Pyrimido large heterocyclic compound as Wee1-Yes double-target inhibitor and application of pyrimido large heterocyclic compound

Abstract

The invention discloses a novel pyrimido large heterocyclic compound with WEE1 and Yes double-target inhibition activity for the first time, and particularly discloses a compound which is used as a WEE1 and Yes double-target inhibitor and has a structure shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, isotope substitute or isomer and polymorphic substance of the compound.

Description

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

[0001] The present invention claims:

[0002] Priority to the prior application, international patent application number PCT / CN2023 / 093349, filed with the International Bureau on May 10, 2023, entitled “Novel pyrimidine heterocyclic compounds as Wee1 inhibitors and their applications”. Technical Field

[0003] The present invention belongs to the field of medicinal chemistry, and specifically includes the world's first disclosure of novel pyrimidine-macroheterocyclic compounds capable of simultaneously inhibiting WEE1 and Yes dual targets, compositions containing such compounds, and methods for using such compounds to prepare drugs for treating or preventing diseases related to WEE1 and / or Yes targets. Background Art

[0004] The cell cycle is a highly regulated and controlled process. The normal cell cycle has checkpoints during the G1 / S, S, and G2 / M phases, allowing sufficient time for DNA damage repair. Under normal circumstances, after DNA damage occurs, TP53 performs a checkpoint during the G1 / S phase, preventing normal DNA repair before the cell enters the G2 phase. If TP53 function is impaired, preventing normal G1 / S checkpoints, the cell enters the G2 phase with the damaged DNA. WEE1, a member of the serine / threonine protein kinase family, plays a crucial role in regulating the G2 / M checkpoint in the cell cycle. WEE1 kinase inhibits CDK kinase activity by phosphorylating Tyr14 and Tyr15, thereby arresting the cell cycle in the G2 / M phase and allowing cells ample time to repair DNA damage. Inhibition of WEE1 abolishes cell cycle arrest and causes cells to enter mitosis prematurely, leading to replication stress and inappropriate mitotic progression.

[0005] WEE1 is overexpressed in many cancers, including breast, lung, cervical, head and neck, ovarian, prostate, melanoma, leukemia, glioblastoma, medulloblastoma, and liver cancer. WEE1 overexpression in cancer cells is a normal response to increased replication stress and is associated with tumor progression and poor disease-free survival. Therefore, WEE1 inhibition has become a promising cancer treatment approach, especially when combined with DNA damage therapy. Numerous studies have demonstrated a synthetic lethal relationship between WEE1 and TP53. In tumor cells with inactivated TP53 mutations, the G1 / S checkpoint is lost, making them highly dependent on the G2 / M checkpoint. In TP53-deficient tumor cells, inhibiting WEE1 prevents normal damage repair, leading to the accumulation of erroneous signals and ultimately apoptosis, ultimately suppressing tumor growth. Therefore, WEE1 inhibitors hold great promise for synthetic lethality in cancers harboring TP53 mutations.

[0006] Although oral small-molecule WEE1 inhibitors have been reported in some literature and patents, and some candidate compounds have entered clinical trials, such as ZN-c3, AZD-1775, IMP 7068, and Debio 0123, single-target Wee1 selective inhibitors generally have weak anti-tumor efficacy, and most clinical candidate molecules suffer from significant drugability deficiencies, such as low efficacy, limited selectivity, rapid metabolism, poor oral absorption, low bioavailability, and a narrow safety window.

[0007] Yes-associated protein (YAP) is a major transcriptional coactivator of the Hippo pathway. It binds to the transcription factor TEAD to regulate downstream targets related to cell proliferation and survival. Unregulated YAP can lead to metastasis and poor prognosis in aggressive tumors, including pancreatic cancer, gastric cancer, and lung cancer. Therefore, inhibitors of the Yes target have the potential to become a promising tumor treatment strategy.

[0008] Studies have found that Yes and Wee1 are co-overexpressed in many malignant tumors, such as pancreatic cancer, small cell lung cancer, gastric cancer, intestinal cancer, and ovarian cancer, playing a significant role in the proliferation, invasion, and metastasis of these tumors. The development of inhibitors that can simultaneously inhibit both Yes and Wee1 targets would be more effective. However, as of the date of this application, no literature or patents worldwide have reported compounds that can simultaneously inhibit both Yes and Wee1 targets.

[0009] Technical Effects

[0010] The inventors unexpectedly discovered for the first time that some of the novel pyrimidine-macroheterocyclic compounds of formula (I) of the present invention can simultaneously inhibit both Yes and Wee1 targets, and have stronger anti-tumor activity and good PK properties compared to single Wee1 target selective compounds with known structures such as DEBIO0123, ZN-c3, NUV-569, etc., and are more suitable as candidate drug development for the prevention or treatment of tumors related to WEE1 and / or Yes targets or signaling pathways.

[0011] Summary of the Invention

[0012] The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer, isotope-substituted product, and polymorph thereof.

[0013] in,

[0014] X0, X1 and X2 are each independently selected from -C(R x )– or -N-;

[0015] L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, a double bond, an acetylenic 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)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-;

[0016] L is absent or selected from O, S, CH2, C(O), S(O), S(O)2, NH, C(O)NH, NHC(O);

[0017] Ring C is selected from heterocyclic groups which are unsubstituted or substituted by R0;

[0018] R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0019] Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, said monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and said alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to multiple selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; or any two R2, R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0020] R1, R d1 、R d2 、R x are independently selected from hydrogen, deuterium, halogen, cyano, oxo (=O), amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2- 10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 Cycloalkyl radical substitution; or R d1 and R d2 、R d1and R5 can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0021] R d3 Any independently selected from hydrogen, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is further optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0022] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0023] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0024] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0025] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0026] q is an integer arbitrarily selected from 0, 1, 2 and 3.

[0027] According to an embodiment of the present invention, X0, X1 and X2 are each independently selected from -C(R x )-or-N-;R x Selected from H, C 1-6 Alkyl (eg, methyl).

[0028] According to an embodiment of the present invention, X0 is -CH-.

[0029] According to an embodiment of the present invention, X1 is N.

[0030] According to an embodiment of the present invention, X2 is N.

[0031] According to an embodiment of the present invention, L is selected from O, S or NH.

[0032] According to an embodiment of the present invention, L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, no substitution or optionally substituted by one, two or more R d1 Substituted with the following groups: 1-6 Alkyl, C 2-6 alkenyl;

[0033] According to an embodiment of the present invention, L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, no substitution or optionally substituted by one, two or more R d1 Substituted with the following groups: CH2, CH2CH2, CH2CH2CH2, CH=CH, CH ＝ CHCH2.

[0034] According to an embodiment of the present invention, L3 is selected from -C(R d1 )(R d1 )-; preferably -C(CH3)(OH)-.

[0035] According to an embodiment of the present invention, L6 is selected from vinylene, and the vinylene is preferably cis.

[0036] According to an embodiment of the present invention, L4, L5 and L7 are the same or different and are independently selected from CH2.

[0037] According to an embodiment of the present invention, each R d1 The same or different, independently selected from H, OH, C 1-6 Alkyl (such as methyl).

[0038] According to an embodiment of the present invention, ring C is selected from a heterocyclic group which is unsubstituted or substituted by R0; the heterocyclic group may be selected from a piperidinyl group (such as ), piperazinyl (such as ), morpholinyl (such as ), azetidinyl (such as ), tetrahydropyrrolidone (such as ),

[0039] According to an embodiment of the present invention, Selected from

[0040] According to an embodiment of the present invention, Selected from

[0041] According to an embodiment of the present invention, R0 is selected from H, C 1-10 Alkyl, C 1-10 Alkoxy, deuterated C 1-10 Alkyl, halogenated C 1-10 Alkyl, HC(O)-, NH2C(O)-, C 1-10 Alkyl-C(O)-, C 1-10 Alkoxy-C(O)-, C 3-8 Cycloalkyl-C(O)-, 3-8 membered heterocyclic group.

[0042] Preferably, R0 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, HC(O)-, NH2C(O)-, C 1-6 Alkyl-C(O)-, C 1-6 Alkoxy-C(O)-, C 3-6 Cycloalkyl-C(O)-, 3-6 membered heterocyclic group.

[0043] According to an embodiment of the present invention, R0 is selected from H, methyl, ethoxy, trideuterated methyl, CF3CH2-, HC(O)-, CH3C(O)-,

[0044] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 aryl or 5-10 membered heteroaryl.

[0045] Preferably, each R1 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy-C(O)-.

[0046] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from H, methyl, deuterium, oxo (=O),

[0047] According to an embodiment of the present invention, each R2 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 aryl or 5-10 membered heteroaryl.

[0048] According to an embodiment of the present invention, each R2 is the same or different and is independently selected from H or C 1-6 Alkyl (such as methyl).

[0049] According to an embodiment of the present invention, each R5 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 aryl or 5-10 membered heteroaryl.

[0050] According to an embodiment of the present invention, each R5 is the same or different and is independently selected from H or C 1-6 Alkyl (such as methyl).

[0051] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof has a structure of formula (II):

[0052] wherein L, L3, L4, L5, L6, L7, X0, X1, X2, R0, R1, R2, R5, m, n, and q are independently defined above.

[0053] According to an embodiment of the present invention, X0, X1 and X2 are each independently selected from -C(R x)– or -N-;

[0054] L3, L4, L5, L6 and L7 are independently selected from the group consisting of absence, a single bond, a double bond, an acetylenic 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)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-;

[0055] L arbitrarily and independently selects O, S or NH;

[0056] R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0057] Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, said monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and said alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to multiple selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; or any two R2, R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0058] R1, R d1 、R d2 、R x independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1- 10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1- 6 alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 Cycloalkyl radical substitution; or R d1 and R d2 or R d1 and R5 can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0059] R d3 Any independently selected from hydrogen, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein, the C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is further optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups;

[0060] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0061] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0062] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0063] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0064] q is an integer arbitrarily selected from 0, 1, 2 and 3.

[0065] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IA):

[0066] Among them, L, X2, R0, R1, R2, R5, R d1 , m, n, q are independently defined as above, and p is arbitrarily selected from integers of 0, 1, 2, 3 and 4.

[0067] According to an embodiment of the present invention, X2 is independently selected from -C(R x )– or -N-;

[0068] L arbitrarily and independently selects O, S or NH;

[0069] R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0070] Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, said monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and said alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to multiple selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; or any two R2, R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0071] R1, R d1 and R x independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 cycloalkyl group; or optionally R d1 and R5 can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0072] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0073] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0074] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0075] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0076] q is an integer arbitrarily selected from 0, 1, 2 and 3;

[0077] p is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0078] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure of formula (IB),

[0079] Among them, R0, R1, R2, R5, R d1 , m, n, q independently have the definitions given above.

[0080] According to an embodiment of the present invention, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0081] Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, said monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and said alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to multiple selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; or any two R2, R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, heterocyclic alkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups;

[0082] R1 and R d1 independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3- 10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 cycloalkyl group substituted; or optionally R d1 and R5 can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0083] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0084] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0085] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0086] n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0087] q is an integer arbitrarily selected from 0, 1, 2 and 3;

[0088] p is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0089] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC),

[0090] wherein R0, R1, R2, m, and n are independently defined as above.

[0091] According to an embodiment of the present invention, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0092] Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1- 10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10Alkyl-substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 together with the carbon atoms to which they are connected on the ring form a 3-8 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 is optionally substituted with 1 to multiple substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0093] R1 is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by one or more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted by one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 cycloalkyl group substituted; or optionally R d1and R5 can form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the cycloalkyl group or heterocyclyl group is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0094] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0095] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0096] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0097] n is an integer arbitrarily selected from 0, 1, 2, 3 and 4.

[0098] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),

[0099] wherein R0 and R2 independently have the definitions described above.

[0100] According to an embodiment of the present invention, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, methylsulfonyl, phosphono; further, the hydrogen on R0 is optionally substituted with one or more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0101] R2 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocyclic alkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10Alkyl-substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 together with the carbon atoms to which they are connected on the ring form a 3-8 membered monocyclic or polycyclic structure, wherein the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure; and the aliphatic ring, heterocyclic ring, a cyclic ring, a spirocyclic ring or a bridged ring structure can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 is optionally substituted with 1 to multiple substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN;

[0102] The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and its isotope;

[0103] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof.

[0104] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (III):

[0105] Among them, ring C, L, X0, X1, X2, R1, R2, R5, R d1 , m, n, q independently have the definitions given above.

[0106] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IIIA),

[0107] Among them, L, X2, R0, R1, R2, R d1 have the definitions stated above independently of each other.

[0108] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure shown below:

[0109] In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has the structure shown below:

[0110] In certain embodiments of the present invention, the compound or its pharmaceutically acceptable salt, isotope substituted product or isomer thereof has the structure of formula (IE):

[0111] The present invention also provides a polymorph of the compound represented by formula (IE),

[0112] According to an embodiment of the present invention, the polymorph includes but is not limited to a non-solvate crystalline form, a hydrate crystalline form or a metastable crystalline form of Compound IE;

[0113] Further according to an embodiment of the present invention, the ansolvate crystalline form may be the following crystalline forms A, B, and C; the hydrate crystalline form may be the following crystalline forms D, E, F, and G; and the metastable crystalline form may be the following crystalline forms H, I, J, K, L, M, N, O, P, and Q:

[0114] For Form A:

[0115] The present invention provides Form A of Compound (IE), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.10±0.2°, 15.72±0.2°, 15.25±0.2° and 20.53±0.2°.

[0116] According to the present invention, the crystalline form A preferably further includes peaks 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°.

[0117] According to the present invention, the crystalline form A more preferably further includes peaks 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°.

[0118] Preferably, the X-ray powder diffraction pattern of the crystalline form A has a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°:

[0119] Table 1

[0120] Preferably, the crystalline form A has the X-ray powder diffraction intensity shown in Table 1.

[0121] Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0122] Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of approximately 180.86°C.

[0123] Preferably, the crystalline form A has a DSC spectrum substantially as shown in FIG2 .

[0124] Preferably, the crystalline form A has a TGA graph substantially as shown in FIG3 .

[0125] For Form B:

[0126] The present invention provides Form B of Compound (IE), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.33±0.2°, 5.18±0.2°, 13.69±0.2°, and 18.72±0.2°;

[0127] According to the present invention, the crystalline form B preferably further includes peaks 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°;

[0128] According to the present invention, the crystalline form B more preferably further includes peaks 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°;

[0129] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form B has a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°:

[0130] Table 2

[0131] Preferably, the crystalline form B has the X-ray powder diffraction intensity shown in Table 2.

[0132] Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG4 .

[0133] Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of approximately 179.71°C.

[0134] Preferably, the crystalline form B has a DSC spectrum substantially as shown in FIG5 .

[0135] Preferably, the crystalline form B has a TGA graph substantially as shown in FIG6 .

[0136] For Form C:

[0137] The present invention provides Form C of Compound (IE), which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.39±0.2°, 12.05±0.2°, 9.70±0.2°, and 18.00±0.2°;

[0138] According to the present invention, the crystalline form C preferably further includes peaks 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°;

[0139] According to the present invention, the crystalline form C more preferably further includes peaks 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°;

[0140] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form C has a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°:

[0141] Table 3

[0142] Preferably, the crystalline form C has the X-ray powder diffraction intensity shown in Table 3.

[0143] Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG7 .

[0144] Preferably, the DSC analysis of the crystalline form C shows an endothermic peak when heated to a peak temperature of approximately 173.43°C.

[0145] Preferably, the crystalline form C has a DSC spectrum substantially as shown in FIG8 .

[0146] Preferably, the crystalline form C has a TGA graph substantially as shown in FIG9 .

[0147] For hydrate crystal form D:

[0148] The present invention provides a hydrated crystalline form D of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 5.20±0.2°, 15.74±0.2°, 22.81±0.2° and 18.39±0.2°;

[0149] According to the present invention, the crystalline form D preferably further includes peaks 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°;

[0150] According to the present invention, the crystalline form D more preferably further includes peaks 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°;

[0151] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form D has a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°:

[0152] Table 4

[0153] Preferably, the crystalline form D has the X-ray powder diffraction intensity shown in Table 4.

[0154] Preferably, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG10 .

[0155] Preferably, the DSC analysis of the crystalline form D shows endothermic peaks near the peak temperatures of 157.79°C and 181.65°C.

[0156] Preferably, the crystalline form D has a DSC spectrum substantially as shown in FIG11 .

[0157] Preferably, the crystalline form D has a TGA pattern substantially as shown in FIG12 .

[0158] For hydrate crystal form E:

[0159] The present invention provides a hydrated crystalline form E of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.54±0.2°, 13.72±0.2°, 9.12±0.2° and 18.35±0.2°;

[0160] According to the present invention, the crystalline form E preferably further includes peaks 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°;

[0161] According to the present invention, the crystalline form E more preferably further includes peaks 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°;

[0162] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form E has a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°:

[0163] Table 5

[0164] Preferably, the crystalline form E has the X-ray powder diffraction intensity shown in Table 5.

[0165] Preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG13 .

[0166] Preferably, the DSC analysis of the crystalline form E shows endothermic peaks near the peak temperatures of 69.77°C and 181.95°C.

[0167] Preferably, the crystalline form E has a DSC spectrum substantially as shown in FIG14 .

[0168] Preferably, the crystalline form E has a TGA pattern substantially as shown in FIG15 .

[0169] For hydrate form F:

[0170] The present invention provides a hydrated crystalline form F of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.08±0.2°, 18.27±0.2°, 6.25±0.2° and 13.73±0.2°;

[0171] According to the present invention, the crystalline form F preferably further includes peaks 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°;

[0172] According to the present invention, the crystalline form F more preferably further includes peaks 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°;

[0173] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form F has a diffraction angle (2θ) as shown in Table 6, wherein the error range of the 2θ angle is ±0.20°:

[0174] Table 6

[0175] Preferably, the crystalline form F has the X-ray powder diffraction intensity shown in Table 6.

[0176] Preferably, the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG16 .

[0177] Preferably, the DSC analysis of the crystalline form F shows endothermic peaks near the peak temperatures of 101.36°C and 177.98°C, and an exothermic peak near 146.72°C.

[0178] Preferably, the crystalline form F has a DSC spectrum substantially as shown in FIG17 .

[0179] Preferably, the crystalline form F has a TGA graph substantially as shown in FIG18 .

[0180] For hydrate form G:

[0181] The present invention provides a hydrated crystalline form G of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.06±0.2°, 14.98±0.2°, 15.76±0.2° and 18.16±0.2°;

[0182] According to the present invention, the crystalline form G preferably further includes peaks 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°;

[0183] According to the present invention, the crystalline form G more preferably further includes peaks 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°;

[0184] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form G has a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°:

[0185] Table 7

[0186] Preferably, the crystalline form G has the X-ray powder diffraction intensity shown in Table 7.

[0187] Preferably, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in Figure 19.

[0188] Preferably, the DSC analysis of the crystalline form G shows an endothermic peak when heated to a peak temperature of approximately 126.74°C.

[0189] Preferably, the crystalline form G has a DSC graph substantially as shown in FIG20 .

[0190] Preferably, the crystalline form G has a TGA graph substantially as shown in Figure 21.

[0191] For metastable form H:

[0192] The present invention provides a metastable crystalline form H of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.02±0.2°, 3.96±0.2°, 12.66±0.2° and 9.35±0.2°;

[0193] According to the present invention, the crystalline form H preferably further includes peaks 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°;

[0194] According to the present invention, the crystalline form H more preferably further includes peaks 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°;

[0195] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form H has a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°:

[0196] Table 8

[0197] Preferably, the crystalline form H has the X-ray powder diffraction intensity shown in Table 8.

[0198] Preferably, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in Figure 22.

[0199] Preferably, the DSC analysis of the crystalline form H shows endothermic peaks near the peak temperatures of 61.06°C and 151.59°C.

[0200] Preferably, the crystalline form H has a DSC spectrum substantially as shown in FIG23 .

[0201] Preferably, the crystalline form H has a TGA graph substantially as shown in FIG. 24 .

[0202] For metastable form I:

[0203] The present invention provides a metastable crystalline form I of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.93±0.2°, 4.37±0.2°, 16.01±0.2° and 7.45±0.2°;

[0204] According to the present invention, the crystalline form I preferably further includes peaks 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°;

[0205] According to the present invention, the crystalline form I more preferably further includes peaks 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°;

[0206] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form I has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°:

[0207] Table 9

[0208] Preferably, the crystalline form I has the X-ray powder diffraction intensity shown in Table 9.

[0209] Preferably, the crystalline Form I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

[0210] For metastable form J:

[0211] The present invention provides a metastable crystalline form J of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 5.78±0.2°, 8.06±0.2°, 12.04±0.2° and 16.19±0.2°;

[0212] According to the present invention, the crystalline form J preferably further includes peaks 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°;

[0213] According to the present invention, the crystalline form J more preferably further includes peaks 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°;

[0214] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form J has a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°:

[0215] Table 10

[0216] Preferably, the crystalline form J has the X-ray powder diffraction intensity shown in Table 10.

[0217] Preferably, the crystalline Form J has an X-ray powder diffraction pattern substantially as shown in Figure 26.

[0218] For metastable form K:

[0219] The present invention provides a metastable crystalline form K of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.05±0.2°, 4.89±0.2°, 4.44±0.2° and 5.92±0.2°;

[0220] According to the present invention, the crystalline form K preferably further includes peaks 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°;

[0221] According to the present invention, the crystalline form K more preferably further includes peaks 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°;

[0222] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form K has a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°:

[0223] Table 11

[0224] Preferably, the crystalline form K has the X-ray powder diffraction intensity shown in Table 11.

[0225] Preferably, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 27.

[0226] For metastable form L:

[0227] The present invention provides a metastable crystalline form L of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 8.67±0.2°, 15.29±0.2°, 14.75±0.2° and 11.76±0.2°;

[0228] According to the present invention, the crystalline form L preferably further includes peaks 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°;

[0229] According to the present invention, the crystalline form L more preferably further includes peaks 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°;

[0230] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form L has a diffraction angle (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°:

[0231] Table 12

[0232] Preferably, the crystalline form L has the X-ray powder diffraction intensity shown in Table 12.

[0233] Preferably, the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 28.

[0234] For metastable form M:

[0235] The present invention provides a metastable crystalline form M of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 8.26±0.2°, 14.79±0.2°, 17.07±0.2° and 14.57±0.2°;

[0236] According to the present invention, the crystalline form M preferably further includes peaks 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°;

[0237] According to the present invention, the crystalline form M more preferably further includes peaks 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°;

[0238] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form M has a diffraction angle (2θ) as shown in Table 13, wherein the error range of the 2θ angle is ±0.20°:

[0239] Table 13

[0240] Preferably, the crystalline form M has the X-ray powder diffraction intensity shown in Table 13.

[0241] Preferably, the crystalline form M has an X-ray powder diffraction pattern substantially as shown in Figure 29.

[0242] For metastable form N:

[0243] The present invention provides a metastable crystalline form N of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.48±0.2°, 5.02±0.2°, 5.55±0.2° and 11.61±0.2°;

[0244] According to the present invention, the crystalline form N preferably further includes peaks 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°;

[0245] According to the present invention, the crystalline form N more preferably further includes peaks 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°;

[0246] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form N has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0247] Table 14

[0248] Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 14.

[0249] Preferably, the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 30.

[0250] For metastable form O:

[0251] The present invention provides a metastable crystalline form O of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.54±0.2°, 3.37±0.2°, 5.96±0.2° and 12.21±0.2°;

[0252] According to the present invention, the crystalline form O preferably further includes peaks 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°;

[0253] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form O has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0254] Table 15

[0255] Preferably, the crystalline form O has the X-ray powder diffraction intensity shown in Table 15.

[0256] Preferably, the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 31.

[0257] For metastable crystal form P:

[0258] The present invention provides a metastable crystalline form P of compound (IE), whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 4.81±0.2°, 4.29±0.2°, 6.08±0.2° and 14.65±0.2°;

[0259] According to the present invention, the crystalline form P preferably further includes peaks 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°;

[0260] According to the present invention, the crystalline form P more preferably further includes peaks 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°;

[0261] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form P has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0262] Table 16

[0263] Preferably, the crystalline form P has the X-ray powder diffraction intensity shown in Table 16.

[0264] Preferably, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 32.

[0265] For metastable crystal form Q:

[0266] The present invention provides a metastable crystalline Form Q of Compound IE, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.96±0.2°, 7.42±0.2°, 14.82±0.2°, and 21.77±0.2°;

[0267] According to the present invention, the crystalline form Q preferably further includes peaks 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°;

[0268] According to the present invention, the crystalline form Q more preferably further includes peaks 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°;

[0269] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form Q has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0270] Table 17

[0271] Preferably, the crystalline form Q has the X-ray powder diffraction intensity shown in Table 17.

[0272] Preferably, the crystalline form Q has an X-ray powder diffraction pattern substantially as shown in Figure 33.

[0273] The second aspect of the present invention provides a method for preparing a polymorph of the aforementioned compound (IE), selected from the following preparation methods:

[0274] Step 1: dissolving or dispersing compound IE in a solvent;

[0275] Step 2: stirring and crystallizing at 0-50°C; or, adding an antisolvent to the clear solution of the compound to precipitate; or, slowly volatilizing the clear solution of the compound;

[0276] According to an embodiment of the present invention, the compound IE is preferably the metastable crystalline form H of the compound IE.

[0277] As a further preferred embodiment, the solvent is water, an organic solvent or a mixed solvent thereof, wherein the organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxide organic solvents or mixtures thereof; preferably, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, methyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene or a mixture thereof.

[0278] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the polymorphs of the aforementioned compound (IE) and a pharmaceutically acceptable carrier.

[0279] The fourth aspect of the present invention provides a use of a polymorph of the aforementioned compound (IE) in the preparation of a medicament for preventing and / or treating WEE1 and / or Yes target-related diseases including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, and psoriasis).

[0280] The present invention also provides a method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the polymorphs of the aforementioned compound (IE) or the pharmaceutical composition.

[0281] According to an embodiment of the present invention, the disease is selected from WEE1 and / or Yes target-related diseases including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases.

[0282] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution and various crystal forms thereof are new compounds and new salt forms and crystal forms thereof selected from the structures disclosed in the embodiments of the present invention.

[0283] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions and various crystal forms thereof.

[0284] According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0285] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0286] The oral dosage form is not particularly limited and may be any oral dosage form known in the art, preferably tablets, capsules, suspensions or oral solutions, etc.

[0287] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient selected from at least one of the following excipients, including but not limited to a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH adjuster, a solubilizer or cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding amounts based on the requirements of the specific dosage form.

[0288] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0289] Another object of the present invention is to provide the use of the above-mentioned compound in the preparation of a drug for preventing and / or treating WEE1 or Yes target-related diseases including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and the like.

[0290] The present invention also provides compounds represented by formulas (I)-(IE), their pharmaceutically acceptable salts, solvates, enantiomers, isotopic substitutions, and various salt forms and crystal forms thereof, as well as the use of such pharmaceutical compositions in preventing and / or treating diseases associated with the WEE1 or / and Yes signaling pathway. Diseases associated with the WEE1 or / and Yes signaling pathway include tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, and so on).

[0291] The present invention also provides a method for preventing and / or treating diseases associated with the WEE1 or Yes signaling pathway, comprising administering to a patient a preventively or therapeutically effective amount of at least one of the compounds of formula (I), pharmaceutically acceptable salts, solvates, enantiomers, and isotopic substitutions thereof, or administering to a patient a preventively or therapeutically effective amount of the aforementioned pharmaceutical composition. The diseases associated with the WEE1 or Yes signaling pathway are as defined above.

[0292] In some embodiments, the patient is a mammal, preferably a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0293] Figure 1 shows the X-ray powder diffraction pattern of the crystalline form A of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0294] Figure 2 shows the DSC graph of the crystalline form A of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0295] Figure 3 shows the TGA chart of the crystalline form A of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0296] Figure 4 shows the X-ray powder diffraction pattern of the crystalline form B of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0297] Figure 5 shows a DSC graph of the crystalline form B of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0298] Figure 6 shows the TGA chart of the crystal form B of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0299] Figure 7 shows the X-ray powder diffraction pattern of the crystalline form C of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0300] Figure 8 shows the DSC graph of the crystalline form C of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0301] Figure 9 shows a TGA chart of the crystalline form C of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0302] Figure 10 shows the X-ray powder diffraction pattern of the hydrated crystal form D of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0303] Figure 11 shows the DSC graph of the hydrated crystal form D of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0304] Figure 12 shows the TGA chart of the hydrate crystal form D of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0305] Figure 13 shows the X-ray powder diffraction pattern of the hydrated crystal form E of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0306] Figure 14 shows a DSC graph of the IE hydrate crystal form E of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0307] Figure 15 shows a TGA chart of the hydrate crystal form E of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0308] Figure 16 shows the X-ray powder diffraction pattern of the hydrated crystal form F of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0309] Figure 17 shows a DSC chart of the crystalline form F of the hydrate of compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0310] Figure 18 shows a TGA chart of the hydrate crystal form F of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0311] Figure 19 shows the X-ray powder diffraction pattern of the hydrated crystal form G of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0312] Figure 20 shows a DSC graph of the hydrated crystal form G of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0313] Figure 21 shows the TGA chart of the hydrate crystal form G of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0314] Figure 22 shows the X-ray powder diffraction pattern of the metastable crystalline form H of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0315] Figure 23 shows the DSC graph of the metastable crystalline form H of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0316] Figure 24 shows the TGA chart of the metastable crystalline form H of the compound IE of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0317] Figure 25 shows the X-ray powder diffraction pattern of the metastable crystalline form I of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0318] Figure 26 shows the X-ray powder diffraction pattern of the metastable crystal form J of the compound IE of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0319] Figure 27 shows the X-ray powder diffraction pattern of the metastable crystalline form K of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0320] Figure 28 shows the X-ray powder diffraction pattern of the metastable crystal form L of the compound IE of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0321] Figure 29 shows the X-ray powder diffraction pattern of the metastable crystalline form M of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0322] Figure 30 shows the X-ray powder diffraction pattern of the metastable crystalline form N of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0323] Figure 31 shows the X-ray powder diffraction pattern of the metastable crystal form O of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0324] Figure 32 shows the X-ray powder diffraction pattern of the metastable crystalline form P of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0325] Figure 33 shows the X-ray powder diffraction pattern of the metastable crystal form Q of the compound IE of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0326] Figure 34 shows a DVS diagram of the crystalline form A of the compound IE of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0327] Figure 35 shows a DVS diagram of the crystal form B of the compound IE of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0328] Figure 36 shows a DVS diagram of Form C of Compound IE of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0329] Figure 37 shows a DVS diagram of Form D of Compound IE of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0330] FIG38 is a diagram showing the single crystal analysis results of compound IE of the present invention.

[0331] Definition and Explanation:

[0332] C 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 ; C 2-10 Selected from C2, C3, C4, C5, C6, C7, C8, C9 and C 10 ; C 3-10 Selected from C3, C4, C5, C6, C7, C8, C9 and C 10 ;

[0333] It should be understood that herein, when describing one, two or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0334] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0335] The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group having 1 to 12 carbon atoms. 1-8 Alkyl", "C 1-6 Alkyl", "C 1- "8 alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0336] The term "alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 12 carbon atoms, preferably "C 2-10 Alkenyl", "C 2-6 Alkenyl". "C 2-10 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C 2-6"Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. It is understood that, in the case where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-2-enyl, )-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex -1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, ( E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0337] The term "haloalkyl" refers to an alkyl group substituted by one, two or more halogens, where halogen and alkyl are as defined above. 1-6 "Alkyl" means a C 1-6 Alkyl, halogen and C 1-6 Alkyl is as defined above.

[0338] The term "deuterated alkyl" refers to an alkyl group substituted by one, two or more deuterium atoms, wherein alkyl is as defined above. 1-6 "Alkyl" means a C substituted with one, two or more deuteriums. 1-6 Alkyl, C 1-6 Alkyl is as defined above.

[0339] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above. The alkylene group is preferably an alkylene group having 1 to 6 carbon atoms (i.e., C1-6 alkyl).

[0340] The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above. The alkylene group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., C 2-6 alkenyl).

[0341] The term "alkynyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2 to 12 carbon atoms, preferably "C 2-10 Alkynyl", C 2-6 Alkynyl. The term "C 2-10 "Alkynyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C 2- 8 alkynyl”), having 2, 3, 4, 5 or 6 carbon atoms (i.e., “C 2-6 Alkynyl”), having 2 or 3 carbon atoms (“C 2-3 The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0342] As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.

[0343] The term "aliphatic ring", "carbocycle" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle may be monocyclic or polycyclic, and may be a saturated cycloalkyl or may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group. In the case of a carbocycle having multiple rings, these rings may form spirocyclic, fused ring and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; and non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.

[0344] The term "cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as fused, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-6 Cycloalkyl". The term "C 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0345] The term "aryl" or "aromatic ring" means: It should be understood that it preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0346] The term "spirocyclic" refers to a ring system in which two rings share one ring atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0347] The term "paracyclic" refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

[0348] The term "bridged ring" refers to a ring system in which two rings share more than 3 ring atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as described above. The term "heterocycle (base)" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms or atomic groups selected from N, O, NH, S, S(O) or S(O)2, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, and can also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group can be bicyclic, and its non-limiting examples include hexahydrocyclopenta [c] pyrrole -2 (1H) - base, hexahydro pyrrolo [1,2-a] pyrazine -2 (1H) - base. The heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

[0349] The term "heterocyclyl" 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 (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic radical can be connected to the rest of the molecule by any one of the carbon atoms or nitrogen atom (if present). The heterocyclic radical can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic radical can include but is not limited to: 4-membered rings, such as azetidinyl, oxetane; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic radical can be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-20-membered heterocyclic group or to a heterocyclic atom on the 3-20-membered heterocyclic group ring. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to another group. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom in the para position may be connected to another group. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0350] As used herein, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, , isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and / or phenoxazinyl, etc.

[0351] The heteroaryl group / heteroaromatic ring may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0352] Unless otherwise specified, heterocyclic groups, heteroaryls, or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, substituted or bonded to other groups at one, two, or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0353] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0354] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts 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 salts of amino acids such as arginine, and organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0355] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0356] As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention wherein the parent compound is modified by acid or base salt formation. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. 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, those derived from inorganic and organic acids, inorganic and organic bases selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, The inorganic base and organic base such as oxalic acid, pamoic 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 are selected from sodium, potassium, magnesium, calcium or amines, diethylamine, triethylamine, ethanolamine and the like.

[0357] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0358] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0359] Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, solvated forms are comparable to unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms.

[0360] As used herein, the term "solvate" refers to an association formed between one or more solvent molecules and a compound 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. Thus, the term "hydrate" refers to an association formed when the solvent molecule is water.

[0361] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0362] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0363] As used herein, "polymorph" refers to a crystalline form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although polymorphs have the same chemical composition, their packing and geometric arrangements differ and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. In a monotropic system, the relative stability of the two solid phases remains unchanged when the temperature changes. In contrast, in a tautotropic system, there is a transition temperature at which the stability of the two phases switches ((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN: 0-8247-0237). This phenomenon of a compound existing in different crystal structures is known as pharmaceutical polymorphism.

[0364] The various crystalline structures of the present invention can be distinguished from each other using various analytical techniques known to those of ordinary skill 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).

[0365] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C (68-77°F).

[0366] As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions is intended to take into account typical peak position and intensity variability. For example, one skilled in the art will appreciate that peak positions (2θ) will vary between XRPD instruments, sometimes by as much as 0.2°. Furthermore, one skilled in the art will appreciate that factors such as XRPD sample preparation, XRPD instrumentation, sample crystallinity, sample dosage, and preferred crystal orientation will result in variations in relative peak intensities in a sample's XRPD diffraction pattern.

[0367] The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0368] The chemical reactions described in the specific embodiments of the present invention are carried out in a suitable solvent, which must be compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0369] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0370] All solvents used in the present invention were commercially available and used without further purification.

[0371] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0372] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0373] The diagrammatic representations of racemic, ambiscalemic, scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration at a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be encompassed within the scope of this invention.

[0374] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0375] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0376] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0377] 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 has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0378] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0379] When a substituent's bond crosses two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, such substituent may be bonded to any atom therein. Combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0380] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0381] The present invention will now be further described by way of examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many methods known in the art of organic synthesis. The examples of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by methods modified therefrom. Preferred methods include, but are not limited to, the methods described below.

[0382] Unless otherwise specified, all solvents used in the present invention are commercially available and do not require further purification when used. The reaction is usually carried out using anhydrous solvents under an inert atmosphere of nitrogen. Nuclear magnetic resonance spectra are measured on 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 Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive and negative modes.

[0383] The present invention uses the following abbreviations: aq represents water; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, an amine protecting group; Boc represents tert-butyloxycarbonyl, an amine protecting group; HOAc represents acetic acid; NaBH(OAc)3 represents sodium triacetoxyborohydride; r.t represents room temperature; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; POCl3 represents phosphorus oxychloride; NaH represents sodium hydride; LAH represents lithium aluminum hydride; Pd(OAc)2 represents palladium(II) acetate; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Et3SiH represents triethylsilane; PPh 3 represents triphenylphosphine; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethyl; MeSO3H represents methanesulfonic acid; Xphos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Lawesson's reagent represents 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphane-2,4-disulfide; NBS represents N-bromosuccinimide; t-BuOK represents 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 azodicarboxylate; DEAD is diethyl azodicarboxylate; DBAD is di-tert-butyl azodicarboxylate; TES is triethylsilane; LDA is lithium diisopropylamide; NBS is N-bromosuccinimide; NIS is N-iodosuccinimide; NCS is N-chlorosuccinimide; DMP is DMP reagent; DMF-DMA is 1,1-dimethoxy-N,N-dimethylmethanamine; TMP is 2,2,6,6-tetramethylpiperidine; NMO is N-methylmorpholine N- oxide; TBSC1 is tert-butyldimethylsilyl chloride; SEMC1 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; HATU is l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolyl[4,5-b]trioxypyridinium hexafluorophosphate; Xphos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; cataCXium A is n-butyl-bis(1-adamantyl)phosphine; DPPP is 1,3-bis(diphenylphosphino)propane; DPPF is 1,1'-bis(diphenylphosphino)ferrocene; HMTA is 1,3,5,7-tetraazaadamantane; PMBC1 is p-methoxybenzyl chloride; HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; EGTA is ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid.

[0384] Compounds can be named manually or using The product is named after the manufacturer. If purchased commercially, the supplier's catalog name can also be used. TLC or LC-MS is usually used to determine whether the reaction is complete. DETAILED DESCRIPTION

[0385] In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

[0386] Example 1. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer (Compound IE):

[0387] 1) Synthesis of 2-(6-bromopyridin-2-yl)hex-5-en-2-ol:

[0388] At 0°C, to a solution of 1-(6-bromopyridin-2-yl)ethane-1-one (10.0 g, 50.0 mmol) in tetrahydrofuran (100 mL) was added but-3-ene-1-methylmagnesium bromide (150 mL, 75.0 mmol). The resulting mixed reaction solution was stirred at room temperature overnight under argon protection. At 0°C, the mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (3×200 ml). The combined organic phase was 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 give 2-(6-bromopyridin-2-yl)hex-5-en-2-ol (6.0 g, yield: 47%), LC-MS m / z: 256 [M+H] + ;

[0389] 2) Synthesis of 2-allyl-1-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one:

[0390] A solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.00 g, 22.5 mmol), 2-(6-bromopyridin-2-yl)hex-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) in dioxane (60 mL) was heated at 90°C and stirred overnight under argon. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were 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 give 2-allyl-1-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.25 g, yield: 58.7%), LCMS m / z: 398 [M+H] + ;

[0391] 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]diazacyclopentadecapentaene-5-one:

[0392] A solution of 2-allyl-1-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (5.25 g, 13.2 mmol) and Grubbs III (1.17 g, 1.32 mmol) in dichloromethane (1.6 L) was heated at 40°C with stirring overnight under argon. 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 give (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (510 mg, yield: 10.5%) and recovered 2-allyl-1-(6-(2-hydroxyhex-5-en-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4.0 g, yield: 76.1%), LC-MS m / z: 370 [M+H]+ ;

[0393] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaene-5-one:

[0394] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-A][1,2]diazacyclopentadecahepten-5-one (510 mg, 1.38 mmol) and m-chloroperbenzoic acid (500 mg, 2.46 mmol) in toluene (50 mL) was stirred at room temperature for 3 hours. The resulting reaction solution was concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without further purification. LC-MS m / z: 402 [M+H] + ;

[0395] 5) Synthesis of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine:

[0396] At 0°C, sodium hydride (3.47 g, 86.82 mmol, 60% content) was added in batches to a solution of 1-methylpiperidin-4-ol (5 g, 43.41 mmol) in tetrahydrofuran (50 mL). The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. 1-Fluoro-2-methyl-4-nitrobenzene (7.4 g, 47.7 mmol) was then added in batches to the above mixed reaction solution. The resulting mixed reaction solution was heated at 50°C and stirred for 17 hours. At 0°C, the reaction solution was quenched with saturated aqueous ammonium chloride solution (50 ml) and extracted with dichloromethane (1×50 mL). The combined organic phase was 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 give 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine (6.5 g, yield: 59.82%), LC-MS m / z: 251 [M+H] + ;

[0397] 6) Synthesis of 3-methyl-4-((1-methylpiperidin-4-yl)oxy)aniline:

[0398] A solution of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine (3.7 g, 14.7 mmol) and palladium on carbon (2.6 g, 10% content) in methanol (40 mL) was stirred overnight at 25°C under a hydrogen atmosphere. The resulting mixed reaction liquid was filtered, and the filter cake was washed with methanol (3 x 20 ml). The filtrate was collected and concentrated under reduced pressure to yield 3-methyl-4-((1-methylpiperidin-4-yl)oxy)aniline (3 g, yield: 92.1%). LC-MS m / z: 221 [M+H] + ;

[0399] 7) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaene-5-one:

[0400] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (500 mg, 1.24 mmol) and 3-methyl-4-((1-methylpiperidin-4-yl)oxy)aniline (328.3 mg, 1.49 mmol) in dioxane (50 mL) 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (490 mg, yield: 73.0%), LC-MS m / z: 542 [M+H] + ;

[0401] 8) Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer:

[0402] (Z)-12-Hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (490 mg, 0.91 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: instrument: SHIMADZU LC-20AP; column: The column was purified by chromatography on a 250*40mm 10μm column; mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% ammonia / methanol (7M); gradient: 60% to 60% B in 24min; flow rate: 80mL / min; column temperature: 20°C; detection wavelength: 254nm to obtain (R,E)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitre-bridged)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or its enantiomer (160mg, yield: 32.6%) (Compound IE). LC-MS m / z: 542[M+H] + ;

[0403] Confirmation of the absolute configuration of compound IE (single crystal cultivation):

[0404] About 5 mg of the metastable form H of compound IE was weighed and dissolved in 1.2 mL of isopropyl acetate and filtered into a 3 mL vial. The vial was then pierced and placed in a 20 mL vial containing 3 mL of n-pentane, and allowed to stand at 25 ° C for crystallization. Plate-like crystals were obtained by gas-liquid diffusion in the isopropyl acetate and n-pentane system, and the product was analyzed and characterized by a single crystal X-ray diffraction pattern (Figure 38). By crystal structure analysis, the single crystal belongs to the triclinic system, the space group is P1, and the unit cell parameters are: α=94.562(2)°,β=94.343(2)°,γ=94.807(2)°, and it was further confirmed that compound IE has one chiral atom, the absolute configuration is R, and the double bond in the ring is cis.

[0405] 1H NMR (400MHz, MeOD-d4): δ8.78(s,1H),7.94(t,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.58(d, J=8.0Hz,1H),7.55(s,1H),7.34(dd,J=8.0,4.0Hz,1H),6.87(d,J=12.0Hz,1H),5.53–5.41( m,2H),4.57(d,J=8.0Hz,2H),4.40(s,1H),2.73(s,2H),2.44(s,2H),2.34(s,3H),2.20(s,3 H),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).

[0406] Example 2. Synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one or its enantiomer (Compound 134):

[0407] The racemate (490 mg, 0.91 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: SHIMADZU LC-20AP; column: (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitre-bridged)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one or its enantiomer (150 mg, 30.6%) was prepared and purified using a 250*40mm 10μm column; mobile phase A: n-hexane; mobile phase B: ethanol (+0.1% 7.0M Ammonia in MeOH), A:B = 40:60; detection wavelength: 254nm; flow rate: 80mL / min; column temperature: RT; column pressure: 100bar. + ;

[0408] 1H NMR (400MHz, MeOD-d4): δ8.78 (d, J=2.8Hz, 1H), 7.94 (td, J=8.0, 2.0Hz, 1H), 7.80 (dd, J=8. 0,2.4Hz,1H),7.58(d,J=7.8Hz,2H),7.34(d,J=8.8Hz,1H),6.87(dd,J=8.8,2.8Hz,1H),5. 54–5.37(m,2H),4.57(d,J=6.2Hz,2H),4.40(s,1H),2.75(s,2H),2.46(s,2H),2.35(d,J=3 .2Hz,3H),2.20(s,3H),2.16(s,1H),2.00(d,J=9.8Hz,3H),1.98–1.77(m,4H),1.68(s,3H).

[0409] Example 3. Synthesis of (R)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (Compound 28):

[0410] A solution of (R,E)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-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]diazacyclopentadecahepten-5-one (50 mg, 0.092 mmol) and palladium on carbon (10 mg) in methanol (2 mL) was stirred at room temperature for 16 hours under a hydrogen atmosphere. The resulting mixed reaction solution 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 purification (acetonitrile: pure water containing 0.1% NH4HCO3 = 5-95% elution) to give (R)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (34 mg, yield: 67%), LC-MS m / z 544 [M+H] + ;

[0411] 1H NMR (400MHz, MeOD-d4): δ8.78(s,1H),8.00(t,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H),7.67(d,J= 8.0Hz,1H),7.66(s,1H),7.34(d,J=4.0Hz,1H),6.90(d,J=8.0Hz,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).

[0412] Example 4. Synthesis of (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (Compound 29):

[0413] A solution of (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (10.0 mg, 0.02 mmol), palladium hydroxide / carbon (5 mg), and Pd / C (5 mg) in methanol (1 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The slurry 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: pure water containing 0.1% NH4HCO3 = 5-95% elution) to give (S)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (8 mg, yield: 79.7%), LC-MS m / z: 544 [M+H] + ;

[0414] 1H NMR (400MHz, MeOD-d4): δ8.79 (s, 1H), 8.01 (t, J = 8.0Hz, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.68(d,J=8.0Hz,1H),7.66(s,1H),7.38(s,1H),6.92(d,J=8.0Hz,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).

[0415] Example 5. Synthesis of (Z)-2-((4-(((1,4-dimethylpiperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 89):

[0416] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (50 mg, 0.12 mmol) and 4-(((1,4-dimethylpiperidin-4-yl)oxy)-3-methylaniline (35 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was heated at 100° C. and stirred overnight. After cooling, the mixture was stirred overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to give (Z)-2-((4-(((1,4-dimethylpiperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (43 mg, yield: 62.2%), LC-MS m / z: 556 [M+H] + ;

[0417] 1H NMR(400MHz,MeOD)δ8.82(s,1H),7.95(t,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H), 7.64(s,1H),7.59(d,J=7.6Hz,1H),7.35(d,J=10.8Hz,1H),6.94(d,J=8.8Hz,1H ),5.52–5.39(m,2H),4.61(d,J=6.4Hz,2H),3.09(s,2H),2.67(s,3H),2.26(d, J=14.8Hz,6H),2.20–2.08(m,2H),2.04–1.83(m,5H),1.68(s,3H),1.27(s,3H).

[0418] Example 6. Synthesis of (Z)-12-hydroxy-2-((2-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 90):

[0419] (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]diazacyclotridecan-5-one (50 mg, 0.12 mmol) and 2-methoxy-4-((1-methylpiperidin-4-yl)oxy)aniline (35 mg, 0.15 mmol) were dissolved in 1,4-dioxane (5 mL) and heated at 100°C with stirring 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 give (Z)-12-hydroxy-2-((2-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (45 mg, yield: 64.8%), LC-MS m / z: 558 [M+H] + ;

[0420] 1H NMR (400MHz, MeOD): δ8.80(s,1H),7.94(t,J=8.0Hz,2H),7.74(d,J=8.0Hz,1H),7.59(d ,J=7.6Hz,1H),6.64(d,J=2.4Hz,1H),6.54(d,J=9.2Hz,1H),5.45(dd,J=17.2,9.2Hz,2 H),4.61(d,J=7.2Hz,2H),4.43(s,1H),3.86(s,3H),2.79-2.72(m,2H),2.48-2.43(m,2 H),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).

[0421] Example 7. Synthesis of 2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclic)pyrimido[4′,5′:3,4]pyrazolo[1,2-g][1]thio[2,7,8]triazacyclic tridecan-5-one 12,12-dioxide (Compound 130):

[0422] 1) Synthesis of N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridine-2-sulfonamide

[0423] To a solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (200 mg, 0.9 mmol) in 1,4-dioxane (2 mL) was added portionwise N,N'-dimethylethylenediamine (87 mg, 0.99 mmol), cuprous iodide (171 mg, 0.9 mmol), and potassium carbonate (311 mg, 2.25 mmol) at room temperature under nitrogen. The resulting mixed reaction solution was heated at 100°C and stirred overnight. The mixed reaction solution was diluted with water and 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 give N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridine-2-sulfonamide (100 mg, yield: 26.5%), LC-MS m / z: 419 [M+H] + ;

[0424] 2) Synthesis of 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(nitrogen heterocyclic)pyrimido[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclotridecan-5-one 12,12-dioxide

[0425] To a solution of N-allyl-6-(2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridine-2-sulfonamide (47 mg, 0.112 mmol) in dichloromethane (2 mL) was added dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromopyridinium)ruthenium(II) (10.3 mg, 0.012 mL) at room temperature under nitrogen. The resulting reaction mixture was heated at 80°C under argon 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 give 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclic tridecan-5-one 12,12-dioxide (40 mg, yield: 91.2%), LC-MS m / z: 391 [M+H] + ;

[0426] 3) Synthesis of 2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-g][1]thio[2,7,8]triazacyclic tridecan-5-one 12,12-dioxide

[0427] To a solution of 2-(methylthio)-10,11-dihydro-5H,7H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-g][1]thia[2,7,8]triazacyclic tridecan-5-one 12,12-dioxide (30 mg, 0.077 mmol) in dichloromethane (2 mL) was added portionwise 3-methyl-4-((1-methylpiperidin-4-yl)oxy)aniline (30 mg, 0.135 mmol) and m-chloroperbenzoic acid (26.5 mg, 0.154 mmol) at room temperature. The resulting mixed reaction solution was heated at 40°C and stirred for 8 hours. The mixed reaction solution was diluted with water and 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 (acetonitrile: containing 0.1% NH3 . The product was purified by elution with pure H2O (5-95% elution) to give 2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-10,11-dihydro-5H,7H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-g][1]thio[2,7,8]triazacyclic tridecan-5-one 12,12-dioxide (6 mg, yield: 13.9%), LC-MS m / z: 563 [M+H] + ;.

[0428] 1 H NMR(400MHz,MeOD)δ8.80(s,1H),8.16(d,J=6.4Hz,2H),7.90(d,J=8.3Hz,1H),7.46– 7.60(m,1H),7.38(s,1H),6.94(d,J=8.8Hz,1H),6.04–6.14(m,1H),5.07(s,3H),4.5 0–4.68(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).

[0429] Example 8. Synthesis of 12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (Compound 1A):

[0430] A solution of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-A][1,2]diazacyclopentadecahepten-5-one (50 mg, 0.092 mmol) and palladium on carbon (10 mg) in methanol (2 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixed reaction solution 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%) to give 12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,8,9,10,11,12-hexahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (30 mg, yield: 60%), LC-MS m / z: 544 [M+H] + ;

[0431] 1 H NMR (400MHz, MeOD-d4): δ8.78(s,1H),8.00(t,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H),7.67(d, J=8.0Hz,1H),7.62(s,1H),7.34(dd,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),4.43(s,1H),3.84 -3.80(m,1H),3.31(t,J=4.0Hz,1H),2.78(s,2H),2.50(s,2H),2.37(s,3H),2.32-2.31(m,2 H),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).

[0432] Example 9. Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 140):

[0433] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0434] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) in toluene (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m / z: 402 [M+H] + ;

[0435] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0436] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (100.0 mg, 0.25 mmol) and 4-((1-methylpiperidin-4-yl)oxy)aniline (76 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was heated at 100°C with stirring overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (20 mg, yield: 15.2%). LC-MS m / z: 528 [M+H] + ;

[0437] 1H NMR (400MHz, MeOD-d4): δ8.81(s,1H),7.95(t,J=8.0Hz,1H),7.79(d,J=12.0 Hz,1H),7.57(t,J=8.0Hz,3H),6.91(d,J=8.0Hz,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)

[0438] Example 10. Synthesis of (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (Compound 141):

[0439] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one

[0440] A solution 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]diazacyclopentadecapentaen-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) in toluene (2 mL) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 402 [M+H] + ;

[0441] 2) Synthesis of (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one

[0442] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (100.0 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidin-4-yl)oxy)aniline (88.3 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was heated at 100°C with stirring overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on a C18 column (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give (Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecapentaen-5-one (20 mg, yield: 14.4%), LC-MS m / z: 558 [M+H] + ;

[0443] 1 H NMR (400MHz, MeOD-d4): δ8.83(s,1H),7.93(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7 .61(d,J=8.0Hz,1H),7.49(d,J=4.0Hz,1H),7.15-7.10(m,1H),6.93(d,J=8.0Hz,1H) ,5.50-5.30(m,2H),4.64(d,J=8.0Hz,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)

[0444] Example 11. Synthesis of (R,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (Compound 143):

[0445] 1) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0446] The racemate (300 mg, 0.81 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column: 250*25mm 10μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MEOH) A:B = 75:25; calibration wavelength: 214nm; flow rate: 100mL / min; column temperature: RT; column pressure: 100bar; injection volume: 4.5mL) was separated and purified to obtain (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (130mg, yield: 43%).

[0447] 2) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0448] A toluene solution (2 mL) of (R,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]diazacyclopentadecahepten-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) was stirred at room temperature for 2 hours. The resulting mixed reaction solution 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] + ;

[0449] 3) Synthesis of (R, Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0450] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (100 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidin-4-yl)oxy)aniline (88 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was heated at 100°C with stirring overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: purification containing 0.1% formic acid = 5-95% elution) to give (R,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (20 mg, yield: 14.4%), LC-MS m / z: 558 [M+H] + ;

[0451] 1 H NMR (400MHz, MeOD-d4): δ8.83(s,1H),7.93(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7 .61(d,J=8.0Hz,1H),7.48(d,J=4.0Hz,1H),7.15-7.10(m,1H),6.93(d,J=8.0Hz,1H) ,5.45-5.30(m,2H),4.64(d,J=8.0Hz,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)

[0452] Example 12. Synthesis of (S,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (Compound 144):

[0453] 1) Synthesis of (S, Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0454] The racemate (300 mg, 0.81 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column: The product was separated and purified using a column chromatography-mass spectrometer (250*25mm 10μm; mobile phase A: Supercritical CO2, mobile phase B: MeOH (+0.1% 7.0mol / l Ammonia in MEOH) A:B = 75:25; calibration wavelength: 214nm; flow rate: 100mL / min; column temperature: RT; column pressure: 100bar; injection volume: 4.5mL) to obtain (S,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]diazacyclopentadecahepten-5-one (150mg, yield: 50%).

[0455] 2) Synthesis of (S, Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0456] A toluene solution (2 mL) of (S, 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]diazacyclopentadecahepten-5-one (100 mg, 0.27 mmol) and m-chloroperbenzoic acid (234 mg, 1.36 mmol) was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 402 [M+H] + ;

[0457] 3) Synthesis of (S, Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one

[0458] A solution of (S,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(aza)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (100 mg, 0.25 mmol) and 3-methoxy-4-((1-methylpiperidin-4-yl)oxy)aniline (88 mg, 0.37 mmol) in 1,4-dioxane (2 mL) was heated at 100°C with stirring overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: purification containing 0.1% formic acid = 5-95% elution) to give (S,Z)-12-hydroxy-2-((3-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclopentadecahepten-5-one (20 mg, yield: 14.4%), LC-MS m / z: 558 [M+H] + ;

[0459] 1H NMR (400MHz, MeOD-d4): δ8.83(s,1H),7.93(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7 .61(d,J=8.0Hz,1H),7.48(d,J=4.0Hz,1H),7.15-7.10(m,1H),6.93(d,J=8.0Hz,1H) ,5.44-5.30(m,2H),4.64(d,J=8.0Hz,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)

[0460] Example 13. Synthesis of 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidin-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]triazol-11-one (Compound 146):

[0461] 1) Synthesis of 2-bromo-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol

[0462] To a solution of 2-bromo-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1.0 g, 4.74 mmol) in tetrahydrofuran (10 mL) was added dropwise pent-4-en-1-ylmagnesium bromide (5 mL, 25.0 mmol, 0.5 M in tetrahydrofuran) at 0°C under argon. The resulting reaction mixture was stirred overnight at room temperature under argon. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) at 0°C and extracted with ethyl acetate (3 × 30 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 silica gel column chromatography (ethyl acetate:petroleum ether = 0-30% elution) to give 2-bromo-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (360 mg, yield: 27%), LC-MS m / z: 282 [M+H] + ;

[0463] 2) Synthesis of 2-allyl-1-(7-hydroxy-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

[0464] 2-allyl-6-(methylthiomethyl)-1,2,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (211 mg, 0.95 mmol), 2-bromo-7-(2-bromo-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-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 .85mmol) in toluene (8mL) under nitrogen protection, heated at 110 ° C and stirred for 8 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3·H2O = 5-95% elution) to give 2-allyl-1-(7-hydroxy-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (234 mg, yield: 58.1%), LC-MS m / z: 424 [M+H] + ;

[0465] 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]triazolo[1,2-a][1,2,4]triazolo[11-one]

[0466] A solution of 2-allyl-1-(7-hydroxy-7-(pent-4-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (234 mg, 0.55 mmol) and Grubbs III (98 mg, 0.11 mmol) in dichloromethane (100 mL) was heated at 40°C with stirring overnight under argon. 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 give 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]triazolododeca-11-one (23 mg, yield: 10.5%), LC-MS m / z: 396 [M+H] + ;

[0467] 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]triazolidine-11-one

[0468] A mixture 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]triazacyclododecain-11-one (50 mg, 0.13 mmol) and Oxone (87.6 mg, 0.25 mmol) in tetrahydrofuran and water (2 mL, v:v = 1:1) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 428 [M+H] + ;

[0469] 5) Synthesis of 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidin-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]triazolidine-11-one

[0470] A solution 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]triazacyclododecan-11-one (45 mg, 0.11 mmol) and 3-methyl-4-((1-methylpiperidin-4-yl)oxy)aniline (75 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was heated at 50°C with stirring for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:purified water containing 0.1% formic acid = 5-95% elution) to give 3a-hydroxy-14-((3-methyl-4-((1-methylpiperidin-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]triazolo[1,2-a][1,2,4]triazolo[11-one] (27 mg, yield: 45.2%), LC-MS m / z: 568 [M+H] + ;

[0471] 1H NMR(400MHz,MeOD-d4)δ8.77(s,1H),7.93(d,J=8.1Hz,1H),7.72(d,J=8.0Hz,1H),7.56(s,1H),7.40–7.32(m,1H) ,6.89(dd,J=16.3,8.9Hz,1H),5.93–5.79(m,1H),5.53(t,J=9.5Hz,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=12.4Hz,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=13.4Hz,4H),1.67–1.55(m,2H).

[0472] Example 14, (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers (Compounds 171A and B)

[0473] 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate

[0474] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2000 mg, 9.95 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (796 mg, 19.9 mmol, content: 60%) and stirred at room temperature for 1 hour. 1-Fluoro-2-methyl-4-nitrobenzene (1850.7 mg, 11.94 mmol) was then added portionwise at room temperature. The resulting mixed reaction solution was stirred at 50°C overnight. After cooling, the mixed reaction solution was quenched with methanol (50 mL) and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate (1100 mg, yield: 32.9%), LC-MS m / z: 337 [M+H] + ;

[0475] 2) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine

[0476] To a solution of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate (1100 mg, 3.27 mmol) in dichloromethane (3 mL) was added dropwise 2,2,2-trifluoroacetic acid (1 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 1 hour. 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) = 5-95% elution) to give 4-(2-methyl-4-nitrophenoxy)piperidine (659 mg, yield: 85.3%), LC-MS m / z: 237 [M+H]+ ;

[0477] 3) Synthesis of 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine

[0478] To a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (659 mg, 2.79 mmol) in tetrahydrofuran (10 mL) at 0°C, sodium hydride (223.2 mg, 5.58 mmol, content: 60%) was added portionwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. Iodomethane-d3 (485 mg, 3.35 mmol) was added portionwise to the mixed reaction solution at room temperature. The resulting mixed reaction solution was heated at 50°C and stirred overnight. After cooling, the mixture was quenched with methanol (20 mL) at 0°C and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine (301 mg, yield: 42.6%), LC-MS m / z: 254 [M+H] + ;

[0479] 4) Synthesis of 3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)aniline

[0480] A solution of 1-(methyl-d3)-4-(2-methyl-4-nitrophenoxy)piperidine (301 mg, 1.19 mmol) and Fe (333 mg, 5.95 mmol) in saturated aqueous ammonium chloride (1 mL) and ethanol (4 mL) was heated to 70°C and stirred overnight. After cooling, the mixed reaction solution 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] + ;

[0481] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0482] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (510 mg, 1.38 mmol) and 3-chloroperoxybenzoic acid (500 mg, 2.46 mmol) in toluene (50 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution 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] + ;

[0483] 6) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge))pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0484] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (400 mg, 0.99 mmol) and 3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)aniline (266 mg, 1.19 mol) in 1,4-dioxane (20 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge))pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (201 mg, yield: 37.3%), LC-MS m / z: 545 [M+H] + ;

[0485] 7), (R, Z) -12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino) -7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge) pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers and the synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomers

[0486] (Z)-12-Hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge))pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (201 mg, 0.37 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: Waters SFC 150; column model: The product was purified using a 250*25 mm 10 m column; 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 mL / min; column temperature: room temperature; column pressure: 100 bar) to obtain two isomers: Compound 171A and Compound 171B.

[0487] Compound 171A: Peak 1 (elution time: 2.389 min): (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (80 mg, yield: 40%), LC-MS m / z: 545 [M+H] + ;

[0488] 1H NMR (400MHz, MeOD): δ8.79(s,1H),,7.95(t,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.59(d,J=7.7Hz,2H),7.35(dd,J=9.0,2.4Hz,1H),6.88(d,J=8.8Hz ,1H),5.48(dd,J=13.4,6.7Hz,2H),4.59(d,J=6.8Hz,2H),4.43(s,1H),2.8 2(s,2H),2.55(s,2H),2.22(s,3H),2.03(s,4H),1.89(s,4H),1.68(s,3H).

[0489] Compound 171B: Peak 2 (elution time: 3.537 min): (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(methyl-d3)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (80 mg, yield: 40%), LC-MS m / z: 545 [M+H] + ;

[0490] 1 H NMR (400MHz, MeOD): δ8.79(s,1H),7.95(t,J=7.9Hz,1H),7.81(d,J=8.1Hz,1H) ,7.58(d,J=7.7Hz,2H),7.35(dd,J=8.7,2.5Hz,1H),6.88(d,J=8.8Hz,1H),5.6 1–5.38(m,2H),4.58(d,J=6.9Hz,2H),4.43(s,1H),2.81(s,2H),2.53(s,2H),2 .21(s,3H),2.06(dd,J=33.8,24.0Hz,4H),1.93(d,J=29.8Hz,4H),1.68(s,3H).

[0491] Example 15, (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers (Compounds 172A and B)

[0492] 1) Synthesis of 1-methylpiperidin-4-butan-4-ol

[0493] To a solution of 1-methylpiperidin-4-one (1.0 g, 8.85 mmol) in tetrahydrofuran (20 mL) at 0°C, NaBD4 (557.5 mg, 13.3 mmol) was added portionwise. The resulting mixed reaction solution was stirred at room temperature overnight. The resulting mixed reaction solution 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] + ;

[0494] 2) Synthesis of 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine-4-d

[0495] To a solution of 1-methylpiperidin-4-butan-4-ol (1 g, 8.62 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (690 mg, 17.24 mmol, content: 60%) in portions at 0°C, and stirred at 0°C for 1 hour. 1-Fluoro-2-methyl-4-nitrobenzene (1.6 g, 10.3 mmol) was added in portions to the mixed reaction solution at 0°C. The resulting mixed reaction solution was heated to 50°C and stirred overnight. 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 give 1-methyl-4-(2-methyl-4-nitrophenoxy)piperidine-4-d (600 mg, yield: 27.7%), LC-MS m / z: 252 [M+H] + ;

[0496] 3) Synthesis of 3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)aniline

[0497] 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) in aqueous ammonium chloride (1 mL) and ethanol (4 mL) was heated at 70°C with stirring 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: 222 [M+H] + ;

[0498] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0499] (Z)-12-Hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (400 mg, 0.99 mmol) and 3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)aniline (266 mg, 1.19 mol) were heated at 100°C with stirring 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (201 mg, yield: 37.3%), LC-MS m / z: 543 [M+H] + ;

[0500] 5), (R, Z) -12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino) -7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge) pyrimido [4', 5': 3,4] pyrazolo [1,2-a] [1,2] diazacyclotridecan-5-one or enantiomers and the synthesis of (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomers

[0501] (Z)-12-Hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (201 mg, 0.37 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: Waters SFC 150; column model: Column size: 250*25mm 10m; mobile phase A: Supercritical CO2; mobile phase B: ETOH (+0.1% 7.0 mol / l Ammonia in MEOH); A:B = 60:40; detection wavelength: 214nm; flow rate: 100mL / min; column temperature: RT; column pressure: 100bar) was purified to obtain two isomers: Compound 172A and Compound 172B:

[0502] Compound 172A: Peak 1 (elution time: 2.338 min): (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (80 mg, yield: 40%), LC-MS m / z: 543 [M+H] + ;

[0503] 1H NMR (400MHz, MeOD): δ8.80(s,1H),7.94(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,2H),7.35(dd,J=8.6,2.6Hz,1H),6.88(d,J=8 .7Hz,1H),5.52–5.43(m,2H),4.59(d,J=6.4Hz,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).

[0504] Compound 172B: Peak 2 (elution time: 3.527 min): (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl-4-d)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (80 mg, yield: 40%), LC-MS m / z: 543 [M+H] + ;

[0505] 1 H NMR (400MHz, MeOD): δ8.80(s,1H),7.94(d,J=7.9Hz,1H),7.82(d,J=8.0Hz,1H),7.59(d,J=7.7Hz,2H),7.35(dd,J=8.6,2.6Hz,1H),6.88(d,J=8 .7Hz,1H),5.52–5.43(m,2H),4.59(d,J=6.7Hz,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).

[0506] Example 16, (R, Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer and (S, Synthesis of Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers (Compounds 173A and B)

[0507] 1) Synthesis of 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine

[0508] To a solution of 1-methylpiperidin-4-ol (3.03 g, 26.30 mmol) in tetrahydrofuran (50 mL) at 0°C, potassium tert-butoxide (5.37 g, 47.82 mmol) was added. 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) was added to the mixed reaction solution at 0°C. The resulting mixed reaction solution was stirred at room temperature for 8 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-55% elution) to give 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine (5.2 g, yield: 71.5%), LC-MS m / z: 305 [M+H] + ;

[0509] 2) Synthesis of 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

[0510] 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 at 80°C and stirred for 6 hours. After cooling, the mixed reaction solution 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] + ;

[0511] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0512] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (217 mg, 0.54 mmol) and 4-(((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (178.2 mg, 0.65 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. and stirred overnight. After cooling, the filtrate was collected. The residue was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (96 mg, yield: 29.8%), LC-MS m / z: 596 [M+H] + ;

[0513] 4), (R, Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer and the synthesis of (S,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomers

[0514] A solution of (Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (96 mg, 0.16 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: SHIMADZU LC-20AP; column model: Column size: 250*25mm 10m; mobile phase A: n-Hexane; mobile phase B: EtOH (+0.1% 7.0 mol / l Ammonia in EtOH), A:B = 50:50; detection wavelength: 214nm; flow rate: 40mL / min; column temp: RT) to obtain two isomers: Compound 173A and Compound 173B:

[0515] Compound 173A: Peak 1 (elution time: 17.883 min): (R,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (40 mg, yield: 41.6%), LC-MS m / z 596 [M+H] + ;

[0516] 1 H NMR (400MHz, MeOD): δ8.87(s,1H),8.21(s,1H),7.95(t,J=8.0Hz,1H),7.78(d, J=8.0Hz,1H),7.68(s,1H),7.63(d,J=8.0Hz,1H),7.19(d,J=8.0Hz,1H),5.51- 5.47(m,2H),4.70-4.67(m,1H),4.63(d,J=6.4Hz,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).

[0517] Compound 173B: Peak 2 (elution time after Peak 1): (S,Z)-12-hydroxy-12-methyl-2-((4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (40 mg, yield: 41.6%), LC-MS m / z 596 [M+H] + ;

[0518] 1 H NMR (400MHz, MeOD): δ8.87(s,1H),8.21(s,1H),7.95(t,J=7.9Hz,1H),7.78(d,J =7.8Hz,1H),7.68(s,1H),7.63(d,J=7.6Hz,1H),7.20(d,J=8.9Hz,1H),5.49(dd ,J=12.4,6.3Hz,2H),4.69(s,1H),4.64(d,J=7.0Hz,2H),2.84(s,2H),2.69(s,2 H),2.46(s,3H),2.18(s,2H),2.05(s,3H),1.97(d,J=18.4Hz,3H),1.71(s,3H).

[0519] Example 17. Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (Compound 174)

[0520] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0521] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (510 mg, 1.38 mmol) and 3-chloroperbenzoic acid (500 mg 2.46 mmol) in toluene (50 mL) was 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] + ;

[0522] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0523] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (500 mg, 1.24 mmol) and 3-methyl-4-((4-methylpiperazin-1-yl)methyl)aniline (328.3 mg, 1.49 mmol) in 1,4-dioxane (50 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (490 mg, yield: 73.0%), LC-MS m / z: 541 [M+H] + ;

[0524] 1H NMR(400MHz,MeOD-d4)δ8.84(s,1H),7.98(t,J=8.0Hz,1H),7.85(d,J=8.0H z,1H),7.68–7.58(m,2H),7.41(d,J=6.8Hz,1H),7.17(d,J=8.4Hz,1H),5.48 (d,J=6.4Hz,2H),4.62(d,J=6.4Hz,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).

[0525] Example 18. Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopentadienyl[c]pyrrol-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 175)

[0526] 1) Synthesis of tert-butyl 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0527] A solution of tert-butyl 5-hydroxyhexahydrocyclopentane[c]pyrrole-2(1H)-carboxylate (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. 1-Fluoro-2-methyl-4-nitrobenzene (409 mg, 2.64 mmol) was then added to the reaction mixture, heated at 50°C and stirred for 2 hours. After cooling, the reaction mixture was quenched by adding methanol (4 mL) at 0°C. 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 give tert-butyl 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylate (450 mg, yield: 70.56%), LC-MS m / z: 363 [M+H] + ;

[0528] 2) Synthesis of 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole

[0529] To a solution of tert-butyl 5-(2-methyl-4-nitrophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (450 mg, 1.24 mmol) in dichloromethane (1.5 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.5 mL) at room temperature. 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 reverse phase column chromatography (MeCN:H2O (0.1% FA) = 5%-95% elution) to give 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (300 mg, yield: 92.13%). LC-MS m / z: 263 [M+H] + ;

[0530] 3) Synthesis of 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole

[0531] A solution of 5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (300 mg, 1.14 mmol), paraformaldehyde (73 mg, 2.29 mmol), and sodium cyanoborohydride (144 mg, 2.29 mmol) in acetic acid (0.3 mL) and dichloromethane (3 mL) was stirred at room temperature for 0.5 hours. The mixed reaction solution was quenched by adding water (3 mL) at room temperature and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN:H2O (0.1% FA) = 5-95% elution) to give 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (200 mg, yield: 63.13%), LC-MS m / z: 277 [M+H]. + ;

[0532] 4) Synthesis of methyl-4-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)aniline

[0533] A solution of 2-methyl-5-(2-methyl-4-nitrophenoxy)octahydrocyclopenta[c]pyrrole (200 mg, 0.72 mmol) and Pd / C (200 mg) in methanol (5.0 mL) was stirred at room temperature under hydrogen protection for 4 hours. The mixed reaction solution 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 reverse-phase column chromatography (MeCN:H2O (0.1% NH3.H2O) = 5-95% elution) to provide 3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)aniline (100 mg, yield: 56.18%), LC-MS m / z: 247 [M+H]. + ;

[0534] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0535] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (108 mg, 0.27 mmol) and 3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)aniline (100 mg, 0.40 mmol) in 1,4-dioxane (2.0 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyloctahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (60 mg, yield: 39.14%). LC-MS m / z: 568 [M+H] + ;

[0536] 1 H NMR (400MHz, MeOD-d4): δ8.80 (s, 1H), 7.98-7.92 (m, 1H), 7.82 (d, J = 8.0Hz ,1H),7.62-7.53(m,2H),7.42-7.38(m,1H),6.90(d,J=8.0Hz,1H),5.53-5. 39(m,2H),4.60(d,J=8.0Hz,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).

[0537] Example 19, (S, Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer and (R, Synthesis of Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomers (Compounds 176A and B)

[0538] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0539] To a solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.54 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (141 mg, 0.81 mmol) in portions at 0°C. The resulting mixed reaction solution was stirred at 0°C for 1 hour. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 386 [M+H] + ;

[0540] 2) Synthesis report of (Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0541] (Z)-12-Hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-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 heated at 50°C with stirring 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 give (Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (200 mg, yield: 78.7%), LC-MS m / z: 490 [M+H] + ;

[0542] 3) Synthesis of (S, Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomer and (R, Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomer

[0543] (Z)-12-Hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (200 mg, 0.41 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: Waters SFC 150, column: The product was purified using a 250*30mm 10m column; 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 mL / min; column temperature: RT; column pressure: 100 bar) to obtain two isomers: Compound 176A and Compound 176B:

[0544] Compound 176A: Peak 1 (elution time: 2.796 min): (S,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (52.92 mg, yield: 29.5%), LC-MS m / z: 490 [M+H] + ;

[0545] 1 H NMR (400MHz, MeOD-d4): δ8.74(s,1H),7.94(t,J=7.6Hz,1H),7.73(d,J=8.4Hz,1H),7.55(d,J=7.6Hz,1H),5.53-5.40(m,2H),4.5 3(d,J=6.8Hz,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).

[0546] Compound 176B: Peak 2 (elution time: 6.63 min): (R,Z)-12-hydroxy-12-methyl-2-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (28.94 mg, yield: 14.4%), LC-MS m / z: 490 [M+H] + ;

[0547] 1H NMR (400MHz, MeOD-d4): δ8.74(s,1H),7.94(t,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.55(d,J=7.6Hz,1H),5.53-5.40(m,2H),4.53(d,J=6 .8Hz,2H),3.91(s,4H),2.51(s,4H),2.32(d,J=10.0Hz,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).

[0548] Example 20. Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers and (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers (Compounds 177A and B)

[0549] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0550] A solution of (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]diazacyclotridecan-5-one (200 mg, 0.52 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (142.8 mg, 0.78 mmol), and ethanol (187.2 mg, 3.12 mmol) in 1,2-dichloroethane (2 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (210 mg, yield: 80.2%), LC-MS m / z: 505 [M+H] + ;

[0551] 2) Synthesis of (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer and (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer

[0552] (Z)-12-Hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (210 mg, 0.42 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: Waters SFC 150; column: The column was purified using a 250*30mm 10m column; mobile phase A: Supercritical CO2; mobile phase B: MeOH (+0.1% 7.0 mol / l Ammonia in MeOH) with an A:B ratio of 50:50; detection wavelength: 214 nm; flow rate: 140 mL / min; column temperature: RT; column pressure: 100 bar) to obtain two isomers: Compound 177A and Compound 177B.

[0553] Compound 177A: Peak 1 (elution time: 1.556 min): (S,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (41.63 mg, 19.8%), LC-MS m / z: 505 [M+H] + ;

[0554] 1 H NMR (400MHz, MeOD-d4): δ8.75(s,1H),7.94(t,J=8.0Hz,1H),7.73(d,J=8.0H z,1H),7.55(d,J=8.0Hz,1H),5.54-5.39(m,2H),4.94(s,2H),4.54(d,J=6.8 Hz,2H),2.99(t,J=12.4Hz,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).

[0555] Compound 177B: Peak 2 (elution time: 5.082 min): (R,Z)-12-hydroxy-12-methyl-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (66.71 mg, yield: 31.7%), LC-MS m / z: 505 [M+H] + ;

[0556] 1H NMR (400MHz, MeOD-d4): δ8.76(s,1H),7.94(t,J=8.0Hz,1H),7.73(d,J=8.0H z,1H),7.55(d,J=7.6Hz,1H),5.54-5.39(m,2H),4.94(s,2H),4.54(d,J=6.4 Hz,2H),2.99(t,J=12.0Hz,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).

[0557] Example 21. Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-morpholinylphenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 178)

[0558] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0559] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.54 mmol) and 3-chloroperoxybenzoic acid (186 mg 1.08 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution 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] + ;

[0560] 2) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-morpholinylphenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0561] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.54 mmol) and 4-morpholinoaniline (115 mg, 0.65 mmol) in 1,4-dioxane (5 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((4-morpholinylphenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (102 mg, yield: 39.4%), LC-MS m / z: 500 [M+H] + ;

[0562] 1 H NMR (400MHz, CDCl3): δ8.85(s,1H),7.89-7.80(m,2H),7.50(d,J=8.0Hz,2H),7.27-7.74(m,2H),6.91(d,J=8.0Hz,2H),5.7 5-5.71(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).

[0563] Example 22. Synthesis of (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphanin-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 180)

[0564] 1) Synthesis of 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azophosphane-4-oxide

[0565] A solution of 1,2-difluoro-4-nitrobenzene (150 mg, 0.94 mmol), potassium carbonate (394 mg, 2.82 mmol) and 4-ethoxy-1,4-azaphosphine-4-oxide (199 mg, 1.2 mmol) in acetonitrile (3 mL) was heated at 70°C and stirred for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to give 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azaphosphine-4-oxide (147 mg, yield: 52%), LC-MS m / z: 303 [M+H] + ;

[0566] 2) Synthesis of 1-(4-amino-2-fluorophenyl)-4-ethoxy-1,4-azophosphane-4-oxide

[0567] A solution of 4-ethoxy-1-(2-fluoro-4-nitrophenyl)-1,4-azinophosphoran-4-oxide (127 mg, 0.42 mmol) and Pd / C (60 mg) in methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 3 hours. The mixed reaction solution 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-azinophosphoran-4-oxide (90 mg, yield: 78%). LC-MS m / z: 273 [M+H] + ;

[0568] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azophosphorin-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0569] (Z)-12-Hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (80 mg, 0.20 mmol), 1-(4-amino-2-fluorophenyl)-4-ethoxy-1,4-azaphosphanin-4-oxide (81 mg, 0.30 mmol), and acetic acid (72 mg, 1.2 mmol) were heated at 50°C with stirring for 16 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% FA) = 30-70% elution) to give (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphanin-1-yl)-3-fluorophenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (25 mg, yield: 21%), LC-MS m / z: 594 [M+H] + ;

[0570] 1 H NMR(400MHz,MeOD-d4)δ8.82(s,1H),7.97(t,J=7.9Hz,1H),7.81–7.71(m,2H),7.61( d,J=7.6Hz,1H),7.25(dd,J=8.6,1.7Hz,1H),7.03(t,J=9.2Hz,1H),5.51–5.37(m,2H ),4.61(d,J=6.8Hz,2H),4.15(p,J=7.1Hz,2H),3.60–3.46(m,2H),3.30–3.23(m,2H) ,2.11(dd,J=22.3,9.7Hz,6H),2.04–1.86(m,2H),1.69(s,3H),1.39(t,J=7.0Hz,3H).

[0571] Example 23. Synthesis of (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azophosphorin-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (Compound 181)

[0572] 1) Synthesis of 4-ethoxy-1-(4-nitrophenyl)-1,4-azophosphane-4-oxide

[0573] A solution of 1-bromo-4-nitrobenzene (300 mg, 1.49 mmol), 4-ethoxy-1,4-aziridine-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-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (125 mg, 0.15 mmol), and cesium carbonate (1450 mg, 4.47 mmol) in 1,4-dioxane (5 mL) was heated at 100°C with stirring overnight under a nitrogen atmosphere. 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 give 4-ethoxy-1-(4-nitrophenyl)-1,4-azinophosphorane-4-oxide (409 mg, yield: 96%), LC-MS m / z: 285 [M+H] + ;

[0574] 2) Synthesis of 1-(4-aminophenyl)-1,4-azophosphane-4-oxide

[0575] A solution of 4-ethoxy-1-(4-nitrophenyl)-1,4-azinophosphoran-4-oxide (300 mg, 1.05 mmol) and Pd / C (150 mg) in methanol (6 mL) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 3 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). The filtrate was collected and concentrated under reduced pressure to give 1-(4-aminophenyl)-1,4-azinophosphoran-4-oxide (247 mg, yield: 92%). LC-MS m / z: 255 [M+H] + ;

[0576] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azophosphorin-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0577] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol), 1-(4-aminophenyl)-4-ethoxy-1,4-azaphosphanin-4-oxide (95 mg, 0.38 mmol), and acetic acid (90 mg, 1.50 mmol) in 1,2-dichloroethane (3 mL) was heated at 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 give (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)phenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (35 mg, yield: 24%), LC-MS m / z: 576 [M+H] + ;

[0578] 1 H NMR(400MHz,MeOD-d4)δ8.78(s,1H),7.94(t,J=7.9Hz,1H),7.78(d,J=8.0Hz, 1H),7.55(dd,J=10.9,8.4Hz,3H),6.95(d,J=9.1Hz,2H),5.52–5.38(m,2H),4. 58(d,J=6.8Hz,2H),4.14(dq,J=14.2,7.1Hz,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=7.0Hz,3H).

[0579] Example 24 (R, Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one and (S, Z) Synthesis of )-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compounds 182A and B):

[0580] 1) Synthesis of 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azophosphane-4-oxide

[0581] A solution of 1-bromo-2-methyl-4-nitrobenzene (300 mg, 1.39 mmol), 4-ethoxy-1,4-aziridine 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-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (117 mg, 0.14 mmol), and cesium carbonate (1350 mg, 4.17 mmol) in 1,4-dioxane (5 mL) was heated at 100°C with stirring overnight under a nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-20% elution) to give 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azaphosphine-4-oxide (400 mg, yield: 96%), LC-MS m / z: 299 [M+H] + ;

[0582] 2) Synthesis of 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azophosphane-4-oxide

[0583] A solution of 4-ethoxy-1-(2-methyl-4-nitrophenyl)-1,4-azinophosphoran-4-oxide (400 mg, 1.33 mol) and Pd / C (200 mg) in methanol (6 mL) was stirred at room temperature for 3 hours under hydrogen protection. The mixed reaction liquid was filtered, the filter cake was washed with methanol (3×20 mL), and the filtrate was collected and concentrated under reduced pressure to give 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azinophosphoran-4-oxide (334 mg, yield: 92%). LC-MS m / z: 269 [M+H] + ;

[0584] 3) Synthesis of (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azophosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0585] A solution of (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]diazacyclotridecen-5-one (100 mg, 0.25 mmol), 1-(4-amino-2-methylphenyl)-4-ethoxy-1,4-azaphosphine-4-oxide (100 mg, 0.37 mmol), and acetic acid (90 mg, 1.50 mmol) in 1,2-dichloroethane (3 mL) was heated at 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 give (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (35 mg, yield: 24%), LC-MS m / z: 590 [M+H] + ;

[0586] 1H NMR (400MHz, MeOD-d4) δ8.79(s,1H),7.97(t,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.61(t,J= 8.9Hz,2H),7.38(dd,J=8.6,2.4Hz,1H),7.02(d,J=8.6Hz,1H),5.53–5.41(m,2H),4.58(d,J= 6.8Hz,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=16.8,8.5Hz,1H),1.93–1.86(m,1H),1.68(s,3H),1.40(t,J=7.0Hz,3H).

[0587] 4), (R, Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphanin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer and the synthesis of (S,Z)-2-((4-(4-ethoxy-4-oxido-1,4-azophosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomers

[0588] (Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (20 mg, 0.03 mmol) was purified by chiral preparative high performance liquid chromatography (chromatographic conditions: system: Waters SFC 80; column: (250*30mm10m; mobile phase A: Supercritical CO2; mobile phase B: EtOH (+0.1% 7.0mol / l Ammonia in MeOH); gradient: A:B = 50:50; detection wavelength: 214nm; flow rate: 70mL / min; column temperature: room temperature; column pressure: 100bar) to obtain two isomers: Compound 182A and Compound 182B:

[0589] Compound 182A: Peak 1 (elution time: 3.817 min): (R, Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (3 mg, yield: 15%).

[0590] 1 H NMR (400MHz, MeOD) δ8.81(s,1H),7.98(t,J=7.8Hz,1H),7.83(d,J=8.1Hz,1H),7.61(t ,J=10.3Hz,2H),7.40(d,J=6.0Hz,1H),7.03(d,J=8.6Hz,1H),5.48(dd,J=13.5,6.8Hz, 2H),4.60(d,J=6.6Hz,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=7.0Hz,3H).

[0591] Compound 182B: Peak 2 (elution time: 5.219 min): (S, Z)-2-((4-(4-ethoxy-4-oxido-1,4-azaphosphorin-1-yl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (2.5 mg, yield: 12.5%).

[0592] 1H NMR (400MHz, MeOD) δ8.81(s,1H),7.98(t,J=7.9Hz,1H),7.83(d,J=8.1Hz,1H),7.61(t,J=10 .3Hz,2H),7.40(d,J=8.6Hz,1H),7.03(d,J=8.6Hz,1H),5.53–5.40(m,2H),4.60(d,J=6.8Hz ,2H),4.16(dd,J=14.5,7.3Hz,2H),3.23(s,2H),3.16(dd,J=13.1,4.8Hz,2H),2.32(s,3H), 2.20–2.06(m,6H),2.01(d,J=13.1Hz,1H),1.90(s,1H),1.68(s,3H),1.40(t,J=7.0Hz,3H).(

[0593] Example 25. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (Compound 183)

[0594] 1) Synthesis of (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine

[0595] To a solution of (R)-1-methylpyrrolidin-3-ol (0.98 g, 9.68 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.775 g, 19.35 mmol, 60% content) at 0°C and stirred at 0°C for 1 hour. 1-Fluoro-2-methyl-4-nitrobenzene (1 g, 6.45 mmol) was then added to the mixture. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (50 mL) at 0°C and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (1 x 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 give (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (240 mg, yield: 15.8%), LC-MS m / z: 237 [M+H] + ;

[0596] 2) Synthesis of (R)-3-methyl-4-((1-methylpyrrolidin-3-yl)oxy)aniline

[0597] To a solution of (R)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (230 mg, 0.97 mmol) and iron (273 mg, 4.87 mmol) in ethanol (2 mL) was added saturated aqueous ammonium chloride (0.5 mL) at room temperature. The resulting reaction mixture was heated at 70°C and stirred for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (1 x 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) = 0%-10% elution) to give (R)-3-methyl-4-((1-methylpyrrolidin-3-yl)oxy)aniline (140 mg, yield: 69.7%), LC-MS m / z: 207 [M+H] + ;

[0598] 3) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomers

[0599] To a solution of (R)-3-methyl-4-((1-methylpyrrolidin-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)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (280 mg, 0.70 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (225 mg, 1.75 mmol). The resulting mixed reaction solution was heated at 90°C and stirred for 6 hours. The resulting mixed reaction solution was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (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 give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((R)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (70 mg, yield: 22.8%), LC-MS m / z: 528 [M+H] + ;

[0600] 1 H NMR(400MHz,MeOD-d4):8.78(s,1H),7.94(t,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.58 (d,J=8.0Hz,2H),7.33(d,J=8.0Hz,1H),6.75(d,J=8.0Hz,1H),5.53-5.44(m,2H),4.88 (s,1H),4.58(d,J=4.0Hz,2H),2.94-2.90(m,1H),2.85(t,J=8.0Hz,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).

[0601] Example 26. Synthesis of (R,Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomer (Compound 184)

[0602] 1) Synthesis of 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide

[0603] A solution of 4-nitroaniline (0.3 g, 2.17 mmol), N,N'-carbonylbis(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 protection. 1-Methylpiperazine (0.326 g, 3.26 mmol) was then added to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was 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=8-10% elution) to give 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide (500 mg, yield: 87%), LC-MS m / z: 265 [M+H] + ;

[0604] 2) Synthesis of N-(4-aminophenyl)-4-methylpiperazine-1-carboxamide

[0605] A solution of 4-methyl-N-(4-nitrophenyl)piperazine-1-carboxamide (300 mg, 1.15 mmol) and Pd / C (181 mg, 1.70 mmol) in methanol (3 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixed reaction solution was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to give N-(4-aminophenyl)-4-methylpiperazine-1-carboxamide (200 mg, yield: 75.2%). LC-MS m / z: 235 [M+H] + ;

[0606] 3), (R, Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomers

[0607] To a solution of 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)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (378 mg, 0.94 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (720 mg, 2.56 mmol). The resulting mixture was heated at 90°C and stirred for 6 hours. The mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (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 give (R,Z)-N-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)phenyl)-4-methylpiperazine-1-carboxamide or enantiomer (150 mg, yield: 31.6%), LC-MS m / z: 556 [M+H] + ;

[0608] 1 H NMR (400MHz, MeOD-d4): 8.82 (s, 1H), 7.96 (t, J = 8.0Hz, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.60 (t, J = 8.0Hz, 3H), 7.31 (d, J = 8.0Hz, 2H), 5.48-5. 44(m,2H),4.605(d,J=4.0Hz,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).

[0609] 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-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer (Compound 185):

[0610] 1) Synthesis of (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone

[0611] 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 mixed reaction solution was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 mL) and purified by C18 reverse phase column chromatography (ACN:H2O=2-5% elution) to give (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone (4 g, yield: 80.4%), LC-MS m / z: 250 [M+H] + ;

[0612] 2) Synthesis of (4-aminophenyl)(4-methylpiperazin-1-yl)methanone

[0613] A solution of (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone (4 g, 16.05 mmol) and iron (4.48 g, 80.25 mmol) in ethanol (32 mL) and aqueous ammonium chloride (8 mL) was heated at 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 give (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (1.2 g, yield: 34.1%). LC-MS m / z: 220 [M+H] + ;

[0614] 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-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomers

[0615] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-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 at 100°C and stirred for 16 hours. After cooling, the resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and purified by C18 reverse phase column chromatography (acetonitrile:purified water = 35-50% elution) to give (R,Z)-12-hydroxy-12-methyl-2-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (60 mg, yield: 44.6%), LC-MS: m / z: 541 [M+H] + ;

[0616] 1 H NMR (400MHz, MeOD-d4) δ8.89(s,1H),7.99(t,J=7.9Hz,1H),7.82(dd,J=13.6,8.3Hz,3H),7.62(d,J=7.6Hz,1H),7.40(d,J=8.6Hz,2H),5 .44(dd,J=14.2,7.1Hz,2H),4.64(d,J=6.7Hz,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).

[0617] Example 28. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or an isomer (Compound 186)

[0618] 1) Synthesis of (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine

[0619] (S)-1-Methylpyrrolidin-3-ol (0.98 g, 9.68 mmol) was added to a solution of sodium hydride (0.465 g, 19.35 mmol, 60% content) in tetrahydrofuran (10 mL) and stirred at 0°C for 1 hour. 1-Fluoro-2-methyl-4-nitrobenzene (1 g, 6.45 mmol) was then added to the mixed reaction solution and stirred at room temperature overnight. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (50 mL) at 0°C 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 (methanol:dichloromethane = 3-8% elution) to give (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (740 mg, yield: 47.1%), LC-MS m / z: 237 [M+H] + ;

[0620] 2) Synthesis of (S)-3-methyl-4-((1-methylpyrrolidin-3-yl)oxy)aniline

[0621] A solution of (S)-1-methyl-3-(2-methyl-4-nitrophenoxy)pyrrolidine (730 mg, 3.09 mmol) and iron (866 mg, 15.47 mmol) in ethanol (6 mL) and saturated aqueous ammonium chloride (1.5 mL) 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 x 50 mL). The combined organic phases were washed with saturated brine (1 x 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) = 0% to 10% elution) to afford (S)-3-methyl-4-((1-methylpyrrolidin-3-yl)oxy)aniline (400 mg, yield: 62.5%). LC-MS m / z: 207 [M+H] + ;

[0622] 3) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or isomers

[0623] To a solution of (S)-3-methyl-4-((1-methylpyrrolidin-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)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or an isomer (351 mg, 0.87 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (282 mg, 2.18 mmol). The resulting reaction mixture was heated at 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 brine (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (ACN / H2O (0.1% FA) = 30-60% elution) to give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(((S)-1-methylpyrrolidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or isomer (90 mg, yield: 23.5%), LC-MS m / z: 528 [M+H] + ;

[0624] 1 H NMR(400MHz,MeOD-d4):8.80(s,1H),7.95(t,J=8.0Hz,1H),7.82(d,J=12.0Hz,1H ),7.59(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),5.50-5.45( m,2H),4.94(s,1H),4.59(d,J=4.0Hz,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).

[0625] Example 29. Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyl-2-azaspiro[3.3]heptane-6-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (Compound 187)

[0626] 1) Synthesis of tert-butyl 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0627] A solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (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-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (79 mg, 0.09 mmol), and cesium carbonate (921 mg, 2.82 mmol) in 1,4-dioxane (2.0 mL) was stirred at 100°C under an argon atmosphere 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 give tert-butyl 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, yield: 45.87%), LC-MS m / z: 348 [M+H] + ;

[0628] 2) Synthesis of N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine

[0629] To a solution of tert-butyl 6-((2-methyl-4-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.43 mmol) in dichloromethane (1.5 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.5 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN / H2O (0.1% FA) = 5%-95% elution) to give N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine (80 mg, yield: 74.93%), LC-MS m / z: 248 [M+H] + ;

[0630] 3) Synthesis of 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine

[0631] A solution of N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine (80 mg, 0.32 mmol), paraformaldehyde (20 mg, 0.64 mmol) and NaBH3CN (41 mg, 0.65 mmol) in acetic acid (0.1 mL) and dichloromethane (10 mL) was stirred at room temperature for 0.5 h. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography (MeCN:H2O (0.1% FA) = 5-95% elution) to give 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine (40 mg, yield: 47.32%), LC-MS m / z: 262 [M+H] + ;

[0632] 4) 2-methyl-N 1 Synthesis of 2-(2-methyl-2-azaspiro[3.3]heptane-6-yl)benzene-1,4-diamine

[0633] A solution of 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine (40 mg, 0.15 mmol) and Pd / C (40 mg) in methanol (2.0 mL) was removed under a hydrogen atmosphere and stirred at room temperature for 4 hours. The mixed reaction liquid 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 reverse phase column chromatography (MeCN:H2O (0.1% NH3.H2O) = 5-95% elution) to give 2-methyl-N-(2-methyl-4-nitrophenyl)-2-azaspiro[3.3]heptane-6-amine. 1 -(2-methyl-2-azaspiro[3.3]heptane-6-yl)benzene-1,4-diamine (20 mg, yield: 56.48%), LC-MS m / z: 232 [M+H] + ;

[0634] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((2-methyl-2-azaspiro[3.3]heptane-6-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0635] A mixture of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (21 mg, 0.052 mmol) and 2-methyl-N 1 A solution of -(2-methyl-2-azaspiro[3.3]heptane-6-yl)benzene-1,4-diamine (20 mg, 0.09 mmol) in isopropanol (1.0 mL) was heated at 70° C. and stirred for 2 hours. After cooling, the mixed reaction solution 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 give (Z)-1 2-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-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (5 mg, yield: 17.30%), LC-MS m / z: 553 [M+H] + ;

[0636] 1 H NMR (400MHz, MeOD) δ8.75 (d, J = 16.0Hz, 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),2.2 4-2.09(m,3H),2.03-1.94(m,3H),1.94-1.76(m,3H),1.69-1.52(m,5H)

[0637] Example 30. Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxaldehyde or its enantiomer (Compound 188)

[0638] 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate

[0639] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (6.225 g, 30.968 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (1.858 g, 77.419 mmol) in portions at 0°C. The resulting mixed reaction solution was stirred at room temperature for 30 minutes. A solution of 1-fluoro-2-methyl-4-nitrobenzene (4 g, 25.806 mmol) in N,N-dimethylformamide (20 mL) was then added dropwise to the mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 3 hours. After cooling, the mixed reaction solution was diluted with water and extracted with ethyl acetate (6 x 300 mL). The combined organic phases were washed with saturated brine (3 x 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 give tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate (2.8 g, yield: 32.3%), LC-MS m / z: 337 [M+H] + ;

[0640] 2) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine

[0641] A solution of tert-butyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate (2.800 g, 8.333 mmol) in dichloromethane (21 mL) and 2,2,2-trifluoroacetic acid (7 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (5 x 60 mL). The combined organic phases were washed with saturated brine (3 x 20 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% to 65% elution) to afford 4-(2-methyl-4-nitrophenoxy)piperidine (1.5 g, yield: 76.3%). LC-MS m / z: 237 [M+H] + ;

[0642] 3) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxaldehyde

[0643] To a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (120 mg, 0.508 mmol) and formamide (27.45 mg, 0.610 mmol) in dichloromethane (2 mL) was added triethylamine (154.068 mg, 1.525 mmol) at room temperature. 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 x 80 mL). The combined organic phases were washed with saturated brine (1 x 20 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% to 65% elution) to afford 4-(2-methyl-4-nitrophenoxy)piperidine-1-carbaldehyde (86 mg, yield: 64.1%). LC-MS m / z: 265 [M+H] + ;

[0644] 4) Synthesis of 4-(4-amino-2-methylphenoxy)piperidine-1-carboxaldehyde

[0645] A solution of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxaldehyde (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 at 70°C with stirring for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 80 mL). The combined organic phases were washed with saturated brine (1 x 20 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% to 65% elution) to afford 4-(4-amino-2-methylphenoxy)piperidine-1-carboxaldehyde (54 mg, yield: 70.8%). LC-MS m / z: 235 [M+H] + ;

[0646] 5) Synthesis of (R, Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxaldehyde or enantiomers

[0647] To a solution of 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)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer (54 mg, 0.135 mmol) in isopropanol (3 mL) was added N,N-diisopropylethylamine (52.115 mg, 0.404 mmol) at room temperature. The resulting mixture was heated at 90°C with stirring for 3 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (1 x 20 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 afford (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carbaldehyde or enantiomer (20 mg, yield: 26.8%), LC-MS m / z: 556 [M+H] + ;

[0648] 1 H NMR (400MHz, MeOD-d4): δ8.80(s,1H),8.04(s,1H),7.96(t,J=7.8Hz,1H),7.82(d ,J=8.4Hz,1H),7.60(d,J=8Hz,1H),7.37(d,J=8.8Hz,1H),6.93(d,J=8.8Hz,1H), 5.50-5.42(m,2H),4.60(d,J=6.4Hz,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).

[0649] Example 31. Synthesis of (R,Z)-2-((4-((1-acetylpiperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer (Compound 189)

[0650] 1) Synthesis of 1-(4-(2-methyl-4-nitrophenoxy)piperidin-1-yl)ethan-1-one

[0651] To a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (310 mg, 1.314 mmol) and acetyl chloride (122.949 mg, 1.576 mmol) in dichloromethane (4 mL) was added triethylamine (398 mg, 3.941 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate (5 x 20 mL). The combined organic phases were washed with saturated brine (3 x 10 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 give 1-(4-(2-methyl-4-nitrophenoxy)piperidin-1-yl)ethan-1-one (186 mg, yield: 50.9%), LC-MS m / z: 279 [M+H] + ;

[0652] 2) Synthesis of 1-(4-(4-amino-2-methylphenoxy)piperidin-1-yl)ethan-1-one

[0653] 1-(4-(2-methyl-4-nitrophenoxy)piperidin-1-yl)ethan-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) and heated at 70°C with stirring for 3 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (4 x 30 mL). The combined organic phases were washed with saturated brine (4 x 20 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 give 1-(4-(4-amino-2-methylphenoxy)piperidin-1-yl)ethan-1-one (66 mg, yield: 39.8%). LC-MS m / z: 249 [M+H] + ;

[0654] 3) Synthesis of (R, Z)-2-((4-((1-acetylpiperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer

[0655] To a solution of 1-(4-(4-amino-2-methylphenoxy)piperidin-1-yl)ethan-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]diazacyclotridecan-5-one or its enantiomer (50 mg, 0.125 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (48.254 mg, 0.374 mmol) at room temperature. The resulting mixture was heated at 90°C with stirring for 3 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (1 x 20 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 afford (R,Z)-2-((4-((1-acetylpiperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (18 mg, yield: 25.3%), LC-MS m / z: 570 [M+H]. + ;

[0656] 1H NMR (400MHz, MeOD-d4): δ8.80-8.77(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),

[0657] Example 32. Synthesis of (R,Z)-2-((4-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomer (Compound 190)

[0658] 1) Synthesis of cyclopropyl (4-(2-methyl-4-nitrophenoxy)piperidin-1-yl)methanone

[0659] To a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (310 mg, 1.314 mmol) and cyclopropanecarbonyl chloride (163.932 mg, 1.576 mmol) in dichloromethane (3 mL) was added triethylamine (38.008 mg, 3.941 mmol) at room temperature. 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 x 30 mL). The combined organic phases were washed with saturated brine (1 x 20 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 give cyclopropyl (4- (2-methyl-4-nitrophenoxy) piperidin-1-yl)methanone (154 mg, yield: 38.6%), LC-MS m / z: 305 [M + H] + ;

[0660] 2) Synthesis of (4-(4-amino-2-methylphenoxy)piperidin-1-yl)(cyclopropyl)methanone

[0661] Cyclopropyl(4-(2-methyl-4-nitrophenoxy)piperidin-1-yl)methanone (154 mg, 0.507 mmol), iron (141.842 mg, 2.533 mmol), and ammonium chloride (80.546 mg, 1.520 mmol) in ethanol (4 mL) and water (1 mL) were heated at 70°C with stirring for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 80 mL). The combined organic phases were washed with saturated brine (1 x 20 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 give (4-(4-amino-2-methylphenoxy)piperidin-1-yl)(cyclopropyl)methanone (66 mg, yield: 47.5%), LC-MS m / z: 275 [M+H] + ;

[0662] 3) Synthesis of (R, Z)-2-((4-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomers

[0663] To a solution of (4-(4-amino-2-methylphenoxy)piperidin-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-(nitrene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer (60 mg, 0.180 mmol) in isopropanol (3 mL) was added N,N-diisopropylethylamine (24.2 mg, 0.1875 mmol) at room temperature. The resulting reaction mixture was heated at 90°C and stirred for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (1 x 20 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 yield (R,Z)-2-((4-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(azene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (23 mg, yield: 25.8%). LC-MS m / z: 596 [M+H]. + ;

[0664] 1 H NMR (400MHz, MeOD-d4): δ8.7(s,1H),7.95(t,J=8Hz,1H),7.81(d,J=8Hz,1H),7.59 (d,J=7.2Hz,2H),7.37-7.34(m,1H),6.92(d,J=8.8Hz,1H),5.53-5.43(m,2H),4.6 4-4.58(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).

[0665] Example 33. Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxylic acid methyl ester or enantiomer (Compound 191)

[0666] 1) Synthesis of methyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate

[0667] To a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (200 mg, 0.85 mmol) and triethylamine (260 mg, 2.55 mmol) in dichloromethane (3 mL) at 0°C was added methyl chloroformate (96 mg, 1.02 mmol). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was quenched with methanol at room temperature. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 295 [M+H] + ;

[0668] 2) Synthesis of methyl 4-(4-amino-2-methylphenoxy)piperidine-1-carboxylate

[0669] A solution of methyl 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxylate (200 mg, 0.68 mmol) and Pd / C (140 mg, 1.36 mmol) in methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixed reaction solution 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 give methyl 4-(4-amino-2-methylphenoxy)piperidine-1-carboxylate (120 mg, yield: 66.8%), LC-MS m / z: 265 [M+H] + ;

[0670] 3) Synthesis of (R, Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxylic acid methyl ester or enantiomer

[0671] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(azacyclo)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer (110 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. A solution of methyl 4-(4-amino-2-methylphenoxy)piperidine-1-carboxylate (110 mg, 0.41 mmol) and acetic acid (97 mg, 1.62 mmol) in 1,2-dichloroethane (1 mL) was then added dropwise to the reaction mixture. The resulting 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%) to give (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxylic acid methyl ester or enantiomer (70 mg, yield: 44.2%), LC-MS m / z: 586 [M+H] + ;

[0672] 1 H NMR (400MHz, MeOD-d4): δ8.77(s,1H),7.94(t,J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),7.58(d,J= 7.6Hz,2H),7.34(dd,J=8.8,2.4Hz,1H),6.88(d,J=8.8Hz,1H),5.53–5.40(m,2H),4.57(d,J=7. 2Hz,2H),4.55–4.50(m,1H),3.73(d,J=3.6Hz,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=13.2,4.0Hz,2H),1.67(s,3H).

[0673] Example 34. Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomer (Compound 192)

[0674] 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxamide

[0675] A mixed reaction solution containing 4-(2-methyl-4-nitrophenoxy)piperidine (200 mg, 0.85 mmol) and urea (51 mg, 0.85 mol) was heated at 120°C and stirred for 16 hours under nitrogen. The resulting mixed reaction solution was purified by C18 reverse 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] + ;

[0676] 2) Synthesis of 4-(4-amino-2-methylphenoxy)piperidine-1-carboxamide

[0677] A solution of 4-(2-methyl-4-nitrophenoxy)piperidine-1-carboxamide (100 mg, 0.36 mmol) and Pd / C (77 mg, 0.72 mmol) in methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixed reaction solution was filtered and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 250 [M+H] + ;

[0678] 3) Synthesis of (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomers

[0679] A solution of (R,Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its 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. 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 then added. The resulting reaction mixture was heated to 50°C and stirred for 1 hour. The residue was purified by C18 column chromatography (MeCN:H2O=0-80%) to give (R,Z)-4-(4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylphenoxy)piperidine-1-carboxamide or enantiomer (25 mg, yield: 17.6%), LC-MS m / z: 571 [M+H] + ;

[0680] 1 H NMR (400MHz, MeOD-d4): δ8.79(s,1H),7.95(t,J=7.6Hz,1H),7.82(d,J=8.0Hz,1H),7.58(d,J=7.6Hz,2H),7.35(dd,J=8.8,2.5Hz,1H),6.90(d,J=8. 8Hz,1H),5.54–5.40(m,2H),4.57(dd,J=12.0,5.0Hz,3H),3.70–3.63(m,2 H),3.40–3.35(m,2H),2.22(s,5H),2.02–1.84(m,4H),1.80–1.65(m,5H).

[0681] Example 35. Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (Compound 193)

[0682] 1) Synthesis of tert-butyl 4-(2-methyl-4-nitrobenzyl)piperidine-1-carboxylate

[0683] A solution of bromo-2-methyl-4-nitrobenzene (200 mg, 0.93 mmol), tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate (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) in tetrahydrofuran (2 mL) was heated at 80°C with stirring overnight under nitrogen. 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 give tert-butyl 4-(2-methyl-4-nitrobenzyl)piperidine-1-carboxylate (120 mg, yield: 38.6%), LC-MS m / z: 335 [M+H] + ;

[0684] 2) Synthesis of 4-(2-methyl-4-nitrobenzyl)piperidine

[0685] To a solution of tert-butyl 4-(2-methyl-4-nitrobenzyl)piperidine-1-carboxylate (120 mg, 0.36 mmol) in dichloromethane (0.9 ml) was added dropwise 2,2,2-trifluoroacetic acid (0.3 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 1 hour. 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) = 5-95% elution) to give 4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, yield: 71.4%), LC-MS m / z: 235 [M+H] + ;

[0686] 3) Synthesis of 1-methyl-4-(2-methyl-4-nitrobenzyl)piperidine

[0687] A solution of 4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, 0.26 mmol), sodium cyanoborohydride (32.76 mg, 0.52 mmol), and paraformaldehyde (11.7 mg, 0.39 mmol) in methanol (2 mL) was stirred at room temperature overnight. 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) = 5-95% elution) to give 1-methyl-4-(2-methyl-4-nitrobenzyl)piperidine (60 mg, yield: 94.4%), LC-MS m / z: 249 [M+H] + ;

[0688] 4) Synthesis of 3-methyl-4-((1-methylpiperidin-4-yl)methyl)aniline

[0689] 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 aqueous ammonium chloride solution (0.2 mL) under nitrogen protection and heated at 70 ° C. and stirred overnight for 2 hours. After cooling, the mixed reaction liquid was filtered and the filter cake was washed with methanol (3 x 15 mL). The collected filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 219 [M+H] + ;

[0690] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0691] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol) and 3-methyl-4-((1-methylpiperidin-4-yl)methyl)aniline (81.75 mg, 0.375 mmol) in dichloromethane (1.5 mL) and 1,2-dichloromethane (1.5 mL) was heated to 50°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% FA) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (5 mg, yield: 3.7%), LC-MS m / z: 540 [M+H] + ;

[0692] 1H NMR (400MHz, MeOD) δ8.82(s,1H),7.95(d,J=7.8Hz,1H),7.84(d,J=7.6Hz,1H),7.60(d,J=7. 2Hz,2H),7.37(d,J=8.2Hz,1H),7.04(s,1H),5.56–5.39(m,2H),4.61(d,J=6.7Hz,2H),2.97 (d,J=11.9Hz,2H),2.56(d,J=7.1Hz,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=12.4Hz,2H).

[0693] 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-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 194)

[0694] 1) Synthesis of (2-methyl-4-nitrophenyl) (4-methylpiperazin-1-yl)methanone

[0695] 1-Methylpiperazine (1000 mg, 10 mmol), 2-methyl-4-nitrobenzoic acid (2715 mg, 15 mmol), 1-methyl-1H-imidazole (3280 mg, 40 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (5620 mg, 20 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at room temperature overnight. 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) = 5-95% elution) to give (2-methyl-4-nitrophenyl)(4-methylpiperazin-1-yl)methanone (1100 mg, yield: 41.8%), LC-MS m / z: 264 [M+H] + ;

[0696] 2) Synthesis of (4-amino-2-methylphenyl) (4-methylpiperazin-1-yl)methanone

[0697] 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 aqueous ammonium chloride (1 mL) and heated at 70°C overnight for 2 hours under nitrogen. After cooling, the reaction mixture was filtered and the filter cake was washed with methanol (3 x 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] + ;

[0698] 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-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0699] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol) and (4-amino-2-methylphenyl)(4-methylpiperazin-1-yl)methanone (87.4 mg, 0.375 mmol) in dichloromethane (1.5 mL) and 1,2-dichloroethane (1.5 mL) 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (0.9 mg, yield: 0.65%), LC-MS m / z: 555 [M+H] + ;

[0700] 1H NMR(400MHz,MeOD)δ8.87(s,1H),8.00(s,1H),7.85–7.78(m,2H),7.62(d,J= 7.8Hz,1H),7.56(d,J=7.6Hz,1H),7.14(d,J=8.4Hz,1H),5.51–5.40(m,2H), 4.63(d,J=6.6Hz,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).

[0701] 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-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 195)

[0702] 1) Synthesis of (S)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone

[0703] A solution of (S)-1,2-dimethylpiperazine (300 mg, 2.63 mmol), 2-methyl-4-nitrobenzoic 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) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The mixed reaction solution was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to give (S)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (300 mg, yield: 41.15%), LC-MS m / z: 278 [M+H] + ;

[0704] 2) Synthesis of (S)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazin-1-yl)methanone

[0705] A saturated aqueous solution of (S)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (300 mg, 1.08 mmol) and iron (303.24 mg, 5.41 mmol) in ethanol (4 mL) was heated at 70°C and stirred for 8 hours. After cooling, the mixed reaction solution 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] + ;

[0706] 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-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0707] (Z)-12-Hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-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 heated at 50°C with stirring 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 give (Z)-2-((4-(((S)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (10 mg, yield: 2.35%), LC-MS m / z: 569 [M+H] + ;

[0708] 1H NMR (400MHz, MeOD-d4): δ8.89–8.84(m,1H),8.01–7.96(m,1H),7.84–7.78(m, 2H),7.62–7.54(m,2H),7.14(d,J=8.0Hz,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).

[0709] Example 38. Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 196)

[0710] 1) Synthesis of (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine

[0711] 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 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 give (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (200 mg, yield: 58.3%), LC-MS m / z: 264 [M+H] + ;

[0712] 2) Synthesis of (S)-4-((3,4-dimethylpiperazin-1-yl)methyl)-3-methylaniline

[0713] (S)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (200 mg, 0.76 mmol) and iron (212.0 mg, 3.78 mmol) dissolved in aqueous ammonium chloride (1 mL) and ethanol (4 mL) were heated at 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered and the filter cake was washed with methanol (3 × 50 mL). The collected filtrate 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: 234 [M+H] + ;

[0714] 3) Synthesis of (Z)-2-((4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0715] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol), (S)-4-((3,4-dimethylpiperazin-1-yl)methyl)-3-methylaniline (87.2 mg, 0.37 mmol), and acetic acid (89.7 mg, 1.50 mmol) in 1,2-dichloroethane (2 mL) was heated at 50°C and stirred for 2 hours. After cooling, the mixed reaction solution was 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 give (Z)-2-((4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (35 mg, yield: 25.4%), LC-MS m / z: 555 [M+H] + ;

[0716] 1H NMR (400MHz, MeOD-d4): δ8.81(s,1H),7.96(t,J=8.0Hz,1H),7.82(d,J=8.0Hz,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 =8.0Hz,2H),3.49-3.42(m,2H),2.87(d,J=12.0Hz,1H),2.78(t,J=12.0Hz,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=8.0Hz,3H).

[0717] 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-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 197)

[0718] 1) Synthesis of (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone

[0719] A solution of 2-methyl-4-nitrobenzoic acid (400.0 mg, 2.21 mmol), (R)-1,2-dimethylpiperazine (378 mg, 3.31 mmol), N,N,N',N'-tetramethylchloroformamidine 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. LCMS confirmed the reaction was complete. After cooling, the resulting 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 give (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (610 mg, yield: 99.6%), LC-MS m / z: 278 [M+H] + ;

[0720] 2) Synthesis of (R)-(4-amino-2-methylphenyl)(3,4-dimethylpiperazin-1-yl)methanone

[0721] A saturated ammonium chloride solution (0.5 mL) and ethanol (2 mL) containing (R)-(3,4-dimethylpiperazin-1-yl)(2-methyl-4-nitrophenyl)methanone (610 mg, 2.2 mmol) and iron (617 mg, 11 mmol) was heated at 70°C and stirred for 2 hours. The reaction was complete as determined by LCMS. After cooling, the mixed reaction solution was filtered and the filter cake was washed with dichloromethane (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 248 [M+H] + ;

[0722] 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-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0723] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-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 at 90°C and stirred for 16 hours. LCMS analysis indicated the reaction was complete. 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 give (Z)-2-((4-(((R)-3,4-dimethylpiperazine-1-carbonyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (10 mg, yield: 6.4%), LC-MS m / z: 569 [M+H] + ;

[0724] 1H NMR(400MHz,MeOD-d4)δ8.88(s,1H),8.23(s,1H),7.99(t,J=8.0Hz,1H),7.86–7.77(m,2H),7.60(dd,J =16.0,8.0Hz,2H),7.16(d,J=8.0Hz,1H),5.46(dd,J=12.0,8.0Hz,2H),4.87(s,1H),4.83(s,1H),4.64( d,J=8.0Hz,2H),4.48(s,1H),3.32(s,1H),3.29–3.26(m,1H),2.93(s,2H),2.49(d,J=16.0Hz,4H),2.2 8(s,3H),2.17(s,1H),1.99(d,J=8.0Hz,1H),1.94–1.85(m,1H),1.69(s,3H),1.26(s,1H),1.03(s,1H).

[0725] Example 40. Synthesis of (Z)-2-((4-((((R)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one (Compound 198)

[0726] 1) Synthesis of (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine

[0727] 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. LCMS confirmed the reaction was complete. After cooling, the resulting mixed reaction solution 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 give (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (300 mg, yield: 87.4%), LC-MS m / z: 264 [M+H] + ;

[0728] 2) Synthesis of (R)-4-((3,4-dimethylpiperazin-1-yl)methyl)-3-methylaniline

[0729] A saturated ammonium chloride solution (0.5 mL) and ethanol (2 mL) containing (R)-1,2-dimethyl-4-(2-methyl-4-nitrobenzyl)piperazine (300 mg, 1.14 mmol) and iron (319 mg, 5.70 mmol) was heated at 70°C and stirred for 2 hours. LCMS detected the reaction to be complete. After cooling, the mixed reaction solution was filtered and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product which was used directly in the next step without further purification. LC-MS m / z: 234 [M+H] + ;

[0730] 3) Synthesis of (Z)-2-((4-((((R)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one

[0731] A solution of (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]diazacyclotridecen-5-one (40 mg, 0.108 mmol) and (R)-4-((3,4-dimethylpiperazin-1-yl)methyl)-3-methylaniline (30 mg, 0.128 mmol) in 1,4-dioxane (2 mL) was heated at 90°C with stirring for 16 hours. LCMS confirmed the reaction was complete. 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 give (Z)-2-((4-((((R)-3,4-dimethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (10 mg, yield: 18.1%), LC-MS m / z: 555 [M+H] + ;

[0732] 1H NMR(400MHz,MeOD-d4)δ8.84(s,1H),7.97(t,J=7.9Hz,1H),7.84(d,J=7.7Hz,1H),7.6 7–7.57(m,2H),7.41(d,J=8.4Hz,1H),7.16(d,J=8.2Hz,1H),5.55–5.37(m,2H),4.87( s,1H),4.83–4.80(m,1H),4.61(d,J=6.9Hz,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=26.6Hz,4H),1.69(s,3H),1.08(d,J=6.3Hz,3H).

[0733] Example 41. Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylbenzamide (Compound 199)

[0734] 1) Synthesis of 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazin-2-one

[0735] To a solution of 4-methylpiperazin-2-one (300 mg, 2.63 mmol) in tetrahydrofuran (10 mL) at 0°C, sodium hydride (175 mg, 4.39 mmol, content: 60%) was added portionwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. 1-(Bromomethyl)-2-methyl-4-nitrobenzene (500 mg, 2.18 mmol) was added to the mixed reaction solution at room temperature. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was quenched with water (20 mL) at 0°C and extracted with ethyl acetate (3 × 20 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 reverse phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to give 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazin-2-one (50 mg, yield: 8.7%), LC-MS m / z: 264 [M+H] + ;

[0736] 2) Synthesis of 1-(4-amino-2-methylbenzyl)-4-methylpiperazin-2-one

[0737] A solution of 4-methyl-1-(2-methyl-4-nitrobenzyl)piperazin-2-one (50 mg, 0.19 mmol) and iron (53 mg, 0.95 mmol) in aqueous ammonium chloride (0.2 mL) and ethanol (0.8 mL) was heated at 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered. The filter cake was washed with methanol (3×10 mL). The collected filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 234 [M+H] + ;

[0738] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methyl-2-oxopiperazin-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0739] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (70 mg, 0.18 mmol), 1-(4-amino-2-methylbenzyl)-4-methylpiperazin-2-one (50 mg, 0.21 mmol), and acetic acid (64.8 mg, 1.08 mmol) in 1,2-dichloroethane (2 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((4-methyl-2-oxopiperazin-1-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (30 mg, yield: 31%), LC-MS m / z: 555 [M+H] + ;

[0740] 1H NMR (400MHz, MeOD-d4): δ8.84(s,1H),7.98(t,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),7.69(s, 1H),7.61(d,J=7.6Hz,1H),7.47-7.42(m,1H),7.11(d,J=8.4Hz,1H),5.53-5.40(m,2H),4.64 (s,2H),4.62(d,J=6.4Hz,2H),3.22(t,J=5.6Hz,2H),3.18(s,2H),2.68(t,J=5.2Hz,2H),2.3 5(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).

[0741] Example 42. Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylbenzamide (Compound 200)

[0742] 1) Synthesis of N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzamide

[0743] 2-Methyl-4-nitrobenzoic acid (100 mg, 0.55 mmol), N 1 , N 1 A solution of 1,2-dimethylethane-1,2-diamine (58.3 mg, 0.66 mmol), HATU (313.5 mg, 0.83 mmol) and DIEA (213 mg, 1.65 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to give N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzoyl (100 mg, yield: 71.8%), LC-MS m / z: 252 [M+H] + ;

[0744] 2) Synthesis of 4-amino-N-(2-(dimethylamino)ethyl)-2-methylbenzamide

[0745] A solution of N-(2-(dimethylamino)ethyl)-2-methyl-4-nitrobenzamide (100 mg, 0.40 mmol) and Pd / C (50 mg, 10%) in 2,2,2-trifluoroethanol (2 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The mixed reaction solution 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] + ;

[0746] 3) Synthesis of (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylbenzamide

[0747] A solution of (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]diazacyclotridecan-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) in 1,2-dichloroethane (2 mL) was heated at 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 give (Z)-N-(2-(dimethylamino)ethyl)-4-((12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)-2-methylbenzamide (6.5 mg, yield: 5.8%), LC-MS m / z: 543 [M+H] + ;

[0748] 1H NMR (400MHz, MeOD-d4): δ8.90-8.85(m,1H),8.00(t,J=8.4Hz,1H),7.84(d,J=7.6Hz,1H),7 .74(s,1H),7.62(d,J=8.0Hz,1H),7.57-7.51(m,1H),7.37(d,J=8.4Hz,1H),5.53-5.40(m,2 H),4.63(d,J=6.0Hz,2H),3.50(t,J=6.8Hz,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).

[0749] Example 43. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomer (Compound 201)

[0750] 1) Synthesis of 3-methyl-9-(2-methyl-4-nitrobenzyl)-3,9-diazaspiro[5.5]undecane

[0751] A solution of 3-methyl-3,9-diazaspiro[5.5]undecane (0.2 g, 1.19 mmol), 2-methyl-4-nitrobenzaldehyde (0.20 g, 1.19 mmol), and sodium cyanoborohydride (0.075 g, 1.19 mol) in methanol (2 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution 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] + .

[0752] 2) Synthesis of 3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undec-3-yl)methyl)aniline

[0753] 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 mixed reaction solution 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 a crude product (0.03 g), which was used directly in the next step. LCMS m / z: 288 [M+H] +

[0754] 3) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or enantiomers

[0755] A solution of (12R,Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (0.1 g, 0.26 mmol), 3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undec-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 at 50°C and stirred for 2 hours. The mixed reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol:dichloromethane = 0-10% elution) to give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((9-methyl-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (0.02 g, yield: 12.66%), LCMS m / z: 609 [M+H] +

[0756] 1H NMR (400MHz, MeOH-d4): δ8.86(s,1H),8.52(s,1H),7.98(t,J=7.6Hz,1H),7.84(d,J= 7.6Hz,1H),7.72(s,1H),7.62(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.27(d,J=8.4H z,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).

[0757] Example 44. Synthesis of (Z)-2-((4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 202)

[0758] 1) Synthesis of tert-butyl (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate

[0759] At 0°C, sodium hydride (125 mg, 3.13 mmol) was added portionwise to a solution of tert-butyl (2S)-3-hydroxy-2-methylazetidine-1-carboxylate (482 mg, 2.57 mmol) in N,N-dimethylformamide (5 mL). The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. 1-Fluoro-2-methyl-4-nitrobenzene (400 mg, 2.57 mmol) was then added to the mixed reaction solution at 0°C. The resulting mixed reaction solution was stirred at 0°C for 3 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (50 ml) at 0°C 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 give tert-butyl (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate (450 mg, yield: 54%), LC-MS m / z: 323 [M+H] + ;

[0760] 2) Synthesis of (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine

[0761] A solution of (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylic acid tert-butyl ester (467 mg, 1.45 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give (2S)-2-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (300 mg, yield: 93%), LC-MS m / z: 223 [M+H] + ;

[0762] 3) Synthesis of (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine

[0763] A solution of (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) in acetic acid (0.3 mL) and dichloromethane (3 mL) was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to give (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine (282 mg, yield: 82%), LC-MS m / z: 237 [M+H] + ;

[0764] 4) Synthesis of 4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylaniline

[0765] A solution of (2S)-1,2-dimethyl-3-(2-methyl-4-nitrophenoxy)azetidine (272 mg, 1.15 mmol) and Pd / C (140 mg) in methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). The filtrate was concentrated under reduced pressure to give 4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylaniline (222 mg, yield: 93.4%), LC-MS m / z: 207 [M+H] + ;

[0766] 5) Synthesis of (Z)-2-((4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0767] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol), 4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylaniline (77 mg, 0.38 mmol), and acetic acid (90 mg, 1.5 mmol) in 1,2-dichloroethane (2 ml) was heated at 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 give (Z)-2-((4-(((2S)-1,2-dimethylazetidin-3-yl)oxy)-3-methylphenyl)amino)-12-hydroxy-12-methyl-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (35 mg, yield: 26.6%), LC-MS m / z: 528 [M+H] + ;

[0768] 1H NMR (400MHz, MeOD-d4) δ8.79(s,1H),7.95(t,J=7.9Hz,1H),7.79(d,J=8.0Hz,1H),7.60(t,J=7.4Hz,2H),7.42 –7.35(m,1H),6.61(d,J=8.8Hz,1H),5.53–5.38(m,2H),5.10(td,J=5.9,2.9Hz,1H),4.71(dd,J=13.3,6.6Hz, 1H),4.58(d,J=7.0Hz,2H),4.30(dd,J=11.4,5.8Hz,1H),4.10(dd,J=11.4,2.7Hz,1H),2.90(s,3H),2.29(s,3 H),2.25–2.10(m,2H),1.99(dd,J=16.8,8.6Hz,1H),1.90(d,J=8.6Hz,1H),1.68(s,3H),1.55(d,J=6.9Hz,3H).

[0769] Example 45. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one and (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-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]diazacyclotridecene-5-one (Compounds 203A and B):

[0770] 1) Synthesis of tert-butyl 4-((2-methyl-4-nitrophenyl)amino)piperidine-1-carboxylate

[0771] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1000 mg, 5.00 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (930 mg, 6.00 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2070 mg, 15.00 mmol) at room temperature. The resulting mixture was heated at 120°C and stirred for 8 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (1 x 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 give tert-butyl 4-((2-methyl-4-nitrophenyl)amino)piperidine-1-carboxylate (900 mg, yield: 53.6%), LC-MS m / z: 336 [M+H] + ;

[0772] 2) Synthesis of N-(2-methyl-4-nitrophenyl)piperidin-4-amine

[0773] A solution of tert-butyl 4-((2-methyl-4-nitrophenyl)amino)piperidine-1-carboxylate (900 mg, 2.69 mmol) in dichloromethane (8 mL) and 2,2,2-trifluoroacetic acid (2 mL) was stirred at room temperature for 8 hours. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (1 x 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 give N-(2-methyl-4-nitrophenyl)piperidin-4-amine (562 mg, yield: 88.9%), LC-MS m / z: 236 [M+H] + ;

[0774] 3) Synthesis of 1-methyl-N-(2-methyl-4-nitrophenyl)piperidin-4-amine

[0775] To a solution of N-(2-methyl-4-nitrophenyl)piperidin-4-amine (800 mg, 3.285 mmol) and acetic acid (462 mg, 7.69 mmol) in methanol (8 mL) was added portionwise paraformaldehyde (231 mg, 7.69 mmol) at 0°C and stirred at room temperature for 1 hour. Sodium cyanoborohydride (485 mg, 7.69 mmol) was then added to the reaction mixture and stirred at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (1 x 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 give 1-methyl-N-(2-methyl-4-nitrophenyl)piperidin-4-amine (700 mg, yield: 82.6%), LC-MS m / z: 250 [M+H] + ;

[0776] 4) 2-methyl-N 1 Synthesis of -(1-methylpiperidin-4-yl)benzene-1,4-diamine

[0777] A solution of methyl-N-(2-methyl-4-nitrophenyl)piperidin-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 atmosphere. The mixed reaction liquid was filtered and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain 2-methyl-N-(2-methyl-4-nitrophenyl)piperidin-4-amine. 1 -(1-methylpiperidin-4-yl)benzene-1,4-diamine (600 mg, yield: 97.4%), LC-MS m / z: 220 [M+H] + ;

[0778] 5) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0779] At room temperature, 2-methyl-N 1To a solution of (1-methylpiperidin-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-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (275 mg, 0.68 mmol) in isopropanol (2 mL) was added N,N-diisopropylethylamine (177 mg, 1.37 mmol). The resulting reaction mixture was heated at 90°C and stirred for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (1 x 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (60 mg, yield: 24.3%), LC-MS m / z: 541 [M+H] + ;

[0780] 1 H NMR(400MHz,MeOD-d4)δ8.75(s,1H),7.92(t,J=7.9Hz,1H),7.82(d,J=8.0Hz ,1H),7.57(d,J=7.6Hz,1H),7.44(s,1H),7.25(dd,J=8.6,2.5Hz,1H),6.63( d,J=8.7Hz,1H),5.56–5.40(m,2H),4.56(d,J=6.9Hz,2H),3.37(d,J=10.0Hz ,1H),2.92(d,J=11.6Hz,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).

[0781] 6) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomer or (S, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecene-5-one or its enantiomer

[0782] (Z)-12-Hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (118 mg, 0.22 mmol) was purified by preparative chiral high performance liquid chromatography (system: SHIMADZU LC-20AP; Column name: (250*25mm10μm; mobile phase A: n-Hexane; mobile phase B: EtOH (+0.1% 7.0mol / l Ammonia in MeOH); A:B: = 50:50; detection wavelength: 254nm; flow rate: 60; column temperature: RT; column pressure: 100bar) to separate and purify two isomers: Compound 203A and Compound 203B:

[0783] Compound 203A: Peak 1 (elution time: 18.865 min); (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (20 mg, yield: 17%), LC-MS m / z: 541 [M+H] + ;

[0784] 1H NMR (400MHz, MeOD-d4) δ8.74(s,1H),7.92(t,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.56(d,J=7.6Hz,1H ),7.44(s,1H),7.24(dd,J=8.6,2.4Hz,1H),6.63(d,J=8.7Hz,1H),5.54–5.41(m,2H),4.55(d,J=6.8Hz ,2H),3.42–3.33(m,1H),2.94(d,J=11.7Hz,2H),2.36(s,3H),2.31(t,J=11.8Hz,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=21.6,10.1Hz,2H).

[0785] Compound 203B: Peak 2 (elution time: 26.148 min); (S,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azacyclic)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (20 mg, yield: 17%)), LC-MS m / z: 541 [M+H] + ;

[0786] 1 H NMR (400MHz, MeOD-d4) δ8.74(s,1H),7.92(t,J=7.9Hz,1H),7.81(d,J=8.1Hz,1H),7.56(d,J=7.6 Hz,1H),7.44(s,1H),7.24(dd,J=8.6,2.4Hz,1H),6.63(d,J=8.7Hz,1H),5.55–5.40(m,2H),4.55( d,J=6.8Hz,2H),3.42–3.36(m,1H),2.93(d,J=11.7Hz,2H),2.35(s,3H),2.29(t,J=11.1Hz,2H),2 .19(dd,J=9.6,5.3Hz,1H),2.16–2.03(m,6H),2.02–1.85(m,2H),1.67(s,3H),1.62–1.50(m,2H).

[0787] Example 46, (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer

[0788] 1) Synthesis of tert-butyl 3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate (Compound 204)

[0789] At 0 ° C, sodium hydride (1110 mg, 46.24 mmol) was added in batches to a solution of tert-butyl 3-hydroxyazetidine 1-carboxylate (4000 mg, 23.14 mmol) in tetrahydrofuran (40 mL), and the resulting mixed reaction solution was stirred at room temperature for 50 minutes. Then, a solution of 1-fluoro-2-methyl-4-nitrobenzene (5376 mg, 34.68 mmol) in tetrahydrofuran (10 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was heated at 90 ° C and stirred for 8 hours. After cooling, the mixed reaction solution was diluted with water and extracted with ethyl acetate (3x 20 mL). The combined organic phase was washed with saturated brine (1x 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 give tert-butyl 3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate (3800 g, yield: 53%), LC-MS m / z: 309 [M+H] + ;

[0790] 2) Synthesis of 3-(2-methyl-4-nitrophenoxy)azetidine

[0791] A solution of tert-butyl 3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate (3800 mg, 12.34 mmol) in dichloromethane (32 mL) and 2,2,2-trifluoroacetic acid (8 mL) was stirred at room temperature for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (1 x 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 give 3-(2-methyl-4-nitrophenoxy)azetidine (2300 mg, yield: 89.5%), LC-MS m / z: 209 [M+H] + ;

[0792] 3) Synthesis of 1-methyl-3-(2-methyl-4-nitrophenoxy)azetidine

[0793] To a solution of 3-(2-methyl-4-nitrophenoxy)azetidine (3400 mg, 16.35 mmol) and acetic acid (1471 mg, 24.52 mmol) in methanol (30 mL) at 0 ° C., paraformaldehyde (981 mg, 32.69 mmol) was added in portions. The resulting mixed reaction solution was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3089 mg, 49.04 mmol) was then added in portions. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (1 x 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 give 1-methyl-3-(2-methyl-4-nitrophenoxy)azetidine (3200 mg, yield: 88%), LC-MS m / z: 223 [M+H] + ;

[0794] 4) Synthesis of 3-methyl-4-((1-methylazetidin-3-yl)oxy)aniline

[0795] 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 atmosphere. The mixed reaction liquid was filtered and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to give 3-methyl-4-((1-methylazetidin-3-yl)oxy)aniline (2596 mg, yield: 93.75%), LC-MS m / z: 193 [M+H] + ;

[0796] 5) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomers

[0797] A solution of 3-methyl-4-((1-methylazetidin-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-(nitrene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (251 mg, 0.63 mmol) in 1,4-dioxane (2 mL) was heated at 90°C with stirring for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (1 x 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 give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-methylazetidin-3-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or enantiomer (60 mg, yield: 22.5%), LC-MS m / z: 514 [M+H] + ;

[0798] 1 H NMR (400MHz, MeOD-d4) δ8.77(s,1H),7.94(t,J=7.9Hz,1H),7.78(d,J=8.0Hz,1H),7.59(d,J= 7.7Hz,2H),7.35(d,J=7.7Hz,1H),6.56(d,J=8.7Hz,1H),5.54–5.37(m,2H),5.04–4.94(m,1H),4.57(d,J=6.9Hz,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=18.5Hz,2H),2.02-1.93(m,1H),1.91(d,J=11.6Hz,1H),1.68(s,3H).

[0799] Example 47. Synthesis of (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (Compound 205)

[0800] 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)-1-(oxetane-3-yl)piperidine

[0801] At room temperature, sodium cyanoborohydride (214 mg, 3.39 mmol) was added to a solution of 4-(2-methyl-4-nitrophenoxy)piperidine (200 mg, 0.85 mmol) and oxetane-3-one (92 mg, 1.27 mmol) in dichloromethane (4 mL). The resulting mixed reaction solution was stirred at room temperature for 6 hours. The mixed reaction solution 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 give 4-(2-methyl-4-nitrophenoxy)-1-(oxetane-3-yl)piperidine (130 mg, yield: 52.5%), LC-MS m / z: 293 [M+H] + ;

[0802] 2) Synthesis of 3-methyl-4-((1-(oxetane-3-yl)piperidin-4-yl)oxy)aniline

[0803] A solution of 4-(2-methyl-4-nitrophenoxy)-1-(oxetane-3-yl)piperidine (120 mg, 0.41 mmol) and Pd / C (65 mg, 0.62 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixed reaction solution was filtered and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to give 3-methyl-4-((1-(oxetane-3-yl)piperidin-4-yl)oxy)aniline (90 mg, yield: 83.6%), LC-MS m / z: 263 [M+H] + ;

[0804] 3) Synthesis of (R, Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomers

[0805] A solution of 3-methyl-4-((1-(oxetan-3-yl)piperidin-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-(nitrene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one or its enantiomer (147 mg, 0.37 mmol), and N,N-isopropylethylamine (118 mg, 0.92 mmol) in isopropanol (1.5 mL) was heated at 90°C and stirred for 6 hours. The resulting reaction mixture was diluted with water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (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 give (R,Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(azene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one or enantiomer (40 mg, yield: 22.5%), LC-MS m / z: 584 [M+H] + ;

[0806] 1 H NMR (400MHz, MeOD-d4): 8.80 (s, 1H), 7.96 (t, J = 4.0Hz, 1H), 7.81 (d, J = 8Hz, 1H),7.59(d,J=8.0Hz,2H),7.42-7.39(m,1H),6.93(d,J=8Hz,1H),5.52-5.4 2(m,2H),4.92-4.88(m,6H),4.83-4.79(m,3H),4.60(d,J=8Hz,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).

[0807] Example 48. Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 206)

[0808] 1) Synthesis of 4-(2-methyl-4-nitrophenoxy)-1-(2,2,2-trifluoroethyl)piperidine

[0809] A solution of 4-(2-methyl-4-nitrophenoxy)piperidine (500 mg, 2.12 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (738 mg, 3.18 mmol) and N,N-diisopropylethylamine (822 mg, 6.36 mmol) in tetrahydrofuran (10 mL) was heated at 80°C and stirred overnight. 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 give 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] + ;

[0810] 2) Synthesis of 3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)aniline

[0811] 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 mixed reaction solution 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] + ;

[0812] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0813] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (80 mg, 0.21 mmol), 3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)aniline (72 mg, 0.25 mmol), and acetic acid (90 mg, 1.5 mmol) in 1,2-dichloroethane (2 mL) was heated at 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 give (Z)-12-hydroxy-12-methyl-2-((3-methyl-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)phenyl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (40 mg, yield: 31.6%), LC-MS m / z: 610 [M+H] + ;

[0814] 1 H NMR (400MHz, MeOD-d4): δ8.78(s,1H),7.94(t,J=8.0Hz,1H),7.80(d,J=8.0Hz,1 H),7.58(d,J=7.6Hz,2H),7.33(dd,J=8.8,2.4Hz,1H),6.86(d,J=8.8Hz,1H),5. 53-5.41(m,2H),4.57(d,J=6.8Hz,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).

[0815] Example 49. Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (Compound 207)

[0816] 1) Synthesis of 4-methyl-5-((1-methylpiperidin-4-yl)oxy)-2-nitropyridine

[0817] A solution of 5-bromo-4-methyl-2-nitropyridine (500.0 mg, 2.30 mmol), 1-methylpiperidin-4-ol (265.0 mg, 2.3 mmol) and potassium carbonate (954.0 mg, 6.91 mmol) in acetonitrile (5 mL) was heated at 90°C and stirred for 8 hours. 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 give 4-methyl-5-((1-methylpiperidin-4-yl)oxy)-2-nitropyridine (300 mg, yield: 51.2%), LC-MS m / z: 252 [M+H] + ;

[0818] 2) Synthesis of 4-methyl-5-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine

[0819] A solution of 4-methyl-5-((1-methylpiperidin-4-yl)oxy)-2-nitropyridine (300.0 mg, 1.20 mmol) and iron (335.0 mg, 5.98 mmol) in aqueous ammonium chloride (1 mL) and anhydrous (4 mL) was heated at 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered and the filter cake was washed with methanol (3×50 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m / z: 222 [M+H] + ;

[0820] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0821] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (100 mg, 0.25 mmol), 4-methyl-5-((1-methylpiperidin-4-yl)oxy)pyridin-2-amine (82.66 mg, 0.37 mmol), and acetic acid (89.8 mg, 1.50 mmol) in 1,2-dichloroethane (2 mL) was heated at 50°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 (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (10 mg, yield: 7.4%), LC-MS m / z: 543 [M+H] + ;

[0822] 1 H NMR (400MHz, MeOD-d4): δ8.78(s,1H),8.52(s,1H),8.10(s,1H),7.82(s,1 H),7.54(d,J=8.0Hz,1H),6.76(s,1H),5.51–5.36(m,2H),5.20(s,1H),4. 58(d,J=8.0Hz,2H),3.28-3.2(m,2H),3.09(s,2H),2.75(s,3H),2.23(s,3 H),2.22–2.12(m,4H),2.10-2.00(m,2H),1.99–1.83(m,2H),1.66(s,3H).

[0823] Example 50. Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 208)

[0824] 1) Synthesis of 4-methyl-N-(1-methylpiperidin-4-yl)-6-nitropyridine-3-amine

[0825] A solution of 5-bromo-4-methyl-2-nitropyridine (400 mg, 1.84 mmol), 1-methylpiperidin-4-amine (210.0 mg, 1.84 mmol) and potassium carbonate (763.0 mg, 5.53 mmol) in acetonitrile (4 mL) was stirred at room temperature for 8 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% NH3.H2O) = 5-95% elution) to give 4-methyl-N-(1-methylpiperidin-4-yl)-6-nitropyridine-3-amine (300 mg, yield: 64.2%), LC-MS m / z: 251 [M+H] + ;

[0826] 2) 4-Methyl-N 5 Synthesis of -(1-methylpiperidin-4-yl)pyridine-2,5-diamine

[0827] A solution of 4-methyl-N-(1-methylpiperidin-4-yl)-6-nitropyridin-3-amine (190 mg, 0.76 mmol) and iron (336.0 mg, 3.78 mmol) in aqueous ammonium chloride (1 mL) and ethanol (4 mL) was heated at 70°C and stirred for 2 hours. After cooling, the mixed reaction solution 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: 221 [M+H] + ;

[0828] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0829] A mixture of (Z)-12-hydroxy-12-methyl-2-(methylsulfonyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (300 mg, 0.75 mmol), 4-methyl-N 5A solution of -(1-methylpiperidin-4-yl)pyridine-2,5-diamine (247 mg, 1.12 mmol) and acetic acid (269.32 mg, 4.49 mmol) in 1,2-dichloroethane (3 mL) was heated at 50°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 (CH3CN:H2O (0.1% NH3.H2O) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-((4-methyl-5-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (20 mg, yield: 4.9%), LC-MS m / z: 542 [M+H] + ;

[0830] 1 H NMR (400MHz, MeOD-d4): δ8.75(s,1H),8.01–7.44(m,4H),6.48(s,1H),5.43(s,2H),4.57(s,2H),3.94(s,1H),3.48( s,2H),3.14(s,2H),2.85(s,3H),2.23-2.22(m,3H),2.14-2.19(m,4H),1.94(s,1H),1.90-1.70(m,3H),1.65(s,3H).

[0831] Example 51. Synthesis of (Z)-12-hydroxy-12-methyl-2-(((R)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 209)

[0832] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0833] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.54 mmol) and 3-chloroperbenzoic acid (186 mg, 1.08 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution 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] + ;

[0834] 2) Synthesis of tert-butyl (3R)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylate

[0835] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azene-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.52 mmol) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (120.5 mg 0.65 mmol) in 1,4-dioxane (5 mL) was heated at 100°C and stirred overnight. After cooling, the mixed reaction solution was concentrated under reduced pressure and purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give (3R)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (162 mg, yield: 62%), LC-MS m / z: 508 [M+H] + ;

[0836] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-(((R)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0837] To a solution of tert-butyl (3R)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylate (162 mg, 0.32 mmol) in dichloromethane (0.9 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.3 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 0.5 hour. 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) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-(((R)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (120 mg, yield: 92.1%), LC-MS m / z: 408 [M+H] + ;

[0838] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-(((R)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0839] To a solution of (Z)-12-hydroxy-12-methyl-2-(((R)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitre-bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (120 mg, 0.29 mmol), 1-methyl-1H-imidazole (118.9 mg, 1.45 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (162.4 mg, 0.58 mmol) and 1-methyl-1H-piperidine-4-carboxylic acid (49.8 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-(((R)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (71 mg, yield: 45.0%), LC-MS m / z: 533 [M+H] + ;

[0840] 1 H NMR (400MHz, MeOD): δ8.73(s,1H),7.93(s,1H),7.76(s,1H),7.57(d,J=6.6Hz,1H),5.51–5.33(m,2H),4.58(s, 2H), 4.01–3.39 (m, 7H), 3.04–2.75 (m, 6H), 2.25 (d, J = 73.5Hz, 4H), 1.98 (dd, J = 29.8, 10.9Hz, 6H), 1.67 (s, 3H).

[0841] Example 52. Synthesis of (Z)-12-hydroxy-12-methyl-2-(((R)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (Compound 210)

[0842] 1) Synthesis of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0843] A solution of (Z)-12-hydroxy-12-methyl-2-(methylthio)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.54 mmol) and 3-chloroperbenzoic acid (186 mg, 1.08 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. The resulting mixed reaction solution 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] + ;

[0844] 2) Synthesis of tert-butyl (3S)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylate

[0845] A solution of (Z)-12-hydroxy-12-methyl-2-(methylsulfinyl)-7,10,11,12-tetrahydro-5H-13,17-(azene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (200 mg, 0.52 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (120.5 mg 0.65 mmol) in 1,4-dioxane (5 mL) was heated at 100°C and stirred overnight. After cooling, the mixed reaction solution was concentrated under reduced pressure and purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give (3S)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (162 mg, yield: 62%), LC-MS m / z: 508 [M+H] + ;

[0846] 3) Synthesis of (Z)-12-hydroxy-12-methyl-2-(((S)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one

[0847] To a solution of tert-butyl (3S)-3-(((Z)-12-hydroxy-12-methyl-5-oxo-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-2-yl)amino)pyrrolidine-1-carboxylate (162 mg, 0.32 mmol) in dichloromethane (0.9 mL) was added dropwise 2,2,2-trifluoroacetic acid (0.3 mL) at room temperature. The resulting mixed reaction solution was stirred at room temperature for 0.5 hour. 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) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-(((S)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (120 mg, yield: 92.1%), LC-MS m / z: 408 [M+H] + ;

[0848] 4) Synthesis of (Z)-12-hydroxy-12-methyl-2-(((S)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one

[0849] To a solution of (Z)-12-hydroxy-12-methyl-2-(((S)-pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridged)pyrimido[4′,5′:3,4]pyrazolo[1,2-a][1,2]diazacyclotridecan-5-one (120 mg, 0.29 mmol), 1-methyl-1H-imidazole (118.9 mg, 1.45 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (162.4 mg, 0.58 mmol) and 1-methyl-1H-piperidine-4-carboxylic acid (49.8 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 reverse phase column chromatography (CH3CN:H2O (0.1% NH4HCO3) = 5-95% elution) to give (Z)-12-hydroxy-12-methyl-2-(((S)-1-(1-methylpiperidine-4-carbonyl)pyrrolidin-3-yl)amino)-7,10,11,12-tetrahydro-5H-13,17-(nitrene bridge)pyrimido[4', 5':3,4]pyrazolo[1,2-a][1,2]diazacyclotridecen-5-one (56 mg, yield: 35.2%), LC-MS m / z: 533 [M+H] + ;

[0850] 1 H NMR (400MHz, MeOD): δ8.73(s,1H),7.93(s,1H),7.76(dd,J=8.1,4.5Hz,1H),7.56(d,J=7.7Hz,1H),5.43(dd,J=17.7,9.2Hz,2H),4.58(s,2H),3.95(s ,1H),3.75(d,J=7.1Hz,2H),3.66–3.47(m,2H),3.45–3.35(m,2H),2.81(d t,J=34.9,11.3Hz,6H),2.41–2.08(m,4H),2.07–1.82(m,6H),1.67(s,3H).

[0851] Example 53. Synthesis of (S)-N-(4-((((R,Z)-12-hydroxy-12-methyl-5-ox...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer, isotope-substituted product, and polymorph thereof, in, X0, X1 and X2 are each independently selected from -C(R x )–or-N-; L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, a double bond, an acetylenic 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)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-; L is absent or selected from O, S, CH2, C(O), S(O), S(O)2, NH, C(O)NH, NHC(O); Ring C is selected from heterocyclic groups which are unsubstituted or substituted by R0; R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to more selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, and CN; or any two R2 and R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; R1, R d1 , R d2 , R x are independently selected from hydrogen, deuterium, halogen, cyano, oxo (=O), amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 Cycloalkyl radical substitution; or R d1 and R d2 , R d1 and R5 may form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3; R d3 Any independently selected from hydrogen, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is further optionally substituted by 1 to more atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturation or partial The substituents of the saturated cycloalkyl or heterocyclic groups are substituted; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; q is an integer arbitrarily selected from 0, 1, 2 and 3.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof, characterized in that: X0, X1 and X2 are each independently selected from -C(R x )-or-N-;R x Selected from H, C 1-6 Alkyl (e.g. methyl); Preferably, X0 is -CH-; Preferably, X1 is N; Preferably, X2 is N.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, enantiomer, isotope-substituted product, and polymorph thereof, characterized in that: L is selected from O, S or NH; Preferably, L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, no substitution or optionally replaced by one, two or more R d1 Substituted with the following groups: 1-6 Alkyl, C 2-6 alkenyl; Preferably, L3, L4, L5, L6 and L7 are the same or different and are independently selected from the group consisting of absence, a single bond, no substitution or optionally replaced by one, two or more R d1 Substituted with the following groups: CH2, CH2CH2, CH2CH2CH2, CH=CH, CH ＝ CHCH2; Preferably, L3 is selected from -C(R d1 )(R d1 )-; preferably -C(CH3)(OH)-; Preferably, L6 is selected from vinylene, and the vinylene is preferably cis; Preferably, L4, L5 and L7 are the same or different and are independently selected from CH2; Preferably, each R d1 The same or different, independently selected from H, OH, C 1-6 Alkyl (eg, methyl).

4. The compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof, characterized in that: Ring C is selected from a heterocyclic group which is unsubstituted or substituted by R0; the heterocyclic group may be selected from a piperidinyl group (such as ), piperazinyl (such as ), morpholinyl (such as ), azetidinyl (such as ), tetrahydropyrrolidone (such as )、 Preferably, Selected from Preferably, Selected from 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof, characterized in that: R0 is selected from H, C 1-10 Alkyl, C 1-10 Alkoxy, deuterated C 1-10 Alkyl, halogenated C 1-10 Alkyl, HC(O)-, NH2C(O)-, C 1-10 Alkyl-C(O)-, C 1-10 Alkoxy-C(O)-, C 3-8 Cycloalkyl-C(O)-, 3-8 membered heterocyclic group; Preferably, R0 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, HC(O)-, NH2C(O)-, C 1- 6-alkyl-C(O)-, C 1-6 Alkoxy-C(O)-, C 3-6 Cycloalkyl-C(O)-, 3-6 membered heterocyclic group; Preferably, R0 is selected from H, methyl, ethoxy, trideuterated methyl, CF3CH2-, HC(O)-, CH3C(O)-, Preferably, each R1 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halo-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl or 5-10 membered heteroaryl Preferably, each R1 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy-C(O)-; Preferably, each R1 is the same or different and is independently selected from H, methyl, deuterium, oxo (=O), Preferably, each R2 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halo-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl or 5-10 membered heteroaryl; Preferably, each R2 is the same or different and is independently selected from H or C 1-6 Alkyl (such as methyl); Preferably, each R5 is the same or different and is independently selected from H, deuterium, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C(O)-, halo-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 6-10 Aryl or 5-10 membered heteroaryl; Preferably, each R5 is the same or different and is independently selected from H or C 1-6 Alkyl (eg, methyl).

6. The compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof, which has the structure of formula (II), in, L, L3, L4, L5, L6, L7, X0, X1, X2, R0, R1, R2, R5, m, n, q are independently defined as described in any one of claims 1 to 5; Preferably, X0, X1 and X2 are each independently selected from -C(R x )–or-N-; L3, L4, L5, L6 and L7 are independently selected from the group consisting of absence, a single bond, a double bond, an acetylenic 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)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-; L arbitrarily and independently selects O, S or NH; R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to more selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, and CN; or any two R2 and R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; R1, R d1 , R d2 , R x are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 Cycloalkyl radical substitution; or R d1 and R d2 or R d1 and R5 may form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3; R d3 Any independently selected from hydrogen, NH2, C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 Heterocyclic group; wherein said C 1-10 Alkyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 1-10 Alkyl acyl, C 1-10 Alkylsulfonyl, C 2-10 Heteroalkyl, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 1-10 Alkyl or C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl substituted C 3-10 The heterocyclic group is further optionally substituted by 1 to more atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 Saturated or partially substituted groups are substituted by substituents of saturated cycloalkyl or heterocyclic groups; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; q is an integer arbitrarily selected from 0, 1, 2 and 3; Preferably, it has the structure of formula (IA), Among them, L, X2, R0, R1, R2, R5, R d1 , m, n, q are independently defined as described in any one of claims 1 to 5, and p is arbitrarily selected from integers of 0, 1, 2, 3 and 4; Preferably, X2 is independently selected from -C(R x )–or-N-; L arbitrarily and independently selects O, S or NH; R0 is independently selected from H, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to more selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, and CN; or any two R2 and R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; R1, R d1 and R x are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R d1 and R5 may form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; q is an integer arbitrarily selected from 0, 1, 2 and 3; p is an integer arbitrarily selected from 0, 1, 2, 3 and 4; Preferably, it has the structure of formula (IB), Among them, R0, R1, R2, R5, R d1 , m, n, q independently have the definitions in any one of claims 1 to 5; Preferably, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; Each R2 or R5 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2- 10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 or R5 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures; and the alicyclic rings, heterocyclic rings, cyclic rings, spirocyclic rings or bridged ring structures can contain 0 to more unsaturated olefinic bonds; furthermore, the hydrogen on R2 or R5 is optionally replaced by 1 to more selected The substituents are selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, and CN; or any two R2 and R5 together with the carbon to which they are attached form a 5-6 membered heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, =O, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one to more alkyl radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, saturated or partially saturated C 3-6 radical substitution of cycloalkyl groups; R1 and R d1 are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C3-10 heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1- 6 alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R d1 and R5 may form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl, heterocyclyl is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; q is an integer arbitrarily selected from 0, 1, 2 and 3; p is an integer arbitrarily selected from 0, 1, 2, 3 and 4; Preferably, it has the structure of formula (IC), Wherein, R0, R1, R2, m, and n are independently defined as described in any one of claims 1 to 5; Preferably, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3-10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic ring, heterocyclic ring, cyclic ring, spiro ring or bridged ring structure can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 is optionally substituted with 1 to multiple substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; R1 is independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkylamino, aryl, heteroaryl, N,N-di(C 1-10 Alkyl)amino, C 1-10 Alkyloxy, C 1-10 Alkyl acyl, C 1-10 Alkyloxy, C 1-10 Alkylsulfonyl, C 1-10 Alkylsulfinyl, C 3-10 Cycloalkylamino, C 3-10 Heterocycloalkylamino, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl acyl, C 3-10 Cycloalkoxyacetyl, C 3-10 Cycloalkylsulfonyl and C 3-10 Cycloalkylsulfinyl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, oxy, and saturated or partially saturated C 3-6 Cycloalkyl substituted, and C 1-6 Alkyl and C 1-6 The alkoxy group is optionally further substituted with one to more radicals selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3 and saturated or partially saturated C 3-6 or optionally R d1 and R5 may form, together with the carbon to which it is attached, a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl, heterocyclyl is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m is an integer arbitrarily selected from 0, 1, 2, 3 and 4; n is an integer arbitrarily selected from 0, 1, 2, 3 and 4; Preferably, it has the structure of formula (ID), Wherein, R0 and R2 independently have the definitions described in any one of claims 1 to 5; Preferably, R0 is independently selected from H, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, alkoxyalkyl, alkynyl, acetyl, mesyl, phosphonyl; further, the hydrogen on R0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, OCH3, carboxyl, OH, CN; R2 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -COOH or selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 1-10 Alkoxy, C 2-10 Heteroalkyl, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 Saturated or partially saturated heterocycloalkyl, C 3- 10 Cycloalkyl or C 3-10 Heterocycloalkyl substituted C 1-10 Alkyl, C 3-10 Cycloalkyl substituted C 2-10 Heteroalkyl, C 3-10 Heterocyclic group, C 1-10 Alkyl-substituted carboxyl or carboxyl substitute, aryl, heteroaryl; or any two R2 together with the carbon atoms connected to them on the ring form a 3-8 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, cyclic rings, spiro rings or bridged ring structures; and the aliphatic ring, heterocyclic ring, cyclic ring, spiro ring or bridged ring structure can contain 0 to multiple unsaturated olefinic bonds; furthermore, the hydrogen on R2 is optionally substituted with 1 to multiple substituents selected from H, deuterium, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, OCH3, carboxyl, OH, CN; The heteroatom represents any heteroatom independently selected from O, N, S, P, S=O and S(=O)2 and isotopes thereof; The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; Preferably, it has the structure of formula (III), Among them, ring C, L, X0, X1, X2, R1, R2, R5, R d1 , m, n, q independently have the definitions in any one of claims 1 to 5; Preferably, it has the structure of formula (IIIA), Among them, L, X2, R0, R1, R2, R d1 Independently of each other, it has the definition of any one of claims 1 to 5; Preferably, it has the structure shown in formula (IE):

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product and polymorph thereof, which has the structure shown below: Preferably, it has the following structure:

8. A polymorph of the compound represented by formula (IE), in, The polymorph is selected from a non-solvate crystalline form, a hydrate crystalline form or a metastable crystalline form of compound IE; Preferably, the ansolvate crystal form may be the following crystal forms A, B, and C; the hydrate crystal form may be the following crystal forms D, E, F, and G; the metastable crystal form may be the following crystal forms H, I, J, K, L, M, N, O, P, and Q; For the crystal form A, it is characterized by: The crystalline form A has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 5.10±0.2°, 15.72±0.2°, 15.25±0.2° and 20.53±0.2°; Preferably, the crystalline form A preferably further comprises peaks 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 crystalline form A more preferably further comprises peaks 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 crystalline form A has a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°: Table 1 Preferably, the crystalline form A has an X-ray powder diffraction intensity as shown in Table 1; Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 1; Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of 180.86°C; Preferably, the crystalline form A has a DSC spectrum substantially as shown in FIG2 ; Preferably, the crystalline form A has a TGA graph substantially as shown in FIG3 ; For the crystal form B, it is characterized by: The crystalline form B has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.33±0.2°, 5.18±0.2°, 13.69±0.2° and 18.72±0.2°; Preferably, the crystalline form B preferably further comprises peaks 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 crystalline form B more preferably further comprises peaks 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 the crystalline form B has a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°: Table 2 Preferably, the crystalline form B has an X-ray powder diffraction intensity as shown in Table 2; Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG4 ; Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of 179.71°C; Preferably, the crystalline form B has a DSC spectrum substantially as shown in FIG5 ; Preferably, the crystalline form B has a TGA graph substantially as shown in Figure 6; For the crystal form C, it is characterized by: The crystalline form C has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 5.39±0.2°, 12.05±0.2°, 9.70±0.2° and 18.00±0.2°; Preferably, the crystalline form C preferably further comprises peaks 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 crystalline form C more preferably further comprises peaks 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 crystalline form C has a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°: Table 3 Preferably, the crystalline form C has an X-ray powder diffraction intensity as shown in Table 3; Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG7 ; Preferably, the DSC analysis of the crystalline form C shows an endothermic peak when heated to a peak temperature of 173.43°C; Preferably, the crystalline form C has a DSC spectrum substantially as shown in FIG8 ; Preferably, the crystalline form C has a TGA graph substantially as shown in FIG9 ; The hydrate crystal form D is characterized by: The crystalline form D has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.20±0.2°, 15.74±0.2°, 22.81±0.2° and 18.39±0.2°; Preferably, the crystalline form D preferably further comprises peaks 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 crystalline form D more preferably further comprises peaks 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 crystalline form D has a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°: Table 4 Preferably, the crystalline form D has an X-ray powder diffraction intensity as shown in Table 4; Preferably, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in Figure 10; Preferably, the DSC analysis of the crystalline form D shows endothermic peaks when heated to peak temperatures near 157.79°C and 181.65°C; Preferably, the crystalline form D has a DSC spectrum substantially as shown in FIG11 ; Preferably, the crystalline form D has a TGA spectrum substantially as shown in Figure 12; The hydrate crystal form E is characterized by: The crystalline form E has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.54±0.2°, 13.72±0.2°, 9.12±0.2° and 18.35±0.2°; Preferably, the crystalline form E preferably further comprises peaks 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 crystalline form E more preferably further comprises peaks 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 crystalline form E has a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°: Table 5 Preferably, the crystalline form E has an X-ray powder diffraction intensity as shown in Table 5; Preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in Figure 13; Preferably, the DSC analysis of the crystalline form E shows endothermic peaks near the peak temperatures of 69.77°C and 181.95°C; Preferably, the crystalline form E has a DSC spectrum substantially as shown in FIG14 ; Preferably, the crystalline form E has a TGA spectrum substantially as shown in Figure 15; The hydrate crystal form F is characterized by: The crystalline form F has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.08±0.2°, 18.27±0.2°, 6.25±0.2° and 13.73±0.2°; Preferably, the crystalline form F preferably further comprises peaks 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 crystalline form F more preferably further comprises peaks 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 crystalline form F has a diffraction angle (2θ) as shown in Table 6, wherein the error range of the 2θ angle is ±0.20°: Table 6 Preferably, the crystalline form F has an X-ray powder diffraction intensity as shown in Table 6; Preferably, the crystalline form F has an X-ray powder diffraction pattern substantially as shown in Figure 16; Preferably, the DSC analysis of the crystalline form F shows endothermic peaks near the peak temperatures of 101.36°C and 177.98°C, and an exothermic peak near 146.72°C; Preferably, the crystalline form F has a DSC spectrum substantially as shown in FIG17 ; Preferably, the crystalline form F has a TGA graph substantially as shown in Figure 18; The hydrate crystal form G is characterized by: The crystalline form G has an X-ray powder diffraction pattern including peaks 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 crystalline form G preferably further comprises peaks 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 crystalline form G more preferably further includes peaks 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 crystalline form G has a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°: Table 7 Preferably, the crystalline form G has an X-ray powder diffraction intensity as shown in Table 7; Preferably, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in Figure 19; Preferably, the DSC analysis of the crystalline form G shows an endothermic peak when heated to a peak temperature of 126.74°C; Preferably, the crystalline form G has a DSC graph substantially as shown in Figure 20; Preferably, the crystalline form G has a TGA graph substantially as shown in Figure 21; For the metastable crystal form H, it is characterized by: The metastable form H has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 6.02±0.2°, 3.96±0.2°, 12.66±0.2° and 9.35±0.2°; Preferably, the crystalline form H preferably further comprises peaks 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 crystalline form H more preferably further comprises peaks 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 a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°: Table 8 Preferably, the crystalline form H has an X-ray powder diffraction intensity as shown in Table 8; Preferably, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in Figure 22; Preferably, the DSC analysis of the crystalline form H shows endothermic peaks near the peak temperatures of 61.06°C and 151.59°C; Preferably, the crystalline form H has a DSC spectrum substantially as shown in FIG23 ; Preferably, the crystalline form H has a TGA graph substantially as shown in Figure 24; For metastable crystal form I, it is characterized by: The metastable form I has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.93±0.2°, 4.37±0.2°, 16.01±0.2° and 7.45±0.2°; Preferably, the crystalline form I preferably further comprises peaks 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 crystalline form I more preferably further comprises peaks 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 crystalline form I has a diffraction angle (2θ) as shown in Table 9, wherein the error of the 2θ angle is The difference range is ±0.20°: Table 9 Preferably, the crystalline form I has an X-ray powder diffraction intensity as shown in Table 9; Preferably, the crystalline form I has an X-ray powder diffraction pattern substantially as shown in Figure 25; For metastable crystal form J, it is characterized by: The metastable form J has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 5.78±0.2°, 8.06±0.2°, 12.04±0.2° and 16.19±0.2°; Preferably, the crystalline form J preferably further comprises peaks 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 crystalline form J more preferably further comprises peaks 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 crystalline form J has a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°: Table 10 Preferably, the crystalline form J has an X-ray powder diffraction intensity as shown in Table 10; Preferably, the crystalline form J has an X-ray powder diffraction pattern substantially as shown in Figure 26; For the metastable crystal form K, it is characterized by: The metastable form K has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 4.05±0.2°, 4.89±0.2°, 4.44±0.2° and 5.92±0.2°; Preferably, the crystalline form K preferably further comprises peaks 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 more preferably further includes the positions at 14.59±0.2°, 9.84±0.2°, 13.38±0.2°, 20.10±0.2°, peaks at diffraction angles (2θ) of 14.08 ± 0.2° and 15.76 ± 0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form K has a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°: Table 11 Preferably, the crystal form K has an X-ray powder diffraction intensity as shown in Table 11; Preferably, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 27; For the metastable crystal form L, it is characterized by: The metastable crystalline form L has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.67±0.2°, 15.29±0.2°, 14.75±0.2° and 11.76±0.2°; Preferably, the crystalline form L preferably further comprises peaks 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 crystalline form L more preferably further comprises peaks 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 crystalline form L has a diffraction angle (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°: Table 12 Preferably, the crystalline form L has an X-ray powder diffraction intensity as shown in Table 12; Preferably, the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 28; For the metastable crystal form M, it is characterized by: The metastable crystalline form M has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.26±0.2°, 14.79±0.2°, 17.07±0.2° and 14.57±0.2°; Preferably, the crystalline form M preferably further comprises peaks 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 crystalline form M more preferably further comprises peaks 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 crystalline form M has a diffraction angle (2θ) as shown in Table 13, wherein the error range of the 2θ angle is ±0.20°: Table 13 Preferably, the crystalline form M has an X-ray powder diffraction intensity as shown in Table 13; Preferably, the crystalline form M has an X-ray powder diffraction pattern substantially as shown in Figure 29; For the metastable crystal form N, it is characterized by: The metastable crystalline form N has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.48±0.2°, 5.02±0.2°, 5.55±0.2° and 11.61±0.2°; Preferably, the crystalline form N preferably further comprises peaks 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 crystalline form N more preferably further comprises peaks 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 crystalline form N has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°: Table 14 Preferably, the crystalline form N has an X-ray powder diffraction intensity as shown in Table 14; Preferably, the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 30; For the metastable crystal form O, it is characterized by: The metastable crystalline form O has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.54±0.2°, 3.37±0.2°, 5.96±0.2° and 12.21±0.2°; Preferably, the crystalline form O preferably further comprises peaks 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 crystalline form O has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°: Table 15 Preferably, the crystalline form O has an X-ray powder diffraction intensity as shown in Table 15; Preferably, the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 31; For the metastable crystal form P, it is characterized by: The metastable crystalline form P has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.81±0.2°, 4.29±0.2°, 6.08±0.2° and 14.65±0.2°; Preferably, the crystalline form P preferably further comprises peaks 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 crystalline form P more preferably further comprises peaks 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 crystalline form P has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°: Table 16 Preferably, the crystal form P has an X-ray powder diffraction intensity as shown in Table 16; Preferably, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 32; For the metastable crystal form Q, it is characterized by: The metastable crystalline form Q has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 4.96±0.2°, 7.42±0.2°, 14.82±0.2° and 21.77±0.2°; Preferably, the crystalline form Q preferably further comprises peaks 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 crystalline form Q more preferably further comprises peaks 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 crystalline form Q has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°: Table 17 Preferably, the crystalline form Q has an X-ray powder diffraction intensity as shown in Table 17; Preferably, the crystalline form Q has an X-ray powder diffraction pattern substantially as shown in Figure 33.

9. The method for preparing the polymorph according to claim 8, comprising the steps of: Step 1: dissolving or dispersing compound IE in a solvent; Step 2: stirring and crystallizing at 0-50°C; or, adding an anti-solvent to the clear solution of the compound to precipitate; or, slowly volatilizing the clear solution of the compound; Preferably, the compound IE is preferably a metastable crystalline form H of the compound IE. Preferably, the solvent is water, an organic solvent or a mixed solvent thereof, and the organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxide organic solvents or mixtures thereof; preferably, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, 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.

10. Use of the compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution or the polymorph according to claim 8 for preparing a drug for preventing and / or treating diseases related to WEE1 and / or Yes targets; Preferably, the disease includes tumor, inflammation, autoimmune disease (such as lupus erythematosus, psoriasis, psoriasis).

11. A pharmaceutical composition, wherein the main active ingredient is the compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution and polymorph thereof or the polymorph according to claim 8, and some other auxiliary ingredients, so that it can be suitable for various forms of pharmaceutical dosage forms such as liquid preparations (including oral liquids, injections, eye drops, etc.), solid preparations (including tablets, capsules, pills, granules, etc.), and the pharmaceutical composition can be used to prepare drugs for preventing and / or treating diseases related to WEE1 and / or Yes targets; Preferably, the disease includes tumor, inflammation, autoimmune disease (such as lupus erythematosus, psoriasis, psoriasis).

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