3.54(m,4H),3.33(d,J=29.6Hz,3H),2.10(d,J=18.5Hz,2H),1. 94–1.77(m,5H),1.63(dt,J=13.6,6.2Hz,1H),0.57(dp,J=12.7,7.8,6.9Hz,4H).

[0453] Example 21: (rac, cis, Z)-12,12-dimethyl-5- 6-(trifluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (21)

[0454]

[0455] Compound 21 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (4-(2-aminoethoxy)-2-methylbutan-2-yl)carbamate was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 40.0 mg of the title product as a white solid.

[0456] LC-MS: m / z 511.20 [M+H] + .

[0457] 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),10.99(s,1H),8.79(s,1H),8.32(d,J=7.8Hz,1H),7.00(d,J=7.8Hz,1H),6.64(s,1H),6.36(s,1H),4.95(s,1 H),3.68-3.53(m,5H),3.47(s,3H),2.29(s,1H),2.16-2.10(m,1H),1.95 (d, J=15.5Hz, 1H), 1.80 (dd, J=9.3, 4.4Hz, 4H), 1.34 (s, 3H), 1.25 (s, 3H).

[0458] Example 22: (rac, cis, Z)-11,11-dimethyl-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (22)

[0459]

[0460] Compound 22 was prepared according to the synthetic method of Example 19, except that tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate was used instead of tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate, to give 70.0 mg of the title product as a white solid.

[0461] LC-MS: m / z 443.20 [M+H] + .

[0462] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),10.68(s,1H),8.69(dd,J=5.5,2.9Hz,1H),8.19-8.10(m,2H),6.65-6.52(m,2H),6.45-6.37(m,1H),5 .03(d,J=4.4Hz,1H),3.74-3.45(m,4H),3.29-2.92(m,4H),2.13(dd,J=21.8,12.3Hz,2H),1.89(d,J=40.0Hz,5H),0.87(s,3H),0.80(s,3H).

[0463] Example 23: (rac, cis, Z)-11,11-dimethyl-5- 6 -(trifluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (23)

[0464]

[0465] Compound 23 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate was used instead of tert-butyl (3-(2-aminoethoxy)-2,2-dimethylpropyl)carbamate, to give 76.0 mg of the title product as a white solid.

[0466] LC-MS: m / z 511.20 [M+H] + .

[0467] 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),10.99(s,1H),8.75–8.68(m,1H),8.30 (d,J=7.7Hz,1H),7.00(d,J=7.7Hz,1H),6.64(s,1H),6.52(dd,J=8.0,5.2Hz ,1H),5.03(d,J=4.0Hz,1H),3.73–3.44(m,4H),3.25–2.91(m,4H),2.17(tdd ,J=19.5,12.8,7.0Hz,2H),1.90(d,J=46.5Hz,5H),0.87(s,3H),0.79(s,3H).

[0468] Example 24: (rac, cis, 12S, Z)-12-methyl-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (24)

[0469]

[0470] Compound 24 was prepared according to the synthetic method of Example 19, except that (S)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester was used instead of (4-hydroxy-2-methylbutan-2-yl)carbamic acid tert-butyl ester to obtain 99.0 mg of the title product as a white solid.

[0471] LC-MS: m / z 429.20 [M+H] + .

[0472] 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),10.69(d,J=18.4Hz,1H),8.83(d,J=39.1Hz,1H),8.22–8.11(m,2H),6.99–6.50(m,3H),5.03(d,J=98.2 Hz,1H),3.51(td,J=9.3,5.5Hz,5H),3.28(d,J=22.5Hz,3H),2.03(d,J=14.8Hz,2H),1.84(s,4H),1.74(s,2H),1.07(dd,J=29.5,6.5Hz,3H).

[0473] Example 25: (rac, cis, 12R, Z)-12-methyl-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclopentadecan-4,14-dione (25)

[0474]

[0475] Compound 25 was prepared according to the synthetic method of Example 19, except that (R)-(4-hydroxybutan-2-yl)carbamic acid tert-butyl ester was used instead of (4-hydroxy-2-methylbutan-2-yl)carbamic acid tert-butyl ester to obtain 93.0 mg of the title product as a white solid.

[0476] LC-MS: m / z 429.20 [M+H] + .

[0477] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.71(s,1H),8.83(d,J=38.4Hz,1H),8.25-8.11(m,2H),7.07-6.31(m,3H),5.03(d,J=98.3Hz, 1H),3.64-3.45(m,5H),3.35-3.23(m,3H),2.40-1.99(m,2H),1.97-1.75(m,4H),1.61(d,J=7.5Hz,2H),1.07(dd,J=29.4,6.5Hz,3H).

[0478] Example 26: (rac, cis, Z)-2 1 Preparation of H-10,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclopentadecan-4,14-dione (26)

[0479]

[0480]

[0481] Compound 26 was prepared according to the synthetic method of Example 12, except that tert-butyl (2-(3-aminopropoxy)ethyl)carbamate was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 10.0 mg of the title product as a white solid.

[0482] LC-MS: m / z 415.10 [M+H] + .

[0483] 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.61(s,1H),8.66(s,1H),8.15(d,J=4.7Hz,1H),8.08(d,J=7.6Hz,1H),6.72- 6.51(m,2H),5.07(s,1H),3.61(s,2H),3.54-3.40(m,4H),3.31(s,3H),3.20(s,1H),2.10(s,1H),1.94-1.76(m,7H).

[0484] Example 27: (rac, cis, Z)-5 3 -Fluorine-2 1Preparation of H-9,13-dioxa-3,6-11-triaza-2(5,3)-pyrazolo-5(1,2)-benzo-1(1,3)-cyclopenta-10(1,3)-cyclobutaneheterocyclotridecane-4,12-dione (27)

[0485]

[0486] Compound 27 was prepared according to the synthetic method of Example 12, except that 2-(bromomethyl)nicotinate was replaced by methyl 2,3-difluorobenzoate, and tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate was replaced by tert-butyl ((1r,3r)-3-(2-aminoethoxy)cyclobutyl)carbamate, to give 14.0 mg of the title product as a white solid.

[0487] LC-MS: m / z 440.10 [M+H] + .

[0488] 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),10.66(s,1H),7.52(d,J=8.0Hz,2H),7 .19(ddd,J=13.8,8.1,1.4Hz,1H),7.08(d,J=6.6Hz,1H),6.69(dt,J=8.2,4.1 Hz,2H),5.11(s,1H),4.34(s,1H),3.97(s,1H),3.41(d,J=8.7Hz,4H),3.30-3 .22(m,1H),2.33(d,J=18.6Hz,3H),2.13(t,J=7.1Hz,4H),1.89-1.69(m,4H).

[0489] Example 28: Preparation of (rac,cis,Z)-6'-(trifluoromethyl)spiro[cyclopropane-1,12'-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclopentadecane]-4',14'-dione (28)

[0490]

[0491] Compound 28 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (1-(2-(2-aminoethoxy)ethyl)cyclopropyl)carbamate was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 47.0 mg of the title product as a white solid.

[0492] LC-MS: m / z 509.10 [M+H] + .

[0493] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),11.05(s,1H),8.82(s,1H),8.33(d,J=7.6Hz,1H),7.01(d,J=7.8Hz,1H),6.86(s,1H),6.55(s,1H),4.98(s,1 H),3.46(d,J=60.7Hz,3H),3.31(s,4H),2.09(d,J=9.4Hz,2H),1.88(s,1H ), 1.82 (dt, J = 12.9, 7.2 Hz, 4H), 1.66-1.58 (m, 1H), 0.58 (d, J = 6.8 Hz, 4H).

[0494] Example 29: (rac, cis, Z)-5 6 -(trifluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (29)

[0495]

[0496] Compound 29 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (3-(2-aminoethoxy)propyl)carbamate was used instead of tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 38.0 mg of the title product as a white solid.

[0497] LC-MS: m / z 483.10 [M+H] + .

[0498] 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 11.02 (d, J = 24.4Hz, 1H), 8.76 (s, 1H) ,8.34(d,J=7.7Hz,1H),7.00(d,J=7.8Hz,1H),6.76(s,1H),6.59(d,J=34.2 Hz,1H),5.02(d,J=47.8Hz,1H),3.59(s,3H),3.48(s,3H),3.30(d,J=7.5Hz ,4H), 2.17(d,J=9.1Hz,1H), 2.00(d,J=14.2Hz,1H), 1.76(d,J=47.7Hz,5H).

[0499] Example 30: (rac, cis, 12S, Z)-12-methyl-5- 6 -(trifluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (30)

[0500]

[0501] Compound 30 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and (S)-(4-(2-aminoethoxy)butan-2-yl)carbamic acid tert-butyl ester was used instead of (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 69.0 mg of the title product as a white solid.

[0502] LC-MS: m / z 497.20 [M+H] + .

[0503] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),11.00(s,1H),8.88(s,1H),8.34(t,J=8.2Hz,1H),7.00(d,J=7.8Hz,2H),6.73–6.48(m,1H),5.03(d ,J=99.8Hz,1H),3.63(d,J=8.8Hz,5H),3.51(td,J=9.2,5.5Hz,3H),2.07(s,2H),1.84(s,4H),1.74(s,2H),1.07(dd,J=31.5,6.4Hz,3H).

[0504] Example 31: (rac, cis, Z)-5 6-(difluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (31)

[0505]

[0506] Compound 31 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(difluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (7-azaspiro[3.5]non-2-yl)carbamate was used instead of tert-butyl (3-(2-aminoethoxy)propyl)carbamate, to give 42.0 mg of the title product as a white solid.

[0507] LC-MS: m / z 465.20 [M+H] + .

[0508] 1 H NMR (400MHz, DMSO-d6) δ12.17 (s, 1H), 10.90 (d, J = 24.8Hz, 1H), 8.75 (s, 1H), 8.2 9(d,J=7.8Hz,1H),6.89–6.78(m,2H),6.74(d,J=7.0Hz,1H),6.58(t,J=16.5Hz, 1H),5.02(d,J=46.8Hz,1H),3.63(d,J=35.4Hz,3H),3.49(s,3H),3.30(d,J=7.6 Hz, 4H), 2.16 (d, J = 10.3Hz, 1H), 2.00 (d, J = 14.6Hz, 1H), 1.76 (d, J = 47.0Hz, 5H).

[0509] Example 32: (rac, cis, Z)-5 6 -(trifluoromethyl)-2 1 Preparation of H-12-oxa-3,6,10-triaza-5(3,2)-pyridin-9(1,4)-piperidin-2(5,3)-pyrazolo-1(1,3)-cyclopentaneheterocyclododecane-4,11-dione (32)

[0510]

[0511]

[0512] Step 1: Preparation of N-(1-(tert-butyl)-5-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)-2-chloro-6-(trifluoromethyl)nicotinamide (32a)

[0513] 2-Chloro-6-(trifluoromethyl)nicotinic acid (500 mg, 2.22 mmol) and compound INT-1 (748 mg, 2.22 mmol) were dissolved in acetonitrile (15 mL) at room temperature. Propylphosphonic anhydride (50% in ethyl acetate) (7.05 g, 11.1 mmol) and N,N-diisopropylethylamine (1.43 mg, 11.1 mmol) were added dropwise. The reaction mixture was warmed to 60°C and reacted overnight. The reaction mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. After concentration, 1.28 g of the title compound was obtained as a red oily liquid.

[0514] LCMS: m / z 545 [M+H] + .

[0515] Step 2: Preparation of tert-butyl (1-(2-(((benzyloxy)carbonyl)amino)ethyl)piperidin-4-yl)carbamate (32b)

[0516] Benzyl (2-bromoethyl)carbamate (1.96 g, 7.60 mmol) and tert-butyl piperidin-4-ylcarbamate (1.5 g, 6.34 mmol) were dissolved in DMF (30 mL) at room temperature, and cesium carbonate (6.20 g, 19.0 mmol) was added. The temperature was raised to 60°C and the reaction was allowed to proceed for 16 hours. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted twice with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1.20 g of the title compound as a white solid.

[0517] LCMS: m / z 378 [M+H] + .

[0518] Step 3: Preparation of tert-butyl (1-(2-aminoethyl)piperidin-4-yl)carbamate (32c)

[0519] At room temperature, tert-butyl (1-(2-(((benzyloxy)carbonyl)amino)ethyl)piperidin-4-yl)carbamate (32b) (1.20 g, 3.18 mmol) was dissolved in tetrahydrofuran (20 mL). Pd / C (5%) (150 mg) was added under a nitrogen atmosphere. The atmosphere was replaced with hydrogen five times, and the mixture was stirred at room temperature overnight. After completion of the reaction, the filtrate was filtered and concentrated to afford 867 mg of the title compound as a brown oil.

[0520] LCMS: m / z 244 [M+H] + .

[0521] The remaining steps were the same as those of Example 7, except that tert-butyl (1-(2-aminoethyl)piperidin-4-yl)carbamate (32c) was used instead of tert-butyl (7-aminoheptyl)carbamate to obtain 20 mg of the title product as a white solid.

[0522] LC-MS: m / z=508[M+H] + .

[0523] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.83(s,1H),8.14(d,J=31.8Hz,2H),6.97(dd,J=40.5,7 .8Hz,2H),6.34(s,1H),5.13-4.81(m,1H),3.39(s,7H),3.13-2.62(m,5H),2.14-1.23(m,11H).

[0524] Example 33: (rac, cis, 12R, Z)-12-methyl-5- 6 -(trifluoromethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridin-2(5,3)-pyrazolo-1(1,3)-cyclopentacyclopentadecan-4,14-dione (33)

[0525]

[0526] Compound 33 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and (R)-(4-(2-aminoethoxy)butan-2-yl)carbamic acid tert-butyl ester was used instead of (7-azaspiro[3.5]nonan-2-yl)carbamate, to give 72.0 mg of the title product as a white solid.

[0527] LC-MS: m / z 497.20 [M+H] + .

[0528] 1H NMR (400MHz, DMSO-d6) δ12.21(s,1H),11.00(s,1H),8.88(s,1H),8.34(t,J=8.2Hz,1H),7.00(d,J=7.8Hz,2H),6.73–6.48(m,1H),5.03(d ,J=99.8Hz,1H),3.63(d,J=8.8Hz,5H),3.51(td,J=9.2,5.5Hz,3H),2.07(s,2H),1.84(s,4H),1.74(s,2H),1.07(dd,J=31.5,6.4Hz,3H).

[0529] Example 34: (rac, cis, Z)-5 6 -(methoxymethyl)-2 1 Preparation of H-9,15-dioxa-3,6,13-triaza-5(3,2)-pyridine-2(5,3)-pyrazole-1(1,3)-cyclopentacyclopentadecan-4,14-dione (34)

[0530]

[0531]

[0532] Compound 34 was prepared according to the synthetic method of Example 12, except that 2-chloro-6-(methoxymethyl)nicotinate was used instead of 2-(bromomethyl)nicotinate, and tert-butyl (7-azaspiro[3.5]non-2-yl)carbamate was used instead of tert-butyl (3-(2-aminoethoxy)propyl)carbamate, to give 37.0 mg of the title product as a white solid.

[0533] LC-MS: m / z 459.2 [M+H] + .

[0534] 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),10.67(d,J=22.6Hz,1H),8.87(d,J=80. 4Hz,1H),8.20(d,J=7.9Hz,1H),6.72(s,1H),6.64–6.49(m,2H),5.02(d,J=45. 3Hz,1H),4.33(s,2H),3.66(s,1H),3.61–3.44(m,5H),3.37(s,3H),3.33–3.25 (m,3H),3.21–3.15(m,1H),2.16(s,1H),2.02–1.92(m,1H),1.88–1.65(m,5H).

[0535] Example 35: Preparation of (rac,cis,1'S,1'R,1'R,Z)-1'-methyl-5'-(trifluoromethyl)-2'H-10,16-dioxa-3,6,14-triaza-5(3,2)-pyridine-2(5,3)-pyrazole-1(1,3)-cyclopentane-cyclohexadecane-4,15-dione (35)

[0536]

[0537] Compound 35 was prepared according to the synthetic method of Example 7, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-fluoronicotinate methyl ester, and (R)-(4-(3-aminopropoxy)butan-2-yl)carbamic acid tert-butyl ester was used instead of (7-aminoheptyl)carbamic acid tert-butyl ester, to give 37.0 mg of the title product as a white solid.

[0538] LC-MS: m / z=511[M+H] + .

[0539] 1HNMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 10.90 (s, 1H), 8.78 (d, J = 5.5Hz, 1H), 8.34–8.19 (m, 1H), 6.9 5(dd,J=8.2,3.0Hz,2H),6.48(s,1H),4.90(t,J=4.0Hz,1H),3.68–3.42(m,8H),2.28–0.91(m,15H).

[0540] Example 36: Preparation of (rac,cis,1'S,1'R,1'S,Z)-1'-methyl-5'-(trifluoromethyl)-21H-10,16-dioxa-3,6,14-triaza-5(3,2)-pyridine-2(5,3)-pyrazole-1(1,3)-cyclopentane-4,15-dione (36)

[0541]

[0542] Compound 36 was prepared according to the synthetic method of Example 7, except that 2-chloro-6-(trifluoromethyl)nicotinate was used instead of 2-fluoronicotinate methyl ester, and (S)-(4-(3-aminopropoxy)butan-2-yl)carbamic acid tert-butyl ester was used instead of (7-aminoheptyl)carbamic acid tert-butyl ester, to give 17.0 mg of the title product as a white solid.

[0543] LC-MS: m / z=511[M+H] + .

[0544] 1HNMR(400MHz,DMSO-d6)δ12.20(s,1H),10.92(s,1H),8.69(s,1H),8.25(s,1H),6.96(d,J=7.7Hz,1H),6.70(d ,J=7.8Hz,1H),6.58(s,1H),5.01(d,J=73.9Hz,1H),3.87–3.38(m,7H),2.43–1.67(m,10H),1.41–0.74(m,4H).

[0545] Biological evaluation

[0546] Experimental Example 1: In vitro kinase assay

[0547] The inhibitory activity of the compounds of the present invention on CDK2 / CyclinE1, GSK3β, and CDK1 / CyclinA2 kinases was detected using the ADP-Glo ​​assay (Promega, V9102).

[0548] CDK2 / Cyclin E1 kinase assay: Test compounds were dissolved in DMSO (Sigma, D8418) at a starting concentration of 100 nM and diluted three-fold using a 10-well gradient. Using an Echo 550, 5 μl of the diluted compound and 2.5 μl of CDK2 / Cyclin E1 kinase (Carna, 04-165) were added to a 384-well reaction plate (Greiner, 784075). The plate was sealed with a film sealer and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. A mixture of 2.5 μl of Histone H1 Protein (SignalChem, H10-54N) and ATP (Promega, V910B) was then added to the reaction plate. The reaction was centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. 5 μl of ADP-Glo ​​detection reagent (Promega, V9102) was then pipetted into the reaction plate, briefly centrifuged, and incubated for 40 minutes. Finally, 10 μl of the kinase detection reagent included with the ADP-Glo ​​(Promega, V9102) kit was added to the reaction plate and incubated for 40 minutes. RLU (relative luminescence unit) values ​​were read using an Envision 2104 Multi-Mode Plate Reader (PerkinElmer, Oct-04). RLU values ​​are used to characterize the extent of enzyme-substrate reaction. GraphPad Prism 8.0 software was used to calculate compound nonlinearity using fitting formulas for experimental data.

[0549] IC 50:Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0550] X represents the log value of compound concentration; Y represents the inhibition level of kinase; Top and Bottom are the Y values ​​of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

[0551] GSK3β activity assay: Test compounds were dissolved in DMSO (Sigma, D8418) at a starting concentration of 50 μM and diluted three-fold over a 10-well gradient. Using an Echo 550, 5 μl of the diluted compound and 2.5 μl of GSK3β kinase (Signalchem, G09-10G) were added to a 384-well reaction plate (Greiner, 784075). The plate was sealed with a film sealer, centrifuged at 1000 g for 30 seconds, and incubated for 10 minutes. A mixture of 2.5 μl of Histone H1 Protein (SignalChem, H10-54N) and ATP (Promega, V910B) was then added to the plate, centrifuged at 1000 g for 30 seconds, and incubated at room temperature for 1 hour. 5 μl of ADP-Glo ​​detection reagent (Promega, V9102) was then added to the plate and incubated for 1 hour. Finally, add 10 μl of the kinase detection reagent included with the ADP-Glo ​​kit (Promega, V9102) to the reaction plate and incubate for 1 hour. Read the relative luminescence units (RLUs) using an Envision 2104 multi-function plate reader (PerkinElmer, Oct-04). RLU values ​​are used to characterize the extent of enzyme-substrate reaction. Experimental data were calculated using GraphPad Prism 8.0 software using a nonlinear fitting formula.

[0552] Compound IC 50 :Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0553] X represents the log value of compound concentration; Y represents the inhibition level of kinase; Top and Bottom are the Y values ​​of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

[0554] CDK1 / CyclinA2 kinase assay: Dissolve the test compound in DMSO (Sigma, D8418) at a starting concentration of 10 μM and dilute three-fold using a 10-well gradient. Add 5 μl of the diluted compound and 2.5 μl of CDK1 / CyclinA2 kinase (Signalchem, C22-18G-10) to a 384-well reaction plate (Greiner, 784075) using an Echo 550. Seal the plate with film, centrifuge briefly for 30 seconds, and incubate for 10 minutes. Then, add 2.5 μl of the substrate Histone H1 Protein (SignalChem, H10-54N) and ATP mixture (Promega, V910B) to the reaction plate. Centrifuge at 1000 g for 30 seconds, and incubate at room temperature for 2 hours. Then, add 4 μl of ADP-Glo ​​detection reagent (Promega, V9102) to the reaction plate, centrifuge briefly, and incubate for 60 minutes. Finally, add 8 μl of the kinase detection reagent included with the ADP-Glo ​​(Promega, V9102) kit to the reaction plate and incubate for 40 minutes. Use an Envision 2104 multi-function plate reader (PerkinElmer, Oct-04) to read the RLU (relative luminescence unit) value. The RLU value is used to characterize the degree of reaction between the enzyme and the substrate. Experimental data were calculated using GraphPad Prism 8.0 software using a nonlinear fitting formula.

[0555] Compound IC 50 :Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0556] X represents the log value of the compound concentration; Y represents the inhibition level of the kinase; Top and Bottom are the Y values ​​of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

[0557] Table 1 provides the IC values ​​of each exemplified compound for CDK2 / Cyclin E1, GSK3β, and CDK1 / CyclinA2. 50 IC 50 The value is "A", indicating a value less than or equal to 10 nM; "B", indicating a value less than or equal to 100 nM; "C", indicating a value less than or equal to 500 nM; and "D" when the value is greater than 500 nM.

[0558] Table 1 Kinase inhibitory activity of the compounds of the present invention

[0559]

[0560]

[0561] Conclusion: This experimental example provides in vitro enzymatic activity data for a series of compounds. The data collected in Table 1 were obtained using the methods described above. This table provides data on the activity and selectivity of the compounds against CDK2 kinase.

[0562] Experimental Example 2: Cell proliferation experiment

[0563] OVCAR3 cell proliferation assay: The CTG experimental method was used to detect the inhibitory level of the compound on the ovarian cancer cell line OVCAR3.

[0564] OVCAR3 cells were cultured in RPMI-1640 (Invitrogen, A10491-01) supplemented with 20% FBS (Gbico, 10099141) and 1% penicillin-streptomycin (Invitrogen, 15140122), along with 0.01 mg / mL insulin (Aladdin, I302196). 5,000 cells were seeded in a 384-well plate (Corning, 3570) and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the test compound was added. The compound was dissolved in DMSO and diluted to a starting concentration of 10 mM. Three-fold dilutions were performed across 10 concentration gradients, with three replicates per gradient. The cell plates were incubated in a 37°C incubator with 5% CO2 for 7 days. The CELL Titer-GLO luminescence assay was used to measure total ATP content to determine cell proliferation. Cells were removed from the 384-well plate and equilibrated at room temperature for 30 minutes. 20 μL of CTG (CTG, Promega, Cat. No. G7572) was added to each well, mixed by vortexing, and incubated at room temperature for 10 minutes. Luminescence values ​​were read using a multifunctional microplate reader (Biotek, Model Cytation 3). GraphPad Prism 8.0 software was used to analyze the logarithmic values ​​of compound responses at different concentrations to determine the IC value of proliferation. 50 .

[0565] Table 2 shows the inhibitory levels of the compounds of the present invention on OVCAR3 cell proliferation. 50 Values ​​are indicated as "A" for values ​​less than or equal to 200 nM; "B" for values ​​less than or equal to 500 nM; "C" for values ​​less than or equal to 1000 nM; and "D" for values ​​greater than 1000 nM.

[0566] Table 2 Inhibitory effects of the compounds of the present invention on OVCAR3 cell proliferation

[0567]

[0568]

[0569] The above data results show that the compound of the present invention has a significant inhibitory effect on the proliferation of OVCAR3 cells.

Claims

1. A compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring A is selected from heteroaryl, aryl, heterocyclyl or cycloalkyl; X is selected from -C(O)-, -S(O)-, -S(O)2-; U is: -L 1 -L 2 -L 3 -; in: L 1 、L 2 、L 3 Each is independently selected from a single bond, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a -NR c -, -O-, -S-, -NHC(O)-, -C(O)NH-, -NHS(O) p -、-S(O) p NH-、-(CR d R e ) m O-、-(CR d R e ) m NH-、-(CR d R e ) m NHC(O)-、-(CR d R e ) m C(O)NH-、-O(CR d R e ) m -、-NH(CR d R e ) m -、-NHC(O)-(CR d R e ) m -、-C(O)NH(CR d R e ) m -, wherein the alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, provided that L 1 、L 2 、L 3 Not all are single bonds; R 1 is selected from hydrogen and alkyl; R 2 is selected from hydrogen and alkyl; Each R 3 Each is independently selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CR d R e ) v OR c 、-OR c 、-C(O)R c 、-OC(O)R c 、-C(O)OR c 、-C(O)NR a R b 、-NHC(O)R c 、-S(O) p R c 、-S(O) p NR a R b 、-NHS(O) p R c wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or Two adjacent R 3 The atoms to which it is attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group; the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R a and R b each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R a and R b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R c selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R d and R e each independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or R d and R e Together with the nitrogen atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; p is 1 or 2; n is an integer from 0 to 3; m is an integer from 1 to 10; v is an integer from 1 to 6.

2. The compound of general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Ring A, U, R 1 、R 2 、R 3 , n as defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-10 membered heteroaryl or a C6-C 10 Aryl.

4. The compound of general formula (I) according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 5-6 membered heteroaryl or phenyl, preferably pyrazolyl, pyridyl, imidazolyl, pyrrolyl, thiazolyl or phenyl.

5. A compound of the general formula (I) according to any one of claims 1 to 4, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVA) or (IVB), or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Z1 is selected from CH or N; Z2 is selected from CH or N; R 1 、R 2 、R 3 , L 1 , L 2 , L 3 , n as defined in claim 1.

6. The compound of general formula (I) according to any one of claims 1 to 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R 3 are independently selected from halogen, cyano, C 1-6 Alkyl, -(CR d R e ) v OR c , wherein the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from halogen; R d and R e are each independently selected from hydrogen and C 1-6 Alkyl; R c Selected from C 1-6 alkyl; v is an integer from 1 to 4, preferably 1 or 2; more preferably 1; n is 0 or 1.

7. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: -L 1 -L 2 -L 3 -Selected from C 1-10 Alkylene, preferably C 4-10 Alkylene.

8. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from single bond, C 1-6 Alkylene, -NR c -、-O-、-S-、-(CR d R e ) m O-、-(CR d R e ) m NH-、-NH(CR d R e ) m -、-(CR d R e ) m NHC(O)-、-(CR d R e ) m C(O)NH-, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl, C 3-6 One or more groups are substituted on the cycloalkyl group; L 2 Selected from C 1-6 Alkylene, -O-, -S-, -NHC(O)-, -C(O)NH-, -(CR d R e ) m O-、-O(CR d R e ) m -、C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl, C 3-6 One or more groups are substituted on the cycloalkyl group; L 3 Selected from single bond, C 1-6 Alkylene, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group, wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group may be further selected from halogen, C 1-6 Alkyl, C 3-6 One or more groups are substituted on the cycloalkyl group; R c Selected from hydrogen or C 1-6 alkyl; R d and R e Each independently selected from hydrogen or C 1-6 alkyl; m is an integer of 1 to 6.

9. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from -O-; L 2 Selected from C 1-6 Alkylene, wherein the C 1-6 The alkylene group is optionally replaced by C 1-6 Alkyl substitution; L 3 Selected from single bond, C 1-6 Alkylene, wherein the C 1-6 Alkylene is optionally selected from C 1-6 Alkyl substitution.

10. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from-NR c -; L 2 Selected from C 1-6 Alkylene, -(CR d R e ) m O-; L 3 Selected from C 1-6 Alkylene, C 3-6 Cycloalkyl, wherein the C 1-6 The alkylene group is optionally replaced by C 1-6 Alkyl substitution; R c Selected from hydrogen or C 1-6 alkyl; R d and R e are each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen; m is an integer of 1 to 6.

11. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from -NH(CR d R e ) m -; L 2 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably C 3-6 Cycloalkyl; L 3 Selected from C 1-6 alkylene; R d and R e are each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen; m is an integer of 1 to 6.

12. A compound of the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from -(CR d R e ) m NHC(O)-; L 2 Selected from C 1-6 Alkylene, -O-, -(CR d R e ) m O-; L 3 Selected from C 1-6 alkylene; R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen; m is an integer of 1 to 6, preferably an integer of 1 to 4, more preferably 1 or 2.

13. A compound of formula (I) according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from-NR c -; L 2 Selected from C 1-6 alkylene; L 3 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably 5-6 membered heterocyclic group.

14. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from -NH(CR d R e ) m -; L 2 Selected from -O(CR d R e ) m -; L 3 Selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, preferably C 3-6 Cycloalkyl; R d and R e Each independently selected from hydrogen or C 1-6 Alkyl, preferably hydrogen.

15. The compound of general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L 1 Selected from C 1-6 Alkylene, preferably C 1-4 alkylene; L 2 is selected from 5-6 membered heterocyclic groups; L 3 Selected from C 3-6 Cycloalkyl.

16. The compound of general formula (I) according to any one of claims 1 to 15, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen and C 1-6 alkyl.

17. A compound of formula (I) according to any one of claims 1 to 16, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from hydrogen and C 1-6 alkyl.

18. A compound of formula (I) according to any one of claims 1 to 17, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

19. A method for preparing a compound of formula (I) according to any one of claims 1 to 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: Compound Ig is heated in an acidic solvent to react and remove the protecting group to obtain a compound of formula (I), wherein the acidic solvent is preferably formic acid or trifluoroacetic acid; Among them, X, ring A, U, R 1 、R 2 、R 3 , n as defined in claim 1.

20. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. Use of a compound of formula (I) according to any one of claims 1 to 18, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for preventing and / or treating diseases associated with CDK2 kinase activity.

22. Use of a compound of the general formula (I) according to any one of claims 1 to 18 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for preventing and / or treating diseases associated with protein-dependent kinase or cyclin signaling pathways.

23. The use according to claim 22, wherein the disease is selected from endometrial cancer, ovarian cancer, breast cancer, primary peritoneal cancer, gastric cancer, and lung cancer.

Images