Pyrimide macroheterocyclic compounds as Wee1-Yes dual-target inhibitors and their applications

Abstract

This invention is the first to disclose novel pyrimide macroheterocyclic compounds having dual target inhibitory activity for WEE1 and Yes, and more specifically, discloses compounds represented by the structure of formula (I) as dual target inhibitors for WEE1 and Yes, or pharmaceutically acceptable salts, solvates, hydrates, isotopic substitutions or isomers thereof, and crystalline polymorphs thereof. [C256] TIFF2026516129000323.tif39170

Description

[Technical Field]

[0001] This invention claims priority to the prior application filed with the International Bureau on May 10, 2023, with international patent application number PCT / CN2023 / 093349, titled "Novel Pyrimide Heterocyclic Compounds as Wee1 Inhibitors and Their Applications."

[0002] The present invention belongs to the field of medicinal chemistry and specifically includes the world's first disclosure of a novel pyrimide macroheterocyclic compound capable of simultaneously inhibiting the dual targets WEE1 and Yes, a composition comprising such a compound, and a method of applying such a compound to the manufacture of a drug for treating or preventing WEE1 and / or Yes target-related diseases. [Background technology]

[0003] The cell cycle is a highly regulated and controlled process. A normal cell cycle has checkpoints in each of the G1 / S, S, and G2 / M phases, allowing sufficient time for DNA damage repair. Normally, after DNA damage, TP53 checks the cell in the G1 / S phase, preventing it from proceeding to the G2 phase until the damaged DNA is repaired. If TP53 function is impaired and the G1 / S phase check is not performed correctly, the cell proceeds to the G2 phase carrying damaged information. WEE1 is a member of the serine / threonine protein kinase family and plays a crucial regulatory role in the G2 / M phase checkpoint process of the cell cycle. WEE1 kinase inhibits the activity of CDK kinase by phosphorylating Tyr14 and Tyr15 of CDK, thereby capturing the G2 / M phase of the cell cycle and giving the cell sufficient time to repair DNA damage. Inhibition of WEE1 eliminates cell cycle arrest and causes cells to enter mitosis prematurely, leading to cell replication stress and impaired mitotic progression.

[0004] WEE1 is overexpressed in many cancers, including breast cancer, lung cancer, cervical cancer, head and neck cancer, ovarian cancer, prostate cancer, melanoma, leukemia, glioblastoma, medulloblastoma, and liver cancer. Overexpression of WEE1 in cancer cells is a normal response to increased pressure on cancer cell replication and has a certain correlation with decreased tumor progression and disease-free survival. Therefore, WEE1 inhibitory therapy is already a very promising cancer treatment method and can be used in combination with the treatment of DNA damage. Extensive studies have demonstrated a synthetic lethal relationship between WEE1 and TP53. In tumor cells with inactivated TP53 mutations, the tumor cells lack G1 / S phase testing function and become highly dependent on G2 / M phase testing. When WEE1 function is inhibited in tumor cells lacking TP53 function, the tumor cells cannot repair damage normally, leading to a constant accumulation of incorrect information, ultimately triggering apoptosis in the tumor cells and achieving a further tumor-inhibiting effect. Therefore, WEE1 inhibitors have enormous synthetic lethal therapeutic value in TP53-mutated cancers.

[0005] Oral small molecule Wee1 inhibitors have already been reported in several publications and patents, and some candidate compounds, such as ZN-c3, AZD-1775, IMP 7068, and Debio 0123, have already entered clinical trials. However, single-target Wee1 selective inhibitors typically have relatively weak therapeutic effects in terms of antitumor growth, and most clinical candidate molecules generally suffer from relatively low efficacy, low selectivity, rapid metabolism, poor oral absorption, low bioavailability, and a narrow safety window, resulting in a relatively large lack of drug potential.

[0006] Yes-related protein (YAP) is a major transcriptional co-activator of the Hippo pathway. By binding to the transcription factor TEAD, it can regulate downstream targets correlated with cell proliferation and survival. Unregulated YAP leads to metastasis and poor prognosis in invasive tumors, including pancreatic, gastric, and lung cancers. Therefore, Yes-targeted inhibitors may be a promising tumor treatment strategy.

[0007] According to research, both Yes and Wee1 are co-overexpressed in many malignant tumors, such as pancreatic cancer, small cell lung cancer, gastric cancer, intestinal cancer, ovarian cancer, etc., and it has been found that they play a significant role in the growth, invasion and metastasis of malignant tumors. Developing an inhibitor that can simultaneously inhibit the targets of Yes and Wee1 will further enhance the therapeutic effect. However, up to the filing date of this patent, there are still no reports or patents in the world on compounds that can simultaneously inhibit the targets of Yes and Wee1.

Summary of the Invention

[0008] An object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer, isotope-substituted form thereof, and a crystal polymorph thereof,

Chemical Formula

[0009] According to embodiments of the present invention, X0, X1, and X2 are each independently -C(R x )- or -N-, selected from R x H, C 1-6 It is selected from alkyl groups (e.g., methyl groups).

[0010] According to embodiments of the present invention, X0 is -CH-.

[0011] According to embodiments of the present invention, X1 is N.

[0012] According to embodiments of the present invention, X2 is N.

[0013] According to embodiments of the present invention, L is selected from O, S, or NH.

[0014] According to embodiments of the present invention, L3, L4, L5, L6, and L7 are homologous or different, and are independently absent, single-bonded, unsubstituted, or optionally one, two, or more R d1 C replaced by 1-6 Alkylene group, C 2-6 Selected from alkenylene groups, According to embodiments of the present invention, L3, L4, L5, L6, and L7 are homologous or different, and are independently absent, single-bonded, unsubstituted, or optionally one, two, or more R d1 Substituted CH2, CH2CH2, CH2CH2CH2, CH=CH, CH = Selected from CHCH2

[0015] According to an embodiment of the present invention, L3 is -C(R d1 )(R d1 )- is selected from, and preferably is -C(CH3)(OH)-.

[0016] According to embodiments of the present invention, L6 is selected from vinylidene groups, and the vinylidene group is preferably in cis form.

[0017] According to an embodiment of the present invention, L4, L5, and L7 are the same or different and are each independently selected from CH2.

[0018] According to an embodiment of the present invention, each R d1 is the same or different and is each independently selected from H, OH, C 1-6 alkyl group (e.g., methyl group).

[0019] According to an embodiment of the present invention, ring C is selected from an unsubstituted or R0-substituted heterocyclyl group, and the heterocyclyl group is a piperidinyl group (e.g.,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0020] According to an embodiment of the present invention,

Chemical formula

[0021] According to embodiments of the present invention, R0 is H, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, deuterated C 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, HC(O)-, NH2C(O)-, C 1-10 Alkyl-C(O)-, C 1-10 Alkoxy-C(O)-, C 3-8 Selected from cycloalkyl-C(O)- and 3- to 8-membered heterocyclyl groups.

[0022] Preferably, R0 is H, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, deuterated C 1-6 Alkyl, halo C 1-6 Alkyl alkyl groups, HC(O)-, NH2C(O)-, C 1-6 Alkyl-C(O)-, C 1-6 Alkoxy-C(O)-, C 3-6 Selected from cycloalkyl-C(O)- and 3- to 6-membered heterocyclyl groups.

[0023] According to embodiments of the present invention, R0 is H, methyl group, ethoxy group, trihydrogenated methyl group, CF3CH2-, HC(O)-, CH3C(O)-, [ka] They are selected from among them.

[0024] According to embodiments of the present invention, each R1 is homologous or different, and independently of each other, H, deuterium, oxo (=O), and C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C(O)-, Halo-C 1-6 Alkyl, halo C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group.

[0025] Preferably, each R1 is homologous or different, and independently of each other, H, deuterium, oxo (=O), and C1-6 An alkyl group, C 1-6 Selected from alkoxy-C(O)-.

[0026] According to an embodiment of the present invention, each R1 is the same or different, and independently of each other is H, a methyl group, deuterium, oxo (=O),

Chemical formula

[0027] According to an embodiment of the present invention, each R2 is the same or different, and independently of each other is H, deuterium, oxo (=O), C 1-6 An alkyl group, C 1-6 An alkoxy group, C 1-6 Alkoxy-C(O)-, haloC 1-6 An alkyl group, haloC 1-6 An alkoxy group, C 1-6 An alkylamino group, C 6-10 Selected from an aryl group or a 5- to 10-member heteroaryl group.

[0028] According to an embodiment of the present invention, each R2 is the same or different, and independently of each other is H or C 1-6 Selected from an alkyl group (for example, a methyl group).

[0029] According to an embodiment of the present invention, each R5 is the same or different, and independently of each other is H, deuterium, oxo (=O), C 1-6 An alkyl group, C 1-6 An alkoxy group, C 1-6 Alkoxy-C(O)-, haloC 1-6 An alkyl group, haloC 1-6 An alkoxy group, C 1-6 An alkylamino group, C 6-10 Selected from an aryl group or a 5- to 10-member heteroaryl group.

[0030] According to an embodiment of the present invention, each R5 is the same or different, and independently of each other is H or C 1-6 Selected from an alkyl group (for example, a methyl group).

[0031] In one aspect of the present invention, the above compound or its pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions and crystalline polymorphs thereof having the structure of formula (II), [ka] Of these, L, L3, L4, L5, L6, L7, X0, X1, X2, R0, R1, R2, R5, m, n, and q have the above definitions independently of each other.

[0032] According to embodiments of the present invention, X0, X1, and X2 are each independently -C(R x )- or -N- selected, L3, L4, L5, L6, and L7 are independently absent, single bond, double bond, acetylene bond, and -C(R d1 )(R d2 )-,-C(R d1 )(R d2 )C(R d1 )(R d2 )-,-OC(R d1 )(R d2 )-,-C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-,-N(R d3 )C(=O)-, -N(R d3 )-, -C(=NR d3 )-,-S(=O)2N(R d3 )-,-N(R d3 )S(=O)2-, -C(R d1 )(R d2 )N(R d3 )-,-N(R d3 )C(R d1 )(R d2 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -N-, -CH-, -S(=O)-, or -S(=O)2- are selected, L is arbitrarily and independently selected from O, S, or NH. R0 is independently selected from H, deuterium, halogen, alkyl group, haloalkyl group, deuterated alkyl group, cycloalkyl group, heterocyclyl group, alkoxyalkyl group, alkynyl group, acetyl group, methylsulfonyl group, and phosphono group. Furthermore, the hydrogen atoms on R0 are optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH3, carboxyl group, OH, and CN. Each R2 or R5 may be homologous or different, and may be independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10R2 or R5 may be selected from alkyl-substituted carboxyl groups or carboxyl-substituted groups, aryl groups, or heteroaryl groups, or any two R2 or R5 may form a 3- to 8-membered monocyclic or polycyclic structure together with carbon atoms linked to it on the ring, and the above monocyclic or polycyclic structure may be optionally selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the above aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings may contain 0 to more unsaturated alkenyl bonds, and furthermore, the hydrogen on R2 or R5 is optionally most preferably H or deuterium. The atoms are substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN, or any two R2 and R5 atoms together with the carbon attached to them form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms on the above aryl groups, saturated or partially saturated cycloalkyl groups, and heterocycloalkyl groups are optionally hydrogen, deuterium, halogens, -CN, -OH, CF3, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl(2), =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R1, R d1 , R d2 , R x These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the above alkyl groups, alkenyl groups, alkynyl groups, aryl groups, saturated or partially saturated cycloalkyl groups, heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogens, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further composed of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or R d1 and R d2 or R d1 R5 may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, and OCH2CH3. R d3This is, arbitrarily and independently, hydrogen, NH2, and C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, of which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can be further optionally hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially substituted groups, such as saturated cycloalkyl groups or heterocyclyl groups. The above heteros represent heteroatoms and their isotopes that are arbitrarily and independently selected from O, N, S, P, S=O, and S(=O)2. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3.

[0033] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof having the structure of formula (IA), [ka] Among them, L, X2, R0, R1, R2, R5, R d1 m, n, and q have the above definitions independently of each other, and p is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0034] According to embodiments of the present invention, X2 is independently -C(R x )- or -N- selected, L is arbitrarily and independently selected from O, S, or NH. R0 is independently selected from H, deuterium, halogen, alkyl group, haloalkyl group, deuterated alkyl group, cycloalkyl group, heterocyclyl group, alkoxyalkyl group, alkynyl group, acetyl group, methylsulfonyl group, and phosphono group. Furthermore, the hydrogen atoms on R0 are optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH3, carboxyl group, OH, and CN. Each R2 or R5 may be homologous or different, and may be independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 R2 or R5 may be selected from alkyl-substituted carboxyl groups or carboxyl-substituted groups, aryl groups, or heteroaryl groups, or any two R2 or R5 may form a 3- to 8-membered monocyclic or polycyclic structure together with carbon atoms linked to it on the ring, and the above monocyclic or polycyclic structure may be optionally selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the above aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings may contain 0 to more unsaturated alkenyl bonds, and furthermore, the hydrogen on R2 or R5 is optionally most preferably H or deuterium. The atoms are substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN, or any two R2 and R5 atoms together with the carbon attached to them form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms on the above aryl groups, saturated or partially saturated cycloalkyl groups, and heterocycloalkyl groups are optionally hydrogen, deuterium, halogens, -CN, -OH, CF3, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl(2), =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R1, R d1 and R x These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10Alkylamino group, aryl group, heteroaryl group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the above alkyl groups, alkenyl groups, alkynyl groups, aryl groups, saturated or partially saturated cycloalkyl groups, heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogens, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further composed of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1 R5 may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, and OCH2CH3. The above heteros represent heteroatoms and their isotopes that are arbitrarily and independently selected from O, N, S, P, S=O, and S(=O)2. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. p is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0035] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope substitution thereof, or an isomer thereof having the structure of formula (IB), [ka] Among them, R0, R1, R2, R5, R d1 m, n, and q have the above definitions independently of each other.

[0036] According to embodiments of the present invention, R0 is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups. Furthermore, the hydrogen atoms on R0 are optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN. Each R2 or R5 may be homologous or different, and may be independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 R2 or R5 may be selected from alkyl-substituted carboxyl groups or carboxyl-substituted groups, aryl groups, or heteroaryl groups, or any two R2 or R5 may form a 3- to 8-membered monocyclic or polycyclic structure together with carbon atoms linked to it on the ring, and the above monocyclic or polycyclic structure may be optionally selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the above aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings may contain 0 to more unsaturated alkenyl bonds, and furthermore, the hydrogen on R2 or R5 is optionally most preferably H or deuterium. The atoms are substituted with one or more substituents selected from halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN, or any two R2 and R5 atoms together with the carbon attached to them form a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen atoms on the above aryl groups, saturated or partially saturated cycloalkyl groups, and heterocycloalkyl groups are optionally hydrogen, deuterium, halogens, -CN, -OH, CF3, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl(2), =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R1 and Rd1 These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the above alkyl groups, alkenyl groups, alkynyl groups, aryl groups, saturated or partially saturated cycloalkyl groups, heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogens, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further composed of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1R5 may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, and OCH2CH3. The above heteros represent heteroatoms and their isotopes that are arbitrarily and independently selected from O, N, S, P, S=O, and S(=O)2. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. p is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0037] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope substitution thereof, or an isomer thereof having the structure of formula (IC), [ka] Of these, R0, R1, R2, m, and n have the above definitions independently of each other.

[0038] According to embodiments of the present invention, R0 is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups. Furthermore, the hydrogen atoms on R0 are optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN. Each R2 can be homologous or different, and can be independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 R2 is selected from alkyl-substituted carboxyl groups or carboxyl-substituted groups, aryl groups, heteroaryl groups, or any two R2 groups together with carbon atoms linked to them on the ring to form a 3- to 8-membered monocyclic or polycyclic structure, and the above monocyclic or polycyclic structure may be optionally selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the above aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings may contain 0 to more unsaturated alkenyl bonds, and furthermore, the hydrogen on R2 is optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN. R1 independently contains hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C 1-10 Alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the above alkyl groups, alkenyl groups, alkynyl groups, aryl groups, saturated or partially saturated cycloalkyl groups, heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogens, -CN, -OH, CF3, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further composed of hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1 R5 may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, and among these, the cycloalkyl group and heterocycloalkyl group may be optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo isomer, CN, CF3, OH, OCH3, and OCH2CH3. The above heteros represent heteroatoms and their isotopes that are arbitrarily and independently selected from O, N, S, P, S=O, and S(=O)2. The above halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, and 4.

[0039] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof having the structure of formula (ID), [ka] Of these, R0 and R2 have the above definitions independently of each other.

[0040] According to embodiments of the present invention, R0 is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups. Furthermore, the hydrogen atoms on R0 are optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN. R2 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10R2 is selected from alkyl-substituted carboxyl groups or carboxyl-substituted groups, aryl groups, heteroaryl groups, or any two R2 groups, together with carbon atoms linked to them on the ring, form a 3- to 8-membered monocyclic or polycyclic structure, and the above monocyclic or polycyclic structure may be optionally selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the above aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings may contain 0 to more unsaturated alkenyl bonds, and furthermore, the hydrogen on R2 is optionally and most preferably substituted with one or more substituents selected from H, deuterium, halogens, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, OCH3, carboxyl groups, OH, and CN. The above heteros represent heteroatoms and their isotopes that are arbitrarily and independently selected from O, N, S, P, S=O, and S(=O)2. The halogens mentioned above are arbitrarily and independently selected from F, Cl, Br, I and their isotopes.

[0041] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope substitution thereof, or an isomer thereof having the structure of formula (III), [ka] Among them, rings C, L, X0, X1, X2, R1, R2, R5, R d1 m, n, and q have the above definitions independently of each other.

[0042] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope substitution thereof, or an isomer thereof having the structure of formula (IIIA), [ka] Among them, L, X2, R0, R1, R2, R d1 These terms have the above definitions independently of each other.

[0043] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof having the structure shown below, [ka] TIFF2026516129000020.tif211170TIFF2026516129000021.tif225170TIFF2026516129000022.tif212170

[0044] In one embodiment of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof having the structure shown below, [ka] TIFF2026516129000024.tif232170TIFF2026516129000025.tif231170TIFF2026516129000026.tif178170

[0045] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof, an isotope-substituted compound, or an isomer thereof having the structure of formula (IE), [ka]

[0046] The present invention further provides crystalline polymorphs of compounds represented by formula (IE). [ka]

[0047] According to embodiments of the present invention, the above-mentioned crystalline polymorphs include, but are not limited to, the solvate crystalline form, hydrate crystalline form, or metastable crystalline form of compound IE. Furthermore, according to embodiments of the present invention, the solvate crystal form may be crystal forms A, B, or C below, the hydrate crystal form may be crystal forms D, E, F, or G below, and the metastable crystal form may be crystal forms H, I, J, K, L, M, N, O, P, or Q below. Regarding crystal form A, The present invention provides a crystalline form A of compound (IE), the X-ray powder diffraction pattern thereof includes peaks located at diffraction angles (2θ) of 5.10±0.2°, 15.72±0.2°, 15.25±0.2° and 20.53±0.2°. According to the present invention, the crystal form A preferably further includes peaks located at diffraction angles (2θ) of 23.66±0.2°, 23.92±0.2°, 17.47±0.2°, 20.14±0.2°, and 24.44±0.2°. According to the present invention, it is even more preferable that the above crystal form A further includes peaks located at diffraction angles (2θ) of 26.66±0.2°, 17.22±0.2°, 26.92±0.2°, 16.48±0.2°, 10.20±0.2° and 21.97±0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form A has the diffraction angle (2θ) shown in Table 1, and the error range of the 2θ angle is ±0.20°. [Table 1]

[0048] Preferably, the above crystal form A has the X-ray powder diffraction intensity shown in Table 1. Preferably, the above crystal form A basically has the X-ray powder diffraction pattern shown in Figure 1. Preferably, DSC analysis of the above crystal form A shows an endothermic peak when heated to a peak temperature of around 180.86°C. Preferably, the above crystal form A basically has the DSC pattern shown in Figure 2. Preferably, the above crystal form A basically has the TGA pattern shown in Figure 3.

[0049] Regarding crystal form B, The present invention provides a crystalline form B of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 10.33±0.2°, 5.18±0.2°, 13.69±0.2° and 18.72±0.2°. According to the present invention, the above crystal form B preferably further includes peaks located at diffraction angles (2θ) of 8.96±0.2°, 11.73±0.2°, 25.89±0.2°, 17.10±0.2°, and 23.20±0.2°. According to the present invention, it is even more preferable that the above crystal form B further includes peaks located at diffraction angles (2θ) of 26.13±0.2°, 24.92±0.2°, 22.77±0.2°, 20.85±0.2°, 17.95±0.2° and 36.45±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form B has the diffraction angle (2θ) shown in Table 2, and the error range of the above 2θ angle is ±0.20°. [Table 2]

[0050] Preferably, the above crystal form B has the X-ray powder diffraction intensity shown in Table 2. Preferably, the above crystal form B basically has the X-ray powder diffraction pattern shown in Figure 4. Preferably, DSC analysis of the above crystal form B shows an endothermic peak when heated to a peak temperature of around 179.71°C. Preferably, the above crystal form B basically has the DSC pattern shown in Figure 5. Preferably, the above crystal form B basically has the TGA pattern shown in Figure 6.

[0051] Regarding crystal form C, The present invention provides a crystalline form C of compound (IE), the X-ray powder diffraction pattern thereof includes peaks located at diffraction angles (2θ) of 5.39±0.2°, 12.05±0.2°, 9.70±0.2° and 18.00±0.2°. According to the present invention, the above crystal form C preferably further includes peaks located at diffraction angles (2θ) of 23.06±0.2°, 21.21±0.2°, 17.30±0.2°, 17.14±0.2°, and 25.09±0.2°. According to the present invention, the above crystal form C more preferably further includes peaks located at diffraction angles (2θ) of 22.39±0.2°, 19.54±0.2°, 13.48±0.2°, 27.27±0.2°, 10.68±0.2° and 5.98±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form C has the diffraction angle (2θ) shown in Table 3, and the error range of the above 2θ angle is ±0.20°. [Table 3]

[0052] Preferably, the above crystal form C has the X-ray powder diffraction intensity shown in Table 3. Preferably, the above crystal form C basically has the X-ray powder diffraction pattern shown in Figure 7. Preferably, DSC analysis of the above crystal form C shows an endothermic peak when heated to a peak temperature of around 173.43°C. Preferably, the above crystal form C basically has the DSC pattern shown in Figure 8. Preferably, the above crystal form C basically has the TGA pattern shown in Figure 9.

[0053] Regarding the hydrate crystal form D, The present invention provides a hydrate crystal form D of compound (IE), the X-ray powder diffraction pattern thereof includes peaks located at diffraction angles (2θ) of 5.20±0.2°, 15.74±0.2°, 22.81±0.2° and 18.39±0.2°. According to the present invention, the crystal form D preferably further includes peaks located at diffraction angles (2θ) of 23.12±0.2°, 7.81±0.2°, 16.78±0.2°, 5.89±0.2°, and 10.43±0.2°. According to the present invention, it is even more preferable that the crystal form D further includes peaks located at diffraction angles (2θ) of 25.44±0.2°, 13.08±0.2°, 15.06±0.2°, 18.96±0.2°, 21.04±0.2° and 21.95±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form D has the diffraction angle (2θ) shown in Table 4, and the error range of the above 2θ angle is ±0.20°. [Table 4]

[0054] Preferably, the crystal form D has the X-ray powder diffraction intensity shown in Table 4. Preferably, the above crystal form D basically has the X-ray powder diffraction pattern shown in Figure 10. Preferably, DSC analysis of the above crystal form D shows endothermic peaks when heated to peak temperatures around 157.79°C and 181.65°C. Preferably, the above crystal form D basically has the DSC pattern shown in Figure 11. Preferably, the crystal form D has basically the TGA pattern shown in Figure 12.

[0055] Regarding the hydrate crystal form E, The present invention provides a hydrate crystal form E of compound (IE), the X-ray powder diffraction pattern thereof includes peaks located at diffraction angles (2θ) of 4.54±0.2°, 13.72±0.2°, 9.12±0.2° and 18.35±0.2°. According to the present invention, the crystal form E preferably further includes peaks located at diffraction angles (2θ) of 15.88±0.2°, 23.00±0.2°, 5.24±0.2°, 23.88±0.2°, and 17.20±0.2°. According to the present invention, the crystal form E more preferably further includes peaks located at diffraction angles (2θ) of 21.72±0.2°, 20.42±0.2°, 23.49±0.2°, 25.01±0.2°, 25.29±0.2° and 9.72±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form E has the diffraction angle (2θ) shown in Table 5, and the error range of the above 2θ angle is ±0.20°. [Table 5]

[0056] Preferably, the above crystal form E has the X-ray powder diffraction intensity shown in Table 5. Preferably, the above crystal form E basically has the X-ray powder diffraction pattern shown in Figure 13. Preferably, DSC analysis of the above crystal form E shows endothermic peaks when heated to peak temperatures of around 69.77°C and 181.95°C. Preferably, the above crystal form E basically has the DSC pattern shown in Figure 14. Preferably, the above crystal form E basically has the TGA pattern shown in Figure 15.

[0057] Regarding the hydrate crystal form F, The present invention provides a hydrate crystal form F of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 9.08±0.2°, 18.27±0.2°, 6.25±0.2° and 13.73±0.2°. According to the present invention, the crystal form F preferably further includes peaks located at diffraction angles (2θ) of 7.52±0.2°, 5.12±0.2°, 10.25±0.2°, 10.50±0.2°, and 15.16±0.2°. According to the present invention, the above crystal form F more preferably further includes peaks located at diffraction angles (2θ) of 15.00±0.2°, 16.60±0.2°, 19.04±0.2°, 21.46±0.2°, 27.60±0.2° and 11.71±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form F has the diffraction angle (2θ) shown in Table 6, and the error range of the above 2θ angle is ±0.20°. [Table 6]

[0058] Preferably, the above crystal form F has the X-ray powder diffraction intensity shown in Table 6. Preferably, the above crystal form F has basically the X-ray powder diffraction pattern shown in Figure 16. Preferably, DSC analysis of the above crystal form F shows endothermic peaks when heated to peak temperatures of around 101.36°C and 177.98°C, and a heat dissipation peak appears around 146.72°C. Preferably, the above crystal form F basically has the DSC pattern shown in Figure 17. Preferably, the above crystal form F basically has the TGA pattern shown in Figure 18.

[0059] Regarding the hydrate crystal form G, The present invention provides a hydrate crystal form G of compound (IE), the X-ray powder diffraction pattern thereof includes peaks located at diffraction angles (2θ) of 9.06±0.2°, 14.98±0.2°, 15.76±0.2° and 18.16±0.2°. According to the present invention, the above crystal form G preferably further includes peaks located at diffraction angles (2θ) of 12.04±0.2°, 20.96±0.2°, 24.12±0.2°, 9.89±0.2°, and 28.54±0.2°. According to the present invention, the above crystal form G more preferably further includes peaks located at diffraction angles (2θ) of 7.93±0.2°, 6.03±0.2°, 25.73±0.2°, 27.70±0.2°, 21.78±0.2° and 24.51±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form G has the diffraction angle (2θ) shown in Table 7, and the error range of the above 2θ angle is ±0.20°. [Table 7]

[0060] Preferably, the above crystal form G has the X-ray powder diffraction intensity shown in Table 7. Preferably, the above crystal form G has basically the X-ray powder diffraction pattern shown in Figure 19. Preferably, DSC analysis of the above crystal form G shows an endothermic peak when heated to a peak temperature of around 126.74°C. Preferably, the above crystal form G basically has the DSC pattern shown in Figure 20. Preferably, the above crystal form G basically has the TGA pattern shown in Figure 21.

[0061] Regarding metastable crystal forms of H, The present invention provides a metastable crystalline form H of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 6.02±0.2°, 3.96±0.2°, 12.66±0.2° and 9.35±0.2°. According to the present invention, the above crystal form H preferably further includes peaks located at diffraction angles (2θ) of 15.49±0.2°, 12.06±0.2°, 4.42±0.2°, 11.38±0.2° and 18.31±0.2°. According to the present invention, the above crystal form H more preferably further includes peaks located at diffraction angles (2θ) of 6.68±0.2°, 13.87±0.2°, 9.88±0.2°, 19.05±0.2°, 17.92±0.2° and 8.94±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form H has the diffraction angle (2θ) shown in Table 8, and the error range of the above 2θ angle is ±0.20°. [Table 8]

[0062] Preferably, the above crystal form H has the X-ray powder diffraction intensity shown in Table 8. Preferably, the above crystal form H basically has the X-ray powder diffraction pattern shown in Figure 22. Preferably, DSC analysis of the above crystalline form H shows endothermic peaks when heated to peak temperatures of around 61.06°C and 151.59°C. Preferably, the above crystal form H basically has the DSC pattern shown in Figure 23. Preferably, the above crystal form H basically has the TGA pattern shown in Figure 24.

[0063] Regarding metastable crystal form I, The present invention provides a metastable crystalline form I of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.93±0.2°, 4.37±0.2°, 16.01±0.2° and 7.45±0.2°. According to the present invention, the above crystal form I preferably further includes peaks located at diffraction angles (2θ) of 6.45±0.2°, 22.79±0.2°, 17.57±0.2°, 17.98±0.2°, and 15.14±0.2°. According to the present invention, the above crystal form I more preferably further includes peaks located at diffraction angles (2θ) of 22.48±0.2°, 16.65±0.2°, 10.00±0.2°, 12.59±0.2°, 20.05±0.2° and 25.54±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form I has the diffraction angle (2θ) shown in Table 9, and the error range of the above 2θ angle is ±0.20°. [Table 9]

[0064] Preferably, the above crystal form I has the X-ray powder diffraction intensity shown in Table 9. Preferably, the above crystal form I basically has the X-ray powder diffraction pattern shown in Figure 25.

[0065] Regarding metastable crystal form J, The present invention provides a metastable crystalline form J of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 5.78±0.2°, 8.06±0.2°, 12.04±0.2° and 16.19±0.2°. According to the present invention, the crystal form J preferably further includes peaks located at diffraction angles (2θ) of 17.14±0.2°, 14.55±0.2°, 10.35±0.2°, 11.59±0.2°, and 19.77±0.2°. According to the present invention, the crystal form J more preferably further includes peaks located at diffraction angles (2θ) of 7.25±0.2°, 20.81±0.2°, 26.22±0.2°, 20.57±0.2°, 24.25±0.2° and 22.62±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form J has the diffraction angle (2θ) shown in Table 10, and the error range of the above 2θ angle is ±0.20°. [Table 10]

[0066] Preferably, the above crystal form J has the X-ray powder diffraction intensity shown in Table 10. Preferably, the above crystal form J basically has the X-ray powder diffraction pattern shown in Figure 26.

[0067] Regarding metastable crystal form K, The present invention provides a metastable crystalline form K of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.05±0.2°, 4.89±0.2°, 4.44±0.2° and 5.92±0.2°. According to the present invention, the crystal form K preferably further includes peaks located at diffraction angles (2θ) of 12.53±0.2°, 7.87±0.2°, 16.76±0.2°, 8.83±0.2°, and 5.55±0.2°. According to the present invention, the crystal form K more preferably further includes peaks located at diffraction angles (2θ) of 14.59±0.2°, 9.84±0.2°, 13.38±0.2°, 20.10±0.2°, 14.08±0.2° and 15.76±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form K has the diffraction angle (2θ) shown in Table 11, and the error range of the above 2θ angle is ±0.20°. [Table 11]

[0068] Preferably, the above crystal form K has the X-ray powder diffraction intensity shown in Table 11. Preferably, the above crystal form K basically has the X-ray powder diffraction pattern shown in Figure 27.

[0069] Regarding the metastable crystal form L, The present invention provides a metastable crystalline form L of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 8.67±0.2°, 15.29±0.2°, 14.75±0.2° and 11.76±0.2°. According to the present invention, the above crystal form L preferably further includes peaks located at diffraction angles (2θ) of 17.44±0.2°, 9.02±0.2°, 26.63±0.2°, 20.65±0.2°, and 7.89±0.2°. According to the present invention, the above crystal form L more preferably further includes peaks located at diffraction angles (2θ) of 17.89±0.2°, 9.53±0.2°, 23.98±0.2°, 19.19±0.2°, 21.18±0.2° and 13.64±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form L has the diffraction angle (2θ) shown in Table 12, and the error range of the above 2θ angle is ±0.20°. [Table 12]

[0070] Preferably, the above crystal form L has the X-ray powder diffraction intensity shown in Table 12. Preferably, the above crystal form L basically has the X-ray powder diffraction pattern shown in Figure 28.

[0071] Regarding the metastable crystal form M, The present invention provides a metastable crystalline form M of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 8.26±0.2°, 14.79±0.2°, 17.07±0.2° and 14.57±0.2°. According to the present invention, the crystal form M preferably further includes peaks located at diffraction angles (2θ) of 11.50±0.2°, 21.18±0.2°, 16.60±0.2°, 20.53±0.2°, and 25.33±0.2°. According to the present invention, the crystal form M more preferably further includes peaks located at diffraction angles (2θ) of 18.43±0.2°, 25.01±0.2°, 7.99±0.2°, 8.98±0.2°, 13.04±0.2° and 24.12±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form M has the diffraction angle (2θ) shown in Table 13, and the error range of the above 2θ angle is ±0.20°. [Table 13]

[0072] Preferably, the above crystal form M has the X-ray powder diffraction intensity shown in Table 13. Preferably, the above crystal form M basically has the X-ray powder diffraction pattern shown in Figure 29.

[0073] Regarding metastable crystalline form N, The present invention provides a metastable crystalline form N of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.48±0.2°, 5.02±0.2°, 5.55±0.2° and 11.61±0.2°. According to the present invention, the above crystal form N preferably further includes peaks located at diffraction angles (2θ) of 3.14±0.2°, 14.70±0.2°, 11.42±0.2°, 7.31±0.2°, and 13.69±0.2°. According to the present invention, the above crystal form N more preferably further includes peaks located at diffraction angles (2θ) of 13.34±0.2°, 9.57±0.2°, 15.71±0.2°, 15.10±0.2°, 12.43±0.2° and 22.05±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form N has the diffraction angle (2θ) shown in Table 14, and the error range of the above 2θ angle is ±0.20°. [Table 14]

[0074] Preferably, the above crystal form N has the X-ray powder diffraction intensity shown in Table 14. Preferably, the above crystal form N basically has the X-ray powder diffraction pattern shown in Figure 30.

[0075] Regarding metastable crystal form O, The present invention provides a metastable crystalline form O of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.54±0.2°, 3.37±0.2°, 5.96±0.2° and 12.21±0.2°. According to the present invention, the above crystal form O preferably further includes peaks located at diffraction angles (2θ) of 7.87±0.2°, 13.89±0.2°, 16.84±0.2°, 21.24±0.2°, and 32.21±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form O has the diffraction angle (2θ) shown in Table 14, and the error range of the above 2θ angle is ±0.20°. [Table 15]

[0076] Preferably, the above crystal form O has the X-ray powder diffraction intensity shown in Table 15. Preferably, the above crystal form O basically has the X-ray powder diffraction pattern shown in Figure 31.

[0077] Regarding the metastable crystal form P, The present invention provides a metastable crystalline form P of compound (IE), the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.81±0.2°, 4.29±0.2°, 6.08±0.2° and 14.65±0.2°. According to the present invention, the above crystal form P preferably further includes peaks located at diffraction angles (2θ) of 12.33±0.2°, 7.89±0.2°, 3.41±0.2°, 17.94±0.2°, and 8.81±0.2°. According to the present invention, the above crystal form P more preferably further includes peaks located at diffraction angles (2θ) of 17.57±0.2°, 7.25±0.2°, 13.37±0.2°, 19.60±0.2° and 20.23±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form P has the diffraction angle (2θ) shown in Table 14, and the error range of the above 2θ angle is ±0.20°. [Table 16]

[0078] Preferably, the above crystal form P has the X-ray powder diffraction intensity shown in Table 16. Preferably, the above crystal form P basically has the X-ray powder diffraction pattern shown in Figure 32.

[0079] Regarding the metastable crystal form Q, The present invention provides a metastable crystalline form Q of compound IE, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 4.96±0.2°, 7.42±0.2°, 14.82±0.2° and 21.77±0.2°. According to the present invention, the above crystal form Q preferably further includes peaks located at diffraction angles (2θ) of 16.75±0.2°, 17.29±0.2°, 15.21±0.2°, 25.67±0.2° and 24.53±0.2°. According to the present invention, the above crystal form Q more preferably further includes peaks located at diffraction angles (2θ) of 9.86±0.2°, 15.76±0.2°, 17.56±0.2°, 22.92±0.2°, 23.67±0.2° and 22.44±0.2°. According to the present invention, preferably, the X-ray powder diffraction pattern of the above crystal form Q has the diffraction angle (2θ) shown in Table 14, and the error range of the above 2θ angle is ±0.20°. [Table 17]

[0080] Preferably, the above crystal form Q has the X-ray powder diffraction intensity shown in Table 17. Preferably, the above crystal form Q basically has the X-ray powder diffraction pattern shown in Figure 33.

[0081] A second aspect of the present invention provides a method for producing crystalline polymorphs of the above compound (IE), Step 1: Dissolve or disperse compound IE in a solvent. Step 2 involves stirring at 0-50°C to crystallize, or adding an antisolvent to the compound clarification solution to precipitate, or slowly volatilizing the compound clarification solution. This manufacturing method was chosen. According to embodiments of the present invention, the above compound IE is preferably the metastable crystalline form H of compound IE.

[0082] In a more preferred form, the solvent is water, an organic solvent, or a mixed solvent thereof, and the organic solvent is selected from alcohol-based, chloroalkane-based, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, sulfoxide-based organic solvents, or mixtures thereof, and preferably the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyl Selected from tyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene, or mixtures thereof.

[0083] A third aspect of the present invention provides a pharmaceutical composition comprising at least one crystalline polymorph of the above compound (IE) and a medicinal carrier.

[0084] A fourth aspect of the present invention provides the use of crystalline polymorphs of the above compound (IE) in the manufacture of drugs for preventing and / or treating WEE1 and / or Yes target-related diseases, including conditions such as tumors, inflammation, and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis).

[0085] The present invention further provides a method for treating a disease, comprising administering to an individual in need of such treatment at least one of the above-mentioned crystalline polymorphs of the compound (IE) or the above-mentioned pharmaceutical composition. According to embodiments of the present invention, the disease is selected from WEE1 and / or Yes target-related diseases, including conditions such as tumors, inflammation, and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis).

[0086] In some embodiments of the present invention, the above-mentioned compounds or their pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions, and various crystalline forms thereof are novel compounds and novel salt forms and crystalline forms thereof selected from structures such as those disclosed in the examples of the present invention.

[0087] The present invention further provides a pharmaceutical composition comprising at least one of a therapeutically effective amount of a compound represented by formula (I), a pharmaceutically acceptable salt, solvate, enantiomer and isotopic substitution thereof, and various crystalline forms thereof.

[0088] According to embodiments of the present invention, the pharmaceutical composition is prepared to be administered by a route selected from oral, injectable, rectal, nasal, pulmonary, topical, oral and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural routes.

[0089] According to embodiments of the present invention, the pharmaceutical composition is preferably administered orally.

[0090] The above oral dosage forms are not particularly limited, and any oral dosage form well known in the art may be used, preferably including oral dosage forms known in the art such as tablets, capsules, suspensions, or oral solutions.

[0091] According to embodiments of the present invention, the pharmaceutical composition may further contain pharmaceutically acceptable adjuvants, which include, but are not limited to, at least one selected from adjuvants such as fillers, disintegrants, adhesives, lubricants, surfactants, flavoring agents, wetting agents, pH adjusters, solubilizers or dissolving aids, and osmotic pressure adjusters. Those skilled in the art can easily determine how to select the appropriate adjuvants and their corresponding doses according to the needs of the specific dosage form.

[0092] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0093] Another object of the present invention is to provide the use of the above compounds in the manufacture of drugs for the prevention and / or treatment of WEE1 or Yes target-related diseases, including tumors, inflammation, and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis).

[0094] The present invention further provides compounds represented by formulas (I) to (IE) above, pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions thereof, and various salt and crystalline forms thereof, as well as the use of the pharmaceutical compositions thereof, in the prevention and / or treatment of diseases associated with the WEE1 and / or Yes signaling pathway. Diseases associated with the WEE1 and / or Yes signaling pathway include conditions such as tumors, inflammation and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis).

[0095] The present invention further provides a method for preventing and / or treating a disease associated with the WEE1 and / or Yes signaling pathway, comprising administering to a patient a prophylactic or therapeutically effective amount of at least one of the compounds represented by formula (I), a pharmaceutically acceptable salt, solvate, enantiomer, and isotope substitute thereof, or administering to a patient a prophylactic or therapeutically effective amount of the above pharmaceutical composition. The above-described disease associated with the WEE1 or Yes signaling pathway has the above-described definition.

[0096] In some embodiments, the patient is a mammal, preferably a human. [Effects of the Invention]

[0097] The inventors have unexpectedly discovered for the first time that some of the novel pyrimide macroheterocyclic compounds of the novel structure of formula (I) according to the present invention can simultaneously inhibit two targets, Yes and Wee1, and possess stronger antitumor activity and better PK properties compared to single Wee1 target-selective compounds with known structures, such as DEBIO0123, ZN-c3, and NUV-569, making them suitable for development as candidate drugs for the prevention or treatment of tumors associated with the Wee1 and / or Yes target or signaling pathway. [Brief explanation of the drawing]

[0098] [Figure 1] This shows the X-ray powder diffraction pattern of crystalline form A of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 2] The DSC pattern of crystalline form A of compound IE according to the present invention is shown. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 3] This shows the TGA pattern of crystalline form A of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 4] This shows the X-ray powder diffraction pattern of crystalline form B of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 5] This shows the DSC pattern of crystalline form B of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 6] This shows the TGA pattern of crystalline form B of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 7] The X-ray powder diffraction pattern of crystalline form C of compound IE according to the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 8] The DSC pattern of the crystalline form C of compound IE according to the present invention is shown. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 9]This shows the TGA pattern of the crystalline form C of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 10] This shows the X-ray powder diffraction pattern of hydrate crystal form D of compound IE according to the present invention. The horizontal coordinate represents the 2θ value (degrees), and the vertical coordinate represents the peak intensity. [Figure 11] This shows the DSC pattern of hydrate crystal form D of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 12] This shows the TGA pattern of hydrate crystal form D of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 13] This shows the X-ray powder diffraction pattern of hydrate crystal form E of compound IE according to the present invention. The horizontal coordinate represents the 2θ value (degrees), and the vertical coordinate represents the peak intensity. [Figure 14] This shows the DSC pattern of the hydrate crystal form E of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 15] This shows the TGA pattern of the hydrate crystal form E of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 16] This shows the X-ray powder diffraction pattern of hydrate crystal form F of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 17] This shows the DSC pattern of the crystalline form F of the hydrate of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 18] This shows the TGA pattern of the hydrate crystal form F of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 19] The X-ray powder diffraction pattern of hydrate crystal form G of compound IE according to the present invention is shown. The horizontal coordinate represents the 2θ value (degrees), and the vertical coordinate represents the peak intensity. [Figure 20] This shows the DSC pattern of the hydrate crystal form G of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 21] This shows the TGA pattern of the hydrate crystal form G of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 22] This shows the X-ray powder diffraction pattern of the metastable crystalline form H of compound IE according to the present invention. The horizontal coordinate represents the 2θ value (degrees), and the vertical coordinate represents the peak intensity. [Figure 23] This shows the DSC pattern of the metastable crystalline form H of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents heat flow (mW). [Figure 24] This shows the TGA pattern of the metastable crystalline form H of compound IE according to the present invention. The horizontal coordinate represents temperature (°C), and the vertical coordinate represents weight (%). [Figure 25] This shows the X-ray powder diffraction pattern of the metastable crystalline form I of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 26] The X-ray powder diffraction pattern of the metastable crystalline form J of compound IE according to the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 27] This shows the X-ray powder diffraction pattern of the metastable crystalline form K of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 28] The X-ray powder diffraction pattern of the metastable crystalline form L of compound IE according to the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 29] The X-ray powder diffraction pattern of the metastable crystalline form M of compound IE according to the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 30] This shows the X-ray powder diffraction pattern of the metastable crystalline form N of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 31] This shows the X-ray powder diffraction pattern of the metastable crystalline form O of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 32]This shows the X-ray powder diffraction pattern of the metastable crystalline form P of compound IE according to the present invention. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 33] The X-ray powder diffraction pattern of the metastable crystalline form Q of compound IE according to the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity. [Figure 34] This shows the DVS pattern of crystalline form A of compound IE according to the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%). [Figure 35] This shows the DVS pattern of crystalline form B of compound IE according to the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%). [Figure 36] This shows the DVS pattern of crystalline form C of compound IE according to the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%). [Figure 37] This shows the DVS pattern of crystalline form D of compound IE according to the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%). [Figure 38] This is a diagram showing the single-crystal analysis results of compound IE according to the present invention.

[0099] Definition and Description C 1-10 This includes C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from C 2-10 This includes C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from C 3-10 This includes C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from, In this specification, when referring to one, two or more, “more than” should be understood to mean integers greater than 2, such as 3 or more, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.

[0100] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0101] The term "alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms. Preferably, "C 1-8 "Alkyl group", "C 1-6 "alkyl group" and "C 1-8 "Alkyl alkyl" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and "C 1-6 "Alkyl group" refers to linear and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl groups are methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, 1,1-dimethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 2-ethylbutyl group, 1-ethylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, or 1,2-dimethylbutyl group, or their isomers.

[0102] The term "alkenyl group" should be understood to refer to a monovalent hydrocarbon group that has one or more double bonds and 2 to 12 carbon atoms in a straight or branched chain, and "C 2-10 "Alkenyl group", "C 2-6 "Alkenyl group" is preferred. 2-10 The term "alkenyl group" should preferably be understood to represent a monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in a straight or branched chain. 2-6The term "alkenyl group" should preferably be understood to represent a monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. If the above alkenyl group contains more than one double bond, the above double bonds may be separated or conjugated from each other. The above alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, (E)-buta-2-enyl group, (Z)-buta-2-enyl group, (E)-buta-1-enyl group, (Z)-buta-1-enyl group, penta-4-enyl group, (E)-penta-3-enyl group, (Z)-penta-3-enyl group, (E)-penta-2-enyl group, (Z)-penta-2-enyl group, (E)-penta- 1-enyl group, (Z)-penta-1-enyl group, hexa-5-enyl group, (E)-hexa-4-enyl group, (Z)-hexa-4-enyl group, (E)-hexa-3-enyl group, (Z)-hexa-3-enyl group, (E)-hexa-2-enyl group, (Z)-hexa-2-enyl group, (E)-hexa-1-enyl group, (Z)-hexa-1-enyl group, isopropenyl group, 2-methylpropa-2-enyl group, 1-methylpropa- 2-enyl group, 2-methylpropa-1-enyl group, (E)-1-methylpropa-1-enyl group, (Z)-1-methylpropa-1-enyl group, 3-methylbuta-3-enyl group, 2-methylbuta-3-enyl group, 1-methylbuta-3-enyl group, 3-methylbuta-2-enyl group, (E)-2-methylbuta-2-enyl group, (Z)-2-methylbuta-2-enyl group, (E)-1-methylbuta-2-enyl group, (Z)-1- These are tilbuta-2-enyl group, (E)-3-methylbuta-1-enyl group, (Z)-3-methylbuta-1-enyl group, (E)-2-methylbuta-1-enyl group, (Z)-2-methylbuta-1-enyl group, (E)-1-methylbuta-1-enyl group, (Z)-1-methylbuta-1-enyl group, 1,1-dimethylpropa-2-enyl group, 1-ethylpropa-1-enyl group, 1-propylvinyl group, and 1-isopropylvinyl group.

[0103] The term "haloalkyl group" refers to an alkyl group substituted with one, two, or more halogens, where the halogen and alkyl group are as defined above. For example, "halo C 1-6 "Alkyl alkyl group" is a C molecule substituted with one, two or more halogens. 1-6 It refers to alkyl groups, halogens and C 1-6 Alkyl groups are defined as described above.

[0104] The term "deuterated alkyl group" refers to an alkyl group substituted with one, two, or more deuterium atoms, where the alkyl group is as defined above. For example, "deuterated C 1-6 "Alkyl group" is a C atom substituted with one, two or more deuterium atoms. 1-6 Refers to an alkyl group, C 1-6 Alkyl groups are defined as described above.

[0105] The term "alkylene group" refers to a divalent alkyl group, of which alkyl groups are defined above. The above alkylene group is an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene group is preferred.

[0106] The term "alkenylene group" refers to a divalent alkenyl group, of which the alkenyl group is defined above. The above alkylene group is an alkenylene group having 2 to 6 carbon atoms (i.e., C 2-6 (Alkenylene group) is preferred.

[0107] The term "alkynyl group" should be understood to refer to a monovalent hydrocarbon group that contains one or more triple bonds and has 2 to 12 carbon atoms in a straight or branched chain, and "C 2-10 "Alkynyl group", C 2-6 Alkynyl group is preferred. 2-10 The term "alkynyl group" refers to a group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C 2-8An "alkynyl group") has 2, 3, 4, 5, or 6 carbon atoms (i.e., "C 2-6 "Alkynyl group"), having 2 or 3 carbon atoms ("C 2-3 It should be understood that the alkynyl group preferably represents a linear or branched monovalent hydrocarbon group. Examples of the above alkynyl groups include ethynyl group, propa-1-inyl group, propa-2-inyl group, buta-1-inyl group, buta-2-inyl group, buta-3-inyl group, penta-1-inyl group, penta-2-inyl group, penta-3-inyl group, penta-4-inyl group, hexa-1-inyl group, hexa-2-inyl group, hexa-3-inyl group, hexa-4-inyl group, hexa-5-inyl group, 1-methylpropa-2-inyl group, 2-methylbuta-3-inyl group, 1-methylbuta-3-inyl group, 1-methylbuta-2-inyl group, 3-methylbuta-1-inyl group, 1-ethylpropa-2-inyl group, 3-methylpenta-4-inyl group, 2-methyl The alkynyl group is ethylpenta-4-inyl, 1-methylpenta-4-inyl, 2-methylpenta-3-inyl, 1-methylpenta-3-inyl, 4-methylpenta-2-inyl, 1-methylpenta-2-inyl, 4-methylpenta-1-inyl, 3-methylpenta-1-inyl, 2-ethylbuta-3-inyl, 1-ethylbuta-3-inyl, 1-ethylbuta-2-inyl, 1-propylpropa-2-inyl, 1-isopropylpropa-2-inyl, 2,2-dimethylbuta-3-inyl, 1,1-dimethylbuta-3-inyl, 1,1-dimethylbuta-2-inyl, or 3,3-dimethylbuta-1-inyl. In particular, the above alkynyl group is ethynyl, propa-1-inyl, or propa-2-inyl.

[0108] As used herein, the term “one or more” means one or more, for example, one, two, three, four, five or more.

[0109] The terms “aliphatic ring,” “carbocyclic ring (group),” or “cycloalkyl group” refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, where a carbocyclic ring may contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), and more preferably 3 to 6 carbon atoms. A carbocyclic ring may be monocyclic or polycyclic, may be a saturated cycloalkyl group, or may optionally contain one, two or more double and / or triple bonds on the ring, thereby forming a so-called cycloalkenyl group or cycloalkynyl group. If a carbocyclic ring has multiple rings, these rings may form spirocyclic, fused, and bridging ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and cyclooctatetraenyl groups, while non-limiting examples of polycyclic carbocycles include decahydronaphthyl or isobornyl groups. The term "cycloalkyl group" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., fused ring, bridging ring, spiro ring) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms. 3-10 "Cycloalkyl group" is preferred, and "C 3-6 A cycloalkyl group is even more preferred. 3-10 The term "cycloalkyl group" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridging ring, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 3-10The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group; or a bicyclic hydrocarbon group such as a bornyl group, indolyl group, hexahydroindolyl group, tetrahydronaphthyl group, decahydronaphthyl group, bicyclo[2.1.1]hexyl group, bicyclo[2.2.1]heptyl group, bicyclo[2.2.1]heptenyl group, 6,6-dimethylbicyclo[3.1.1]heptyl group, 2,6,6-trimethylbicyclo[3.1.1]heptyl group, bicyclo[2.2.2]octyl group, 2,7-diazaspiro[3,5]nonyl group, 2,6-diazaspiro[3,4]octyl group; or a tricyclic hydrocarbon group such as an adamantyl group.

[0110] The terms "aryl group" or "aromatic ring" should be understood to preferably refer to a monovalent aromatic or partially aromatic monocyclic, dicyclic (e.g., fused ring, bridging ring, spirocyclic) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a monoaromatic ring or a fused polyaromatic ring. 6-14 "Aryl group" is preferred. 6-14 An aryl group is a monovalent aromatic or partially aromatic monocyclic, dicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 "aryl group"), especially a ring having 6 carbon atoms ("C6 aryl group"), for example a phenyl group or a biphenyl group, or a ring having 9 carbon atoms ("C9 aryl group"), for example an indanyl group or an indenyl group, or a ring having 10 carbon atoms ("C 10 "aryl group"), for example, a tetrahydronaphthyl group, a dihydronaphthyl group or a naphthyl group, or a ring having 13 carbon atoms ("C 13 "aryl group"), for example, a fluorenyl group, or a ring having 14 carbon atoms ("C" 14 It should be understood that it is preferable to show an aryl group, for example, an anthyl group. 6-20When an aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, the substitution site is not limited and may be, for example, at the ortho, para, or meta position.

[0111] The term "spiro ring" refers to a ring system in which two rings share one ring-forming atom, and may include aliphatic rings, heterorings, aromatic rings, or heteroaromatic rings as described above.

[0112] The term "ring fusion" refers to a ring system in which two rings share two ring-forming atoms, and may include aliphatic rings, heterocyclic rings, aromatic rings, or heteroaromatic rings as described above.

[0113] The term “bridged ring” refers to a ring system in which two rings share three or more ring-forming atoms, which may include aliphatic rings, heterocycles, aromatic rings, or heteroaromatic rings as described above. The term “heterocyclyl(group)” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms or groups of atoms selected from N, O, NH, S, S(O) or S(O)2, but not containing -OO-, -OS- or -SS- ring portions, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, of which 1 to 4 are heteroatoms (e.g., 1, 2, 3, and 4), and more preferably 3 to 6 ring atoms (e.g., 3, 4, 5, and 6). The heterocyclyl group may be linked to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present) or an oxygen or sulfur atom (especially if an onium salt is formed). The above heterocyclyl groups may include condensed or crosslinked rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, and diazepanyl groups, with piperidinyl and pyrrolidinyl groups being preferred. Polycyclic heterocyclyl groups include spirocyclic, condensed, and crosslinked heterocyclyl groups, and may also be benzo-condensed heterocyclyl groups such as dihydroisoquinolyl. The above heterocyclyl group may be bicyclic, and non-limiting examples include hexahydrocyclopenta[c]pyrrole-2(1H)-yl and hexahydropyrrole[1,2-a]pyrazine-2(1H)-yl.The heterocyclyl group may be partially unsaturated, that is, it may contain one or more double bonds, non-limiting examples of which include a dihydrofuranyl group, a dihydropyranyl group, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazine group, a 4,5-dihydroxazolyl group, or a 4H-[1,4]thiadinyl group.

[0114] The term "heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., fused ring, bridging ring, spiro ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, for example, 1, 2, 3, 4, 5 or more heteroatoms, of which N and S may be optionally oxidized to various oxidation states such that nitrogen oxide, -S(O)-, or -S(O)2- states are formed. Preferably, the heterocyclyl group may be selected from "3- to 10-membered heterocyclyl groups". The term "3- to 10-membered heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S, and N. The heterocyclyl group may be linked to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclyl group may include condensed or bridging rings and spirocyclic rings. In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as an azetidinyl group or an oxetanyl group, a 5-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a 6-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a 7-membered ring such as a diazepanyl group. The heterocyclyl group may optionally be benzo-condensed. The heterocyclyl group may be bicyclic, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, but is not limited to these.The heterocyclyl group may be partially unsaturated, that is, it may contain one or more double bonds, for example, a dihydrofuranyl group, a dihydropyranyl group, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 1,2,3,5-tetrahydroxazolyl group, or a 4H-[1,4]thiadinyl group, but is not limited to these, or it may be benzo-condensed, for example, a dihydroisoquinolyl group, but is not limited to these. When the above 3-20 membered heterocyclyl group is linked to another group to constitute the compound of the present invention, the carbon atoms in the 3-20 membered heterocyclyl group may be linked to the other group, or the heterocyclic atoms in the 3-20 membered heterocyclyl ring may be linked to the other group. For example, when the 3-20 membered heterocyclyl group is selected from piperazinyl groups, the nitrogen atom in the piperazinyl group may be linked to the other group. Alternatively, if the 3-20 membered heterocyclyl group is selected from piperidinyl groups, the nitrogen atom in the piperidinyl ring and the carbon atom at its para position may be linked to other groups. The heterocyclyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0115] In this specification, the term “heteroaryl group / heteroaromatic ring” refers to a heteroaromatic system comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, nitrogen, and phosphorus. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), and more preferably 5-membered or 6-membered. Non-limiting examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo derivatives such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, or pyrazolyl. This includes, but is not limited to, lydinyl groups, pyridadinyl groups, pyrimidinyl groups, pyrazinyl groups, triazinyl groups, and their benzo derivatives such as quinolyl groups, quinazolinyl groups, and isoquinolyl groups, or azosin groups, indolidinyl groups, purinyl groups, and their benzo derivatives, or sinnolinyl groups, phthalazinyl groups, quinazolinyl groups, quinoxalinyl groups, naphthylidinyl groups, pteridinyl groups, carbazolyl groups, acridinyl groups, phenadinyl groups, phenothiazinyl groups and / or phenoxadinyl groups.

[0116] The heteroaryl group / heteroaromatic ring may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one, two or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0117] Unless otherwise specified, heterocyclyl groups, heteroaryl groups, or heteroaromatic rings include all possible isomeric forms thereof, e.g., their positional isomers. Therefore, non-limiting examples for some explanation may include forms in which they are substituted at one, two or more positions, such as the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if any), or bonded to other groups, and include thienyl or thienylidenyl groups, including pyridine-2-yl, pyridylidene-2-yl, pyridine-3-yl, pyridylidene-3-yl, pyridylidene-3-yl, pyridine-4-yl and pyridylidene-4-yl, thienyl groups or thienylidenyl groups, including thienyl-2-yl, thienylidene-2-yl, thienylidene-3-yl and thienylidene-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, and pyrazole-5-yl.

[0118] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that, within the bounds of reliable medical judgment, is free from excessive toxicity, irritation, allergic reactions or other problems or complications, is commensurate with a reasonable benefit-to-hazard ratio, and is suitable for use in contact with human and animal tissues.

[0119] The term "pharmaceutically acceptable salt" refers to a salt of a compound according to the present invention, which is produced from a compound found in the present invention having a specific substituent and a relatively non-toxic acid or base. If a compound according to the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of base with the neutral form of such compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, or magnesium salts or similar salts. If a compound according to the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of acid with the neutral form of such compound in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, for example, salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid; and salts of organic acids, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and further include salts of amino acids (e.g., arginine); and salts of organic acids, such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Some specific compounds according to the present invention can be converted into either a base or an acid addition salt by containing basic and acidic functional groups.

[0120] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid using conventional methods and then isolating the parent compound. The difference between the parent form of the compound and its various salt forms lies in several physical properties, such as differences in solubility in polar solvents.

[0121] As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds according to the present invention, in which the parent compound is modified by salt formation with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, and alkali metal or organic salts of acidic groups such as carboxylic acids. pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, and quaternary ammonium salts of the parent compound. Conventional non-toxic salts include, but are not limited to, salts derived from inorganic acids and organic acids, and inorganic bases and organic bases. The inorganic and organic acids mentioned above include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate group, carbonic acid, citric acid, EDTA, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide salt, hydroxyl group, hydroxynaphthalene, isethionic acid, lactic acid, and lactose. The inorganic base is selected from dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, emponic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid, and the inorganic base and organic base are selected from Na, potassium, magnesium, calcium, etc. or from amines, diethylamine, triethylamine, ethanolamine, etc.

[0122] The pharmaceutically acceptable salts according to the present invention can be synthesized from parent compounds containing an acid group or a base by conventional chemical methods. In general, the method for producing such salts is as follows: They are produced by reacting those compounds in the form of a free acid or base with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0123] In addition to the salt form, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein are readily converted to the compounds of the present invention by chemical reaction under physiological conditions. The prodrugs may also be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0124] Some of the compounds of the present invention may exist in a non-solvated form or a solvated form, including a hydrated form. Generally, the solvated form corresponds to the non-solvated form, and both are included within the scope of the present invention. Some of the compounds of the present invention may exist in a polycrystalline or amorphous form.

[0125] In this specification, the term "solvate" refers to an aggregate formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Accordingly, the term "hydrate" refers to an aggregate formed by a solvent molecule that is water.

[0126] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below. Unless otherwise specified, any particular phrase or term should not be considered uncertain or ambiguous, but should be understood in its ordinary sense. Where a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0127] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living organism, contribute to the absorption of the active ingredient, and further exert biological activity.

[0128] As used herein, "polymorphs" refer to crystalline forms that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms, and / or ions constituting the crystal. Polymorphs have the same chemical composition but differ in their stacking and geometric arrangement, and can exhibit similar physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, and dissolution rate. Depending on their temperature-stability relationship, two polymorphs may be simple or tautomorphic. In a simple system, the relative stability between the two solid phases remains unchanged when the temperature changes. In contrast, in a tautomorphic system, there is a transition temperature at which the stability of the two phases is transformed (Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN: 8247-0237). The phenomenon of such compounds existing in different crystalline structures is called drug polymorphism.

[0129] The various crystal structures of the present invention can be distinguished from one another using various analytical techniques known to those skilled in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0130] As used herein, "room temperature" or "RT" refers to an ambient temperature of 20-25°C (68-77°F).

[0131] The term "essentially the same" as used herein with respect to X-ray diffraction peak positions means that typical peak positions and intensity variability should be considered. For example, those skilled in the art will understand that the peak position (2θ) can be affected by differences in XRPD instruments, and such changes can reach as much as 0.2°. Furthermore, those skilled in the art will understand that factors such as the method of preparing the XRPD sample, the XRPD instrument, the crystallinity of the sample, the amount of sample used, and the preferred orientation of the crystals can cause changes in the relative peak intensity in the XRPD diffraction pattern of the sample.

[0132] The intermediate compounds according to the present invention can be produced by several synthesis methods well known to those skilled in the art, including specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0133] The chemical reactions of specific embodiments of the present invention are completed in a suitable solvent, which must be suitable for the chemical changes of the present invention and the necessary reagents and materials. To obtain the compounds of the present invention, those skilled in the art may need to modify or select synthesis steps or reaction processes based on existing embodiments.

[0134] The present invention will be described in detail below with reference to examples, but these examples do not imply any limitation to the present invention.

[0135] All solvents used in this invention are commercially available and can be used without further purification.

[0136] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0137] Some of the compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond. Racemates, diastereomers, geometric isomers, and individual isomers are all included within the scope of the present invention.

[0138] In this specification, the illustration of racemic, ambiscalemic and scalemic, or enantiomeric pure compounds follows Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, the absolute configuration of stereocenters is indicated by wedge-shaped bonds and dashed bonds. Where compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomeric forms are all included within the scope of the present invention.

[0139] The compounds according to the present invention may have specific geometric or stereoisomeric forms. The present invention assumes that all compounds, including cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, and (L)-isomers, as well as their racemic mixtures and other mixtures, such as mixtures enriched with enantiomers or diastereomers, fall within the scope of the present invention. Substituents such as alkyl groups may have other chiral carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0140] Optically active (R)- and (S)- isomers and D- and L isomers can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a compound according to the present invention, it can be produced by asymmetric synthesis or by induction with a chiral auxiliary agent, and the mixture of the obtained diastereomers is separated and the decomposition of the groups is assisted to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and the diastereomer is separated by fractional crystallization or chromatography known in the art, and further recovered to obtain the pure enantiomer. The separation of enantiomers and diastereomers is generally completed by chromatography, which employs a chiral stationary phase and is optionally combined with a chemical induction method (e.g., generating a carbamate from an amine).

[0141] The compounds according to the present invention may contain non-natural proportion atomic isotopes in one or more atoms constituting the compound. For example, tritium ( 3 H), Iodine-125 ( 125 I) or C-14 ( 14 The compound may be labeled with a radioactive isotope such as C). Transformations involving all isotopes of the compound according to the present invention, whether radioactive or not, are all included within the scope of the present invention.

[0142] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is free from toxicity and side effects to the host or patient. Typical carriers include water, oil, vegetables and minerals, creams, detergent substrates, ointment substrates, etc. These substrates include suspending agents, tackifiers, transdermal accelerators, etc. These formulations are well known to technicians in the fields of cosmetics or topical drugs. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0143] If any of the variables (e.g., R) appear one or more times in the composition or structure of a compound, the definitions in each case are independent. Therefore, for example, if a group is substituted with 0 to 2 R atoms, that group can be optionally substituted with at most 2 R atoms, and in each case, there are independent choices for R. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0144] If a substituent can be linked across two atoms on a ring, then such substituent can be linked to any atom on that ring. If it is not specified which atom a listed substituent links to a compound included in the chemical structure but not specifically mentioned, then such substituent can be linked to any atom. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0145] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0146] The present invention will be further illustrated below with reference to examples. The examples shown below are for illustrative purposes only and do not limit the scope of the present invention. The compounds of the present invention can be produced by many methods known in the field of organic synthesis. The examples of the present invention can be synthesized by the methods described below, and by synthetic methods known in the field of organic synthesis chemistry, or by improved methods based thereon. Preferred methods include, but are not limited to, the methods described below.

[0147] Unless otherwise specified, all solvents used in this invention are commercially available and do not require further purification before use. Reactions are typically carried out in an inert atmosphere of nitrogen gas using anhydrous solvents. Nuclear magnetic resonance spectra are measured using a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts are reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110 / and 1956A) LC / MS or a Shimadzu MS (DAD is SPD-M20A(LC)) and a Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with one electrospray ion source (ESI) operating in positive and negative modes.

[0148] This invention adopts the following abbreviations: aq represents water, DCM represents dichloromethane, PE represents petroleum ether, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, ƒ represents ethyl acetate, EtOH represents ethanol, MeOH represents methanol, Cbz represents the amine protecting group benzyloxycarbonyl group, Boc represents the amine protecting group tert-butyloxycarbonyl group, HOAc represents acetic acid, NaBH(OAc)3 represents sodium triacetoxyborohydride, rt represents room temperature, THF represents tetrahydrofuran, Boc2O represents di-tert-butyldicarbonate, TFA represents trifluoroacetic acid, DIPEA represents diisopropylethylamine, and Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]di 부4-disulfide is represented, NBS is N-bromosuccinimide, t-BuOK is potassium tert-butoxide, DIPEA is diisopropylethylamine, SOCl2 is thionyl chloride, CS2 is carbon disulfide, TsOH is 4-toluenesulfonic acid, MTBE is tert-butyl methyl ether, i-PrOH is 2-propanol, DAST is diethylaminosulfur trifluoride, DIAD is diisopropyl azodicarboxylic acid, DEAD is diethyl azodicarboxylic acid, DBAD is di-tert-butyl azodicarboxylic acid, TES is triethylsilane, LDA is lithium diisopropylamide, NBS is N-bromosuccinimide, and NIS is N-iodosuccinimide. NCS is N-chlorosuccinimide, DMP is DMP reagent, DMF-DMA is 1,1-dimethoxy-N,N-dimethylmethaneamine, TMP is 2,2,6,6-tetramethylpiperidine, NMO is N-methylmorpholine N-oxide, TBSCl is tert-butyldimethylsilyl chloride, SEMCl is 2-(trimethylsilyl)ethoxymethyl chloride, NFSI is N-fluorobenzenesulfonamide, AIBN is azobisisobutyronitrile, EDCI is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBT is hydroxybenzotriazole, TBAF is tetra-n-butylammonium fluoride, and HATU is 1-[bis(dimethylamino)methylene]- 1H-1,2,3-Triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate, Xphos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, cataCXium A is n-butyl-di(1-adamantyl)phosphine, DPPP is 1,3-bis(diphenylphosphino)propane, DPPF is 1,1'-bis(diphenylphosphino)ferrocene, and HMTA is 1,3,5,7-tetraadamantane, PMBCl is p-methoxybenzyl chloride, HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, and EGTA is ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid.

[0149] Compounds may be named manually, using ChemDraw®, or, in the case of commercial purchase, using the supplier's catalog name. Typically, TLC or LC-MS is used to determine whether the reaction is complete. [Modes for carrying out the invention]

[0150] The following examples have been given to illustrate the present invention in more detail, but the scope of the present invention is not limited to these.

[0151] Example 1: Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound IE) 1) Synthesis of 2-(6-bromopyridine-2-yl)hexa-5-en-2-ol [ka] Under 0°C conditions, 1-(6-bromopyridine-2-yl)ethane-1-one (10.0 g, 50.0 mmol) was dissolved in tetrahydrofuran (100 mL), to which buta-3-en-1-ylmagnesium bromide (150 mL, 75.0 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature under argon gas protection. Under 0°C conditions, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-30%) to obtain 2-(6-bromopyridine-2-yl)hexa-5-en-2-ol (6.0 g, yield 47%). LC-MS m / z: 256 [M + H] + ,

[0152] 2) Synthesis of 2-allyl-1-(6-(2-hydroxyhexa-5-en-2-yl)pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one [ka] A 60 mL solution of dioxane containing 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (5.00 g, 22.5 mmol), 2-(6-bromopyridine-2-yl)hexa-5-en-2-ol (5.75 g, 22.4 mmol), N,N'-dimethylethylenediamine (2.18 g, 24.7 mmol), cuprous iodide (4.25 g, 22.3 mmol), and potassium carbonate (4.34 g, 31.4 mmol) was heated to 90°C under argon gas protection and stirred overnight. After cooling, the resulting reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated brine (1 × 100 mL) and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-50%) to obtain 2-allyl-1-(6-(2-hydroxyhexa-5-en-2-yl)pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (5.25 g, yield 58.7%). LCMS m / z: 398[M+H] + ,

[0153] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of 2-allyl-1-(6-(2-hydroxyhexa-5-en-2-yl)pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (5.25 g, 13.2 mmol) and Grubbs III (1.17 g, 1.32 mmol) in dichlorodichlorodioxide (1.6 L) was heated to 40°C under argon gas protection and stirred overnight. After cooling, the reaction mixture was concentrated under pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20-65%) to obtain (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (510 mg, yield 10.5%) and recovered to obtain 2-allyl-1-(6-(2-hydroxyhexa-5-en-2-yl)pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (4.0 g, yield 76.1%). LC-MS m / z: 370[M+H] + ,

[0154] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-A][1,2]diazacyclotridecine-5-one (510 mg, 1.38 mmol) and m-chloroperbenzoic acid (500 mg, 2.46 mmol) were dissolved in toluene (50 mL) and stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H]+ ,

[0155] 5) Synthesis of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine [ka] Under conditions of 0°C, sodium hydride (3.47 g, 86.82 mmol, 60% content) was added in several portions to a tetrahydrofuran (50 mL) solution containing 1-methylpiperidine-4-ol (5 g, 43.41 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 hours. Then, 1-fluoro-2-methyl-4-nitrobenzene (7.4 g, 47.7 mmol) was added to the reaction mixture in several portions. The resulting reaction mixture was heated to 50°C and stirred for 17 hours. Under conditions of 0°C, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with dichloromethane (1 × 50 mL). The combined organic phases were washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to obtain 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine (6.5 g, yield 59.82%). LC-MS m / z: 251 [M+H] + ,

[0156] 6) Synthesis of 3-methyl-4-((1-methylpiperidine-4-yl)oxy)aniline [ka] A methanol solution (40 mL) containing 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine (3.7 g, 14.7 mmol) and palladium carbon (2.6 g, 10% content) was stirred overnight at 25°C under a hydrogen gas atmosphere. The resulting reaction mixture was filtered, and the filter cake was washed with methanol (3 × 20 mL). The filtrate was collected, and 3-methyl-4-((1-methylpiperidine-4-yl)oxy)aniline (3 g, 92.1% yield) was concentrated under reduced pressure. LC-MS m / z: 221 [M + H]+ ,

[0157] 7) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A 50 mL solution of dioxane containing (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (500 mg, 1.24 mmol) and 3-methyl-4-((1-methylpiperidine-4-yl)oxy)aniline (328.3 mg, 1.49 mmol) was heated to 100°C and stirred overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10%) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (490 mg, yield 73.0%). LC-MS m / z: 542[M+H] + ,

[0158] 8) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (490 mg, 0.91 mmol) was subjected to preparative supercritical fluid chromatography (chromatographic conditions: instrument: SHIMADZU LC-20AP, column: DAISELCHIRALPAK® IC, 250 × 40 mm 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol containing 0.1% ammonia / methanol (7 M), gradient: 60% to 60% B in 24 min, flow rate: 80 mL / min, column temperature: 20°C, detection wavelength: 254 Purified by LC-MS m / z: 542 [M+H], (R,E)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (160 mg, yield 32.6%) (compound IE). LC-MS m / z: 542 [M+H] + ,

[0159] Confirmation of the absolute configuration of compound IE (culturing of single crystals) Approximately 5 mg of the metastable crystalline form H of compound IE was weighed and dissolved in 1.2 mL of isopropyl acetate, and filtered into a 3 mL vial. Then, a hole was made in the vial and the solution was placed in a 20 mL vial containing 3 mL of n-pentane, and crystallization was allowed to occur at 25°C. Plate-like crystals were obtained from the isopropyl acetate and n-pentane system by gas-liquid diffusion, and the products were characterized by analysis of single-crystal X-ray diffraction patterns (Figure 38). Analysis of the crystal structure revealed that the single crystal belongs to the triclinic system, with a space group of P1. The unit cell parameters were a=8.2644(3) angstroms, b=8.2701(3) angstroms, c=45.8129(16) angstroms, α=94.562(2)°, β=94.343(2)°, and γ=94.807(2)°. Furthermore, it was confirmed that compound IE has one chiral atom, an absolute configuration of R, and a cis double bond within the ring. 1 H NMR (400 MHz, MeOD-d4):δ 8.78 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.34 (dd, J = 8.0, 4.0 Hz, 1H), 6.87 (d, J = 12.0 Hz, 1H), 5.53 - 5.41 (m, 2H), 4.57 (d, J = 8.0 Hz, 2H), 4.40 (s, 1H), 2.73 (s, 2H), 2.44 (s, 2H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 - 2.16 (m, 1H), 2.16-2.08 (m, 1H), 2.06 - 1.96 (m, 3H), 1.92 - 1.79 (m, 3H), 1.67 (s, 3H).

[0160] Example 2: Synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 134) [ka] A racemic mixture (490 mg, 0.91 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: system: SHIMADZU LC-20AP, column: DAISELCHIRALPAK® IC 250×40 mm 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (+0.1% 7.0 M Ammonia in MeOH), A:B=40:60, detection wavelength: 254 nm, flow rate: 80 mL / min, column temperature: RT, column pressure: 100 (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (150 mg, 30.6%) was obtained by fractionation and purification using a bar. LC-MS m / z: 542[M+H] + , 1H NMR (400 MHz, MeOD-d4): δ 8.78 (d, J = 2.8 Hz, 1H), 7.94 (td, J= 8.0, 2.0 Hz, 1H), 7.80 (dd, J = 8.0, 2.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.8, 2.8 Hz, 1H), 5.54 - 5.37 (m, 2H), 4.57 (d, J = 6.2 Hz, 2H), 4.40 (s, 1H), 2.75 (s, 2H), 2.46 (s, 2H), 2.35 (d, J = 3.2 Hz, 3H), 2.20 (s, 3H), 2.16 (s, 1H), 2.00 (d, J = 9.8 Hz, 3H), 1.98 - 1.77 (m, 4H), 1.68 (s, 3H).

[0161] Example 3, Synthesis of (R)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 28) [ka] (R,E)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (50 mg, 0.092 mmol) and palladium carbon (10 mg) were dissolved in methanol (2 mL) and stirred at room temperature for 16 hours under a hydrogen atmosphere. The resulting reaction mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The collected filtrate was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH4HCO3 = 5-95% elution) to obtain (R)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (34 mg, yield 67%). LC-MS m / z 544[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.78 (s, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.41 (s, 1H), 3.88-3.84 (m, 1H), 3.31-3.30(m,1H), 2.72(s,2H), 2.43-2.39(m,3H), 2.32(s,4H), 2.23(s,1H), 2.14-2.11(m,3H), 2.01-1.98(m,2H), 1.93-1.90(m,1H), 1.89-1.86(m,2H), 1.51(s,6H), 1.29(s,1H).

[0162] Example 4, Synthesis of (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 29) [ka] (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (10.0 mg, 0.02 mmol), palladium / carbon hydroxide (5 mg), and Pd / C (5 mg) were dissolved in methanol (1 mL) and stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The reaction mixture was filtered and the filter cake was washed with methanol (3 × 5 mL). The collected filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH₄HCO₃ in pure water = 5-95% elution) to obtain (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (8 mg, yield 79.7%). LC-MS m / z: 544[M+H] + , 1H NMR (400 MHz, MeOD-d4):δ 8.79 (s, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.86 (s, 1H), 3.88-3.84 (m, 1H), 3.31-3.30 (m,1H), 3.11-2.98 (m, 2H), 2.78-2.58 (m, 2H), 2.48 (s, 3H), 2.25-2.19 (m, 2H), 2.06 (s,3H), 2.20-1.93 (m, 6H), 1.51(s,5H), 1.29 (s,2H).

[0163] Example 5, Synthesis of (Z)-2-((4-(((1,4-dimethylpiperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 89) [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (50 mg, 0.12 mmol) and 1,4-dioxane (5) prepared by dissolving 4-(((1,4-dimethylpiperidine-4-yl)oxy)-3-methylaniline (35 mg, 0.15 mmol) The solution (mL) was heated to 100°C and stirred overnight. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain (Z)-2-((4-(((1,4-dimethylpiperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (43 mg, yield 62.2%). LC-MS m / z: 556[M+H] + , 1 H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 10.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.52 - 5.39 (m, 2H), 4.61 (d, J = 6.4 Hz, 2H), 3.09 (s, 2H), 2.67 (s, 3H), 2.26 (d, J = 14.8 Hz, 6H), 2.20 - 2.08 (m, 2H), 2.04 - 1.83 (m, 5H), 1.68 (s, 3H), 1.27 (s, 3H).

[0164] Example 6, Synthesis of (Z)-12-hydroxy-2-((2-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 90) [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (50 mg, 0.12 mmol) and 2-methoxy-4-((1-methylpiperidine-4-yl)oxy)aniline (35 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL) and heated to 100°C and stirred overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain (Z)-12-hydroxy-2-((2-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (45 mg, yield 64.8%). LC-MS m / z: 558[M+H] + , 1H NMR (400 MHz, MeOD): δ 8.80 (s, 1H), 7.94 (t, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 9.2 Hz, 1H), 5.45 (dd, J = 17.2, 9.2 Hz, 2H), 4.61 (d, J = 7.2 Hz, 2H), 4.43 (s, 1H), 3.86 (s, 3H), 2.79-2.72 (m, 2H), 2.48-2.43 (m, 2H), 2.34 (s, 3H), 2.24-2.16 (m, 2H), 2.04-1.98 (m, 3H), 1.90-1.82 (m, 3H), 1.68 (s, 3H).

[0165] Example 7, Synthesis of 2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide (compound 130) 1) Synthesis of N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-sulfonamide [ka] At room temperature and under nitrogen gas protection, 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (200 mg, 0.9 mmol) was dissolved in a 1,4-dioxane (2 mL) solution to which N,N'-dimethylethylenediamine (87 mg, 0.99 mmol), cuprous iodide (171 mg, 0.9 mmol), and potassium carbonate (311 mg, 2.25 mmol) were added in several portions. The resulting reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was diluted with water, extracted with ethyl acetate (3 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 10-20% elution) to obtain N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-sulfonamide (100 mg, yield 26.5%). LC-MS m / z: 419[M+H] + ,

[0166] 2) Synthesis of 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide [ka] At room temperature and under nitrogen gas protection, N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridine-2-sulfonamide (47 mg, 0.112 mmol) was dissolved in dichloromethane (2 mL), to which dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromopyridine)ruthenium(II) (10.3 mg, 0.012 mL) was added. The resulting reaction mixture was heated to 80°C under argon gas protection and stirred for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane (3 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:dichloromethane = 10-20% elution) to obtain 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide (40 mg, yield 91.2%). LC-MS m / z: 391[M+H] + ,

[0167] 3) Synthesis of 2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide [ka] At room temperature, 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide (30 mg, 0.077 mmol) was dissolved in a 2 mL solution of dichloromethane, to which 3-methyl-4-((1-methylpiperidine-4-yl)oxy)aniline (30 mg, 0.135 mmol) and m-chloroperbenzoic acid (26.5 mg, 0.154 mmol) were added in several portions. The resulting reaction mixture was heated to 40°C and stirred for 8 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (3 × 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (using pure water containing acetonitrile: 0.1% NH3H2O ​​= 5-95% elution) to obtain 2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecine-5-one 12,12-dioxide (6 mg, yield 13.9%). LC-MS m / z: 563[M+H] + , 1 H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 8.16 (d, J = 6.4 Hz, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.46 - 7.60 (m, 1H), 7.38 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.04 - 6.14 (m, 1H), 5.07 (s, 3H), 4.50 - 4.68 (m, 1H), 3.89 - 4.00 (m, 1H), 3.77 - 3.87 (m, 1H), 3.57 - 3.64 (m, 1H), 3.18 - 3.23 (m, 1H), 2.99 - 3.09 (m, 1H), 2.75 (s, 3H), 2.26 (s, 3H), 2.07 - 2.19 (m, 3H), 2.03 (s, 2H).

[0168] Example 8: Synthesis of 12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 1A) [ka] (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-A][1,2]diazacyclotridecine-5-one (50 mg, 0.092 mmol) and palladium carbon (10 mg) were dissolved in methanol (2 mL) and stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The collected filtrate was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: 0.1% pure water containing NH4HCO3 = 5-95%) to obtain 12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (30 mg, yield 60%). LC-MS m / z: 544[M+H] + , 1H NMR (400 MHz, MeOD-d4):δ 8.78 (s, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.34(dd, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.43 (s, 1H),3.84-3.80 (m, 1H), 3.31 (t, J= 4.0 Hz, 1H), 2.78 (s, 2H), 2.50 (s, 2H), 2.37 (s, 3H), 2.32-2.31 (m, 2H), 2.23-2.21 (m, 3H), 2.02-1.98 (m, 2H), 1.89-1.84 (m, 3H), 1.51 (s, 6H), 1.36-1.34(m, 2H).

[0169] Example 9, Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 140) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) were dissolved in toluene (2 mL) and stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0170] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A 1,4-dioxane (2 mL) solution containing (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100.0 mg, 0.25 mmol) and 4-((1-methylpiperidine-4-yl)oxy)aniline (76 mg, 0.37 mmol) was heated to 100°C and stirred overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (20 mg, yield 15.2%). LC-MS m / z: 528[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.81 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 12.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 3H), 6.91 (d, J = 8.0 Hz, 2H), 5.50-5.40 (m, 2H), 4.62-4.58 (m, 2H), 4.42-4.37 (m, 1H), 2.78-2.72 (m, 2H), 2.46-2.39 (m, 2H), 2.33 (s, 3H), 2.24-2.15 (m, 2H), 2.03-1.97 (m, 3H), 1.92-1.87(m,3H), 1.88(s,3H).

[0171] Example 10: Synthesis of (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 141) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) were dissolved in toluene (2 mL) and stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which can be used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0172] 2) Synthesis of (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A 1,4-dioxane (2 mL) solution containing (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100.0 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidine-4-yl)oxy)aniline (88.3 mg, 0.37 mmol) was heated to 100°C and stirred overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (20 mg, yield 14.4%). LC-MS m / z: 558[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.83 (s, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 4.0 Hz, 1H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.50-5.30 (m, 2H), 4.64 (d, J = 8.0 Hz,2H), 4.27 (s, 1H), 3.71 (s, 3H), 2.82 (s, 2H), 2.46-2.32 (m, 5H), 2.30-2.10 (m, 2H), 2.01-1.92(m, 3H), 1.91-1.79(m,3H), 1.69(s, 3H).

[0173] Example 11: Synthesis of (R,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 143) 1) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A racemic mixture (300 mg, 0.81 mmol) was separated and subjected to preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 15 0, column: DAIELCHIRALCEL® AS 250 × 25 mm 10 μm, mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MEOH) A:B = 75:25, detection wavelength: 214 nm, flow rate: 100 mL / min, column temperature: RT, column pressure: 100 bar, injection volume: 4.5 mL). Separation and purification using (mL) yielded (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (130 mg, yield 43%).

[0174] 2) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) were dissolved in a toluene solution (2 mL) and stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0175] 3) Synthesis of (R,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A 1,4-dioxane (2 mL) solution containing (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidine-4-yl)oxy)aniline (88 mg, 0.37 mmol) was heated to 100°C and stirred overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (R,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (20 mg, yield 14.4%). LC-MS m / z: 558[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.83 (s, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.45-5.30 (m, 2H), 4.64 (d, J = 8.0 Hz,2H), 4.26 (s, 1H), 3.71 (s, 3H), 2.81 (s, 2H), 2.45-2.32 (m, 5H), 2.30-2.10 (m, 2H), 2.00-1.92(m,3H), 1.99-1.77(m,3H), 1.69(s,3H).

[0176] Example 12: Synthesis of (S,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 144) 1) Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A racemic mixture (300 mg, 0.81 mmol) was separated and subjected to preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 15 0, column: DAIELCHIRALCEL® AS 250 × 25 mm 10 μm, mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MEOH) A:B = 75:25, detection wavelength: 214 nm, flow rate: 100 mL / min, column temperature: RT, column pressure: 100 bar, injection volume: 4.5 mL). Separation and purification using (mL) yielded (S,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (150 mg, 50% yield).

[0177] 2) Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (S,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) were dissolved in a toluene solution (2 mL) and stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0178] 3) Synthesis of (S,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A 1,4-dioxane (2 mL) solution containing (S,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidine-4-yl)oxy)aniline (88 mg, 0.37 mmol) was heated to 100°C and stirred overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (S,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (20 mg, yield 14.4%). LC-MS m / z: 558[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.83 (s, 1H), 7.93 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.44-5.30 (m, 2H), 4.64 (d, J = 8.0 Hz,2H), 4.27 (s, 1H), 3.71 (s, 3H), 2.82 (s, 2H), 2.49-2.34 (m, 5H), 2.30-2.08 (m, 2H), 2.02-1.92(m,3H), 1.91-1.79(m,3H), 1.69(s,3H).

[0179] Example 13: Synthesis of 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecene-11-one (compound 146) 1) Synthesis of 2-bromo-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol [ka] At 0°C and under argon gas protection, 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one (1.0 g, 4.74 mmol) was dissolved in tetrahydrofuran (10 mL), to which penta-4-en-1-ylmagnesium bromide (5 mL, 25.0 mmol, 0.5 M tetrahydrofuran solution) was added dropwise. The resulting reaction mixture was stirred overnight at room temperature under argon gas protection. At 0°C, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-30% elution) to obtain 2-bromo-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (360 mg, yield 27%). LC-MS m / z: 282[M+H] + ,

[0180] 2) Synthesis of 2-allyl-1-(7-hydroxy-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrzolo[3,4-d]pyrimidine-3-one [ka] 2-allyl-6-(methylthiomethyl)-1,2,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (211 mg, 0.95 mmol), 2-bromo-7-(2-bromo-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (320 mg, 1.14 mmol), cuprous iodide (90 mg, 0.47 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (54 mg, 0.38 mmol), and potassium phosphate (604 mg, 2.85 mmol) dissolved in toluene (8 The solution (mL) was heated to 110°C under nitrogen gas protection and stirred for 8 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (using pure water containing acetonitrile: 0.1% NH3H2O ​​= 5-95% elution) to obtain 2-allyl-1-(7-hydroxy-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrzolo[3,4-d]pyrimidine-3-one (234 mg, yield 58.1%). LC-MS m / z: 424[M+H] + ,

[0181] 3) Synthesis of 3a-hydroxy-14-(methylthio)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecene-11-one [ka] A solution of 2-allyl-1-(7-hydroxy-7-(penta-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (234 mg, 0.55 mmol) and Grubbs III (98 mg, 0.11 mmol) in dichloromethane (100 mL) was heated to 40°C under argon gas protection and stirred overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 20-65% elution) to obtain 3a-hydroxy-14-(methylthio)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazaciclodecene-11-one (23 mg, yield 10.5%). LC-MS m / z: 396[M+H] + ,

[0182] 4) Synthesis of 3a-hydroxy-14-(methylsulfonyl)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecene-11-one [ka] 3a-Hydroxy-14-(methylthio)-3,3a,4,5,6,9-Hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecen-11-one (50 mg, 0.13 mmol) and oxone (87.6 mg, 0.25 mmol) were dissolved in tetrahydrofuran and mixed with water (2 mL, v:v=1:1). The mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which could be used directly in the next step without further purification. LC-MS m / z:428[M+H]+ ,

[0183] 5) Synthesis of 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecen-11-one [ka] A 1,4-dioxane (1 mL) solution containing 3a-hydroxy-14-(methylsulfonyl)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecen-11-one (45 mg, 0.11 mmol) and 3-methyl-4-((1-methylpiperidine-4-yl)oxy)aniline (75 mg, 0.34 mmol) was heated to 50°C and stirred for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidine-4-yl)oxy)phenyl)amino)-3,3a,4,5,6,9-hexahydro-2H,11H-1,17-(cyclohexane[1,2]diylidene)cyclopenta[e]pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2,4]triazacyclododecen-11-one (27 mg, yield 45.2%). LC-MS m / z: 568[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.77 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.40 - 7.32 (m, 1H), 6.89 (dd, J = 16.3, 8.9 Hz, 1H), 5.93 - 5.79 (m, 1H), 5.53 (t, J = 9.5 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.27 (dd, J = 14.9, 4.4 Hz, 1H), 4.11 (dd, J = 14.8, 10.9Hz, 1H), 3.61 (d, J = 12.4 Hz, 1H), 3.50 - 3.41 (m, 2H), 3.19 - 3.10 (m, 2H), 2.99 - 2.91 (m, 5H), 2.50 - 2.35 (m, 3H), 2.27 (s, 4H), 2.18 (s, 1H), 2.15 - 1.98 (m, 3H), 1.83 (t, J = 13.4 Hz, 4H), 1.67 - 1.55 (m, 2H).

[0184] Example 14, (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomers (compounds 171A and B) 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate [ka] To a tetrahydrofuran (20 mL) solution containing 2000 mg, 9.95 mmol of 4-hydroxypiperidine-1-formate tert-butyl, sodium hydride (796 mg, 19.9 mmol, 60% content) was added and the mixture was stirred at room temperature for 1 hour. Then, at room temperature, 1-fluoro-2-methyl-4-nitrobenzene (1850.7 mg, 11.94 mmol) was added in several portions. The resulting reaction mixture was heated to 50°C and stirred overnight. After cooling, methanol (50 mL) was added to the reaction mixture to quench it, and the mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH4HCO3) = 5-95% elution) to obtain 1100 mg, 32.9% yield of 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate tert-butyl. LC-MS m / z:337[M+H] + ,

[0185] 2) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine [ka] Under room temperature conditions, 1 mL of 2,2,2-trifluoroacetic acid was added dropwise to a 3 mL solution of dichloromethane containing 1100 mg (3.27 mmol) of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate. The resulting reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH4HCO3) = 5-95% elution) to obtain 4-(2-methyl-4-nitrophenoxy)piperidine (659 mg, yield 85.3%). LC-MS m / z: 237 [M+H] + ,

[0186] 3) Synthesis of 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine [ka] At 0°C, 4-(2-methyl-4-nitrophenoxy)piperidine (659 mg, 2.79 mmol) was dissolved in tetrahydrofuran (10 mL) solution, to which sodium hydride (223.2 mg, 5.58 mmol, 60% content) was added in several portions. The resulting reaction mixture was stirred at room temperature for 1 hour. At room temperature, iodomethane-d3 (485 mg, 3.35 mmol) was added to the reaction mixture in several portions. The resulting reaction mixture was heated to 50°C and stirred overnight. After cooling, methanol (20 mL) was added at 0°C to quench the mixture, and it was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1%NH4HCO3) = 5-95% elution) to obtain 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine (301 mg, yield 42.6%). LC-MS m / z:254[M+H] + ,

[0187] 4) Synthesis of 3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxyaniline [ka] A solution of 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine (301 mg, 1.19 mmol) and Fe (333 mg, 5.95 mmol) dissolved in saturated ammonium chloride aqueous solution (1 mL) and ethanol (4 mL) was heated to 70°C and stirred overnight. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 224 [M + H] + ,

[0188] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (510 mg, 1.38 mmol) and 3-chloroperbenzoic acid (500 mg, 2.46 mmol) were dissolved in toluene (50 mL) and stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0189] 6) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno))pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (400 mg, 0.99 mmol) and 3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)aniline (266 mg, 1.19 mol) in 1,4-dioxane (20 mL) was heated to 100°C and stirred overnight. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1%NH4HCO3) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno))pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (201 mg, yield 37.3%). LC-MS m / z: 545[M+H] + ,

[0190] 7) (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and Synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno))pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (201 mg, 0.37 mmol) was analyzed by chiral preparative high-performance liquid chromatography (chromatographic conditions: system Waters SFC 150, column type DAISELCHIRALCEL® AD, column 250×25 mm 10 m, mobile phase A Supercritical CO2, mobile phase B EtOH (+0.1% 7.0 mol / l Ammonia in MeOH), A:B=65:35, detection wavelength 214 nm, flow rate 100 m). The compounds were purified by a method (mL / min, column temperature at room temperature, column pressure at 100 bar) to obtain two isomers, compound 171A and compound 171B.

[0191] Compound 171A was identified as (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (80 mg, 40% yield) at peak 1 (peak appearance time 2.389 min). LC-MS m / z: 545[M+H] + , 1H NMR (400 MHz, MeOD):δ 8.79 (s, 1H), , 7.95 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.35 (dd, J = 9.0, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.48 (dd, J = 13.4, 6.7 Hz, 2H), 4.59 (d, J = 6.8 Hz, 2H), 4.43 (s, 1H), 2.82 (s, 2H), 2.55 (s, 2H), 2.22 (s, 3H), 2.03 (s, 4H), 1.89 (s, 4H), 1.68 (s, 3H).

[0192] Compound 171B was identified as (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (80 mg, 40% yield) at peak 2 (peak appearance time 3.537 min). LC-MS m / z: 545[M+H] + , 1 H NMR (400 MHz, MeOD): δ 8.79 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.61 - 5.38 (m, 2H), 4.58 (d, J = 6.9 Hz, 2H), 4.43 (s, 1H), 2.81 (s, 2H), 2.53 (s, 2H), 2.21 (s, 3H), 2.06 (dd, J = 33.8, 24.0 Hz, 4H), 1.93 (d, J = 29.8 Hz, 4H), 1.68 (s, 3H).

[0193] Example 15, (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomers (compounds 172A and B) 1) Synthesis of 1-methylpiperidine-4-butan-4-ol [ka] Under 0°C conditions, 1-methylpiperidine-4-one (1.0 g, 8.85 mmol) was dissolved in a 20 mL solution of T-tetrahydrofuran, to which NaBD4 (557.5 mg, 13.3 mmol) was added in several portions. The resulting reaction mixture was stirred overnight at room temperature. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 117 [M+H] + ,

[0194] 2) Synthesis of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine-4-d [ka] At 0°C, sodium hydride (690 mg, 17.24 mmol, 60% content) was added in several portions to a tetrahydrofuran (20 mL) solution containing 1-methylpiperidine-4-butan-4-ol (1 g, 8.62 mmol), and the mixture was stirred at 0°C for 1 hour. At 0°C, 1-fluoro-2-methyl-4-nitrobenzene (1.6 g, 10.3 mmol) was added to the above reaction mixture in several portions. The resulting reaction mixture was heated to 50°C and stirred overnight. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH3.H2O) = 5-95% elution) to obtain 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine-4-d (600 mg, yield 27.7%). LC-MS m / z:252[M+H] + ,

[0195] 3) Synthesis of 3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxyaniline [ka] A solution of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine-4-d (600 mg, 2.39 mmol) and iron (669.3 mg, 11.95 mmol) dissolved in ammonium chloride (1 mL) and ethanol (4 mL) was heated to 70°C and stirred for 2 hours. After cooling, the reaction mixture was filtered, the filter cake was washed with methanol (3 × 50 mL), and the filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 222 [M + H] + ,

[0196] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (400 mg, 0.99 mmol) and 3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)aniline (266 mg, 1.19 mol) were dissolved in 1,4-dioxane (20 mL) and heated to 100°C and stirred overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (201 mg, yield 37.3%). LC-MS m / z: 543[M+H] + ,

[0197] 5) (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and Synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (201 mg, 0.37 mmol) was analyzed by chiral preparative high-performance liquid chromatography (chromatographic conditions: system Waters SFC 150, column type DAIELCHIRALCEL®AD, column size 250×25 mm 10 μm, mobile phase A Supercritical CO2, mobile phase B ETOH (+0.1% 7.0 mol / l Ammonia in MEOH), A:B=60:40, detection wavelength 214 nm, flow rate 100 The compounds were purified by a method (mL / min, column temperature RT, column pressure 100 bar) to obtain two isomers, compound 172A and compound 172B.

[0198] Compound 172A was identified as (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (80 mg, 40% yield) at peak 1 (peak appearance time 2.338 min). LC-MS m / z: 543[M+H] + , 1H NMR (400 MHz, MeOD): δ 8.80 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.35 (dd, J = 8.6, 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.52 - 5.43 (m, 2H), 4.59 (d, J = 6.4 Hz, 2H), 2.73 (s, 2H), 2.45 (s, 2H), 2.34 (s, 3H), 2.21 (s, 3H), 1.99 (s, 4H), 1.87 (s, 4H), 1.68 (s, 3H).

[0199] Compound 172B was identified as (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (80 mg, 40% yield) at peak 2 (peak appearance time 3.527 min). LC-MS m / z: 543[M+H] + , 1 H NMR (400 MHz, MeOD): δ 8.80 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.35 (dd, J = 8.6, 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.52 - 5.43 (m, 2H), 4.59 (d, J = 6.7 Hz, 2H), 2.73 (s, 2H), 2.45 (s, 2H), 2.34 (s, 3H), 2.21 (s, 3H), 1.99 (s, 4H), 1.87 (s, 4H), 1.68 (s, 3H).

[0200] Example 16, (R,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomers (compounds 173A and B) 1) Synthesis of 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine [ka] At 0°C, potassium tert-butoxide (5.37 g, 47.82 mmol) was added to a tetrahydrofuran (50 mL) solution containing 1-methylpiperidine-4-ol (3.03 g, 26.30 mmol). At 0°C, 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-55% elution) to obtain 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (5.2 g, yield 71.5%). LC-MS m / z: 305[M+H] + ,

[0201] 2) Synthesis of 4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)aniline [ka] A solution of 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (3 g, 9.86 mmol), iron (2.75 g, 49.3 mmol), and ammonium chloride (5.27 g, 98.6 mmol) in ethanol (30 mL) and water (3 mL) was heated to 80°C and stirred for 6 hours. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 275 [M + H] + ,

[0202] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (217 mg, 0.54 mmol) and 1,4-dioxane (10) prepared by dissolving 4-(((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)aniline (178.2 mg, 0.65 mmol) The solution (mL) was heated to 100°C and stirred overnight. After cooling, the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH4HCO3)=5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (96 mg, yield 29.8%). LC-MS m / z: 596[M+H] + ,

[0203] 4) (R,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and Synthesis of (S,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (96 mg, 0.16 mmol) was analyzed by chiral preparative high-performance liquid chromatography (chromatographic conditions: system SHIMADZU LC-20AP, column type DAISELCHIRALPAK®IE, column size 250×25 mm 10 μm, mobile phase A n-Hexane, mobile phase B EtOH (+0.1% 7.0 mol / l Ammonia in EtOH), A:B=50:50, detection wavelength 214°). The two isomers, compound 173A and compound 173B, were obtained by purification using a method (nm, flow rate 40 mL / min, column temp RT).

[0204] Compound 173A was identified as (R,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (40 mg, yield 41.6%) at peak 1 (peak appearance time 17.883 min). LC-MS m / z 596[M+H] + , 1H NMR (400 MHz, MeOD): δ 8.87 (s, 1H), 8.21 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.51-5.47 (m, 2H), 4.70-4.67 (m, 1H), 4.63 (d, J = 6.4 Hz, 2H), 2.86-2.82 (m, 2H), 2.69-2.65 (m, 2H), 2.46 (s, 3H), 2.21-2.16 (m, 2H), 2.07-1.98 (m, 6H), 1.71 (s, 3H).

[0205] Compound 173B was identified as (S,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidine-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (40 mg, yield 41.6%) at peak 2 (peak appearance time after peak 1). LC-MS m / z 596[M+H] + , 1H NMR (400 MHz, MeOD): δ 8.87 (s, 1H), 8.21 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 5.49 (dd, J = 12.4, 6.3 Hz, 2H), 4.69 (s, 1H), 4.64 (d, J = 7.0 Hz, 2H), 2.84 (s, 2H), 2.69 (s, 2H), 2.46 (s, 3H), 2.18 (s, 2H), 2.05 (s, 3H), 1.97 (d, J = 18.4 Hz, 3H), 1.71 (s, 3H).

[0206] Example 17, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 174) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (510 mg, 1.38 mmol) and 3-chloroperbenzoic acid (500 mg, 2.46 mmol) were dissolved in toluene (50 mL) and stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 402[M+H] + ,

[0207] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (500 mg, 1.24 mmol) and 3-methyl-4-((4-methylpiperazine-1-yl)methyl)aniline (328.3 mg, 1.49 mmol) in 1,4-dioxane (50 mL) was heated to 100°C and stirred overnight. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 0-10% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (490 mg, yield 73.0%). LC-MS m / z: 541[M+H]+ , 1 H NMR (400 MHz, MeOD-d4) δ 8.84 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.41 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.48 (d, J= 6.4 Hz, 2H), 4.62 (d, J = 6.4 Hz, 2H), 3.48 (s, 2H), 2.51 (s, 7H), 2.36 (s, 3H), 2.29 (s, 3H), 2.25 - 2.11 (m, 2H), 2.00 (s, 1H), 1.93 (s, 1H), 1.69 (s, 3H).

[0208] Example 18, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 175) 1) Synthesis of 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate [ka] A solution of 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate (400 mg, 1.76 mmol) and sodium hydride (141 mg, 3.52 mmol, 60% content) in tetrahydrofuran (4.0 mL) was stirred at room temperature for 1 hour. Then, 1-fluoro-2-methyl-4-nitrobenzene (409 mg, 2.64 mmol) was added to the reaction mixture, and the mixture was heated to 50°C and stirred for 2 hours. After cooling, methanol (4 mL) was added to the reaction mixture at 0°C to quench it. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate (450 mg, yield 70.56%). LC-MS m / z: 363[M+H] + ,

[0209] 2) Synthesis of 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole [ka] Under room temperature conditions, 450 mg (1.24 mmol) of 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate was dissolved in 1.5 mL of dichloromethane, to which 0.5 mL of 2,2,2-trifluoroacetic acid was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%FA)=5%~95% elution) to obtain 300 mg (92.13% yield) of 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole. LC-MS m / z: 263[M+H] + ,

[0210] 3) Synthesis of 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole [ka] A solution of 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (300 mg, 1.14 mmol), paraformaldehyde (73 mg, 2.29 mmol), and sodium borohydride (144 mg, 2.29 mmol) dissolved in acetic acid (0.3 mL) and dichloromethane (3 mL) was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with water (3 mL) at room temperature and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%FA)=5-95% elution) to obtain 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (200 mg, yield 63.13%). LC-MS m / z: 277 [M+H] + ,

[0211] 4) Synthesis of methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxyaniline [ka] A methanol solution containing 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (200 mg, 0.72 mmol) and Pd / C (200 mg) was stirred at room temperature for 4 hours under hydrogen gas protection. The reaction mixture was filtered, the filter cake was washed with methanol (3 × 5 mL), and the filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain 3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxyaniline (100 mg, yield 56.18%). LC-MS m / z: 247[M+H] + ,

[0212] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (108 mg, 0.27 mmol) and 3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxy)aniline (100 mg, 0.40 mmol) in 1,4-dioxane (2.0 mL) was heated to 100°C and stirred for 16 hours. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%NH3.H2O)=5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrole-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (60 mg, yield 39.14%). LC-MS m / z: 568[M+H] + , 1H NMR (400 MHz, MeOD-d4):δ 8.80 (s, 1H), 7.98-7.92 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.62-7.53 (m, 2H), 7.42-7.38 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 5.53-5.39 (m, 2H), 4.60 (d, J=8.0 Hz, 2H), 3.61 (s, 1H), 3.20-3.07 (m, 4H), 2.87 (s, 3H), 2.32-2.10 (m, 8H), 2.08-1.96 (m, 3H), 1.95-1.84 (m, 2H), 1.68 (s, 3H).

[0213] Example 19, (S,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (R, Synthesis of Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomers (compounds 176A and B) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] Under 0°C conditions, (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.54 mmol) was dissolved in dichloromethane (2 mL), to which 3-chloroperbenzoic acid (141 mg, 0.81 mmol) was added in several portions. The resulting reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 386 [M+H] + ,

[0214] 2) Synthesis report of (Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5,5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.52 mmol), 3-methyl-3,9-diazaspiro[5.5]undecane (130.1 mg, 0.78 mmol), and acetic acid (187.2 mg, 3.12 mmol) were dissolved in 1,2-dichloroethane (2 mL) and heated to 50°C and stirred for 1 hour. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, yield 78.7%). LC-MS m / z: 490[M+H] + ,

[0215] 3) Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (R,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.41 mmol) was subjected to chiral preparative high-performance liquid chromatography (chromatographic conditions: system: Waters SFC 150, column: DAISELCHIRALCEL® AD 250 × 30 mm 10 μm, mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MEOH), A:B ratio: 50:50, detection wavelength: 214 nm, flow rate: 120 The compounds were purified by a method (mL / min, column temperature RT, column pressure 100 bar) to obtain two isomers, compound 176A and compound 176B.

[0216] Compound 176A was identified as (S,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (52.92 mg, yield 29.5%) at peak 1 (peak appearance time 2.796 min). LC-MS m / z: 490[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ8.74 (s, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 5.53-5.40 (m, 2H), 4.53 (d, J = 6.8 Hz, 2H), 3.92 (s, 4H), 2.59 (s, 4H), 2.38 (s, 3H), 2.27-2.08 (m, 2H), 2.02-1.86 (m, 2H), 1.67(s, 7H), 1.61-1.52 (m, 4H).

[0217] Compound 176B was identified as (R,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (28.94 mg, yield 14.4%) at peak 2 (peak appearance time 6.63 min). LC-MS m / z:490[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ8.74 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 5.53-5.40 (m, 2H), 4.53 (d, J = 6.8 Hz, 2H), 3.91 (s, 4H), 2.51 (s, 4H), 2.32 (d, J = 10.0 Hz, 3H), 2.24-2.07 (m, 2H), 2.02-1.86 (m, 2H), 1.67(s, 3H), 1.64(s, 4H), 1.55(s, 4H).

[0218] Example 20, Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compounds 177A and B) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.52 mmol), 1-methyl-4-(piperidine-4-yl)piperazine (142.8 mg, 0.78 mmol), and ethanol (187.2 mg, 3.12 mmol) were dissolved in a 1,2-dichloroethane (2 mL) solution and heated to 50°C and stirred for 1 hour. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (210 mg, yield 80.2%). LC-MS m / z: 505[M+H] + ,

[0219] 2) Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (210 mg, 0.42 mmol) was subjected to chiral preparative high-performance liquid chromatography (chromatographic conditions: system: Waters SFC 150, column: DAISELCHIRALCEL® AD 250×30 mm 10 μm, mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MeOH), A:B ratio: 50:50, detection wavelength: 214 nm, flow rate: 140 mL / min, column temperature: RT, column pressure: 100 The compounds were purified using a filtration method (bar) to obtain two isomers, compound 177A and compound 177B.

[0220] Compound 177A was identified as (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (41.63 mg, 19.8%) at peak 1 (peak appearance time 1.556 min). LC-MS m / z: 505[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ 8.75 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.54-5.39 (m, 2H), 4.94 (s, 2H), 4.54 (d, J = 6.8 Hz, 2H), 2.99 (t, J = 12.4 Hz, 2H), 2.80-2.34 (m, 9H), 2.28 (s, 3H), 2.22-2.07 (m, 2H), 2.04-1.94 (m, 3H), 1.93-1.84 (m, 1H), 1.67 (s, 3H), 1.52-1.37 (m, 2H).

[0221] Compound 177B was identified as (R,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidine-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (66.71 mg, yield 31.7%) at peak 2 (peak appearance time 5.082 min). LC-MS m / z: 505[M+H] + , 1H NMR (400 MHz, MeOD-d4): δ 8.76 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 5.54-5.39 (m, 2H), 4.94 (s, 2H), 4.54 (d, J = 6.4 Hz, 2H), 2.99 (t, J = 12.0 Hz, 2H), 2.80-2.39 (m, 9H), 2.28 (s, 3H), 2.22-2.07 (m, 2H), 2.04-1.94 (m, 3H), 1.93-1.84 (m, 1H), 1.67 (s, 3H), 1.52-1.37 (m, 2H).

[0222] Example 21: Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-morpholinophenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 178) 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.54 mmol) and 3-chloroperbenzoic acid (186 mg, 1.08 mmol) were dissolved in a 5 mL solution of dichloromethane and stirred at room temperature for 3 hours. The resulting mixed reaction was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 386 [M+H] + ,

[0223] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-morpholinophenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (200 mg, 0.54 mmol) and 4-morpholinoaniline (115 mg, 0.65 mmol) in 1,4-dioxane (5 mL) was heated to 100°C and stirred overnight. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH4HCO3) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((4-morpholinophenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (102 mg, yield 39.4%). LC-MS m / z: 500[M+H] + , 1 H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 7.89-7.80 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.27-7.74 (m, 2H), 6.91 (d, J = 8.0 Hz, 2H), 5.75-5.71 (m, 1H), 4.50-4.30 (m, 2H), 3.89-3.84 (m, 4H), 3.20-3.09 (m, 4H), 2.22 - 1.91 (m, 3H), 1.80-1.70 (m, 1H), 1.68 (s, 3H).

[0224] Example 22, Synthesis of (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 180) 1) Synthesis of 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azaphosfinan-4-oxide [ka] A 3 mL solution of acetonitrile containing 1,2-difluoro-4-nitrobenzene (150 mg, 0.94 mmol), potassium carbonate (394 mg, 2.82 mmol), and 4-ethoxy-1,4-azaphosfinan-4-oxide (199 mg, 1.2 mmol) was heated to 70°C and stirred for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azaphosfinan-4-oxide (147 mg, yield 52%). LC-MS m / z: 303 [M+H] + ,

[0225] 2) Synthesis of 1-(4-amino-2-fluorophenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide [ka] A methanol solution containing 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azaphosfinan-4-oxide (127 mg, 0.42 mmol) and Pd / C (60 mg) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 3 hours. The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 20 mL). The filtrate was collected and concentrated under pressure to obtain 1-(4-amino-2-fluorophenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide (90 mg, yield 78%). LC-MS m / z: 273 [M+H] + ,

[0226] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (80 mg, 0.20 mmol), 1-(4-amino-2-fluorophenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide (81 mg, 0.30 mmol), and acetic acid (72 mg, 1.2 mmol) were dissolved in 1,2-dichloroethane (2 mL) and heated to 50°C and stirred for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% FA) = 30-70% elution) to obtain (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (25 mg, yield 21%). LC-MS m / z: 594[M+H] + , 1 H NMR (400 MHz, MeOD-d4) δ 8.82 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.25 (dd, J = 8.6, 1.7 Hz, 1H), 7.03 (t, J = 9.2 Hz, 1H), 5.51 - 5.37 (m, 2H), 4.61 (d, J = 6.8 Hz, 2H), 4.15 (p, J = 7.1 Hz, 2H), 3.60 - 3.46 (m, 2H), 3.30 - 3.23 (m, 2H), 2.11 (dd, J = 22.3, 9.7 Hz, 6H), 2.04 - 1.86 (m, 2H), 1.69 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H).

[0227] Example 23, Synthesis of (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 181) 1) Synthesis of 4-ethoxy-1-(4-nitrophenyl)-1,4-azaphosfinan-4-oxide [ka] A 5 mL solution of 1,4-dioxane containing 1-bromo-4-nitrobenzene (300 mg, 1.49 mmol), 4-ethoxy-1,4-azaphosfinan-4-oxide (364 mg, 2.24 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (125 mg, 0.15 mmol), and cesium carbonate (1450 mg, 4.47 mmol) was heated to 100°C under a nitrogen atmosphere and stirred overnight. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain 4-ethoxy-1-(4-nitrophenyl)-1,4-azaphosfinan-4-oxide (409 mg, 96% yield). LC-MS m / z: 285 [M+H] + ,

[0228] 2) Synthesis of 1-(4-aminophenyl)-1,4-azaphosfinan-4-oxide [ka] A methanol solution containing 4-ethoxy-1-(4-nitrophenyl)-1,4-azaphosfinan-4-oxide (300 mg, 1.05 mmol) and Pd / C (150 mg) was stirred at room temperature for 3 hours under a hydrogen gas atmosphere (1 atm). The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 20 mL). The filtrate was collected and concentrated under reduced pressure to obtain 1-(4-aminophenyl)-1,4-azaphosfinan-4-oxide (247 mg, 92% yield). LC-MS m / z: 255 [M+H] + ,

[0229] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol), 1-(4-aminophenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide (95 mg, 0.38 mmol), and acetic acid (90 mg, 1.50 mmol) were dissolved in a 3 mL solution of 1,2-dichloroethane and heated to 50°C and stirred for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 30-70% elution) to obtain (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (35 mg, yield 24%). LC-MS m / z: 576[M+H] + , 1 H NMR (400 MHz, MeOD-d4) δ 8.78 (s, 1H), 7.94 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 10.9, 8.4 Hz, 3H), 6.95 (d, J = 9.1 Hz, 2H), 5.52 - 5.38 (m, 2H), 4.58 (d, J = 6.8 Hz, 2H), 4.14 (dq, J = 14.2, 7.1 Hz, 2H), 4.03 - 3.88 (m, 2H), 3.54 - 3.43 (m, 2H), 2.17 (s, 2H), 2.03 - 1.84 (m, 6H), 1.67 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

[0230] Example 24, (R,Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one and (S, Synthesis of Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compounds 182A and B) 1) Synthesis of 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azaphosfinan-4-oxide [ka] A 1,4-dioxane (5 mL) solution containing 1-bromo-2-methyl-4-nitrobenzene (300 mg, 1.39 mmol), 4-ethoxy-1,4-azaphosfinan 4-oxide (340 mg, 2.08 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (117 mg, 0.14 mmol), and cesium carbonate (1350 mg, 4.17 mmol) was heated to 100°C and stirred overnight under a nitrogen atmosphere. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-20% elution) to obtain 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azaphosfinan-4-oxide (400 mg, 96% yield). LC-MS m / z: 299 [M+H] + ,

[0231] 2) Synthesis of 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide [ka] A methanol solution containing 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azaphosfinan-4-oxide (400 mg, 1.33 mol) and Pd / C (200 mg) was stirred at room temperature for 3 hours under hydrogen gas protection. The reaction mixture was filtered, the filter cake was washed with methanol (3 × 20 mL), and the filtrate was collected and concentrated under reduced pressure to obtain 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide (334 mg, 92% yield). LC-MS m / z: 269 [M + H] + ,

[0232] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxide-1,4--azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol), 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azaphosfinan-4-oxide (100 mg, 0.37 mmol), and acetic acid (90 mg, 1.50 mmol) were dissolved in a 3 mL solution of 1,2-dichloroethane and heated to 50°C and stirred for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% FA) = 30-70% elution) to obtain (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (35 mg, yield 24%). LC-MS m / z: 590[M+H] + , 1 H NMR (400 MHz, MeOD-d4) δ 8.79 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.9 Hz, 2H), 7.38 (dd, J = 8.6, 2.4 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 5.53 - 5.41 (m, 2H), 4.58 (d, J = 6.8 Hz, 2H), 4.20 - 4.11 (m, 2H), 3.29 - 3.19 (m, 2H), 3.18 - 3.09 (m, 2H), 2.31 (s, 3H), 2.21 - 2.05 (m, 6H), 1.99 (dd, J = 16.8, 8.5 Hz, 1H), 1.93 - 1.86 (m, 1H), 1.68 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

[0233] 4) (R,Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer and Synthesis of bi(S,Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (20 mg, 0.03 mmol) was analyzed by chiral preparative high-performance liquid chromatography (chromatographic conditions: system Waters SFC 80, column DAISELCHIRALPAK® AD, 250 × 30 mm 10 μm, mobile phase A Supercritical CO2, mobile phase B EtOH (+0.1% 7.0 mol / l Ammonia in MeOH), gradient A:B=50:50, detection wavelength 214 nm, flow rate 70 The compounds were purified by a method (mL / min, column temperature at room temperature, column pressure at 100 bar) to obtain two isomers, compound 182A and compound 182B.

[0234] Compound 182A was identified as (R,Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (3 mg, yield 15%) at peak 1 (peak appearance time 3.817 min). 1 H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 10.3 Hz, 2H), 7.40 (d, J = 6.0 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.48 (dd, J = 13.5, 6.8 Hz, 2H), 4.60 (d, J = 6.6 Hz, 2H), 4.19 - 4.14 (m, 2H), 3.23 (s, 2H), 3.18 - 3.09 (m, 2H), 2.32 (s, 3H), 2.14 - 2.04 (m, 6H), 2.00 (s, 1H), 1.89 (s, 1H), 1.68 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

[0235] Compound 182B was identified as (S,Z)-2-((4-(4-ethoxy-4-oxide-1,4-azaphosfinan-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (2.5 mg, yield 12.5%) at peak 2 (peak appearance time 5.219 min). 1H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 10.3 Hz, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.53 - 5.40 (m, 2H), 4.60 (d, J = 6.8 Hz, 2H), 4.16 (dd, J = 14.5, 7.3 Hz, 2H), 3.23 (s, 2H), 3.16 (dd, J = 13.1, 4.8 Hz, 2H), 2.32 (s, 3H), 2.20 - 2.06 (m, 6H), 2.01 (d, J = 13.1 Hz, 1H), 1.90 (s, 1H), 1.68 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H).

[0236] Example 25, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 183) 1) Synthesis of (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine [ka] At 0°C, (R)-1-methylpyrrolidine-3-ol (0.98 g, 9.68 mmol) was dissolved in tetrahydrofuran (10 mL), to which sodium hydride (0.775 g, 19.35 mmol, 60% content) was added, and the mixture was stirred at 0°C for 1 hour. Then, 1-fluoro-2-methyl-4-nitrobenzene (1 g, 6.45 mmol) was added to the above mixture. The resulting reaction mixture was stirred overnight at room temperature. At 0°C, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 3-8% elution) to obtain (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (240 mg, yield 15.8%). LC-MS m / z: 237 [M+H] + ,

[0237] 2) Synthesis of (R)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline [ka] At room temperature, (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (230 mg, 0.97 mmol) and iron (273 mg, 4.87 mmol) were dissolved in ethanol (2 mL), to which saturated ammonium chloride aqueous solution (0.5 mL) was added. The resulting reaction mixture was heated to 70°C and stirred for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 0%~10% elution) to obtain (R)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline (140 mg, yield 69.7%). LC-MS m / z:207[M+H] + ,

[0238] 3) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (R)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline (120 mg, 0.58 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (280 mg, 0.70 mmol) were dissolved in isopropanol (2 mL), to which N,N-diisopropylethylamine (225 mg, 1.75 mmol) was added. The resulting mixed reaction was heated to 90°C and stirred for 6 hours. The resulting mixed reaction was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated saline (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN / H2O (0.1% FA) = 30-60% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (70 mg, yield 22.8%). LC-MS m / z: 528[M+H] + , 1H NMR (400 MHz, MeOD-d4): 8.78 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz,1H), 6.75 (d, J = 8.0 Hz, 1H),5.53-5.44 (m, 2H),4.88(s, 1H),4.58 (d, J = 4.0 Hz,2H),2.94-2.90(m,1H),2.85(t, J=8.0 Hz,2H),2.58-2.52(m, 1H),2.41(s, 3H), 2.39-2.32(m, 1H), 2.19-2.13(m, 5H), 2.02-1.89(m, 3H), 1.68(s, 3H).

[0239] Example 26, Synthesis of (R,Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomer (compound 184) 1) Synthesis of 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide [ka] A solution of 4-nitroaniline (0.3 g, 2.17 mmol), N,N'-carbonyldi(1,2,4-triazole) (0.535 g, 3.26 mmol), and triethylamine (0.65 g, 6.52 mmol) in dichloromethane (4 mL) was stirred at room temperature for 1 hour under argon gas protection. Then, 1-methylpiperazine (0.326 g, 3.26 mmol) was added to the above reaction mixture. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated saline (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 8-10% elution) to obtain 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide (500 mg, yield 87%). LC-MS m / z:265[M+H] + ,

[0240] 2) Synthesis of N-(4-aminophenyl)-4-methylpiperazine-1-carboxamide [ka] A methanol (3 mL) solution containing 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide (300 mg, 1.15 mmol) and Pd / C (181 mg, 1.70 mmol) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain N-(4-aminophenyl)-4-methylpiperazine-1-carboxamide (200 mg, yield 75.2%). LC-MS m / z: 235 [M+H] + ,

[0241] 3) (R,Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomer [ka] N,N-diisopropylethylamine (720 mg, 2.56 mmol) was added to a solution of isopropanol (2 mL) containing N-(4-aminophenyl)-4-methylpiperazine-1-carboxamide (200 mg, 0.85 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (378 mg, 0.94 mmol). The resulting reaction mixture was heated to 90°C and stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated saline solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%FA) = 30-60% elution) to obtain (R,Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomer (150 mg, yield 31.6%). LC-MS m / z: 556[M+H] + , 1H NMR (400 MHz, MeOD-d4): 8.82 (s, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 3H), 7.31 (d, J = 8.0 Hz, 2H), 5.48-5.44 (m, 2H), 4.605 (d, J = 4.0 Hz, 2H), 3.64-3.58 (m, 4H),2.68-2.65 (m, 4H),2.48 (s, 3H),2.25-2.14 (m, 2H),1.99-1.92 (m, 2H),1.68 (s, 3H).

[0242] Example 27, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 185) 1) Synthesis of (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone [ka] A solution of 1-methylpiperazine (2 g, 19.97 mmol), 4-nitrobenzoyl chloride (4.45 g, 23.96 mmol), and triethylamine (6.06 g, 59.91 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL) and purified by C18 reversed-phase column chromatography (ACN:H2O=2-5% elution) to obtain (4-methylpiperazine-1-yl)(4-nitrophenyl)methanone (4 g, yield 80.4%). LC-MS m / z:250[M+H] + ,

[0243] 2) Synthesis of (4-aminophenyl)(4-methylpiperazine-1-yl)methanone [ka] (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone (4 g, 16.05 mmol) and iron (4.48 g, 80.25 mmol) were dissolved in ethanol (32 mL) and an aqueous solution of ammonium chloride (8 mL). The mixture was heated to 70°C and stirred for 2 hours. After cooling, the reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was collected and concentrated under reduced pressure to obtain (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (1.2 g, yield 34.1%). LC-MS m / z: 220 [M+H] + ,

[0244] 3) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (100 mg, 0.25 mmol), (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (82.23 mg, 0.38 mmol), and trifluoroacetic acid (0.043 g, 0.38 mmol) in isopropanol (1.5 mL) was heated to 100°C and stirred for 16 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and purified by C18 reverse-phase column chromatography (acetonitrile:pure water = 35-50% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (60 mg, yield 44.6%). LC-MS: m / z: 541[M+H] + , 1 H NMR (400 MHz, MeOD-d4) δ 8.89 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.82 (dd, J = 13.6, 8.3 Hz, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 5.44 (dd, J = 14.2, 7.1 Hz, 2H), 4.64 (d, J = 6.7 Hz, 2H), 3.66 (s, 4H), 2.50 (s, 4H), 2.34 (s, 3H), 2.17 (s, 2H), 2.06 - 1.85 (m, 2H), 1.69 (s, 3H).

[0245] Example 28: Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or its isomer (compound 186) 1) Synthesis of (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine [ka] (S)-1-methylpyrrolidine-3-ol (0.98 g, 9.68 mmol) was added to a tetrahydrofuran (10 mL) solution containing sodium hydride (0.465 g, 19.35 mmol, 60% content) and stirred at 0°C for 1 hour. Then, 1-fluoro-2-methyl-4-nitrobenzene (1 g, 6.45 mmol) was added to the above reaction mixture and stirred overnight at room temperature. At 0°C, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated saline solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 3-8% elution) to obtain (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (740 mg, yield 47.1%). LC-MS m / z:237[M+H] + ,

[0246] 2) Synthesis of (S)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline [ka] (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (730 mg, 3.09 mmol) and iron (866 mg, 15.47 mmol) were dissolved in ethanol (6 mL) and saturated ammonium chloride aqueous solution (1.5 mL). The mixture was heated to 70°C and stirred for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated saline solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 0%~10% elution) to obtain (S)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline (400 mg, yield 62.5%). LC-MS m / z: 207 [M+H] + ,

[0247] 3) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or its isomer [ka] (S)-3-methyl-4-((1-methylpyrrolidine-3-yl)oxy)aniline (150 mg, 0.73 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or its isomer (351 mg, 0.87 mmol) were dissolved in isopropanol (2 mL), to which N,N-diisopropylethylamine (282 mg, 2.18 mmol) was added. The resulting reaction mixture was heated to 90°C and stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated saline solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN / H2O (0.1% FA) = 30-60% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or its isomer (90 mg, yield 23.5%). LC-MS m / z: 528[M+H] + , 1H NMR (400 MHz, MeOD-d4): 8.80 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 12.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz,1H),5.50-5.45 (m, 2H),4.94 (s, 1H),4.59 (d, J = 4.0 Hz, 2H), 3.05-3.02 (m, 3H), 2.73-2.71(m, 1H), 2.30 (s, 3H), 2.45-2.38 (m, 1H), 2.23-2.14 (m, 5H), 2.07-1.89 (m, 3H), 1.68 (s, 3H).

[0248] Example 29, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyl-2-azaspiro[3,3]heptan-6-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 187) 1) Synthesis of 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-formate tert-butyl [ka] A 1,4-dioxane (2.0 mL) solution containing tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-formate (200 mg, 0.94 mmol), 1-bromo-2-methyl-4-nitrobenzene (305 mg, 1.41 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (79 mg, 0.09 mmol), and cesium carbonate (921 mg, 2.82 mmol) was heated to 100°C and stirred for 16 hours under an argon gas atmosphere. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain tert-butyl 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-formate (150 mg, yield 45.87%). LC-MS / z:348[M+H] + ,

[0249] 2) Synthesis of N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptan-6-amine [ka] Under room temperature conditions, 150 mg (0.43 mmol) of tert-butyl 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-formate was dissolved in 1.5 mL of dichloromethane, to which 0.5 mL of 2,2,2-trifluoroacetic acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN / H2O (0.1% FA) = 5%~95% elution) to obtain N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine (80 mg, yield 74.93%). LC-MS m / z: 248 [M+H] + ,

[0250] 3) Synthesis of 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptan-6-amine [ka] N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptan-6-amine (80 mg, 0.32 mmol), paraformaldehyde (20 mg, 0.64 mmol), and NaBH3CN (41 mg, 0.65 mmol) were dissolved in acetic acid (0.1 mL) and dichloromethane (10 mL). The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O (0.1% FA) = 5-95% elution) to obtain 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptan-6-amine (40 mg, yield 47.32%). LC-MS m / z: 262 [M+H] + ,

[0251] 4) 2-methyl-N 1 Synthesis of (2-methyl-2-azaspiro[3,3]heptan-6-yl)benzene-1,4-diamine [ka] A methanol (2.0 mL) solution containing 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptan-6-amine (40 mg, 0.15 mmol) and Pd / C (40 mg) was stirred at room temperature for 4 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain 2-methyl-N 1 -(2-methyl-2-azaspiro[3,3]heptan-6-yl)benzene-1,4-diamine (20 mg, yield 56.48%) was obtained. LC-MS m / z: 232[M+H] + ,

[0252] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyl-2-azaspiro[3,3]heptan-6-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (21 mg, 0.052 mmol) and 2-methyl-N 1 -(2-methyl-2-azaspiro[3.3]heptan-6-yl)benzene-1,4-diamine ((20 mg, 0.09 mmol) dissolved in isopropanol (1.0 The solution (mL) was heated to 70°C and stirred for 2 hours. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%NH3.H2O)=5~95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyl-2-azaspiro[3,3]heptan-6-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (5 mg, yield 17.30%). LC-MS m / z: 553[M+H] + , 1H NMR (400 MHz, MeOD) δ 8.75 (d, J = 16.0 Hz, 1H), 7.96-7.78 (m, 1H), 7.70 (s, 1H), 7.57-7.42 (m, 1H), 6.70-6.42 (m, 3H), 5.62-5.41 (m, 2H), 4.59-4.43 (m, 2H), 4.09-3.88 (m, 3H), 3.29-3.18 (m, 3H), 3.03-2.84 (m, 2H), 2.24-2.09 (m, 3H), 2.03-1.94 (m, 3H), 1.94-1.76 (m, 3H), 1.69-1.52 (m, 5H).

[0253] Example 30, Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carbaldehyde or enantiomer (compound 188) 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate [ka] Under 0°C conditions, sodium hydride (1.858 g, 77.419 mmol) was added in several batches to a 30 mL solution of N,N-dimethylformamide containing tert-butyl 4-hydroxypiperidine-1-formate (6.225 g, 30.968 mmol), and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, a 20 mL solution of N,N-dimethylformamide containing 1-fluoro-2-methyl-4-nitrobenzene (4 g, 25.806 mmol) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (6 × 300 mL). The combined organic phases were washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate (2.8 g, yield 32.3%). LC-MS m / z: 337 [M+H] + ,

[0254] 2) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine [ka] 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate tert-butyl (2.800 g, 8.333 mmol) was dissolved in dichloromethane (21 mL) and 2,2,2-trifluoroacetic acid (7 mL) solution, which were stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (5 × 60 mL). The combined organic phase was washed with saturated saline solution (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 4-(2-methyl-4-nitrophenoxy)piperidine (1.5 g, yield 76.3%). LC-MS m / z: 237 [M+H] + ,

[0255] 3) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carbaldehyde [ka] At room temperature, 120 mg, 0.508 mmol of 4-(2-methyl-4-nitrophenoxy)piperidine and 27.45 mg, 0.610 mmol of formamide were dissolved in 2 mL of dichloromethane, to which triethylamine (154.068 mg, 1.525 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 80 mL). The combined organic phases were washed with saturated brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 4-(2-methyl-4-nitrophenoxy)piperidine-1-carbaldehyde (86 mg, yield 64.1%). LC-MS m / z:265[M+H] + ,

[0256] 4) Synthesis of 4-(4-amino-2-methylphenoxy)piperidine-1-carbaldehyde [ka] A solution of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carbaldehyde (86 mg, 3.06 mmol), NH4Cl (51.795 mmol, 0.977 mmol), and Fe (91.212 mg, 1.629 mmol) in ethanol (2 mL) and water (0.5 mL) was heated to 70°C and stirred for 3 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3 × 80 mL). The combined organic phase was washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 4-(4-amino-2-methylphenoxy)piperidine-1-carbaldehyde (54 mg, yield 70.8%). LC-MS m / z:235[M+H] + ,

[0257] 5) Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carbaldehyde or enantiomer [ka] At room temperature, 4-(4-amino-2-methylphenoxy)piperidine-1-carbaldehyde (38.07 mg, 0.162 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (54 mg, 0.135 mmol) were dissolved in isopropanol (3 mL), to which N,N-diisopropylethylamine (52.115 mg, 0.404 mmol) was added. The resulting reaction mixture was heated to 90°C and stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carbaldehyde or enantiomer (20 mg, yield 26.8%). LC-MS m / z: 556[M+H] + , 1H NMR (400 MHz, MeOD-d4): δ 8.80 (s, 1H), 8.04 (s, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.50-5.42 (m, 2H), 4.60 (d, J = 6.4 Hz, 2H), 3.72-3.65 (m, 2H), 3.58-3.54 (m, 1H), 3.48-3.41 (m, 2H), 2.23 (s, 3H), 2.19-2.13 (m, 1H), 2.06-1.73 (m, 7H), 1.68 (s, 3H).

[0258] Example 31, Synthesis of (R,Z)-2-((4-((1-acetylpiperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 189) 1) Synthesis of 1-(4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)ethane-1-one [ka] Under room temperature conditions, triethylamine (398 mg, 3.941 mmol) was added to a 4 mL solution of dichloromethane containing 4-(2-methyl-4-nitrophenoxy)piperidine (310 mg, 1.314 mmol) and acetyl chloride (122.949 mg, 1.576 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (5 × 20 mL). The combined organic phases were washed with saturated saline solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 1-(4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)ethane-1-one (186 mg, yield 50.9%). LC-MS m / z:279[M+H] + ,

[0259] 2) Synthesis of 1-(4-(4-amino-2-methylphenoxy)piperidine-1-yl)ethane-1-one [ka] 1-(4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)ethane-1-one ((186 mg, 0.6699 mmol), iron (18.338 mg, 3.345 mmol), and ammonium chloride (70.921 mg, 1.338 mmol) were dissolved in ethanol (4 mL) and water (1 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (4 × 30 mL). The combined organic phase was washed with saturated saline solution (4 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 1-(4-(4-amino-2-methylphenoxy)piperidine-1-yl)ethane-1-one (66 mg was obtained, with a yield of 39.8%. LC-MS m / z: 249 [M+H] + ,

[0260] 3) Synthesis of (R,Z)-2-((4-((1-acetylpiperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] At room temperature, 1-(4-(4-amino-2-methylphenoxy)piperidine-1-yl)ethane-1-one (37.107 mg, 0.150 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (50 mg, 0.125 mmol) were dissolved in isopropanol (2 mL), to which N,N-diisopropylethylamine (48.254 mg, 0.374 mmol) was added. The resulting reaction mixture was heated to 90°C and stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (R,Z)-2-((4-((1-acetylpiperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (18 mg, yield 25.3%). LC-MS m / z: 570[M+H] + , 1H NMR (400 MHz, MeOD-d4): δ 8.80-8.77 (m, 1H), 7.78-7.93 (m, 1H), 7.82-7.79 (m, 1H), 7.61-7.55 (m, 2H), 7.38-7.33 (m, 1H), 6.94-6.89 (m, 1H), 5.52-5.40 (m, 2H), 4.59 (s, 3H), 3.79-3.72 (m, 2H), 3.63-3.57 (m, 1H), 3.54-3.48 (m, 1H), 2.24-2.22 (m, 4H), 2.13 (s, 4H), 2.04-1.89 (m, 4H), 1.86-1.74 (m, 2H), 1.68 (s, 3H).

[0261] Example 32, Synthesis of (R,Z)-2-((4-((1-(cyclopropanecarbonyl)piperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 190) 1) Synthesis of cyclopropyl(4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)methanone [ka] At room temperature, triethylamine (38.008 mg, 3.941 mmol) was added to a 3 mL solution of dichloromethane containing 4-(2-methyl-4-nitrophenoxy)piperidine (310 mg, 1.314 mmol) and cyclopropane carbonyl chloride (163.932 mg, 1.576 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain cyclopropyl (4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)methanone (154 mg, yield 38.6%). LC-MS m / z:305[M+H] + ,

[0262] 2) Synthesis of (4-(4-amino-2-methylphenoxy)piperidine-1-yl)(cyclopropyl)methanone [ka] Cyclopropyl (4-(2-methyl-4-nitrophenoxy)piperidine-1-yl)methanone (154 mg, 0.507 mmol), iron (141.842 mg, 2.533 mmol), and ammonium chloride (80.546 mg, 1.520 mmol) were dissolved in ethanol (4 mL) and water (1 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 80 mL). The combined organic phase was washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (4-(4-amino-2-methylphenoxy)piperidine-1-yl)(cyclopropyl)methanone (66 mg, yield 47.5%). LC-MS m / z:275[M+H] + ,

[0263] 3) Synthesis of (R,Z)-2-((4-((1-(cyclopropanecarbonyl)piperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] At room temperature, (4-(4-amino-2-methylphenoxy)piperidine-1-yl)(cyclopropyl)methanone (49.197 mg, 0.180 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (60 mg, 0.180 mmol) were dissolved in isopropanol (3 mL), to which N,N-diisopropylethylamine (24.2 mg, 0.1875 mmol) was added. The resulting reaction mixture was heated to 90°C and stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated saline solution (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (R,Z)-2-((4-((1-(cyclopropanecarbonyl)piperidine-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (23 mg, yield 25.8%). LC-MS m / z: 596[M+H] + , 1H NMR (400 MHz, MeOD-d4): δ 8.7 (s, 1H), 7.95 (t, J = 8 Hz, 1H), 7.81 (d, J= 8 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.37-7.34 (m, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.53-5.43 (m, 2H), 4.64-4.58 (m, 3H), 3.99 (s, 1H), 3.77 (s, 2H), 3.60 (s, 1H), 2.23 (s, 3H), 2.16 (s, 1H), 2.03-1.96 (m, 3H), 1.93-1.86 (m, 2H), 1.75 (s, 1H), 1.68 (s, 2H), 0.90-0.80 (m, 4H).

[0264] Example 33, Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-formate methyl ester or enantiomer (compound 191) 1) Synthesis of methyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate [ka] Under 0°C conditions, methyl chloroformate (96 mg, 1.02 mmol) was added to a 3 mL solution of dichloromethane containing 200 mg, 0.85 mmol of 4-(2-methyl-4-nitrophenoxy)piperidine and 260 mg, 2.55 mmol of triethylamine. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with methanol at room temperature. The resulting reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 295 [M+H] + ,

[0265] 2) Synthesis of methyl 4-(4-amino-2-methylphenoxy)piperidine-1-formate [ka] A methanol solution (3 mL) containing 200 mg, 0.68 mmol of 4-(2-methyl-4-nitrophenoxy)piperidine-1-formate methyl and 140 mg, 1.36 mmol of Pd / C was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 0-60% elution) to obtain 120 mg, 66.8% yield of 4-(4-amino-2-methylphenoxy)piperidine-1-formate methyl. LC-MS m / z: 265 [M+H] + ,

[0266] 3) Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-formate methyl ester or enantiomer [ka] (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (110 mg, 0.27 mmol) and 3-chloroperbenzoic acid (70 mg, 0.41 mmol) were dissolved in a 1 mL dichloromethane solution and stirred at 0°C for 1 hour. Then, a 1 mL solution of 4-(4-amino-2-methylphenoxy)piperidine-1-formate methyl (110 mg, 0.41 mmol) and acetic acid (97 mg, 1.62 mmol) was added dropwise to the above reaction mixture. The resulting reaction mixture was heated to 50°C and stirred for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by C18 reverse-phase column chromatography (MeCN:H2O=0-80% elution) to obtain (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-formate methyl ester or enantiomer (70 mg, yield 44.2%). LC-MS m / z: 586[M+H] + , 1H NMR (400 MHz, MeOD-d4):δ 8.77 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.53 - 5.40 (m, 2H), 4.57 (d, J = 7.2 Hz, 2H), 4.55 - 4.50 (m, 1H), 3.73 (d, J = 3.6 Hz, 1H), 3.70 (s, 3H), 3.69 - 3.66 (m, 1H), 3.48 - 3.40 (m, 2H), 2.20 (s, 3H), 2.16 (s, 2H), 2.02 - 1.86 (m, 4H), 1.73 (dd, J = 13.2, 4.0 Hz, 2H), 1.67 (s, 3H).

[0267] Example 34, Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomer (compound 192) 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxamide [ka] A reaction mixture of 4-(2-methyl-4-nitrophenoxy)piperidine (200 mg, 0.85 mmol) and urea (51 mg, 0.85 mol) was heated to 120°C under nitrogen gas protection and stirred for 16 hours. The resulting reaction mixture was purified by C18 reversed-phase column chromatography (MeCN:H2O=0%~60% elution) to obtain 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxamide (100 mg, yield 42.3%). LC-MS m / z:280[M+H] + ,

[0268] 2) Synthesis of 4-(4-amino-2-methylphenoxy)piperidine-1-carboxamide [ka] A methanol (3 mL) solution containing 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxamide (100 mg, 0.36 mmol) and Pd / C (77 mg, 0.72 mmol) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 250 [M+H] + ,

[0269] 3) Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomer [ka] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (100 mg, 0.27 mmol) and 3-chloroperbenzoic acid (70 mg, 0.41 mmol) in dichloromethane (1 mL) was stirred at 0°C for 1 hour. Then, a solution of 4-(4-amino-2-methylphenoxy)piperidine-1-carboxamide (100 mg, 0.41 mmol) and acetic acid (97 mg, 1.62 mmol) in 1,2-dichloroethane (1 mL) was added, and the resulting mixed reaction solution was heated to 50°C and stirred for 1 hour. The residue was purified by C18 column chromatography (MeCN:H2O=0~80%) to obtain (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomer (25 mg, yield 17.6%). LC-MS m / z: 571[M+H] + , 1 H NMR (400 MHz, MeOD-d4):δ 8.79 (s, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.54 - 5.40 (m, 2H), 4.57 (dd, J = 12.0, 5.0 Hz, 3H), 3.70 - 3.63 (m, 2H), 3.40 - 3.35 (m, 2H), 2.22 (s, 5H), 2.02 - 1.84 (m, 4H), 1.80 - 1.65 (m, 5H).

[0270] Example 35, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 193) 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrobenzyl)piperidine-1-formate [ka] A tetrahydrofuran (2 mL) solution containing bromo-2-methyl-4-nitrobenzene (200 mg, 0.93 mmol), 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-formate tert-butyl (604.5 mg, 1.86 mmol), potassium carbonate (385 mg, 2.79 mmol), silver oxide (539.4 mg, 2.325 mmol), and Pd(dppf)Cl2 (68.1 mg, 0.093 mmol) was prepared and heated under nitrogen gas protection for 80°C. o The mixture was heated to 14C and stirred overnight. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN: H2O (0.1% FA) = 5-95% elution) to obtain tert-butyl 4-(2-methyl-4-nitrobenzyl)piperidine-1-formate (120 mg, yield 38.6%). LC-MS m / z: 335 [M+H] + ,

[0271] 2) Synthesis of 4-(2-methyl-4-nitrobenzyl)piperidine [ka] Under room temperature conditions, 120 mg (0.36 mmol) of 4-(2-methyl-4-nitrobenzyl)piperidine-1-formate tert-butyl was dissolved in 0.9 ml of dichloromethane, to which 0.3 mL of 2,2,2-trifluoroacetic acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1% FA) = 5-95% elution) to obtain 4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, yield 71.4%). LC-MS m / z: 235 [M+H] + ,

[0272] 3) Synthesis of 1-methyl-4-(2-methyl-4-nitrobenzyl)piperidine [ka] A methanol (2 mL) solution containing 4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, 0.26 mmol), sodium borohydride (32.76 mg, 0.52 mmol), and paraformaldehyde (11.7 mg, 0.39 mmol) was stirred overnight at room temperature. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1% FA) = 5-95% elution) to obtain 1-methyl-4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, yield 94.4%). LC-MS m / z: 249 [M+H] + ,

[0273] 4) Synthesis of 3-methyl-4-((1-methylpiperidine-4-yl)methyl)aniline [ka] 1-methyl-4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, 0.24 mmol) and iron (67.74 mg, 1.21 mmol) were dissolved in ethanol (0.8 mL) and saturated ammonium chloride aqueous solution (0.2 mL). The mixture was heated to 70°C under nitrogen gas protection and stirred for 2 hours. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 15 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 219 [M+H] + ,

[0274] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol) and 3-methyl-4-((1-methylpiperidine-4-yl)methyl)aniline (81.75 mg, 0.375 mmol) were dissolved in dichloromethane (1.5 mL) and 1,2-dichloromethane (1.5 mL). The mixture was heated to 50°C and stirred overnight. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% FA) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (5 mg, yield 3.7%). LC-MS m / z: 540[M+H] + , 1 H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 5.56 - 5.39 (m, 2H), 4.61 (d, J = 6.7 Hz, 2H), 2.97 (d, J = 11.9 Hz, 2H), 2.56 (d, J = 7.1 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.15 (s, 4H), 2.00 (s, 1H), 1.93 (s, 1H), 1.73 (s, 1H), 1.69 (s, 1H), 1.68 (s, 3H), 1.57 (s, 1H), 1.38 (d, J = 12.4 Hz, 2H).

[0275] Example 36, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 194) 1) Synthesis of (2-methyl-4-nitrophenyl)(4-methylpiperazine-1-yl)methanone [ka] 1-methylpiperazine (1000 mg, 10 mmol), 2-methyl-4-nitrobenzeneformic acid (2715 mg, 15 mmol), 1-methyl-1H-imidazole (3280 mg, 40 mmol), and N,N,N',N'-tetramethylchlorideformamidine hexafluorophosphate (5620 mg, 20 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred overnight at room temperature. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1% FA) = 5-95% elution) to obtain (2-methyl-4-nitrophenyl)(4-methylpiperazine-1-yl)methanone (1100 mg, yield 41.8%). LC-MS m / z: 264 [M+H] + ,

[0276] 2) Synthesis of (4-amino-2-methylphenyl)(4-methylpiperazine-1-yl)methanone [ka] 2-methyl-4-nitrophenyl)(4-methylpiperazin-1-yl)methanone (500 mg, 1.9 mmol) and iron (532.3 mg, 9.5 mmol) were dissolved in ethanol (4 mL) and saturated ammonium chloride aqueous solution (1 mL). The mixture was heated to 70°C under nitrogen gas protection and stirred overnight for 2 hours. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 15 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 234 [M + H] + ,

[0277] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol) and (4-amino-2-methylphenyl)(4-methylpiperazin-1-yl)methanone (87.4 mg, 0.375 mmol) were dissolved in dichloromethane (1.5 mL) and 1,2-dichloroethane (1.5 mL). The mixture was heated to 50°C and stirred overnight. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% FA) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (0.9 mg, yield 0.65%). LC-MS m / z: 555[M+H] + , 1 H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.00 (s, 1H), 7.85 - 7.78 (m, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.51 - 5.40 (m, 2H), 4.63 (d, J = 6.6 Hz, 2H), 4.58 (s, 2H), 3.81 (s, 2H), 2.53 (s, 2H), 2.37 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.17 (s, 2H), 2.00 (s, 1H), 1.89 (s, 1H), 1.69 (s, 3H).

[0278] Example 37, Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 195) 1) Synthesis of (S)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone [ka] (S)-1,2-dimethylpiperazine (300 mg, 2.63 mmol), 2-methyl-4-nitrobenzeneformic acid (714.0 mg, 3.94 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.5 g, 3.95 mmol), and N,N-diisopropylethylamine (1.7 g, 13.18 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 8 hours. The mixed reaction solution was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH3.H2O) = 5-95% elution) to obtain (S)-(3,4-dimethylpiperazine-1-yl)(2-methyl-4-nitrophenyl)methanone (300 mg, yield 41.15%). LC-MS m / z:278[M+H] + ,

[0279] 2) Synthesis of (S)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazine-1-yl)methanone [ka] (S)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (300 mg, 1.08 mmol) and iron (303.24 mg, 5.41 mmol) were dissolved in a saturated ammonium chloride aqueous solution (1 mL) and ethanol (4 mL). The mixture was heated to 70°C and stirred for 8 hours. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 248 [M + H] + ,

[0280] 3) Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (300 mg, 0.75 mmol), (S)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazin-1-yl)methanone (277 mg, 1.12 mmol), and acetic acid (269 mg, 4.48 mmol) were dissolved in 1,2-dichloroethane (5 mL) and heated to 50°C and stirred for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to obtain (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (10 mg, yield 2.35%). LC-MS m / z: 569[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ 8.89 - 8.84 (m, 1H), 8.01 - 7.96 (m, 1H), 7.84 - 7.78 (m, 2H), 7.62 - 7.54 (m, 2H), 7.14 (d, J= 8.0 Hz, 1H), 5.51 - 5.38 (m, 2H), 4.67-4.60 (m, 2H), 4.49 - 4.42 (m, 1H), 3.48 - 3.36 (m, 1H), 3.28-3.13 (m, 1H), 3.05 - 2.81 (m, 2H), 2.41 - 2.16 (m, 10H), 2.02-1.86 (m, 2H), 1.68 (s, 3H), 1.22-0.98 (m, 3H).

[0281] Example 38: Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 196) 1) Synthesis of (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine [ka] A solution of 1-(bromomethyl)-2-methyl-4-nitrobenzene (300 mg, 1.3 mmol), (S)-1,2-dimethylpiperazine (148.7 mg, 1.3 mol), and potassium carbonate (540 mg, 3.91 mmol) in acetonitrile (3 mL) was stirred at room temperature for 8 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH3.H2O) = 5-95% elution) to obtain (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (200 mg, yield 58.3%). LC-MS m / z: 264 [M+H] + ,

[0282] 2) Synthesis of (S)-4-((3,4-dimethylpiperazine-1-yl)methyl)-3-methylaniline [ka] (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (200 mg, 0.76 mmol) and iron (212.0 mg, 3.78 mmol) were dissolved in an aqueous solution of ammonium chloride (1 mL) and ethanol (4 mL). The mixture was heated to 70°C and stirred for 2 hours. After cooling, the reaction mixture was filtered, and the filter cake was washed with methanol (3 × 50 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 234 [M + H] + ,

[0283] 3) Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol), (S)-4-((3,4-dimethylpiperazine-1-yl)methyl)-3-methylaniline (87.2 mg, 0.37 mmol), and acetic acid (89.7 mg, 1.50 mmol) were dissolved in a 1,2-dichloroethane (2 mL) solution and heated to 50°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (35 mg, yield 25.4%). LC-MS m / z: 555[M+H] + , 1H NMR (400 MHz, MeOD-d4):δ 8.81 (s, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.41-7.38 (m, 1H), 7.15 (d, J = 8.0Hz, 1H), 5.53 - 5.40 (m, 2H), 4.59 (d, J= 8.0 Hz, 2H), 3.49-3.42 (m, 2H), 2.87 (d, J= 12.0 Hz, 1H), 2.78 (t, J = 12.0 Hz, 2H), 2.47 - 2.20 (m, 11H), 2.03-1.95 (m, 2H), 1.94 - 1.88 (m, 1H), 1.68 (s, 3H), 1.09 (d, J = 8.0 Hz, 3H).

[0284] Example 39, Synthesis of (Z)-2-((4-(((R)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 197) 1) Synthesis of (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone [ka] A solution of 2-methyl-4-nitrobenzeneformic acid (400.0 mg, 2.21 mmol), (R)-1,2-dimethylpiperazine (378 mg, 3.31 mmol), N,N,N',N'-tetramethylchloridoformamidine hexafluorophosphate (1.2 g, 4.42 mmol), and 1-methyl-1H-imidazole (725 mg, 8.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at room temperature for 16 hours. The completion of the reaction was confirmed by LC-MS. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (610 mg, yield 99.6%). LC-MS m / z: 278[M+H] + ,

[0285] 2) Synthesis of (R)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazine-1-yl)methanone [ka] A saturated ammonium chloride solution (0.5 mL) containing (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (610 mg, 2.2 mmol) and iron (617 mg, 11 mmol), and a solution of ethanol (2 mL) were heated to 70°C and stirred for 2 hours. The completion of the reaction was confirmed by LC-MS. After cooling, the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 248 [M + H] + ,

[0286] 3) Synthesis of (Z)-2-((4-(((R)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (110 mg, 0.274 mmol) and (R)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazin-1-yl)methanone (169 mg, 0.686 mmol) in 1,4-dioxane (2 mL) was heated to 90°C and stirred for 16 hours. The completion of the reaction was confirmed by LC-MS. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (MeCN:H2O(0.1%NH3.H2O)=5-95% elution) to obtain (Z)-2-((4-(((R)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (10 mg, yield 6.4%). LC-MS m / z: 569[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.88 (s, 1H), 8.23 ​​(s, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.60 (dd, J = 16.0, 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 5.46 (dd, J = 12.0, 8.0 Hz, 2H), 4.87 (s, 1H), 4.83 (s, 1H), 4.64 (d, J = 8.0 Hz, 2H), 4.48 (s, 1H), 3.32 (s, 1H), 3.29 - 3.26 (m, 1H), 2.93 (s, 2H), 2.49 (d, J = 16.0 Hz, 4H), 2.28 (s, 3H), 2.17 (s, 1H), 1.99 (d, J = 8.0 Hz, 1H), 1.94 - 1.85 (m, 1H), 1.69 (s, 3H), 1.26 (s, 1H), 1.03 (s, 1H).

[0287] Example 40, Synthesis of (Z)-2-((4-((((R)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 198) 1) Synthesis of (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine [ka] A solution of 1-(bromomethyl)-2-methyl-4-nitrobenzene (300.0 mg, 1.304 mmol), (R)-1,2-dimethylpiperazine (149 mg, 1.3004 mmol), and potassium carbonate (540 mg, 3.913 mmol) in acetonitrile (2.0 mL) was stirred at room temperature for 16 hours. The reaction was confirmed by LC-MS. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O(0.1%NH3.H2O)=5-95% elution) to obtain (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (300 mg, yield 87.4%). LC-MS m / z: 264[M+H] + , 2) Synthesis of (R)-4-((3,4-dimethylpiperazine-1-yl)methyl)-3-methylaniline [ka] A saturated ammonium chloride solution (0.5 mL) containing (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (300 mg, 1.14 mmol) and iron (319 mg, 5.70 mmol), mixed with ethanol (2 mL), was heated to 70°C and stirred for 2 hours. The reaction was confirmed by LC-MS. After cooling, the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 234 [M + H] + ,

[0288] 3) Synthesis of (Z)-2-((4-((((R)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (40 mg, 0.108 mmol) and (R)-4-((3,4-dimethylpiperazine-1-yl)methyl)-3-methylaniline (30 mg, 0.128 mmol) in 1,4-dioxane (2 mL) was heated to 90°C and stirred for 16 hours. The completion of the reaction was confirmed by LC-MS. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CAN:H2O(0.1%NH3.H2O)=5-95% elution) to obtain (Z)-2-((4-((((R)-3,4-dimethylpiperazine-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (10 mg, yield 18.1%). LC-MS m / z: 555[M+H] + , 1 H NMR (400 MHz, MeOD-d4) δ 8.84 (s, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 5.55 - 5.37 (m, 2H), 4.87 (s, 1H), 4.83 - 4.80 (m, 1H), 4.61 (d, J = 6.9 Hz, 2H), 3.46 (s, 2H), 2.91 - 2.70 (m, 4H), 2.36 (s, 6H), 2.20 - 2.14 (m, 1H), 1.97 (d, J= 26.6 Hz, 4H), 1.69 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H).

[0289] Example 41, Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylbenzamide (compound 199) 1) Synthesis of 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazine-2-one [ka] At 0°C, sodium hydride (175 mg, 4.39 mmol, 60% content) was added in several portions to a tetrahydrofuran (10 mL) solution containing 4-methylpiperazine-2-one (300 mg, 2.63 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. At room temperature, 1-(bromomethyl)-2-methyl-4-nitrobenzene (500 mg, 2.18 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature overnight. At 0°C, water (20 mL) was added to the reaction mixture to quench it, and it was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to obtain 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazin-2-one (50 mg, yield 8.7%). LC-MS m / z: 264 [M+H] + ,

[0290] 2) Synthesis of 1-(4-amino-2-methylbenzyl)-4-methylpiperazine-2-one [ka] A solution of 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazine-2-one (50 mg, 0.19 mmol) and iron (53 mg, 0.95 mmol) dissolved in ammonium chloride (0.2 mL) and ethanol (0.8 mL) was heated to 70°C and stirred for 2 hours. After cooling, the reaction mixture was filtered. The filtered cake was washed with methanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 234 [M + H] + ,

[0291] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methyl-2-oxopiperazine-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (70 mg, 0.18 mmol), 1-(4-amino-2-methylbenzyl)-4-methylpiperazine-2-one (50 mg, 0.21 mmol), and acetic acid (64.8 mg, 1.08 mmol) were dissolved in a 1,2-dichloroethane (2 mL) solution and heated to 50°C and stirred for 1 hour. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methyl-2-oxopiperazine-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (30 mg, yield 31%). LC-MS m / z: 555[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ 8.84 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.47-7.42 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.53-5.40 (m, 2H), 4.64 (s, 2H), 4.62 (d, J = 6.4 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), 3.18 (s, 2H), 2.68 (t, J = 5.2 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 2.23-2.10 (m, 2H), 2.03-1.96 (m, 1H), 1.93-1.85 (m, 1H), 1.69(s, 3H).

[0292] Example 42, Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylbenzamide (compound 200) 1) Synthesis of N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzamide [ka] 2-Methyl-4-nitrobenzeneformic acid (100 mg, 0.55 mmol), N 1 , N 1 A solution of N,N-dimethylformamide (2 mL) containing dimethylethane-1,2-diamine (58.3 mg, 0.66 mmol), HATU (313.5 mg, 0.83 mmol), and DIEA (213 mg, 1.65 mmol) was stirred at room temperature for 2 hours. The reaction mixture was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH3.H2O) = 5-95% elution) to obtain N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzoyl (100 mg, yield 71.8%). LC-MS m / z: 252 [M+H] + ,

[0293] 2) Synthesis of 4-amino-N-(2-(dimethylamino)ethyl)-2-methylbenzamide [ka] A solution of N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzeneformamide (100 mg, 0.40 mmol) and Pd / C (50 mg, 10%) in 2,2,2-trifluoroethanol (2 mL) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with 2,2,2-trifluoroethanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 222 [M + H] + ,

[0294] 3) Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylbenzamide [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (80 mg, 0.21 mmol), 4-amino-N-(2-(dimethylamino)ethyl)-2-methylbenzamide (55.7 mg, 0.25 mmol), and acetic acid (90 mg, 1.5 mmol) were dissolved in a 1,2-dichloroethane (2 mL) solution and heated to 50°C and stirred for 1 hour. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to obtain (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-2-yl)amino)-2-methylbenzamide (6.5 mg, yield 5.8%). LC-MS m / z: 543[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ 8.90-8.85 (m, 1H), 8.00 (t, J = 8.4 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.53-5.40 (m, 2H),4.63 (d, J= 6.0 Hz, 2H), 3.50 (t, J = 6.8 Hz, 2H), 2.65-2.56 (m, 2H), 2.41 (s, 3H), 2.34 (s, 6H), 2.29-2.20 (m, 1H), 2.19-2.10 (m, 1H), 2.05-1.96 (m, 1H), 1.94-1.83 (m, 1H), 1.69 (s, 3H).

[0295] Example 43, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5,5]undecane-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 201) 1) Synthesis of 3-methyl-9-(2-methyl-4-nitrobenzyl)-3,9-diazaspiro[5.5]undecane [ka] A methanol (2 mL) solution containing 3-methyl-3,9-diazaspiro[5.5]undecane (0.2 g, 1.19 mmol), 2-methyl-4-nitrobenzenecarbaldehyde (0.20 g, 1.19 mmol), and sodium borohydride (0.075 g, 1.19 mol) was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1 elution) to obtain 3-methyl-9-(2-methyl-4-nitrobenzyl)-3,9-diazaspiro[5.5]undecane (0.2 g, yield 53.01%). LCMS m / z: 318 [M+H] + .

[0296] 2) Synthesis of 3-methyl-4-((9-methyl-3,9-diazaspiro[5,5]undecane-3-yl)methylaniline [ka] 3-methyl-9-(2-methyl-4-nitrobenzyl)-3,9-diazaspiro[5.5]undecane (0.05 g, 0.16 mmol) and Pd / C (0.017 g) were dissolved in ethyl acetate (0.5 mL) and stirred at room temperature for 1 hour under hydrogen protection. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (0.5 mL x 3). The filtrate was collected and concentrated under reduced pressure to obtain the crude product (0.03 g). This was used directly in the next step. LC-MS m / z: 288 [M+H]+ ,

[0297] 3) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5,5]undecane-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] A solution of (12R,Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (0.1 g, 0.26 mmol), 3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)methyl)aniline (0.090 g, 0.31 mmol), and acetic acid (18.6 mg, 0.31 mmol) in 1,2-dichloroethane (1 mL) was heated to 50°C and stirred for 2 hours. The mixed reaction was concentrated under reduced pressure and purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5,5]undecane-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (0.02 g, yield 12.66%). LCMS m / z: 609[M+H] + , 1H NMR (400 MHz, MeOH-d4): δ 8.86 (s, 1H), 8.52 (s, 1H), 7.98 (t, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.49 - 5.40 (m, 2H), 4.62 (s, 2H), 3.84 (s, 2H), 3.09 (s, 4H), 2.82 (s, 4H), 2.76 (s, 3H), 2.40 (s, 3H), 2.17 (s, 2H), 2.01 (s, 1H), 1.90 (s, 1H), 1.76 (s, 4H), 1.69 (s, 7H).

[0298] Example 44, Synthesis of (Z)-2-((4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 202) 1) Synthesis of (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-tert-butyl formate [ka] Under conditions of 0°C, sodium hydride (125 mg, 3.13 mmol) was added in several portions to a solution of (2S)-3-hydroxy-2-methylazetidine-1-formate tert-butyl (482 mg, 2.57 mmol) in N,N-dimethylformamide (5 mL). The resulting reaction mixture was stirred at room temperature for 0.5 hours. After that, 0 oUnder conditions C, 1-fluoro-2-methyl-4-nitrobenzene (400 mg, 2.57 mmol) was added to the above reaction mixture. The resulting reaction mixture was stirred at 0°C for 3 hours. At 0°C, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-30% elution) to obtain (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-tert-butyl formate (450 mg, yield 54%). LC-MS m / z: 323 [M + H] + ,

[0299] 2) Synthesis of (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine [ka] (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-formate tert-butyl (467 mg, 1.45 mmol) was dissolved in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) solution, which was stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (300 mg, yield 93%). LC-MS m / z: 223 [M+H] + ,

[0300] 3) Synthesis of (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine [ka] (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (322 mg, 1.45 mmol), NaBH3CN (182 mg, 2.9 mmol), and paraformaldehyde (43 mg, 1.45 mmol) were dissolved in acetic acid (0.3 mL) and dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to obtain (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine (282 mg, yield 82%). LC-MS m / z: 237 [M+H] + ,

[0301] 4) Synthesis of 4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylaniline [ka] (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine (272 mg, 1.15 mmol) and Pd / C (140 mg) were dissolved in methanol (3 mL) and stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol (3 × 20 mL). The resulting filtrate was concentrated under reduced pressure to obtain 4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylaniline (222 mg, yield 93.4%). LC-MS m / z: 207[M+H] + ,

[0302] 5) Synthesis of (Z)-2-((4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (100 mg, 0.25 mmol), 4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylaniline (77 mg, 0.38 mmol), and acetic acid (90 mg, 1.5 mmol) were dissolved in a 1,2-dichloroethane (2 ml) solution, which was heated to 50°C and stirred for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O (0.1% FA) = 30-70% elution) to obtain (Z)-2-((4-(((2S)-1,2-dimethylazetidine-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (35 mg, yield 26.6%). LC-MS m / z: 528[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.79 (s, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.42 - 7.35 (m, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.53 - 5.38 (m, 2H), 5.10 (td, J = 5.9, 2.9 Hz, 1H), 4.71 (dd, J = 13.3, 6.6 Hz, 1H), 4.58 (d, J = 7.0 Hz, 2H), 4.30 (dd, J = 11.4, 5.8 Hz, 1H), 4.10 (dd, J = 11.4, 2.7 Hz, 1H), 2.90 (s, 3H), 2.29 (s, 3H), 2.25 - 2.10 (m, 2H), 1.99 (dd, J = 16.8, 8.6 Hz, 1H), 1.90 (d, J = 8.6 Hz, 1H), 1.68 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H).

[0303] Example 45, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one and (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compounds 203A and B) 1) Synthesis of 4-((2-methyl-4-nitrobenzene)amino)piperidine-1-formate tert-butyl [ka] At room temperature, potassium carbonate (2070 mg, 15.00 mmol) was added to a solution of 10 mL of dimethyl sulfoxide of 4-aminopiperidine-1-formate tert-butyl (1000 mg, 5.00 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (930 mg, 6.00 mmol). The resulting reaction mixture was heated to 120°C and stirred for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 4-((2-methyl-4-nitrobenzene)amino)piperidine-1-formate tert-butyl (900 mg, yield 53.6%). LC-MS m / z:336[M+H] + ,

[0304] 2) Synthesis of N-(2-methyl-4-nitrophenyl)piperidine-4-amine [ka] 900 mg, 2.69 mmol of 4-((2-methyl-4-nitrobenzene)amino)piperidine-1-formate tert-butyl was dissolved in dichloromethane (8 mL) and 2,2,2-trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated saline solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain N-(2-methyl-4-nitrophenyl)piperidine-4-amine (562 mg, yield 88.9%). LC-MS m / z: 236 [M+H] + ,

[0305] 3) Synthesis of 1-methyl-N-(2-methyl-4-nitrophenyl)piperidine-4-amine [ka] Under 0°C conditions, paraformaldehyde (231 mg, 7.69 mmol) was added in several batches to a methanol (8 mL) solution containing N-(2-methyl-4-nitrophenyl)piperidine-4-amine (800 mg, 3.285 mmol) and acetic acid (462 mg, 7.69 mmol), and the mixture was stirred at room temperature for 1 hour. Then, sodium borohydride (485 mg, 7.69 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for another 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated saline solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 1-methyl-N-(2-methyl-4-nitrophenyl)piperidine-4-amine (700 mg, yield 82.6%). LC-MS m / z: 250 [M+H] + ,

[0306] 4) 2-methyl-N 1 Synthesis of (1-methylpiperidine-4-yl)benzene-1,4-diamine [ka] A solution of methyl-N-(2-methyl-4-nitrophenyl)piperidine-4-amine (700 mg, 2.81 mmol) and palladium hydroxide (787 mg, 5.62 mmol) in 2,2,2-trifluoroacetic acid (7 mL) was stirred at room temperature for 2 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure, and 2-methyl-N 1 -(1-methylpiperidine-4-yl)benzene-1,4-diamine (600 mg, 97.4% yield) was obtained. LC-MS m / z: 220 [M+H] + ,

[0307] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] Under room temperature conditions, 2-methyl-N 1 N,N-diisopropylethylamine (177 mg, 1.37 mmol) was added to a solution of (1-methylpiperidine-4-yl)benzene-1,4-diamine (100 mg, 0.46 mmol) and (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (275 mg, 0.68 mmol) in isopropanol (2 mL). The resulting mixed reaction was heated to 90°C and stirred for 2 hours. After cooling, the mixed reaction was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated saline (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (60 mg, yield 24.3%). LC-MS m / z: 541[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.75 (s, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.25 (dd, J = 8.6, 2.5 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 5.56 - 5.40 (m, 2H), 4.56 (d, J = 6.9 Hz, 2H), 3.37 (d, J = 10.0 Hz, 1H), 2.92 (d, J = 11.6 Hz, 2H), 2.35 (s, 3H), 2.32 - 2.13 (m, 7H), 2.07 (d, J = 11.8 Hz, 2H), 2.01 - 1.94 (m, 1H), 1.93 - 1.86 (m, 1H), 1.67 (s, 3H), 1.56 (dd, J = 21.4, 10.1Hz, 2H),

[0308] 6) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer or (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (118 mg, 0.22 mmol) was subjected to preparative chiral high-performance liquid chromatography (system: SHIMADZU LC-20AP, Column name: DAISELCHIRALPAK(registered trademark)IG, 250×25 mm 10 μm, mobile phase A:n-Hexane, mobile phase B: EtOH (+0.1% 7.0 mol / L Ammonia in MeOH), A:B=50:50, detection wavelength: 254 The compounds were separated and purified using a method (nm, flow rate 60, column temperature RT, column pressure 100 bar) to obtain two isomers, compound 203A and compound 203B.

[0309] Compound 203A showed peak 1 (peak appearance time 18.865 min), (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (20 mg, yield 17%), LC-MS m / z: 541[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.74 (s, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.24 (dd, J = 8.6, 2.4 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 5.54 - 5.41 (m, 2H), 4.55 (d, J = 6.8 Hz, 2H), 3.42 - 3.33 (m, 1H), 2.94 (d, J = 11.7 Hz, 2H), 2.36 (s, 3H), 2.31 (t, J = 11.8 Hz, 2H), 2.22 - 2.16 (m, 1H), 2.15 - 2.04 (m, 6H), 2.02 - 1.94 (m, 1H), 1.93 - 1.85 (m, 1H), 1.67 (s, 3H), 1.56 (dd, J = 21.6, 10.1 Hz, 2H).

[0310] Compound 203B showed peak 2 (peak appearance time 26.148 min), (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidine-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (20 mg, yield 17%), LC-MS m / z: 541[M+H]. + , 1H NMR (400 MHz, MeOD-d4) δ 8.74 (s, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.24 (dd, J = 8.6, 2.4 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 5.55 - 5.40 (m, 2H), 4.55 (d, J = 6.8 Hz, 2H), 3.42 - 3.36 (m, 1H), 2.93 (d, J = 11.7 Hz, 2H), 2.35 (s, 3H), 2.29 (t, J = 11.1 Hz, 2H), 2.19 (dd, J = 9.6, 5.3 Hz, 1H), 2.16 - 2.03 (m, 6H), 2.02 - 1.85 (m, 2H), 1.67 (s, 3H), 1.62 - 1.50 (m, 2H).

[0311] Example 46, (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer 1) Synthesis of 3-(2-methyl-4-nitrophenoxy)azetidine-1-formate tert-butyl (compound 204) [ka] Under conditions of 0°C, sodium hydride (1110 mg, 46.24 mmol) was added in several portions to a tetrahydrofuran (40 mL) solution containing 3-hydroxyazetidine 1-formate tert-butyl (4000 mg, 23.14 mmol), and the resulting reaction mixture was stirred at room temperature for 50 minutes. Then, a tetrahydrofuran (10 mL) solution containing 1-fluoro-2-methyl-4-nitrobenzene (5376 mg, 34.68 mmol) was added dropwise to the reaction mixture. The resulting reaction mixture was heated to 90°C and stirred for 8 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain tert-butyl 3-(2-methyl-4-nitrophenoxy)azetidine-1-formate (3800 g, yield 53%). LC-MS m / z: 309 [M+H] + ,

[0312] 2) Synthesis of 3-(2-methyl-4-nitrophenoxy)azetidine [ka] 3-(2-methyl-4-nitrophenoxy)azetidine-1-formate tert-butyl (3800 mg, 12.34 mmol) was dissolved in dichloromethane (32 mL) and 2,2,2-trifluoroacetic acid (8 mL) solution, which were stirred at room temperature for 8 hours. The mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated saline solution (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 3-(2-methyl-4-nitrophenoxy)azetidine (2300 mg, yield 89.5%). LC-MS m / z: 209 [M+H] + ,

[0313] 3) Synthesis of 1-methyl-3-(2-methyl-4-nitrophenoxy)azetidine [ka] Under 0°C conditions, 3-(2-methyl-4-nitrophenoxy)azetidine (3400 mg, 16.35 mmol) and acetic acid (1471 mg, 24.52 mmol) were dissolved in methanol (30 mL), to which paraformaldehyde (981 mg, 32.69 mmol) was added in several portions. The resulting reaction mixture was stirred at room temperature for 1 hour. Then, sodium borohydride cyanohydride (3089 mg, 49.04 mmol) was added in several portions. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain 1-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (3200 mg, yield 88%). LC-MS m / z: 223 [M+H] + ,

[0314] 4) Synthesis of 3-methyl-4-((1-methylazetidine-3-yl)oxy)aniline [ka] A solution of 1-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (3200 mg, 14.41 mmol) and palladium hydroxide (4036 mg, 28.83 mmol) in 2,2,2-trifluoroethanol (30 mL) was stirred at room temperature for 8 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain 3-methyl-4-((1-methylazetidine-3-yl)oxy)aniline (2596 mg, yield 93.75%). LC-MS m / z: 193 [M+H] + ,

[0315] 5) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] A 1,4-dioxane (2 mL) solution containing 3-methyl-4-((1-methylazetidine-3-yl)oxy)aniline (100 mg, 0.52 mmol) and (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (251 mg, 0.63 mmol) was heated to 90°C and stirred for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (ACN (0.1% FA): water (0.1% FA) = 25%~65% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidine-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (60 mg, yield 22.5%). LC-MS m / z: 514[M+H] + , 1H NMR (400 MHz, MeOD-d4) δ 8.77 (s, 1H), 7.94 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.35 (d, J= 7.7 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 5.54 - 5.37 (m, 2H), 5.04 - 4.94 (m, 1H), 4.57 (d, J = 6.9 Hz, 2H), 4.44 - 4.34 (m, 2H), 3.98 - 3.88 (m, 2H), 2.84 (s, 3H), 2.24 (s, 3H), 2.18 (d, J = 18.5 Hz, 2H), 2.02-1.93 (m, 1H), 1.91 (d, J = 11.6 Hz, 1H), 1.68 (s, 3H).

[0316] Example 47, Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (compound 205) 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)-1-(oxetan-3-yl)piperidine [ka] At room temperature, 200 mg, 0.85 mmol of 4-(2-methyl-4-nitrophenoxy)piperidine and 92 mg, 1.27 mmol of oxetan-3-one were dissolved in 4 mL of dichloromethane, to which sodium borohydride (214 mg, 3.39 mmol) was added. The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40-70% elution) to obtain 4-(2-methyl-4-nitrophenoxy)-1-(oxetan-3-yl)piperidine (130 mg, yield 52.5%). LC-MS m / z: 293 [M+H] + ,

[0317] 2) Synthesis of 3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxyaniline [ka] A methanol (2 mL) solution containing 4-(2-methyl-4-nitrophenoxy)-1-(oxetan-3-yl)piperidine (120 mg, 0.41 mmol) and Pd / C (65 mg, 0.62 mmol) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain 3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxy)aniline (90 mg, yield 83.6%). LC-MS m / z: 263 [M+H] + ,

[0318] 3) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer [ka] A solution of 3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxy)aniline (80 mg, 0.31 mmol), (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (147 mg, 0.37 mmol), and N,N-isopropylethylamine (118 mg, 0.92 mmol) in isopropanol (1.5 mL) was heated to 90°C and stirred for 6 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated saline solution (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (MeCN:H2O (0.1% FA) = 30-60% elution) to obtain (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one or enantiomer (40 mg, yield 22.5%). LC-MS m / z: 584[M+H] + , 1H NMR (400 MHz, MeOD-d4): 8.80 (s, 1H), 7.96 (t, J = 4.0 Hz, 1H), 7.81(d, J = 8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.42-7.39 (m, 1H), 6.93 (d, J = 8 Hz,1H),5.52-5.42 (m, 2H),4.92-4.88 (m, 6H), 4.83-4.79 (m, 3H),4.60 (d, J = 8 Hz, 2H),4.49 (s, 1H), 3.32(s, 1H), 3.24(s, 1H),2.25 (s, 3H),2.17-1.9 (m, 6H), 1.68 (s, 3H).

[0319] Example 48, Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 206) 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)-1-(2,2,2-trifluoroethyl)piperidine [ka] A solution of 4-(2-methyl-4-nitrophenoxy)piperidine (500 mg, 2.12 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (738 mg, 3.18 mmol), and N,N-diisopropylethylamine (822 mg, 6.36 mmol) in tetrahydrofuran (10 mL) was heated to 80°C and stirred overnight. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (CH3CN:H2O (0.1%NH3.H2O) = 5-95% elution) to obtain 4-(2-methyl-4-nitrophenoxy)-1-(2,2,2-trifluoroethyl)piperidine (400 mg, yield 59.0%). LC-MS m / z: 319 [M+H]+ LC-MS m / z:319[M+H] + ,

[0320] 2) Synthesis of 3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxyaniline [ka] A solution of 4-(2-methyl-4-nitrophenoxy)-1-(2,2,2-trifluoroethyl)piperidine (200 mg, 0.63 mmol) and Pd / C (100 mg) in 2,2,2-trifluoroethanol (2.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed with 2,2,2-trifluoroethanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m / z: 289 [M + H] + ,

[0321] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one [ka] (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (80 mg, 0.21 mmol), 3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxy)aniline (72 mg, 0.25 mmol), and acetic acid (90 mg, 1.5 mmol) were dissolved in a 1,2-dichloroethane (2 mL) solution and heated to 50°C and stirred for 1 hour. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse-phase column chromatography (CH3CN:H2O(0.1%NH3.H2O) = 5-95% elution) to obtain (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidine-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimide[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (40 mg, yield 31.6%). LC-MS m / z: 610[M+H] + , 1 H NMR (400 MHz, MeOD-d4): δ 8.78 (s, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H),7.33 (dd, J= 8.8, 2.4Hz, 1H),6.86 (d, J = 8.8 Hz, 1H), 5.53-5.41 (m, 2H), 4.57 (d, J= 6.8 Hz, 2H), 4.43-4.35 (m, 1H), 3.22-3.11 (m, 2H), 3.02-2.92 (m, 2H),2.74-2.64 (m, 2H), 2.21 (s, 3H), 2.15-1.79 (m, 8H), 1.68 (s, 3H).

[0322] Example 49, Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidine-4-yl)oxy)pyridine-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azeno)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecine-5-one (compound 207) 1) Synthesis of 4-methyl-5-((1-methylpiperidine-4-yl)oxy)-2-nitropyridine [ka] A solution of 5-bromo-4-methyl-2-nitropyridine (500.0 mg, 2.30 mmol), 1-methylpiperidine-4-ol (265.0 mg, 2.3 mmol), and potassium carbonate (954.0 mg, 6.91 mmol) in acetonitrile (5 mL) was heated to 90°C and s...

Claims

1. A compound represented by formula (I) or its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, and crystalline polymorphs thereof, 【Chemical 235】 Eventually, X d1 , d3 , 2 , 2 , d1 , d3 , d3 , d2 , 2 , d3 , d3 , d3 , d2 , d3 and X 1 and X 2 is each independently selected from -C(R x )- or -N-, and L 3 , L 4 , L 5 , L 6 and L 7 are the same or different and are, independently of one another, absent, a single bond, a double bond, an acetylene bond, -C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O)N(R d3 )-, -N(R d3 )C(=O)-, -N(R d3 )-, -C(=NR d3 )-, -S(=O) 2 N(R d3 )-, -N(R[[ID=5i]] d3 )S(=O) 2 -, -C(R d1 )(R d2 )N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -N-, -CH-, -S(=O)- or -S(=O) 2 - and are selected from L does not exist or is O, S, CH 2 , C(O), S(O), S(O) 2 Selected from NH, C(O), NH, NHC(O), Ring C is either unsubstituted or R 0 Selected from heterocyclyl groups substituted with, R 0 The group is independently selected from H, deuterium, halogen, alkyl group, haloalkyl group, deuterated alkyl group, cycloalkyl group, heterocyclyl group, alkoxyalkyl group, alkynyl group, acetyl group, methylsulfonyl group, and phosphono group, and further, R 0 The hydrogen atoms above can be optionally H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, or OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, Each R 2 or R 5 These can be homologous or different, and are independent of each other: hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 or R 5 R forms a 3- to 8-membered monocyclic or polycyclic structure with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 or R 5 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 substituted with one or more substituents selected from carboxyl groups, OH, and CN, or any two R groups 2 , R 5 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 (Alkyl group) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R 1 、R d1 、R d2 、R x are independently hydrogen, deuterium, halogen, cyano group, oxo (=O), amino group, hydroxy group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-10 alkylamino group, aryl group, heteroaryl group, N,N - di(C 1-10 alkyl)amino group, C 1-10 alkyloxy group, C 1-10 alkylacyl group, C 1-10 alkyloxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamine group, C 3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group, C 3-10 cycloalkylacyl group, C 3-10 cycloalkoxyacetyl group, C<000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Substituted with one or more groups selected from cycloalkyl groups, or R d1 and R d2 , R d1 and R 5 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, R d3 This is, arbitrarily and independently, hydrogen and NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, among which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can be further optionally hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially substituted groups, such as saturated cycloalkyl groups or heterocyclyl groups. The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. Compounds or their pharmaceutically acceptable salts, solvates, enantiomers and isotopic substitutions, and crystalline polymorphs thereof.

2. X 0 , X 1 and X 2 Each of these independently applies -C(R x ) - or -N- selected, R x H, C 1-6 Selected from alkyl groups (e.g., methyl group), Preferably, X 0 is -CH-, Preferably, X 1 is N, Preferably, X 2 It is characterized by being N, The compound described in claim 1, or its pharmaceutically acceptable salts, solvates, enantiomers, and isotope-substituted derivatives, and its crystalline polymorphs.

3. L is selected from O, S, or NH. Preferably, L 3 , L 4 , L 5 , L 6 and L 7 R are homologous or different, and are independently non-existent, single-bonded, unsubstituted, or optionally one, two, or more R elements. d1 C replaced by 1-6 Alkylene group, C 2-6 Selected from alkenine groups, Preferably, L 3 , L 4 , L 5 , L 6 and L 7 R are homologous or different, and are independently non-existent, single-bonded, unsubstituted, or optionally one, two, or more R elements. d1 CH replaced by 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH=CH, CH = CH CH 2 Selected from, Preferably, L 3 -C(R d1 ) (R d1 ) - selected from, preferably -C (CH 3 ) (OH)-, Preferably, L 6 The vinylidene group is selected from vinylidene groups, and the vinylidene group is preferably in cis form. Preferably, L 4 , L 5 and L 7 CH are homologous or different, and are independent of each other. 2 Selected from, Preferably, each R d1 H, OH, and C are homologous or different, and are independent of each other. 1-6 Characterized by being selected from alkyl groups (e.g., methyl groups), The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof, and crystalline polymorph thereof.

4. Ring C is either unsubstituted or R 0 Selected from heterocyclyl groups substituted with, the heterocyclyl group is a piperidinyl group (for example, 【Chemistry 236】 ), piperazinyl group (for example, 【Chemistry 237】 ), morpholinyl group (for example, 【Chemical 238】 ), azetidinyl group (for example, 【Chemistry 239】 ), tetrahydropyrrolidinyl group (for example, 【Chemistry 240】 You can be chosen from among them. Preferably, 【Chemistry 241】 Selected from, Preferably, 【Chemistry 242】 Characterized by being selected from, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof, and a crystalline polymorph thereof.

5. R 0 H, C 1-10 Alkyl alkyl group, C 1-10 Alkoxy group, deuterated C 1-10 Alkyl, halo C 1-10 Alkyl alkyl groups, HC(O)-, NH 2 C(O)-, C 1-10 Alkyl-C(O)-, C 1-10 Alkoxy-C(O)-, C 3-8 Selected from cycloalkyl-C(O)- and 3- to 8-membered heterocyclyl groups, Preferably, R 0 H, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, deuterated C 1-6 Alkyl, halo C 1-6 Alkyl alkyl groups, HC(O)-, NH 2 C(O)-, C 1-6 Alkyl-C(O)-, C 1-6 Alkoxy-C(O)-, C 3-6 Selected from cycloalkyl-C(O)- and 3- to 6-membered heterocyclyl groups, Preferably, R 0 H, methyl group, ethoxy group, trihydromethyl group, CF 3 CH 2 -, HC(O)-, CH 3 C(O)-, 【Chemistry 243】 Selected from, Preferably, each R 1 They are homologous or different, and independently of each other are H, deuterium, oxo (=O), and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C(O)-, Halo-C 1-6 Alkyl, halo C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups Preferably, each R 1 They are homologous or different, and independently of each other are H, deuterium, oxo (=O), and C. 1-6 Alkyl alkyl group, C 1-6 Selected from alkoxy-C(O)-, Preferably, each R 1 They are homologous or different, and independently of each other are H, methyl group, deuterium, oxo (=O), 【Chemistry 244】 Selected from, Preferably, each R 2 They are homologous or different, and independently of each other are H, deuterium, oxo (=O), and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C(O)-, Halo-C 1-6 Alkyl, halo C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group, Preferably, each R 2 They are homologous or different, and H or C independently of each other. 1-6 Selected from alkyl groups (e.g., methyl group), Preferably, each R 5 They are homologous or different, and independently of each other are H, deuterium, oxo (=O), and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy-C(O)-, Halo-C 1-6 Alkyl, halo C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group, Preferably, each R 5 They are homologous or different, and H or C independently of each other. 1-6 Characterized by being selected from alkyl groups (e.g., methyl groups), A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof, and a crystalline polymorph thereof.

6. Having the structure of formula (II), 【Chemistry 245】 Eventually, L, L 3 , L 4 , L 5 , L 6 , L 7 , X 0 , X 1 , X 2 , R 0 , R 1 , R 2 , R 5 m, n, and q each have independently defined terms as described in any one of claims 1 to 5. Preferably, X 0 , X 1 and X 2 Each of these independently applies -C(R x ) - or -N- selected, L 3 , L 4 , L 5 , L 6 and L 7 These are independently absent, single bond, double bond, acetylene bond, -C(R) d1 ) (R d2 )-, -C(R d1 ) (R d2 )C(R d1 ) (R d2 )-,-OC(R d1 ) (R d2 )-, -C(R d1 ) (R d2 )O-, -C(=O)N(R d3 )-, -N(R d3 )C(=O)-, -N(R d3 )-, -C(=NR d3 )-, -S (=O) 2 N(R) d3 )-, -N(R d3 )S (=O) 2 -, -C (R d1 ) (R d2 )N(R d3 )-, -N(R d3 )C(R d1 ) (R d2 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -N-, -CH-, -S(=O)- or -S(=O) 2 - Selected from, L is arbitrarily and independently selected from O, S, or NH. R 0 The group is independently selected from H, deuterium, halogen, alkyl group, haloalkyl group, deuterated alkyl group, cycloalkyl group, heterocyclyl group, alkoxyalkyl group, alkynyl group, acetyl group, methylsulfonyl group, and phosphono group, and further, R 0 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, Each R 2 or R 5 These can be homologous or different, and are independent of each other: hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 or R 5 R forms a 3- to 8-membered monocyclic or polycyclic structure with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 or R 5 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 substituted with one or more substituents selected from carboxyl groups, OH, and CN, or any two R groups 2 , R 5 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 (Alkyl group) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R 1 , R d1 , R d2 , R x These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C) 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, and heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or R d1 and R d2 or R d1 and R 5 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, R d3 This is, arbitrarily and independently, hydrogen and NH 2 , C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 Selected from heterocyclyl groups, among which the above C 1-10 Alkyl alkyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 1-10 Alkylacyl group, C 1-10 Alkyl sulfonyl group, C 2-10 Heteroalkyl groups, C 3-10 Cycloalkyl groups, C 3-10 Heterocycloalkyl groups, C 3-10 C substituted with cyclic hydrocarbon groups 1-10 Alkyl alkyl group or C 3-10 Cycloalkyl groups, C 3-10 C substituted with heterocycloalkyl groups 3-10 The heterocyclyl group can be further optionally hydrogen, deuterium, halogen, oxo, CN, OH, and C. 3-10 Substituted with one or more substituents selected from saturated or partially substituted groups, such as saturated cycloalkyl groups or heterocyclyl groups. The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. Preferably, it has the structure of formula (IA), 【Chemistry 246】 Among them, L, X 2 , R 0 , R 1 , R 2 , R 5 , R d1 m, n, and q are independent of each other and have the definitions described in any one of claims 1 to 5, and p is an integer arbitrarily selected from 0, 1, 2, 3, and 4. Preferably, X 2 Independently, -C(R x ) - or -N- selected, L is arbitrarily and independently selected from O, S, or NH. R 0 The group is independently selected from H, deuterium, halogen, alkyl group, haloalkyl group, deuterated alkyl group, cycloalkyl group, heterocyclyl group, alkoxyalkyl group, alkynyl group, acetyl group, methylsulfonyl group, and phosphono group, and further, R 0 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, Each R 2 or R 5 These can be homologous or different, and are independent of each other: hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 or R 5 R forms a 3- to 8-membered monocyclic or polycyclic structure with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 or R 5 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 substituted with one or more substituents selected from carboxyl groups, OH, and CN, or any two R groups 2 , R 5 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 (Alkyl group) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R 1 , R d1 and R x These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C) 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, and heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1 and R 5 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. p is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. Preferably, it has the structure of formula (IB), 【Chemistry 247】 Eventually, R 0 , R 1 , R 2 , R 5 , R d1 m, n, and q each have independently defined terms as described in any one of claims 1 to 5. Preferably, R 0 The group is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups, and further, R 0 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, Each R 2 or R 5 These can be homologous or different, and are independent of each other: hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 or R 5 R forms a 3- to 8-membered monocyclic or polycyclic structure with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 or R 5 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 substituted with one or more substituents selected from carboxyl groups, OH, and CN, or any two R groups 2 , R 5 Together with the carbon attached thereto, it forms a 5-6 membered heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, and the hydrogen on the aryl group, saturated or partially saturated cycloalkyl group, or heterocycloalkyl group can optionally be hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 (Alkyl group) 2 , =O, and saturated or partially saturated C 3-6 Substituted with a cycloalkyl group selected from C 1-6 Alkyl and C 1-6 The alkoxy group can optionally consist of hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 , saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, R 1 and R d1 These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C) 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, and heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1 and R 5 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, 4, and 5. q is an integer arbitrarily chosen from 0, 1, 2, and 3. p is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. Preferably, it has the structure of formula (IC), 【Chemistry 248】 Eventually, R 0 , R 1 , R 2 m and n have the definitions described in any one of claims 1 to 5, independently of each other. Preferably, R 0 The group is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups, and further, R 0 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, Each R 2 These can be homologous or different, and are independent of each other: hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 R forms a 3- to 8-membered monocyclic or polycyclic structure with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, R 1 These are independently hydrogen, deuterium, halogen, cyano group, amino group, hydroxyl group, and C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 1-10 Alkylamino group, aryl group, heteroaryl group, N,N-di(C) 1-10 alkyl)amino group, C 1-10 Alkyloxy group, C 1-10 Alkylacyl group, C 1-10 Alkyloxy group, C 1-10 Alkyl sulfonyl group, C 1-10 Alkyl sulfinyl group, C 3-10 Cycloalkylamine group, C 3-10 Heterocycloalkylamino group, C 3-10 Cycloalkoxy group, C 3-10 Cycloalkylacyl group, C 3-10 Cycloalkoxyacetyl group, C 3-10 Cycloalkylsulfonyl group and C 3-10 Selected from cycloalkylsulfinyl groups, and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, and heterocycloalkyl groups may optionally contain hydrogen, deuterium, halogen, -CN, -OH, or CF. 3 , C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, -NH 2 , -NHC 1-6 Alkyl alkyl, -N(C) 1-6 Alkyl) 2 , oxy group, and saturated or partially saturated C 3-6 Substituted with one or more cycloalkyl groups, and C 1-6 Alkyl and C 1-6 The alkoxy group can optionally be further modified with hydrogen, deuterium, halogen, oxo, CN, or CF. 3 , OH, OCH 3 OCH 2 CH 3 and saturated or partially saturated C 3-6 Substituted with one or more groups selected from cycloalkyl groups, or optionally R d1 and R 5 It may form a 5-6 membered aryl group or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group together with the carbon attached thereto, of which the cycloalkyl group and heterocycloalkyl group may optionally consist of hydrogen, deuterium, halogen, oxo, CN, and CF. 3 , OH, OCH 3 OCH 2 CH 3 Substituted by one or more groups selected from, The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. m is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. n is an integer arbitrarily chosen from 0, 1, 2, 3, and 4. Preferably, it has the structure of formula (ID), 【Chemistry 249】 Eventually, R 0 , R 2 Each has independently the definition described in any one of claims 1 to 5. Preferably, R 0 The group is independently selected from H, alkyl groups, haloalkyl groups, deuterated alkyl groups, cycloalkyl groups, heterocyclyl groups, alkoxyalkyl groups, alkynyl groups, acetyl groups, methylsulfonyl groups, and phosphono groups, and further, R 0 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, R 2 These are independently hydrogen, deuterium, halogen, -CN, -OH, -SH, and -NH 2 Selected from -COOH, or C 1-10 Alkyl alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group or C 1-10 Alkoxy group, C 2-10 Heteroalkyl groups, C 3-10 Saturated or partially saturated cycloalkyl groups, C 3-10 Saturated or partially saturated heterocycloalkyl groups, C 3-10 Cycloalkyl groups or C 3-10 C substituted with heterocycloalkyl groups 1-10 Alkyl alkyl group, C 3-10 C substituted with a cycloalkyl group 2-10 Heteroalkyl groups, C 3-10 Heterocyclyl group, C 1-10 A carboxyl group or carboxyl group-substituted derivative with an alkyl group, an aryl group, or a heteroaryl group, selected from any two of these R groups. 2 R forms a 3- to 8-membered monocyclic or polycyclic structure together with carbon atoms linked to it on the ring, and the monocyclic or polycyclic structure may be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, fused rings, spirocyclic rings, or bridging rings, and the aliphatic ring, heterocyclic ring, fused ring, spirocyclic ring, or bridging ring structure may contain 0 to 10 unsaturated alkenyl bonds, and further, 2 The hydrogen atoms above are optionally and most preferably H, deuterium, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, OCH 3 , substituted with one or more substituents selected from carboxyl groups, OH, and CN, The aforementioned heterozygotes are arbitrarily and independently O, N, S, P, S=O, and S(=O). 2 This represents heteroatoms and their isotopes selected from, The halogens are arbitrarily and independently selected from F, Cl, Br, I and their isotopes. Preferably, it has the structure of formula (III), [Chemical 250] Among them, rings C, L, and X 0 , X 1 , X 2 , R 1 , R 2 , R 5 , R d1 m, n, and q each have independently defined terms as described in any one of claims 1 to 5. Preferably, it has the structure of formula (IIIA), 【Chemistry 251】 Among them, L, X 2 , R 0 , R 1 , R 2 , R d1 Each has independently the definition described in any one of claims 1 to 5. Preferably, having a structure represented by formula (IE), 【Chemistry 252】 A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof, and a crystalline polymorph thereof.

7. It has the following structure: 【Chemistry 253】 【change】 【change】 【change】 Preferably, having the following structure: 【Chemistry 254】 【change】 【change】 【change】 A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, enantiomer, and isotope-substituted compound thereof, and a crystalline polymorph thereof.

8. A crystalline polymorph of the compound represented by formula (IE), 【Chemistry 255】 Eventually, The aforementioned crystalline polymorph is selected from the solvate crystalline form, hydrate crystalline form, or metastable crystalline form of compound IE. Preferably, the solvate crystal form may be crystal forms A, B, or C below, the hydrate crystal form may be crystal forms D, E, F, or G below, and the metastable crystal form may be crystal forms H, I, J, K, L, M, N, O, P, or Q below. Crystal form A is characterized by the following: The aforementioned crystal form A has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 5.10±0.2°, 15.72±0.2°, 15.25±0.2°, and 20.53±0.2°. Preferably, the crystal form A further contains peaks located at diffraction angles (2θ) of 23.66±0.2°, 23.92±0.2°, 17.47±0.2°, 20.14±0.2°, and 24.44±0.2°. Preferably, the crystal form A further includes peaks located at diffraction angles (2θ) of 26.66±0.2°, 17.22±0.2°, 26.92±0.2°, 16.48±0.2°, 10.20±0.2°, and 21.97±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form A has the diffraction angle (2θ) shown in Table 1, and the error range of the 2θ angle is ±0.20°. Table 37 Preferably, the crystal form A has the X-ray powder diffraction intensity shown in Table 1, Preferably, the crystal form A basically has the X-ray powder diffraction pattern shown in Figure 1, Preferably, the DSC analysis of the crystal form A shows an endothermic peak when heated to a peak temperature of around 180.86°C. Preferably, the crystal form A basically has the DSC pattern shown in Figure 2, Preferably, the crystal form A basically has the TGA pattern shown in Figure 3, Crystal form B is characterized by the following: The aforementioned crystal form B has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 10.33±0.2°, 5.18±0.2°, 13.69±0.2°, and 18.72±0.2°. Preferably, the crystal form B further contains peaks located at diffraction angles (2θ) of 8.96±0.2°, 11.73±0.2°, 25.89±0.2°, 17.10±0.2°, and 23.20±0.2°. Preferably, the crystal form B further includes peaks located at diffraction angles (2θ) of 26.13±0.2°, 24.92±0.2°, 22.77±0.2°, 20.85±0.2°, 17.95±0.2°, and 36.45±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form B has the diffraction angle (2θ) shown in Table 2, and the error range of the 2θ angle is ±0.20°. Table 38 Preferably, the crystal form B has the X-ray powder diffraction intensity shown in Table 2, Preferably, the crystal form B basically has the X-ray powder diffraction pattern shown in Figure 4, Preferably, the DSC analysis of crystal form B shows an endothermic peak when heated to a peak temperature of around 179.71°C. Preferably, the crystal form B basically has the DSC pattern shown in Figure 5, Preferably, the crystal form B basically has the TGA pattern shown in Figure 6, Crystal form C is characterized by the following: The aforementioned crystal form C has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 5.39±0.2°, 12.05±0.2°, 9.70±0.2°, and 18.00±0.2°. Preferably, the crystal form C further contains peaks located at diffraction angles (2θ) of 23.06±0.2°, 21.21±0.2°, 17.30±0.2°, 17.14±0.2°, and 25.09±0.2°. Preferably, the crystal form C further includes peaks located at diffraction angles (2θ) of 22.39±0.2°, 19.54±0.2°, 13.48±0.2°, 27.27±0.2°, 10.68±0.2°, and 5.98±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form C has the diffraction angle (2θ) shown in Table 3, and the error range of the 2θ angle is ±0.20°. Table 39 Preferably, the crystal form C has the X-ray powder diffraction intensity shown in Table 3, Preferably, the crystal form C has basically the X-ray powder diffraction pattern shown in Figure 7, Preferably, the DSC analysis of the crystalline form C shows an endothermic peak when heated to a peak temperature of around 173.43°C. Preferably, the crystal form C has basically the DSC pattern shown in Figure 8, Preferably, the crystal form C basically has the TGA pattern shown in Figure 9, Hydrate crystal form D is characterized by the following: The aforementioned crystal form D has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 5.20±0.2°, 15.74±0.2°, 22.81±0.2°, and 18.39±0.2°. Preferably, the crystal form D further includes peaks located at diffraction angles (2θ) of 23.12±0.2°, 7.81±0.2°, 16.78±0.2°, 5.89±0.2°, and 10.43±0.2°. Preferably, the crystal form D further includes peaks located at diffraction angles (2θ) of 25.44±0.2°, 13.08±0.2°, 15.06±0.2°, 18.96±0.2°, 21.04±0.2°, and 21.95±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form D has the diffraction angle (2θ) shown in Table 4, and the error range of the 2θ angle is ±0.20°. Table 40 Preferably, the crystal form D has the X-ray powder diffraction intensity shown in Table 4, Preferably, the crystal form D basically has the X-ray powder diffraction pattern shown in Figure 10, Preferably, DSC analysis of the crystal form D shows endothermic peaks when heated to peak temperatures around 157.79°C and 181.65°C. Preferably, the crystal form D basically has the DSC pattern shown in Figure 11, Preferably, the crystal form D basically has the TGA pattern shown in Figure 12, Hydrate crystal form E is characterized by the following: The aforementioned crystal form E has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.54±0.2°, 13.72±0.2°, 9.12±0.2°, and 18.35±0.2°. Preferably, the crystal form E further contains peaks located at diffraction angles (2θ) of 15.88±0.2°, 23.00±0.2°, 5.24±0.2°, 23.88±0.2°, and 17.20±0.2°. Preferably, the crystal form E further includes peaks located at diffraction angles (2θ) of 21.72±0.2°, 20.42±0.2°, 23.49±0.2°, 25.01±0.2°, 25.29±0.2°, and 9.72±0.2°, Preferably, the X-ray powder diffraction pattern of the crystal form E has the diffraction angle (2θ) shown in Table 5, and the error range of the 2θ angle is ±0.20°. Table 41 Preferably, the crystal form E has the X-ray powder diffraction intensity shown in Table 5, Preferably, the crystal form E basically has the X-ray powder diffraction pattern shown in Figure 13, Preferably, DSC analysis of the crystal form E shows endothermic peaks when heated to peak temperatures of around 69.77°C and 181.95°C. Preferably, the crystal form E basically has the DSC pattern shown in Figure 14, Preferably, the crystal form E basically has the TGA pattern shown in Figure 15, Hydrate crystal form F is characterized by the following: The aforementioned crystal form F has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 9.08±0.2°, 18.27±0.2°, 6.25±0.2°, and 13.73±0.2°. Preferably, the crystal form F further includes peaks located at diffraction angles (2θ) of 7.52±0.2°, 5.12±0.2°, 10.25±0.2°, 10.50±0.2°, and 15.16±0.2°. Preferably, the crystal form F further includes peaks located at diffraction angles (2θ) of 15.00±0.2°, 16.60±0.2°, 19.04±0.2°, 21.46±0.2°, 27.60±0.2° and 11.71±0.2°, Preferably, the X-ray powder diffraction pattern of the crystal form F has the diffraction angle (2θ) shown in Table 6, and the error range of the 2θ angle is ±0.20°. Table 42 Preferably, the crystal form F has the X-ray powder diffraction intensity shown in Table 6, Preferably, the crystal form F has basically the X-ray powder diffraction pattern shown in Figure 16, Preferably, DSC analysis of the crystal form F shows that when heated to peak temperatures of around 101.36°C and 177.98°C, an endothermic peak appears, and when heated to around 146.72°C, a heat dissipation peak appears. Preferably, the crystal form F has basically the DSC pattern shown in Figure 17, Preferably, the crystal form F has basically the TGA pattern shown in Figure 18, Hydrate crystal form G is characterized by the following: The aforementioned crystal form G has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 9.06±0.2°, 14.98±0.2°, 15.76±0.2°, and 18.16±0.2°. According to the present invention, the crystal form G preferably further includes peaks located at diffraction angles (2θ) of 12.04±0.2°, 20.96±0.2°, 24.12±0.2°, 9.89±0.2°, and 28.54±0.2°. According to the present invention, it is even more preferable that the crystal form G further includes peaks located at diffraction angles (2θ) of 7.93±0.2°, 6.03±0.2°, 25.73±0.2°, 27.70±0.2°, 21.78±0.2° and 24.51±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form G has the diffraction angle (2θ) shown in Table 7, and the error range of the 2θ angle is ±0.20°. Table 43 Preferably, the crystal form G has the X-ray powder diffraction intensity shown in Table 7, Preferably, the crystal form G has basically the X-ray powder diffraction pattern shown in Figure 19, Preferably, DSC analysis of the crystal form G shows an endothermic peak when heated to a peak temperature of around 126.74°C. Preferably, the crystal form G has basically the DSC pattern shown in Figure 20, Preferably, the crystal form G basically has the TGA pattern shown in Figure 21, Metastable crystalline form H is characterized by the following: The metastable crystalline form H has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 6.02±0.2°, 3.96±0.2°, 12.66±0.2°, and 9.35±0.2°. Preferably, the crystal form H further contains peaks located at diffraction angles (2θ) of 15.49±0.2°, 12.06±0.2°, 4.42±0.2°, 11.38±0.2°, and 18.31±0.2°. Preferably, the crystal form H further includes peaks located at diffraction angles (2θ) of 6.68±0.2°, 13.87±0.2°, 9.88±0.2°, 19.05±0.2°, 17.92±0.2°, and 8.94±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form H has the diffraction angle (2θ) shown in Table 8, and the error range of the 2θ angle is ±0.20°. Table 44 Preferably, the crystalline form H has the X-ray powder diffraction intensity shown in Table 8, Preferably, the crystalline form H basically has the X-ray powder diffraction pattern shown in Figure 22, Preferably, DSC analysis of the crystalline form H shows endothermic peaks when heated to peak temperatures of around 61.06°C and 151.59°C. Preferably, the crystalline form H basically has the DSC pattern shown in Figure 23, Preferably, the crystal form H basically has the TGA pattern shown in Figure 24, Metastable crystal form I is characterized by the following: The aforementioned metastable crystal form I has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.93±0.2°, 4.37±0.2°, 16.01±0.2°, and 7.45±0.2°. Preferably, the crystal form I further contains peaks located at diffraction angles (2θ) of 6.45±0.2°, 22.79±0.2°, 17.57±0.2°, 17.98±0.2°, and 15.14±0.2°. Preferably, the crystal form I further includes peaks located at diffraction angles (2θ) of 22.48±0.2°, 16.65±0.2°, 10.00±0.2°, 12.59±0.2°, 20.05±0.2°, and 25.54±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form I has the diffraction angle (2θ) shown in Table 9, and the error range of the 2θ angle is ±0.20°. Table 45 Preferably, the crystal form I has the X-ray powder diffraction intensity shown in Table 9, Preferably, the crystal form I basically has the X-ray powder diffraction pattern shown in Figure 25, Metastable crystal form J is characterized by the following: The metastable crystal form J has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 5.78±0.2°, 8.06±0.2°, 12.04±0.2°, and 16.19±0.2°. Preferably, the crystal form J further contains peaks located at diffraction angles (2θ) of 17.14±0.2°, 14.55±0.2°, 10.35±0.2°, 11.59±0.2°, and 19.77±0.2°. Preferably, the crystal form J further includes peaks located at diffraction angles (2θ) of 7.25±0.2°, 20.81±0.2°, 26.22±0.2°, 20.57±0.2°, 24.25±0.2°, and 22.62±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form J has the diffraction angle (2θ) shown in Table 10, and the error range of the 2θ angle is ±0.20°. Table 46 Preferably, the crystal form J has the X-ray powder diffraction intensity shown in Table 10, Preferably, the crystal form J basically has the X-ray powder diffraction pattern shown in Figure 26, Metastable crystal form K is characterized by the following: The metastable crystal form K has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.05±0.2°, 4.89±0.2°, 4.44±0.2°, and 5.92±0.2°. Preferably, the crystal form K further contains peaks located at diffraction angles (2θ) of 12.53±0.2°, 7.87±0.2°, 16.76±0.2°, 8.83±0.2°, and 5.55±0.2°. Preferably, the crystal form K further includes peaks located at diffraction angles (2θ) of 14.59±0.2°, 9.84±0.2°, 13.38±0.2°, 20.10±0.2°, 14.08±0.2°, and 15.76±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form K has the diffraction angle (2θ) shown in Table 11, and the error range of the 2θ angle is ±0.20°. Table 47 Preferably, the crystal form K has the X-ray powder diffraction intensity shown in Table 11, Preferably, the crystal form K basically has the X-ray powder diffraction pattern shown in Figure 27, Metastable crystal form L is characterized by the following: The metastable crystal form L has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 8.67±0.2°, 15.29±0.2°, 14.75±0.2°, and 11.76±0.2°. Preferably, the crystal form L further contains peaks located at diffraction angles (2θ) of 17.44±0.2°, 9.02±0.2°, 26.63±0.2°, 20.65±0.2°, and 7.89±0.2°. Preferably, the crystal form L further includes peaks located at diffraction angles (2θ) of 17.89±0.2°, 9.53±0.2°, 23.98±0.2°, 19.19±0.2°, 21.18±0.2°, and 13.64±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form L has the diffraction angle (2θ) shown in Table 12, and the error range of the 2θ angle is ±0.20°. Table 48 Preferably, the crystal form L has the X-ray powder diffraction intensity shown in Table 12, Preferably, the crystal form L basically has the X-ray powder diffraction pattern shown in Figure 28, Metastable crystal form M is characterized by the following: The metastable crystal form M has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 8.26±0.2°, 14.79±0.2°, 17.07±0.2°, and 14.57±0.2°. Preferably, the crystal form M further includes peaks located at diffraction angles (2θ) of 11.50±0.2°, 21.18±0.2°, 16.60±0.2°, 20.53±0.2°, and 25.33±0.2°. Preferably, the crystal form M further includes peaks located at diffraction angles (2θ) of 18.43±0.2°, 25.01±0.2°, 7.99±0.2°, 8.98±0.2°, 13.04±0.2°, and 24.12±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form M has the diffraction angle (2θ) shown in Table 13, and the error range of the 2θ angle is ±0.20°. Table 49 Preferably, the crystal form M has the X-ray powder diffraction intensity shown in Table 13, Preferably, the crystal form M basically has the X-ray powder diffraction pattern shown in Figure 29, Metastable crystalline form N is characterized by the following: The metastable crystal form N has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.48±0.2°, 5.02±0.2°, 5.55±0.2°, and 11.61±0.2°. Preferably, the crystal form N further contains peaks located at diffraction angles (2θ) of 3.14±0.2°, 14.70±0.2°, 11.42±0.2°, 7.31±0.2°, and 13.69±0.2°. Preferably, the crystal form N further includes peaks located at diffraction angles (2θ) of 13.34±0.2°, 9.57±0.2°, 15.71±0.2°, 15.10±0.2°, 12.43±0.2°, and 22.05±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form N has the diffraction angle (2θ) shown in Table 14, and the error range of the 2θ angle is ±0.20°. Table 50 Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 14, Preferably, the crystal form N basically has the X-ray powder diffraction pattern shown in Figure 30, Metastable crystal form O is characterized by the following: The metastable crystal form O has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.54±0.2°, 3.37±0.2°, 5.96±0.2°, and 12.21±0.2°. Preferably, the crystal form O further contains peaks located at diffraction angles (2θ) of 7.87±0.2°, 13.89±0.2°, 16.84±0.2°, 21.24±0.2°, and 32.21±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form O has the diffraction angle (2θ) shown in Table 14, and the error range of the 2θ angle is ±0.20°. Table 51 Preferably, the crystal form O has the X-ray powder diffraction intensity shown in Table 15, Preferably, the crystal form O basically has the X-ray powder diffraction pattern shown in Figure 31, Metastable crystal form P is characterized by the following: The metastable crystal form P has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.81±0.2°, 4.29±0.2°, 6.08±0.2°, and 14.65±0.2°. Preferably, the crystal form P further contains peaks located at diffraction angles (2θ) of 12.33±0.2°, 7.89±0.2°, 3.41±0.2°, 17.94±0.2°, and 8.81±0.2°. Preferably, the crystal form P further includes peaks located at diffraction angles (2θ) of 17.57±0.2°, 7.25±0.2°, 13.37±0.2°, 19.60±0.2°, and 20.23±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form P has the diffraction angle (2θ) shown in Table 14, and the error range of the 2θ angle is ±0.20°. Table 52 Preferably, the crystal form P has the X-ray powder diffraction intensity shown in Table 16, Preferably, the crystal form P has basically the X-ray powder diffraction pattern shown in Figure 32, Metastable crystal form Q is characterized by the following: The aforementioned metastable crystal form Q has an X-ray powder diffraction pattern that includes peaks located at diffraction angles (2θ) of 4.96±0.2°, 7.42±0.2°, 14.82±0.2°, and 21.77±0.2°. Preferably, the crystal form Q further contains peaks located at diffraction angles (2θ) of 16.75±0.2°, 17.29±0.2°, 15.21±0.2°, 25.67±0.2°, and 24.53±0.2°. Preferably, the crystal form Q further includes peaks located at diffraction angles (2θ) of 9.86±0.2°, 15.76±0.2°, 17.56±0.2°, 22.92±0.2°, 23.67±0.2°, and 22.44±0.2°. Preferably, the X-ray powder diffraction pattern of the crystal form Q has the diffraction angle (2θ) shown in Table 14, and the error range of the 2θ angle is ±0.20°. Table 53 Preferably, the crystal form Q has the X-ray powder diffraction intensity shown in Table 17, Preferably, the crystal form Q has basically the X-ray powder diffraction pattern shown in Figure 33. Crystal polymorphs.

9. A method for producing a crystalline polymorph according to claim 8, Step 1 involves dissolving or dispersing compound IE in a solvent, Step 2 involves stirring at 0-50°C to crystallize, or adding an antisolvent to the compound clarification solution to precipitate, or slowly volatilizing the compound clarification solution. Preferably, the compound IE is the metastable crystalline form H of compound IE. Preferably, the solvent is water, an organic solvent, or a mixture thereof, and the organic solvent is selected from alcohol-based, chloroalkane-based, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, sulfoxide-based organic solvents, or mixtures thereof, and preferably, the organic solvent is methanol, ethanol, n-propyl alcohol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyl Selected from tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, trichloroethane, carbon tetrachloride, methyl-tert-butyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene, or mixtures thereof. Manufacturing method.

10. The use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted thereof or a crystalline polymorph according to claim 8, used in the manufacture of a drug for preventing and / or treating a WEE1 and / or Yes target-related disease, Preferably, the disease includes tumors, inflammation, and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis). use.

11. The main active ingredient is a compound described in any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted thereof and its crystalline polymorph or the crystalline polymorph described in claim 8, and several other auxiliary components, and is a pharmaceutical composition that can be applied to various drug dosage forms, such as liquid formulations (including oral solutions, injections, eye drops, etc.) and solid formulations (including tablets, capsules, pills, granules, etc.), and is usable in the manufacture of drugs that prevent and / or treat WEE1 and / or Yes target-related diseases. Preferably, the disease includes tumors, inflammation, and autoimmune diseases (e.g., lupus erythematosus, psoriasis, psoriasis). Pharmaceutical composition.

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