Dicarbonyl inhibitor, preparation method therefor and use thereof

Abstract

The present invention relates to a dicarbonyl inhibitor, a preparation method therefor and the use thereof. Specifically, the compound of the present invention has a structure represented by formula (I0). Also disclosed are a preparation method for the compound and the use thereof as a KRAS mutation inhibitor. The compound has good inhibitory effect on KRAS mutation, and has better pharmacodynamic and pharmacokinetic properties and low toxic and side effects.

Description

Dicarbonyl inhibitors, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a dicarbonyl inhibitor, its preparation method, and its application. Background Technology

[0002] Approximately one-quarter of all human cancers are caused by RAS mutations, resulting in nearly one million deaths annually. Within the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (primarily non-small cell lung cancer).

[0003] KRAS protein is a small GTPase encoded by the KRAS gene and is an important regulatory protein for cell growth. Once activated, KRAS can activate multiple signaling pathways, promoting cell proliferation. The most common sites of KRAS protein gene mutation are codons 12, 13, and 61, with codon 12 mutations being the most frequent. The most prevalent KRAS G12 mutations are G12A, G12C, G12D, G12V, and G12S mutations, with G12C, G12D, and G12V mutations primarily occurring in NSCLC, CRC, and pancreatic cancer. To date, no drugs targeting multiple KRAS mutations have been approved for marketing.

[0004] Because the target protein of KRAS mutations is pathologically associated with a variety of diseases, especially lung cancer, pancreatic cancer, and colorectal cancer, there is a current need for novel KRAS mutation inhibitors for clinical treatment. Highly active KRAS mutation inhibitors can more effectively treat diseases such as cancers caused by KRAS mutations and have the potential to reduce off-target effects, thus meeting a more urgent clinical need. Summary of the Invention

[0005] One object of the present invention is to provide a novel class of compounds that have inhibitory effects on KRAS mutations and / or better pharmacodynamic properties.

[0006] In a first aspect of the invention, a compound of formula (I0) is provided, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, crystal form, hydrate, solvate, prodrug, or combination thereof.

[0007] in,

[0008] W is selected from: O, S, or N(R) w ); R wSelected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy, OH, or CN; the substitution refers to substitution by one or more R groups;

[0009] Ring A is selected from the following group, either substituted or unsubstituted: H, C3-C. 10 Cycloalkyl, 4-10 saturated or unsaturated heterocyclic groups, wherein the heterocyclic group or cycloalkyl group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, P, S and O, and the substitution refers to substitution by one or more R.

[0010] Alternatively, ring A is selected from C4 cycloalkyl, -(NRpRq), or -(RpRqN(R)), wherein Rp and Rq, together with the N atom they are attached to, form substituted or unsubstituted groups from the following group: 4-7 membered saturated or partially saturated monocyclic heterocyclic groups, 7-10 membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more groups, each independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic groups, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 ethynyl; wherein the alkyl, alkenyl, ethynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0011] R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R;

[0012] R b2 and R b3 Each is independently selected from the following group: H, D, halogen, or CN;

[0013] R L1Selected from the following group of substituted or unsubstituted groups: none, bonded, -O-, -S-, -NH-, -N(C1-C3 alkyl)-, -O-(C1-C3 alkylene)-, -S-(C1-C3 alkylene)-, -N(C1-C3 alkyl)-(C1-C3 alkylene)-, or -C≡C-; wherein, the substitution refers to being substituted by one or more R groups;

[0014] R L2 Selected from the following group, whether substituted or unsubstituted: unsubstituted, bonded, C3-C6 cycloalkylene, 4-6 membered heterocyclic, -C1-C6 alkylene-C3-C6 cycloalkylene-, or -C1-C6 alkylene-4-6 membered heterocyclic-; wherein the heterocyclic group has 1-3 heteroatoms, each independently selected from N, S and O, and the substitution refers to substitution by one or more R;

[0015] R L3 Selected from the following group of substituted or unsubstituted groups: none, bonded, C1-C6 alkylene, -O-, -S-, -NH-, -N(C1-C3 alkyl)-, -O-(C1-C3 alkylene)-, -S-(C1-C3 alkylene)-, or -N(C1-C3 alkyl)-(C1-C3 alkylene)-; wherein, the substitution refers to being substituted by one or more R groups;

[0016] The ring C is selected from the following group: C6-C, whether substituted or unsubstituted. 14 The aryl or 5-14 membered heteroaryl or 5-14 membered saturated or unsaturated heterocyclic group contains 1-3 heteroatoms each independently selected from N, S and O; wherein the substitution refers to substitution by one or more R;

[0017] R c Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, -(C1-C6 alkylene)-phenyl, -(C1-C6 alkylene)-6 membered heteroaryl, or two adjacent Rs on the same side. c The ring atoms attached to it together form substituted or unsubstituted 5-7 membered heterocyclic groups or C5-C7 cycloalkyl groups; wherein, each R c Optionally replaced by halogen or deuterium; nc is selected from the group consisting of: 0, 1, 2, 3, 4, 5, or 6;

[0018] Or, R b1 and R cThe divalent group is linked by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R groups;

[0019] Ring D is selected from substituted or unsubstituted 5-10 membered heterocyclic groups; wherein the heterocyclic group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution is by one or more R.

[0020] R d The group is selected from the following group, whether substituted or unsubstituted: deuterium, amino, cyano, nitro, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halo-C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group, wherein the substitution refers to substitution by one or more R; nd is 0, 1, 2, 3, 4, 5, or 6;

[0021] Ring G is selected from the following group of substituted or unsubstituted groups: 4-10 membered heterocyclic groups, C6-C 14 Aryl or 5-14 membered heteroaryl; wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution refers to substitution by one or more R;

[0022] R g The group is selected from the following group, whether substituted or unsubstituted: deuterium, cyano, amino, oxo, nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 deuteratedalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein, the substitution refers to substitution by one or more R; ng is selected from the following group: 0, 1, 2, 3, 4, 5 or 6;

[0023] X is selected from the following group, whether substituted or unsubstituted:

[0024] key;

[0025] -(L) n -C1-C6 alkylene-, -(L) n -C3-C 14 Cycloalkylene -, -(L) n -4-14-membered heterocyclic group-, -(L) n -C6-C 10 Alpha-aryl-, -(L) n -5-14-methyl-hybrid aryl-;

[0026] -(L) n -C3-C 14 Cycloalkylene-C1-C6 alkylene-, -(L) n -4-14 membered heterocyclic group-C1-C6 alkylene group-,-(L) n -C6-C 10 arylene-C1-C6 alkylene-, -(L) n -5-10-membered heteroaryl-C1-C6 alkylene-;

[0027] -(L) n -O-C1-C6 alkylene-, -(L) n -O-C3-C 14 Cycloalkylene -, -(L) n -O-4-14-membered heterocyclic group-, -(L) n -O-C6-C 10 Alpha-aryl-, -(L) n -O-5-14-pyroaryl-;

[0028] -(L) n -N(R 3 )-C1-C6 alkylene-、-(L) n -N(R 3 )-C3-C 14 Cycloalkylene -, -(L) n -N(R 3 )-4-14-membered heterocyclic group-、-(L) n -N(R 3 )-C6-C 10 Alpha-aryl-, -(L) n -N(R 3 )-5-14-pyroaryl-; or

[0029] -(L) n -N(R 3 )-、-R x1 -(L) n -N(R 3 )-R x2 -or-R x1 -N(R 3 )-(L) n -R x2 -; n is 0, 1, 2, 3, 4, 5, or 6;

[0030] L is independently selected from the following group of substituent or unsubstituted groups: none, O, S, -N(R) 3 )-, methylene (-CH2-), -C3-C 14Cycloalkyl-, -4-14-membered heterocyclic-; wherein, the substitution refers to substitution by one or more R;

[0031] Among them, R 3 Each group is independently selected from the following group, either substituted or unsubstituted: H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group; wherein, substitution means substitution by one or more R groups;

[0032] R x1 and R x2 Each group is independently selected from the following group: substituted or unsubstituted: bond, -C1-C6 alkylene-, -C3-C 14 Cycloalkylene-, -4-14 membered heterocyclic-; the substitution refers to the substitution of one or more hydrogens on the group by R;

[0033] R L4 Selected from the group consisting of: bond, O, -NH-, -N(C1-C4 alkyl)-, or -N(C3-C6 cycloalkyl)-, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more R groups;

[0034] R L5 Selected from the following groups, whether substituted or unsubstituted: hydrogen, C1-C6 alkyl, C3-C4 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7 ... 14 Cycloalkyl, 4-14 membered heterocyclic, C6-C 10 Aryl, 4-12 heteroaryl, -(C1-C6 alkylene)-C3-C 14 Cycloalkyl, -(C1-C6 alkylene)-4-14 membered heterocyclic, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-4-12 heteroaryl, -(C3-C 10 (cycloalkylene)-C6-C 10 Aryl, -(4-11-membered heterocyclic)-C6-C 10 Aryl, -(C3-C 10 -(4-11-heterocyclic)-4-12-membered heteroaryl, -NR1R2, -(C1-C3 alkylene)-NR1R2;

[0035] Wherein, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, or, R1 and R2 and the N atom they are connected to together form a substituted or unsubstituted 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R;

[0036] Each R may be the same or different, and each is independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclic-O-, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -C(O)-4-7 membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6 membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6 membered heterocyclic-oxy)-(C1-C6 alkylene)-, (C1-C6 alkyl)-vinylene, deuterated (C1-C6 alkyl)-vinylene, halogenated (C1-C6 alkyl)-vinylene (C1-C6 alkyl)-ethynyl, deuterated (C1-C6 alkyl)-ethynyl, halogenated (C1-C6 alkyl)-ethynyl, (C3-C6 cycloalkyl)-ethynyl, (4-6 membered heterocyclic)-ethynyl, (C3-C6 cycloalkyl)-ethynyl or (4-6 membered heterocyclic)-C3-C6 ethynyl; wherein the alkylene, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy.

[0037] In another preferred embodiment, in the compound represented by formula (I0),

[0038] A is selected from the following group, whether substituted or unsubstituted: H, C3-C 10 Cycloalkyl, 4-10 saturated or unsaturated heterocyclic groups, wherein the heterocyclic group or cycloalkyl group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution refers to substitution by one or more R.

[0039] In another preferred embodiment, in the compound represented by formula (I0),

[0040] R b1Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R;

[0041] R b2 and R b3 Each is independently selected from the following group: H, D, halogen, or CN;

[0042] R c Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, -(C1-C6 alkylene)-phenyl, -(C1-C6 alkylene)-6 membered heteroaryl, or two adjacent Rs on the same side. c The ring atoms attached to it together form substituted or unsubstituted 5-7 membered heterocyclic groups or C5-C7 cycloalkyl groups; wherein, each R c Optionally replaced by halogen or deuterium; nc is selected from the group consisting of: 0, 1, 2, 3, 4, 5, or 6.

[0043] In another preferred embodiment, in the compound represented by formula (I0),

[0044] Each R may be the same or different, and each is independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclic-O-, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -C(O)-4-7 membered heterocyclic, C6-C 10Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6 membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6 membered heterocyclic-oxy)-(C1-C6 alkylene)-, (C1-C6 alkyl)-vinylene, deuterated (C1-C6 alkyl)-ethylene Alkenyl, halogenated (C1-C6 alkyl)-vinylene, (C1-C6 alkyl)-ethynyl, deuterated (C1-C6 alkyl)-ethynyl, halogenated (C1-C6 alkyl)-ethynyl, (C3-C6 cycloalkyl)-ethynyl or (4-6 membered heterocyclic)-ethynyl; wherein the alkylene, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, oxo (=O), C1-C4 alkyl, halogenated C1-C4 alkyl.

[0045] In another preferred example, W is O.

[0046] In another preferred example, W is NMe.

[0047] In another preferred embodiment, W is NOH.

[0048] In another preferred example, W is NCN.

[0049] In another preferred embodiment, W is NO-CH3 or NO-CH2CH3.

[0050] In another preferred embodiment, ring G is selected from the group consisting of substituted or unsubstituted lower groups: 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more R groups; preferably, ring G is selected from the group consisting of substituted or unsubstituted lower groups: 5 membered heteroaryl; more preferably, ring G is selected from the group consisting of substituted or unsubstituted lower groups:

[0051] In another preferred embodiment, R g Selected from the following group, whether substituted or unsubstituted: deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 deuteralkyl, C3-C5 cycloalkyl, or 4-6 membered heterocyclic group; wherein, the substitution refers to substitution by one or more R; ng is selected from the following group: 0, 1, or 2.

[0052] In another preferred embodiment, ring G is selected from...

[0053] In another preferred embodiment, ring G is selected from...

[0054] In another preferred example, ng is selected from 0.

[0055] In another preferred embodiment, R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: deuterium, hydroxyl, nitro, cyano, amino, halogen, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, ester, and C3-C6 cycloalkyl.

[0056] In another preferred embodiment, R b1 Selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, hydroxyl, nitro, cyano, amino, halogen, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, and C3-C6 cycloalkyl; preferably, R b1 The substituted ethyl group refers to a group that is substituted with methoxy, trifluoromethyl, cyclopropyl, or trifluoromethoxy.

[0057] In another preferred embodiment, R b2 and R b3 Each can be H or D independently.

[0058] In another preferred embodiment, R b1 Selected from methoxy-substituted ethyl groups; R b2 Selected from H;R b3 Selected from H.

[0059] In another preferred embodiment, R b1 It is selected from isopropyl, trifluoromethoxy-substituted ethyl, trifluoromethyl-substituted ethyl, or cyclopropyl-substituted ethyl.

[0060] In another preferred embodiment, R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, hydroxyl, nitro, cyano, amino, halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, deuterated C1-C4 alkoxy, ester group, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclic-O-.

[0061] In another preferred embodiment, R b1 Selected from trifluoromethoxy-substituted ethyl, trideuteroxy-substituted ethyl, ethoxy-substituted ethyl, difluoromethoxy-substituted ethyl, cyclopropyloxy-substituted ethyl, or oxacyclobutyloxy Substituted ethyl group.

[0062] In another preferred embodiment, X is selected from the key.

[0063] In another preferred embodiment, X is selected from...

[0064] In another preferred embodiment, the compound has the structure shown in Formula I:

[0065] In the formula,

[0066] Rings A and R L1 R L2 R L3 R b1 R b2 R b3 , ring C, R c nc, ring G, Rg, ng, ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0067] In another preferred embodiment, the compound has a structure represented by formula AI or BI:

[0068] In the formula,

[0069] Rings A and R L1 R L2 R L3 R b1 , ring C, R c nc, ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0070] In another preferred embodiment, the ring C is selected from substituted or unsubstituted 8-10-membered heteroaryl groups or 8-10-membered saturated or unsaturated heterocyclic groups; wherein the heteroaryl and heterocyclic groups contain 1-3 heteroatoms each independently selected from N, S and O, and the substitution refers to substitution by one or more R groups; preferably, the ring C is selected from substituted or unsubstituted benzo5-6-membered heteroaryl groups, substituted or unsubstituted benzo5-6-membered unsaturated heterocyclic groups, and substituted or unsubstituted pentaaryl-6-membered heteroaryl groups, and the substitution refers to substitution by one or more R groups;

[0071] More preferably, the ring C is selected from the following group of substituted or unsubstituted groups:

[0072] In another preferred embodiment, ring C is selected from substituted rings. Preferred

[0073] In another preferred embodiment, ring C is selected from substituted rings. Preferred

[0074] In another preferred embodiment, ring C is selected from substituted rings. Preferred

[0075] In another preferred embodiment, ring C is selected from substituted rings. Preferred

[0076] In another preferred embodiment, ring C is selected from substituted rings. Preferred

[0077] In another preferred embodiment, ring C is selected from...

[0078] In another preferred embodiment, R c Selected from the group consisting of: H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C5 cycloalkyl, halo-C3-C5 cycloalkyl, -(C1-C4 alkylene)-C3-C5 cycloalkyl, halo-(C1-C4 alkylene)-C3-C5 cycloalkyl; nc selected from the group consisting of: 1 or 2; preferably, R c Selected from ethyl, cyclopropyl, fluorocyclopropyl, ... nc is selected from 1.

[0079] In another preferred embodiment, R b1 and R c1 The divalent group is linked by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0080] In another preferred embodiment, R b1 and R c (better location R) c1The divalent group is linked by a divalent group, and the divalent group has the following structure: -M1-M2-M3-, wherein M1 and M3 are each independently selected from the group consisting of: bond, C1-C3 alkyl-substituted or unsubstituted -C1-C3 alkylene-, C1-C3 alkyl-substituted or unsubstituted -C2-C4 alkenyl-, C1-C3 alkyl-substituted or unsubstituted -C2-C4 alkyne-; M2 is selected from the group consisting of: -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0081] In another preferred embodiment, the compound has the structure shown in formula AII or formula BII:

[0082] In the formula,

[0083] R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0084] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0085] R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R;

[0086] Or, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0087] Rings A and R L1 R L2 R L3 , ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0088] In another preferred embodiment, the compound has the structure shown in formula AII or formula BII:

[0089] R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0090] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0091] Or R c1 and R c2 The groups are connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to being substituted by one or more R groups;

[0092] R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R;

[0093] Or, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0094] Rings A and R L1 R L2 R L3 , ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0095] In another preferred embodiment, the compound has a structure represented by formula AII or formula BII, wherein,

[0096] R c1Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0097] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0098] Rings A and R L1 R L2 R L3 R b1 , ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0099] In another preferred embodiment, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of -C1-C3 alkylene-, -O-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0100] In another preferred embodiment, R b1 and R c1 Linked by divalent groups selected from the following group: -CH2-O-CH2CH2-, -CH(CH3)-O-CH2CH2-, -CH(CH3)-O-CH2CH2-CH2-, -CH(CH3)-O-CH2CH(CH3)-, -CH(CH3)-N(CH3)-CH2CH2-, -CH(CH3)-N(CH3)-CH2CH(CH3)-, -CH(CH3)-N(CH3)-C(O)CH2-.

[0101] In another preferred embodiment, R b1 and R c1 Linked by divalent groups selected from the following group: -CH2-O-CH2CH2-, -CH(CH3)-O-CH2CH2-, -CH(CH3)-O-CH2CH(CH3)-, -CH(CH3)-N(CH3)-CH2CH2-, -CH(CH3)-N(CH3)-CH2CH(CH3)-, -CH(CH3)-N(CH3)-C(O)CH2-.

[0102] In another preferred embodiment, R b1 and R c1 Linked by divalent groups selected from the following group: -CH(CH3)-O-CH2CH2-, -CH(CH3)-O-CH2CH2-CH2-.

[0103] In another preferred embodiment, R b1 and R c1 The atoms connected to each other form a ring structure.

[0104] In another preferred example, "-R" L1 -R L2 -R L3 -" or "-R" L3 -R L2 -R L1 The group selected from the following group (substituted or unsubstituted): bond, -(C1-C6 alkylene)-O-, -(C1-C6 alkylene)-S-, -(C1-C6 alkylene)-N(C1-C3 alkyl)-, C3-C6 cycloalkylene, 4-6 membered heterocyclic group, -(C1-C4 alkylene)-C≡C-, -C1-C3 alkylene-C3-C6 cycloalkylene-(C1-C3 alkylene)-S-, -C1-C3 alkylene-C3-C4 cycloalkylene-(C1-C3 alkylene) -O-, -C1-C3 alkylene-C3-C4 cycloalkylene-(C1-C3 alkylene)-N(C1-C3 alkyl)-, -C1-C6 alkylene-4-6 heterocyclic-(C1-C3 alkylene)-O-, -C1-C6 alkylene-4-6 heterocyclic-(C1-C3 alkylene)-S-, -C1-C6 alkylene-4-6 heterocyclic-(C1-C3 alkylene)-N(C1-C3 alkyl)-, wherein the substitution refers to substitution by one or more R.

[0105] In another preferred example, "-R" L1 -R L2 -R L3 -" or "-R" L3 -R L2 -R L1 - Selected from the following group: key, The preferred location is the key.

[0106] In another preferred example, -R L1 -R L2 -R L3 -or-R L3 -R L2 -R L1 - Selected from key.

[0107] In another preferred example, -R L1 -R L2 -R L3 -or-R L3 -R L2 -R L1 -Selected from

[0108] In another preferred example, -R L1 -R L2 -R L3 -or-R L3 -R L2 -R L1 -Selected from

[0109] In another preferred embodiment, the compound has the structure shown in formula AIII-A, AIII-B, AIII-C, AIII-D, or BIII-A, BIII-B, BIII-C, or BIII-D:

[0110] In the formula,

[0111] R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C3 alkylene)-C3-C6 cycloalkyl, -(C1-C3 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0112] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0113] Or R c1 and R c2 The groups are connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to substitution by one or more R groups;

[0114] Ring A, Ring D, R d nd, X, R L4 R L5 The definitions of R and R are as described in the first aspect of this invention.

[0115] In another preferred embodiment, the compound has the structure shown in formula AIII-A, AIII-B, AIII-C, AIII-D, or BIII-A, BIII-B, BIII-C, or BIII-D:

[0116] Among them, R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C3 alkylene)-C3-C6 cycloalkyl, -(C1-C3 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0117] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0118] Or R c1 and R c2 The groups are connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to substitution by one or more R groups;

[0119] R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R;

[0120] Or, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R.

[0121] Ring A, Ring D, R d nd, X, R L4 R L5 The definitions of R and R are as described in the first aspect of this invention.

[0122] In another preferred embodiment, R c1 Methyl, ethyl, cyclopropyl, fluorocyclopropyl, trifluoroethyl, Difluoroethyl, monofluoroethyl; preferably, R c1 Methyl, ethyl, cyclopropyl, fluorocyclopropyl, trifluoroethyl, Monofluoroethyl.

[0123] In another preferred embodiment, R c4 For H and F.

[0124] In another preferred embodiment, R c3 For H and F.

[0125] In another preferred embodiment, R c2 For H.

[0126] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 It is an ethyl group.

[0127] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 It is cyclopropyl.

[0128] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 It is a fluorocyclopropyl group.

[0129] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 for

[0130] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 for

[0131] In another preferred embodiment, R c2 R c3 and R c4 Each is independently H; R c1 for

[0132] In another preferred embodiment, R c1 and R c2 They connect to form -CH2-CH2-CH2-.

[0133] In another preferred embodiment, R c3 and R c4Each is independently H; R c1 and R c2 They connect to form -CH2-CH2-CH2-.

[0134] In another preferred embodiment, R is selected from the group consisting of: deuterium, methylene (=CH2), halomethylene (=CH2), oxo (=O), cyano, amino, nitro, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, haloC1-C4 alkoxy, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups.

[0135] In another preferred embodiment, ring A is selected from the following group of substituted or unsubstituted groups: H, C3-C 10 Cycloalkyl, 4-10 saturated or unsaturated heterocyclic groups, wherein the heterocyclic group or cycloalkyl group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, P, S and O, and the substitution refers to substitution by one or more R.

[0136] In another preferred embodiment, ring A is selected from the following group of substituted or unsubstituted groups: C3-C7 monocyclic cycloalkyl, C7-C 10 Bicyclic cycloalkyl (preferably C7-C9 bicyclic cycloalkyl), 4-7 member saturated monocyclic heterocyclic group, 7-10 member saturated bicyclic heterocyclic group (preferably 7-9 member saturated bicyclic heterocyclic group), wherein the bicyclic heterocyclic group or bicyclic cycloalkyl group is bridged ring, spirocyclic or fused ring (preferably spirocyclic), and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution refers to substitution by one or more R.

[0137] In another preferred embodiment, Selected from the following group of groups, whether substituted or unsubstituted:

[0138] hydrogen,

[0139] Among them, R a Selected from the following group of substituted or unsubstituted groups: C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more R groups; the substitution refers to being substituted by one or more R groups.

[0140] In another preferred embodiment, Selected from the following group of groups, whether substituted or unsubstituted:

[0141] In another preferred embodiment, ring A is selected from substituted or unsubstituted 6-9 membered heterocyclic groups, preferably 6-membered heterocyclic groups or 7-9 membered spirocyclic heterocyclic groups, wherein substitution refers to being substituted by one or more R.

[0142] In another preferred embodiment, ring A is selected from a substituted or unsubstituted 6-membered heterocyclic group containing 2 nitrogen atoms, and the substitution refers to being substituted by one or more R atoms.

[0143] In another preferred embodiment, ring A is selected from -NRpRq, wherein Rp and Rq are each independently a substituted or unsubstituted subgroup: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group; or, Rp and Rq and the N atom they are connected to together form a substituted or unsubstituted subgroup: 4-7 membered monocyclic heterocyclic group, 7-10 membered saturated bicyclic heterocyclic group, wherein the monocyclic heterocyclic group and the saturated bicyclic heterocyclic group contain one or two N atoms, and the substitution refers to being substituted by one or more R atoms.

[0144] In another preferred embodiment, ring A is selected from the following group:

[0145] In another preferred embodiment, ring A is selected from the following group:

[0146] In another preferred embodiment, Selected from the following group:

[0147] In another preferred embodiment, Selected from the following group:

[0148] In another preferred embodiment, ring D is selected from substituted or unsubstituted 6-8 membered heterocyclic groups (preferably 6-7 membered heterocyclic groups); wherein the heterocyclic group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution refers to substitution by one or more R.

[0149] Preferably, ring D is selected from the following group: More preferably, ring D is

[0150] In another preferred embodiment, R d Selected from the following group: deuterium, halogen, oxo group, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, halogenated C1-C3 alkyl, C1-C3 deuterated alkyl, where nd is 0, 1 or 2.

[0151] In another preferred embodiment, ring D is selected from the following group:

[0152] In another preferred example, nd is selected from 0.

[0153] In another preferred embodiment, X is selected from the group consisting of substituted or unsubstituted groups:

[0154] Bond; -C1-C6 alkylene-;

[0155] -C3-C 14 Cycloalkylene -, -C1-C6 alkylene -C3-C 14 Cycloalkylene -, -C1-C6 alkylene -C3-C 14 Cycloalkylene-C1-C6 alkylene-;

[0156] -4-14-membered heterocyclic-, -C1-C6 alkylene-4-14-membered heterocyclic-, -C1-C6 alkylene-4-14-membered heterocyclic-C1-C6 alkylene-;

[0157] -C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-C1-C6 alkylene-;

[0158] -5-10 heteroaryl-, -C1-C6 alkylene-5-10 heteroaryl-, -C1-C6 alkylene-5-10 heteroaryl-C1-C6 alkylene-;

[0159] -C3-C7 cycloalkylene-C6-C 10 aryl-,-4-7-membered heterocyclic-C6-C 10 Alpha-;

[0160] -C3-C7 cycloalkylene-C6-C 10 arylene-C1-C6 alkylene-,-4-7 membered heterocyclic-C6-C 10 arylene-C1-C6 alkylene-;

[0161] -C3-C7 cycloalkyl-5-10 heteroalkyl-, -4-7 heteroalkyl-5-10 heteroalkyl-;

[0162] -C3-C7 heterocyclic alkyl-5-10 heterocyclic aryl-C1-C6 heterocyclic-, -4-7 heterocyclic alkyl-5-10 heterocyclic aryl-C1-C6 heterocyclic-;

[0163] -C1-C4 alkylene-O-C1-C6 alkylene-, -C1-C4 alkylene-O-C3-C 14 Cycloalkylene-, -C1-C4 alkylene-O-4-14 heterocyclic-, -C1-C4 alkylene-O-C6-C 10 arylene-, -C1-C4 alkylene-O-5-10-membered heteroarylene-;

[0164] -C1-C4 alkylene-N(R) 3 -C1-C6 alkylene-, -C1-C4 alkylene-N(R) 3 )-C3-C 14 Cycloalkylene-, -C1-C4 alkylene-N(R) 3 )-4-14-membered heterocyclic -,-C1-C4 alkylene-N(R 3 )-C6-C 10 arylene-,-C1-C4 alkylene-N(R) 3 )-5-10-aryl heteroaryl-;

[0165] -R x1 -N(R 3 )-OR x2 -、-R x1 -ON(R 3 )-R x2 - or -R x1 -N(R 3 )-N(R 3 )-R x2 -;

[0166] in,

[0167] R 3 Each group is independently selected from the following group: substituted or unsubstituted: H, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group; the substitution refers to the substitution of one or more hydrogens on the group by R;

[0168] R x1 and R x2 Each group is independently selected from the following group: substituted or unsubstituted: bond, -C1-C6 alkylene-, -C3-C 14 Cycloalkyl-, -4-14-membered heterocyclic-; the substitution refers to the substitution of one or more hydrogens on the group by R.

[0169] In another preferred embodiment, X is selected from the group consisting of substituted or unsubstituted groups:

[0170] key;

[0171] -C1-C6 alkylene-, -C3-C 14Cycloalkylene-C1-C6 alkylene-, -4-14 membered heterocyclic-C1-C6 alkylene-;

[0172] -C3-C 11 Cycloalkylene -, -C1-C6 alkylene -C3-C 11 Cycloalkylene -, -C1-C6 alkylene -C3-C 11 Cycloalkylene-C1-C6 alkylene-, -4-14 membered heterocyclic-C3-C 14 Cycloalkylene-;

[0173] -4-11-membered heterocyclic-, -C1-C6 alkylene-4-11-membered heterocyclic-, -C1-C6 alkylene-4-11-membered heterocyclic-C1-C6 alkylene-, -C3-C 14 Cycloalkyl-4-14-membered heterocyclic-;

[0174] -C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-C1-C6 alkylene-, -C3-C 11 Cycloalkyl-C6-C 10 aryl-,-4-11-membered heterocyclic-C6-C 10 Aspartic-, -C3-C 11 Cycloalkyl-C6-C 10 arylene-C1-C6 alkylene-,-4-11 heterocyclic-C6-C 10 arylene-C1-C6 alkylene-;

[0175] -5-6-membered heteroaryl-, -C1-C6 alkylene-5-6-membered heteroaryl-, -C1-C6 alkylene-5-6-membered heteroaryl-C1-C6 alkylene-, -C3-C 11 Cycloalkyl-5-6-membered heteroaryl-, -4-11-membered heterocyclic-5-6-membered heteroaryl-, -C3-C 11 Cycloalkyl-5-6-membered heteroaryl-C1-C6 alkylene-, -4-11-membered heterocyclic-5-6-membered heteroaryl-C1-C6 alkylene-;

[0176] -C1-C4 alkylene-O-C1-C6 alkylene-, -C1-C4 alkylene-O-C3-C 10 Cycloalkylene-, -C1-C4 alkylene-O-4-11 heterocyclic-, -C1-C4 alkylene-O-C6-C 10 arylene-, -C1-C4 alkylene-O-5-6-membered heteroarylene-;

[0177] -C1-C4 alkylene-N(R) 3 -C1-C6 alkylene-, -C1-C4 alkylene-N(R) 3 )-C3-C 11 Cycloalkylene-, -C1-C4 alkylene-N(R) 3 )-4-11-membered heterocyclic -,-C1-C4 alkylene-N(R 3 )-C6-C 10 arylene-,-C1-C4 alkylene-N(R) 3 )-5-6-aryl heteroaryl-;

[0178] -R x1 -N(R 3 )-OR x2 -、-R x1 -ON(R 3 )-R x2 - or -R x1 -N(R 3 )-N(R 3 )-R x2 -;

[0179] R x1 R 3 and R x As described above, substitution refers to the replacement of one or more hydrogen atoms on a group by R.

[0180] In another preferred embodiment, R x1 and R x2 Each group is independently selected from the following group: substituted or unsubstituted: bond, -C1-C6 alkylene-, -C3-C 11 Cycloalkyl-, -4-11-membered heterocyclic-; the substitution refers to the substitution of one or more hydrogens on the group by R.

[0181] In another preferred example, X is selected from the following group:

[0182] key;

[0183] Methylene, Ethylene

[0184] Or select from the following group:

[0185] Or select from the following group:

[0186] Or select from the following group:

[0187] Or select from the following group:

[0188] Or select from the following group:

[0189] Or select from the following group:

[0190] -ON(CH3)-, -N(CH3)-N(CH3)-.

[0191] In another preferred embodiment, R L4 Selected from the group consisting of: bond, -O-, -NH-, -N(C1-C3 alkyl)-, or -N(C3-C6 cycloalkyl)-, wherein the alkyl and cycloalkyl are optionally substituted by one or more deuterium, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, or halogenated C1-C3 alkoxy.

[0192] In another preferred embodiment, R L4 Selected from the key, or -N(CH3)-.

[0193] In another preferred embodiment, R L5 Selected from the following groups, whether substituted or unsubstituted: hydrogen, C1-C6 alkyl, C3-C4 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7 ... 10 Cycloalkyl, 4-11 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(C1-C3 alkylene)-C3-C 11 Cycloalkyl, -(C1-C3 alkylene)-4-11 heterocyclic, -(C1-C3 alkylene)-phenyl, -(C1-C3 alkylene)-5-6 heteroaryl, -(C3-C7 cycloalkylene)-phenyl, -(4-7 heterocyclic alkylene)-phenyl, -(4-7 heterocyclic alkylene)-5-6 heteroaryl, -(C3-C7 cycloalkylene)-5-6 heteroaryl, -NR1R2, -(C1-C3 alkylene)-NR1R2.

[0194] In another preferred embodiment, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R atoms.

[0195] In another preferred embodiment, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C4 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-11 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R atoms.

[0196] In another preferred embodiment, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C4 alkyl, C3-C7 cycloalkyl, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-11 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R atoms.

[0197] In another preferred embodiment, R L5 Selected from the following groups, whether substituted or unsubstituted: C3-C7 cycloalkyl, 4-8 heterocyclic, -(C1-C3 alkylene)-5-6 heteroaryl, -NR1R2.

[0198] In another preferred embodiment, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, C1-C4 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic groups, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-8 membered heterocyclic group, the heterocyclic group containing 1-3 heteroatoms each independently selected from N, O and S; the substitution refers to being substituted by one or more R atoms.

[0199] In another preferred embodiment, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, C1-C4 alkyl, C3-C7 cycloalkyl, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-8 membered heterocyclic group, the heterocyclic group containing 1-3 heteroatoms each independently selected from N, O and S; the substitution refers to being substituted by one or more R atoms.

[0200] In another preferred embodiment, R L5 Selected from the following group of substituted or unsubstituted groups: -(C3 cycloalkylene)-phenyl (e.g.) R v2 (e.g., phenyl), -(C3 cycloalkylene)-5-6 heteroaryl (e.g.) R v2 The substitution is defined as being substituted by one or more R groups, such as -NR1R2 (4-6 membered heterocyclic groups, -NR1R2), where R1 and R2 are as defined above.

[0201] In another preferred embodiment, RL5 Selected from the following group of substituted or unsubstituted groups: -(C3 cycloalkylene)-phenyl (e.g.) R v2 (e.g., phenyl), -(C3 cycloalkylene)-5-6 heteroaryl (e.g.) R v2 (e.g., heteroaryl), -NR1R2, wherein R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-6 membered heterocyclic group (preferably a 4-membered heterocyclic group), wherein the heterocyclic group contains one N atom, and the substitution refers to being substituted by one or more R atoms.

[0202] In another preferred embodiment, R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-6 membered heterocyclic group, the heterocyclic group containing one N atom; the substitution refers to being substituted by one or two R atoms.

[0203] In another preferred embodiment, R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-membered heterocyclic group, the heterocyclic group containing one N atom; the substitution refers to being substituted by two R atoms.

[0204] In another preferred embodiment, R L5 It is -NR1R2, and R1 and R2 and the N atom they are connected to form Where R V1 and R V2 Each of the following groups can be independently represented as an oxo group (=O), cyano group, ester group, amino group, amide group, sulfone group, urea group, C1-C6 alkyl group, deuterated C1-C6 alkyl group, halo-C1-C6 alkyl group, C1-C6 alkylidene group, halo-C1-C6 alkylidene group, C1-C6 alkylamino group, C1-C6 hydroxyalkyl group, C3-C6 cycloalkyl group, 4-7 membered heterocyclic group, -C(O)-4-7 membered heterocyclic group, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy;

[0205] Ideally, R V1 and R V2Each of the following groups is independently cyano, hydroxy, halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, deuterated C1-C4 alkyl, halo-C1-C4 alkyl, ethynyl, C3-C6 ethynyl, C3-C4 cycloalkyl, 4-5 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein the alkyl, ethynyl, phenyl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxy, cyano, amino, C1-C4 alkyl, C1-C4 alkoxy;

[0206] Ideally, R V1 and R V2 Each of the following groups, whether substituted or unsubstituted, is independently: C1-C4 alkyl, ethynyl, C3-C6 ethynyl; the substitution refers to substitution by a group selected from the following group: halogen, hydroxyl, cyano, amino, C1-C4 alkyl, C1-C4 alkoxy;

[0207] Ideally, R V1 R is a substituted or unsubstituted C1-C4 alkyl group. V2 The acetylene group may be substituted or unsubstituted; the substitution refers to substitution by a group selected from the group consisting of: halogen, hydroxyl, cyano, amino, C1-C4 alkyl, and C1-C4 alkoxy.

[0208] In another preferred embodiment, R L5 Selected from the substituted or unsubstituted group: -(C3 cycloalkylene)-phenyl or -(C3 cycloalkylene)-5-6 heteroaryl, and having the following structure: Among them, R V2 Selected from the group consisting of phenyl or 5-6 heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy.

[0209] R V1 Selected from the following groups: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy;

[0210] Ideally, R V1 Selected from H;

[0211] R V2 Selected from the group consisting of phenyl or 5-6 heteroaryl groups; the aryl and heteroaryl groups are also optionally substituted by groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy.

[0212] In another preferred embodiment, R L5 Selected from -(C3 cycloalkylene)-phenyl (e.g.) R v2 (e.g., phenyl), -(C3 cycloalkylene)-5-6 heteroaryl (e.g.) R v2 (for heteroaryl), or Among them, each R V1 and R V2 As defined above.

[0213] In another preferred embodiment, R L5 Not for

[0214] In another preferred embodiment, R L5 Selected from the following group:

[0215] Methyl, ethyl, isopropyl, isopropylmethyl, tert-butylmethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl

[0216] Or select from the following group:

[0217] -NH2, -NH(CH3), -N(CH3)2

[0218] Or select from the following group:

[0219] Or select from the following group:

[0220] In another preferred embodiment, R L5 Selected from the following group:

[0221] Or select from the following group:

[0222] In another preferred embodiment, R L5 Selected from the following group:

[0223] Or select from the following group:

[0224] In another preferred embodiment, the compound has the structure shown in Formula AII:

[0225] in,

[0226] X is the key;

[0227] R L4 For key;

[0228] R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium;

[0229] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0230] Or, R c1 and R c2 Connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to being substituted by one or more R groups;

[0231] R b1 Selected from methoxy-substituted ethyl groups;

[0232] Or, R b1 and R c1 The divalent group is linked by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R groups;

[0233] Ring D is selected from nd is 0;

[0234] Ring A is selected from substituted C4 cycloalkyl groups, where substitution means being substituted by one or more R groups;

[0235] Alternatively, ring A is selected from -(NRpRq) or -(RpRqN(R)), wherein Rp and Rq, together with the N atom they are attached to, form substituted or unsubstituted groups from the following group: 6-membered saturated or partially saturated monocyclic heterocyclic groups, 7-10-membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more (preferably three) groups, each independently selected from the following group: deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, phenyl, 5-6-membered heterocyclic groups. Aryl, C2-C6 alkenyl, ethynyl, C3-C6 ethynyl; wherein the alkyl, alkenyl, ethynyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0236] R L5 Selected from the following group (substituted or unsubstituted): 4-membered nitrogen-containing heterocyclic groups, wherein substitution refers to substitution by one or more of the following groups: deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, -C(O)-4-7-membered heterocyclic groups, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy;

[0237] Or, R L5Selected from the following groups, whether substituted or unsubstituted: -(C3 cycloalkylene)-phenyl, -(C3 cycloalkylene)-5-6 heteroaryl, wherein the substitution refers to substitution by one or more of the following groups: H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy;

[0238] The constraint is R L5 Not selected from:

[0239] R L1 R L2 R L3 As defined above.

[0240] In another preferred embodiment, the compound has the structure shown in formula AII, wherein,

[0241] X is selected from the key;

[0242] Ring A is selected from substituted C4 cycloalkyl groups, where substitution means being substituted by one or more R groups;

[0243] Alternatively, ring A is selected from -(NRpRq) or -(RpRqN(R)), wherein Rp and Rq and the N atom they are connected to together form substituted or unsubstituted groups from the following group: 6-membered saturated or partially saturated monocyclic heterocyclic groups, 7-10-membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more (preferably three) groups, each independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, phenyl, 5-6-membered heterocyclic groups. Heteroaryl, C2-C6 alkenyl, ethynyl, C3-C6 ynyl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0244] Ring D is selected from the following group: Preferably, ring D is selected from...

[0245] nd is selected from 0;

[0246] R L4 Selected from key;

[0247] R L5 Selected from the following group (substituted or unsubstituted): 4-membered nitrogen-containing heterocyclic groups, wherein substitution refers to substitution by one or more of the following groups: deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, -C(O)-4-7-membered heterocyclic groups, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy;

[0248] Or, R L5 Selected from the following groups, whether substituted or unsubstituted: -(C3 cycloalkylene)-phenyl, -(C3 cycloalkylene)-5-6 heteroaryl, wherein the substitution refers to substitution by one or more of the following groups: H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy;

[0249] The constraint is R L5 Not selected from:

[0250] R L1 R L2 R L3 R b1 R c1 R c2 R c3 R c4 The definitions of R are as described above.

[0251] In another preferred embodiment, the compound has the structure shown in formulas AIV-A and AIV-AA:

[0252] in,

[0253] nv is selected from 1 or 0;

[0254] When nv is selected as 1:

[0255] V is selected from N;

[0256] R V1 and R V2 Each group is independently selected from the following groups: oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkylidene, halo-C1-C6 alkylidene, C1-C6 alkylamino, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -C(O)-4-7 membered heterocyclic, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy;

[0257] When nv is selected as 0:

[0258] V is selected from CH;

[0259] R V1 Selected from the following group: H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy;

[0260] R V2 Selected from the group consisting of phenyl or 5-6 heteroaryl; wherein the benzene and heteroaryl groups are optionally substituted by groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy.

[0261] Rings A and R b1 R c1 R c2 Rc3 R c4 Defined as described above.

[0262] In another preferred embodiment, when V is N and nv is 1, R V1 and R V2 Each is independently selected from the following group: C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, ethynyl, C3-C6 ethynyl;

[0263] Alternatively, when V is CH and nv is 0, R V1 Selected from the following group: H, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl; R V2 Selected from the group consisting of phenyl or pyridyl; wherein the phenyl or pyridyl group is optionally substituted with a group selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy.

[0264] In another preferred embodiment, ring A is -(NRpRq); wherein Rp and Rq, together with the N atom they are connected to, form substituted or unsubstituted groups from the following group: 4-7 membered saturated or partially saturated monocyclic heterocyclic groups (preferably 6 membered saturated or partially saturated heterocyclic groups), 7-10 membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more (preferably three) groups independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, benzene The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7 heterocyclic, phenyl, 5-6 heteroaryl, C1-C3 alkylidene, and halo-C1-C3 alkylidene.

[0265] In another preferred embodiment, ring A is -(RpRqN(R)); where Rp, Rq and R are defined as described above.

[0266] In another preferred embodiment, the compounds represented by formula AIV-A and formula AIV-AA,

[0267] Ring A is selected from

[0268] Q is either N or CH;

[0269] R w1 Selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, ethynyl, C3-C6 ynyl (preferably, R w1 Selected from the group consisting of substituted or unsubstituted groups: C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 alkynyl, or 4-membered heterocyclic group; wherein the alkyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, phenyl, 5-6-membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0270] R w2 and R w3 Each is independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl (preferably, R). w2 and R w3 Each is independently selected from C1-C3 alkyl groups;

[0271] R w2’ and R w3’ Each is independently selected from the following group: H, deuterium, C1-C6 alkyl;

[0272] Or, R w2 and R w2’ 、or R w2 and R w3 Interconnection causes ring A to form a 7-10 quinary saturated spirocyclic bicyclic heterocyclic group or a saturated bridged bicyclic heterocyclic group;

[0273] The substitution referred to here means being replaced by one or more R;

[0274] w1 and w2 are each independently 1 or 2.

[0275] In another preferred embodiment, ring A is selected from... Among them, R w1 Selected from the following group, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, or C3-C6 ynyl (preferably, R w1Selected from the group consisting of substituted or unsubstituted groups: C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 alkynyl, or 4-membered heterocyclic group (preferably nitrogen-containing 4-membered heterocyclic group or oxygen-containing 4-membered heterocyclic group), wherein the substitution refers to being substituted by one or more groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, 4-5-membered heterocyclic group, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0276] R W2 and R W3 Each is independently selected from the group consisting of: H, deuterium, C1-C6 alkyl groups (preferably R). W2 and R W3 Selected from methyl).

[0277] In another preferred embodiment, R w1 Selected from the following group: methyl, ethyl, isopropyl, cyclopropyl, oxetyl, cyanomethyl, cyanoethyl, propynyl, butynyl, cyclopropyl-substituted propynyl, oxetyl-substituted propynyl.

[0278] In another preferred embodiment, ring A has a pair of opposite configurations; more preferably, ring A has the configuration shown below.

[0279] In another preferred embodiment, in the compounds represented by formula AIV-A and formula AIV-AA, ring A is selected from...

[0280] R W1 R W2 、or R W3 Defined as described above.

[0281] In another preferred embodiment, ring A has a pair of opposite configurations; more preferably, ring A has the configuration shown below.

[0282] In another preferred embodiment, the compound has the structure shown in formulas AV-A and AV-AA:

[0283] R w1 Selected from the following group, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, ethynyl, or C3-C6 ethynyl (preferably, R w1Selected from the following group (substituted or unsubstituted): C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 alkynyl, or 4-membered heterocyclic group; the substitution is selected from halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, 4-5-membered heterocyclic group, C1-C3 alkylidene, halo-C1-C3 alkylidene;

[0284] R w2 and R w3 Each is independently selected from the group consisting of: H, deuterium, C1-C6 alkyl groups (preferably, R). w2 and R w3 Selected from methyl);

[0285] R b1 R c1 R c2 R c3 R c4 V, R V1 R V2 The definitions of nv are as described above.

[0286] In another preferred embodiment, the compounds represented by formulas AIV-A and AIV-AA and the compounds represented by formulas AV-A and AV-AA,

[0287] R c1 The compounds are C1-C3 alkyl, cyclopropyl, halocyclopropyl, methylenecyclopropyl, or halomethylenecyclopropyl; preferably R c1 It is ethyl;

[0288] R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN;

[0289] Or R c1 and R c2 The following groups are connected together to form substituted or unsubstituted groups: -CH2-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-CH2-CH2-, or -CH2-CH2-O-; the substitution refers to being substituted by one or more R groups;

[0290] R b1 Ethyl groups are methoxylated;

[0291] Or, R b1 and R c1The divalent group is linked by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R groups;

[0292] When V is N; and nv is 1, R V1 and R V2 Each is independently selected from the group consisting of C1-C3 alkyl and C2-C3 alkynyl groups; wherein the alkyl and alkynyl groups are optionally substituted by groups selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, and C1-C4 alkoxy groups.

[0293] Or when V is CH; when nv is 0, R V1 Selected from H, halogens, or C1-C3 alkyl groups; R V2 Selected from the group consisting of: phenyl, pyridyl; wherein the phenyl and pyridyl groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy.

[0294] In another preferred embodiment, the compound has the structure shown in formulas AVI-A and AVI-AA:

[0295] R b1 R c1 R c2 R c3 R c4 V, R V1 R V2 、nv、R W1 R W2 R W3 Defined as described above.

[0296] In another preferred embodiment, the compound has the structure shown in formula AE-A, formula AE-B, formula AE-C, formula AE-D, formula BE-A, formula BE-B, formula BE-C, or formula BE-D:

[0297] in,

[0298] Ring A, Ring D, R d nd, X, R L4 and R L5 The definition is as described in the first aspect of this invention.

[0299] In another preferred embodiment, the compound is selected from the group consisting of:

[0300] Group A is selected from:

[0301] Or select from:

[0302] Or select from:

[0303] Or select from:

[0304] Or select from:

[0305] Or select from:

[0306] Or select from:

[0307] Or select from:

[0308] Or selected from:

[0309] Or select from:

[0310] Or select from:

[0311] Or select from:

[0312] Or select from:

[0313] Or select from:

[0314] Or select from:

[0315] Or select from:

[0316] Or select from:

[0317] Group B is selected from:

[0318] Or select from:

[0319] Or select from:

[0320] Or select from:

[0321] In another preferred embodiment, each group is the corresponding group in the compound prepared in the example.

[0322] In another preferred embodiment, the compound is the compound prepared in the examples.

[0323] In another preferred embodiment, the heteroaryl, heterocyclic, cycloalkyl, and aryl groups may be monocyclic, bridged, fused, or spirocyclic depending on the number of carbon atoms.

[0324] In a second aspect of the invention, a pharmaceutical composition is provided comprising one or more compounds described in the first aspect of the invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated derivatives, crystal forms, hydrates, solvates, prodrugs, or combinations thereof; and a pharmaceutically acceptable carrier.

[0325] In a second aspect of the invention, there is provided the use of the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated form, crystal form, hydrate, solvate, prodrug, or combination thereof, or the pharmaceutical composition described in the second aspect of the invention, for the preparation of a medicament for the prevention and / or treatment of diseases related to the activity or expression level of KRAS mutations, preferably, said diseases being tumors or disorders.

[0326] In another preferred embodiment, the tumor is selected from the group consisting of: pancreatic cancer, colorectal cancer, lung cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, bladder cancer, or combinations thereof.

[0327] In another preferred embodiment, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0328] In another preferred embodiment, the disorder is selected from the group consisting of endocrine disorders.

[0329] In a fourth aspect of the invention, a method for treating cancer or disorder associated with the activity or expression level of a KRAS mutation is provided, comprising administering a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated form, hydrate, solvate, prodrug, or combination thereof, or a pharmaceutical composition of the second aspect of the invention, to a subject in need.

[0330] In another preferred embodiment, the method is performed in vitro.

[0331] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0332] Through extensive and in-depth research, the inventors unexpectedly prepared a novel class of compounds that inhibit KRAS mutations and / or exhibit better pharmacodynamic properties. Based on this, the inventors completed this invention.

[0333] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0334] The term "alkyl" refers to a straight-chain or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts via a carbon atom on a ring or a non-cyclic atom), preferably a straight-chain or branched alkane group, containing 1-20 carbon atoms, such as 1-18 carbon atoms, particularly 1-18 carbon atoms, preferably containing 1-10 carbon atoms (C1-C10), and more preferably containing 1-6 carbon atoms (C1-C6). Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. In this invention, alkyl also includes substituted alkyl groups. "Substituted alkyl" means that one or more positions in an alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here aIt can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 ynyl, 5-14 membered heterocycles, or C6-C14 aromatic rings, R b R c and R d It can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocycles or C6-C14 aromatic rings, or R b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 ynyl, 5-14 membered heterocycles, or C6-C14 aromatic rings. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocycles, or aromatic rings, can be optionally substituted.

[0335] In this article, chemical structures are written from left to right (e.g., (CR) Le R Lf (-O) Unless otherwise explicitly defined, this includes the right-to-left form, i.e. (CR) Le R Lf -O can be (CR) Le R Lf )-O or O-(CR Le R Lf ).

[0336] As used herein, the term "alkylene" (also referred to herein as "alkylene chain") refers especially to those "alkylenes" located in the middle or not at the end of a molecule or group (such as "alkylenes" in Y, and L4) and as substituents (such as C3-C). 10 The "alkylene" in cycloalkyl-(C1-C6 alkylene)-O- refers to a linking group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, used to connect two different atoms, or a group formed by removing a hydrogen atom from the atom containing the unsaturated bond of an alkyl or substituted alkyl group, such as methylene or methylene (-CH2-), ethylene, etc. Propylene Isopropylidene Butylene (e.g.) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ), etc. Furthermore, the term also includes alkylene groups (such as C1-C...). 18 An alkylene group is bounded by a cycloalkylene group (such as C3-C4).20 Replaced by (cycloalkylene), for example, "C1-C 18 Alkylene C3-C 20 "Cycloalkylene" or "C3-C" 20 Cycloalkyl C1-C 18 "alkylene". In this invention, alkylene also includes substituted alkylene, and the substituents can be halogenated (-CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0337] As used herein, the term "alkylidene" (also referred to herein as "terminal alkylidene"), especially "alkylidene" as a terminal substituent (as in R), refers to a group formed by removing a hydrogen atom from the atom containing the unsaturated bond of an alkyl or substituted alkyl group, thus connecting it to the rest of the molecule via a double bond, such as methylene (or terminal methylene or methylidene). ), Ethylene (e.g.) ), propylidene (e.g.) ), isopropylidene (e.g.) ), butylene, pentylene, hexylene, heptylene, etc. Furthermore, the term also includes alkylene (e.g., C1-C18 alkylene) where one methylene group is replaced by a cycloalkylene (e.g., C3-C20 cycloalkylene), for example, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkyl C1-C18 alkylene". In this invention, alkylene also includes substituted alkylene, where the substituent can be halogenated (e.g., alkylene). -CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0338] The terms "C1-C6 alkylene C3-C6 cycloalkylene" or "C3-C6 cycloalkylene C1-C6 alkylene" have the same meaning, referring to groups formed by removing two hydrogen atoms from cycloalkyl or alkylcycloalkyl groups, such as... Etc. Preferably, it is C1-C4 alkylene C3-C6 cycloalkylene. In this invention, "C1-C6 alkylene C3-C6 cycloalkylene" or "C3-C6 cycloalkylene C1-C6 alkylene" also includes substituted "C1-C6 alkylene C3-C6 cycloalkylene" or "C3-C6 cycloalkylene C1-C6 alkylene", and the substituent can be halogenated, hydroxyl, cyano, nitro, etc.; the terms "C1-C6 alkylene-4-6 membered heterocyclic" or "4-6 membered heterocyclic-C1-C6 alkylene" have similar meanings, and are preferably "C1-C4 alkylene-4-6 membered heterocyclic" or "4-6 membered heterocyclic-C1-C4 alkylene".

[0339] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. Alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups. In this invention, alkenyl groups also include substituted alkenyl groups, and the substituents can be halogenated, hydroxylated, cyano, nitro, etc.

[0340] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. The alkynyl group is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. The alkynyl group includes, but is not limited to, ethynyl, propynyl, or similar groups. In this invention, the alkynyl group also includes substituted alkynyl groups, which can be halogenated, hydroxyl, cyano, nitro, etc.

[0341] In this invention, the term "cycloalkyl" refers to a fully saturated or partially unsaturated (preferably fully saturated) cyclic hydrocarbon compound group comprising 1-4 rings, each ring containing 3-8 carbon atoms. The term "C3-C..." 20 "" refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The cycloalkyl group is preferably C3-C. 14 Cycloalkyl, more preferably C3-C 10 Cycloalkyl groups, more preferably C3-C6 monocyclic cycloalkyl groups, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. In this invention, "cycloalkyl" includes substituted cycloalkyl groups, and typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b Rc P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, or heteroaryl, R b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e The group can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, or heteroaryl. The typical substituents mentioned above can be optionally substituted. Typical substitutions also include spirocyclic, pyrimidine-fused, or fused-ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaryl), pyrimidine-fused cycloalkyl, pyrimidine-fused cycloalkenyl, pyrimidine-fused cyclocyclic heterocyclic (excluding heteroaryl), fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic cycloalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclic, and heteroaryl groups can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.

[0342] The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

[0343] wait.

[0344] In this invention, the term "heterocyclic group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic systems), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "4-20 membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclic group" has the same meaning as "saturated or unsaturated heterocyclic group". The "heterocyclic group" is preferably a 4-14 membered heterocyclic group (including but not limited to 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic systems), more preferably a 4-12 membered heterocyclic group, even more preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group, a 7-11 membered bicyclic or tricyclic heterocyclic group, even more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group. Each heterocyclic group contains a heterocycle with 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0345] The term "4-20 membered subheterocyclic group" refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:

[0346] wait.

[0347] In this invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, particularly monocyclic and bicyclic groups. Specifically, "C6-C..." 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. The aryl group is preferably C6-C. 10 Aryl. Aryl groups include phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have these rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group where one or more positions are substituted, particularly 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, heteroaryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NRb C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aryl groups, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0348] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Specifically, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. Heteroaryl groups are preferably 5- to 10-membered rings, more preferably 5- or 6-membered, such as pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester.

[0349] In this invention, the term "alkoxy" refers to an alkoxy group having a straight or branched chain, including alkyl-O- and alkyl-O-alkyl groups, wherein "C1-C 18 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 18 carbon atoms, including C1-C2. 18 Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0350] In this invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 20 "Cycloalkyloxy" refers to C3-C 20cycloalkyl-O-, wherein, C3-C 20 The definition of cycloalkyl is as described above.

[0351] In this invention, the term "heterocyclic oxy group" refers to the heterocyclic group -O-, wherein "4-20 membered heterocyclic oxy group" refers to the 4-20 membered heterocyclic group -O-, and the definition of the 4-20 membered heterocyclic group is as described above.

[0352] In this invention, the term "C1-C" is used. 18 "Alkyloxy" refers to "C1-C 18 An alkoxy group is formed by removing one hydrogen atom.

[0353] In this invention, the term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0354] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0355] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0356] In this invention, the term "hydroxyl group" refers to a group with the structure OH.

[0357] In this invention, the term "nitro" refers to a group containing the structure NO2.

[0358] In this invention, the term "cyano" refers to a group containing the structure CN.

[0359] In this invention, the term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic. The ester group is preferably -COO C1-C6 alkyl.

[0360] The term "amine" refers to a group with the structure -NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). In one embodiment, at least one of R' and R" is not H. R' and R" can be the same or different in the dialkylamine fragment. The amino group is preferably NH2, NHC1-C6 alkyl, or N(C1-C6 alkyl)2; more preferably NHC1-C6 alkyl or N(C1-C6 alkyl)2.

[0361] The term "amide group" refers to a group with the structure -CONR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). R' and R" can be the same or different in the dialkylamine segment. The amide group is preferably -CONH2, -CONH (C1-C6 alkyl), or -CONH (C3-C6 cycloalkyl).

[0362] The term "sulfone" refers to a group with the structure -SO2R', where R' can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above. The sulfone group is preferably -SO2C1-C6 alkyl.

[0363] The term "ureido" refers to a group with the structure -NRCONR'R", where R, R', and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclic or substituted heterocyclic, as defined above. R, R', and R" can be the same or different in the dialkylamine segment. Ureido is preferably -NHCONH2 or -NHCONH (C1-C6 alkyl).

[0364] The term "heterocyclic alkyl" refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl; and R' represents a heterocyclic or substituted heterocyclic group.

[0365] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureyl groups, etc.

[0366] The term "sulfonyl" refers to a group with the structure -S(O)2R, where R can independently represent an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl; and R' represents a heterocyclic or substituted heterocyclic group, as defined above. The sulfonyl group is preferably -S(O)2C1-C6 alkyl.

[0367] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0368] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0369] In this invention, "multiple" refers to 2, 3, 4, and 5.

[0370] Active ingredients

[0371] As used herein, “compound of the present invention” means a compound of formula I, and also includes compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated derivatives, crystal forms, hydrates, solvates, prodrugs, or combinations thereof.

[0372] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0373] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0374] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0375] The prodrugs and solvates of the compounds in this invention are also included within the scope of this invention. The term "prodrug" here refers to a compound that, in the course of treatment of a related disease, undergoes a chemical transformation through metabolism or a chemical process to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0376] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0377] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0378] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0379] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0380] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0381] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0382] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0383] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0384] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0385] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0386] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0387] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0388] Preparation method

[0389] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0390] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0391] Preferably, the compounds of the present invention are prepared by the following method:

[0392] (i) In an inert solvent, in the presence of a base, with or without a Pd or Cu catalyst, and with or without a condensing agent, the compound of formula X-1 reacts with the compound of formula X-2 to give the compound of formula I.

[0393] LG1 and LG2 are leaving groups, each independently selected from: H, OH, halogens, OTf, OTs, OMs, -B(OH)2, -B(KBF3), -Sn( nBu)3、 wait;

[0394] The Pd catalyst is selected from: Pd(OAc)2, Pd(dba)2, Pd2(dba)3, XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos PdG4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;

[0395] The Cu catalyst is selected from: Cu, CuI, Cu(acac)2, etc.;

[0396] Rings A and R L1 R L2 R L3 R b1 R b2 R b3 , ring C, R c nc, ring D, R d , nd, ring G, R g ,ng,X,R L4 and R L5 The definition is as described above.

[0397] Pharmaceutical Compositions and Administration

[0398] The pharmaceutical compositions described in this invention are used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0399] The compound of formula (I) can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I is preferred. Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of either drug alone.

[0400] Drugs or active ingredients that can be used in combination with compounds of general formula (I) include, but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F... 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocalatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip BTK inhibitors (such as alisib, Buparlisib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib). The pharmaceutical compositions of this invention include (but are not limited to) ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.; MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.); mTOR inhibitors (such as Vistusertib), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof. The dosage forms of the pharmaceutical compositions of this invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release formulations, or nanoformulations.

[0401] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0402] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0403] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0404] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0405] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0406] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0407] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0408] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0409] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0410] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0411] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0412] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0413] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound or its crystal form represented by Formula I or Formula AI-AV, a pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0414] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound of general formula (I) as described in the present invention, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition as described in the present invention for inhibiting KRAS mutations.

[0415] Compared with the prior art, the main advantages of the present invention include:

[0416] (1) The compound has a good inhibitory effect on KRAS mutation;

[0417] (2) The compound has better pharmacodynamic and pharmacokinetic properties and lower toxic side effects.

[0418] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0419] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0420] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0421] NMR was performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

[0422] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC determinations were performed using an Agilent 1100 high-performance chromatograph (Microsorb 5micron C18 100x 3.0 mm column).

[0423] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Qingdao 200-300 mesh silica gel as the support.

[0424] The starting materials used in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature reported in the field.

[0425] Unless otherwise specified, all reactions in this invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is ℃.

[0426] Intermediate synthesis examples:

[0427] Int I-1(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthetic route 1 for H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0428] Step 1: Preparation of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0429] (S)-3-bromo-5-indole-2-(1-methoxyethyl)pyridine (70.0 g, 205 mmol, 1.00 eq) and benzyl piperazine-1-carboxylate (51.9 g, 235 mmol, 45.4 mL, 1.15 eq) were dissolved in 1000 mL of toluene. Pd(OAc)2 (2.30 g, 10.2 mmol, 0.05 eq), BINAP (2.55 g, 4.09 mmol, 0.02 eq), and Cs2CO3 (200 g, 614 mmol, 3.00 eq) were added to the mixture, which was then replaced three times with N2 and stirred at 100 °C for 16 hours. After the reaction solution was cooled, 1000 mL of water was added to the reaction solution, and the mixture was extracted three times with 3000 mL of ethyl acetate. The organic phase was washed with 1000 mL of saturated brine, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by rapid silica gel column chromatography to obtain the target product (51.0 g, 117.42 mmol, 57.4% yield).

[0430] LC-MS: m / z 434 (M+H) + . 1 H NMR(400MHz, CDCl3)δ8.31(d,J=2.6Hz,1H),7.42-7.32(m,5H),7.31(d,J=2.6Hz, 1H),5.18(s,2H),4.86(q,J=6.4Hz,1H),3.72-3.66(m,4H),3.29(s,3H),3.21(br s,4H),1.47(d,J=6.4Hz,3H)

[0431] Step 2: Preparation of (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborcyclopentan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0432] (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (54.0 g, 124 mmol, 1.00 eq), B2pin2 (47.4 g, 187 mmol, 1.50 eq), Pd(dppf)Cl2 (9.10 g, 12.4 mmol, 0.10 eq), and KOAc (30.5 g, 311 mmol, 2.50 eq) were dissolved in 700 mL of toluene, substituted three times with N2, and stirred at 90 °C under nitrogen for 16 hours. After cooling, 700 mL of water was added to the reaction solution, and the mixture was extracted three times with 1000 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product (65.0 g) was obtained by neutral alumina column chromatography. No further purification was required, and the product was used directly in the next reaction.

[0433] Step 3: Preparation of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0434] (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (38.0 g, 51.3 mmol, 1.25 eq) was dissolved in 300 mL of anhydrous dioxane and 50 mL of water. 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (26.5 g, 41.0 mmol, 1.00 eq), K3PO4 (19.1 g, 90.2 mmol, 2.20 eq), and Pd(dppf)Cl2 (3.00 g, 4.10 mmol, 0.10 eq) were added under a nitrogen atmosphere. The mixture was substituted three times with N2, and stirred at 75°C under nitrogen for 16 hours. The reaction system was cooled to room temperature, quenched with 500 mL of water, extracted three times with 600 mL of ethyl acetate, the organic phase was washed with 200 mL of saturated brine, dried with anhydrous Na2SO4, filtered, and then evaporated to dryness. The target product (15.5 g, 17.7 mmol, 43.3% yield) was obtained by rapid silica gel column purification.

[0435] LC-MS: m / z 873 (M+H) + . 1 H NMR (400MHz, CDCl3) δ9.33 (br s,1H),8.47-8.16(m,1H),7.82(s,1H),7.72-7.54(m,3H),7.49-7.28(m,12H),7.26-7.2 0(m,2H),5.17(s,2H),4.48-4.38(m,1H),3.73-3.58(m,5H),3.39-3.03(m,10H),2.85(br d,J=2.9Hz,1H),1.45(br d,J=6.6Hz,2H),1.38(br d,J=6.8Hz,2H),1.32-1.19(m,2H),1.12-0.82(m,8H),0.63(br d, J = 14.4 Hz, 4 H).

[0436] Step 4: Preparation of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0437] (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (15.5 g, 17.7 mmol, 1.00 eq) and Cs₂CO₃ (17.3 g, 53.2 mmol, 3.00 eq) were dissolved in 200 mL of DMF. EtI (5.53 g, 35.5 mmol, 2.84 mL, 2.00 eq) was added under ice-water bath, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, 400 mL of water was added to the reaction solution, and the mixture was extracted three times with 800 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous Na₂SO₄, filtered, and then evaporated to dryness to obtain the target product (25.0 g, crude product). No further purification is required; it can be used directly in the next reaction.

[0438] LC-MS: m / z 901 (M+H) + .

[0439] Step 5: Preparation of (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0440] (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (15.5 g, 17.2 mmol, 1.00 eq) was dissolved in 200 mL of DMF, and CsF (13.1 g, 85.9 mmol, 5.00 eq) was added. The mixture was substituted three times with N2, and then stirred at 60 °C for 48 hours. After the reaction was complete, 300 mL of water was added to the reaction solution, and the mixture was extracted three times with 900 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain the target product (3.40 g, 5.12 mmol, 29.8% yield). Simultaneously, chiral isomers of the target product (3.45 g, crude product) were obtained.

[0441] LC-MS: m / z 663 (M+H) + .

[0442] Step 6: Preparation of (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborcyclopentan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0443] (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (3.30 g, 4.97 mmol, 1.00 eq), B2pin2 (1.89 g, 7.46 mmol, 1.50 eq), Pd(dppf)Cl2 (364 mg, 497 μmol, 0.10 eq), and KOAc (976 mg, 9.95 mmol, 2.00 eq) were dissolved in 40 mL of toluene, substituted three times with N2, and then stirred at 90 °C for 5 hours. After the reaction was complete, 50 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phase was washed with 40 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and then evaporated to dryness to obtain the crude product. Rapid silica column purification yielded the target product (3.20 g, 4.50 mmol, 90.55% yield).

[0444] Step 7: Preparation of methyl (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate

[0445] (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborcyclopentan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (3.20 g, 4.50 mmol, 1.00 eq), (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butyl) Methyl hexahydropyridazine-3-carboxylate (2.36 g, 4.95 mmol, 1.10 eq), K3PO4 (2.39 g, 11.26 mmol, 2.50 eq), and Pd(dppf)Cl2 (329.45 mg, 450.26 μmol, 0.10 eq) were dissolved in dioxane (6 mL), H2O (6 mL), and toluene (18 mL), and the mixture was replaced three times with N2. The mixture was stirred at 70 °C under nitrogen protection for 3 hours. The reaction mixture was quenched with 30 mL of water, extracted with 80 mL of ethyl acetate, washed with 20 mL of brine, dried over Na2SO4, and concentrated by filtration under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to obtain the target product (3.10 g, 3.16 mmol, 70.2% yield).

[0446] LC-MS: m / z 981 (M+H) + .

[0447] Step 8: Preparation of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid

[0448] Methyl (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate (3.10 g, 3.16 mmol, 1.00 eq) and LiOH (1.66 g, 69.4 mmol, 22.0 eq) were dissolved in THF (15 mL) and H₂O (15 mL), and the solution was replaced three times with N₂. The mixture was then stirred for 2 hours at 25 °C under nitrogen protection. Tetrahydrofuran was removed from the solvent by concentration under reduced pressure. The remaining aqueous phase was adjusted to pH 5 by slow dropwise addition of 1N HCl solution under ice bath conditions, and then extracted with 50 mL (25 mL x 2) of dichloromethane. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product (2.90 g, 3.00 mmol, 94.9% yield). No further purification was required; it was used directly in the next reaction.

[0449] LC-MS: m / z 967 (M+H) + .

[0450] Step 9: 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 Preparation of β-(S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0451] (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazin-3-carboxylic acid (2.90 g, 2.40 mmol, 1.00 eq), DIEA (12.4 g, 96.0 mmol, 16.7 mL, 40.0 eq), EDCI (13.8 g, 72.0 mmol, 30.0 eq) and HOBt (3.24 g, 24.0 mmol, 10.0 eq) were dissolved in acetonitrile (100 mL) and stirred at 25 °C for 16 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. 20 mL of 1N HCl solution was added, and the mixture was extracted with 50 mL of DCM. The extract was washed with 20 mL of brine, dried over Na₂SO₄, and concentrated by filtration under reduced pressure to obtain the crude product. The crude product was then purified by rapid silica gel column chromatography to give the target compound (1.26 g, 1.33 mmol, 55.3% yield).

[0452] LC-MS: m / z 949 (M+H) + .

[0453] Step 10: ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of tert-butyl H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)carboxylate

[0454] 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-12 Benzyl 6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (1.26 g, 1.33 mmol, 1.00 eq) and Pd(OH)₂ (932 mg, 6.64 mmol, 5.00 eq) were dissolved in methanol (20 mL) and purged three times with hydrogen. The mixture was stirred at 25 °C under hydrogen protection for 2 hours. After the reaction was complete, the solution was concentrated by vacuum filtration to give the target compound (1.00 g, 1.23 mmol, 92.4% yield). No further purification was required, and the compound was used directly in the next reaction.

[0455] LC-MS: m / z 815 (M+H) + .

[0456] Step 11: ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of tert-butyl H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)carboxylate

[0457] ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)tert-butyl carboxylate (1.00 g, 1.23 mmol, 1.00 eq) was dissolved in methanol (10 mL), and AcOH (221 mg, 3.68 mmol, 3.00 eq) was added. The mixture was stirred at 25 °C for 0.5 h, and then NaBH3CN (92.7 mg, 1.48 mmol, 1.20 eq) and HCHO (221 mg, 2.73 mmol, 37% purity, 2.22 eq) were added. The mixture was stirred at 25 °C for 3 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. 20 mL of water was added, and the mixture was extracted with 80 mL of DCM:MeOH (5:1) solution. The mixture was washed with 20 mL of brine, dried over Na2SO4, and concentrated by filtration under reduced pressure to obtain the target product (1.02 g, 1.23 mmol, 100% yield) as a yellow solid. No further purification is required; it can be used directly in the next reaction.

[0458] LC-MS: m / z 829 (M+H) + .

[0459] Step 12: (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0460] ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)tert-butyl carboxylate (1.02 g, 1.23 mmol, 1.00 eq) was dissolved in DCM (10 mL), and HCl / dioxane (4 M, 1.54 mL, 5.00 eq) was added. The mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The crude product was stirred with MTBE at 25 °C for 30 min and then filtered to obtain the target product (940 mg, 1.23 mmol, 99.8%).

[0461] LC-MS: m / z 729 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.41(br s,1H),8.58-8.46(m,4H),8.42(s,1H),7.89(s,1H),7.75(br d,J=7.3Hz,2H),7.60(d,J=8.6Hz,1H),5.52(br s,1H),5.32(br s,1H),4.26-4.17(m,3H),4.13-4.08(m,2H),4.04-3.94(m,2H),3.62(br s,2H),3.58-3.55(m,4H),3.50(br d,J=13.0Hz,3H),3.41-3.28(m,3H),3.24-3.14(m,2H),3.18(br d,J=9.0Hz,1H),2.89-2.73(m,4H),1.93(br d,J=14.5Hz,1H),1.81(br s,1H),1.75(br s,1H),1.60(br s,1H),1.43-1.40(m,3H),1.06(br t,J=6.8Hz,3H),0.75(s,3H),0.66(br s,3H).

[0462] Int I-1(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1Synthetic route 2 for H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0463] Step 1: Preparation of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-3-yl)propyl acetate

[0464] Under argon protection, potassium acetate (22.8 g, 0.232 mol, 2.5 eq), Pd(dppf)Cl2 (6.8 g, 0.0091 mol, 0.1 eq), and phenazine diborate (58.96 g, 0.232 mol, 2.5 eq) were added to a solution of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (30 g, 0.093 mol, 1.00 eq) in dioxane (300 mL). The resulting reaction solution was reacted at 90 °C for 3.5 h, then cooled to room temperature, and water (750 mL) and ethyl acetate (1250 mL) were added. The mixture was filtered through diatomaceous earth to collect the organic phase, and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (31 g, 89% yield).

[0465] Step 2: Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionate

[0466] Under argon protection, a mixed solution of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-3-yl)propyl acetate (19 g, 0.051 mol, 1.00 eq) and (S)-3-(4-bromothiazolyl)-2-((tert-butoxycarbonyl)amino)propionate methyl dioxane (22.36 g, 0.061 mol, 1.20 eq) in dioxane (200 mL) and water (20 mL) was prepared, and potassium phosphate (27.16 g, 0.128 mol, 2.5 eq) and Pd(dppf)Cl2 (3.75 g, 0.0051 mol, 0.1 eq) were added. The resulting reaction solution was reacted at 85°C for 5.5 h, then cooled to room temperature, and water (400 mL) and ethyl acetate (1000 mL) were added. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (19 g, 70% yield).

[0467] LC-MS: m / z 530 (M+H) + .

[0468] Step 3: Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate

[0469] NIS (6.44 g, 0.029 mol, 0.95 eq) was added to a DMF (160 mL) solution of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butyloxycarbonyl)amino)propionate (16 g, 0.03 mol, 1.00 eq). The resulting reaction solution was reacted at 50 °C for 3 h, then cooled to room temperature, and water (500 mL) and ethyl acetate (600 mL) were added. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (15.6 g, 81% yield).

[0470] LC-MS: m / z 656 (M+H) + .

[0471] Step 4: Preparation of (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid

[0472] Methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (15.6 g, 0.0244 mol, 1.00 eq) was added to a THF solution (160 mL) containing water (30 mL), lithium hydroxide hydrate (5.0 g, 0.119 mol, 5.00 eq), and methanol (30 mL). The resulting reaction mixture was stirred at room temperature for 3 h, followed by concentration under reduced pressure. The residue was added to water (400 mL), and the pH was adjusted to 4–5 with 2 M hydrochloric acid, followed by extraction with DCM (150 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and dried to give the target product (15 g). No further purification was required; it was used directly in the next reaction.

[0473] LC-MS: m / z 600 (M+H) + .

[0474] Step 5: Preparation of methyl (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylate

[0475] At 0 °C, HATU (28 g, 0.074 mol, 1.6 eq) was added to DCM (550 mL) containing (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazo-2-yl)propionic acid (27.5 g, 0.046 mol, 1.00 eq), (S)-hexahydropyridazine-3-carboxylic acid methyl ester (12.4 g, 0.069 mol, 1.5 eq), and N-methylmorpholine (18.6 g, 0.184 mol, 4 eq). The resulting reaction mixture was stirred at 0 °C for 3 h, and then quenched with water (200 mL). The organic phase was collected, and the aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (20 g, 60% yield).

[0476] LC-MS: m / z 726 (M+H) + .

[0477] Step 6: Preparation of (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid

[0478] A solution of methyl hexahydropyridazine-3-carboxylate (20.0 g, 0.027 mol, 1.00 eq) in THF (120 mL) was mixed with 20 mL of MeOH and 20 mL of water containing lithium hydroxide monohydrate (1.39 g, 0.033 mol, 1.2 eq). The resulting reaction mixture was added to the system at 25 °C and stirred for 15 min. The mixture was then cooled to 0 °C, and 200 mL of DCM and 100 mL of water were added and stirred. The pH was then adjusted to 4-5 with 4N hydrochloric acid. The organic phase was collected, and the aqueous phase was extracted with 100 mL of DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was stirred with ethyl acetate (80 mL) to form a dispersed solid. Isopropyl ether (320 mL) was slowly added. The resulting mixture was stirred at 25 °C for 1 h and then filtered. The filter cake was dried to obtain the target product (14 g, 73% yield).

[0479] LC-MS: m / z 712 (M+H) + .

[0480] Step 7: ((6) 3 S,4S,Z)-1 2 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)aminocarbamate tert-butyl ester

[0481] At 25°C, a solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid (3.6 g, 5.06 mmol, 1.00 eq) in DMF (80 mL) was slowly added to a solution of N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (6.2 g, 22.1 mmol, 4.40 eq) and N-methylimidazolium (3.0 g, 36.52 mmol, 7.20 eq) in DMF (130 mL). The addition was completed over 1-2 h. The resulting reaction solution was reacted at 25°C for 15 min, and then DCM (200 mL) and water (100 mL) were added to separate the layers. The organic phase was collected, and the aqueous phase was extracted with DCM (50 mL). The combined organic phases were washed once with 5% saline (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (2.6 g, 74% yield).

[0482] LC-MS: m / z 694 (M+H) + .

[0483] Step 8: 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 Preparation of β-(S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0484] ((6) 3 S,4S,Z)-1 2 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)aminocarbamate tert-butyl ester (2.30 g, 3.32 mmol), (S)-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)boronic acid (3.98 g, 9.96 mmol), and K3PO4 (2.46 g, 11.62 mmol) were dissolved in dioxane (28 mL) and water (5 mL). The mixture was purged three times with argon, followed by the addition of Pd(dppf)Cl2 (364 mg, 0.498 mmol). The resulting reaction solution was purged three times with argon and then stirred at 75 °C for 16 h. The reaction solution was cooled to room temperature and then quenched with water (80 mL), followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target product (2.0 g, 65.4% yield).

[0485] LC-MS: m / z 921 (M+H) + .

[0486] Step 9: 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 Preparation of β-(S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0487] 4-(5-((6 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2Benzyl 6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (2.0 g, 2.17 mmol) and cesium carbonate (3.50 g, 10.85 mmol) were added to a 20 mL DMF solution containing 1.02 g (6.51 mmol) of iodoethane. The reaction mixture was stirred at room temperature for 16 h, then water (50 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target product (0.75 g, 36.4% yield) and the non-target chiral isomer (1.12 g).

[0488] LC-MS: m / z 949 (M+H) + .

[0489] The experimental procedures in steps 10, 11, and 12 are the same as those in Int I-1 synthesis route 1.

[0490] Int I-1(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthetic route 3 for H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0491] Step 1: ((6) 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)aminocarbamate tert-butyl ester

[0492] Under argon protection, ((6) 3 S,4S,Z)-12 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Toluene (20 mL) of a solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)aminocarbamate (1 g, 1.44 mmol) was added with potassium acetate (495 mg, 5.05 mmol, 3.5 eq) and S-Phos (236 mg, 0.4 eq). After purging with argon, pinacolborane (3.69 g, 28.84 mmol, 20 eq) and Pd2(dba)3 (264 mg, 0.2 eq) were added at room temperature. The reaction mixture was then reacted at 60 °C for 2 h after purging with argon, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After separation of the organic phase, the residue was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target compound (0.4 g, 40% yield).

[0493] LC-MS: m / z 694 (M+H) + .

[0494] Step 2: 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 Preparation of β-(S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0495] Under argon protection, ((6) 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1In a toluene solution (6 mL) of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-4-yl)aminocarbamate tert-butyl ester (300 mg, 0.43 mmol), potassium phosphate (275 mg, 1.30 mmol, 3.0 eq) and (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carbamate benzyl ester (281 mg, 0.65 mmol, 1.5 eq) were added. The mixture was purged with argon, and Pd(dtbpf)Cl2 (264 mg, 0.2 eq) was added at room temperature. The reaction mixture was then purged with argon again, and reacted at 70 °C for 2 hours, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After separation of the organic phase, the mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target compound (300 mg, 76% yield).

[0496] LC-MS: m / z 921 (M+H) + .

[0497] The experimental procedures in steps three, four, five, and six are the same as those in Int I-1 synthesis route 2.

[0498] Int I-1(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthetic route 4 for H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0499] Step 1: Preparation of ethyl (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropionate

[0500] Under argon protection, sodium hydroxide (13.5 g, 0.337 mol, 2.5 eq) was added to a DMF solution of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropionic acid (58 g, 0.135 mol, 1.0 eq) at 0 °C (406 mL, 7 V). Iodoethane (52.6 g, 0.337 mol, 2.5 eq) was then added dropwise. After the addition was complete, the reaction mixture was slowly brought to room temperature and reacted overnight. Then, a semi-saturated brine solution (1000 mL) was added under ice bath conditions, followed by extraction with methyl tert-butyl ether (1000 mL x 2). The combined organic phases were washed successively with a semi-saturated ammonium chloride aqueous solution (1000 mL) and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (63 g, 0.129 mol, yield 95%). No further purification was required, and it was used directly in the next reaction.

[0501] LC-MS: m / z 487 (M+H) + .

[0502] Step 2: Preparation of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol

[0503] Under argon protection, lithium aluminum hydride (6.9 g, 0.18 mol, 1.4 eq) was added in portions to 900 mL of THF at 0 °C, followed by dropwise addition of ethyl (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropionate in 360 mL of THF. The temperature was controlled to remain below -10 °C during the addition. After the addition was complete, the reaction mixture was kept at this temperature for 4 h. Then, water (7 mL), 15% sodium hydroxide aqueous solution (7 mL), and water (21 mL) were added dropwise to the system sequentially. After the addition was complete, the reaction mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (57.8 g, 0.130 mol, 100% yield). No further purification was required, and it was used directly in the next reaction.

[0504] LC-MS: m / z 445 (M+H) + .

[0505] Step 3: Preparation of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol hydrochloride

[0506] (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol (57.8 g, 0.130 mol, 1.0 eq) was dissolved in xylene (150 mL, 3V). The mixture was heated to 100 °C and stirred for 1 h, then heated to 140 °C and stirred for 4 h, before being cooled to room temperature. Isopropanol (465 mL, 8V) and a solution of hydrogen chloride in isopropanol (5 M in THF, 63 mL, 0.315 mol, 2.5 eq) were added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred for 1 h, and seed crystals were added. The product precipitated slowly, and the mixture was stirred for another 2 h to allow crystallization. The mixture was then cooled to 0 °C and stirred for another 0.5 h. After filtration and drying, the target product (25.6 g, 0.053 mol, yield 41%) was obtained.

[0507] LC-MS: m / z 445 (M+H) + .

[0508] Step 4: Preparation of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0509] (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol hydrochloride (25.6 g, 0.053 mol, 1.0 eq) was dissolved in DCM (385 mL) and stirred until dissolved. Then, DMAP (0.325 g, 0.00266 mol, 0.05 eq) and triethylamine (16.17 g, 0.1598 mol, 3.00 eq) were added. Acetic anhydride (5.44 g, 0.053 mol, 1.00 eq) was added dropwise to the resulting reaction solution at 0 °C, with the temperature controlled to not exceed 5 °C during the addition. After the addition was complete, the mixture was slowly raised to room temperature and reacted for 5 h. The reaction solution was then cooled to 0–5 °C and water (500 mL) was added. The aqueous phase was separated and extracted with DCM (200 mL). The combined organic phases were washed successively with dilute hydrochloric acid (0.5 M, 300 mL), water, and saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (25.8 g, 0.053 mol, 100% yield). No further purification was required, and it was used directly in the next reaction.

[0510] LC-MS: m / z 487 (M+H) + .

[0511] Step 5: Preparation of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0512] Under argon protection, 4,4'-di-tert-butyl-2,2'-bipyridine (219 mg, 0.815 mmol, 0.15 eq), 1,5-cyclooctadiene iridium chloride dimer (183 mg, 0.272 mmol, 0.05 eq), and phenanthyl borate (1.8 g, 7.06 mmol, 1.3 eq) were added sequentially to a cyclohexane (50 mL) solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (2.64 g, 5.43 mmol, 1.0 eq), respectively. The reaction mixture was heated to 68 °C and reacted for 3.5 h, then cooled to room temperature and concentrated under reduced pressure. The residue was separated by rapid chromatography to give the target product (2.6 g, 4.9 mol, 90% yield).

[0513] LC-MS: m / z 531 (M+H) + .

[0514] Step 6: Preparation of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0515] Oxygen was bubbled and stirred in a solution of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (10.0 g, 18.9 mmol, 1.00 eq), N-methylpiperazine (18.9 g, 188.7 mmol, 10.00 eq), trimethyl phosphate (9.8 g, 69.8 mmol, 3.70 eq), and copper acetate (17.3 g, 94.3 mmol, 5.00 eq) in dichloromethane (160 mL) at 25 °C for 20 h. Then, saturated ammonium chloride (100 mL) was added and stirred for 10 min, followed by the addition of 20 g of diatomaceous earth and stirring for 15 min. The mixture was then filtered. The filtrate was separated, and the organic phase was washed once more with saturated ammonium chloride solution (50 mL) and then separated again. The resulting organic phase was concentrated under reduced pressure. The residue was separated by rapid chromatography to obtain the target product (4.6 g, 7.87 mmol, yield 42%).

[0516] LC-MS: m / z 585 (M+H) + .

[0517] Step 7: Preparation of (S)-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid

[0518] Under argon protection, a mixture of 2-methyltetrahydrofuran (9 mL) and methanol (6 mL) containing (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.0 g, 5.10 mmol, 1.00 eq), B2(OH)4 (691 mg, 7.70 mmol, 1.50 eq), XPhos (49 mg, 0.10 mmol, 0.02 eq), XPhos Pd G3 (43 mg, 0.05 mmol, 0.01 eq), and potassium pentovanate (1.51 g, 10.71 mmol, 2.10 eq) was reacted at 30 °C for 2 h. The reaction was then quenched by adding water (3 mL), followed by dilution with methanol (9 mL) and filtration. The filtrate was separated by rapid chromatography to obtain the target product (3.3 g, 4.97 mmol, yield 96%).

[0519] LC-MS: m / z 551 (M+H) + .

[0520] Step 8: Preparation of (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid

[0521] Under argon protection, (S)-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid (3.6 g, 5.40 mmol, 1.00 eq) and (S)-1-((S)-3-(4-bromothiazol-2-ji1)-2-((butoxycarbonyl)amine) Methyl hexahydropyridazine-3-carboxylate (3.9 g, 8.10 mmol, 1.50 eq), Pd(dtbpf)Cl2 (177 mg, 0.27 mmol, 0.05 eq), and K2CO3 (3.0 g, 21.70 mmol, 4.00 eq) in 1,4-dioxane (36 mL) and water (11 mL) were reacted at 75 °C for 2 h, followed by cooling to 25 °C. Methanol (20 mL), water (10 mL), sodium hydroxide (434 mg, 10.8 mmol, 2.00 eq), and lithium hydroxide monohydrate (177 mg, 27.1 mmol, 5.00 eq) were added sequentially to the resulting mixture. The mixture was stirred for 3 h, then the pH was adjusted to 3–4 with 4N hydrochloric acid, and the organic solvent was removed by vacuum concentration. The residue was extracted twice with a mixed solvent of dichloromethane (50 mL) and methanol (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (4.0 g, 4.73 mmol, yield 87%).

[0522] LC-MS: m / z 847 (M+H) + .

[0523] Step 9: ((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)tert-butyl carbamate

[0524] N,N,N',N'-Tetramethylchloromethamidine hexafluorophosphate (5.8 g, 20.7 mmol, 4.50 eq) and N-methylimidazolium (2.8 g, 34.6 mmol, 7.50 eq) were dissolved in MeCN (120 mL), stirred until dissolved, and then slowly added to a solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazin-3-carboxylic acid (3.9 g, 4.60 mmol, 1.00 eq) in 80 mL of 1,4-dioxane at 25 °C for 1-2 h. After the addition was complete, the reaction mixture was stirred for 15 min. Then, DCM (200 mL) and water (100 mL) were added to separate the phases. The aqueous phase was extracted with DCM (50 mL), and the combined organic phases were washed with 5% saline (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (3.3 g, 3.98 mmol, yield 86%).

[0525] LC-MS: m / z 729 (M+H) + .

[0526] The tenth experimental procedure is the same as that of Int I-1 synthesis route 1.

[0527] Int I-1'(6 3 S,4S,Z)-1 2 -(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4-amino-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthetic route 1 for H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0528] Step 1: Preparation of (S)-3-(5-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0529] To a mixture of acetonitrile (90 mL, 15 V) and water (18 mL, 3 V) containing (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (5.95 g, 11.23 mmol, 1.0 eq), sodium iodide (4.2 g, 28.07 mmol, 2.5 eq), sodium nitrite (1.16 g, 16.84 mmol, 1.5 eq), 1,10-phenanthroline (0.405 g, 2.245 mmol, 0.2 eq), and cuprous iodide (0.214 g, 1.123 mmol, 0.1 eq), sodium iodide was added. The mixture was reacted at 55 °C for 18 h, then cooled to room temperature, and water (200 mL) and ethyl acetate (200 mL) were added. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with semi-saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to give the target product (3.54 g, 5.784 mmol, yield 51.5%).

[0530] LC-MS: m / z 613 (M+H) + .

[0531] Step 2: Preparation of (S)-3-(5-bromo-2-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0532] Under argon protection, tert-butyldimethyl(2-propynoxy)silane (1.134 g, 6.352 mol, 1.15 eq), Pd(PPh3)2Cl2 (203 mg, 0.289 mmol, 0.05 eq), cuprous iodide (110 mg, 0.578 mmol, 0.1 eq), and DIEA (1.5 g, 11.569 mmol, 2 eq) were added to a solution of (S)-3-(5-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.54 g, 5.784 mmol, 1.00 eq) in acetonitrile (70 mL), 1 H-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (70 mL). The reaction mixture was reacted at room temperature for 5 h, followed by the addition of water (150 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (80 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (3.62 g, 5.533 mmol, yield 95%).

[0533] LC-MS: m / z 655 (M+H)+ .

[0534] Step 3: Preparation of (S)-3-(5-bromo-1-ethyl-2-(5-(3-hydroxyprop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0535] At -5 to 0 °C, TBAF (16.61 mL, 16.61 mmol, 3.00 eq) was added dropwise to a THF (72 mL) solution of (S)-3-(5-bromo-2-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.62 g, 5.533 mmol, 1.00 eq). The resulting reaction mixture was stirred at -5 to 0 °C for 30 min, then slowly raised to room temperature for 3 h, followed by the addition of water (150 mL) and ethyl acetate (2000 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (2.5 g, 4.63 mmol, yield 83%).

[0536] LC-MS: m / z 541 (M+H) + .

[0537] Step 4: Preparation of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(3-(((methanesulfonyl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0538] At 0–5 °C, DIEA (1.8 g, 13.89 mmol, 3 eq) was added to 50 mL of dichloromethane containing (S)-3-(5-bromo-1-ethyl-2-(5-(3-hydroxyprop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (2.5 g, 4.63 mmol, 1.00 eq), followed by dropwise addition of 10 mL of dichloromethane containing methanesulfonic anhydride (1.21 g, 6.94 mmol, 1.5 eq). After the addition was complete, the reaction mixture was slowly heated to room temperature for 3 h, then cooled to 0–5 °C, and water (80 mL) and dichloromethane (50 mL) were added. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic phases were washed with semi-saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (2.37 g, 3.834 mmol, yield 83%).

[0539] LC-MS: m / z 619 (M+H) + .

[0540] Step 5: Preparation of (S)-3-(2-(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0541] At 0–5 °C, DIEA (1.49 g, 11.5 mmol, 3 eq) was added dropwise to a solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(3-((methanesulfonyl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (2.37 g, 3.834 mmol, 1.00 eq) in 50 mL of dichloromethane, followed by the dropwise addition of 1,4-oxazacycloheptane (776 mg, 7.67 mmol, 2 eq). After the addition was complete, the reaction mixture was slowly raised to room temperature and reacted for 6 h, then cooled to 0–5 °C, and water (100 mL) and dichloromethane (50 mL) were added. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic phases were washed with semi-saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (2.15 g, 3.45 mmol, 90% yield).

[0542] LC-MS: m / z 624 (M+H) + .

[0543] Step 6: Preparation of methyl (S)-1-((S)-3-(4-(2-(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)thiazolyl)-2-((butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate

[0544] Under argon protection, Pd(dppf)Cl2 (140 mg, 0.192 mmol) was added to a mixture of dioxane (15 mL) and water (3 mL) of (S)-3-(2-(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropyl acetate (800 mg, 1.28 mmol), (2-((S)-2-((butoxycarbonyl)amino)-3-((S)-3-(methoxyformyl)tetrahydropyridazin-1(2H)-yl)-3-oxopropyl)thiazolyl-4-yl)boronic acid (849 mg, 1.92 mmol), and K3PO4 (440 mg, 4.48 mmol). The reaction mixture was heated to 75°C and stirred for 1 hour, followed by the addition of water (50 mL) and extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by rapid chromatography to obtain the target product (270 mg, 0.287 mmol, yield 22.4%).

[0545] LC-MS: m / z 942 (M+H) + .

[0546] Step 7: Preparation of (S)-1-((S)-3-(4-(2-(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazolyl)-2-((butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid

[0547] Lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added to a mixed solution of methyl hexahydropyridazine-3-carboxylate (270 g, 0.287 mmol) in tetrahydrofuran (2 mL), methanol (0.5 mL), and water (0.5 mL). The reaction mixture was stirred at room temperature for 1 h, then cooled in an ice-water bath, and the pH was adjusted to 2–3 with 2 M dilute hydrochloric acid. The resulting mixture was purified by high-performance preparative liquid chromatography to obtain the target product (220 mg, 0.248 mmol, yield 86.4%).

[0548] LC-MS: m / z 887 (M+H) + .

[0549] The experimental procedures in steps eight and nine are the same as those in Int I-1 synthesis route 4.

[0550] Int I-1”6 3 S,4S,Z)-4-amino-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-1 5 ,1 6 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 4 Synthetic route 1 for H-8-oxo-2(4,2)-thiazolyl-1(8,1)-pyrrole[3,2,1-ij]quinoline-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0551] Step 1: Preparation of (S)-4-(5-((6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0552] Under argon protection, (S)-4-(5-ethynyl-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (9.5 g, 25 mmol), 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (9.3 g, 27 mmol), triethylamine (12.7 g, 125 mmol), CuI (480 mg, 2.5 mmol), and Pd(pph3)2Cl2 (1.78 g, 2.5 mmol) in DMF (100 mL) were reacted at room temperature for 1–2 h, followed by the addition of ethyl acetate. The mixture was washed three times with saturated brine and then concentrated under reduced pressure. The residue was separated by rapid chromatography to give the target product (9.6 g, 16.3 mmol, yield 65.2%).

[0553] LC-MS: m / z 589 (M+H) + .

[0554] Step 2: Preparation of (S)-4-(5-(8-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0555] Under argon protection, a DMF solution of (S)-4-(5-((6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (9.6 g, 16.3 mmol) and PdCl2 (580 mg, 20%) was reacted at 70–75°C for 3–4 h, followed by cooling to room temperature and the addition of ethyl acetate. The mixture was washed three times with saturated brine and then concentrated under reduced pressure. The residue was separated by rapid chromatography to give the target product (4.5 g, 7.6 mmol, yield 46.9%).

[0556] LC-MS: m / z 589 (M+H) + .

[0557] Step 3: Preparation of (S)-4-(5-(8-bromo-1-formyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0558] At -5°C, phosphorus oxychloride (7.8 g, 50 mmol) was added dropwise to DMF (40 mL). The resulting reaction solution was stirred for 20 min, followed by the dropwise addition of (S)-4-(5-(8-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (3.3 g, 5.6 mmol) in DMF (40 mL) at -5°C. After the addition was complete, the reaction solution was allowed to rise naturally to room temperature, then heated to 45°C and reacted for 1–2 h. The resulting mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure. The residue was separated by rapid chromatography to give the target product (2.7 g, 4.38 mmol, yield 57.6%).

[0559] LC-MS: m / z 617 (M+H) + .

[0560] Step 4: Preparation of benzyl 4-(5-(8-bromo-1-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxopropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate

[0561] Under argon protection, LDA (4.5 mL, 2 M) was added dropwise to a 20 mL THF solution of methyl isobutyrate (1.4 g, 13.7 mmol) at -70°C. After the addition was complete, the reaction mixture was kept at this temperature for 45 min, followed by the dropwise addition of a 20 mL THF solution of (S)-4-(5-(8-bromo-1-formyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (2.2 g, 3.6 mmol). After the addition was complete, the reaction mixture was kept at this temperature for 2 h, followed by quenching with saturated ammonium chloride and extraction twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was separated by rapid chromatography to obtain the target product (2.0 g, 2.78 mmol, yield: 77.3%).

[0562] LC-MS: m / z 719 (M+H) + .

[0563] Step 5: Preparation of (S)-4-(5-(8-bromo-1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0564] Under argon protection, TFA (8.4 g, 73.7 mmol) was added dropwise to a solution of 4-(5-(8-bromo-1-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxypropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (2.0 g, 2.78 mmol) and triethylsilane (2.8 g, 24 mmol) in DCM (50 mL) at -10°C. After the addition was complete, the reaction solution was allowed to rise naturally to room temperature for 1–2 h. The reaction solution was then quenched by adding back to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was separated by rapid chromatography to obtain the target product (1.55 g, 2.2 mmol, yield 79.1%).

[0565] LC-MS: m / z 703 (M+H) + .

[0566] Step 6: Preparation of (S)-3-(8-bromo-2-(2-(1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-yl)-2,2-dimethylpropane-1-ol

[0567] Under argon protection, at -20°C, LiAlH4 (168 mg, 4.4 mmol) was added to 20 mL of THF containing (S)-4-(5-(8-bromo-1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (1.55 g, 2.2 mmol). The reaction mixture was stirred at this temperature for 40 min, followed by quenching with saturated ammonium chloride solution, and then extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated brine and then concentrated under reduced pressure to obtain the target product (1.7 g). No purification was required; it was used directly in the next reaction.

[0568] LC-MS: m / z 541 (M+H) + .

[0569] Step 7: Preparation of (S)-4-(5-(8-bromo-1-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0570] Sodium bicarbonate (200 mg) was added to a mixture of acetonitrile (18 mL) and water (6 mL) of (S)-3-(8-bromo-2-(2-(1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-yl)-2,2-dimethylpropane-1-ol (1.7 g), and the temperature was lowered to 0°C. Then, CBzCl (500 mg) was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 1–2 h, then quenched with sodium bicarbonate, and extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated brine and then concentrated under reduced pressure. The residue was separated by rapid chromatography to obtain the target product (1.5 g, 2.22 mmol, quantitative yield).

[0571] LC-MS: m / z 675 (M+H) + .

[0572] Step 8: Preparation of (S)-4-(5-(1-(3-hydroxy-2,2-dimethylpropyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0573] The experimental procedure is the same as step 6 of the Int I-1 synthesis route 1.

[0574] LC-MS: m / z 723 (M+H) + .

[0575] Step 9: Preparation of methyl hexahydropyridazine-3-carboxylate.

[0576] The experimental procedure is the same as step 7 of the Int I-1 synthesis route 1.

[0577] LC-MS: m / z 993 (M+H) + .

[0578] Step 10: Preparation of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-8-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid

[0579] The experimental procedure is the same as step 8 of the Int I-1 synthesis route 1.

[0580] LC-MS: m / z 979 (M+H) + .

[0581] Step 11 4-(5-((6) 3 S,4S,Z)-4-((tert-Butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-1 5 ,1 6 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 4 H-8-O-2(4,2)-Thiazolyl-1(8,1)-Pyrrole[3,2,1-ij]quinoline-6(1,3)pyridazinecycloundecane-1 2 Preparation of β-(S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester

[0582] The experimental procedure is the same as step nine of the Int I-1 synthesis route 1.

[0583] LC-MS: m / z 961 (M+H) + .

[0584] Step 12 (6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 5 ,1 6 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 4Preparation of H-8-oxo-2(4,2)-thiazolyl-1(8,1)-pyrrole[3,2,1-ij]quinoline-6(1,3-pyridazinecycloundecane-4-yl)tert-butyl carbamate

[0585] The experimental procedure is the same as step 10 of the Int I-1 synthesis route.

[0586] LC-MS: m / z 827 (M+H) + .

[0587] Step 13 (6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 5 ,1 6 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 4 Preparation of H-8-oxo-2(4,2)-thiazolyl-1(8,1)-pyrrole[3,2,1-ij]quinoline-6(1,3-pyridazinecycloundecane-4-yl)tert-butyl carbamate

[0588] The experimental procedure is the same as step eleven of the Int I-1 synthesis route 1.

[0589] LC-MS: m / z 841 (M+H) + .

[0590] Step Fourteen (6) 3 S,4S,Z)-4-amino-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-1 5 ,1 6 6 1 6 2 6 3 6 4 6 5 6 6 -octahydro-1 4 Preparation of H-8-oxo-2(4,2)-thiazolyl-1(8,1)-pyrrole[3,2,1-ij]quinoline-6(1,3)-pyridazinecycloundecane-5,7-dione hydrochloride

[0591] The experimental procedure is the same as step 12 of the Int I-1 synthesis route 1.

[0592] LC-MS: m / z 741 (M+H) + .

[0593] The following intermediates were synthesized using different starting materials according to the above method:

[0594] Int I-2(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 4 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0595] LC-MS: m / z 747 (M+H) + .

[0596] Int I-3(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 6 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0597] LC-MS: m / z 747 (M+H) + .

[0598] Int I-4(6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 7 -Fluorine-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0599] LC-MS: m / z 747 (M+H) + .

[0600] Int I-5(6 3 S,4S,Z)-4-amino-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0601] LC-MS: m / z 724 (M+H) + .

[0602] Int I-6(6 3 S,4S,Z)-1 2 -(5-(3-(2-oxo-6-azaspiro[3.3]heptane-6-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4-amino-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0603] LC-MS: m / z 752 (M+H) + .

[0604] Int I-7(6 3 S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(5-(3-(4-(fluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0605] LC-MS: m / z 782 (M+H) + .

[0606] Int I-8(6 3 S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(5-(3-(4-(difluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0607] LC-MS: m / z 800 (M+H) + .

[0608] Int I-9(6 3 S,4S,Z)-4-amino-1 1 -Ethyl-1 2-(5-(4-(fluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0609] LC-MS: m / z 744 (M+H) + .

[0610] Int I-10(6 3 S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(5-(4-(difluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride

[0611] LC-MS: m / z 762 (M+H) + .

[0612] Int II-1(6 4 S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0613] LC-MS: m / z 741 (M+H) + .

[0614] Int II-2(6 4 S,4S,Z)-4-amino-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0615] LC-MS: m / z 736 (M+H) + .

[0616] Int II-3(6 4 S,4S,Z)-1 2 -(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4-amino-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0617] LC-MS: m / z 780 (M+H) + .

[0618] Int II-4(6 4 S,4S,Z)-4-amino-1 1 -(cyclopropylmethyl)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0619] LC-MS: m / z 767 (M+H) + .

[0620] Int II-5(6 4 S,4S,Z)-4-amino-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -(cyclopropylmethyl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0621] LC-MS: m / z 762 (M+H) + .

[0622] Int II-6(6 4 S,4S,Z)-1 2 -(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4-amino-1 1 -(cyclopropylmethyl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0623] LC-MS: m / z 762 (M+H) + .

[0624] Int II-7(6 4 S,4S,Z)-4-amino-1 1 -Cyclopropyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0625] LC-MS: m / z 753 (M+H) + .

[0626] Int II-8(6 4 S,4S,Z)-4-amino-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Cyclopropyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0627] LC-MS: m / z 748 (M+H) + .

[0628] Int II-9(6 4 S,4S,Z)-1 2 -(5-(3-(1,4-oxazol-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-4-amino-1 1 -Cyclopropyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-5,7-dione hydrochloride

[0629] LC-MS: m / z 792 (M+H) + .

[0630] Synthesis Example:

[0631] Example A1 N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 46 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 N 2 Preparation of 1-dimethyloxalyldiamine trifluoroacetate

[0632] Under the ice bath, (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 The solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-5,7-dione hydrochloride (15 mg, 0.02 mmol) in N,N-dimethylacetamide (0.5 mL) was successively supplemented with N,N-diisopropylethylamine (18 mg, 0.14 mmol, 7 eq), 2-(dimethylamino)-2-oxoacetic acid (4.8 mg, 0.04 mmol, 2 eq), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (15 mg, 0.04 mmol, 2 eq). The resulting mixture was reacted at room temperature for 1 hour and then filtered. The filtrate was separated by preparative HPLC to give the target product (8.76 mg, 51% yield).

[0633] LC-MS: m / z 828 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.87(s,1H),9.13(d,J=8Hz,1H),8.50-8.48(m,2H),7.83(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8 Hz,1H),7.39(d,J=4Hz,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H),5.50(t,J=8Hz,1H),5.21(d,J=12Hz,1H),4.33-4.11( m,5H),4.04-4.01(m,2H),3.61-3.52(m,5H),3.38-3.26(m,3H),3.21(s,3H),3.11-3.02(m,5H),2.94-2.76(m,6H),2.46- 2.43(m,1H),2.10-2.07(m,1H),1.81-1.76(m,2H),1.57-1.48(m,1H),1.35(d,J=8Hz,3H),0.92-0.89(m,5H),0.35(s,3H).

[0634] The following examples were synthesized using different starting materials according to the method of Example A1:

[0635] Example A2 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxo-4-(pyrrolin-1-yl)butyramide trifluoroacetate

[0636] LC-MS: m / z 882 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),8.52-8.50(m,2H),8.37(d,J=8Hz,1H),7.82(s,1H),7.77(d,J=8Hz,1H),7.59(d,J= 8Hz,1H),7.41-7.40(m,1H),7.23(s,1H),7.10(s,1H),6.98(s,1H),5.57(t,J=8Hz,1H),5.11(d,J=12Hz,1H),4.34-4.13 (m,5H),4.06-4.02(m,2H),3.59(m,3H),3.31-3.04(m,13H),2.98-2.94(m,1H),2.88(s,3H),2.81-2.74(m,1H),2.48-2. 42(m,4H),2.10-2.06(m,1H),1.92-1.74(m,6H),1.58-1.48(m,1H),1.36(d,J=8Hz,3H),0.92-0.89(m,5H),0.37(s,3H).

[0637] Example A3 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxo-4-(piperidin-1-yl)butyramide trifluoroacetate

[0638] LC-MS: m / z 882 (M+H) + .

[0639] Example A4 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 64 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-morpholino-4-oxobutyramide trifluoroacetate

[0640] LC-MS: m / z 898 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.50-8.49(m,2H),8.35(d,J=8Hz,1H),7.80(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz,1H ),7.40-7.39(m,1H),7.23(s,1H),7.10(s,1H),6.98(s,1H),5.56(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.34-4.10(m,5H),4.04-4 .00(m,2H),3.58-3.55(m,8H),3.33-3.29(m,2H),3.22-3.04(m,8H),2.96-2.92(m,1H),2.87(s,3H),2.81-2.72(m,2H),2.55(m ,2H),2.47-2.42(m,2H),2.09-2.05(m,1H),1.80(s,2H),1.59-1.45(m,2H),1.35(d,J=8Hz,3H),0.92-0.89(m,5H),0.36(s,3H).

[0641] Example A5 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-(4-methylpiperazin-1-yl)-4-oxobutyramide trifluoroacetate

[0642] LC-MS: m / z 911 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.82(s,2H),8.52-8.50(m,2H),8.41(d,J=8Hz,1H),7.82(s,1H),7.76(d,J=8Hz,1H),7.59(d,J= 8Hz,1H),7.41-7.40(m,1H),7.24(s,1H),7.11(s,1H),6.99(s,1H),5.56(t,J=8Hz,1H),5.11(d,J=12Hz,1H),4.47(s,1H ),4.35-4.02(m,8H),3.59(m,3H),3.36-3.32(m,2H),3.23-3.07(m,10H),2.98-2.78(m,10H),2.62-2.59(m,2H),2.46-2 .43(m,2H),2.12-2.09(m,1H),1.81-1.75(m,2H),1.57-1.51(m,1H),1.36(d,J=8Hz,3H),0.92-0.90(m,5H),0.37(s,3H).

[0643] Example A6 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-4-(4-(fluoromethylene)piperidin-1-yl)-4-oxobutyramide trifluoroacetate

[0644] LC-MS: m / z 926 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.70(s,1H),8.50-8.49(m,2H),8.36(d,J=8Hz,1H),7.81(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz,1H),7.39( s,1H),6.87(s,1H),6.65(s,1H),5.55(t,J=8Hz,1H),5.11(d,J=12Hz,1H),4.33-4.11(m,5H),4.04-4.00(m,2H),3.58-3.44(m,5H),3.29 -3.03(m,8H),2.96-2.92(m,1H),2.86(s,3H),2.80-2.73(m,2H),2.67(s,1H),2.58-2.54(m,3H),2.45-2.41(m,2H),2.32(s,1H),2.27( s,1H),2.17(s,1H),2.09-2.05(m,2H),1.97(s,1H),1.78(s,2H),1.56-1.47(m,1H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0645] Example A7 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxo-4-(piperazin-1-yl)butyramide trifluoroacetate

[0646] LC-MS: m / z 897 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.91(s,1H),8.84(s,2H),8.52-8.50(m,2H),8.41(d,J=12Hz,1H),7.82(s,1H),7.76(d,J=8Hz,1H),7.59(d,J=8H z,1H),7.40(s,1H),7.26(s,1H),7.13(s,1H),7.00(s,1H),5.56(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.34-4.12(m,5H),4.06-4.00(m,2H) ,3.67-3.54(m,6H),3.32(m,2H),3.23(s,3H),3.17-3.07(m,8H),2.9 7-2.94(m,1H),2.88(s,3H),2.81-2.75(m,1H),2.69-2.67(m,2H),2. 61-2.57(m,2H),2.46-2.42(m,1H),2.11-2.07(m,1H),1.82(s,2H),1 .59-1.50(m,1H),1.36-1.35(m,3H),0.93-0.90(m,5H),0.37(s,3H).

[0647] Example A8 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxobutyramide trifluoroacetate

[0648] LC-MS: m / z 923 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.93(s,1H),9.02-8.95(m,2H),8.50-8.49(m,2H),8.38-8.35(m,1H),7.80(s,1H),7.75(d,J=8Hz,1H),7.57(d ,J=8Hz,1H),7.39(s,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),5.55(t,J=8Hz,1H),5.09(d,J=12Hz,1H),4.33-4.12(m,5H),4.03(s, 4H),3.88(d,J=12Hz,2H),3.45(d,J=12Hz,2H),3.33(d,J=12Hz,2H),3.22-3.04(m,8H),2.96(d,J=12Hz,2H),2.86(s,3H),2.81-2.64( m,3H),2.44-2.41(m,2H),2.09-2.07(m,1H),1.88-1.74(m,5H),1.62-1.48(m,2H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0649] Example A9 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxo-4-(2,7-diazaspiro[4,4]nonane-2-yl)butyramide trifluoroacetate

[0650] LC-MS: m / z 937 (M+H) + .

[0651] Example A10 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-oxo-4-(2,9-diazaspiro[5.5]undecane-9-yl)butyramide trifluoroacetate

[0652] LC-MS: m / z 965 (M+H) + .

[0653] Example A11 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(3-(morpholino-4-formyl)azacyclobutane-1-yl)acetamide trifluoroacetate

[0654] LC-MS: m / z 939 (M+H) + .

[0655] Example A12 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(3-(morpholino-4-carboxyl)pyrrolin-1-yl)acetamide trifluoroacetate

[0656] LC-MS: m / z 953 (M+H) + LC-MS: m / z 953 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.19-10.09(m,1H),9.77(s,1H),9.15-9.08(m,1H),8.50-8.49(m,2H),7.84(s,1H),7.76(d, J=8Hz,1H),7.58(d,J=8Hz,1H),7.39(d,J=4Hz,1H),5.64(t,J=8Hz,1H),5.24(d,J=12Hz,1H),4.34-4.10(m,6H),4.04- 3.99(m,2H),3.68-3.49(m,14H),3.21-3.04(m,9H),2.95-2.76(m,5H),2.56-2.53(m,1H),2.46-2.43(m,2H),2.33-2.2 0(m,2H),2.10-2.07(m,2H),1.82-1.77(m,2H),1.59-1.47(m,1H),1.35(d,J=8Hz,3H),0.93-0.89(m,5H),0.36(s,3H).

[0657] Example A13 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(4-(morpholino-4-formyl)piperidin-1-yl)acetamide trifluoroacetate

[0658] LC-MS: m / z 967 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ9.90-9.79(m,2H),9.18(d,J=8Hz,1H),8.50-8.49(m,2H),7.84(s,1H),7.76(d,J=8Hz,1H ),7.58(d,J=8Hz,1H),7.39(s,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H),5.64(t,J=8Hz,1H),5.24(d,J=12Hz,1H ),4.32-4.09(m,5H),4.04-4.00(m,3H),3.62-3.55(m,12H),3.27-3.04(m,11H),2.93-2.76(m,6H),2.47-2.43(m, 1H),2.10-2.07(m,1H),1.92-1.81(m,6H),1.59-1.51(m,1H),1.35(d,J=4Hz,3H),0.92-0.89(m,5H),0.37(s,3H).

[0659] Example A14 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(3-(morpholino-4-formyl)piperidin-1-yl)acetamide trifluoroacetate

[0660] LC-MS: m / z 967 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.76-9.65(m,1H),9.26-9.17(m,1H),8.50-8.49(m,2H),7.83(d,J=4Hz,1H),7.76(d,J =8Hz,1H),7.58(d,J=8Hz,1H),7.39(s,1H),7.22(s,1H),7.10(s,1H),6.96(s,1H),5.63(t,J=8Hz,1H),5.23(d ,J=12Hz,1H),4.32-4.00(m,8H),3.63-3.52(m,12H),3.21-3.02(m,10H),2.93-2.77(m,5H),2.47-2.43(m,1H) ,2.10-2.06(m,1H),1.86-1.76(m,5H),1.56-1.49(m,1H),1.35(d,J=4Hz,3H),0.92-0.89(m,5H),0.37(s,3H).

[0661] Example A15 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-(6-(morpholino-4-formyl)-2-azaspiro[3.3]heptane-2-yl)acetamide trifluoroacetate

[0662] LC-MS: m / z 979 (M+H) + .

[0663] Example A16 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 65 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-(6-(morpholino-4-formyl)-2-azaspiro[3,4]octane-2-yl)acetamide trifluoroacetate

[0664] LC-MS: m / z 993 (M+H) + .

[0665] Example A17 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(8-(morpholino-4-formyl)-2-azaspiro[4.5]decane-2-yl)acetamide trifluoroacetate

[0666] LC-MS: m / z 1021 (M+H) + .

[0667] Example A18 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(3-(morpholino-4-formyl)azacyclobutane-1-yl)propionamide trifluoroacetate

[0668] LC-MS: m / z 953 (M+H) + .

[0669] Example A19 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(3-(morpholino-4-carboxyl)pyrrolo-1-yl)propionamide trifluoroacetate

[0670] LC-MS: m / z 967 (M+H) + .

[0671] Example A20 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)pyridazinecycloundecane-4-yl)-2-(4-(morpholino-4-formyl)piperidin-1-yl)propionamide trifluoroacetate

[0672] LC-MS: m / z 981 (M+H) + .

[0673] Example A21 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 16 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-(6-(morpholino-4-formyl)-2-azaspiro[3.3]heptane-2-yl)propionamide trifluoroacetate

[0674] LC-MS: m / z 993 (M+H) + .

[0675] Example A22 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0676] LC-MS: m / z 894 (M+H) + .

[0677] Example A22 was chirally split to obtain Examples A22A and A22B: (2R,4s,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate and (2S,4r,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0678] Example A22A

[0679] LC-MS: m / z 894 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.51-8.49(m,2H),8.12(d,J=8Hz,1H),7.79(s,1H),7.74(d,J=8Hz,1H),7.57(d ,J=8Hz,1H),7.09(s,1H),6.63(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.35-4.11(m,5H),4.05-3.96(m,2H) ,3.57-3.47(m,5H),3.23-3.08(m,6H),3.02-2.92(m,2H),2.88-2.73(m,5H),2.67(s,1H),2.43(d,J=12Hz,1H),2.33 (s,1H),2.23-1.93(m,9H),1.84-1.74(m,2H),1.56-1.47(m,2H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0680] Example A22B

[0681] LC-MS: m / z 894 (M+H) + .

[0682] Example A23 N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 N 6 -Dimethylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0683] LC-MS: m / z 922 (M+H) + .

[0684] Example A23 was chirally split to obtain Examples A23A and A23B: (2R,4s,6R)-N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 N 6 -Dimethylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate and (2S,4r,6S)-N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 N 6 -Dimethylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0685] Example A23A

[0686] LC-MS: m / z 922 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.83 (s, 1H), 8.50-8.48 (m, 2H), 8.14 (d, J = 8Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8Hz, 1H), 7 .57(d,J=8Hz,1H),7.40(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.35-4.12(m,5H),4.04-4.00(m,2H) ,3.57-3.52(m,4H),3.31-2.93(m,11H),2.86-2.72(m,8H),2.67(s,1H),2.43-2.33(m,2H),2.25-2.17(m,4H), 2.08-1.98(m,5H),1.83-1.74(m,2H),1.57-1.47(m,2H),1.35(d,J=8Hz,,3H),0.91-0.85(m,5H),0.37(s,3H).

[0687] Example A23B

[0688] LC-MS: m / z 922 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 8.50-8.48 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8Hz, 1H), 7 .57(d,J=8Hz,1H),7.40(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.35-4.12(m,5H),4.04-4.00(m,2H) ,3.57-3.50(m,4H),3.27-2.93(m,11H),2.86-2.73(m,8H),2.67(s,1H),2.43-2.33(m,2H),2.28-2.16(m,4H), 2.08-1.94(m,5H),1.83-1.74(m,2H),1.59-1.47(m,2H),1.35(d,J=8Hz,,3H),0.91-0.85(m,5H),0.34(s,3H).

[0689] Example A24 6-(azacyclobutane-1-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0690] LC-MS: m / z 934 (M+H) + .

[0691] Example A24 was chirally resolved to obtain Examples A24A and A24B: (2R,4s,6R)-6-(azacyclobutane-1-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 26 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide, and (2S,4r,6S)-6-(azacyclobutane-1-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0692] Example A24A

[0693] LC-MS: m / z 934 (M+H) + .

[0694] Example A24B

[0695] LC-MS: m / z 934 (M+H) + .

[0696] Example A25 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-(pyrrolidone-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0697] LC-MS: m / z 948 (M+H) + .

[0698] Example A25 was chirally split to obtain Examples A25A and A25B: (2R,4s,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-(pyrrolidone-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate, and (2S,4r,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-(pyrrolidone-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0699] Example A25A

[0700] LC-MS: m / z 948 (M+H) + .

[0701] Example A25B

[0702] LC-MS: m / z 948 (M+H) + .

[0703] Example A26 N-((6) 3 S,4S,Z)-1 1-Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(morpholino-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0704] LC-MS: m / z 964 (M+H) + .

[0705] Example A26 was chirally split to obtain Examples A26A and A26B: (2R,4s,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-(morpholino-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate and (2S,4r,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(morpholino-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0706] Example A26A

[0707] LC-MS: m / z 964 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 8.50-8.48 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8Hz, 1H), 7.5 7(d,J=8Hz,1H),7.40(s,1H),5.51(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.35-4.11(m,5H),4.04-4.00(m,2H),3.58 -3.51(m,8H),3.28-2.93(m,13H),2.87(s,3H),2.79-2.72(m,2H),2.44-2.40(m,1H),2.33(s,1H),2.23-2.16(m, 4H),2.07-1.97(m,5H),1.82-1.74(m,2H),1.57-1.47(m,2H),1.35(d,J=8Hz,3H),0.92-0.87(m,5H),0.35(s,3H).

[0708] Example A26B

[0709] LC-MS: m / z 964 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 8.50-8.48 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.80 (s, 1 H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz,1H),7.40(s,1H),5.51(t,J=8Hz,1H),5.10(d,J =12Hz,1H),4.35-4.11(m,5H),4.04-4.00(m,2H),3.58-3.51(m,8H),3.31-2.93(m,13 H),2.87(s,3H),2.79-2.72(m,2H),2.44-2.40(m,1H),2.33-2.16(m,5H),2.09-1.95(m 5H),1.82-1.74(m,2H),1.57-1.45(m,2H),1.35(d,J=8Hz,3H),0.92-0.87(m,5H),0.35(s,3H).

[0710] Example A27 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-(4-methylpiperazine-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0711] LC-MS: m / z 977 (M+H) + .

[0712] Example A28 6-(3,8-bisazaspiro[3.2.1]octane-3-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0713] LC-MS: m / z 989 (M+H) + .

[0714] Example A29(2S)-1-(2-(((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)amino)-2-oxoethyl)-N,N-dimethylazacyclobutane-2-carboxamide trifluoroacetate

[0715] LC-MS: m / z 897 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.91(s,1H),9.77(s,1H),9.08(d,J=8Hz,1H),8.50-8.48(m,2H),7.85(s,1H),7.76(d,J=8Hz,1H ),7.58(d,J=8Hz,1H),7.40(s,1H),5.62(t,J=8Hz,1H),5.41(t,J=12Hz,1H),5.24(d,J=12Hz,1H),4.33-4.12(m,5H),4. 08-4.00(m,5H),3.60-3.58(m,2H),3.41-3.38(m,2H),3.21-3.14(m,5H),3.11-3.03(m,3H),2.92-2.75(m,12H),2.47-2 .33(m,3H),2.09-2.06(m,1H),1.81-1.76(m,2H),1.57-1.49(m,1H),1.35(d,J=8Hz,3H),0.93-0.89(m,5H),0.37(s,3H).

[0716] Example A30(2R)-1-(2-(((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)amino)-2-oxoethyl)-N,N-dimethylazacyclobutane-2-carboxamide trifluoroacetate

[0717] LC-MS: m / z 897 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.95 (s, 2H), 9.08 (d, J = 8Hz, 1H), 8.52-8.50 (m, 2H), 7.86 (s, 1H), 7.78 (d, J = 8Hz, 1H), 7. 60(d,J=8Hz,1H),7.40(s,1H),5.64(t,J=8Hz,1H),5.44(t,J=12Hz,1H),5.24(d,J=12Hz,1H),4.33-4.12(m,5H), 4.08-3.98(m,5H),3.60-3.58(m,2H),3.41-3.38(m,2H),3.22-3.05(m,8H),2.94-2.77(m,12H),2.47-2.35(m,3 H),2.11-2.08(m,1H),1.82-1.76(m,2H),1.57-1.49(m,1H),1.37(d,J=8Hz,3H),0.95-0.91(m,5H),0.37(s,3H).

[0718] Example A31 N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0719] LC-MS: m / z 908 (M+H) + .

[0720] Examples A32A and A32B(2S,4r,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 26 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(piperidin-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0721] and (2R,4s,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(piperidin-1-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0722] Example A32A

[0723] LC-MS: m / z 964 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.50 - 8.48 (m, 2H), 8.13 (d, J = 8 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.39 (s, 1H), 5.51 (t, J = 8 Hz, 1H), 5.10 (d, J = 12 Hz, 1H), 4.38 - 4.11 (m, 5H), 4.03 - 3.99 (m, 2H), 3.58 - 3.51 (m, 4H), 3.27 - 3.03 (m, 14H), 3.00 - 2.93 (m, 2H), 2.86 (s, 3H), 2.79 - 2.72 (m, 1H), 2.69 - 2.66 (m, 1H), 2.43 (d, J = 12 Hz, 1H), 2.33 (s, 1H), 2.22 - 2.16 (m, 4H), 2.08 - 2.05 (m, 4H), 1.80 - 1.77 (m, 2H), 1.58 - 1.52 (m, 2H), 1.45 - 1.38 (m, 4H), 1.35 (d, J = 8 Hz, 3H), 0.91 - 0.88 (m, 5H), 0.35 (s, 3H).

[0724] Example A32B

[0725] LC-MS: m / z 964 (M + H) + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.51 - 8.49 (m, 2H), 8.14 (d, J = 8 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.39 (s, 1H), 5.51 (t, J = 8 Hz, 1H), 5.10 (d, J = 12 Hz, 1H), 4.35 - 4.12 (m, 5H), 4.03 - 3.99 (m, 2H), 3.58 - 3.51 (m, 4H), 3.27 - 3.03 (m, 14H), 3.00 - 2.93 (m, 2H), 2.86 (s, 3H), 2.81 - 2.72 (m, 1H), 2.80 - 2.65 (m, 1H), 2.43 (d, J = 12 Hz, 1H), 2.33 (s, 1H), 2.28 - 2.16 (m, 4H), 2.10 - 1.93 (m, 4H), 1.80 - 1.77 (m, 2H), 1.58 - 1.51 (m, 2H), 1.46 - 1.38 (m, 4H), 1.35 (d, J = 8 Hz, 3H), 0.91 - 0.88 (m, 5H), 0.35 (s, 3H).

[0726] Examples A33A and A33B (2S,4R,6S)-6-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0727] and (2R,4S,6R)-6-((1R,4R)-2-oxo-5-azabicyclo[2.2.1]heptane-5-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0728] Example A33A

[0729] LC-MS: m / z 976 (M+H) + .

[0730] Example A33B

[0731] LC-MS: m / z 976 (M+H) + .

[0732] Example A34(2S,4R,6S)-6-((1S,4S)-2-oxo-5-azabicyclo[2.2.1]heptane-5-formyl)-N-((63 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0733] LC-MS: m / z 976 (M+H) + .

[0734] Examples A35A and A35B (2S,4S,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-3-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0735] and (2R,4R,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-3-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0736] Example A35A

[0737] LC-MS: m / z 978 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 8.50-8.49 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8Hz, 1H), 7.57 (d, J = 8Hz, 1H), 7.39(s,1H),5.50(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.33-4.11(m,5H),4.04-4.00(m,2H),3.82-3.75(m,2H),3.61-3.51(m,5H) ,3.31-3.08(m,12H),3.00-2.93(m,2H),2.86(s,3H),2.79-2.67(m,2H),2.43(d,J=12Hz,1H),2.27-2.16m,4H),2.07-1.97(m,5H) ,1.82-1.74(m,2H),1.57-1.48(m,1H),1.35(d,J=8Hz,3H),1.23-1.21(m,2H),1.10-1.09(m,2H),0.91-0.85(m,5H),0.34(s,3H).

[0738] Example A35B

[0739] LC-MS: m / z 978 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.50-8.49(m,2H),8.16(d,J=8Hz,1H),7.80(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz,1H) ,7.39(s,1H),5.51(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.35-4.11(m,5H),4.03-4.00(m,2H),3.81-3.76(m,2H),3.61-3.51(m,5H ),3.32-3.07(m,12H),3.00-2.93(m,2H),2.85(s,3H),2.79-2.67(m,2H),2.43(d,J=12Hz,1H),2.32-2.16m,4H),2.09-1.97(m,5H ),1.80-1.73(m,2H),1.55-1.47(m,1H),1.35(d,J=8Hz,3H),1.23-1.19(m,2H),1.10-1.09(m,2H),0.91-0.88(m,5H),0.34(s,3H).

[0740] Examples A36A and A36B(2S,4R,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-3-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0741] and (2R,4S,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 64 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-3-methylmorpholino-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0742] Example A36A

[0743] LC-MS: m / z 978 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.50-8.49 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8Hz, 1H), 7.57 (d, J = 8Hz, 1H), 7. 39(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.33-4.11(m,5H),4.02-4.00(m,2H),3.81-3.75(m,2H),3.60-3.51(m,5H),3.31 -3.07(m,12H),3.00-2.93(m,2H),2.86(s,3H),2.79-2.72(m,1H),2.67(m,1H),2.43(d,J=12Hz,1H),2.25-2.16m,4H),2.10-2.05(m, 5H),1.81-1.74(m,2H),1.57-1.43(m,1H),1.35(d,J=8Hz,3H),1.22-1.19(m,2H),1.11-1.09(m,2H),0.91-0.88(m,5H),0.35(s,3H).

[0744] Example A36B

[0745] LC-MS: m / z 978 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.50-8.49 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 8Hz, 1H), 7.57 (d, J = 8Hz, 1H), 7. 39(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.34-4.11(m,5H),4.04-4.00(m,2H),3.81-3.75(m,2H),3.57-3.49(m,5H),3.28 -3.06(m,12H),3.01-2.93(m,2H),2.86(s,3H),2.79-2.73(m,1H),2.67(m,1H),2.43(d,J=12Hz,1H),2.33-2.16m,4H),2.08-1.96(m, 5H),1.81-1.74(m,2H),1.56-1.46(m,1H),1.35(d,J=8Hz,3H),1.23-1.21(m,2H),1.10-1.08(m,2H),0.91-0.88(m,5H),0.35(s,3H).

[0746] Examples A37A and 37B(2S,4S,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-2-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0747] and (2R,4R,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 63 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-2-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0748] Example A37A

[0749] LC-MS: m / z 978 (M+H) + .

[0750] Example A37B

[0751] LC-MS: m / z 978 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 8.50-8.49 (m, 2H), 8.14 (d, J = 8Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8Hz, 1H), 7.57 (d, J = 8Hz, 1H),7.39(s,1H),5.51(t,J=8Hz,1H),5.10(t,J=12Hz,1H),4.34-4.09(m,5H),4.04-4.00(m,2H),3.79-3.76(m,1H),3.57-3. 54(m,5H),3.31-3.04(m,11H),3.00-2.92(m,2H),2.88-2.61(m,6H),2.67(s,1H),2.43(d,J=12Hz,1H),2.34-2.19(m,5H),2. 08-1.93(m,5H),1.80-1.74(m,2H),1.56-1.47(m,1H),1.35(d,J=8Hz,3H),1.10-1.07(m,3H),0.91-0.88(m,5H),0.35(s,3H).

[0752] Examples A38A and A38B(2S,4S,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-2-methylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0753] and (2R,4R,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-2-methylmorpholino-4-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0754] Example A38A

[0755] LC-MS: m / z 978 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.50 - 8.49 (m, 2H), 8.15 (d, J = 8 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 12 Hz, 1H), 7.58 (d, J = 12 Hz, 1H), 7.39 (s, 1H), 5.51 (t, J = 8 Hz, 1H), 5.11 (t, J = 12 Hz, 1H), 4.34 - 4.10 (m, 5H), 4.04 - 3.99 (m, 2H), 3.79 - 3.75 (m, 1H), 3.57 - 3.51 (m, 5H), 3.31 - 3.00 (m, 11H), 2.94 - 2.86 (m, 4H), 2.81 - 2.59 (m, 5H), 2.43 (d, J = 12 Hz, 1H), 2.33 - 2.24 (m, 5H), 2.17 - 2.03 (m, 5H), 1.81 - 1.76 (m, 2H), 1.56 - 1.48 (m, 1H), 1.35 (d, J = 8 Hz, 3H), 1.09 - 1.07 (m, 3H), 0.92 - 0.88 (m, 5H), 0.34 (s, 3H).

[0756] Example A38B

[0757] LC-MS: m / z 978 (M + H) + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.50 - 8.49 (m, 2H), 8.16 (d, J = 8 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 12 Hz, 1H), 7.58 (d, J = 12 Hz, 1H), 7.39 (s, 1H), 5.51 (t, J = 8 Hz, 1H), 5.11 (d, J = 12 Hz, 1H), 4.34 - 3.99 (m, 7H), 3.80 - 3.75 (m, 1H), 3.61 - 3.51 (m, 5H), 3.28 - 2.93 (m, 13H), 2.86 (s, 3H), 2.80 - 2.63 (m, 3H), 2.43 (d, J = 12 Hz, 1H), 2.33 - 2.17 (m, 5H), 2.08 - 1.95 (m, 5H), 1.95 - 1.75 (m, 2H), 1.56 - 1.48 (m, 1H), 1.35 (d, J = 8 Hz, 3H), 1.10 - 1.06 (m, 3H), 0.92 - 0.88 (m, 5H), 0.34 (s, 3H).

[0758] Examples A39A and A39B (2S,4r,6S)-N-((6 3 S,4S,Z)-1 1-Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(1,4-oxazon-4-formyl)spiro[3.3]heptane-2-carboxamide,

[0759] and (2R,4s,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-(1,4-oxazono-4-formyl)spiro[3.3]heptane-2-carboxamide

[0760] Example A39A

[0761] LC-MS: m / z 978 (M+H) + . 11H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.46 - 8.45 (m, 1H), 8.17 (d, J = 8 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.22 - 7.21 (m, 1H), 5.51 (t, J = 8 Hz, 1H), 5.11 (d, J = 12 Hz, 1H), 4.33 - 4.13 (m, 5H), 3.66 - 3.58 (m, 6H), 3.53 - 3.51 (m, 2H), 3.46 - 3.43 (m, 2H), 3.30 - 3.12 (m, 10H), 3.02 - 2.94 (m, 2H), 2.80 - 2.74 (m, 1H), 2.69 - 2.67 (m, 1H), 2.48 - 2.42 (m, 4H), 2.35 - 2.33 (m, 1H), 2.26 - 2.18 (m, 7H), 2.09 - 2.07 (m, 4H), 1.82 - 1.70 (m, 4H), 1.55 - 1.47 (m, 1H), 1.35 (d, J = 8 Hz, 3H), 0.93 - 0.86 (m, 5H), 0.35 (s, 3H).

[0762] Example A39B

[0763] LC-MS: m / z 978 (M + H) + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.46 - 8.45 (m, 1H), 8.18 (d, J = 8 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.22 - 7.21 (m, 1H), 5.52 (t, J = 8 Hz, 1H), 5.11 (d, J = 12 Hz, 1H), 4.33 - 4.13 (m, 5H), 3.66 - 3.58 (m, 6H), 3.53 - 3.50 (m, 2H), 3.46 - 3.43 (m, 2H), 3.30 - 3.12 (m, 10H), 3.03 - 2.94 (m, 2H), 2.80 - 2.73 (m, 1H), 2.69 - 2.67 (m, 1H), 2.48 - 2.42 (m, 4H), 2.35 - 2.33 (m, 1H), 2.31 - x2.18 (m, 7H), 2.12 - 1.97 (m, 4H), 1.82 - 1.70 (m, 4H), 1.57 - 1.47 (m, 1H), 1.35 (d, J = 8 Hz, 3H), 0.93 - 0.86 (m, 5H), 0.35 (s, 3H).

[0764] Examples A40A, A40B, A40C, and A40D(2S,4R,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-1-oxa-6-azaspiro[3.5]nonane-6-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0765] (2R,4S,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((R)-1-oxa-6-azaspiro[3.5]nonane-6-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0766] (2S,4R,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-1-oxa-6-azaspiro[3.5]nonane-6-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate,

[0767] and (2R,4S,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-1-oxa-6-azaspiro[3.5]nonane-6-formyl)spiro[3.3]heptane-2-carboxamide trifluoroacetate

[0768] Example A40A

[0769] LC-MS: m / z 1004 (M+H) + .

[0770] Example A40B

[0771] LC-MS: m / z 1004 (M+H) + .

[0772] Example A40C

[0773] LC-MS: m / z 1004 (M+H) + .

[0774] Example A40D

[0775] LC-MS: m / z 1004 (M+H) + .

[0776] Example A41 6-((3R,5S)-3,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0777] LC-MS: m / z 992 (M+H) + .

[0778] Example A41 was chirally resolved to obtain Examples A41A and A41B: (2S,4R,6S)-6-((3R,5S)-3,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide,

[0779] and (2R,4S,6R)-6-((3R,5S)-3,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0780] Example A41A

[0781] LC-MS: m / z 992 (M+H) + .

[0782] Example A41B

[0783] LC-MS: m / z 992 (M+H) + .

[0784] Example A42 6-((3S,5S)-3,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0785] LC-MS: m / z 992 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.44(s,1H),8.17(d,J=8Hz,1H),7.79(s,1H),7.74(d,J=8Hz,1H),7.56(d ,J=8Hz,1H),7.21(s,1H),5.51(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.32-4.12(m,5H),3.88-3.78(m,2H),3.57 (s,2H),3.29-3.11(m,9H),3.01-2.92(m,2H),2.78-2.71(m,2H),2.45-2.41(m,4H),2.33-1.94(m,14H),1.80- 1.74(m,2H),1.56-1.45(m,2H),1.33(d,J=8Hz,3H),1.23(s,3H),1.22(s,3H),0.91-0.87(m,6H),0.33(s,3H).

[0786] Example A43 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-3-ethylmorphorline-4-formyl)spiro[3.3]heptane-2-carboxamide

[0787] LC-MS: m / z 992 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.54–8.41(m,2H),8.15(d,J=9.3Hz,1H),7.80(d,J=2.2Hz,1H),7.74(m,1H),7.56(d,J= 8.6Hz,1H),7.22(d,J=2.9Hz,1H),5.52(t,J=9.1Hz,1H),5.10(d,J=12.2Hz,1H),4.34–4.05(m,6H),3.73(m,2H) ,3.50(m,4H),3.27(m,J=5.6Hz,5H),3.23(s,3H),3.15(d,J=16.5Hz,2H),3.02–2.92(m,2H),2.88–2.68(m,2H), 2.49–2.39(m,5H),2.34–1.97(m,12H),1.87–1.40(m,6H),1.34(d,J=6.1Hz,3H),1.02–0.71(m,9H),0.35(s,3H).

[0788] Example A44 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 64 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-3-isopropylmorpholino-4-formyl)spiro[3.3]heptane-2-carboxamide

[0789] LC-MS: m / z 1006 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.47(m,2H),8.19–8.13(m,1H),7.80(d,J=2.9Hz,1H),7.74(m,1H),7.56(d,J=8.6Hz,1H),7. 22(d,J=2.9Hz,1H),5.52(t,J=9.2Hz,1H),5.12–5.06(m,1H),4.34–4.12(m,6H),3.94–3.86(m,2H),3.78–3.73(m,1H ),3.58(s,2H),3.44(m,2H),3.27(m,4H),3.23(s,3H),3.21–3.11(m,3H),3.03–2.94(m,2H),2.78(m,2H),2.47(m,4H ),2.35–1.95(m,14H),1.80(m,2H),1.53(m,1H),1.34(d,J=6.1Hz,3H),1.00–0.88(m,9H),0.76(m,3H),0.35(s,3H).

[0790] Example A45 6-(4-(dimethylamino)piperidine-1-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0791] LC-MS: m / z 1005 (M+H) + .

[0792] Examples A46A and A46B(2S,4S,6S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-6-((S)-2-methylpiperidin-1-formyl)spiro[3.3]heptane-2-carboxamide,

[0793] and (2R,4R,6R)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-6-((S)-2-methylpiperidin-1-formyl)spiro[3.3]heptane-2-carboxamide

[0794] Example A46A

[0795] LC-MS: m / z 976 (M+H) + .

[0796] Example A46B

[0797] LC-MS: m / z 976 (M+H) + .

[0798] Examples A47A and A47B: (2S,4S,6S)-6-((2S,5S)-2,5-dimethylpyrrolidone-1-formyl)-N-((6 3S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide,

[0799] and (2R,4R,6R)-6-((2S,5S)-2,5-dimethylpyrrolidone-1-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0800] Example A47A

[0801] LC-MS: m / z 976 (M+H) + .

[0802] Example A47B

[0803] LC-MS: m / z 976 (M+H) + .

[0804] Examples A48A and A48B (2S,4r,6S)-6-(3-azabicyclo[3.1.0]hexane-3-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 63 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide,

[0805] and (2R,4s,6R)-6-(3-azabicyclo[3.1.0]hexane-3-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0806] Example A48A

[0807] LC-MS: m / z 960 (M+H) + .

[0808] Example A48B

[0809] LC-MS: m / z 960 (M+H) + .

[0810] Example A49 6-((2S,5S)-2,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0811] LC-MS: m / z 992 (M+H) + .

[0812] Example A50 6-((2R,5S)-2,5-dimethylmorpholino-4-formyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)spiro[3.3]heptane-2-carboxamide

[0813] LC-MS: m / z 992 (M+H) + .

[0814] Example B1 N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 N 2 -Dimethylcyclopropyl-1,1-dicarboxamide trifluoroacetate

[0815] LC-MS: m / z 868 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.86(s,1H),8.50-8.48(m,2H),7.88(d,J=8Hz,1H),7.81(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz,1H ),7.40(d,J=4Hz,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H),5.50(t,J=8Hz,1H),5.08(d,J=12Hz,1H),4.35-4.00(m,8H),3.61- 3.48(m,5H),3.26-3.22(m,5H),3.11-3.05(m,2H),2.99-2.86(m,8H),2.80-2.73(m,1H),2.44-2.41(m,1H),2.09-2.06(m,1H), 1.79-1.75(m,2H),1.56-1.47(m,1H),1.35(d,J=8Hz,3H),1.24-1.20(m,1H),1.15-1.07(m,2H),0.92-0.88(m,5H),0.35(s,3H).

[0816] Example C1 N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylmalonamide trifluoroacetate

[0817] LC-MS: m / z 948 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 8.69 (d, J = 8Hz, 1H), 8.50-8.47 (m, 2H), 8.01 (d, J = 4Hz, 1H), 7.96 (d, J = 8Hz, 1H), 7.82 (s, 1H), 7.75-7. 65(m,3H),7.58(d,J=8Hz,1H),7.39(d,J=4Hz,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),6.91(t,J=8Hz,1H),5.69-5.63(m,1H),5.56(t,J =8Hz,1H),5.12(d,J=12Hz,1H),4.33-4.11(m,5H),4.01(s,2H),3.37-3.33(m,4H),3.22-3.09(m,8H),2.95(d,J=12Hz,2H),2.86(s,3H),2. 75(s,3H),2.44-2.41(m,2H),2.10-2.06(m,1H),1.79-1.75(m,2H),1 .56-1.45(m,4H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0818] Example C2 N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylsuccinyldiamine trifluoroacetate

[0819] LC-MS: m / z 962 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.99 (s, 1H), 8.50-8.49 (m, 2H), 8.39 (d, J = 8Hz, 1H), 8 .01(d,J=4Hz,1H),7.96(d,J=4Hz,1H),7.79(s,1H),7.75-7.65(m,2H),7.57(d ,J=8Hz,1H),7.39(d,J=4Hz,1H),7.26(s,2H),7.13(s,2H),7.00(s,2H),6.91( t,J=8Hz,1H),5.71-5.66(m,1H),5.55(t,J=8Hz,1H),5.11(d,J=12Hz,1H),4.3 3-4.11(m,5H),4.01(s,2H),3.57(s,2H),3.34-3.31(m,2H),3.22(s,3H),3.1 6-3.06(m,4H),2.96(d,J=12Hz,1H),2.86(s,3H),2.79-2.73(m,3H),2.63-2.5 8(m,2H),2.55-2.53(m,1H),2.44-2.41(m,1H),2.10-2.06(m,1H),1.81-1.75( m,2H),1.56-1.45(m,4H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0820] Example C3 N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylglutaramide trifluoroacetate

[0821] LC-MS: m / z 976 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 8.50-8.48 (m, 2H), 8.35 (d, J = 8Hz, 1H) ,8.04(d,J=8Hz,1H),7.97(d,J=4Hz,1H),7.76(s,1H),7.74-7.72(m,2H),7. 57(d,J=8Hz,1H),7.39(d,J=4Hz,1H),7.25(s,2H),7.12(s,2H),7.00(s,2H) ,6.93(t,J=8Hz,1H),5.75-5.70(m,1H),5.53(t,J=8Hz,1H),5.11(d,J=12Hz ,1H),4.33-4.11(m,5H),4.05-4.00(m,2H),3.33-3.29(m,2H),3.22(s,3H) ,3.18-3.04(m,5H),2.96(d,J=12Hz,1H),2.86(s,3H),2.85(s,1H),2.72(s, 3H),2.44-2.39(m,3H),2.32-2.18(m,3H),2.09-2.06(m,1H),1.84-1.78(m, 3H),1.54-1.47(m,3H),1.35(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0822] Example C4 N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylhexadiamide trifluoroacetate

[0823] LC-MS: m / z 990 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 8.50-8.48 (m, 2H), 8.33 (d, J = 8Hz, 1H), 8.00 (d,J=4Hz,1H),7.96(d,J=4Hz,1H),7.78(s,1H),7.75(d,J=8Hz,1H),7.63(s,1H), 7.57(d,J=8Hz,1H),7.39(d,J=4Hz,1H),7.25(s,1H),7.12(s,1H),7.00(s,1H),6. 90(t,J=8Hz,1H),5.75-5.69(m,1H),5.53(t,J=8Hz,1H),5.11(d,J=12Hz,1H),4.3 3-4.11(m,5H),4.04-4.00(m,2H),3.57(s,2H),3.30(m,3H),3.22(s,3H),3.18-3 .04(m,5H),2.96(d,J=12Hz,1H),2.86(s,3H),2.79-2.76(m,1H),2.72(s,3H),2.4 4-2.40(m,3H),2.26-2.16(m,2H),2.09-2.06(m,1H),1.80-1.76(m,2H),1.61-1.5 2(m,4H),1.47(d,J=8Hz,3H),1.34(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[0824] Example C5 (trans)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,3-Methylcyclohexane-1,3-dicarboxamide trifluoroacetate

[0825] LC-MS: m / z 1016 (M+H)+ . 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.50-8.49 (m, 2H), 8.26 (d, J = 8Hz, 1H), 8.0 6(d,J=8Hz,1H),7.97(d,J=4Hz,1H),7.82(s,1H),7.75(d,J=8Hz,1H),7.68(s,1 H),7.58(d,J=8Hz,1H),7.39(d,J=4Hz,1H),7.23(s,1H),7.10(s,1H),6.97(s,1 H),6.94(t,J=8Hz,1H),5.78-5.73(m,1H),5.54(t,J=8Hz,1H),5.11(d,J=12Hz,1 H),4.35-4.11(m,5H),4.04-4.00(m,2H),3.58(s,3H),3.55-3.51(m,2H),3.33( d,J=12Hz,1H),3.23(s,3H),3.21-3.08(m,4H),2.97(d,J=12Hz,1H),2.86(s,3H) ,2.82(s,3H),2.76-2.66(m,1H),2.43-2.33(m,2H),2.10-2.07(m,1H),1.91-1. 63(m,6H),1.60-1.48(m,5H),1.40-1.25(m,6H),0.92-0.88(m,5H),0.35(s,3H).

[0826] Example C6 (cis)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,3-Methylcyclohexane-1,3-dicarboxamide trifluoroacetate

[0827] LC-MS: m / z 1016 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.50-8.49 (m, 2H), 8.23 ​​(d, J = 8Hz, 1H), 8.0 5(d,J=8Hz,1H),7.95(d,J=4Hz,1H),7.80(s,1H),7.75(d,J=8Hz,1H),7.70(s,1H ),7.58(d,J=8Hz,1H),7.39(d,J=4Hz,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H ),6.93(t,J=8Hz,1H),5.75-5.70(m,1H),5.49(t,J=8Hz,1H),5.09(d,J=12Hz,1H ),4.35-4.11(m,5H),4.04-4.00(m,2H),3.57(s,3H),3.55-3.51(m,1H),3.32(d ,J=12Hz,1H),3.23(s,3H),3.19-3.06(m,4H),2.97(d,J=12Hz,1H),2.86(s,3H), 2.80(s,3H),2.75-2.66(m,2H),2.43-2.33(m,2H),2.10-2.07(m,1H),1.94-1.7 1(m,6H),1.65-1.62(m,1H),1.56-1.25(m,10H),0.92-0.88(m,5H),0.35(s,3H).

[0828] Example C7 (trans)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,3-Methylcyclobutane-1,3-dicarboxamide trifluoroacetate

[0829] LC-MS: m / z 988 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 8.50-8.49 (m, 2H), 8.28-8.22 (m, 1H), 8.00-7.94 (m, 2H), 7.81 (d, J = 12Hz, 1H), 7.75-7.72 (m, 1H), 7.62-7.55 (m,2H),7.39(s,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H),6.91(t,J=8 Hz,1H),5.73-5.62(m,1H),5.58-5.51(m,1H),5.11(d,J=12Hz,1H),4.35- 4.11(m,5H),4.04-4.00(m,2H),3.58(s,2H),3.41-3.28(m,3H),3.22(s, 3H),3.19-3.05(m,5H),2.96(d,J=12Hz,1H),2.86(s,3H),2.78-2.74(m, 1H),2.65-2.59(m,3H),2.44-2.22(m,6H),2.09-2.07(m,1H),1.79(s,2H ),1.57-1.45(m,4H),1.35(d,J=4Hz,3H),0.92-0.88(m,5H),0.35(s,3H).

[0830] Example C8 (cis)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,3-Methylcyclobutane-1,3-dicarboxamide trifluoroacetate

[0831] LC-MS: m / z 988 (M+H) + .

[0832] Example C9 (trans)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,4-methylcyclohexane-1,4-dicarboxamide trifluoroacetate

[0833] LC-MS: m / z 1016 (M+H) + .

[0834] Example C10 (cis)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 3 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,4-methylcyclohexane-1,4-dicarboxamide trifluoroacetate

[0835] LC-MS: m / z 1016 (M+H) + .

[0836] Example C11 N2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0837] LC-MS: m / z 1028 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.44(d,J=4Hz,1H),8.14-8.11(m,1H),7.88(s,1H),7.78(s,1H),7.73(d,J=8Hz,1H),7.56(d,J=8 Hz,1H),7.48(d,J=8Hz,1H),7.21(d,J=4Hz,1H),6.58-6.55(m,1H),5.73-5.72(m,2H),5.67-5.61(m,1H),5.51(t,J=8Hz,1H),5.08(d, J=12Hz,1H),4.32-4.12(m,5H),3.57(s,2H),3.27-3.25(m,5H),3.21(s,3H),3.18-3.11(m,2H),3.03-2.92(m,2H),2.78-2.72(m,1H), 2.47-2.42(m,5H),2.33-1.96(m,13H),1.79(s,2H),1.54-1.46(m,2H),1.38-1.32(m,6H),1.24(s,2H),0.91-0.88(m,5H),0.35(s,3H).

[0838] Example C11 was chirally resolved to obtain isomers Example C11A and Example C11B: (2R,4S,6R)-N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide,

[0839] and (2S,4R,6S)-N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0840] Example C11A

[0841] LC-MS: m / z 1028 (M+H) + .

[0842] Example C11B

[0843] LC-MS: m / z 1028 (M+H) + .

[0844] Example C12(trans)-N1-((R)-1-(2-aminopyridin-3-yl)ethyl)-N 2 -((6 3S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,2-Methylcyclopropane-1,2-dicarboxamide trifluoroacetate

[0845] LC-MS: m / z 974 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.69 (d, J = 8Hz, 1H), 8.55 (s, 1H), 8.50-8.49 (m ,1H),7.92(d,J=4Hz,1H),7.80(s,1H),7.77(d,J=8Hz,1H),7.63(d,J=8Hz,2H),7.43 -7.42(m,1H),7.22(s,1H),7.10(s,1H),6.97(s,1H),6.83(t,J=8Hz,1H),5.66(t,J =8Hz,1H),5.41-5.36(m,1H),5.14(d,J=12Hz,1H),4.29-4.25(m,2H),4.12-4.00(m, 5H),3.81-3.75(m,5H),3.33(d,J=16Hz,1H),3.22-3.14(m,3H),3.10-3.00(m,5H), 2.87(s,3H),2.83-2.67(m,2H),2.61-2.56(m,3H),2.16(t,J=8Hz,2H),2.04-2.02(m ,1H),1.83-1.70(m,2H),1.58-1.48(m,1H),1.31(d,J=8Hz,3H),1.24-1.18(m,1H),1 .14-1.08(m,1H),1.06(d,J=8Hz,2H),0.98(t,J=8Hz,3H),0.82(s,3H),0.48(s,3H).

[0846] Example C13 (cis)-N1-((R)-1-(2-aminopyridin-3-yl)ethyl)-N2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 1,2-Methylcyclopropane-1,2-dicarboxamide trifluoroacetate

[0847] LC-MS: m / z 974 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.91-8.75(m,1H),8.50-8.46(m,2H),8.05-7.95(m,2H),7.81-7.69(m,2H),7.57-7.54(m,1H), 7.39(s,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),6.95-6.89(m,1H),5.73-5.65(m,1H),5.61-5.51(m,1H),5.12-5.08(m,1H),4.34 -4.11(m,5H),4.02(m,2H),3.65-3.56(m,5H),3.38-3.31(m,2H),3.24-3.04(m,7H),2.91-2.86(m,5H),2.78-2.67(m,2H),2.45-2.4 2(m,1H),2.24-2.05(m,3H),1.81(m,2H),1.50(t,J=4Hz,3H),1.35(d,J=4Hz,3H),1.25-1.15(m,2H),0.91-0.89(m,5H),0.35(s,3H).

[0848] Example C14 N 2 -((S)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0849] LC-MS: m / z 1028 (M+H) + .

[0850] Example C14 was chirally resolved to obtain isomers Example C14A and Example C14B: (2R,4R,6R)-N 2 -((S)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate,

[0851] and (2S,4S,6S)-N 2 -((S)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0852] Example C14A

[0853] LC-MS: m / z 1028 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.50-8.48(m,2H),8.15(d,J=8Hz,1H),8.04(d,J=8Hz,1H),7.96(d,J=4Hz,1H),7.79(s,1H), 7.75-7.69(m,2H),7.57(d,J=8Hz,1H),7.39(s,1H),6.94(t,J=8Hz,1H),5.69-5.64(m,1H),5.51(t,J=8Hz,1H),5.10(d,J=12Hz,1 H),4.35-4.13(m,5H),4.04-4.01(m,2H),3.58-3.51(m,3H),3.28-2.93(m,12H),2.87(s,3H),2.78-2.73(m,2H),2.67-2.62(m,4H ),2.44-2.40(m,1H),2.32-2.06(m,9H),1.83-1.77(m,2H),1.57-1.44(m,4H),1.35(d,J=8Hz,3H),0.92-0.87(m,5H),0.35(s,3H).

[0854] Example C14B

[0855] LC-MS: m / z 1028 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.74(s,1H),8.50-8.48(m,2H),8.17(d,J=8Hz,1H),8.03(d,J=8Hz,1H),7.95(d,J=4Hz,1H),7.79(s,1H), 7.74-7.66(m,2H),7.57(d,J=8Hz,1H),7.39(s,1H),6.93(t,J=8Hz,1H),5.69-5.64(m,1H),5.51(t,J=8Hz,1H),5.09(d,J=12Hz,1 H),4.33-4.13(m,5H),4.04-3.99(m,2H),3.57-3.51(m,3H),3.28-2.93(m,12H),2.87(s,3H),2.82-2.73(m,2H),2.67-2.62(m,4H ),2.43-2.39(m,1H),2.33-1.97(m,9H),1.83-1.76(m,2H),1.56-1.45(m,4H),1.35(d,J=8Hz,3H),0.91-0.87(m,5H),0.34(s,3H).

[0856] Example C15 N 2 -((R)-1-(3-aminopyrazin-2-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0857] LC-MS: m / z 1029 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.50-8.49 (m, 2H), 8.15 (d, J = 8Hz, 1H), 7.89 (d, J = 4Hz, 1H), 7.80 (d, J = 4Hz, 1H), 7.75-7.7 3(m,2H),7.58(d,J=8Hz,1H),7.45(s,1H),5.77-5.72(m,1H),5.52(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.34-4.10(m,5H),4.0 6-4.02(m,2H),3.58-3.52(m,5H),3.31-3.06(m,10H),3.02-2.95(m,2H),2.87(s,3H),2.79-2.73(m,1H),2.59-2.56(m,4H),2 .44-2.41(m,1H),2.33-2.00(m,9H),1.83-1.77(m,2H),1.56-1.48(m,2H),1.41-1.34(m,5H),0.92-0.88(m,5H),0.35(s,3H).

[0858] Example C16 N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-N 6 -((R)-1-(pyridazin-4-yl)ethyl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0859] LC-MS: m / z 1014 (M+H) + .

[0860] Example C16 was chirally split to obtain Examples C16A and C16B: (2R,4S,6R)-N 2 -((6 3 S,4S,Z)-1 1-Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-N 6 -((R)-1-(pyridazin-4-yl)ethyl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate,

[0861] and (2S,4R,6S)-N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-N 6 -((R)-1-(pyridazin-4-yl)ethyl)spiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0862] Example C16A

[0863] LC-MS: m / z 1014 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.22-9.13(m,1H),9.07(s,1H),8.51-8.49(m,2H),8.15-8.11(m,1H),7.80(s,1H),7 .75(d,J=8Hz,1H),7.57(d,J=8Hz,1H),7.51-7.48(m,1H),7.39(s,1H),5.70-5.65(m,1H),5.51(t,J=8Hz,1H),5.10(d,J= 12Hz,1H),4.34-4.11(m,5H),4.03-4.00(m,2H),3.58-3.47(m,6H),3.28-2.93(m,10H),2.86(s,2H),2.79-2.66(m,4H),2 .55(s,1H),2.43-1.96(m,10H),1.83-1.74(m,2H),1.55-1.47(m,4H),1.35(d,J=4Hz,3H),0.92-0.85(m,5H),0.35(s,3H).

[0864] Example C16B

[0865] LC-MS: m / z 1014 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.21-9.13(m,1H),9.07(s,1H),8.51-8.49(m,2H),8.16-8.11(m,1H),7.80(s,1H),7 .75(d,J=8Hz,1H),7.57(d,J=8Hz,1H),7.54-7.48(m,1H),7.39(s,1H),5.70-5.65(m,1H),5.52(t,J=8Hz,1H),5.10(d,J= 12Hz,1H),4.34-4.11(m,5H),4.03-4.00(m,2H),3.58-3.50(m,6H),3.28-2.93(m,10H),2.86(s,2H),2.79-2.66(m,4H),2 .55(s,1H),2.43-1.96(m,10H),1.83-1.74(m,2H),1.55-1.47(m,4H),1.34(d,J=4Hz,3H),0.92-0.85(m,5H),0.35(s,3H).

[0866] Example C17 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N6 -((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0867] LC-MS: m / z 1082 (M+H) + .

[0868] Example C18 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 4 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0869] LC-MS: m / z 1046 (M+H) + .

[0870] Example C19 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1-Ethyl-1 6 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0871] LC-MS: m / z 1046 (M+H) + .

[0872] Example C20 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 7 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0873] LC-MS: m / z 1046 (M+H) + .

[0874] Example C21 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0875] LC-MS: m / z 930 (M+H) + .

[0876] Example C22 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0877] LC-MS: m / z 1023 (M+H) + .

[0878] Example C23 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 2 -(5-(3-(1,4-oxazetane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1-Ethyl-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0879] LC-MS: m / z 1067 (M+H) + .

[0880] Example C24 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-12-(5-(3-(4-(fluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0881] LC-MS: m / z 1081 (M+H) + .

[0882] Example C25 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1-Ethyl-12-(5-(3-(4-(difluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylspiro[3.3]heptane-2,6-dicarboxamide

[0883] LC-MS: m / z 1099 (M+H) + .

[0884] Example C26 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N6-((6 3 S,4S,Z)-1 1 -Ethyl-12-(5-(4-(fluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylazaspiro[3.3]heptane-2,6-dicarboxamide

[0885] LC-MS: m / z 1043 (M+H) + .

[0886] Example C27 N 2 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N6-((6 3 S,4S,Z)-1 1 -Ethyl-12-(5-(4-(difluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 2 -Methylazaspiro[3.3]heptane-2,6-dicarboxamide

[0887] LC-MS: m / z 1061 (M+H) + .

[0888] Example C28 N 2 -(1-(1H-indazol-7-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-2-azaspiro[3.3]heptane-2,6-dicarboxamide

[0889] LC-MS: m / z 1052 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ12.24(s,1H),8.48(s,1H),8.44(d,J=2.9Hz,1H),8.12(d,J=12.4Hz,2H),7.78(t,J=6.4Hz,1H),7.71(t,J=8.0Hz,2H),7. 55(d,J=8.4Hz,1H),7.29(d,J=7.8Hz,1H),7.21(s,1H),7.12(t,J=7.7Hz ,2H),6.07(d,J=7.1Hz,1H),5.75(s,1H),5.51(t,J=9.0Hz,1H),5.08(d,J =12.1Hz,1H),4.33–4.09(m,6H),3.57(s,2H),3.26(m,4H),3.22(d,J=1. 6Hz,3H),3.15–3.11(m,1H),3.03–2.89(m,3H),2.86–2.70(m,3H),2.66( s,3H),2.42(m,2H),2.21(s,3H),2.20–1.95(m,8H),1.78(s,3H),1.56(d ,J=7.1Hz,3H),1.33(d,J=6.1Hz,3H),0.90(d,J=8.2Hz,6H),0.34(s,3H).

[0890] Example C29 N 2 -(1-(3H-3H-imidazol[4,5-c]pyridin-4-yl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-2-azaspiro[3.3]heptane-2,6-dicarboxamide

[0891] LC-MS: m / z 1053 (M+H) + .

[0892] Example C30 N6 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-2-azaspiro[3.3]heptane-2,6-dicarboxamide

[0893] LC-MS: m / z 1029 (M+H) + .

[0894] Example C31 N 5 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 5 -Methylspiro[2,3]hexane-1,5-dicarboxamide

[0895] LC-MS: m / z 1014 (M+H) + .

[0896] Example C32 N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 5 -((6 3 S,4S,Z)-11 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylspiro[2,3]hexane-1,5-dicarboxamide

[0897] LC-MS: m / z 1014 (M+H) + .

[0898] Example C32 was chirally split to obtain Examples C32A, C32B, C32C, and C32D: (1R,3S,5S)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 5 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0899] (1R,3R,5R)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 5 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 62 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0900] (1S,3R,5S)-N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 5 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0901] (1S,3S,5R)- and N 1 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 5 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 1 -Methylspiro[2,3]hexane-1,5-dicarboxamide

[0902] Example C32A

[0903] LC-MS: m / z 1014 (M+H) + .

[0904] Example C32B

[0905] LC-MS: m / z 1014 (M+H) + .

[0906] Example C32C

[0907] LC-MS: m / z 1014 (M+H) + .

[0908] Example C32D

[0909] LC-MS: m / z 1014 (M+H) + .

[0910] Example C33 N 2 -(1-(2-aminophenyl)ethyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 2-Methyl-2-azaspiro[3.3]heptane-2,6-dicarboxamide trifluoroacetate

[0911] LC-MS: m / z 1014 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.68-9.59(m,2H),8.88-8.80(m,1H),8.56-8.49(m,3H),8.16(d,J=8Hz,1H),7.80(d,J=4Hz,1H),7. 75-7.72(m,1H),7.58(d,J=8Hz,2H),7.43-7.26(m,2H),7.29-7.26(m,1H),5.52(t,J=8Hz,1H),5.10(d,J=12Hz,1H),4.33-4. 12(m,6H),4.04-4.00(m,2H),3.58-3.52(m,3H),3.32-2.93(m,12H),2.86(s,3H),2.80-2.73(m,2H),2.45-2.39(m,4H),2.3 3-2.21(m,4H),2.16-2.04(m,5H),1.83-1.76(m,2H),1.54-1.48(m,4H),1.35(d,J=8Hz,3H),0.92-0.88(m,5H),0.35(s,3H).

[0912] Example C34 1-(3-(((R)-1-(2-aminopyridin-3-yl)ethyl)(methyl)formyl)cyclobutyl)-N 6 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)azacyclobutane-3-carboxamide

[0913] LC-MS: m / z 1043 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.46(m,2H),8.36(d,J=9.0Hz,1H),7.87(m,1H),7.80(d,J=3.5Hz,1H),7.72(m,1H),7.55(d,J=8.7Hz,1H),7.48(d,J =7.4Hz,1H),7.21(d,J=2.9Hz,1H),6.56(m,1H),5.73(m,2H),5.65(m,1H),5.55(t,J=9.2Hz,1H),5.11(d,J=12.2Hz,1H),4.39–4.06(m,6H), 3.58(s,2H),3.47(m,1H),3.27(m,6H),3.21(s,3H),3.16–3.10(m,2H) ,2.96(m,1H),2.76(m,2H),2.53(s,3H),2.42(m,2H),2.23(m,3H),2.0 8(d,J=11.5Hz,3H),1.94(m,2H),1.78(m,3H),1.54(m,2H),1.37(d,J=7.0Hz,3H),1.33(d,J=6.0Hz,3H),0.91(d,J=6.7Hz,6H),0.35(s,3H).

[0914] Example C35 N-((R)-1-(2-aminopyridin-3-yl)ethyl)-1-(3-(((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)formyl)cyclobutyl)-N-methylazacyclobutane-3-carboxamide

[0915] LC-MS: m / z 1043 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.52–8.41(m,2H),8.25(m,1H),7.88(m,1H),7.79(d,J=1.7Hz,1H),7.73(m,1H),7.55(d,J=8.7Hz,1H),7.49(m,1H),7. 21(d,J=2.9Hz,1H),6.56(m,1H),5.73(d,J=3.0Hz,2H),5.64(m,1H),5. 53(t,J=8.9Hz,1H),5.09(d,J=12.1Hz,1H),4.34–3.99(m,6H),3.58(s,2 H),3.50–3.42(m,1H),3.26(m,5H),3.22(s,3H),3.19–3.12(m,2H),3.0 4(m,2H),2.95(d,J=14.3Hz,1H),2.75(m,2H),2.48(s,3H),2.46(m,5H) ,2.22(s,3H),2.09(m,3H),1.96(t,J=9.0Hz,2H),1.83(m,3H),1.52(m, 1H),1.39(m,3H),1.33(d,J=6.1Hz,3H),0.98–0.82(m,6H),0.34(s,3H).

[0916] Examples C36A and 36B N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-N 6 -((R)-1-(pyridin-3-yl)ethyl)spiro[3.3]heptane-2,6-dicarboxamide,

[0917] and N 2 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 6 -Methyl-N 6 -((S)-1-(pyridin-3-yl)ethyl)spiro[3.3]heptane-2,6-dicarboxamide

[0918] Example C36A

[0919] LC-MS: m / z 1013 (M+H) + .

[0920] Example C36B

[0921] LC-MS: m / z 1013 (M+H) + .

[0922] Examples C37A, 37B, C37C, and C37D(1S,3S,5S)-N 5 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 5 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0923] (1R,3S,5R)-N 5 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 1 -((6 3S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 5 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0924] (1R,3R,5S)-N 5 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 5 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0925] and (1S,3R,5R)-N 5 -((R)-1-(2-aminopyridin-3-yl)ethyl)-N 1 -((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-N 5 -Methylspiro[2,3]hexane-1,5-dicarboxamide,

[0926] Example C37A

[0927] LC-MS: m / z 1014 (M+H) + .

[0928] Example C37B

[0929] LC-MS: m / z 1014 (M+H) + .

[0930] Example C37C

[0931] LC-MS: m / z 1014 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.55–8.40(m,3H),7.87(m,1H),7.78(s,1H),7.72(m,1H),7.55(d,J=8.7Hz,1H),7.48(m,1H),7.21 (d,J=2.9Hz,1H),6.56(m,1H),5.74(s,2H),5.67(d,J=7.0Hz,1H),5.53(t,J=9.1Hz,1H),5.09(d,J=12.1Hz,1H),4.42–3.9 8(m,6H),3.56(m,2H),3.40(m,4H),3.26(t,J=5.1Hz,4H),3.21(m,4H),2.93(m,1H),2.79–2.65(m,2H),2.57(m,1H),2.46( m,4H),2.35–2.16(m,6H),2.16–1.98(m,2H),1.83–1.70(m,3H),1.49(m,1H),1.35(m,6H),0.95–0.82(m,7H),0.34(s,3H).

[0932] Example C37D

[0933] LC-MS: m / z 1014 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.52–8.28(m,3H),8.04–7.71(m,3H),7.64–7.45(m,2H),7.21(d,J=2.9Hz,1H),6.65 –6.54(m,1H),5.92(s,1H),5.82–5.54(m,3H),5.06(m,1H),4.53–3.88(m,6H),3.57(s,2H),3.46(m,4H),3.2 6(m,4H),3.24–3.13(m,4H),3.00–2.91(m,1H),2.82–2.63(m,2H),2.56(m,1H),2.46(m,4H),2.22(s,6H),2. 10(m,2H),1.83–1.71(m,3H),1.56–1.48(m,1H),1.46–1.25(m,6H),1.05–0.65(m,7H),0.33(d,J=5.4Hz,3H).

[0934] Example D1 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxopropionamide trifluoroacetate

[0935] LC-MS: m / z 799 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.92(s,1H),8.94(d,J=8Hz,1H),8.50-8.49(m,2H),7.80(s,1H),7.75(d,J=8Hz,1H),7.57(d,J =8Hz,1H),7.39(s,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),5.54(t,J=8Hz,1H),5.22(d,J=12Hz,1H),4.32-4.11(m,5 H),4.04-4.00(m,2H),3.62-3.52(m,3H),3.35-3.31(m,1H),3.21-3.06(m,5H),2.94-2.76(m,5H),2.43-2.33(m,4H),2 .09-2.05(m,1H),1.80(s,2H),1.57-1.49(m,1H),1.35-1.34(m,3H),1.28-1.16(m,2H),0.90-0.89(m,5H),0.37(s,3H).

[0936] Example D2 2-Cyclopropyl N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0937] LC-MS: m / z 825 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.97(d,J=8Hz,1H),8.50-8.49(m,2H),7.80(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8Hz ,1H),7.40(s,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),5.56(t,J=8Hz,1H),5.23(d,J=12Hz,1H),4.32-4.11(m,5H),4.04 -4.00(m,2H),3.62-3.59(m,2H),3.35-3.31(m,2H),3.21-3.04(m,6H),2.95-2.76(m,6H),2.46-2.43(m,1H),2.10-2.08(m, 1H),1.81(s,2H),1.56-1.50(m,1H),1.35-1.33(m,3H),1.18-1.16(m,2H),1.10-1.02(m,2H),0.95-0.89(m,5H),0.37(s,3H)

[0938] Example D3 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-phenylacetamide trifluoroacetate

[0939] LC-MS: m / z 861 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.82(s,1H),9.51(d,J=8Hz,1H),8.51-8.50(m,2H),8.02(d,J=8Hz,1H),7.87(s,1H),7.78-7.74(m,2 H),7.64-7.57(m,3H),7.40(s,1H),7.24(s,1H),7.11(s,1H),6.98(s,1H),5.71(t,J=8Hz,1H),5.29(d,J=12Hz,1H),4.32-4.1 1(m,5H),4.04-4.02(m,2H),3.52(m,1H),3.46-3.43(m,2H),3.37-3.31(m,2H),3.22(m,5H),3.11-3.05(m,2H),2.95-2.87(m, 5H),2.47-2.43(m,1H),2.12-2.09(m,1H),1.83(s,2H),1.60-1.51(m,1H),1.39-1.34(m,3H),0.92-0.89(m,5H),0.37(s,3H).

[0940] Example D4 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0941] LC-MS: m / z 839 (M+H) + .

[0942] Example D5 2-((1r,2R,3S)-2,3-dimethylcyclopropyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0943] LC-MS: m / z 853 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.63(s,1H),8.89(d,J=8Hz,1H),8.50-8.49(m,2H),7.80(s,1H),7.75(d,J=8Hz,1H),7.58(d,J=8Hz,1H) ,7.44(s,1H),5.54(t,J=8Hz,1H),5.22(t,J=12Hz,1H),4.35-4.09(m,5H),4.05-4.02(m,2H),3.66-3.61(m,4H),3.34-3.30(m,1H ),3.22-3.16(m,5H),3.11-3.04(m,2H),2.94-2.87(m,4H),2.83-2.73(m,2H),2.43(s,1H),2.32-2.30(m,1H),2.10-2.06(m,1H) ,1.83-1.78(m,2H),1.70-1.59(m,2H),1.55-1.49(m,1H),1.36(d,J=8Hz,3H),1.15-1.13(m,6H),0.93-0.88(m,5H),0.38(s,3H).

[0944] Example D6 2-CyclobutylN-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0945] LC-MS: m / z 839 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),9.00(d,J=8Hz,1H),8.50-8.48(m,2H),7.80(s,1H),7.74(d,J=8Hz,1H),7.57(d,J=8H z,1H),7.39(d,J=4Hz,1H),5.55(t,J=8Hz,1H),5.19(d,J=12Hz,1H),4.34-4.11(m,5H),4.04-3.99(m,2H),3.91-3.87(m,1 H),3.58-3.51(m,3H),3.22-3.17(m,3H),3.09-3.05(m,2H),2.95-2.86(m,4H),2.81-2.73(m,2H),2.56-2.54(m,4H),2.45 -2.41(m,2H),2.20-1.95(m,6H),1.84-1.75(m,2H),1.57-1.47(m,1H),1.35(d,J=8Hz,3H),0.92-0.86(m,5H),0.36(s,3H).

[0946] Example D7 2-Cyclopentyl N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0947] LC-MS: m / z 853 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),9.00(d,J=8Hz,1H),8.50-8.48(m,2H),7.81(s,1H),7.75(d,J=8Hz,1H),7.57(d ,J=8Hz,1H),7.40(d,J=4Hz,1H),5.57(t,J=8Hz,1H),5.21(d,J=12Hz,1H),4.33-4.10(m,5H),4.03-4.00(m,2H),3.6 1-3.49(m,5H),3.31-3.17(m,5H),3.11-3.03(m,2H),2.95-2.75(m,5H),2.56-2.54(m,1H),2.45-2.41(m,1H),2.32( s,1H),2.12-2.06(m,1H),1.88-1.67(m,6H),1.59-1.48(m,5H),1.35(d,J=8Hz,3H),0.92-0.87(m,5H),0.36(s,3H).

[0948] Example D8 2-Cyclohexyl N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0949] LC-MS: m / z 867 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.99(d,J=8Hz,1H),8.50-8.48(m,2H),7.82(s,1H),7.75(d,J=8Hz,1H),7.57(d,J=8 Hz,1H),7.40(d,J=4Hz,1H),5.56(t,J=8Hz,1H),5.21(d,J=12Hz,1H),4.39-4.10(m,5H),4.04-4.01(m,2H),3.62-3.47(m ,5H),3.22-3.02(m,6H),2.95-2.73(m,5H),2.67(s,1H),2.45-2.41(m,1H),2.33-2.32(m,1H),2.10-1.95(m,2H),1.89-1 .71(m,6H),1.65-1.62(m,1H),1.55-1.48(m,1H),1.35(d,J=8Hz,3H),1.30-1.16(m,5H),0.92-0.87(m,5H),0.36(s,3H).

[0950] Example D9 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(oxacyclobutane-3-yl)-2-oxoacetamide trifluoroacetate

[0951] LC-MS: m / z 841 (M+H) + .

[0952] Example D10 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(tetrahydrofuran-3-yl)acetamide trifluoroacetate

[0953] LC-MS: m / z 855 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),9.12(m,1H),8.49(m,2H),7.82(d,J=3.1Hz,1H),7.74(m,1H),7.57(d,J=8.7H z,1H),7.40(d,J=2.9Hz,1H),5.57(t,J=9.0Hz,1H),5.21(d,J=12.1Hz,1H),4.41–4.08(m,6H),4.02(m,2H),3.92–3 .72(m,4H),3.67(m,2H),3.57(m,2H),3.22(d,J=1.1Hz,3H),3.08(m,2H),2.95(m,1H),2.87(d,J=3.6Hz,3H),2.78 (m,1H),2.41(m,2H),2.04(m,4H),1.81(m,2H),1.50(m,2H),1.34(d,J=6.1Hz,3H),0.99–0.73(m,6H),0.36(s,3H).

[0954] Example D11 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(tetrahydro-2H-pyran-4-yl)acetamide trifluoroacetate

[0955] LC-MS: m / z 869 (M+H)+ .

[0956] Example D12 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)-2-oxoacetamide trifluoroacetate

[0957] LC-MS: m / z 865 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.65(s,1H),9.17(d,J=8Hz,1H),8.61(s,1H),8.49(s,2H),8.12(s,1H),7.90(s,1H),7.75(d,J=8Hz,1H),7 .57(d,J=8Hz,1H),7.42(s,1H),5.65(t,J=8Hz,1H),5.22(d,J=12Hz,1H),4.35-4.09(m,5H),4.05-4.01(m,2H),3.91(s,3H),3.63- 3.52(m,4H),3.37-3.34(m,1H),3.22(s,3H),3.18-3.16(m,1H),3.11-3.04(m,2H),2.95-2.77(m,5H),2.67(s,1H),2.45-2.42(m,1 H),2.12-2.08(m,1H),1.85-1.78(m,2H),1.59-1.51(m,1H),1.36(d,J=8Hz,3H),1.21-1.19(m,1H),0.92-0.88(m,5H),0.37(s,3H).

[0958] Example D13 2-(2-aminothiazolyl-4-yl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide

[0959] LC-MS: m / z 883 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.27(d,J=8Hz,1H),8.49(s,1H),8.44(s,1H),7.99(s,1H),7.81(s,1H),7.74(d,J=8Hz,1H ),7.56(d,J=8Hz,1H),7.36(s,2H),7.21(s,1H),5.62(t,J=8Hz,1H),5.23(d,J=12Hz,1H),4.33-4.11(m,5H),3.62 -3.54(m,3H),3.28-3.27(m,5H),3.20(s,3H),2.94(d,J=12Hz,1H),2.84-2.76(m,2H),2.46-2.45(m,4H),2.22(s, 3H),2.12-2.09(m,1H),1.84-1.79(m,2H),1.56-1.48(m,2H),1.34(d,J=8Hz,,3H),0.92-0.88(m,5H),0.37(s,3H).

[0960] Example D14 3-Cyclopropyl-N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxopropionamide trifluoroacetate

[0961] LC-MS: m / z 839 (M+H) + .

[0962] Example D15 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-4-methyl-2-oxopentanamide trifluoroacetate

[0963] LC-MS: m / z 841 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.76(s,1H),8.97(d,J=8Hz,1H),8.50-8.48(m,2H),7.81(s,1H),7.74(d,J=8Hz,1H),7.57(d,J=8H z,1H),7.40(s,1H),5.54(t,J=8Hz,1H),5.21(d,J=12Hz,1H),4.34-4.10(m,5H),4.04-4.00(m,2H),3.63-3.53(m,3H),3.34 -3.31(m,1H),3.20(s,3H),3.19-3.16(m,2H),3.11-3.03(m,2H),2.95-2.91(m,1H),2.86(s,3H),2.82-2.61(m,4H),2.46- 2.42(m,1H),2.14-2.04(m,2H),1.84-1.78(m,2H),1.57-1.47(m,2H),1.35(d,J=8Hz,3H),0.93-0.88(m,11H),0.37(s,3H).

[0964] Example D16 N-((6) 3S,4S,Z)-1 2 -(5-(3-(azacyclobutan-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0965] LC-MS: m / z 834 (M+H) + .

[0966] Example D17 N-((6) 3 S,4S,Z)-1 2 -(5-(3-(1,4-oxazetane-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0967] LC-MS: m / z 878 (M+H) + .

[0968] Example D18 N-((6) 3 S,4S,Z)-1 2 -(5-(3-(4-(fluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0969] LC-MS: m / z 892 (M+H) + .

[0970] Example D19 N-((6) 3 S,4S,Z)-1 2 -(5-(3-(4-(difluoromethylene)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0971] LC-MS: m / z 910 (M+H) + .

[0972] Example D20 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(4-(fluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0973] LC-MS: m / z 854 (M+H) + .

[0974] Example D21 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(4-(difluoromethylene)piperidin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,4)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0975] LC-MS: m / z 872 (M+H) + .

[0976] Example D22 N-((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[0977] LC-MS: m / z 893 (M+H) + .

[0978] Example D23 N-((6) 3 S,4S,Z)-1 4 -Fluorine-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 1 10,10-trimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide

[0979] LC-MS: m / z 843 (M+H) + .

[0980] Example D24 N-((6) 3 S,4S,Z)-1 6 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 1 10,10-trimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide

[0981] LC-MS: m / z 843 (M+H) + .

[0982] Example D25 N-((6) 3 S,4S,Z)-1 7 -Fluorine-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1 1 10,10-trimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide

[0983] LC-MS: m / z 843 (M+H) + .

[0984] Example D26 2-(3-oxabicyclo[3.1.0]hexane-6-yl)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0985] LC-MS: m / z 867 (M+H) + .

[0986] Example D26 was chirally separated to obtain Examples D26A and D26B: 2-((trans)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0987] and 2-((cis)-3-oxabicyclo[3.1.0]hexane-6-yl)-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide trifluoroacetate

[0988] Example D26A

[0989] LC-MS: m / z 867 (M+H) + .

[0990] Example D26B

[0991] LC-MS: m / z 867 (M+H) + .

[0992] Example D27 N-((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-((trans)-2-phenylcyclopropyl)acetamide

[0993] LC-MS: m / z 901 (M+H) + .

[0994] Example D28 N-((6) 3 S,4S,Z)-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-((cis)-2-phenylcyclopropyl)acetamide

[0995] LC-MS: m / z 901 (M+H) + .

[0996] Example D28 was chirally split to obtain Examples D28A and D28B: N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(1S,2R)-2-phenylcyclopropyl)acetamide,

[0997] and N-((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(1R,2S)-2-phenylcyclopropyl)acetamide

[0998] Example D28A

[0999] LC-MS: m / z 901 (M+H) + .

[1000] Example D28B

[1001] LC-MS: m / z 901 (M+H) + .

[1002] Example D29 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2R)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1003] LC-MS: m / z 839 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.92(d,J=9.0Hz,1H),8.50(t,J=2.4Hz,2H),7.80(s,1H),7.73(m,1H),7.57(d,J=8.6Hz,1H),7. 40(d,J=3.0Hz,1H),5.56(t,J=9.0Hz,1H),5.21(d,J=12.2Hz,1H),4.37–4.08(m,6H),4.02(d,J=13.2Hz,2H),3.60(t,J=8.9Hz,3H),3 .21(s,3H),3.09(m,2H),2.97–2.91(m,2H),2.86(d,J=3.3Hz,3H),2.79(m,1H),2.42(m,2H),2.09(m,1H),1.81(m,2H),1.79–1.71(m, 2H),1.53(m,2H),1.35(d,J=6.1Hz,3H),1.30–1.27(m,1H),1.09(d,J=6.2Hz,3H),1.06–1.02(m,1H),0.98–0.83(m,6H),0.37(s,3H).

[1004] Example D30 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2R)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1005] LC-MS: m / z 839 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.97(d,J=8.7Hz,1H),8.51(dd,J=5.6,2.3Hz,2H),7.82(s,1H),7.75(d,J=8.6Hz,1H),7.58 (d,J=8.7Hz,1H),7.42(d,J=2.9Hz,1H),5.57(d,J=8.8Hz,1H),5.24(d,J=12.1Hz,1H),4.34–4.14(m,6H),4.04(m,2H),3.62(m,2H ),3.32(m,3H),3.23(s,3H),3.09(m,2H),2.93(m,1H),2.88(d,J=4.0Hz,3H),2.63–2.59(m,1H),2.43(m,2H),2.10(m,1H),1.82( m,2H),1.49(m,2H),1.36(d,J=6.1Hz,3H),1.31(m,1H),1.16(d,J=6.0Hz,3H),1.10–1.06(m,1H),0.99–0.80(m,6H),0.38(s,3H).

[1006] Examples D31A, D31B, D31C, and D31D: N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1007] N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 56 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2R)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1008] N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2R)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1009] and N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopropyl)-2-oxoacetamide trifluoroacetate

[1010] Example D31A

[1011] LC-MS: m / z 853 (M+H) + .

[1012] Example D31B

[1013] LC-MS: m / z 853 (M+H) + .

[1014] Example D31C

[1015] LC-MS: m / z 853 (M+H) + .

[1016] Example D31D

[1017] LC-MS: m / z 853 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.87(s,1H),9.01(d,J=8Hz,1H),8.50-8.48(m,2H),7.82(s,1H),7.75(d,J=8Hz,1H ),7.57(d,J=8Hz,1H),7.39(s,1H),5.54(t,J=8Hz,1H),5.22(t,J=12Hz,1H),4.35-4.11(m,5H),4.05-3.96 (m,2H),3.61-3.49(m,5H),3.22-3.03(m,9H),2.96-2.74(m,5H),2.45-2.41(m,2H),2.10-1.93(m,5H),1.8 3-1.74(m,2H),1.65-1.47(m,3H),1.35(d,J=8Hz,3H),1.14(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[1018] Example D32 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(spiro[3.3]heptane-2-yl)acetamide

[1019] LC-MS: m / z 879 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.73(s,1H),9.00(d,J=9.0Hz,1H),8.49(m,2H),7.82(s,1H),7.74(m,1H),7.57(d,J= 8.7Hz,1H),7.40(d,J=2.9Hz,1H),5.55(m,1H),5.19(d,J=12.2Hz,1H),4.33–4.11(m,6H),4.02(m,2H),3.73(m ,2H),3.59–3.54(m,3H),3.22(s,3H),3.09(m,2H),2.95(s,1H),2.90–2.82(m,3H),2.80–2.75(m,1H),2.43(m, 2H),2.23–2.00(m,8H),1.88–1.75(m,5H),1.50(m,2H),1.34(d,J=6.1Hz,3H),0.96–0.79(m,6H),0.36(s,3H).

[1020] Example D33 2-(3,3-difluorocyclopropyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide

[1021] LC-MS: m / z 875 (M+H) + .

[1022] Examples D34A, D34B, D34C, and D34D N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 65 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2S)-2-methylcyclopentyl)-2-oxoacetamide,

[1023] N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2R)-2-methylcyclopentyl)-2-oxoacetamide,

[1024] N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2R)-2-methylcyclopentyl)-2-oxoacetamide

[1025] and N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-methylcyclopentyl)-2-oxoacetamide

[1026] Example D34A

[1027] LC-MS: m / z 867 (M+H) + .

[1028] Example D34B

[1029] LC-MS: m / z 867 01 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.02(d,J=8Hz,1H),8.48-8.44(m,2H),7.80(s,1H),7.73(d,J=8Hz,1H),7.57(d,J=8Hz,1H),7.21(d,J =4Hz,1H),5.56(t,J=8Hz,1H),5.21(d,J=12Hz,1H),4.31-4.12(m,5H),3.61-3.50(m,3H),3.36(m,1H),3.28-3.13(m,9H),2.9 5-2.91(m,1H),2.82-2.74(m,1H),2.47-2.43(m,4H),2.33-2.31(m,1H),2.22(s,3H),2.17-2.07(m,3H),2.02-1.91(m,2H),1. 85-1.77(m,3H),1.76-1.65(m,2H),1.60-1.49(m,2H),1.34(d,J=8Hz,3H),1.00(d,J=8Hz,3H),0.91-0.88(m,5H),0.35(s,3H).

[1030] Example D34C

[1031] LC-MS: m / z 867 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.02-8.95(m,1H),8.48-8.44(m,2H),7.81(d,J=4Hz,1H),7.73(d,J=8Hz,1H ),7.56(d,J=8Hz,1H),7.22(s,1H),5.56(t,J=8Hz,1H),5.22(t,J=12Hz,1H),4.33-4.11(m,5H),3.7 7-3.50(m,7H),3.22-3.12(m,5H),2.96-2.67(m,3H),2.45-2.41(m,2H),2.32-2.25(m,3H),2.17-2. 07(m,2H),2.01-1.89(m,3H),1.86-1.44(m,8H),1.34(d,J=8Hz,3H),1.00-0.80(m,9H),0.36(s,3H).

[1032] Example D34D

[1033] LC-MS: m / z 867 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.02-8.94(m,1H),8.48-8.44(m,2H),7.81(d,J=4Hz,1H),7.73(d,J=8Hz,1H),7 .56(s,1H),7.22(s,1H),5.53(t,J=8Hz,1H),5.20(d,J=12Hz,1H),4.33-4.11(m,5H),3.72-3.51(m,4H) ,3.28-3.20(m,10H),2.93-2.66(m,3H),2.45-2.41(m,2H),2.35-2.23(m,3H),2.14-2.07(m,1H),2.03- 1.63(m,8H),1.60-1.45(m,3H),1.34(d,J=8Hz,3H),1.29-1.25(m,2H),1.02-0.80(m,9H),0.36(s,3H).

[1034] Example D35 2-((S)-3,3-difluorocyclopentyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 63 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide

[1035] LC-MS: m / z 889 (M+H) + .

[1036] Example D36 2-((R)-3,3-difluorocyclopentyl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide

[1037] LC-MS: m / z 889 (M+H) + .

[1038] Example D37 2-(bicyclo[3.1.0]hexane-3-yl)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxoacetamide

[1039] LC-MS: m / z 865 (M+H) + .

[1040] Example D38 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(tetrahydrofuran-2-yl)acetamide

[1041] LC-MS: m / z 855 (M+H) + .

[1042] Example D39 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxo-2-(spiro[3.3]heptane-2-yl)acetamide

[1043] LC-MS: m / z 879 (M+H) + .

[1044] Example D40 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 65 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(furan-2-yl)-2-oxoacetamide trifluoroacetate

[1045] LC-MS: m / z 851 (M+H) + .

[1046] Example D41 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-3,4-dimethyl-2-oxopentamide

[1047] LC-MS: m / z 855 (M+H) + .

[1048] Example D42 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-3-methyl-2-oxopentanamide trifluoroacetate

[1049] LC-MS: m / z 841 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.06(d,J=9.3Hz,1H),8.51(d,J=5.5Hz,2H),7.84(d,J=3.5Hz,1H),7.75(d,J=8.6Hz,1H), 7.58(d,J=9.0Hz,1H),7.41(m,1H),5.57(m,1H),5.24(m,1H),4.39–4.11(m,6H),4.03(m,2H),3.60(m,3H),3.24(s, 3H),3.07(m,2H),2.96(m,1H),2.90(d,J=21.6Hz,3H),2.80–2.76(m,1H),2.45(m,2H),2.13–2.01(m,2H),1.82(m,2 H),1.65(m,2H),1.53(m,2H),1.36(d,J=6.2Hz,3H),1.06(m,3H),0.99–0.89(m,6H),0.88–0.84(m,3H)0.37(s,3H).

[1050] Example D43 3-Cyclopropyl-N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxobutyramide

[1051] LC-MS: m / z 853 (M+H) + .

[1052] Example D44 N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 66 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(1-methylcyclopropyl)-2-oxobutyramide trifluoroacetate

[1053] LC-MS: m / z 839 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.84(s,1H),9.12(d,J=8.7Hz,1H),8.49(m,2H),7.85(s,1H),7.75(m,1H),7.57(d,J=8.7Hz,1H),7 .40(d,J=2.9Hz,1H),5.53–5.47(m,1H),5.20(d,J=12.2Hz,1H),4.38–4.08(m,6H),4.02(m,2H),3.59(m,2H),3.34(m,2H), 3.22(s,3H),3.10(d,J=12.8Hz,2H),2.93(d,J=14.3Hz,1H),2.86(d,J=3.2Hz,3H),2.78(m,1H),2.43(d,J=14.6Hz,2H),2. 09(m,1H),1.81(m,2H),1.63–1.40(m,4H),1.34(d,J=6.1Hz,3H),1.29(s,3H),1.00(m,2H),0.95–0.80(m,6H),0.36(s,3H).

[1054] Examples D45A, D45B, D45C, and D45D N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2S)-2-ethylcyclopentyl)-2-oxoacetamide,

[1055] N-((6 3 S,4S,Z)-11 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1R,2R)-2-ethylcyclopentyl)-2-oxoacetamide,

[1056] N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2R)-2-ethylcyclopentyl)-2-oxoacetamide,

[1057] and N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-((1S,2S)-2-ethylcyclopentyl)-2-oxoacetamide

[1058] Example D45A

[1059] LC-MS: m / z 881 (M+H) + .

[1060] Example D45B

[1061] LC-MS: m / z 881 (M+H) + .

[1062] Example D45C

[1063] LC-MS: m / z 881 (M+H) + .

[1064] Example D45D

[1065] LC-MS: m / z 881 (M+H) + .

[1066] Example D46 3-Cyclopropyl-N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxopentanamide trifluoroacetate

[1067] LC-MS: m / z 867 (M+H) + .

[1068] Examples D47A and D47B(3R)-3-cyclopentyl-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxobutyramide trifluoroacetate,

[1069] and (3S)-3-cyclopentyl-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-oxobutyramide trifluoroacetate

[1070] Example D47A

[1071] LC-MS: m / z 881 (M+H) + .

[1072] Example D47B

[1073] LC-MS: m / z 881 (M+H) + .

[1074] Example D48 N-((6) 3 S,4S,Z)-1 2 -(5-(3-(1,4-oxazaphen-4-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-O-2(4,2)-Thiazolyl-1(5,3)-Indole-6(1,3)-Pyridazinecycloundecane-4-yl)-2-O-2-((cis)-2-phenylcyclopropyl)acetamide

[1075] LC-MS: m / z 940 (M+H) + .

[1076] Example E1 N-((((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)aminocarbamate)oxy)-N-methylcyclopropylformamide

[1077] LC-MS: m / z 870 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 8.62 (d, J = 8Hz, 1H), 8.51-8.50 (m, 2H), 7.86 (s, 1H), 7.77 (d, J = 8Hz, 1H), 7.59 (d, J = 8Hz, 1H), 7.4 1(s,1H),7.25(s,1H),7.12(s,1H),6.99(s,1H),5.34(t,J=8Hz,1H),5.24(d,J=12Hz,1H),4.35-4.12(m,5H),4.05-4.02(m,2H),3.68 -3.53(m,5H),3.23-3.20(m,6H),3.12-3.06(m,2H),2.97(d,J=12Hz,1H),2.87(s,3H),2.82-2.78(m,1H),2.46-2.43(m,1H),2.11-2. 08(m,1H),1.90-1.82(m,3H),1.55-1.50(m,2H),1.36(d,J=8Hz,3H),1.25(s,1H),0.93-0.88(m,5H),0.85-0.74(m,3H),0.37(s,3H).

[1078] Example F1 2-Cyclopropyl-N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(hydroxyimine)acetamide trifluoroacetate

[1079] LC-MS: m / z 840 (M+H) + .

[1080] Example F1 was chirally resolved to obtain isomers Example F1A and Example F1B: (E)-2-cyclopropyl-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(hydroxyimine)acetamide trifluoroacetate and (Z)-2-cyclopropyl-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(hydroxyimine)acetamide trifluoroacetate

[1081] Example F1A

[1082] LC-MS: m / z 840 (M+H) + .

[1083] Example F1B

[1084] LC-MS: m / z 840 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),9.66(s,1H),8.50-8.35(m,2H),7.83(d,J=4Hz,1H),7.75(d,J=8Hz,1H),7 .57(d,J=8Hz,1H),7.39(s,1H),5.52(t,J=8Hz,1H),5.15(d,J=12Hz,1H),4.32-4.11(m,5H),4.04-4.01(m,2H), 3.57-3.48(m,4H),3.30-3.17(m,4H),3.10-3.03(m,2H),2.95-2.67(m,6H),2.43-2.40(m,1H),2.32-1.97(m,5H ),1.82-1.67(m,2H),1.56-1.45(m,2H),1.35(d,J=8Hz,3H),1.15-1.04(m,2H),0.92-0.72(m,6H),0.35(s,3H).

[1085] Example F2 2-Cyclopropyl-N-((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-(methoxyimino)acetamide

[1086] LC-MS: m / z 854 (M+H) + .

[1087] Example F3 2-(cyanoimine)-2-cyclopropyl-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)acetamide

[1088] LC-MS: m / z 849 (M+H) + .

[1089] Examples F4A and F4B(E)-2-cyclopropyl-2-(ethoxyimino)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)pyridazinecycloundecane-4-yl)acetamide trifluoroacetate, and (Z)-2-cyclopropyl-2-(ethoxyimino)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)acetamide trifluoroacetate

[1090] Example F4A

[1091] LC-MS: m / z 868 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.80 (d, J = 8 Hz, 1H), 8.50 (d, J = 4 Hz, 1H), 8.46 (s, 1H), 7.86 (s, 1H), 7.76 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.39 (s, 1H), 5.49 (t, J = 8 Hz, 1...

Claims

1. A compound of formula (I0), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated form, crystal form, hydrate, solvate, prodrug, or combination thereof. in, W is selected from: O, S, or N(R) w ); R w Selected from the following group, whether substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy, OH, or CN; the substitution refers to substitution by one or more R groups; Ring A is selected from the following group, either substituted or unsubstituted: H, C3-C. 10 Cycloalkyl, 4-10 saturated or unsaturated heterocyclic groups, wherein the heterocyclic group or cycloalkyl group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, P, S and O, and the substitution refers to substitution by one or more R. Alternatively, ring A is selected from C4 cycloalkyl, -(NRpRq), or -(RpRqN(R)), wherein Rp and Rq, together with the N atom they are attached to, form substituted or unsubstituted groups from the following group: 4-7 membered saturated or partially saturated monocyclic heterocyclic groups, 7-10 membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more groups, each independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic groups, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 ethynyl; wherein the alkyl, alkenyl, ethynyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene; R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R; R b2 and R b3 Each is independently selected from the following group: H, D, halogen, or CN; R L1 Selected from the following group of substituted or unsubstituted groups: none, bonded, -O-, -S-, -NH-, -N(C1-C3 alkyl)-, -O-(C1-C3 alkylene)-, -S-(C1-C3 alkylene)-, -N(C1-C3 alkyl)-(C1-C3 alkylene)-, or -C≡C-; wherein, the substitution refers to being substituted by one or more R groups; R L2 Selected from the following group, whether substituted or unsubstituted: unsubstituted, bonded, C3-C6 cycloalkylene, 4-6 membered heterocyclic, -C1-C6 alkylene-C3-C6 cycloalkylene-, or -C1-C6 alkylene-4-6 membered heterocyclic-; wherein the heterocyclic group has 1-3 heteroatoms, each independently selected from N, S and O, and the substitution refers to substitution by one or more R; R L3 Selected from the following group of substituted or unsubstituted groups: none, bonded, C1-C6 alkylene, -O-, -S-, -NH-, -N(C1-C3 alkyl)-, -O-(C1-C3 alkylene)-, -S-(C1-C3 alkylene)-, or -N(C1-C3 alkyl)-(C1-C3 alkylene)-; wherein, the substitution refers to being substituted by one or more R groups; The ring C is selected from the following group: C6-C, whether substituted or unsubstituted. 14 The aryl or 5-14 membered heteroaryl or 5-14 membered saturated or unsaturated heterocyclic group contains 1-3 heteroatoms each independently selected from N, S and O; wherein the substitution refers to substitution by one or more R; R c Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, -(C1-C6 alkylene)-phenyl, -(C1-C6 alkylene)-6 membered heteroaryl; or, two adjacent Rs on the same side. c The ring atoms attached to it together form substituted or unsubstituted 5-7 membered heterocyclic groups or C5-C7 cycloalkyl groups; wherein, each R c Optionally replaced by halogen or deuterium; nc is selected from the group consisting of: 0, 1, 2, 3, 4, 5, or 6; Or, R b1 and R c The divalent group is linked by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R groups; Ring D is selected from substituted or unsubstituted 5-10 membered heterocyclic groups; wherein the heterocyclic group is a monocyclic, bicyclic bridged ring, bicyclic spirocyclic or bicyclic fused ring, and the heterocyclic group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution is by one or more R. R d The group is selected from the following group, whether substituted or unsubstituted: deuterium, amino, cyano, nitro, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halo-C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group, wherein the substitution refers to substitution by one or more R; nd is 0, 1, 2, 3, 4, 5, or 6; Ring G is selected from the following group of substituted or unsubstituted groups: 4-10 membered heterocyclic groups, C6-C 14 Aryl or 5-14 membered heteroaryl; wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms each independently selected from N, NH, S and O, and the substitution refers to substitution by one or more R; R g The group is selected from the following group, whether substituted or unsubstituted: deuterium, cyano, amino, oxo, nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 deuteratedalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein, the substitution refers to substitution by one or more R; ng is selected from the following group: 0, 1, 2, 3, 4, 5 or 6; X is selected from the following group, whether substituted or unsubstituted: key; -(L) n -C1-C6 alkylene-, -(L) n -C3-C 14 Cycloalkylene -, -(L) n -4-14-membered heterocyclic group-, -(L) n -C6-C 10 Alpha-aryl-, -(L) n -5-14-methyl-hybrid aryl-; -(L) n -C3-C 14 Cycloalkylene-C1-C6 alkylene-, -(L) n -4-14 membered heterocyclic group-C1-C6 alkylene group-,-(L) n -C6-C 10 arylene-C1-C6 alkylene-, -(L) n -5-10-membered heteroaryl-C1-C6 alkylene-; -(L) n -O-C1-C6 alkylene-, -(L) n -O-C3-C 14 Cycloalkylene -, -(L) n -O-4-14-membered heterocyclic group-, -(L) n -O-C6-C 10 Alpha-aryl-, -(L) n -O-5-14-pyroaryl-; -(L) n -N(R 3 )-C1-C6 alkylene-、-(L) n -N(R 3 )-C3-C 14 Cycloalkylene -, -(L) n -N(R 3 )-4-14-membered heterocyclic group-、-(L) n -N(R 3 )-C6-C 10 Alpha-aryl-, -(L) n -N(R 3 )-5-14-pyroaryl-; or -(L) n -N(R 3 )-、-R x1 -(L) n -N(R 3 )-R x2 -or-R x1 -N(R 3 )-(L) n -R x2 -; n is 0, 1, 2, 3, 4, 5, or 6; L is independently selected from the following group of substituent or unsubstituted groups: none, O, S, -N(R) 3 )-, methylene (-CH2-), -C3-C 14 Cycloalkyl-, -4-14-membered heterocyclic-; wherein, the substitution refers to substitution by one or more R; Among them, R 3 Each group is independently selected from the following group, either substituted or unsubstituted: H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group; wherein, substitution means substitution by one or more R groups; R x1 and R x2 Each group is independently selected from the following group: substituted or unsubstituted: bond, -C1-C6 alkylene-, -C3-C 14 Cycloalkylene-, -4-14 membered heterocyclic-; the substitution refers to the substitution of one or more hydrogens on the group by R; R L4 Selected from the group consisting of: bond, -O-, -NH-, -N(C1-C4 alkyl)-, or -N(C3-C6 cycloalkyl)-, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more R groups; R L5 Selected from the following groups, whether substituted or unsubstituted: hydrogen, C1-C6 alkyl, C3-C4 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7 ... 14 Cycloalkyl, 4-14 membered heterocyclic, C6-C 10 Aryl, 4-12 heteroaryl, -(C1-C6 alkylene)-C3-C 14 Cycloalkyl, -(C1-C6 alkylene)-4-14 membered heterocyclic, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-4-12 heteroaryl, -(C3-C 10 (cycloalkylene)-C6-C 10 Aryl, -(4-11-membered heterocyclic)-C6-C 10 Aryl, -(C3-C 10 -(4-11-heterocyclic)-4-12-membered heteroaryl, -NR1R2, -(C1-C3 alkylene)-NR1R2; Wherein, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, or, R1 and R2 and the N atom they are connected to together form a substituted or unsubstituted 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R; Each R may be the same or different, and each is independently selected from the following group: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclic-O-, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -C(O)-4-7 membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6 membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6 membered heterocyclic-oxy)-(C1-C6 alkylene)-, (C1-C6 alkyl)-vinylene, deuterated (C1-C6 alkyl)-vinylene, halogenated (C1-C6 alkyl)-vinylene (C1-C6 alkyl)-ethynyl, deuterated (C1-C6 alkyl)-ethynyl, halogenated (C1-C6 alkyl)-ethynyl, (C3-C6 cycloalkyl)-ethynyl, (4-6 membered heterocyclic)-ethynyl, (C3-C6 cycloalkyl)-ethynyl or (4-6 membered heterocyclic)-C3-C6 ethynyl; wherein the alkylene, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in Formula I: In the formula, Rings A and R L1 R L2 R L3 R b1 R b2 R b3 , ring C, R c nc, ring G, Rg, ng, ring D, R d nd, X, R L3 and R L5 The definition is as described in claim 1.

3. The compound according to claim 1, characterized in that, The compound has the structure shown in formula AI or formula BI: In the formula, Rings A and R L1 R L2 R L3 R b1 , ring C, R c nc, ring D, R d nd, X, R L4 and R L5 The definition is as described in claim 1.

4. The compound according to claim 1, characterized in that, The compound has the structure shown in formula AII or formula BII: In the formula, R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium; R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN; Or R c1 and R c2 The groups are connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to substitution by one or more R groups; R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R; Or, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R. Rings A and R L1 R L2 R L3 , ring D, R d nd, X, R L4 and R L5 The definition is as described in claim 1.

5. The compound according to claim 1, characterized in that, The compound has the structure shown in formula AIII-A, AIII-B, AIII-C, AIII-D, or formula BIII-A, BIII-B, BIII-C, or BIII-D: In the formula, R c1 Selected from the following group: H, deuterium, halogen, oxo (=O), cyano, amino, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, -(C1-C3 alkylene)-C3-C6 cycloalkyl, -(C1-C3 alkylene)-4-6 membered heterocyclic, wherein each R c1 It can be optionally replaced by halogen or deuterium; R c2 R c3 and R c4 Each is independently selected from the following group: H, D, halogen, or CN; Or R c1 and R c2 The groups are connected together to form substituted or unsubstituted subgroups: -CH2-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-CH2-CH2-; the substitution refers to substitution by one or more R groups; R b1 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to substitution by one or more R; Or, R b1 and R c1 The divalent group is linked into a ring by a divalent group, and the divalent group is composed of one or more segments selected from the group consisting of: -C1-C3 alkylene-, -CH=CH-, -C≡C-, -O-, -S-, -NH-, -N(CH3)-, -C(O)NH-, -C(O)N(CH3)-; and the divalent group is further substituted by one or more R. Ring A, Ring D, R d nd, X, R L4 R L5 The definitions of R and R are as described in claim 1.

6. The compound according to claim 1, characterized in that, X is selected from the following group, whether substituted or unsubstituted: key; -C1-C6 alkylene-, -C3-C 14 Cycloalkylene-C1-C6 alkylene-, -4-14 membered heterocyclic-C1-C6 alkylene-; -C3-C 14 Cycloalkylene -, -C1-C6 alkylene -C3-C 14 Cycloalkylene -, -C1-C6 alkylene -C3-C 14 Cycloalkylene-C1-C6 alkylene-, -4-14 membered heterocyclic-C3-C 14 Cycloalkylene-; -4-14-membered heterocyclic-, -C1-C6 alkylene-4-14-membered heterocyclic-, -C1-C6 alkylene-4-14-membered heterocyclic-C1-C6 alkylene-, -C3-C 14 Cycloalkyl-4-14-membered heterocyclic-; -C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-,-C1-C6 alkylene-C6-C 10 arylene-C1-C6 alkylene-, -C3-C7 cycloalkylene-C6-C 10 aryl-,-4-7-membered heterocyclic-C6-C 10 arylene-,-C3-C7 cycloalkylene-C6-C 10 arylene-C1-C6 alkylene-,-4-7 heterocyclic-C6-C 10 arylene-C1-C6 alkylene-; -5-10-membered heteroaryl-, -C1-C6-alkylene-5-10-membered heteroaryl-, -C1-C6-alkylene-5-10-membered heteroaryl-C1-C6-alkylene-, -C3-C7-cycloalkylene-5-10-membered heteroaryl-, -4-7-membered heterocyclic-5-10-membered heteroaryl-, -C3-C7-cycloalkylene-5-10-membered heteroaryl-C1-C6-alkylene-, -4-7-membered heterocyclic-5-10-membered heteroaryl-C1-C6-alkylene-; -C1-C4 alkylene-O-C1-C6 alkylene-, -C1-C4 alkylene-O-C3-C 14 Cycloalkylene-, -C1-C4 alkylene-O-4-14 heterocyclic-, -C1-C4 alkylene-O-C6-C 10 arylene-, -C1-C4 alkylene-O-5-10-membered heteroarylene-; -C1-C4 alkylene-N(R) 3 -C1-C6 alkylene-, -C1-C4 alkylene-N(R) 3 )-C3-C 14 Cycloalkylene-, -C1-C4 alkylene-N(R) 3 )-4-14-membered heterocyclic -,-C1-C4 alkylene-N(R 3 )-C6-C 10 arylene-,-C1-C4 alkylene-N(R) 3 )-5-10-aryl heteroaryl-; -R x1 -N(R 3 )-O-R x2 -、-R x1 -O-N(R 3 )-R x2 -, or -R x1 -N(R 3 )-N(R 3 )-R x2 -; in, R 3 Each group is independently selected from the following group: substituted or unsubstituted: H, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group; the substitution refers to the substitution of one or more hydrogens on the group by R; R x1 and R x2 Each group is independently selected from the following group: substituted or unsubstituted: bond, -C1-C6 alkylene-, -C3-C 14 Cycloalkylene-, -4-14 membered heterocyclic-; the substitution refers to the substitution of one or more hydrogens on the group by R; Preferably, X is selected from the following group: key; Methylene, Ethylene Or select from the following group: Or select from the following group: Or select from the following group: Or select from the following group: Or select from the following group: Or select from the following group: -ON(CH3)-, -N(CH3)-N(CH3)-.

7. The compound according to claim 1, characterized in that, R L5 Selected from the following groups, whether substituted or unsubstituted: hydrogen, C1-C6 alkyl, C3-C4 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7 ... 10 Cycloalkyl, 4-11 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -(C1-C3 alkylene)-C3-C 11 Cycloalkyl, -(C1-C3 alkylene)-4-11 heterocyclic, -(C1-C3 alkylene)-phenyl, -(C1-C3 alkylene)-5-6 heteroaryl, -(C3-C7 cycloalkylene)-phenyl, -(4-7 heterocyclic)-phenyl, -(4-7 heterocyclic)-5-6 heteroaryl, -(C3-C7 cycloalkylene)-5-6 heteroaryl, -NR1R2, -(C1-C3 alkylene)-NR1R2; Wherein, R1 and R2 are each independently selected from the following group of substituted or unsubstituted groups: H, D, C1-C4 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, or, R1 and R2 and the N atom they are connected to together form a substituted or unsubstituted 4-11 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein the heterocyclic group and the heteroaryl group contain 1-3 heteroatoms each independently selected from N, O and S, and the substitution refers to being substituted by one or more R; Ideally, R L5 The subgroup is selected from the following groups, whether substituted or unsubstituted: C3-C7 cycloalkyl, 4-7 membered heterocyclic, -(C1-C3 alkylene)-5-6 membered heteroaryl, -NR1R2, wherein R1 and R2 are each independently selected from the following groups, whether substituted or unsubstituted: H, C1-C4 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-7 membered heterocyclic group, wherein the heterocyclic group contains 1-3 heteroatoms each independently selected from N, O and S; the substitution refers to being substituted by one or more R atoms; Ideally, R L5 The subgroup is selected from the following groups, whether substituted or unsubstituted: -(C3 cycloalkylene)-phenyl, -(C3 cycloalkylene)-5-6-membered heteroaryl, 4-6-membered heterocyclic group, -NR1R2, wherein R1 and R2 are each independently selected from the following groups, whether substituted or unsubstituted: H, C1-C4 alkyl, C3-C7 cycloalkyl, 3-7-membered heterocyclic group, or R1 and R2 and the N atom they are connected to form a substituted or unsubstituted 4-membered heterocyclic group, wherein the heterocyclic group contains one N atom, and the substitution refers to being substituted by one or more R atoms; Better yet, R L5 Selected from the following group: Methyl, ethyl, isopropyl, isopropylmethyl, tert-butylmethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl Or select from the following group: -NH2, -NH(CH3), -N(CH3)2, Or select from the following group: Or select from the following group:

8. The compound according to claim 1, characterized in that, The compound has the structure shown in formula AII, wherein, X is selected from the key; R L4 Selected from key; nd is selected from 0; Ring D is selected from the following group: Preferably, ring D is selected from... Ring A is selected from substituted C4 cycloalkyl groups, where substitution means being substituted by one or more R groups; Alternatively, ring A is selected from -(NRpRq) or -(RpRqN(R)), wherein Rp and Rq, together with the N atom they are attached to, form substituted or unsubstituted groups from the following group: 6-membered saturated or partially saturated monocyclic heterocyclic groups, 7-10-membered saturated bicyclic heterocyclic groups; the substitution refers to substitution by one or more (preferably three) groups, each independently selected from the following group: deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, C1-C6 alkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, phenyl, 5-6-membered heterocyclic groups. Aryl, C2-C6 alkenyl, ethynyl, C3-C6 ethynyl; wherein the alkyl, alkenyl, ethynyl, cycloalkyl, aryl, heteroaryl and heterocyclic groups are optionally substituted by groups selected from the group consisting of: deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, C1-C3 alkylidene, halo-C1-C3 alkylidene; R L5 Selected from the following group (substituted or unsubstituted): 4-membered nitrogen-containing heterocyclic groups, wherein substitution refers to substitution by one or more of the following groups: deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkylidene, halogenated C1-C6 alkylidene, C1-C6 alkylamine, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic groups, -C(O)-4-7-membered heterocyclic groups, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy; Or, R L5 Selected from the following groups, whether substituted or unsubstituted: -(C3 cycloalkylene)-phenyl, -(C3 cycloalkylene)-5-6 heteroaryl, wherein the substitution refers to substitution by one or more of the following groups: H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy; The constraint is R L5 Not selected from: R L1 R L2 R L3 R b1 R c1 R c2 R c3 R c4 The definitions of R are as described above.

9. The compound according to claim 8, characterized in that, The compounds have the structures shown in formulas AIV-A and AIV-AA: in, nv is selected from 1 or 0; When nv is selected as 1: V is selected from N; R V1 and R V2 Each group is independently selected from the following groups: oxo (=O), cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkylidene, halo-C1-C6 alkylidene, C1-C6 alkylamino, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -C(O)-4-7 membered heterocyclic, C6-C 10 Aryl, 5-10-membered heteroaryl, C2-C6 alkenyl, C2-C6 fluoroalkenyl, ethynyl, C3-C6 alkenyl, (C3-C6 cycloalkyl)-(C1-C6 alkylene)-, (4-6-membered heterocyclic)-(C1-C6 alkylene)-, (C1-C6 alkoxy)-(C1-C6 alkylene)-, (C3-C6 cycloalkyl-oxy)-(C1-C6 alkylene)-, (4-6-membered heterocyclic-oxy)-(C1-C6 alkylene)-; wherein, the alkylene, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by groups selected from the group consisting of: halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy; When nv is selected as 0: V is selected from CH; R V1 Selected from the following group: H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy; R V2 Selected from the group consisting of phenyl or 5-6 heteroaryl groups; wherein the aryl and heteroaryl groups are optionally substituted by groups selected from the group consisting of H, deuterium, halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy; Rings A and R b1 R c1 R c2 R c3 R c4 Defined as described above.

10. The compound according to claim 9, characterized in that, The compounds described above have structures represented by formulas AV-A and AV-AA: R w1 Selected from the following group, substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, ethynyl, or C3-C6 ethynyl (preferably, R w1 Selected from the following group (substituted or unsubstituted): C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 alkynyl, or 4-membered heterocyclic group; the substitution is selected from halogen, hydroxyl, nitro, cyano, amino, sulfone, oxo (=O), C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, 4-5-membered heterocyclic group, C1-C3 alkylidene, halo-C1-C3 alkylidene; R w2 and R w3 Each is independently selected from the group consisting of: H, deuterium, C1-C6 alkyl groups (preferably, R). w2 and R w3 Selected from methyl); R b1 R c1 R c2 R c3 R c4 V, R V1 R V2 The definitions of nv are as described above.

11. The compound according to any one of claims 1-10, characterized in that, The compounds are selected from the following group: Group A is selected from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or selected from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Or select from: Group B is selected from: Or select from: Or select from: Or select from:

12. A pharmaceutical composition, characterized in that, It comprises one or more compounds as described in any one of claims 1-11, or pharmaceutically acceptable salts, stereoisomers, tautomers, deuterated derivatives, crystal forms, hydrates, solvates, prodrugs, or combinations thereof; And pharmaceutically acceptable carriers.

13. The use of a compound as described in any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, crystal form, hydrate, solvate, prodrug, or combination thereof, or a pharmaceutical composition as described in claim 9, characterized in that, This is used to prepare a drug for the prevention and / or treatment of diseases related to the activity or expression level of KRAS mutations, preferably, the diseases being tumors or disorders.

14. The use as described in claim 13, characterized in that, The tumors mentioned are selected from the following group: pancreatic cancer, colorectal cancer, lung cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, bladder cancer, or combinations thereof.

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